Growth hormone secretagogues: two receptor routes to one pituitary cell

One cell, two receptors

A secretagogue is a substance that makes a cell secrete something. Here the term covers every compound that prompts the pituitary to release GH; the paper that cloned the second receptor keeps it for the synthetic molecules that act there.³

The GHRH receptor

Cell study GHRH is a hypothalamic peptide that acts on the somatotroph.⁵ Its receptor, cloned in 1992, has the seven membrane-spanning segments of a G protein-coupled receptor and resembles the receptors for secretin and vasoactive intestinal peptide.² When GHRH acted on it in cultured cells, cyclic AMP rose, and in the rat its messenger RNA was found predominantly, if not exclusively, in the anterior pituitary.²

The ghrelin receptor

Review The second route was found backwards, drug before hormone: neither the receptor nor its natural ligand was known when the work began.¹⁶

Animal study In 1984 a synthetic hexapeptide, now known as GHRP-6, was reported to release GH in rats, monkeys, lambs and calves without releasing LH, FSH, TSH or prolactin.¹⁷¹⁸ Its authors wrote that it had the attributes of a hormone that regulates the pituitary.¹⁷

Cell study In 1996 a group at Merck cloned the receptor these compounds act on, from the pituitary and hypothalamus of swine and humans, and took it as support for the idea that the compounds mimic an undiscovered hormone.³

Review That hormone, ghrelin, was identified in 1999: a 28-residue peptide first isolated from rat stomach, with an eight-carbon fatty acid on its third residue that is essential for receptor binding.⁸ The receptor, GHS-R1a, belongs to the rhodopsin-like family of G protein-coupled receptors, and the review proposed naming it the ghrelin receptor.⁸

Cell study A 2017 anti-doping study names this receptor as the target of the GHRPs, and found receptor-binding activity in urine from excretion studies of GHRP-6, hexarelin and ipamorelin.⁷ The two receptors are of different types, one resembling the secretin receptor and one rhodopsin-like, and the ghrelin receptor was also cloned from a level higher, the hypothalamus.²³⁸

Pulses, somatostatin and feedback

Review GH is secreted in pulses.¹ The hypothalamus sets the rhythm through two opposing hormones, stimulatory GHRH and inhibitory somatostatin.⁹ Negative feedback loops sense circulating GH and insulin-like growth factor 1 (IGF-1) and act at both the pituitary and the hypothalamus.¹

Animal study Somatostatin restrains the second route as well as the first: in the 1984 study it inhibited the GH response to the hexapeptide.¹⁷

Review The author of a 2005 review, a developer of these compounds, reasoned that the size of a GH pulse could be raised in four ways: more GHRH release, stronger GHRH signalling in the somatotroph, less somatostatin release, or a blocked somatostatin signal.¹⁶ The review states that the GH secretagogues, which it calls ghrelin mimetics, act through all four.¹⁶

Human study Healthy men were sampled overnight before and one week after receiving CJC-1295, a long-acting GHRH analogue that binds to albumin in the blood and has a half-life of about eight days.⁶ GH was still secreted in pulses of unchanged frequency and size; what rose was the trough level between pulses, 7.5-fold, together with mean GH and IGF-I.⁶

Why the two routes are studied together

Human study The first reason is synergy. In 18 healthy men the hexapeptide released GH, and submaximal amounts of it given with GHRH did so synergistically; the authors took this to suggest that the two act independently.¹⁰

Human study The second is dependence. In nine healthy men, a GHRH antagonist given beforehand removed most of the GH response to GHRP-6, so GHRP-6 needs the body’s own GHRH for most of that response.¹¹

The third is regulatory: the World Anti-Doping Agency lists GHRH analogues, GH secretagogues and GHRPs together as growth hormone releasing factors, prohibited at all times, and names all six peptides.¹⁹

Six molecules compared

The table gives each molecule as its source describes it.^4567182021

Human study Natural GHRH is short-lived. In human plasma an enzyme removes its first two residues, leaving a product with less than a thousandth of the activity, and in volunteers the intact hormone had a half-life of 6.8 minutes.²² Tesamorelin’s added group sits at that same end of the chain, and CJC-1295’s albumin binding is covered in the guide to half-life extension strategies.⁵⁶

Animal study In rats, hexarelin and GHRP-6 were similarly effective at releasing GH.²⁰ In swine, GHRP-6 and GHRP-2 raised ACTH and cortisol as well as GH, while ipamorelin did not raise them beyond the levels seen after GHRH.²¹

Human evidence

Human study The human studies cited here are physiology experiments in healthy volunteers, and they measured hormone concentrations in blood over hours.^6101122 In the 1990 study, prolactin and cortisol rose about two-fold at the highest GHRP level tested.¹⁰

Review A 1999 drug review described the treatment data on sermorelin in children with GH deficiency as limited.⁴ Trial evidence for individual compounds is set out on their own pages.

Which became licensed medicines

Each statement below was checked against the authority’s own page on 8 October 2026.

• Sermorelin. The FDA approved Geref (sermorelin acetate) on 28 December 1990 for evaluating the ability of the pituitary somatotroph to secrete GH, and a second presentation on 26 September 1997 for idiopathic GH deficiency in children with growth failure.¹² The maker discontinued both in 2008 and the approvals were withdrawn at its request in 2009; the FDA later determined that neither was withdrawn from sale for reasons of safety or effectiveness.¹² Health Canada’s Drug Product Database lists no sermorelin product.¹⁵
• Tesamorelin. The FDA approved Egrifta (tesamorelin acetate) on 10 November 2010.¹³ The Egrifta SV label gives one indication, the reduction of excess abdominal fat in HIV-infected adults with lipodystrophy, and says the product is not indicated for weight loss management.⁵ Health Canada’s database lists two Egrifta entries: one marketed from 23 June 2015 and cancelled on 30 September 2022, and one cancelled before marketing.²³²⁴
• CJC-1295, GHRP-6, hexarelin and ipamorelin. None appears as an active ingredient in Health Canada’s Drug Product Database or in the FDA’s approved-drug data.¹⁴¹⁵ The FDA’s compounding pages put GHRP-6 and ipamorelin acetate in category 2, bulk substances that may present significant safety risks, and CJC-1295 among those whose nominations were withdrawn.²⁵ A Health Canada advisory of 9 April 2026 named CJC-1295 and ipamorelin among examples of unauthorized injectable peptide drugs it had seized.²⁶

A ghrelin-receptor agonist from outside this list did reach FDA approval: macimorelin (Macrilen), which its label calls a GH secretagogue receptor agonist, approved on 20 December 2017 for the diagnosis of adult GH deficiency.²⁷²⁸

Horizon Peptides supplies sermorelin, GHRP-6, hexarelin and the other three compounds for laboratory research use only.