In plain English
Growth hormone (GH) is made by cells in the pituitary, a pea-sized gland under the brain. It is released in bursts (pulses), not at a steady rate [2].
Two messages from the hypothalamus (a control area at the base of the brain) set those pulses. GHRH says “release”. Somatostatin says “stop” [3, 6]. A third messenger, ghrelin, comes mainly from the stomach and also triggers release [10].
Once in the blood, GH acts on cells directly and also causes the body to make IGF-1 (insulin-like growth factor 1), much of it in the liver [12, 13]. GH and IGF-1 then signal back to the brain and pituitary to slow further release. This is called negative feedback [2].
Most of this picture comes from decades of laboratory, animal and human physiology studies, summarised in review articles [1, 2]. Many details, such as the exact role of IGF-1 made in tissues, are still debated [13].
The short version
- GHRH turns GH release on; somatostatin turns it off [3, 6].
- Ghrelin acts through its own receptor, the GHS-R [9, 10].
- IGF-1 carries many of GH’s signals and feeds back on the system [2, 12].
Key facts
| Component | Type | Main source | Receptor | Role in the axis |
|---|---|---|---|---|
| GHRH | Peptide hormone | Hypothalamus [3] | GHRH receptor, a GPCR linked to cAMP [4, 5] | Stimulates GH release |
| Somatostatin | Cyclic peptide | Hypothalamus [6] | Five GPCRs, SST1–SST5 [7] | Inhibits hormone secretion, including GH [6, 7] |
| Ghrelin | 28-amino-acid acylated peptide | Mainly stomach [8, 10] | Growth hormone secretagogue receptor (GHS-R), a GPCR [9, 10] | Stimulates GH release [10] |
| Growth hormone | Protein hormone | Somatotroph cells of the anterior pituitary [2] | GH receptor, a cytokine-type receptor using JAK2 [12] | Acts directly and by inducing IGF-1 [12] |
| IGF-1 | Peptide growth factor | Liver and most other tissues [13] | IGF-1 receptor, a receptor tyrosine kinase [14] | Mediates many GH actions; feedback [2, 13] |
The hypothalamus and pituitary: where the axis starts
GH is produced by somatotroph cells in the anterior pituitary gland. Its blood levels show a pulsatile pattern. Secretion is mainly controlled by hypothalamic factors released into the hypophyseal portal system, a small network of blood vessels that links the hypothalamus with the pituitary [2].
Mathematical analysis of these pulses (deconvolution analysis) has been applied across mammalian species, including humans, and shows that the pattern varies with sex and hormonal environment [1]. Several hormonal and neuronal inputs shape the pulses, including GHRH, somatostatin and ligands of the GHS receptor [1, 2].
The study of brain peptide hormones that control the pituitary was recognised in the 1977 Nobel Prize in Physiology or Medicine, awarded in part to Roger Guillemin and Andrew Schally “for their discoveries concerning the peptide hormone production of the brain” [20].
GHRH: the “on” signal
Growth hormone-releasing hormone (GHRH, also called growth hormone-releasing factor) was first isolated and characterised in 1982 from a human pancreatic tumour that had caused excess GH secretion [3].
GHRH binds the pituitary GHRH receptor (GHRH-R). When this receptor was cloned in 1992, it was shown to have seven membrane-spanning segments, the hallmark of a G protein-coupled receptor (GPCR). It bound GHRH with high affinity, stimulated cAMP production, and was expressed mainly in the anterior pituitary. It is related to the receptors for secretin and vasoactive intestinal peptide [4]. Splice variants of GHRH-R have since been found in other tissues [5]. For background on GPCRs and cAMP, see How Peptide Signalling Works.
Somatostatin: the “off” signal
Somatostatin was isolated from the hypothalamus in 1973 as a polypeptide that inhibits the secretion of pituitary GH [6]. It is a cyclic peptide with potent inhibitory actions on hormone secretion and on nerve-cell excitability [7].
Somatostatin acts through five GPCRs, named SST1 to SST5. They share common structures and signalling mechanisms but differ in where they are found and how they are regulated [7]. Natural somatostatin has a very short half-life in plasma; see Why Peptides Break Down.
Ghrelin and the GHS receptor: a third input
The ghrelin story began with synthetic compounds. From 1976, researchers developed unnatural growth hormone-releasing peptides (GHRPs). Studies in the early 1980s showed their activity differed from GHRH, which suggested an undiscovered natural regulator of GH secretion [8]. GHRPs and related compounds fall into three chemical classes, peptides, partial peptides and non-peptides, and probably all act through the same receptor [8].
In 1996 that receptor was cloned. The growth hormone secretagogue receptor (GHS-R) is a GPCR found in the pituitary and in the arcuate and ventromedial hypothalamus, and it defined a pathway for controlling pulsatile GH release [9].
The natural ligand was identified in 1999 and named ghrelin. Purified from rat stomach, it is a 28-amino-acid peptide with an n-octanoyl (fatty acid) group attached to serine 3. This modification is essential for its activity. Ghrelin released GH both in vitro and in vivo, and human ghrelin differs from rat ghrelin at only two amino acids [10]. Since then, reviews have described a wide range of additional ghrelin actions beyond GH release, in areas such as gut motility, gastric acid secretion and glucose metabolism [11].
Growth hormone and its receptor
GH acts through the growth hormone receptor. This receptor exists as a pre-formed pair (a constitutive dimer). Hormone binding rotates and realigns the two halves, bringing together the associated kinase JAK2, which becomes activated. JAK2 then phosphorylates the receptor, allowing adaptor proteins to bind and pass the signal on [12]. GH acts both directly through this receptor and indirectly by inducing IGF-1 [12].
IGF-1 and the somatomedin hypothesis
The original somatomedin hypothesis proposed that pituitary GH controls body growth through circulating IGF-1 (also called somatomedin C), produced only by the liver [13]. That view has been revised. IGF-1 is now known to be produced by most, if not all, tissues. In mice in which the IGF-1 gene was deleted only in the liver, circulating IGF-1 fell sharply, yet postnatal growth and development were normal and free IGF-1 levels were normal. The relative roles of circulating and locally produced IGF-1 are still being worked out [13].
IGF-1 acts through the IGF-1 receptor, which, like the insulin receptor, is a receptor tyrosine kinase [14]. IGF-1 receptor signalling is linked to the MAPK and PI3K pathways [15].
Feedback: how the axis limits itself
GH release is restrained by multiple negative feedback loops that detect changes in circulating GH or IGF-1. These loops operate at both the pituitary and the hypothalamus, which suggests built-in redundancy [2]. GH release is also higher in particular physiological states, such as the neonatal period, pregnancy, low blood glucose and prolonged food deprivation [2].
Research compound classes linked to the axis
Laboratories study several classes of synthetic compounds that act on parts of this axis. They are listed here by class only. Each compound has its own evidence base, and no class-level effect should be assumed for any single compound.
| Class | Receptor | Examples named in the 2026 WADA Prohibited List [16] | Library pages |
|---|---|---|---|
| GHRH analogues | GHRH receptor | CJC-1295, sermorelin, tesamorelin | Sermorelin, Tesamorelin, CJC-1295 no DAC |
| Growth hormone-releasing peptides (GHRPs) | GHS-R | GHRP-2 (pralmorelin), GHRP-6, hexarelin | GHRP-2, GHRP-6 |
| Growth hormone secretagogues (GHS) | GHS-R | Ipamorelin, ibutamoren (MK-677), lenomorelin (ghrelin) | Ipamorelin |
| IGF-1 and analogues | IGF-1 receptor | IGF-1 (mecasermin) and its analogues | IGF-1 LR3 |
Somatropin (recombinant human growth hormone) is listed by Sport Integrity Australia among therapeutic peptides that are registered medicines [17]. That product is a regulated pharmaceutical and is not equivalent to research-grade material.
What this means in Australia
ARTG. Medicines must be evaluated by the TGA and included on the Australian Register of Therapeutic Goods (ARTG) before they can be supplied as medicines. Peptide products that are not on the ARTG are unapproved therapeutic goods [19].
Poisons Standard. The Poisons Standard (October 2026) has class entries that cover this axis [18]:
| Entry | Status [18] |
|---|---|
| Growth hormone releasing hormones (GHRHs) | Schedule 4 and Appendix D, clause 5 |
| Growth hormone releasing peptides (GHRPs) | Class entry; named members GHRP-6 and pralmorelin (GHRP-2) are Schedule 4 and Appendix D, clause 5 |
| Growth hormone secretagogues (GHSs) | Class entry; named member ipamorelin is Schedule 4 and Appendix D, clause 5 |
| Insulin-like growth factors | Schedule 4 and Appendix D, clause 5. Insulin-like growth factor I and mecasermin are each Schedule 4 |
Schedule 4 means prescription-only. Appendix D, clause 5 means possessing the substance without authority is illegal. Whether a class entry captures a specific compound that is not named is a legal question [18].
TGA position. In April 2026 the TGA named CJC-1295 among its examples of unapproved peptide products and stated that a “research use only” disclaimer does not make supply lawful, and does not change regulatory status, permit importation, or remove advertising or supply obligations [19].
Sport. The WADA Prohibited List class S2.2.4 covers growth hormone releasing factors, including GHRH and its analogues, growth hormone secretagogues and GHRPs. Class S2.3 includes IGF-1 and its analogues [16]. Sport Integrity Australia lists CJC-1295, ibutamoren (MK-677) and ipamorelin among unapproved peptides prohibited in sport [17].
This is general information, not legal advice. Laws change; check the current Poisons Standard and TGA guidance.
Frequently asked questions
What is the growth hormone axis?
It is the system that controls growth hormone release from the anterior pituitary. GHRH stimulates release, somatostatin inhibits it, ghrelin adds a stimulatory input, and GH and IGF-1 provide negative feedback [2, 3, 6, 10].
What is the difference between GHRH and ghrelin?
They are different peptides acting on different receptors. GHRH comes from the hypothalamus and acts on the GHRH receptor; ghrelin comes mainly from the stomach and acts on the GHS-R [4, 9, 10].
What does somatostatin do to growth hormone?
Somatostatin inhibits GH secretion. It acts through five G protein-coupled receptors, SST1 to SST5 [6, 7].
How is IGF-1 related to growth hormone?
GH induces IGF-1, which mediates many of GH’s actions. IGF-1 is made in the liver and most other tissues, and it acts through a receptor tyrosine kinase [12, 13, 14].
Are GHRPs and growth hormone secretagogues scheduled in Australia?
The Poisons Standard (October 2026) has class entries for both. Named members such as GHRP-6, pralmorelin (GHRP-2) and ipamorelin are Schedule 4 and Appendix D, clause 5 [18].
References
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- de Sousa LMM, Vicente VAN, Donato J Jr. Negative Feedback Loops and Hormonal Factors that Regulate GH Secretion. Endocrinology. 2025;166(10):bqaf139. doi:10.1210/endocr/bqaf139. PMID: 40908533
- Guillemin R, Brazeau P, Böhlen P, et al. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585–587. doi:10.1126/science.6812220. PMID: 6812220
- Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992;6(10):1734–1744. doi:10.1210/mend.6.10.1333056. PMID: 1333056
- Halmos G, Szabo Z, Dobos N, et al. Growth hormone-releasing hormone receptor (GHRH-R) and its signaling. Rev Endocr Metab Disord. 2025;26(3):343–352. doi:10.1007/s11154-025-09952-x. PMID: 39934495
- Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973;179(4068):77–79. doi:10.1126/science.179.4068.77. PMID: 4682131
- Günther T, Tulipano G, Dournaud P, et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol Rev. 2018;70(4):763–835. doi:10.1124/pr.117.015388. PMID: 30232095
- Bowers CY. History to the discovery of ghrelin. Methods Enzymol. 2012;514:3–32. doi:10.1016/B978-0-12-381272-8.00001-5. PMID: 22975043
- Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977. doi:10.1126/science.273.5277.974. PMID: 8688086
- Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660. doi:10.1038/45230. PMID: 10604470
- Müller TD, Nogueiras R, Andermann ML, et al. Ghrelin. Mol Metab. 2015;4(6):437–460. doi:10.1016/j.molmet.2015.03.005. PMID: 26042199
- Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol. 2010;6(9):515–525. doi:10.1038/nrendo.2010.123. PMID: 20664532
- Le Roith D, Bondy C, Yakar S, et al. The somatomedin hypothesis: 2001. Endocr Rev. 2001;22(1):53–74. doi:10.1210/edrv.22.1.0419. PMID: 11159816
- Choi E, Duan C, Bai XC. Regulation and function of insulin and insulin-like growth factor receptor signalling. Nat Rev Mol Cell Biol. 2025;26(7):558–580. doi:10.1038/s41580-025-00826-3. PMID: 39930003
- Werner H. The IGF1 Signaling Pathway: From Basic Concepts to Therapeutic Opportunities. Int J Mol Sci. 2023;24(19):14882. doi:10.3390/ijms241914882. PMID: 37834331
- World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. wada-ama.org. Accessed 11 October 2026.
- Sport Integrity Australia. Peptides explained. sportintegrity.gov.au. Accessed 11 October 2026.
- Therapeutic Goods (Poisons Standard—October 2026) Instrument 2026 (F2026L01327). Federal Register of Legislation. legislation.gov.au/F2026L01327/latest/text. Accessed 11 October 2026.
- Therapeutic Goods Administration. Understanding your responsibilities when importing, compounding and supplying unapproved peptide products. Safety advisory, 13 April 2026. tga.gov.au. Accessed 11 October 2026.
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