[MEGATHREAD] All Major Growth Pathways for Height

sdram4 · May 10, 2026

EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)

The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.
Proliferative zone: Chondrocytes divide and form columns.
Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.
Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.
Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.
Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.
Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.
Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.
Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.
Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).
Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.
Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.
Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.
PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.
As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).
Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)
Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)
Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle
Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.
Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.
rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.
Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.
WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.
Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.
Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.
Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.
WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.
KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.
Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)
Enhances extracellular matrix (ECM) production (collagen, proteoglycans)
Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.
Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.
Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.
Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.
Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.
Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.
Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).
High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.
Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)
Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.
Regulated by age, obesity, bodily inflammation, and hormones.
In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.
Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.
Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.

VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.

Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.
Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.
Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.
Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.
Increased HGH secretion amplitude.
Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).
Increases extracellular matrix production (collagen II, proteoglycans).
Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.
Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.
Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).
Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.
Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.
Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).
Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).
Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.
Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.
Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation
BMP4 - Often redundant with BMP2
BMP6 & BMP7 - Prominent in the hypertrophic zones
BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation
Promotes chondrocyte hypertrophy (major contributor to bone lengthening)
Enhances extracellular matrix production and mineralization
Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.
Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.
Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.
Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.
Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator
Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.
PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone
Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells
Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).
Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.
Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.
GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

zenserenity · May 10, 2026

woah high effort

polarpop · May 10, 2026

I see potential in this thread.

imnotagreyceliswear · May 10, 2026

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
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VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

Bunch of useless info + straight from chatgpt nigga

iniuria · May 10, 2026

bump
so high effort. used ai checker and it aint. mirin man :02Hype:

ill be reading this often

zenserenity · May 10, 2026

imnotagreyceliswear said:
Bunch of useless info + straight from chatgpt nigga

remove your ugh fag its not ai

iniuria · May 10, 2026

imnotagreyceliswear said:
Bunch of useless info + straight from chatgpt nigga

yea i mean skimming thru it again its for sure ai enhanced. wonder how much he put in himself

imnotagreyceliswear · May 10, 2026

iniuria said:
yea i mean skimming thru it again its for sure ai enhanced. wonder how much he put in himself

yea nobody would put effort into making thread about bunch of useless bullshit, just know to what roids do sleep good, keep ur diet good and thats it no need to making megathread everybody dnring ts

iniuria · May 10, 2026

imnotagreyceliswear said:
yea nobody would put effort into making thread about bunch of useless bullshit, just know to what roids do sleep good, keep ur diet good and thats it no need to making megathread everybody dnring ts

just using my brain for like 4 secs made me realise how pointless this thread is. theres enough information on ALL of these in botb already . making posts like these are pointless now. lack of images also makes it high probability of ai enhancement

JeffReincarnate · May 10, 2026

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
View attachment 5039383

VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me

I dont understand any of this shit? what the fuck nigga this is a word salad

sdram4 · May 10, 2026

iniuria said:
just using my brain for like 4 secs made me realise how pointless this thread is. theres enough information on ALL of these in botb already . making posts like these are pointless now. lack of images also makes it high probability of ai enhancement

What images would you like me to put?

Chen417 · May 10, 2026

mirin brahski

sdram4 · May 10, 2026

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
View attachment 5039383

VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

bump

Lord_Chudd · May 12, 2026

iniuria said:
just using my brain for like 4 secs made me realise how pointless this thread is. theres enough information on ALL of these in botb already . making posts like these are pointless now. lack of images also makes it high probability of ai enhancement

Stfu MilkGoy

Lyndon · May 12, 2026

The problem with all this is that is useful to people that actually know what all this terminology mean
But most niggas around here have 0 clue about it, so they won't really understand it
Either way looks nice

sdram4 · May 12, 2026

MediterraneanMoid said:
The problem with all this is that is useful to people that actually know what all this terminology mean
But most niggas around here have 0 clue about it, so they won't really understand it
Either way looks nice

ty brah

, meant for individuals with a baseline of knowledge so it was hard for me to formulate everything into less complicated words

cc000 · Jun 29, 2026

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
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VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

mirin

Nutty chud · Jun 29, 2026

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
View attachment 5039383

VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

What abt raw milk+healthy=holy height

khazarianmafia73 · Jun 29, 2026

mirin da effort

pierrewillascend · Sunday at 3:22 PM

sdram4 said:
ty brah , meant for individuals with a baseline of knowledge so it was hard for me to formulate everything into less complicated words

Question i wont be using a test base so how much should my anavar dose be

markmcc · Sunday at 3:36 PM

Skimmed through, nobody reading all this but give botb for effort unless it’s ai

bluebandz · Sunday at 7:26 PM

dnr maybe i’ll read later repped for effort should be botb

occipital · Tuesday at 6:09 AM

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
View attachment 5039383

VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

bumping this high effort thread.

jewing · Tuesday at 7:49 AM

mirin effort, but you forgot masaii jumps and heelsmashing

Noriju · 2026-07-18T02:07:49-0500

sdram4 said:
EVERY SINGLE PRIMARY PATHWAY REQUIRED TO FORCE YOUR BODY TO GROW
This thread is addressing every major pathway that regulates growth (in no particular order), with actual growth plate biology and what substances to take that properly agonize/inhibit these areas. I will try to summarize and uncomplicate things as much as possible.

I. HGH/IGF-1 AXIS

(This will by far be the longest and most in-depth pathway, so if you are disinterested skip to the next few.)
The HGH to IGF-1 axis is the primary endocrine regulator of longitudinal bone growth throughout the body, and is naturally secreted in pulses by the anterior pituitary gland, which is stimulated via GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin. Afterwards, GH binds to the GH receptors (GHR) on target tissues, most notably the liver and therefore producing IGF-1 via JAK2-STAT5 pathway activation. IGF-1 Circulates mostly bound to IGF-binding proteins (mostly IGFBP-3 and acid-labile subunit/ALS) forming a ternary complex prolonging it's half-life and acts in endocrine, paracrine, and autocrine manners. Local IGF-1 is produced in growth plate chondrocytes and other tissues under GH stimulation.

To fully understand how this pathway works, the mechanism of how growth occurs needs to be understood.

Resting/germinal zone: Has stem-like chondrocytes.

Proliferative zone: Chondrocytes divide and form columns.

Hypertrophic zone: Cells physically enlarge, produce matrix, and calcify (osteoblasts replace with bone, this process is called endochondral ossification.).

GH and IGF-1 act in a coordinated dual effector, where GH itself directly stimulates differentiation of the resting zone stem cells into proliferating and dividing chondrocytes, and also induces local IGF-1 production in the growth plate.
IGF-1 (systemic and local) drives proliferation of the chondrocytes, hypertrophy, and matrix production, leading to bone elongation.

Now that we have water out of the way, how do we exploit these pathways to prevent closure and force growth?
In a growth promoting stack, you always want to have an HGH base. Similar to how roidcels typically have testosterone as a base, HGH provides a basic driver of growth that acts on the most centralized system regarding the proliferation and differentiation of the cells in your plates. You have several different options for how you may want to hit this pathway.

Recombinant HGH (rHGH) - By far the most simple way to hit the pathway is by exogenously introducing it into your system. Doses anywhere between 4-10 IU's can act as a base for your stack, and no more than ~18-20+, as any more than this could force you into an acromegaloid state with fucked up growth, 50 year old bone age and harsh edema during puberty. I recommend adding basic potassium-sparing diuretics (Eplerenone, HCTZ + Amiloride, or Furosemide as an emergency debloat) and tracking your blood sugar if your dose is high. Use Dihydroberberine for regulating blood sugar, and potentially could be paired with insulin (dangerous) for real blood sugar management/bodybuilding purposes.

Secretegogues - The second best way is by using HGH secretegogues to force your body to pump out as much HGH/GHRH as possible. There are several obvious contenders, such as:

Ibutamoren (MK-677) - Basic, well known ghrelin agonist. Dramatically raises baseline HGH.

Acetamoren (Newer, untested analogue) - Very similar to Ibutamoren, slightly more potent, less sides + hunger effect.

Capromorelin - Potent, shorter half-life + higher spikes. Hard to source.

Anamorelin - Less potent by the milligram, allegedly strong effects on lean muscle mass + body weight. Approved in Japan for cancer-related cachexia/anorexia.

Macimorelin - In trials for adult growth hormone deficiency, shorter half life. First-in-class for FDA.

Depending on the dosage range, this could give you anywhere from 3-8 IU's of equivalent HGH if you use proper dosing and management with the right kind of secretegogue. These typically work via ghrelin agonism, which tricks your body into producing more HGH, and also making you insatiably hungry. This works well for bulking, however taking an appetite reducer or night-time dosing could potentially mitigate some hunger effects.
Somatostatin inhibition is also a very niche topic to look into, and one specific compound named Mestinon acts as such. It is a reversible acetylcholinesterase inhibitor in synapses, which increases acetylcholine levels and prolongs its action at cholinergic receptors (mainly muscarinic in the hypothalamus for this effect.) Increased acetylcholine stimulates cholinergic neurons that regulate somatostatin-producing neurons in the hypothalamus. Since acetylcholine inhibits somatostatin release, cholinergic activation suppresses somatostatinergic tone. There are actual studies showing evidence that Mestinon induces a several-fold increase in HGH without actually forcing it's release. Pairing this with a secretegogue could theoretically dramatically increase the effects in which it acts upon.

3. Increlex (why this is cope) - Increlex and/or IGF-1 LR3 by itself does not effectively produce longitudinal bone growth due to a factor called the somatomedin hypothesis.
This posited that HGH mainly works by stimulating IGF-1, and was therefore was refined into the dual effector theory, which states that GH binds to GHR on the resting zone (germinal/progenitor) chondrocytes/stem-like cells (e.g. PTHrP+ skeletal stem cells). This promotes differentiation/recruitment of the progenitors into the proliferative pool, and stimulates local production to finish the process.

Since exogenous IGF-1 primarily acts on already-committed proliferative and pre-hypertrophic chondrocytes via IGF-1R, promoting proliferation, hypertrophy, and differentiation towards mineralization/apoptosis/ossification (whichever one). This thickens the growth plate (increased hypertrophic zone) and can cause a short term increase in velocity if you aren't deficient, but then accelerates depletion of the progenitor reserve without replenishment. This results in rapid maturation/ossification. If you plan to do IGF-1 LR3 and/or Increlex, use relatively smaller doses than what is absolutely needed, and proportionally pair it with HGH (and maybe an aromatase inhibitor) so they both work together. TLDR: Short term height velocity followed by rapid maturation.

II. FGFR3

FGFR1-4 (Fibroblast Growth Factor Receptors 1-4) are tyrosine kinase inhibitors (blocks cell growth) that mediate FGF signaling, which plays highly complex and mostly inhibitory roles in regulating endochondral ossification and longitudinal growth at the epiphyseal plate. Inhibiting these receptors, particularly FGFR3, dramatically accelerates linear growth by relieving negative regulation on chondrocyte proliferation/differentiation/hypertrophic zone dynamics. Best validated in achondroplasia and related FGFR3 gain-of-function disorders, but also works in normal bone physiology.

Longitudinal bone growth occurs the same way we described before. Resting zone progenitors, proliferative zone, hypertrophy, and then mineralization. FGF ligands (especially FGF18 from the perichondrium) binds to FGFRs on chondrocytes, activating pathways like MAPK/ERK, STAT1, and others that generally restrain growth. Different FGFRs have zone specific functions, so there are different outcomes upon inhibition. We will specifically focus on FGFR3.

FGFR3 is the strongest negative regulator of linear growth among the FGFR family. It is highly expressed in proliferating and pre-hypertrophic chondrocytes. Activation inhibits proliferation, delays hypertrophic differentiation, reduces growth plate height, and downregulates important pathways like Indian hedgehog (Ihh) and BMP4, which coordinate chondrocyte and osteoblast activity.

Gain-of-function mutations: (G380R in ACH) causes constitutive overactivation and severe impairment of chondrocyte proliferation/differentiation, rhizomelic short stature and achondroplasia.

Loss-of-function mutations: Skeletal overgrowth, expanded proliferative and hypertrophic zones, increased chondrocyte proliferation, and longer bones.

Pharmacologically inhibiting FGFR3 is a very common topic among "heightmaxxers", especially on tiktok, however using basic pan-inhibitors (inhibiting a range of FGFRs) like Erdafitinib or Infigratinib can cause serious and detrimental side effects. I will go through the 3 most spoken of inhibitors. To clarify, FGFR3 inhibitors do not typically cause acceleration of bone age.

Infigratinib - An oral, ATP-competitive selective FGFR1-3 inhibitor was primarily developed for FGFR-altered cancers like most inhibitors (cholangiocarcinoma) but advanced extensively in achondroplasia due to it inhibiting mutant and wild-type FGFR3 in the growth plate. It causes strong, dose-dependent acceleration in height velocity and most confirmed a 91% increase in height velocity under treatment. Generally well tolerated.

Erdafitinib - Pan-FGFR inhibitor (potent on 1-4), FDA approved for FGFR-altered urothelial carcinoma. Highly documented accelerated linear growth and growth plate widening in pre-pubertal children for cancer (completely independent growth of HGH, IGF-1, or Testosterone in blood panel reports). Causes significant overgrowth, but this is often times uncontrolled and leads to deformities such as scoliosis/genu varum. Higher toxicity burden due to potent and broadened inhibiton, such as hyperphosphatemia, stomatitis, dry mouth, diarrhea, nail toxicities, etc.. (all dose dependent and may/may not happen).

Dabogratinib (TYRA-300) - First-in-class, highly selective, potent oral FGFR3 inhibitor specifically designed for skeletal dysplasias (and certain cancers). Early clinical development for achondroplasia (Phase 2 BEACH301 ongoing in children 3-10, open plates). Strong preclinical increases in long bone length, restoration of plate architecture and expected to translate into heavily meaningful AHV gains in humans. Favorable side effect profile, however is highly expensive and relatively unavailable to the public.

Vepugratinib (LOXO-435) - Extremely potent FGFR3 inhibitor with approximately ~360x-fold selectivity for FGFR3 compared to FGFR1/FGFR2. Very niche/experimental, most likely less expensive than TYRA-300.

Meclozine - An OTC motion sickness medication that "downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells". This source also states, "downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation.", and "Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling." This is a commonly cited characteristic of Meclozine, and has very high potential to be an effective FGFR3 inhibitor. It does not seem like extremely high doses of Meclozine are needed to achieve this inhibition either, as some studies used only 25 milligrams to enhance arm span in ACH children (OTC dose.)

FGFR3 inhibitors are not just limited to these 5, as there are tens of inhibitors designed for both achondroplasia + cancer purposes. These are the most likely FGFR3 inhibitors to truly work for skeletal growth. If you plan on researching for yourself, an isolated inhibitor that targets FGFR3 and as little other pathways as possible to prevent any harsh side effects.

III. PTHrP

PTHrP (Parathyroid Hormone-related Protein) is a critical local regulator of endochondral ossification and longitudinal height growth. It is structurally related to parathyroid hormone (PTH) and shares the same receptor (PTH1R), a G-protein-coupled receptor. Unlike PTH, which is produced primarily from the parathyroid glands for stabilizing calcium levels, PTHrP is produced locally in many tissues. This includes the growth plate.
PTHrP is expressed in the resting zone of progenitor chondrocytes, with the Ihh/PTHrP negative feedback loop being the master regulator of balancing proliferation and differentiation.

Chondrocytes in the resting/periarticular region produce PTHrP.

PTHrP diffuses and binds PTH1R on proliferative and pre-hypertrophic chondrocytes, which delays hypertrophic differentiation, maintaining/prolonging proliferation, and keeps the chondrocytes in the cell cycle longer. This expands the proliferative pool and growth plate height.

As chondrocytes move farther from the PTHrP source and stop proliferating, they express Indian Hedgehog (Ihh).

Ihh signals back (directly and indirectly) to make more PTHrP in the reserve zone, and also promotes proliferation and columnar organization independently of PTHrP in some aspects.

This loop sets the pace of differentiation: PTHrP slows the transition to hypertrophy (prevents premature maturation), while Ihh ensures there's enough PTHrP to maintain the system. It also coordinates perichondrial osteoblast differentiation.

Mechanistic Actions:

Suppresses Runx2 (pro-hypertrophy transcription factor)

Phosphorylates SOX9 (maintains chondrocyte phenotype and proliferation)

Inhibits p57 (cyclin-dependent kinase inhibitor), prolongs cell cycle

Opposes pathways that drive terminal differentiation (certain FGF signaling)

By keeping more chondrocytes proliferating for longer and preventing them from exiting the cycle too soon, PTHrP increases the total output of the growth plate (more cells, more hypertrophy, more bone elongation per unit of time). Knockout models show severe shortening with premature hypertrophy and reduced proliferation. Overexpression delays maturation. The question is, what substances can we use to activate this system?

Teriparatide (PTH(1-34)) - Teriparatide is recombinant human parathyroid hormone fragment 1-34. It is the first FDA-approved anabolic osteoporosis agent, and is administered as a daily subcutaneous injection. It increases trabecular bone mineral density, and mimics PTHrP actions. Increases chondrocyte proliferation, delays hypertrophic differentiation, and increases the height of the growth plate in preclinical models. It has also been shown to enhance mandibular growth and long bone parameters in adolescent animal studies. For optimal anabolic outcomes, any PTHrP component/analog should be administered/targeted via pulsatile signaling, not an acromegaloid flat state of constantly high PTHrP.

Abaloparatide - A synthetic 34-amino-acid analog of PTHrP, with ~76% homology to PTHrP and 41% to PTH. It is also given as a daily subcutaneous injection, and binds to PTH1R with greater selectivity for the RG conformation (pulsatile signaling) versus R0 (prolonged signaling). This leads to a stronger anabolic bias, with robust stimulation of bone formation with relatively less stimulation of bone resorption compared to teriparatide. It activates cAMP/PKA signaling effectively while minimizing prolonged downstream effects that drive RANKL and bone resorption.

rPTH (PTH(1-84)) - PTH, or full-length parathyroid hormone is the native 84-amino-acid hormone secreted by the parathyroid glands. This recombinant form is approved for the treatment of hypoparathyroidism. Like teriparatide, it binds to the PTH1R, however the full-length molecule has additional C-terminal domains that influence receptor internalization, clearance and signaling bias. Same core pathway activation as PTHrP and PTH(1-34), but the extended structure leads to a longer half life and altered receptor trafficking. More balanced effect on calcium stability/homeostasis. Harder to control pulsatile signaling.

Forskolin - A natural diterpene extracted from the plant Coleus forskohlii. It is used as a research tool rather than a drug, and contrary to popular belief, Forskolin is not a plant but rather the extract of one. It is a direct and potent activator of adenylate cyclase, the enzyme responsible for converting ATP into cyclic AMP (cAMP). This leads to rapid, robust and receptor independent elevation of intracellular cAMP levels, which strongly activates protein kinase A (PKA). For clarity, native PTHrP/PTH binds to PTH1R --> Gs protein --> activates adenylate cyclase --> more cAMP --> PKA. Forskolin bypasses this confusing cascade of signaling and directly raises cAMP, replicating the highly dominant cascade used by PTHrP used in growth plate chondrocytes. Has cardiovascular/strong vasodilator and positive inotrope effects, and unsuitable for therapeutic use.

TLDR: Benefits the growth plate in almost every possible functioning way.

IV. Wnt/β-catenin

The canonical Wnt/β-catenin pathway is a highly conserved cascade of signals that plays a critical role in skeletal development, growth plate function and longitudinal growth. It centers on the stabilization and nuclear translocation of β-catenin, which acts as a transcriptional co-activator to drive target gene expression (Axin2, Cyclin D1, Runx2, Osterix).

Without Wnt ligands, a destruction complex (Axin, APC, GSK3B, CK1) phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. Cytoplasmic β-catenin levels therefore stay low.

WIth Wnt ligands, (Wnt31, Wnt10b) binding frizzled + LRP5/6 cop-receptors, the destruction complex is inhibited (disheveled recruitment, GSK3B inhibition). β-catenin accumulates, translocates to the nucleus, and partners with TCF/LEF transcription factors to activate genes promoting cell proliferation, survival, and lineage-specific differentiation.

Wnt/β-catenin promotes mesenchymal condensation and chondrogenic commitment but can inhibit early chondrocyte differentiation of constantly active. It strongly promotes chondrocyte proliferation and columnar organization (like Cyclin D1). Appropriate levels support hypertrophy and endochondral ossification (via Runx2, Osterix, Ihh). Excessive or badly timed activation disrupts boundaries and can accelerate maturation, and insufficient signaling impairs the ossification process. The goal is to keep it elevated but not constantly agonized.

Overall effects on linear growth:

Enhances chondrocyte proliferation and survival, leads to taller growth plates.

Promotes osteoblastogenesis and bone formation on the metaphyseal side, efficient replacement of cartilage with bone.

Coordinates with other pathways (Ihh/PTHrP, FGF, BMP, GH/IGF-1)

Genetic evidence provides gain-of-function in β-catenin or LRP5 increases bone mass and can enhance growth parameters, loss impairs skeletal elongation. Transient or controlled activation can support elongation, constant activation causes anomalies (joint issues, premature changes). Here are the best substances to support this pathway:

I3O (Indirubin-3'-oxime) - A derivative of indirubin (natural sources like indigo plants). Acts as a GSK3β inhibitor. By inhibiting this pathway, it prevents β-catenin from being destroyed, allowing it to accumulate, enter the nucleus, and drive Wnt target genes. Direct intracellular activation of the pathway.

Laduviglusib - Potent, orally active GSK-3α/β inhibitor that acts similarly to I30. It allows β-catenin to accumulate, and drives Wnt target genes. Very clinically promising.

WAY-316606 - Small molecule that inhibits sFRP-1 (Secreted Frizzled-Related Protein 1), an extracellular antagonist of Wnt signaling. Normally binds to the ligands and prevents Wnt from doing it's job, but by blocking sFRP-1, it frees up endogenous Wnt ligands to bind to their receptors. Leads to downstream β-catenin stabilization.

KY19382 - An orally bioavailable, small molecule substance that was designed to promote hair growth, however has good function for signaling Wnt via blocking CXXC5-DVL, which suppresses Wnt signaling, and inhibits GSK3β.

Lithium Oroate - Inhibits GSK3β (Mg²⁺ competition and Ser9 phosphorylation). Activates Wnt/β-catenin independently of LRP5. Rescues glucocorticoid-impaired growth in metatarsals (+~56% recovery of length via Wnt + cell cycle genes), increases growth plate width in birds, promotes MSC proliferation and osteoblastogenesis. Human data mixed but anabolic at low doses. Interesting source related to Lithium and height.

The Wnt/β-catenin pathway is very complex and ties into many different, minor systems. So if it was hard to understand, basically upregulating the Wnt/β-catenin pathway is beneficial, but full agonization can cause possible defects/premature closure in some circumstances.

V. mTOR/mTORC1

Mechanistic Target of Rapamycin, particularly mTORC1, is a master nutrient and growth factor-sensing kinase complex that integrates signals from amino acids (most notably leucine), insulin/IGF-1, ATP, oxygen, and mechanical loading to regular protein synthesis, cell growth, proliferation, metabolism, differentiation, etc..
mTOR exists in two complexes: mTORC1 (rapamycin-sensitive, nutrient/growth focused) and mTORC2 (less nutrient sensitive, cytoskeleton/Akt-focused). mTORC1 is the relevant focus for growth.

mTORC1 is a key positive regulator of endochondral ossification in the growth plate, although its effects are dose, timing and context dependent (not more = better). Key mechanisms:

Promotes chondrocyte proliferation and protein synthesis (via S6K1, 4E-BP1, ribosome biogenesis) Drives chondrocyte hypertrophy (Cell enlargement, a major contributor to bone lengthening. Hypertrophic cells can swell 5-10x.)

Enhances extracellular matrix (ECM) production (collagen, proteoglycans)

Interacts with the Ihh/PTHrP loop: mTORC1 regulates PTHrP expression (via S6K1-GLI2) and responds to mechanical loading to influence Ihh. Coordinates proliferation and differentiation.

Supports skeletal stem cells in the resting zone, appropriate mTORC1 activation promotes symmetric division of progenitors, expanding the pool for sustained growth.

Inhibition/Activation:

Loss-of-function mutations: - Reduced limb length, impaired, chondrogenesis, delayed hypertrophy, reduced matrix synthesis, dwarfism-like phenotypes.

Moderate activation: - Increases growth plate height, chondrocyte size, and longitudinal growth.

Overactivation: - Disorders resting zone stem cell niche, impairs organized differentiation, fails to produce net lengthening or shortens bones due to disorganization.

Balanced, pulsatile/nutrient-timed mTORC1 supports the best/most optimal growth plate function, especially when combined with HGH/IGF-1 (which both strongly activate it). It is also a central driver of muscle protein synthesis, potently activated by resistance training, leucine-rich protein and IGF-1/Insulin signaling. Leucine is the most potent single amino acid activator via Rag GTPases and Rheb.

L-Leucine / HMB (β-hydroxy-β-methylbutyrate) - Rag GTPase/Ragulator --> mTORC1 lysosomal recruitment.

Phosphatidic acid - Direct FRB domain binding on the mTOR kinase, mediator brand/food-grade.

Ecdysterone - PI3K/AKT upstream activation, activates mTORC1 via this pathway.

Ibutamoren/GHSR Agonists - GH --> IGF-1 --> IRS-1 --> PI3k --> AKT --> mTORC1

The mTORC1 pathway is another pathway that ties into many complex and regulated growth systems, and is hard to directly activate due to the way it functions. Moderate/slightly elevated mTORC1 signaling is most optimal, full agonism/inhibition will ruin your plates.

VI. ERα

Estrogen Receptor Alpha (ERα) is the primary receptor mediating estrogen's effects on bone maturation, plate closure and the regulation of longitudinal growth in both sexes. It is expressed in all stages of the growth plate chondrocyte.

Low/moderate estrogen signaling via ERα - Supports pubertal growth spurt (enhanced GH/IGF-1 secretion and direct chondrocyte proliferation effect).

High estrogen signaling via ERα - Accelerates growth plate senescence, reduces proliferative zone height, stunts growth, promotes chondrocyte ossification, and causes epiphyseal fusion (closure). This permanently stops longitudinal bone growth.

This is commonly seen in castratos, which are males castrated at a young age to keep their youthful voice. Due to their being no ovaries to directly produce estrogen and no testicles to produce testosterone (no testosterone to convert to aromatase), their growth is continued into adulthood, oftentimes reaching adult heights of 6'2-6'6+.

The main types of estrogen produced in the male body include:

Estradiol (E2 / 17β-estradiol) - The most potent and biologically active estrogen in males. Responsible for most ERα (and ERβ) activation in the bones, brain, and other various tissues. Normal adult range is approximately 10-40 pg/mL.

Estrone (E1) - Less potent than E2 (weaker affinity for ERα). Produced mainly from androstenedione. Normal adult male range is approximately 10-60 pg/mL. Levels often rise with age/obesity (More fat cells = more aromatase in the tissues, especially abdominal fat.)

Estriol (E3) - Very weak estrogen, minimal in males (mainly a pregnancy metabolite).

~15% of circulating estrogens come directly from the testes, 85% from peripheral aromatization of androgens (testosterone to estradiol, androstenedione to estrone). Adipose tissue, bone, brain, and the skin are major sites. Levels increase with age, obesity, or high testosterone substrate.
However, estrogen is essential in males for bone health, brain function, libido, erectile function, spermatogenesis, and preventing excessive bone resorption (no sex drive, infertile, no bone mass).

Aromatase is a cytochrome P450 enzyme that catalyzes the irreversible conversion of androgens to estrogens (the last step in estrogen biosynthesis). It removes a methyl group and aromatizes the A-ring of testosterone/androstenedione.

Highly expressed in adipose tissue/fat mass, Leydig cells (testes), brain, skin, and bone.

Regulated by age, obesity, bodily inflammation, and hormones.

In the growth plate, local aromatization of testosterone provides estrogen that acts directly on chondrocytes via ERα to regulate maturation and eventual closure. Blocking aromatase throughout the body can delay plate closure whilst preserving/increasing testosterone levels.

These are the top 3 most commonly used third-generation aromatase inhibitors, ranked via potency for estrogen suppression.

Letrozole - Suppresses whole-body aromatization by >99% at standard 2.5 mg daily dose. Profoundly potent, reduces estradiol the most. Strongest delay in bone maturation in off-label height contexts, commonly paired with rHGH. Higher risk of overly crashing estrogen if not dosed carefully (start very low, 0.25 2-3x a week, go up until you hit your sweet spot). Very effective at raising testosterone as a secondary effect.

Anastrozole - Potent but less potent than letrozole, suppresses by 96-97% at 1 mg daily. Commonly used in bodybuilding and some pediatric endocrinology protocols for estrogen control. More tolerable and less aggressive estrogen crash.

Exemestane - Slightly less potent than letrozole, however uniquely permanently inactivates the aromatase enzyme (suicidal inhibitor, new enzyme must be synthesized). Has mild androgenic activity via its metabolite 17β-hydroexemestane, may help preserve bone and libido better. Milder on lipids and bone, dosed 12.5-25 mg daily or every other day.

Aromatase inhibitors are best used in late puberty or when there is high bone age advancement, in which case preventing plate closure with the inhibition of aromatase would be deemed necessary. There are also some studies/experiments done with SERM's (Selective Estrogen Receptor Modulators), however results are mixed with certain substances like Tamoxifen or Raloxifene. This thread has more information about ERβ and the secondary estrogenic characteristics.
View attachment 5039383

VII. Androgen Receptor

The androgen receptor is a ligand-activated nuclear receptor that mediates the effects of testosterone and its more potent metabolite dihydrotestosterone (DHT). In the context of longitudinal growth, AR is expressed in growth plate chondrocytes (especially resting and hypertrophic zones), osteoblasts, osteocytes, and various other types of bone cells. It can strongly stimulate the GH/IGF-1 axis by increasing GH pulse amplitude, increase muscle mass and mechanical loading on bones (mechanotransduction signals), and contribute to the pubertal growth spurt via overall anabolic drive.

Do androgens themselves drive growth plate closure/skeletal bone age advancement?
No.
Estrogen via ERα (look above) is the dominant driver of bone maturation and plate closure. This is evidence from aromatase deficient/ERa-mutant males (with testosterone), they continue growing high into adulthood with open plates despite very high testosterone levels. This proves that androgens do not play a significant role in directly advancing bone age.

Androgens promote linear growth via both direct and indirect mechanisms, especially in early to mid puberty. It promotes chondrocyte proliferation, proteoglycan synthesis, and local IGF-1 production via the AR in chondrocytes. This expands the proliferative zone and supports production of matrix. Non aromatizable androgens like DHT can stimulate these effects in some models. At low doses, certain oral anabolic steroids have been used to treat idiopathic short stature.

Oxandrolone (Anavar) - Mildly androgenic, non-aromatizable and highly anabolic steroid that is strongly associated with growth velocity increases (2-4 cm/year extra) in boys with CDGP and girls with Turner syndrome when added to GH. It does not suppress GH but can increase GH pulse amplitude in some pubertal boys. Likely acts on the growth plate via AR agonism and local IGF-1 production/overall anabolism.

Stanozolol (Winstrol) - Non-aromatizable, DHT-derivative androgenic/anabolic steroid. Low water retention, used in older protocols for growth promotion. Effective for treating short stature.

Halotestin (Fluoxymesterone) - Extremely potent, oral, non-aromatizable androgen. Strong AR agonist with a low (but manageable) therapeutic window due to organ toxicity. Historically used at very low doses (<5 mg) for growth spurts due to powerful anabolic signaling.

Mechanisms:

Direct AR stimulation of chondrocyte proliferation and matrix synthesis.

Synergy with rHGH via increase in local IGF-1 in cartilage and amplification of HGH effects on the growth plate.

Increased HGH secretion amplitude.

Improved nutrition utilization and muscle loading.

These 3 oral anabolic steroids are relatively safe when used at lower doses during puberty, and may cause some androgenic side effects in the meantime (although not enough to significantly impact quality of life) such as voice deepening, balding (if super prone), acne, and bodily hair growth, along with various other androgenic effects.

VIII. CNP / NPR2

CNP (C-type Natriuretic Peptide) and its primary receptor NPR2 (Natriuretic Peptide Receptor 2, also known as GC-B or guanylyl cyclase-B) form one of the most extreme and powerful stimulatory pathways for longitudinal bone growth. It is a 22-amino-acid peptide belonging to the natriuretic peptide family (along with ANP and BNP). It is produced locally in many tissues, including the growth plate in proliferative and pre-hypertrophic chondrocytes, brain, endothelium, and bone.

NPR2 is the specific transmembrane receptor for CNP. When CNP binds to NPR2, it activates it's intracellular guanylyl cyclase domain, dramatically increasing intracellular cGMP (cyclic guanosine monophosphate). Elevated cGMP activates protein kinase G (PKG) which mediates most downstream effects. This pathway is completely distinct from the receptors ANP/BNP use (NPR1/GC-A), which are more involved in blood pressure/fluid balance.

CNP/NPR2 is a major positive regulator of endochondral ossification and one of the strongest known stimulators of linear growth.

Strongly stimulates chondrocyte proliferation and hypertrophy (cell enlargement).

Increases extracellular matrix production (collagen II, proteoglycans).

Opposes FGFR3 signaling via cGMP/PKG, which reduced MAPK/ERK signaling downstream of FGFR3.

Interacts with the Ihh/PTHrP loop by maintaining the proliferative pool and regulating the pace of differentiation.

Promotes growth plate height and delays senescence.

Genetic Evidence:

Loss-of-function mutations in CNP/NPR2 - Severe short stature (acromesomelic dysplasia, type Maroteaux).

Gain-of-function/overexpression in CNP/NPR2 - Unusually tall stature and overgrowth.

CNP also causes local vasodilation and has anti-fibrotic and anti-hypertrophic effects in the heart and vessels. It is less potent on blood pressure than ANP/BNP. CNP also preferentially stimulates long bone growth more than flat bone growth, and is expressed in the CNS and may modulate neuronal development and pain. It is also involved in ovarian follicle development and uterine function, minor lipolytic effects and energy balance, and mild debloating/natriuretic (sodium-excreting) effects, however is much weaker than ANP/BNP. As you can tell, CNP does far more than just make someone taller.

Vosoritide - You saw this coming, it is a daily subcutaneous CNP analog approved for achondroplasia in children with open growth plates, it increases annualized height velocity by 1.5-2+ cm/year above placebo, and in some cases even 8+ cm/year with sustained benefits over multiple years and improved bodily proportionality. Because of this, it even works in the presence of strong FGFR3 activation.

Navepegritide - A long-acting, once-weekly prodrug of CNP. Developed by Ascendis Pharma and received FDA accelerated approval for children with achondroplasia aged 2+ with open plates. Native CNP has a short half life of minutes, so vosoritide requires daily injections. Navepegritide uses TransCon technology, CNP is linked to an inert carrier, protecting it from rapid clearance and releasing active CNP slowly and continuously over the week.

Icaritin - The main bioactive flavonoid from the herb Epimedium (Horny Goat Weed) is widely available as a supplement. It does not directly activate NPR2 like CNP analogs, but it potentiates the pathway indirectly via inhibiting PDE5 (similar to sildenafil), PDE5 breaks down cGMP (the second messenger produced when CNP binds to NPR2). By inhibiting PDE5, Icaritin slows the degradation of cGMP. This allows for higher and prolonged intracellular cGMP levels after CNP/NPR2 activation. This amplified downstream PKG signaling, which promotes chondrocyte proliferation, hypertrophy, matrix production, and antagonism of FGFR3-MAPK inhibitory effects. Icarrin/Icaritin has been shown to target many different pathways outside of this one, so I would highly recommend it. Sometimes the most useful things are just right in front of your face.

IX. TGF-β / Smad2/3

TGF-β (Transforming Growth Factor Beta) / Smad2/3 signaling is a critical regulatory pathway in the growth plate with very biphasic and context dependent effects on chondrocyte behavior. It generally acts as a break on terminal maturation whilst supporting earlier stages.

TGF-β isoforms (mainly TGF-β1, -β2, and -β3) bind to type II and type I receptors (TβRII and ALK5/TβRI). This activates the canonical Smad pathway:

Phosphorylation of Smad2 and Smad3 (receptor-regulated Smads).

Smad2/3 complex with Smad4, translocate to the nucleus, and regulate target genes (often in cooperation with other transcription factors like Runx2, Sox9).

Non-canonical pathways (MAPK/ERK, p38, PI3K, etc.) are secondarily activated.

Smad2/3 is the primary mediator of TGF-β's cartilage effects, with Smad3 playing a more dominant role in inhibiting hypertrophy.
In the early stages (resting/proliferative chondrocytes) it is generally supportive, promoting proliferation, extracellular matrix synthesis, (collagen II, aggrecan), and maintains the chondrogenic phenotype. It can also help expand the progenitor pool. It is a strong inhibitor of terminal hypertrophy, repressing key markers (collagen X, Runx2, MMP13) and delays the transition from pre-hypertrophic to hypertrophic chondrocytes, preventing premature maturation and ossification.
By delaying terminal differentiation and hypertrophy, TGF-β/Smad2/3 helps maintain a taller proliferative zone and organized plate architecture. This allows more cycles of proliferation before cells exist to hypertrophy. However, because hypertrophy itself (cell enlargement) contributes significantly to longitudinal growth (5-10x volume increase), excessive or prolonged TGF-β signaling can slow net elongation by holding this phase back too strongly. We want balanced/upregulated TGF-β signaling.

Human TGF-beta 1 Recombinant Protein - Synthetic TGF-β, or any of it's isoforms like 2 and 3 could work as well.

Human Activin A Recombinant Protein - Protein that plays a key role in cell growth, differentiation, and various physiological processes. This includes reproductive function and would healing, and belongs to the TGF family and signals through SMAD2/3 proteins to regulate these functions.

Angiotensin II - Strongly upregulates TGF-β1 production via Smad2 phosphorylation, nuclear translocation of phosphorlyated SMad2 and Smad4, and increased Smad DNA binding activity and overexpression.

There are many other secondary TGF-β agonists out there, such as GDF-8 Myostatin, GDF-11, Nodal, TSP-1, etc.. However these are all within certain contexts, and some substances like MMP2/MMP9, Plasmin, and αvβ6 / αvβ8 integrins can activate latent TGF-β. It's a very tricky pathway.

X. BMPs

The Bone Morphogenetic Protein (BMP) family consists of a large group of growth factors within the TGF-β superfamily. They are highly essential for skeletal development, chondrogenesis, and longitudinal bone growth.
BMPs bind to type 1 (BMPR1A/ALK3, BMPR1B/ALK6) and type 2 serine/threonine kinase receptors. This leads to phosphorylation of Smad1/5/8 (R-Smads), which complex with Smad4 and enter the nucleus to regulate target genes (Runx2, Osterix, Ihh). Non canonical pathways such as p38, MAPK, ERK, and PI3K also contribute.

BMP2 - Important for chondrocyte proliferation and maturation

BMP4 - Often redundant with BMP2

BMP6 & BMP7 - Prominent in the hypertrophic zones

BMP9 - Potent osteogenic potential

BMP/Smad1/5/8 signaling is primarily pro-growth and pro-hypertrophic, acting as a key accelerator of endochondral ossification. It generally opposes the anti-hypertrophic effects of TGF-β/Smad2/3. Specifically,

Stimulates chondrocyte proliferation

Promotes chondrocyte hypertrophy (major contributor to bone lengthening)

Enhances extracellular matrix production and mineralization

Coordinates with Ihh/PTHrP loop, upregulates Ihh, promotes proliferation and regulates the pace of differentiation.

Negatively regulates FGF signaling and supports progression toward terminal differentiation and ossification.

BMP signaling drives both proliferation and the hypertrophic contribution to elongation, leading to accelerated longitudinal growth when appropriately active.

Genetic Evidence:

Loss-of-function mutations in BMPs - Impairs proliferation and maturation leading to shorter bones, constitutive activation can accelerate hypertrophy and bone formation.

Gain-of-function/overexpression mutations in BMPs - Disorganized plates/premature maturation, high risk of bone age advancement and eating up the proliferative pool.

BMPs are highly anabolic for bone, they strongly promote osteoblast differentiation and bone formation on the metaphyseal side, ensuring efficient replacement of cartilage with bone.

Statins (Simvastatin, Lovastatin) - Increase BMP2 expression and signaling, used in some bone-healing contexts, preclinical data shows enhanced chondrogenesis and bone formation.

Icaritin (again) - Upregulates BMP2 , BMP4, and Runx2 via cAMP. Supports osteoblast differentiation and has shown benefits in bone growth models, and also supports CNP via PDE5 inhibition.

Resveratrol - Activates BMP7 signaling and enhances osteogenic differentiation.

Like most pathways, you want some upregulation of this pathway but not full agonism, since TGF-β and BMPs are somewhat opposite, it's better to slightly elevate both.

XI. Hedgehog

Hedgehog ligands (Sonic, Indian, Desert) bind to the transmembrane receptor Patched (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo), a GPCR-like protein. When a hedgehog ligand binds Ptch1, it relieves inhibition of Smo. The activated Smo then promotes the formation of active Gli transcription factors (mainly Gli1, Gli2, as activators and Gli3 as repressor when processed).

Gli2 acts as a transcriptional activator

Gli3 is processed into a repressor form (Gli3R) without Hh signaling, since Hh signaling prevents this repression (called de-repression).

This confusing mechanism leads to the transcription of target genes involved in proliferating, differentiation, and patterning. Ihh is expressed mainly by pre-hypertrophic chondrocytes, and it orchestrates the famous Ihh-PTHrP negative feedback loop.

Ihh stimulates PTHrP expression in the resting zone.

PTHrP keeps chondrocytes proliferating and delays hypertrophy

This loop maintains the proper distance and balance between proliferation and differentiation, optimizing growth plate height and sustained elongation.

Indian Hedgehog Signaling also:

Directly stimulates chondrocyte proliferation in the proliferative zone

Regulates chondrocyte differentiation into pre-hypertrophic and hypertrophic cells

Promotes osteoblast differentiation in the perichondrium and primary spongiosa (essential for turning cartilage into bone).

Maintains resting zone skeletal stem cell pool and supports vascular invasion of new bone.

Genetic Evidence:

Loss-of-function mutations: Extreme dwarfism, disorganized growth plates, lack of osteoblasts, and death.
Gain-of-function mutations: Increased long bone growth, bodily length, although overactivation could potentially cause medulloblastomas.

Activating Smoothened bypasses the need for the Indian Hedgehog ligand.

Smoothened Agonist (SAG) - Potent and widely used direct agonist of Smo to force longitudinal bone growth via skeletal stem cell activation, and for medulloblastoma research.

Purmorphamine - Used for in vitro work, promotes osteoblast differentiation but is typically more toxic and less for human use. Bad bioavailability.

GSA-10 - Quinolinecarboxamide Smo agonist from a very distinct chemical class, activating Smo and promoting very strong osteogenic differentiation. Works non-canonically, designed with the pharmacokinetics of SAG in mind. Generally best and the most potent by far, good bioavailability so ~0.5-1 mg could work.

Keep in mind that calculating estimates for all of these substances listed is both hard and the mathematics are calculated (having to find studies and calculate plasma concentrations and half-life/metabolism etc..). I would do my own research to find out what dose of which substance works best for you.
If you have any suggestions as for what pathways/genre I should write on, tell me.

Amazing fabulous post of exceeding grandeur

[MEGATHREAD] All Major Growth Pathways for Height

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