Growth hormone secretagogues (GHS) are molecules studied for their ability to make the pituitary gland release growth hormone (GH). Research so far has found that these molecules can reach the same end point by different routes or pathways. This article compares how the two classes work, covering the receptors they act on, how long they act, and the synergy seen when the two are combined. The evidence comes from current studies in cultured cells (in vitro) and in living animals and people (in vivo). Most of these molecules are still under research and are not approved for human consumption.
Two classes of molecules trigger GH release.
The first class is the growth hormone-releasing hormone (GHRH) analogs, which act on the growth hormone-releasing hormone receptor (GHRHR), a class B G protein-coupled receptor (GPCR). GHRHR sits on the somatotroph cells of the pituitary.
The second class is the ghrelin receptor agonists, often called growth hormone-releasing peptides (GHRPs) or ghrelin mimetics. These act on the growth hormone secretagogue receptor type 1a (GHS-R1a), which is expressed in the brain as well as in the periphery. The stomach-derived hormone ghrelin also activates it.
The two receptors set off different signaling pathways inside the cell. Both lead to GH release, though at different levels.
GHRH, or one of its analogs, binds to GHRHR. The activated receptor engages stimulatory G proteins (Gs) inside the cell. Those proteins switch on adenylyl cyclase, which raises levels of cyclic AMP (cAMP) inside the cell. cAMP then activates protein kinase A (PKA). PKA promotes the gene activity that supports GH production. Raised cAMP also increases calcium (Ca2+) levels inside the cell, and that contributes to GH release.
Sermorelin is an analog of GHRH and its shortest fully active fragment, matching the first 29 amino acids. It acts for a very short time, approximately 10 to 20 minutes.
Tesamorelin is a stabilized analog of the longer GHRH(1-44) sequence, developed to resist rapid breakdown and to act for longer. Of the GHRH analogs, it has progressed furthest in formal clinical development.
CJC-1295 is a chemically stabilized analog. Its base sequence carries amino acid substitutions that make it harder for enzymes to cut. The version bearing a Drug Affinity Complex (DAC) also carries a linker. That linker binds covalently to circulating albumin.
Teichman and colleagues reported in 2006 on healthy adults given a single subcutaneous administration of the DAC form. In those adults, GH and insulin-like growth factor I stayed elevated over several days, with an estimated half-life of six to eight days [4]. This human finding is the clearest demonstration of how far design can extend the duration of a GHRH analog.
GHS-R1a couples predominantly to a different set of G proteins, the Gq proteins. Gq signals through phospholipase C. That pathway generates inositol trisphosphate and diacylglycerol, and it also mobilizes calcium (Ca2+) inside the cell. The calcium triggers GH release at the pituitary.
Ghrelin mimetics also act at the hypothalamus, the main site of GHRH expression, and in cultured cells researchers have observed them increasing GHRH expression. This class of molecules is also involved in stimulating release of other pituitary hormones. GHRP-6 and GHRP-2 are potent stimulators of GH release, but animal studies show that they also induce release of other pituitary hormones.
Raun and colleagues reported in 1998 on conscious pigs. In those pigs, both GHRP-6 and GHRP-2 increased plasma ACTH and cortisol, whereas ipamorelin, an analog of five amino acids, released GH without significantly raising ACTH or cortisol levels [3]. On that basis, the authors described ipamorelin as the first ghrelin receptor agonist whose selectivity for GH release was comparable to that of GHRH.
Hexarelin is another potent member of the family. It is associated with additional pituitary effects, and with receptor desensitization on repeated exposure.
Researchers have also reported that hexarelin acts on cardiac CD36 scavenger receptors, an action distinct from its action at GHS-R1a. Bodart and colleagues demonstrated that CD36 mediates cardiovascular actions of GHRPs in the heart, independent of GH release, suggesting a possible cardioprotective mechanism specific to this class of secretagogue [5].
In summary, GHRH analogs are selective for the GHRH receptor and for GH release, while ghrelin mimetics differ among themselves in selectivity. GHRP-6, GHRP-2 and hexarelin tend to induce release of other pituitary hormones. Ipamorelin is selective for GH release.
Resistance to degradation largely determines how long these analogs act, both in vitro and in vivo. Sermorelin and the non-DAC form of CJC-1295 degrade relatively quickly. The peptide GHRPs produce short, pulsed GH release. Tesamorelin sits in the middle for stability. The DAC form of CJC-1295 acts longest, sustained for days by its albumin binding.
None of these findings should be used to inform dosing decisions. Side effects and other factors in how the body handles these molecules would need to be considered separately.
The most striking preclinical finding is what happens when the two classes are combined. Because they act through distinct receptors and distinct signaling pathways, a GHRH analog and a ghrelin mimetic given together have been shown to produce synergistic GH release. Synergy means the combined effect is larger than the two separate effects added together.
Cheng and colleagues reported in 1989 on primary rat pituitary cells grown in culture. In those cultures, GHRP-6 had no effect on cAMP inside the cells, while GHRH tripled it. Given together, the two still produced synergistic GH release, which indicates that the two systems act through different signaling pathways toward the same outcome [1].
Bowers and colleagues reported in 1990 that, in healthy men, a GHRP and GHRH given together released GH synergistically [2].
Taken together, the in vitro and in vivo findings give a consistent picture of synergy between two complementary systems.
Much of the foundational pharmacology comes from pituitary cell cultures and from a limited number of animal and human studies. The compounds also differ widely in how thoroughly researchers have characterized them, ranging from tesamorelin, which reached formal clinical study, to peptides whose evidence base remains largely preclinical.
Findings on GH and IGF-I secretion are pharmacodynamic measurements taken in study settings, and they should not be extrapolated to individual outcomes.
Natural and synthetic GHS divide into two groups: GHRH analogs, which act on the GHRH receptor through Gs-mediated pathways, and ghrelin mimetics, which act on GHS-R1a through Gq-mediated pathways. The two groups differ in the receptors they engage and in how long they act. Preclinical and human studies also demonstrate synergistic GH release when the two classes are combined. The material discussed here is for research use only, and the evidence above describes what has been investigated, not what any individual should expect.
References
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