Growth hormone is secreted by the anterior pituitary in a pulsatile pattern, with the largest pulse occurring during slow-wave sleep approximately 90 minutes after sleep onset. GH drives fat metabolism, protein synthesis, tissue repair, immune function, and cognitive performance. Its decline with age, approximately 15 per cent per decade after peak in the mid-twenties, contributes to the changes in body composition, recovery capacity, sleep architecture, and skin quality that characterise middle age. Growth hormone secretagogues stimulate endogenous GH release rather than replacing it exogenously, offering a physiologically more nuanced approach.
Sermorelin
Sermorelin is a synthetic analogue of the first 29 amino acids of human growth hormone-releasing hormone, the hypothalamic peptide that naturally triggers pituitary GH secretion. It was licensed by the FDA as a pharmaceutical for childhood growth hormone deficiency diagnosis and later for adult growth hormone deficiency, before patent expiry moved it predominantly to compounding pharmacies. Sermorelin stimulates GH release through the physiological GHRH receptor pathway, maintaining the normal pituitary feedback mechanisms that prevent supraphysiological GH levels. Human studies show that sermorelin treatment increases GH and IGF-1 toward more youthful levels, with associated improvements in lean mass, fat mass, and skin thickness.
Ipamorelin
Ipamorelin is a synthetic pentapeptide that acts as a selective agonist at the ghrelin receptor in the pituitary, stimulating GH release through a different pathway than sermorelin. It is notable for its high selectivity: unlike GHRP-6 and other ghrelin receptor agonists, Ipamorelin stimulates GH release without significantly increasing cortisol or ACTH, reducing the off-target effects that limit other compounds in this class. Combining Ipamorelin with CJC-1295 activates both GHRH and ghrelin receptor pathways simultaneously, producing synergistic GH release greater than either alone. This combination is among the most commonly used in longevity-focused peptide protocols.
Benefits and Evidence
Human studies of GH secretagogues in adults with age-related GH decline show: reductions in visceral and subcutaneous fat, particularly visceral fat which is most metabolically harmful; increases in lean body mass; improvements in sleep quality and architecture, specifically increasing slow-wave sleep depth; improvements in skin thickness and texture; improved bone mineral density with long-term use; and enhanced recovery from exercise and injury. The magnitude of these effects is generally modest compared to direct GH administration but is achieved through physiological mechanisms with a more favourable safety profile.
Side Effects and Safety
GH secretagogues are generally well tolerated. The most common side effects are injection site reactions, transient water retention in the first weeks of use due to sodium retention effects of GH, and mild increases in fasting glucose in susceptible individuals. They should not be used in the presence of active malignancy. They are not recommended for use by anyone under 25, as endogenous GH levels are already high and the pituitary axis is fully active. They should be used under the supervision of a practitioner who can monitor IGF-1 levels to ensure GH is not elevated above the target physiological range.