Tesamorelin

Tesamorelin is a synthetic analog of human growth hormone-releasing hormone (GHRH) consisting of the full 44-amino acid GHRH(1-44) sequence modified by the addition of a trans-3-hexenoic acid group at the N-terminus. This modification enhances the peptide's stability and resistance to enzymatic degradation by dipeptidyl peptidase-IV (DPP-IV), which rapidly cleaves native GHRH. Developed by Theratechnologies Inc., tesamorelin was approved by the FDA in November 2010 under the brand name Egrifta for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. HIV-associated lipodystrophy is a metabolic condition characterized by abnormal redistribution of body fat, including excess visceral adipose tissue (VAT) accumulation in the abdominal region. This condition is associated with increased cardiovascular risk, insulin resistance, and significant psychological distress for affected patients. Tesamorelin addressed an unmet clinical need by providing a targeted approach to reduce VAT through physiological stimulation of the growth hormone axis, rather than through supraphysiological GH replacement. The mechanism is fundamentally different from exogenous growth hormone administration. Tesamorelin stimulates the patient's own pituitary gland to produce and release growth hormone in a pulsatile, physiological pattern. This maintains the normal feedback mechanisms that regulate GH secretion, resulting in a more favorable safety profile compared to direct GH injection. Clinical trials demonstrated significant VAT reduction, improved lipid profiles, and reductions in trunk fat. Research continues to explore tesamorelin's effects on hepatic steatosis, cognitive function, and metabolic parameters. Tesamorelin is available by prescription for its approved indication and for research purposes.

Tesamorelin acts through the GHRH receptor to produce downstream metabolic effects: **GHRH Receptor Agonism**: Tesamorelin binds to GHRH receptors on somatotroph cells in the anterior pituitary gland, stimulating synthesis and secretion of endogenous growth hormone. The trans-3-hexenoic acid modification at the N-terminus protects the peptide from DPP-IV cleavage, significantly extending its effective half-life compared to native GHRH. **Pulsatile GH Secretion**: Unlike direct GH administration, tesamorelin preserves the natural pulsatile pattern of growth hormone release. This is important because pulsatile GH signaling activates different downstream pathways than continuous exposure, and it maintains negative feedback regulation through IGF-1 and somatostatin, reducing the risk of GH excess. **Lipolysis and Visceral Fat Reduction**: Tesamorelin-stimulated GH acts on adipose tissue to promote lipolysis, particularly in visceral fat depots. GH activates hormone-sensitive lipase in adipocytes, releasing stored triglycerides as free fatty acids for oxidation. Visceral adipose tissue is particularly responsive to GH-mediated lipolysis due to its high density of GH receptors and beta-adrenergic receptors. **IGF-1 Axis Activation**: GH stimulated by tesamorelin induces hepatic production of insulin-like growth factor 1 (IGF-1). IGF-1 mediates many of GH's anabolic effects including protein synthesis, and elevated IGF-1 levels serve as a biomarker confirming tesamorelin's biological activity. Clinical trials consistently show dose-dependent IGF-1 increases. **Hepatic and Metabolic Effects**: Emerging research suggests tesamorelin reduces hepatic fat content and improves markers of non-alcoholic fatty liver disease (NAFLD). GH-mediated reductions in hepatic lipogenesis and increased fatty acid oxidation are proposed mechanisms for this effect.

Tesamorelin has been evaluated in rigorous Phase III clinical trials and ongoing research: **Pivotal Phase III Trials**: Two large randomized, double-blind, placebo-controlled trials (Studies 1 and 2) enrolled over 800 HIV-infected patients with lipodystrophy. After 26 weeks, tesamorelin-treated patients showed an average 15–18% reduction in visceral adipose tissue (measured by CT scan), compared to a 5% increase in placebo groups. Trunk fat, waist circumference, and patient-reported body image scores also improved significantly. **Lipid and Metabolic Effects**: Clinical trials demonstrated improvements in triglyceride levels (mean reduction of 50 mg/dL) and favorable changes in total cholesterol/HDL ratios. Notably, tesamorelin did not worsen glucose tolerance in most patients, although fasting glucose showed modest increases in some subgroups, warranting monitoring. **Hepatic Steatosis Research**: A randomized controlled trial by Stanley et al. (2014) demonstrated that tesamorelin reduced hepatic fat fraction by 37% (measured by MR spectroscopy) in HIV-infected patients with NAFLD, compared to a 10% increase in the placebo group. This finding has generated significant interest in tesamorelin for liver disease applications. **Cognitive Function Studies**: Intriguing preliminary research by Baker et al. has explored tesamorelin's effects on cognitive function in healthy older adults. Studies showed improvements in executive function and verbal memory, potentially mediated through IGF-1's neurotrophic effects. These findings require further investigation. **Long-Term Extension Data**: Open-label extension studies following patients for up to 18 months showed maintained VAT reduction with continued therapy. However, VAT reaccumulated upon treatment discontinuation, indicating the need for ongoing administration to sustain benefits.

Tesamorelin dosing is well-established through clinical trials and FDA labeling: **FDA-Approved Dose**: The approved dose is 2 mg administered once daily via subcutaneous injection into the abdomen. This is the dose used in pivotal Phase III trials. **Administration**: Tesamorelin is provided as a lyophilized powder requiring reconstitution with sterile water. Injection sites should be rotated within the abdominal area. It should be administered on an empty stomach or at least 30 minutes before food. **Treatment Duration**: Clinical trials evaluated 26-week treatment courses. Extension studies continued for up to 18 months. Periodic reassessment of treatment benefit is recommended. **Monitoring**: IGF-1 levels should be monitored as a biomarker of GH response. Glucose and HbA1c monitoring is recommended due to GH's effects on insulin sensitivity. **Note**: The 2 mg daily dose reflects the FDA-approved labeling for HIV lipodystrophy. Use outside this indication is off-label. Tesamorelin requires a prescription for its approved indication; for research applications, it is available for research purposes only.

Tesamorelin's safety profile is well-characterized through large clinical trials: **Common Effects (≥5% incidence)**: - Injection site reactions (erythema, pruritus, pain, irritation) — the most frequently reported adverse event - Arthralgia (joint pain) - Peripheral edema - Myalgia (muscle pain) - Paraesthesia (tingling/numbness) **Metabolic Effects**: - Modest increases in fasting glucose and HbA1c in some patients - IGF-1 elevation (expected pharmacological effect; excessive elevation may require dose adjustment) - Fluid retention-related symptoms typically resolve within the first few weeks **Serious Considerations**: - Contraindicated in patients with active malignancy due to GH's potential growth-promoting effects - Contraindicated in pregnancy (Category X) - Hypersensitivity reactions including rare cases of anaphylaxis have been reported - Should be used with caution in patients with pre-existing diabetes **Long-Term Data**: Extension studies up to 18 months did not reveal new safety signals. The adverse event profile was consistent with expected GH-mediated effects.