How GHRH analogues and ghrelin-receptor agonists release growth hormone through two separate receptor systems, why the two pathways act synergistically, and what the key animal and human studies actually found.
Growth hormone (GH) is released from somatotroph cells of the anterior pituitary in pulses rather than at a steady rate. Those pulses are shaped by several inputs: growth hormone-releasing hormone (GHRH) from the hypothalamus, which stimulates release; somatostatin, which inhibits it; and ghrelin, which acts through a receptor of its own. Growth hormone secretagogues are compounds that stimulate GH release through one of the stimulatory pathways, and they have become standard tools for studying the GH axis in cell, animal and human research. This guide explains the two main families, how they differ at the receptor level, and what the landmark studies showed.
GHRH was first isolated in 1982 from a human pancreatic tumor that had caused acromegaly by secreting it [1]. It acts on the GHRH receptor, a G-protein-coupled receptor on pituitary somatotrophs. The N-terminal portion of the hormone carries its receptor activity, and synthetic analogues keep that region while changing other features to improve stability or duration:
The second family was discovered in the reverse of the usual order: the synthetic compounds came first, and the receptor and its natural ligand were identified later. In 1984, Bowers and colleagues described a synthetic hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (later known as GHRP-6), that released GH in vitro and in vivo without releasing LH, FSH, TSH or prolactin [4]. It was active in rats, monkeys, lambs and calves, and its GH response was inhibited by somatostatin [4].
The receptor these compounds act on, the growth hormone secretagogue receptor (GHS-R), is also a G-protein-coupled receptor. Once it had been cloned, the search for its endogenous ligand ended in 1999, when Kojima and colleagues purified ghrelin from rat stomach: a 28-residue peptide whose n-octanoyl group on serine 3 is essential for activity [5]. Their report concluded that GH release is regulated not only by hypothalamic GHRH but also by ghrelin, through a mechanism distinct from GHRH [5]. Research compounds in this family include GHRP-6, GHRP-2, hexarelin and ipamorelin.
Because GHRH analogues and GHRPs act through different receptors, combining them does more than simply adding their effects. The clearest early human evidence comes from a 1990 study in 18 healthy men. The synthetic GHRP raised mean peak serum GH from 1.2 µg/L after placebo to 68.7 µg/L at the highest level tested, and submaximal amounts of GHRP given together with GHRH stimulated GH release synergistically [6]. The authors interpreted the synergy as evidence that the two peptides act independently, and that GHRP activity reflected a separate physiological system still waiting to be characterized [6].
The same study recorded an early selectivity signal: prolactin and cortisol rose about twofold, but only at the highest GHRP level tested, while LH and TSH did not change over the first hour [6]. Synergy between the two pathways is the reason GHRH-plus-GHRP designs appear so often in the literature on GH secretion, and it is also why such studies need single-agent arms alongside any combination arm before an interaction can be claimed.
Early GHRPs were not perfectly selective for GH. In a 1998 pharmacology study from Novo Nordisk, both GHRP-6 and GHRP-2 increased plasma ACTH and cortisol in conscious swine [7]. Ipamorelin, a pentapeptide with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2, released GH from primary rat pituitary cells with potency and efficacy similar to GHRP-6 and acted through the same GHRP-type receptor [7]. Unlike the other two, it did not raise ACTH or cortisol above the levels seen with GHRH, even at amounts more than 200-fold above its ED50 for GH release [7]. None of the secretagogues tested changed FSH, LH, prolactin or TSH. The authors described ipamorelin as the first GHRP-receptor agonist with a selectivity for GH release similar to that of GHRH [7].
The short half-life of native GHRH limits how long a single exposure stimulates the pituitary [2][3]. CJC-1295 was designed to get around this by binding to serum albumin. In two randomized, placebo-controlled trials in healthy adults aged 21 to 61, a single administration of CJC-1295 increased mean plasma GH concentrations 2- to 10-fold for 6 days or more and IGF-I concentrations 1.5- to 3-fold for 9 to 11 days [2]. The estimated half-life was 5.8 to 8.1 days, and with repeated administration, mean IGF-I stayed above baseline for up to 28 days [2].
A common assumption is that a long-acting GHRH analogue must flatten the natural pulse pattern into a continuous plateau. The data do not bear that out. When Ionescu and Frohman sampled blood every 20 minutes over a 12-hour overnight period in healthy men aged 20 to 40, before and one week after a single administration of CJC-1295, GH pulse frequency and pulse magnitude were unchanged [3]. What rose was trough, or basal, GH, which increased 7.5-fold, along with a 46% increase in mean GH and a 45% increase in IGF-I [3]. Pulsatility was preserved.
Without the albumin-binding group, modified GRF(1-29) is expected to act for a much shorter time. The choice between the two forms is therefore largely a choice of question: acute GH responses that closely follow each exposure, or sustained stimulation of the axis over days.
Tesamorelin has been studied extensively in human clinical trials. In a randomized trial published in the New England Journal of Medicine, 412 adults with HIV and accumulated abdominal fat were randomized to tesamorelin or placebo for 26 weeks [8]. Visceral adipose tissue measured by CT fell 15.2% with tesamorelin and rose 5.0% with placebo; triglycerides and the ratio of total to HDL cholesterol also improved, IGF-I rose 81.0%, and no significant differences were seen in glycemic measures [8].
Tesamorelin is approved in the United States as Egrifta for reducing excess abdominal fat in adults with HIV-associated lipodystrophy. The tesamorelin sold by Northbridge Research Labs is a research material. It is not Egrifta and is not intended for any clinical use.
A few practical points recur in this literature. GH is secreted in pulses, so single time-point measurements can mislead; studies of secretion dynamics rely on frequent sampling, as in the 20-minute overnight design described above [3]. IGF-I, which reflects GH action over a longer window, is a common complementary readout [2][3]. Species matters: GH responses and effects on ACTH and cortisol differ between rats, swine and humans [4][7]. And because the two families act through different receptors, receptor antagonists and single-agent arms are what allow a study to attribute an effect to one pathway or to an interaction between them.
Note: These research compounds are intended for in vitro and animal research. They are sold for laboratory research use only and are not for human or veterinary use.
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Research Use Only: The information in this article is for educational and research purposes only. All products mentioned are intended for laboratory research use only and are not approved for human or veterinary use.