Tesamorelin

Tesamorelin is a synthetic analogue of human growth hormone-releasing hormone (GHRH) consisting of the full 44-amino acid hGRF(1-44) sequence modified with a trans-3-hexenoic acid group at the N-terminus. This modification confers resistance to enzymatic degradation while preserving full GHRH receptor agonist activity. Developed by Theratechnologies, tesamorelin is the only GHRH analogue approved by the FDA (as Egrifta) for the treatment of excess abdominal fat in HIV-infected patients with lipodystrophy.

Tesamorelin occupies a unique position among GH secretagogues as the only one with an FDA-approved indication. Its mechanism preserves the physiological pulsatile pattern of GH secretion, unlike exogenous GH administration which produces supraphysiological, non-pulsatile levels. Recent research has expanded interest beyond HIV lipodystrophy to include non-alcoholic fatty liver disease (NAFLD), where tesamorelin has demonstrated hepatoprotective effects potentially independent of its visceral fat-reducing properties.

Tesamorelin acts as a full agonist at the GHRH receptor (GHRHR) on anterior pituitary somatotrophs. Receptor activation stimulates the Gs/adenylyl cyclase/cAMP/PKA pathway, promoting both synthesis and pulsatile release of growth hormone. The resulting GH elevation increases hepatic IGF-1 production, which mediates many of tesamorelin's downstream metabolic effects. Critically, the somatostatin feedback loop remains intact — endogenous somatostatin continues to modulate GH release, preventing the supraphysiological, sustained GH elevations seen with exogenous GH administration.

The visceral fat reduction appears to be mediated through GH's lipolytic effects on visceral adipocytes, which express higher GH receptor density than subcutaneous adipocytes. GH activates hormone-sensitive lipase and inhibits lipoprotein lipase in visceral fat, promoting triglyceride hydrolysis and free fatty acid release for oxidation. The hepatoprotective effects observed in NAFLD may involve both reduced hepatic lipid delivery (secondary to visceral lipolysis) and direct GH-mediated effects on hepatocyte lipid metabolism, including suppression of de novo lipogenesis through STAT5 signaling.