Research perspective on the simplified growth hormone release system

The Three Core Hormones

If you form the letter V with your fingers, you essentially have the basic outline of the growth hormone release system. One finger represents the growth hormone–releasing hormone (GHRH), while the other represents somatostatin.

At the base of the V, both of these hormones converge. Here lie the somatotroph cells (also called somatotropic cells or growth hormone–releasing cells). These are the cells that produce and store growth hormone (GH) most of the time.

In this simplified system, there are therefore three hormones at play. GHRH, originating in the brain, contacts the somatotroph cells and triggers them to release some of the GH that has been produced and stored [1]. If these cells were to release GH continuously, they would quickly deplete their stores. GH would be secreted immediately as it is synthesized. This is what we call “continuous release” of GH: a constant low-level drip of the hormone, but without major pulses or surges.

What triggers GH release? The brain-derived GHRH. If GHRH were continuously active, GH release would also be continuous [1].

The second brain-derived hormone, somatostatin, functions as the “off switch.” It too acts on somatotroph cells, instructing them not to release GH. When somatostatin is present and GHRH is absent, GH is not released. This gives the cells sufficient time to synthesize and store GH [1,2].

One might wonder whether humans can function with only continuous GH release. We can—up until puberty. However, growth, development, and maturation require pulsatile GH secretion, coordinated with the timed release of sex hormones [2,3].

Another question arises: what happens if both GHRH and somatostatin are present at the same time at the base of the V? The answer is that somatostatin is generally stronger, and GH will not be released [1].

Ghrelin (GHRP): The Fourth Hormone in the GH Release System

For completeness, a fourth hormone should be added to this system. GH itself is the end product, the final outcome of all this regulatory activity. The other three hormones determine how, when, and how much GH is released.

From the gastrointestinal tract comes ghrelin, produced during states of hunger. Ghrelin can cross into the pituitary gland, where the somatotroph cells reside. Like GHRH and somatostatin, it interacts directly with these cells, counteracting the inhibitory effect of somatostatin and enhancing GH release [3,4].

In fact, ghrelin can trigger GH release even in the presence of somatostatin. However, its primary role is to create a permissive environment for GHRH activity. When GHRH acts in the presence of ghrelin, the outcome is synergistic GH release [4,5].

The synthetic form of ghrelin, designed specifically to act on GH release, is known as the growth hormone–releasing peptide (GHRP) [5].

Which GHRP?

• Ipamorelin produces a GH release effect comparable to GHRP-6 but, even at higher doses, does not stimulate prolactin or cortisol production. It also does not cause desensitization [5].

• GHRP-6 may slightly increase prolactin and cortisol at higher doses, but still within the normal range [5].

• GHRP-2 is a stronger GH stimulator, though it can elevate prolactin and cortisol at higher doses [5].

• Hexarelin is the most potent GHRP but carries the greatest risk of raising prolactin and cortisol levels and causing desensitization [5].

Which GHRH? (CJC-1295, GRF 1-29, Sermorelin, Modified Forms)

The body’s natural GHRH consists of 44 amino acids, but only the first 29 are biologically active—GRF(1-29). The problem is that natural GHRH is rapidly degraded by enzymes, which is why synthetic analogues are used, such as CJC-1295 or Mod GRF(1-29) [6].

CJC-1295 with DAC allows for prolonged GH stimulation, though it tends to elevate basal GH levels rather than induce distinct pulses [6].

References

1. Giustina, A., & Veldhuis, J. D. (1998). Endocrine Reviews, 19(6), 717–797.

2. Tannenbaum, G. S., & Ling, N. (1984). Endocrinology, 115(5), 1952–1957.

3. Ho, K. Y. et al. (1987). J Clin Endocrinol Metab, 64(1), 51–58.

4. Kojima, M. et al. (1999). Nature, 402(6762), 656–660.

5. Ghigo, E. et al. (2001). Hormone Research, 55(Suppl 1), 21–29.

6. Teichman, S. L. et al. (2006). J Clin Endocrinol Metab, 91(3), 799–805.