Growth Hormone Secretagogues: Two Routes to Growth Hormone Release

A growth hormone secretagogue is a substance that makes the pituitary gland release more of the body's own growth hormone, rather than supplying growth hormone directly. "Secretagogue" simply means something that causes secretion.

Growth hormone (GH) is made by somatotroph cells in the pituitary, a small gland at the base of the brain. Its release is controlled by signals from the hypothalamus and from the stomach. Secretagogues copy one of two of those signals. Because the body's own control systems remain partly in place, the hormone pattern produced by a secretagogue differs from that produced by injecting growth hormone. This feature is often cited in marketing, but it does not by itself show any health benefit.

The term covers a mixed group: peptide analogues of hypothalamic GHRH, synthetic growth hormone-releasing peptides (GHRPs), and small molecules that act on the ghrelin receptor. They differ in chemistry, in which receptor they use and, importantly, in the evidence behind them.

Route 1: the GHRH receptor. Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that acts on pituitary somatotrophs to stimulate the synthesis and pulsatile release of growth hormone [1]. Drugs on this route are modified versions of GHRH:

• Sermorelin, the first 29 amino acids of human GHRH.
• Tesamorelin, a stabilized GHRH analogue that binds human GHRH receptors with potency similar to the natural hormone in laboratory tests [1].
• CJC-1295, a GHRH analogue designed to last longer in the body. In healthy adults, its long-acting form raised GH and IGF-1 for days after a single injection, with an estimated half-life of 5.8 to 8.1 days [2].

Route 2: the ghrelin receptor. In the 1980s, chemists made small synthetic peptides, including GHRP-6, that released growth hormone through a receptor distinct from the GHRH receptor. That receptor, GHS-R1a, was cloned in 1996, and its natural activator was identified in 1999 as ghrelin, a 28-amino-acid peptide from the stomach that needs a fatty-acid side chain to work [3]. Drugs on this route include GHRP-6, GHRP-2 (pralmorelin), hexarelin and ipamorelin, plus orally active compounds such as macimorelin and anamorelin [4][5].

The two routes are complementary. In healthy young men, ghrelin and GHRH given together released more growth hormone than either alone, a synergistic effect [6]. Ghrelin-receptor agonists also act beyond growth hormone: ghrelin itself stimulates appetite, which is the basis for anamorelin's use in cancer-related weight loss [5].

Growth hormone is not released at a steady rate. It comes in pulses, with larger bursts during sleep. This rhythm results from a push-pull between GHRH, which stimulates release, and somatostatin, a hypothalamic peptide that inhibits it.

Growth hormone acts partly by prompting the liver to make IGF-1 (insulin-like growth factor 1). IGF-1 carries many of growth hormone's effects on tissues and also feeds back to the hypothalamus and pituitary to dampen further release. This negative feedback is one reason secretagogue effects are limited by the body's own controls, and why IGF-1 is the usual blood marker in studies of these substances.

Secretagogues mostly amplify the existing pattern. In one small study, repeated hexarelin injections increased the size of growth hormone pulses but not how often they occurred; a later test injection produced a blunted response, consistent with some loss of responsiveness after repeated exposure [7]. Long-acting CJC-1295, by contrast, raised IGF-1 for well over a week after dosing [2], showing that pharmacology can change the rhythm in ways that differ from normal physiology.

Statuses match our individual profiles, which give regulatory sources for each compound. FDA has placed GHRP-2, GHRP-6 and ipamorelin in a category of bulk substances that may present significant safety risks when compounded, and has noted safety concerns for CJC-1295 [8]. For what an approval does and does not cover, see what FDA approval means.

Tesamorelin has the strongest treatment evidence. In a 26-week randomized trial in people with HIV and excess abdominal fat, visceral (deep belly) fat fell by 15.2% with tesamorelin and rose by 5.0% with placebo; IGF-1 rose by 81% [9]. The label notes that long-term cardiovascular safety has not been established and that it is not indicated for weight loss [1].

Macimorelin was approved on diagnostic accuracy, not on treatment benefit: a single oral dose is used to see whether the pituitary can release growth hormone [4].

Anamorelin illustrates the gap between a body-composition change and a functional benefit. In two phase 3 trials in 979 people with advanced lung cancer and cachexia, it increased lean body mass over 12 weeks but did not improve handgrip strength [10].

A similar pattern appeared with an oral ghrelin mimetic, ibutamoren (MK-677; not a peptide), in a two-year trial in 65 healthy older adults. It raised GH and IGF-1 into the young-adult range and increased fat-free mass, but did not change strength or function [11].

For CJC-1295, GHRP-6, GHRP-2, hexarelin and ipamorelin, human data consist mainly of short studies that measure hormone responses, diagnostic testing and small trials in specific illnesses [7][2]. Claims about muscle building, fat loss, recovery, sleep or slowing ageing in healthy people are not supported by controlled trials measuring those outcomes. See why animal studies don't always predict human results.

When reading a claim about any secretagogue, it helps to ask four questions. Was the study in people, and in which people: healthy volunteers, older adults, or patients with a specific disease? Was the outcome a hormone level, a body-composition scan, or something a person would notice, such as strength, function or quality of life? Was there a placebo group, and how long did the study last? And was the substance tested the same compound and formulation as the one being described? Results for one long-acting GHRH analogue, for example, cannot simply be transferred to a differently made product sold under a similar name.

• IGF-1 elevation. The tesamorelin label states that the effects of prolonged IGF-1 elevation are unknown and advises monitoring; among patients treated for 26 weeks, 47% had IGF-1 above 2 standard deviation scores [1]. Because IGF-1 promotes cell growth, the label also asks prescribers to consider cancer risk carefully.
• Blood sugar. Growth hormone opposes insulin. Tesamorelin can cause glucose intolerance, with elevated HbA1c in 5% of treated patients vs 1% on placebo at 26 weeks [1]. In the ibutamoren trial, fasting glucose rose and insulin sensitivity fell [11]. FDA notes blood-glucose increases among its concerns about GHRP-6 [8].
• Cortisol and prolactin. Ghrelin and hexarelin raised prolactin, ACTH and cortisol, as well as growth hormone, in healthy volunteers [6]. FDA lists possible effects on cortisol among its concerns about GHRP-6 [8].
• Fluid retention and heart rhythm. Fluid retention is listed for tesamorelin [1], and macimorelin's label warns that it can prolong the QT interval on an ECG [4].
• Unregulated products. For compounded or online versions, FDA cites risks of immune reactions and impurities. It also notes reports of serious adverse events, including death when ipamorelin was given intravenously in a study of gut motility [8].

Long-term safety, including cancer incidence, has not been studied for most of these compounds.

The World Anti-Doping Agency (WADA) Prohibited List places growth hormone-releasing factors in class S2 (peptide hormones, growth factors and related substances), prohibited at all times. The class covers GHRH and its analogues, growth hormone secretagogues and their mimetics, and growth hormone-releasing peptides, and names compounds including CJC-1295, sermorelin, tesamorelin, ipamorelin, anamorelin, macimorelin, ibutamoren (MK-677), examorelin (hexarelin), GHRP-2 and GHRP-6 [12]. Athletes with a genuine medical need must follow the therapeutic use exemption process. See our guide to WADA peptide rules.