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Growth Hormone Axis & Peptide Regulation

Growth hormone (GH) secretion is not random. It follows a tightly orchestrated pattern --- pulsatile bursts primarily during deep sleep, regulated by a push-pull system of stimulatory and inhibitory signals from the hypothalamus, stomach, liver, and the pituitary gland itself.

Growth hormone (GH) secretion is not random. It follows a tightly orchestrated pattern --- pulsatile bursts primarily during deep sleep, regulated by a push-pull system of stimulatory and inhibitory signals from the hypothalamus, stomach, liver, and the pituitary gland itself. The hypothalamic-pituitary axis that controls GH is one of the most precisely tuned endocrine feedback loops in the body, and it is the axis that therapeutic peptides like CJC-1295, ipamorelin, and sermorelin are designed to engage.

Understanding how the axis works --- the receptors, the feedback loops, the pulsatile timing --- is necessary for understanding how these peptides produce their effects and where their limitations lie.

Table of Contents

The GH/IGF-1 Axis: An Overview

Human growth hormone (HGH, or somatotropin) is a 191-amino-acid single-chain polypeptide produced by somatotroph cells in the anterior pituitary gland. In children, it drives linear growth. In adults, its main role shifts to regulating metabolism --- promoting protein synthesis, stimulating lipolysis, and maintaining lean body mass and bone density.

GH secretion is controlled by three primary regulators:

  1. Growth hormone-releasing hormone (GHRH) --- stimulatory, produced in the hypothalamus
  2. Somatostatin (SST) --- inhibitory, produced in the hypothalamus and other tissues
  3. Ghrelin --- stimulatory, produced primarily in the stomach

These three signals converge on the somatotroph cells of the anterior pituitary to determine the amplitude and timing of GH pulses. GH then acts on target tissues both directly (through the GH receptor) and indirectly through insulin-like growth factor 1 (IGF-1), which is primarily produced by the liver.

The axis completes itself with negative feedback: both GH and IGF-1 loop back to suppress GHRH release and stimulate somatostatin secretion, preventing runaway hormone production.

GHRH: The On Switch

Growth hormone-releasing hormone is a 44-amino-acid polypeptide produced by neurons in the arcuate nucleus of the hypothalamus. These neurons send their axon terminals to the median eminence, where GHRH is released into the portal venous system --- the dedicated blood supply connecting the hypothalamus to the anterior pituitary.

When GHRH reaches the pituitary, it binds to the GHRH receptor (GHRHR) on somatotroph cells. GHRHR is a G protein-coupled receptor that signals through the cAMP pathway: binding activates adenylyl cyclase, raises intracellular cAMP, and activates protein kinase A (PKA). This cascade does two things simultaneously:

Short-term: PKA triggers the release of GH from preformed secretory vesicles, producing an immediate pulse of GH into the bloodstream.

Long-term: PKA activates the transcription factor CREB, which drives GH gene expression and stimulates somatotroph cell proliferation. This means GHRH does not just release stored GH --- it also replenishes the supply and expands the cells that make it.

A 2025 review in Reviews in Endocrine and Metabolic Disorders summarized the current understanding: GHRH stimulates GH release and synthesis, drives somatotroph proliferation, is negatively regulated by somatostatin, GH, and IGF-1, and changes across the lifespan and in response to metabolic challenges. Recent RNA sequencing data clarifies that GHRH expression in humans is predominantly hypothalamic, with some basal ganglia presence.

GHRH is the foundation of the entire axis. Without it, GH pulsatility collapses. Mutations in the GHRH receptor cause severe GH deficiency and dwarfism.

Somatostatin: The Off Switch

Somatostatin is a cyclic peptide produced by neuroendocrine neurons in the periventricular and ventromedial nuclei of the hypothalamus (the form relevant to GH regulation is SST-14, a 14-amino-acid peptide). Like GHRH, it reaches the pituitary via the portal blood supply.

Somatostatin binds to five receptor subtypes (sst1 through sst5), all G protein-coupled receptors, on the surface of somatotroph cells. The relevant subtypes for GH suppression are primarily sst2 and sst5. Binding activates inhibitory G proteins (Gi), which suppress adenylyl cyclase activity --- directly opposing GHRH's stimulatory signal. Somatostatin also activates potassium channels and inhibits voltage-gated calcium channels, hyperpolarizing the cell and blocking the calcium influx needed for GH vesicle exocytosis.

The relationship between GHRH and somatostatin is what generates the pulsatile pattern of GH secretion. The classic model proposed alternating bursts of GHRH and somatostatin release from the hypothalamus. When somatostatin tone drops, GHRH-stimulated GH release surges. When somatostatin rises, GH secretion is suppressed. More recent models suggest somatostatin may be the primary pacemaker --- its periodic withdrawal, rather than GHRH bursts, may be what dictates pulse timing.

Somatostatin also acts beyond the pituitary. It inhibits GHRH release at the hypothalamic level, suppresses thyroid-stimulating hormone (TSH), inhibits gastrointestinal hormone secretion, and reduces pancreatic insulin and glucagon release. This broad inhibitory profile is why somatostatin analogs (like octreotide and lanreotide) are used clinically to treat GH excess in acromegaly and hormone-secreting tumors.

Ghrelin and the Growth Hormone Secretagogue Receptor

Ghrelin added a third dimension to GH regulation when it was identified in 1999. Produced primarily by X/A-like enteroendocrine cells in the gastric fundus, ghrelin is a 28-amino-acid peptide with a unique post-translational modification: an octanoyl group attached to the serine at position 3 (acyl ghrelin). This acylation is required for binding to its receptor.

The ghrelin receptor, formally called the growth hormone secretagogue receptor type 1a (GHS-R1a), is expressed on pituitary somatotrophs and on GHRH neurons in the hypothalamus. GHS-R1a is a G protein-coupled receptor that signals primarily through Gq/11, activating phospholipase C and triggering inositol trisphosphate (IP3)-mediated calcium release from the endoplasmic reticulum. This is a fundamentally different signaling pathway from GHRH's cAMP route.

Ghrelin stimulates GH secretion through at least three mechanisms:

  1. Direct pituitary action. Ghrelin binds GHS-R1a on somatotrophs, triggering calcium influx and GH exocytosis.
  2. Hypothalamic amplification. Ghrelin stimulates GHRH neurons in the arcuate nucleus, boosting GHRH release into the portal circulation.
  3. Somatostatin suppression. Ghrelin inhibits somatostatin-releasing neurons, removing the brake on GH secretion.

The combined effect is substantial. When GHRH and ghrelin are administered together, the GH response is synergistic, not merely additive --- the two signals converge through different second messenger systems (cAMP and calcium) on the same somatotroph cells, producing GH pulses larger than either stimulus alone.

Ghrelin also functions as the "hunger hormone." Its levels rise during fasting and fall after eating, linking nutritional status directly to GH secretion. Functionally, the ghrelin-GH connection is protective against hypoglycemia --- during fasting, elevated ghrelin boosts GH, which in turn promotes lipolysis and maintains blood glucose.

Recent research points to AMP-activated protein kinase (AMPK) as a shared downstream mediator. Evidence suggests that an AMPK-dependent mechanism mediates both the GH response to GHRH and ghrelin, providing a molecular link between cellular energy sensing and GH release.

IGF-1: The Downstream Effector and Feedback Signal

GH does not act in isolation. Much of its anabolic and growth-promoting effects are mediated through IGF-1 (insulin-like growth factor 1), a 70-amino-acid peptide produced predominantly by the liver in response to GH receptor activation.

When GH binds to the GH receptor on hepatocytes, it activates the JAK2-STAT5 signaling pathway. STAT5 proteins translocate to the nucleus and drive transcription of the IGF-1 gene. The resulting IGF-1 is released into the bloodstream, where it circulates bound to IGF-binding proteins (primarily IGFBP-3 and the acid-labile subunit), giving it a much longer half-life than GH itself.

This pharmacokinetic difference is clinically important. GH is secreted in pulses with a half-life of roughly 10 to 20 minutes, making single blood draws unreliable indicators of GH status. IGF-1, by contrast, circulates continuously with stable levels that reflect the integrated 24-hour GH secretion. That is why IGF-1 measurement is the standard biomarker for assessing GH axis function.

IGF-1 closes the feedback loop through two routes:

At the hypothalamus: IGF-1 inhibits GHRH gene expression and stimulates somatostatin secretion, reducing the drive for GH release.

At the pituitary: IGF-1 directly inhibits spontaneous and GHRH-stimulated GH secretion from somatotroph cells.

GH itself also feeds back directly. It stimulates somatostatin release and inhibits its own secretion at the pituitary level, creating a short-loop feedback independent of IGF-1.

A 2024 review in Frontiers in Endocrinology highlighted that portal insulin delivery is another regulator of the GH/IGF-1 axis --- insulin modulates hepatic GH receptor synthesis, linking metabolic status to GH sensitivity. This explains why GH resistance develops in conditions like poorly controlled type 1 diabetes, where portal insulin is deficient.

The Pulsatile Pattern: Why Timing Matters

GH secretion follows a circadian and ultradian rhythm. Roughly two-thirds of daily GH output occurs during the night, with about 70% of that released during the first episode of slow-wave (deep) sleep. During waking hours, smaller pulses occur roughly every 2 to 3 hours, with troughs between pulses where GH levels can be nearly undetectable.

This pulsatility is not incidental --- it is functionally necessary. Continuous GH exposure and pulsatile GH exposure produce different downstream effects. Pulsatile GH preferentially activates STAT5b in the liver, driving IGF-1 production and sexually dimorphic gene expression patterns. Continuous GH exposure activates a broader set of signaling pathways and is associated with the GH profile seen in female physiology.

Several factors modulate the pulse pattern:

  • Age: GH secretion declines approximately 14% per decade after age 30, a process sometimes called somatopause.
  • Body composition: Visceral fat is a potent suppressor of GH. Free fatty acids inhibit both spontaneous and GHRH-stimulated GH secretion.
  • Exercise: Acute exercise is one of the strongest physiological stimulators of GH release, mediated through increased GHRH and reduced somatostatin.
  • Fasting: Prolonged fasting raises ghrelin and GH, promoting lipolysis to maintain energy supply.
  • Sleep quality: Disrupted slow-wave sleep blunts the nocturnal GH surge.

How Therapeutic Peptides Interact with the Axis

The peptides used in research and clinical settings to stimulate GH secretion target the same receptor systems described above. They fall into two categories based on which receptor they activate.

GHRH Analogs: Engaging the GHRH Receptor

Sermorelin is a synthetic analog of the first 29 amino acids of GHRH (GHRH 1-29). It is the minimal active fragment needed to activate the GHRH receptor. Sermorelin was FDA-approved for diagnostic testing and treatment of GH deficiency in children (though that approval was later withdrawn for commercial, not safety, reasons). It activates the same cAMP/PKA pathway as endogenous GHRH but has a short plasma half-life of roughly 10 to 20 minutes.

CJC-1295 is a modified GHRH(1-29) analog. In its DAC (Drug Affinity Complex) form, a maleimidopropionic acid linker enables covalent binding to serum albumin, extending the half-life to approximately 6 to 8 days. In randomized placebo-controlled trials, single subcutaneous injections of CJC-1295 with DAC increased mean GH levels 2- to 10-fold for more than 6 days and boosted IGF-1 levels 1.5- to 3-fold for 9 to 11 days (Teichman et al., 2006). The version without DAC (sometimes called modified GRF 1-29) retains the amino acid substitutions that resist DPP-4 cleavage but lacks the albumin-binding component, giving it a much shorter duration of action.

Tesamorelin is the only GHRH analog currently FDA-approved for a therapeutic indication --- specifically for reducing excess abdominal fat in HIV-associated lipodystrophy. It is a modified GHRH(1-44) with a trans-3-hexenoic acid group attached to the N-terminus.

Ghrelin Receptor Agonists: Engaging GHS-R1a

Ipamorelin is a synthetic pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) that selectively binds GHS-R1a. Its standout feature is selectivity: ipamorelin stimulates GH release with potency comparable to GHRP-6 but, remarkably, does not raise ACTH or cortisol at doses up to 200-fold higher than the ED50 for GH release (Raun et al., 1998). This makes it the most selective growth hormone-releasing peptide (GHRP) identified to date.

GHRP-6 is a hexapeptide derived from met-enkephalin structure. It binds GHS-R1a and potently stimulates GH release, but it also raises ACTH, cortisol, and prolactin --- off-target effects that limit its research appeal compared to ipamorelin. GHRP-6 also stimulates appetite through ghrelin receptor activation.

GHRP-2 is slightly more potent than GHRP-6 for GH release (lower ED50) but shows similar off-target cortisol and ACTH stimulation. In comparative pharmacology studies, GHRP-2 had the lowest ED50 (0.6 nmol/kg) but also a lower maximal GH response ceiling compared to ipamorelin or GHRP-6.

MK-677 (ibutamoren) is not a peptide but a non-peptide ghrelin mimetic that binds the same GHS-R1a receptor. Orally bioavailable, it raises GH and IGF-1 levels over 24-hour periods and has been studied in clinical trials for growth hormone deficiency and age-related muscle wasting.

The Synergy of Dual-Receptor Activation

The most pharmacologically interesting approach combines a GHRH analog with a ghrelin receptor agonist. When CJC-1295 (activating the GHRH receptor via cAMP) is administered alongside ipamorelin (activating GHS-R1a via calcium signaling), the two pathways converge on the same somatotroph cell through different second messenger systems. The result is synergistic --- total GH output exceeds the sum of the individual responses.

This dual-receptor approach also more closely mimics physiology, where endogenous GHRH and ghrelin work in concert. However, it is important to note that no large-scale human clinical trials have evaluated the CJC-1295/ipamorelin combination for any specific therapeutic indication. The individual peptides have research data behind them, but the combination remains investigational.

All of these peptides preserve the axis's negative feedback mechanisms. Because they stimulate endogenous GH production rather than supplying exogenous GH directly, the pituitary can still downregulate its response when GH and IGF-1 levels rise. This is often cited as a theoretical safety advantage over recombinant GH administration, though comparative long-term safety data is limited.

None of these peptides (except tesamorelin for its specific indication) are FDA-approved for performance, anti-aging, or bodybuilding use, and GH secretagogues are prohibited at all times by WADA.

FAQ

What is the GH/IGF-1 axis?

The GH/IGF-1 axis is the hormonal feedback system that regulates growth hormone production. GHRH and ghrelin stimulate GH release from the pituitary. GH then stimulates IGF-1 production from the liver. IGF-1 and GH feed back to the hypothalamus and pituitary to suppress further GH release. Somatostatin acts as the primary inhibitory signal throughout the loop.

Why does GH come in pulses rather than a steady stream?

The pulsatile pattern is generated by the alternating influence of GHRH and somatostatin from the hypothalamus. Pulsatile GH and continuous GH activate different downstream signaling profiles in target tissues, with pulsatile delivery preferentially driving IGF-1 production and sex-specific gene expression. The pulse pattern is also more efficient at stimulating lipolysis and protein synthesis.

How do GHRH analogs like CJC-1295 differ from recombinant GH?

GHRH analogs stimulate the pituitary to produce and release its own GH, preserving the body's natural feedback loops and pulsatile secretion pattern. Recombinant GH (like somatropin) directly supplies exogenous hormone, bypassing pituitary regulation. GHRH analogs produce smaller, more physiological GH increases, while exogenous GH can suppress endogenous production through negative feedback.

What makes ipamorelin more selective than GHRP-6 or GHRP-2?

All three bind the ghrelin receptor (GHS-R1a), but ipamorelin does not stimulate ACTH or cortisol release at any tested dose. GHRP-6 and GHRP-2 both raise cortisol and ACTH levels. The structural basis for this selectivity is not fully understood, but it likely relates to differences in how each peptide interacts with the receptor's binding pocket and the downstream G protein coupling it induces.

Does the GH axis decline with age?

Yes. GH secretion decreases approximately 14% per decade after age 30, driven by reduced GHRH signaling, increased somatostatin tone, decreased ghrelin sensitivity, and changes in body composition (increased visceral fat suppresses GH). This age-related decline in GH secretion is termed somatopause.

Can peptides reverse somatopause?

In research settings, GH secretagogues can increase GH and IGF-1 levels in older adults to ranges seen in younger individuals. Whether these hormonal changes translate to meaningful clinical outcomes (improved body composition, bone density, functional capacity) remains an open question without definitive large-scale trial evidence. For a deeper discussion of the biology involved, see the hypothalamic-pituitary axis.

The Bottom Line

The GH/IGF-1 axis operates as a precision feedback system where GHRH provides the drive, somatostatin provides the brake, and ghrelin provides a metabolic override linked to nutritional status. Therapeutic peptides engage this system at defined receptor targets: GHRH analogs like CJC-1295 and sermorelin work through the cAMP pathway on the GHRH receptor, while ghrelin receptor agonists like ipamorelin work through calcium signaling on GHS-R1a. Combining both pathways produces a synergistic effect that more closely mimics natural physiology.

The axis's built-in feedback loops mean that secretagogue-stimulated GH production self-regulates in a way that direct GH injection does not. But this regulatory advantage is also a ceiling --- the axis can only produce so much GH before negative feedback dampens the response. For researchers and clinicians working with these peptides, understanding the axis is not optional. It is the mechanism that defines both the potential and the limits of GH secretagogue therapy.

References

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  8. Teichman, S.L., et al. (2006). Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. Journal of Clinical Endocrinology & Metabolism, 91(3), 799-805. PMID: 16352683

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