Sermorelin

Sermorelin is a synthetic peptide equivalent to the first 29 amino acids (1–29), which contains the active part of native, hypothalamic growth hormone-releasing hormone (somatorelin; GHRH), which itself exists as a 37, 40, or 44 amino acid peptide.

Growth hormone replacement therapy (GHRT) using recombinant human growth hormone (rhGH) has been embraced by many age management practitioners as one of the most effective methods for opposing somatic senescence currently available. However, its routine use has been controversial because few clinical studies have been performed to determine the potential risks of long-term therapy. Also, certain medical and legal issues have not been resolved causing some practitioners to restrict their use of the product. Some of these issues include the fact that:

• Improper dosing can lead to side effects that may be serious in some patients,
• Injection of hGH creates unnatural conditions of exposure to the hormone that may erode normal physiology,
• The Code of Federal Regulations specifically forbids the use of rhGH in adults except for treatment of AIDS or human growth hormone deficiency (GHD) diagnosed pursuant to regularly accepted guidelines.

While there is a wealth of information showing that long-term administration of rhGH reduces intrinsic disease and extends life in adults suffering pathogenic GHD, consensus on whether extrapolation of those data to the aging condition is justified has not been reached (Perls et al 2005). Most of the major concerns derive from the fact that rhGH is mitogenic and may awaken latent cancers, that improper dose selection may promote metabolic disorders such as diabetes, and perhaps that pharmacological presentation may exacerbate decline of endocrine function by distorting essential hormonal interactions. Of course, all these concerns are speculative and will not be resolved until sufficient scientific evidence for or against GHRT eventually accumulate. In the interim, the value of rhGH in GHRT will continue to be debated; unfortunately based more upon personal prejudice than objective information.

Despite the eventual outcome to the “Great Hormone Debate” as it has been titled in media articles (Landsmann 2006), certain negative aspects of GHRT using rhGH cannot be disputed and justify searching for a better alternative. For example, “square wave” or pharmacological presentation of the exogenous hormone cannot be avoided since it is administered as a bolus, subcutaneous injection. Since the amount of rhGH entering the general circulation is not controlled by normal feedback mechanisms, tissue exposure to elevated concentrations is persistent and eventually may lead to tachyphylaxis and reduced efficacy. Also, because the body cannot modulate tissue exposure to rhGH, the practitioner is required to “best guess” the appropriate dosage based upon little other than serum measurements of insulin-like growth factor-1 (IGF-1) and subjective comments from the patient about perceived responses to the hormone. Thus, it would seem that an alternative method(s) of GHRT that circumvented these problems would be of great value so long as it retained the positive attributes of rhGH.

One possibility that is receiving growing attention is the use of GH secretagogues to promote pituitary health and function during aging. An example of such molecules is growth hormone releasing factor 1–29 NH₂-acetate, or sermorelin, that recently became available to practitioners for use in longevity medicine (Merriam et al 2001). Other alternatives include orally active growth hormone-releasing peptides that are currently being developed by pharmaceutical companies. Some of these have been reported to be effective at improving physical performance in the elderly (Fahy 2006). However, it is unlikely that they will be marketed for several years. On the other hand, sermorelin, an analog of naturally occurring growth hormone-releasing hormone (GHRH) whose activity declines during aging, may presently offer a more immediate and better alternative to rhGH for GHRT in aging (Russell-Aulet et al 2001). The molecule was commercially produced and marketed for many years as an alternative to rhGH for use in children with growth retardation, but it could not compete with rhGH and was withdrawn as a therapeutic entity by the manufacturer. Paradoxically sermorelin failed as a growth-promoting agent in children for the very reason that it is a better alternative for GHRT in aging adults. Growth-deficient children need higher doses of growth hormone than can be achieved by stimulating production of their own hormone, whereas the beneficial effects of sermorelin on pituitary function and simulation of youthful growth hormone secretory dynamics in aging adults have little effect on growth rate in children. Unlike exogenous rhGH that causes production of the bioactive hormone IGF-1 from the liver, sermorelin simulates the patients own pituitary gland by binding to specific receptors to increase production and secretion of endogenous hGH. Because sermorelin increases endogenous hGH by stimulating the pituitary gland, it has certain physiological and clinical advantages over hGH that include:

• Effects are regulated by negative feedback involving the inhibitory neurohormone, somatostatin, so that unlike administration of exogenous rhGH, overdoses of endogenous hGH are difficult if not impossible to achieve,
• Because of the interactive effects of sermorelin and somatostain, release of hGH by the pituitary is episodic or intermittent rather than constant as with injected rhGH.
• Tachphylaxis is avoided because sermorelin-induced release of pituitary hGH is not “square wave”, but instead simulates more normal physiology,
• Sermorelin stimulates pituitary gene transcription of hGH messenger RNA, increasing pituitary reserve and thereby preserving more of the growth hormone neuroendocrine axis, which is the first to fail during aging (Walker et al 1994).
• Pituitary recrudescence resulting from sermorelin helps slow the cascade of hypophyseal hormone failure that occurs during aging thereby preserving not only youthful anatomy but also youthful physiology (Villalobos et al 1997).

Finally, there is the question of lawful practice. Unlike rhGH which has legal restrictions on its clinical use, the off-label prescribing of sermorelin is not prohibited by federal law. Thus, it can be carefully employed and evaluated by the practitioner to objectively determine whether it provides greater benefits with less risk to his/her patients. In support of this effort, the Society for Applied Research in Aging will be providing sermorelin free of cost on a competitive basis to practitioners willing to study its effects under protocol conditions and to report the outcomes in a peer-reviewed journal such as Clinical Interventions in Aging. Hopefully, through such efforts we can contribute to development of a paradigm for evidence-based GHRT in clinical age management.

Sermorelin [GHRH-(1-29)], is the “prototypical” GHS, as it is a GHRH analog derived from the first 29 amino acids of the GHRH protein (23). Sermorelin impacts the hypothalamic-pituitary-somatotropic axis, unlike other GHS which function via the ghrelin/GHS-R pathway. GHRH receptor activation leads to cAMP production via the G_s protein/adenylate cyclase and mitogen-activated protein kinase pathways (24).

Sermorelin has been employed in both the diagnosis and treatment of GH deficiency although there is limited research on its use in the setting of hypogonadism (23). Gelander et al. evaluated the short-term effects of 1 mg sermorelin and GHRH 1–40 injections on GH, IGF-1, prolactin, follicle-stimulating hormone (FSH), and LH levels in short children with pulsatile GH secretion (25). Participants were non-randomly allocated into 2 groups. One group was first treated with sermorelin followed by GHRH 1–40 with a one-week interval between treatments. The other group received both peptides in reverse order. It was noted that both peptides increased GH by a similar magnitude; however, sermorelin also produced small acute rises in prolactin, FSH, and LH. These findings revealed that sermorelin promotes changes in GH levels similar to those observed with endogenous GHRH. Simultaneously, sermorelin uniquely stimulated both FSH and LH release, implying a potential role in the treatment of hypogonadism via the stimulation of endogenous testosterone production. Consistent with this observation, in a later study examining GH-deficient rats, sermorelin therapy was shown to result in an increase in testosterone secretion (26).

Corpas et al. evaluated sermorelin’s effects on GH and IGF-1 levels in 9 young men 22 to 33 years old and 10 elderly men 60 to 78 years old (27). All 10 elderly men were given 14 days of twice daily injections of either low (0.5 mg) or high dose (1 mg) sermorelin which was then held for 14 days before being restarted for another 14-day period. Measured outcomes included serum GH, IGF-1, IGFBP-3, and testosterone levels in addition to body weight, BMI, and waist-hip ratio. In the elderly men, high-dose sermorelin treatment elevated mean 24-h GH, peak GH amplitude, and GH area under the peaks. The older men had lower baseline IGF-1 levels when compared to the younger men but sermorelin treatment resulted in elevations in IGF-1 in a dose-response fashion to levels approaching those of the younger men. In addition, the elevations in IGF-1 remained above baseline levels in the elderly men even 2 weeks after stopping sermorelin, suggesting that sermorelin can produce longer lasting effects. Compared to baseline, the mean peak GH secretory responses were significantly increased in elderly men at both low and high doses.

No significant correlations were observed between total body weight and sermorelin treatment, but the study did not account for concurrent fat loss and muscle gain. Consistent with this, patients’ waist-hip ratio and GH peak following sermorelin actually showed an age-independent inverse correlation. Additionally, in elderly men, serum testosterone levels were positively correlated with 24-h mean GH levels although it should be noted that these improvements in testosterone were not statistically significant. The authors also observed that the areas under GH peaks at night were significantly higher than those during the day for both young and elderly men, confirming that the majority of GH release occurs at night irrespective of age. These findings highlight that sermorelin is an effective stimulator of GH and IGF-1 levels in elderly men with reduced IGF-1 levels.

Vittone et al. conducted a prospective study to analyze the effects of once nightly injections of sermorelin in healthy elderly men (28). A total of 11 men aged 64 to 76 years were given 2 mg of subcutaneous sermorelin nightly for 6 weeks. Following this, GH, IGF-1, skeletal muscle function, body composition, and endocrine-metabolic functions were measured as outcomes. Sermorelin therapy almost doubled the 12-h mean amount of GH released, but no significant changes to mean peak amplitude and number of peaks were observed. Essentially, sermorelin was found to augment the duration of rhythmic GH release without pushing serum levels above physiologic norms. Analysis of the nocturnal GH production showed that this increase in GH release was limited to approximately 2 h after sermorelin administration. Interestingly, the authors observed that IGF-1 levels did not significantly increase at 2 or 6 weeks of nightly treatment, while the Corpas study showed significant increases in IGF-1 with twice daily treatment. This suggests that the timing and frequency of sermorelin treatment significantly affects IGF-1 levels, with a higher frequency of administration resulting in more significant IGF-1 increases. With regards to body composition, this study failed to observe any significant changes of body weight, BMI, waist-hip ratio, lean body mass, or percent total fat mass. Sermorelin did however lead to significant improvements in 2 of the 6 muscle strength tests and the abdominal crunch, a test of muscle endurance. However, as with the Corpas et al. study, no significant changes in testosterone levels were observed. Interestingly, a decrease in mean systolic blood pressure was observed as an effect of sermorelin treatment. These findings support the conclusion that sermorelin can stimulate GH and IGF-1 secretion, but that this is dependent both on the frequency of dosing and the timing of serum hormone measurement.

Similar to the study above, Khorram et al. conducted a single-blind randomized placebo-controlled trial to evaluate the effects of sermorelin in both elderly men and women but elected for an extended treatment duration of 5 months (29). Ten women and nine men between 55 and 71 years old were administered 4 weeks of nightly subcutaneous placebo followed by 16 weeks of 10 µg/kg of sermorelin. The outcomes measured included GH response, IGF-1, IGFBP-1, IGFBP-3, body composition, serum lipids, and metabolic effects. The authors observed that sermorelin led to significant increases in GH release for the 2 h after administration and the 12-h mean GH levels at both 4 week and 16 weeks of treatment compared to placebo for both genders. No changes were observed with GH pulse frequency or amplitude. Subsequently, levels of IGF-1, IGFBP-3, and GH binding proteins (GHBP) were each increased. IGF-1 levels rose significantly by 2 weeks of treatment and remained elevated until 12 weeks before declining at 16 weeks. No changes in body weight, body fat mass, or dietary intake were observed in either gender. However, in men, lean body mass was significantly increased by 1.26 kg. In both genders, a significant increase in skin thickness was observed after 16 weeks. For men, no changes in testosterone levels were observed but a significant increase in insulin sensitivity was noted along with improvements in wellbeing and libido. These results highlight that, compared to the short-term treatment in the Vittone study, longer term treatment with sermorelin results in increases in GH and IGF-1 in addition to changes in body composition seen with increased lean body mass. Although body weight, body fat, and testosterone levels were unchanged, these findings demonstrate the potential for sermorelin as adjunctive or alternative therapy in hypogonadal men, and further highlight the need for additional long-term studies.

Sigalos et al. conducted a retrospective review assessing the effects of combined Growth hormone-releasing peptides (GHRP)-2, GHRP-6, and sermorelin therapy in 14 hypogonadal men on TTh (30). These men were given thrice daily 100 µg doses of this combined GHS therapy via subcutaneous injection for an average period of 134 days following which IGF-1, T, FT, E, LH, and FSH were measured at follow-up intervals of 90, 180, and 270 days. The authors noted that GHS combination therapy led to significant increases in IGF-1 at all three follow-up timepoints. Subjects who were also treated with either an aromatase inhibitor or tamoxifen therapy for hyperestrogenemia or gynecomastia saw elevations in IGF-1, but these increases were less pronounced than those observed in men not receiving anti-estrogen therapy. However, the retrospective nature of the study, small sample size, and strict inclusion criteria limit a broader applicability of the findings. Additionally, the lack of comparator groups receiving GHS monotherapy and data regarding changes in body composition restrict the ability to fully understand the impact of the individual GHS. Despite these shortcomings, these findings highlight that sermorelin can lead to elevations in IGF-1 when used in conjunction with other GHS, showing the potential role of sermorelin in the treatment of hypogonadism.

The study’s results also emphasize the role of sermorelin as a potent GH and IGF-1 stimulator, which can yield significant increases in lean body mass. Although rare adverse events such as nausea, facial flushing, and redness at the injection site were noted, sermorelin appears to have a very favorable safety profile. Future large, longitudinal studies are needed to better characterize sermorelin’s potential complementary role in management of hypogonadal males and men with SH.