Tesamorelin：内臓脂肪減少研究のためのGHRHアナログ

For informational purposes only. This article does not constitute medical advice. Consult a qualified healthcare provider for any health-related decisions.

What Is Tesamorelin?

Tesamorelin (brand name Egrifta, later Egrifta SV) is a synthetic analog of human growth hormone-releasing hormone (GHRH, also known as growth hormone-releasing factor or GRF). Developed by Theratechnologies Inc. and manufactured by EMD Serono, tesamorelin is the only GHRH analog currently approved by the FDA, with a specific indication for the reduction of excess abdominal fat in HIV-infected adult patients with lipodystrophy. The compound consists of the full 44-amino-acid sequence of human GHRH(1-44) with a trans-3-hexenoic acid modification at the N-terminus, which improves stability and resistance to enzymatic degradation.

The fundamental pharmacological distinction of tesamorelin from exogenous growth hormone is that tesamorelin acts upstream in the hypothalamic-pituitary-GH axis: rather than providing exogenous GH directly, it stimulates the pituitary somatotroph cells to produce and release endogenous growth hormone in a pulsatile, physiologically regulated manner. This distinction has important implications for both efficacy and safety.

Property	Detail
Generic Name	Tesamorelin (tesamorelin acetate)
Brand Name	Egrifta / Egrifta SV
Developer	Theratechnologies Inc.
Class	Growth hormone-releasing hormone (GHRH) analog
Structure	Modified hGHRH(1-44) amide
N-Terminal Modification	Trans-3-hexenoic acid
Administration	2 mg once-daily subcutaneous injection
Half-Life	Approximately 26-38 minutes
FDA Approval	November 2010
Approved Indication	Reduction of excess abdominal fat in HIV lipodystrophy

Mechanism of Action

Tesamorelin's mechanism of action is distinct from both exogenous growth hormone and from GH-releasing peptides (GHRPs) or ghrelin mimetics. Understanding this distinction is important for appreciating its pharmacological profile.

GHRH Receptor Activation

Tesamorelin binds to and activates the GHRH receptor (GHRHR) on anterior pituitary somatotroph cells. This receptor is a G protein-coupled receptor that signals through the Gs-adenylyl cyclase-cAMP-PKA pathway, leading to increased intracellular calcium and subsequent exocytosis of GH-containing secretory granules. Importantly, this mechanism preserves the pulsatile nature of GH secretion and maintains the normal feedback regulation of the GH axis.

Physiological GH Release

Because tesamorelin works through the natural regulatory pathway, the resulting GH elevation is subject to somatostatin-mediated negative feedback. When GH and IGF-1 levels rise, somatostatin release from the hypothalamus increases, tempering further GH secretion. This self-limiting mechanism provides a theoretical safety advantage over exogenous GH administration, where supraphysiological levels can be sustained without regard to feedback.

Visceral Fat Reduction

The primary mechanism by which tesamorelin reduces visceral fat is through the downstream effects of elevated endogenous GH. Growth hormone promotes lipolysis in visceral adipose tissue (VAT), which is particularly enriched in GH receptors compared to subcutaneous fat depots. GH activates hormone-sensitive lipase (HSL) in visceral adipocytes, promoting the breakdown of stored triglycerides and the release of free fatty acids for oxidation. The preferential effect on visceral rather than subcutaneous fat is a notable characteristic of GH-mediated lipolysis and is particularly relevant for the HIV lipodystrophy population, where visceral fat accumulation is a defining feature of the syndrome.

Research Landscape

HIV Lipodystrophy Trials

The clinical development of tesamorelin focused primarily on HIV-associated lipodystrophy, a metabolically significant condition characterized by abnormal fat redistribution (visceral fat accumulation with peripheral fat wasting) occurring in patients receiving antiretroviral therapy. Key trial results include:

• Phase 3 pivotal trial: 816 HIV-infected patients with lipodystrophy randomized to tesamorelin 2 mg or placebo for 26 weeks. Tesamorelin reduced VAT by approximately 15.2% compared to a 5.0% increase in the placebo group. The treatment also improved patient-reported body image distress and trunk fat appearance.
• Extension study: Patients who continued tesamorelin for an additional 26 weeks (total 52 weeks) maintained the VAT reduction. However, patients who were re-randomized from tesamorelin to placebo experienced a return of visceral fat toward baseline levels, indicating that continued treatment is necessary to maintain the benefit.
• Metabolic parameters: Studies demonstrated improvements in triglyceride levels and a trend toward improved non-HDL cholesterol with tesamorelin treatment, consistent with the metabolic effects of normalized GH signaling.

Non-HIV Research Applications

Beyond HIV lipodystrophy, tesamorelin has been investigated in several other research contexts:

• NAFLD/NASH: Research has evaluated tesamorelin's effects on hepatic fat content in HIV-infected patients with fatty liver disease, with results showing significant reductions in liver fat fraction and potential improvements in hepatic fibrosis markers.
• Cognitive function: Preliminary studies have explored whether tesamorelin-induced GH/IGF-1 elevation might benefit cognitive function in aging populations, based on the known role of the GH axis in brain health. Early results have suggested possible improvements in executive function, though this research remains preliminary.
• General visceral obesity: Off-label interest in tesamorelin for non-HIV visceral fat reduction exists, though the compound is not approved for this indication and the evidence base is limited to the HIV-lipodystrophy population.

Key Studies

The most impactful publications on tesamorelin include the Phase 3 registration trials (published in JAMA and the Journal of Clinical Endocrinology and Metabolism) and subsequent studies evaluating effects on liver fat and metabolic parameters. The NAFLD studies are particularly noteworthy, as they suggest that tesamorelin's effects may extend beyond simple fat redistribution to meaningful improvements in organ-specific metabolic dysfunction.

Safety Profile

Adverse Effect	Frequency	Notes
Injection site reactions	~8-13%	Most common; erythema, pruritus, pain
Arthralgia (joint pain)	~8-13%	Related to GH elevation; usually mild
Peripheral edema	~5-6%	Fluid retention from GH effects
Myalgia (muscle pain)	~4-5%	Related to GH elevation
Paresthesia	~3-5%	Including carpal tunnel-like symptoms
Nausea	~3-4%	Generally mild

The side effect profile of tesamorelin is largely attributable to its GH-elevating effects and is generally consistent with those seen with exogenous GH, though potentially milder due to the physiological regulation of the response. IGF-1 elevations occur with tesamorelin use and require monitoring. The compound is contraindicated during pregnancy, in patients with active malignancy, and in patients with disruption of the hypothalamic-pituitary axis (since the mechanism requires intact pituitary function).

Comparison to Related Compounds

Tesamorelin is most directly comparable to sermorelin, another GHRH analog (GHRH 1-29) that was previously approved in the United States but whose commercial availability has been limited. Both compounds work through the GHRH receptor to stimulate endogenous GH release, but tesamorelin's N-terminal modification provides improved stability and potency. Unlike GH secretagogues such as ipamorelin or CJC-1295 that act through the ghrelin receptor (GHS-R), tesamorelin works exclusively through the GHRH receptor pathway.

Compared to exogenous GH, tesamorelin offers the theoretical advantage of preserving pulsatile, feedback-regulated GH secretion. However, exogenous GH provides more predictable and controllable GH elevations and does not require intact pituitary function.

Current Status

Tesamorelin remains FDA-approved and commercially available as Egrifta SV (a single-vial formulation that simplified the original two-vial reconstitution). Its use is primarily limited to the approved indication of HIV-associated lipodystrophy, though off-label use and research interest in broader applications continue. The compound's unique mechanism of stimulating endogenous GH release through the natural regulatory pathway maintains its relevance in the landscape of GH-axis-modulating therapeutics.