Tesamorelin

Tesamorelin (TH9507/Egrifta) is a stabilized analog of full-length human GHRH(1-44) modified with a trans-3-hexenoic acid group at the N-terminal tyrosine. This modification protects the peptide from dipeptidyl peptidase-IV (DPP-IV) cleavage at the Ala2-Asp3 bond, the primary site of native GHRH degradation. Tesamorelin was approved by the FDA in 2010 for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy, making it the first and only GHRH analog approved for a lipodystrophy indication. As a full-length GHRH analog (44 amino acids), tesamorelin activates the GHRH receptor to stimulate endogenous GH production and secretion, producing physiological pulsatile GH release patterns. Clinical trials demonstrated its ability to reduce visceral adipose tissue (VAT) and improve trunk fat distribution in the HIV lipodystrophy population.

Tesamorelin has been investigated for its agonist activity at the GHRH receptor on anterior pituitary somatotrophs. The trans-3-hexenoic acid modification at the N-terminus prevents DPP-IV from cleaving the Ala2-Asp3 bond, extending the peptide’s bioactive half-life compared to native GHRH. Upon GHRHR binding, tesamorelin activates Gs-coupled adenylyl cyclase signaling, increasing cAMP and activating PKA, which promotes GH gene transcription and secretory granule exocytosis. Researchers observed that tesamorelin stimulates endogenous GH pulses that activate hepatic IGF-1 production and downstream lipolytic signaling in adipose tissue. In clinical trials, the resulting GH elevation was associated with preferential reduction of visceral (as opposed to subcutaneous) adipose tissue, likely due to the high density of GH receptors on visceral adipocytes. Studies suggest that GH-mediated lipolysis in visceral fat is mediated through hormone-sensitive lipase activation and adipose triglyceride lipase upregulation.

FDA Approval Studies

Falutz et al. (2007) conducted the pivotal clinical trial demonstrating that tesamorelin reduced visceral adipose tissue in HIV-associated lipodystrophy. Researchers observed significant trunk fat reduction by CT imaging compared to placebo [1].

IGF-1 and Body Composition

Stanley et al. (2014) investigated the metabolic effects of tesamorelin beyond VAT reduction, observing improvements in triglycerides, cholesterol parameters, and carotid intima-media thickness in the HIV lipodystrophy population [2].

Cognitive Effects

Baker et al. (2012) investigated tesamorelin’s effects on cognition in elderly subjects and observed improvements in executive function tests, suggesting GH/IGF-1 modulation may influence CNS function [3].