NOT FOR HUMAN CONSUMPTION

Tesamorelin binds GHRH receptors (GHRHR) on pituitary somatotrophs → Gs–cAMP–PKA–CREB signaling → GH pulse generation. Peripheral GH activates GHR–JAK2–STAT5 in liver and adipose, boosting IGF-1 and lipid-flux enzymes; somatostatin and IGF-1 provide negative feedback that preserves physiologic rhythms.

2.2 Down-stream Biology

3. Pharmacokinetics

Absorption: Rapid after SC injection; Tmax ~1 h.
Half-life (parent): ~1–2 h; pharmacodynamic effects persist via induced GH pulses and IGF-1 (24–48 h).
Distribution: Primary site of action is pituitary; systemic effects mediated by GH/IGF-1; minimal direct BBB penetration.
Clearance: Peptidase degradation; no known CYP interactions.
Dosing: Daily SC abdomen; rotate sites. EGRIFTA SV 2 mg vs EGRIFTA WR 1.28 mg—not interchangeable. FDA Prescribing Information

4. Pre-clinical and Translational Evidence

4.1 HIV-Associated Lipodystrophy (core indication)

Multiple RCTs demonstrate clinically meaningful VAT loss, triglyceride reduction, and improved adipokines over 26–52 weeks, with VAT rebound off-drug and re-response upon re-treatment. NEJM; AIDS

4.2 Hepatic Steatosis / MASH in HIV

12-month randomized data show reduced hepatic fat and lower fibrosis-progression risk; mechanisms likely include GH-dependent lipid flux and IGF-1 anti-fibrotic signaling. Lancet HIV; Hepatology Communications

4.3 Cognitive Aging

A 20-week placebo-controlled trial in healthy older adults and those with MCI reported improved executive function and memory with tesamorelin-class GHRH analog therapy, correlating with IGF-1 increases. Archives of Neurology; JAMA Neurology

4.4 Cardiometabolic Risk

VAT responders show higher HDL, lower TG, and reduced inflammatory markers; risk modeling suggests favorable shifts in 10-year ASCVD risk. JCEM; Journal of Clinical Lipidology

4.5 Body Composition & Physical Function

DXA/CT sub-studies indicate preferential visceral-fat loss with maintenance or slight gain of lean mass and improved abdominal comfort/mobility. Obesity; AIDS

5. Emerging Clinical Interests

6. Safety and Tolerability

Common: Injection-site reactions, edema, arthralgia/myalgia, paresthesia/carpal-tunnel-like symptoms (fluid retention).
Endocrine: IGF-1 elevation—monitor; glucose intolerance can emerge (check FPG/HbA1c; adjust antidiabetics).
Contraindications: Pregnancy, active malignancy, hypersensitivity (e.g., mannitol).
Oncology: Theoretical IGF-1-driven mitogenic risk; discontinue if malignancy occurs.
Ophthalmic/OSA: Fluid shifts may unmask/worsen retinopathy or sleep apnea.

Comparative safety matrix

7. Regulatory Landscape

Approved use: Reduction of excess abdominal fat in HIV-associated lipodystrophy.
Formulations (US): EGRIFTA SV 2 mg and EGRIFTA WR 1.28 mg once daily SC; not interchangeable.
Limitations of use: Not indicated for general weight loss; continue therapy only if VAT reduction is documented. FDA Prescribing Information

8. Future Directions

• Metabolic phenotyping: Trials in HIV-NAFLD/MASH and sarcopenic obesity with imaging/biopsy endpoints.

• Combination therapy: Pairing with GLP-1/GIP agonists or SGLT2 inhibitors to amplify hepatic and cardiometabolic outcomes while managing glycaemia.

• Precision dosing: IGF-1 SDS-guided titration to balance efficacy and safety.

• Formulation science: Long-acting depot or alternative delivery (e.g., transdermal, intranasal) to improve adherence.

Selected References

Falutz J. et al. Randomized trials of tesamorelin in HIV lipodystrophy—VAT reduction and metabolic effects. New England Journal of Medicine; AIDS.
Stanley T.L. et al. Tesamorelin for HIV-associated NAFLD—reduced liver fat and fibrosis-progression risk. Lancet HIV; Hepatology Communications.
Engelson E.S. et al. Body-image and QoL outcomes with tesamorelin. HIV Medicine; AIDS Care.
Johnen H. et al. Adipokines, triglycerides, and inflammatory markers in VAT responders. Journal of Clinical Endocrinology & Metabolism.
Baker L.D. et al. GHRH analog (tesamorelin) improves cognition in older adults with/without MCI. Archives of Neurology; JAMA Neurology.
Grunfeld C. et al. Glycaemic safety and IGF-1 monitoring across tesamorelin RCTs. Diabetes Care; AIDS.
Theratechnologies. EGRIFTA SV/WR Prescribing Information—indication, dosing, contraindications, monitoring.