Sermorelin: the 29-amino-acid fragment at the heart of the growth hormone axis

Why a fragment of a brain hormone matters

How does the brain tell a child to grow, or an adult body to keep repairing tissue? The answer is a relay of chemical messages that runs from the brain to the pituitary gland, then to the liver and almost every other organ. Endocrinologists call it the growth hormone axis, and sermorelin is a copy of its first link.

That makes sermorelin a useful reference point. The other GHRH-type compounds in our library, tesamorelin and CJC-1295 (see CJC-1295 and ipamorelin), are both re-engineered versions of the same hormone. Understanding sermorelin, and the axis it plugs into, explains what all of them are trying to do.

The tumour that gave up a brain hormone

For decades, researchers suspected that the hypothalamus, a small region at the base of the brain, made a hormone that switched on growth hormone release. Finding it proved brutally hard. Roger Guillemin's laboratory, hunting for it in hypothalamic extracts, instead found the opposite signal: somatostatin, which blocks growth hormone, published in 1973 ^[3]. Guillemin shared the 1977 Nobel Prize in Physiology or Medicine for this generation of discoveries about the brain's peptide hormones, five years before the growth-hormone-releasing factor was finally identified ^[3].

The answer came from an unexpected place. In 1982, Thorner and colleagues described a 21-year-old woman with the features of acromegaly, a disease of excess growth hormone ^[1]. Pituitary surgery found no tumour, only enlarged growth-hormone-producing tissue. A scan then revealed a 5-centimetre tumour in the tail of her pancreas. When surgeons removed it, her growth hormone level fell from 70 to 3 ng/ml within two hours ^[1]. The tumour had been making the missing releasing hormone.

A pancreatic tumour was pumping out a hormone the brain normally makes in tiny amounts. Removing it dropped the patient's growth hormone from 70 to 3 ng/ml in two hours.

That same year, Guillemin's group at the Salk Institute isolated the hormone from a different patient's pancreatic tumour, diagnosed in France by Geneviève Sassolas ^[2,3]. They published its full sequence: 44 amino acids, ending in an amide group. A synthetic copy was fully active ^[2].

Two years later, Ling and colleagues trimmed the molecule from its far end. Fragments down to 29 amino acids kept full intrinsic activity, with about half the potency of the 44-residue hormone in rat pituitary cells ^[4]. That 29-residue amide is sermorelin: Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2.

How the growth hormone axis works

Think of the system as a car with an accelerator, a brake and a speedometer.

• The accelerator is GHRH. Released by the hypothalamus, it travels a short distance to the pituitary and tells somatotroph cells to make and release growth hormone (GH) ^[5].
• The brake is somatostatin. Also from the hypothalamus, it suppresses GH release. The tug of war between the two produces GH in bursts, or pulses, rather than a steady drip ^[5].
• The speedometer is IGF-1. GH acts on the liver, which releases insulin-like growth factor 1 (IGF-1), and many tissues also make IGF-1 locally ^[6]. Much of what people call "growth hormone action" is IGF-1 action ^[6]. Rising IGF-1 then feeds back to the brain and pituitary to slow GH down ^[5].

The result is a self-limiting loop. GH secretion also changes over a lifetime: in a study of 21 healthy men aged 21 to 71, each decade of age cut daily GH production by about 14% at a normal body mass index ^[7]. That decline is one reason GHRH analogues were studied in older adults.

Sermorelin presses the accelerator. Because it works upstream, the brake and the speedometer still operate: if IGF-1 climbs, feedback can rein GH back in. Researchers studying older men saw GHRH as attractive for exactly this reason, because it raises GH and IGF-1 while preserving the physiological pattern of GH release ^[8]. Injecting GH itself bypasses the loop.

The weakness is speed. Blood contains an enzyme, dipeptidyl peptidase-4 (DPP-4), that snips the first two amino acids off GHRH and leaves a fragment with less than a thousandth of the activity. After an intravenous dose of native GHRH(1-44) in healthy people, the intact hormone had a half-life of 6.8 minutes ^[9]. Much of the later chemistry in this field is about fixing that problem.

What the research shows

As a diagnostic test

Sermorelin's first approved use was diagnostic. Given intravenously, it tests whether the pituitary can release GH. A 1999 review found it a rapid and relatively specific test, with fewer false-positive results than other provocative tests in children without GH deficiency ^[10]. Its blind spot is important: a normal response cannot rule out GH deficiency caused by a problem in the hypothalamus, because sermorelin bypasses the hypothalamus ^[10]. Transient facial flushing and injection-site pain were the most common side effects ^[10].

In children with growth hormone deficiency

The Geref International Study Group ran an open-label, multicentre study of 110 prepubertal children with untreated GH deficiency ^[11]. Of the 86 eligible for efficacy analysis, mean height velocity rose from 4.1 cm per year at baseline to 8.0 cm per year at 6 months and 7.2 cm per year at 12 months. At 6 months, 74% were classed as good responders, and the study found no excessive rise in IGF-1 and no change in fasting glucose ^[11].

There was no placebo group, and the review literature notes that increases in height velocity were smaller than with daily recombinant GH in comparable studies, and that the effect on final adult height had yet to be determined ^[10].

In older adults

Small studies tested whether GHRH could reverse the age-related drop in GH. In a 1992 study, 10 healthy men with an average age of 68 took GHRH(1-29) twice daily for 14 days in two dose arms. In the higher-dose arm, 24-hour GH and IGF-1 rose to levels that no longer differed from those of 9 young men ^[8].

Longer and simpler regimens were less convincing. In 11 men aged 64 to 76 given a single nightly injection for 6 weeks, nocturnal GH rose, but IGF-1 did not change. Two of six strength measures improved, while body composition, glucose and lipids did not change ^[12]. The authors concluded that single nightly doses were less effective than multiple daily doses ^[12].

What we don't know yet

• Long-term effects in adults. The adult studies were small and lasted weeks to months. There are no large trials of function, fractures, quality of life or mortality.
• Whether raised GH translates into benefit. GH rose in these studies, but IGF-1 did not always follow, and body composition and strength changes were inconsistent ^[8,12].
• Final height. Even in children, the approved use, the effect on final adult height had yet to be determined when the main review was published ^[10].
• IGF-1 and cancer risk. Higher circulating IGF-1 is associated with some cancers in population studies. We cover that evidence in our IGF-1 LR3 article. Whether modest, feedback-limited increases from GHRH carry any such risk is unknown.
• Material quality outside medicine. Since Geref left the market, sermorelin outside clinical trials comes from many sources. Identity and purity have to be checked lot by lot; see how to read a COA.

Regulatory status

• United States. Geref injection for diagnostic use was approved on 28 December 1990, and Geref for idiopathic GH deficiency in children with growth failure on 26 September 1997 ^[13]. EMD Serono notified the FDA in 2008 that both were being discontinued, and the approvals were withdrawn effective 18 June 2009 ^[13]. In March 2013 the FDA determined that neither product had been withdrawn for reasons of safety or effectiveness, which allows generic applications to reference them ^[13].
• European Union. Sermorelin has no centralised EU marketing authorisation in the EMA's medicines database ^[14].
• Sport. GHRH and its analogues, including sermorelin, are listed under S2.2.4 of the WADA Prohibited List and are prohibited at all times ^[15].

In the lab: handling and storage

Sermorelin is normally supplied as a lyophilised (freeze-dried) powder. Common practice is long-term storage at −20 °C, with 2–8 °C acceptable for short periods, protected from light and moisture. Once reconstituted, solutions are usually kept cold and divided into single-use aliquots to avoid repeated freeze-thaw cycles. Because plasma DPP-4 rapidly inactivates native GHRH ^[9], experiments in serum-containing media should account for enzymatic degradation. Identity is best confirmed by mass spectrometry; the expected molecular weight is about 3,358 g/mol.

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