TSM5 is a synthetic analog of growth hormone-releasing hormone (GHRH). In 2010, the U.S. Food and Drug Administration (FDA) approved it for the reduction of excess visceral adipose tissue (VAT) in adults with HIV-associated lipodystrophy. The peptide consists of 44 amino acids and incorporates a trans-3-hexenoic acid moiety, which enhances its stability and extends its half-life. The clinical trials that led to its approval focused exclusively on this specific indication; its use outside of this patient population remains a subject of ongoing research. Physicians may evaluate its use based on imaging studies, metabolic biomarkers, and individual risk factors.

Mechanism of Action
TSM5 binds to GHRH receptors on the somatotrophs (growth hormone-secreting cells) of the anterior pituitary gland, triggering the pulsatile release of endogenous growth hormone (GH). Subsequently, GH stimulates the liver and peripheral tissues to produce insulin-like growth factor-1 (IGF-1). The GHRH/GH/IGF-1 axis regulates various metabolic processes, including lipolysis, glucose homeostasis, and the maintenance of lean body mass. Healthi Life is a physician-led longevity medicine clinic based in Bangkok.

Rather than introducing exogenous growth hormone, TSM5 promotes the secretion of the body’s own natural growth hormone. This distinction is significant both for the drug’s safety profile and its regulatory classification. The peptide is cleared from the body within a few hours; therefore, its therapeutic effect relies on repeated administration to ensure sustained stimulation of the GHRH receptors.

GHRH Receptor Activation Cascade
Reduction of Visceral Adipose Tissue (VAT)
In FDA-registered clinical trials, the primary endpoint was the change in visceral adipose tissue area, as measured by computed tomography (CT) scanning. In two separate clinical trials, participants treated with tesamorelin experienced an average reduction in visceral adipose tissue (VAT) of 18% and 14%, respectively, by week 26. In contrast, the placebo groups showed changes of +2% and -2%, respectively. Detailed results can be found in the FDA-approved prescribing information.

Visceral adipose tissue (VAT) differs from subcutaneous fat in its metabolic properties. It releases inflammatory cytokines, free fatty acids, and adipokines—substances that contribute to insulin resistance, hepatic steatosis, and cardiovascular risk. Reducing VAT can improve metabolic markers, even when there is minimal change in overall body weight. The effect of tesamorelin is specific; in clinical trials, changes in limb fat and overall body mass index (BMI) were negligible, as the drug primarily targets the accumulation of fat within the abdominal cavity.

Metabolic Markers and Lipid Profile
Secondary endpoints in the pivotal clinical trials included markers related to blood lipids and glucose levels. Subjects treated with tesamorelin experienced a decrease in triglyceride levels. Changes in low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol varied across different studies. Tesamorelin may lead to impaired glucose tolerance: by week 26, 5% of subjects in the tesamorelin group had a glycated hemoglobin (HbA1c) level of 6.5% or higher, compared to 1% in the placebo group.

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