¶ Tesamorelin
Tesamorelin (trade name Egrifta) is a synthetic peptide analogue of growth hormone-releasing hormone (GHRH). It is currently the only GHRH analogue approved by the US Food and Drug Administration (FDA) for the reduction of excess abdominal visceral adipose tissue (VAT) in HIV-infected patients with lipodystrophy.
Beyond its approved indication, Tesamorelin has attracted significant interest in the longevity and metabolic health communities for its ability to restore endogenous growth hormone (GH) secretion, improve body composition, reduce liver fat, and potentially enhance cognitive function.
¶ Mechanism of Action
Tesamorelin consists of the 44 amino acid sequence of human GHRH with a trans-3-hexenoic acid group added to the N-terminus. This modification significantly increases its stability and resistance to enzymatic degradation by dipeptidyl peptidase-4 (DPP-4), extending its half-life compared to native GHRH[1].
¶ Pulsatile GH Release
Unlike exogenous recombinant human growth hormone (rhGH), which provides a steady, non-physiological elevation of GH levels, Tesamorelin stimulates the pituitary gland to release GH in a pulsatile manner. This preserves the body's natural negative feedback loops (somatostatin inhibition), theoretically reducing the risk of side effects associated with constant GH elevation, such as severe insulin resistance, fluid retention, and carpal tunnel syndrome[2].
Upon binding to GHRH receptors on pituitary somatotrophs, Tesamorelin triggers the synthesis and release of GH, which subsequently stimulates the liver to produce Insulin-Like Growth Factor 1 (IGF-1).
¶ Clinical Applications and Evidence
¶ HIV-Associated Lipodystrophy (FDA Approved)
The primary evidence for Tesamorelin comes from large Phase 3 clinical trials in HIV patients with lipodystrophy (abnormal fat accumulation).
- Visceral Fat Reduction: Treatment with 2mg of Tesamorelin daily for 26 weeks resulted in a 15-20% reduction in visceral adipose tissue (VAT) compared to placebo[3][4].
- Maintenance Requirement: Studies indicate that VAT re-accumulates after cessation of therapy, suggesting that long-term or cyclic maintenance may be necessary[4:1].
- GRADE Assessment: High Certainty for visceral fat reduction in the indicated population.
¶ Non-Alcoholic Fatty Liver Disease (NAFLD)
Tesamorelin has shown promise in treating NAFLD, a condition closely linked to metabolic aging and insulin resistance.
- A randomized, double-blind trial published in The Lancet HIV (2019) demonstrated that Tesamorelin significantly reduced liver fat content (hepatic lipid accumulation) and prevented the progression of liver fibrosis in HIV patients with NAFLD[5].
- The mechanism appears to involve both lipolytic effects of GH and direct modulation of oxidative pathways in the liver.
¶ Cognitive Function
Emerging research suggests Tesamorelin may benefit cognitive health, particularly in the context of metabolic dysfunction.
- 2024 Findings: A study investigating Tesamorelin in patients with HIV and abdominal obesity found improvements in executive function and verbal memory. This is hypothesized to be mediated by increased IGF-1, which has neuroprotective and neurotrophic properties[6][7].
- Mechanism: GHRH receptors are present in the brain, and GHRH itself may have direct effects on sleep and cognition independent of the GH/IGF-1 axis, although Tesamorelin's poor blood-brain barrier penetration suggests the effects are primarily GH/IGF-1 mediated.
¶ Longevity and Body Composition (Off-Label)
In the context of healthy aging, Tesamorelin is used off-label to address "somatopause"—the age-related decline in GH and IGF-1.
- Body Composition: Anecdotal reports and extrapolation from HIV data suggest it can improve the lean muscle-to-fat ratio in non-HIV populations, though large-scale trials in healthy adults are lacking.
- Safety Advantage: Compared to direct HGH injections, Tesamorelin is considered safer for long-term optimization because it is less likely to push IGF-1 into supraphysiological ranges that might accelerate aging or cancer risk.
¶ Safety and Side Effects
Tesamorelin is generally well-tolerated, but specific safety considerations exist.
¶ Common Side Effects
- Injection Site Reactions: Redness, itching, or pain at the injection site (most common).
- Arthralgia: Joint pain and muscle stiffness, typically mild.
- Edema: Mild fluid retention, though less frequent than with hGH.
¶ Metabolic Considerations
- Glucose Control: Because GH counteracts insulin, Tesamorelin can theoretically increase blood glucose. Clinical trials showed a small increase in HbA1c in some patients, but it generally remained within clinically acceptable limits. It is contraindicated in patients with active malignancy or hypopituitarism[3:1].
- IGF-1 Elevation: Tesamorelin increases IGF-1 levels. While this is the desired therapeutic effect, excessive IGF-1 is theoretically linked to cancer cell proliferation. Routine monitoring of IGF-1 levels is standard practice in longevity clinics.
¶ Dosing and Administration
- Standard Dose: 2 mg injected subcutaneously once daily.
- Timing: Typically administered at night or before bed to mimic the body's natural nocturnal GH spike.
- Reconstitution: Tesamorelin is supplied as a lyophilized powder requiring reconstitution with bacteriostatic water.
- Cycling: While FDA trials used continuous dosing, many longevity practitioners prescribe cycles (e.g., 5 days on/2 days off, or 3 months on/1 month off) to mitigate potential receptor desensitization, although data on desensitization with Tesamorelin is conflicting.
¶ References
Ferdinandi ES, et al. Preclinical pharmacology and safety of tesamorelin, a GHRH analog, in animals. Basic Clin Pharmacol Toxicol. 2007. ↩︎
Clemmons DR, et al. Effects of tesamorelin on body composition and metabolic parameters in HIV-infected patients with abdominal fat accumulation. J Clin Endocrinol Metab. 2010. ↩︎
Falutz J, et al. Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation. AIDS. 2010. ↩︎ ↩︎
Spooner LM, et al. Tesamorelin: a growth hormone-releasing factor analogue for the treatment of HIV-associated lipodystrophy. Ann Pharmacother. 2012. ↩︎ ↩︎
Stanley TL, et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019. ↩︎
Grinspoon SK, et al. Effects of Tesamorelin on Neurocognitive Impairment in Persons With HIV and Abdominal Obesity. Clinical Infectious Diseases. 2024. ↩︎
Baker LD, et al. Growth hormone-releasing hormone improves cognitive function in healthy older adults. Arch Neurol. 2012. ↩︎