Tesamorelin

Tesamorelin is human GHRH(1-44) with a trans-3-hexenoyl group attached to the N-terminal tyrosine, which blocks DPP-4 cleavage and extends the effective half-life while preserving full GHRH-receptor activity. Because the resulting GH release remains pulsatile and under normal negative feedback, IGF-1 rises but stays largely within physiological range. Visceral adipose tissue is unusually rich in GH receptors and lipolytically responsive, which is why the fat loss is regionally selective rather than general: registration trials showed roughly 15 to 18 percent reduction in visceral adipose tissue at 26 weeks with little change in subcutaneous fat. There is also good evidence for reduced liver fat, and separate work has examined it in mild cognitive impairment on the basis that GHRH raises brain GABA and improves executive function in older adults.

Targets: GHRH receptor (GHRHR), Visceral adipose tissue lipolysis, IGF-1 axis, Hepatic fat

• · The dose used in the phase 3 trials: 2 mg daily, reconstituted from two 1 mg vials.
• · 1.4 mg daily from a single 2 mg vial. Bioequivalent exposure to the original 2 mg dose.
• · 1.28 mg daily. The formulations are explicitly not interchangeable - vial count, reconstitution and storage all differ.
• · Grey-market users commonly run 1 to 2 mg nightly for 12 to 26 weeks. Anything below about 1 mg has no trial support for the visceral-fat effect.

Work out your exact syringe units →

• very commonInjection-site erythema, pruritus, pain or rash— The most common adverse event in the trials; rotate abdominal sites.
• commonArthralgia and joint stiffness— Dose-related GH effect.
• commonPeripheral oedema
• commonMyalgia and muscle stiffness
• commonParaesthesia and hypoaesthesia— Often the first sign of fluid-driven nerve compression.
• uncommonIncreased glucose and new-onset or worsened diabetes— A labelled warning; glucose should be checked before and during treatment.
• uncommonCarpal tunnel syndrome
• uncommonHypersensitivity reactions including rash and urticaria— Anti-tesamorelin IgG antibodies were detected in about 50 percent of patients at 26 weeks and 47 percent at 52 weeks in the registration trials, without demonstrated loss of efficacy; roughly half of those cross-reacted with endogenous GRF. Frank hypersensitivity reactions are much less common.

• Disruption of the hypothalamic-pituitary axis from hypophysectomy, pituitary tumour or surgery, head irradiation or head trauma.
• Active malignancy - the label explicitly requires that any active cancer be resolved first.
• Pregnancy, since it offers no benefit and could impair glucose tolerance.
• Known hypersensitivity to tesamorelin or mannitol.

• cautionCorticosteroids — GH alters 11-beta-HSD-1 activity, so patients on cortisone or prednisone may need dose adjustment; the label calls this out specifically.
• cautionCytochrome P450 substrates — GH can suppress CYP-mediated metabolism, which matters for narrow-therapeutic-index drugs.
• cautioninsulin — Expect increased insulin requirements in diabetics.
• synergysemaglutide — A popular off-label pairing: GLP-1 for total mass, tesamorelin for the visceral compartment. No trial data on the combination.

• · Fasting glucose and HbA1c at baseline and periodically - this is a labelled requirement, not a nicety.
• · IGF-1 at baseline and every 6 to 12 months; sustained levels above the age-adjusted range warrant a dose review.
• · Waist circumference or, ideally, a CT/MRI visceral fat measurement at baseline and 26 weeks.
• · Clinical surveillance for malignancy, per the label.

FDA-approved (Egrifta 2010, Egrifta SV, Egrifta WR 2025) for reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Prescription-only; all other uses are off-label. Prohibited in sport under WADA S2.

• Falutz et al. 2007 NEJM, tesamorelin phase 3 in HIV-associated abdominal fat accumulation (trial)
• Egrifta SV and Egrifta WR FDA prescribing information (label)
• Stanley et al., tesamorelin and hepatic fat in HIV-associated NAFLD (trial)

The sequence was verified directly against UniProt P01286: mature human GHRH is YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL, 44 residues, and tesamorelin is that with a hexenoyl cap on the N-terminus. Two things follow. First, this is the full-length hormone rather than the minimal active fragment, so it carries whatever stability and receptor-interaction contribution residues 30 to 44 provide. Second, the single N-terminal acylation is doing all the pharmacokinetic work, and it is a remarkably economical piece of chemistry - one modification instead of the four in Mod GRF 1-29. The regional selectivity of the fat loss is the interesting part and it is not marketing. Visceral adipose tissue expresses GH receptor more densely than subcutaneous fat and is more lipolytically responsive to GH; GH activates hormone-sensitive lipase and adipose triglyceride lipase through a route that suppresses the antilipolytic action of insulin. Because portal drainage delivers visceral lipolysis products straight to the liver, mobilising that compartment also reduces hepatic fat, which is exactly what Stanley's Lancet HIV trial found - a randomised, double-blind, placebo-controlled demonstration of reduced liver fat in HIV-associated NAFLD, with a follow-up transcriptomic analysis showing downregulation of hepatic fibrosis and inflammation gene sets. That is a genuinely unusual level of mechanistic corroboration for anything in this class. Because release remains pulsatile and IGF-1 feedback remains intact, IGF-1 stays largely within physiological range - the visceral fat effect is achieved without the supraphysiological IGF-1 that a DAC-conjugated GHRH analogue produces. The separate cognition work rests on a different observation: GHRH administration raises brain GABA levels and improved executive function in older adults and in mild cognitive impairment in Baker's controlled trial, an effect that appears to be GHRH-driven rather than simply GH-driven.

The most consequential error is treating the three branded formulations as interchangeable. EGRIFTA at 2 mg, EGRIFTA SV at 1.4 mg and EGRIFTA WR at 1.28 mg deliver bioequivalent exposure through different vial counts, different reconstitution procedures and different storage rules - and the label states explicitly that they are not interchangeable. Reading a generic peptide guide instead of the specific carton is how people end up dosing wrong. Second, the glucose warning is real and is where this compound actually hurts people. Someone with prediabetes who starts tesamorelin for visceral fat and does not check HbA1c can convert to frank diabetes while congratulating themselves on their waistline. Third, the effect reverses. Visceral fat returns within roughly six months of stopping, so the mental model of a 12-week cycle producing a permanent change is wrong - this is maintenance therapy or it is nothing. Fourth, on the grey market, dose is the problem: 1 to 2 mg daily is a lot of peptide, it is expensive, and low-dose protocols at 500 mcg have no trial support whatsoever for the visceral effect. Fifth, immunogenicity is worth knowing about: anti-tesamorelin IgG antibodies appeared in 50 percent of patients at 26 weeks and 47 percent at 52 weeks in the registration trials, with roughly 60 percent of those cross-reacting with endogenous GHRH. Efficacy was not demonstrably lost, but 85 percent of the patients who had hypersensitivity reactions had antibodies.

1. 1.4 mgLabel - no titration — EGRIFTA SV is 1.4 mg daily from a single 2 mg vial, and EGRIFTA WR is 1.28 mg daily. The label does not titrate; the dose is fixed and the trials used a fixed dose. This is unusual in this class and worth respecting.
2. 1 mgOff-label soft start, weeks 1 to 2 — Some clinicians start around 1 mg for a fortnight when arthralgia or fluid retention is a concern, then move to full dose. There is no trial support for this, but it costs nothing and the side effects that make people quit are front-loaded.
3. 2 mgWeek 3 onward — 2 mg daily is the original EGRIFTA phase 3 dose and the one every efficacy number comes from. Anything below about 1 mg has no trial support for the visceral-fat effect at all, which is worth knowing before buying a cheap low-dose protocol.

• GHRH receptor (GHRHR), pituitary somatotroph — Full agonist with potency comparable to native GHRH(1-44); no published Kd differential

  Gs coupling, cAMP, PKA, CREB. Pulsatile GH release preserved, with IGF-1 negative feedback intact - which is why IGF-1 rises but generally stays in range.

• Visceral adipose tissue (indirect, via GH receptor) — Not applicable

  The clinical signature. 15 to 18 percent reduction in visceral adipose tissue at 26 weeks in the phase 3 programme, with little change in subcutaneous fat.

• Hepatic fat (indirect) — Not applicable

  Reduced hepatic fat fraction in a randomised placebo-controlled trial in HIV-associated NAFLD, with corresponding changes in hepatic fibrosis and inflammation transcriptomic signatures.

• Dipeptidyl peptidase-4 (evaded, not inhibited) — The hexenoyl cap sterically blocks access to the Tyr1-Ala2 bond

  Extends functional half-life relative to native GHRH without altering receptor pharmacology.

• Falutz et al., phase 3 randomised placebo-controlled trial of tesamorelin in HIV-infected patients with abdominal fat accumulation 3 · n=412 · 26 weeks · 2007

  Reduction in visceral adipose tissue at 26 weeks. Published in the New England Journal of Medicine in 2007. The participant figure here is the commonly cited enrolment for this study and should be treated as approximate - it was not confirmed from the abstract in this session.

• Falutz et al., pooled analysis of two multicentre double-blind placebo-controlled phase 3 trials with safety extension 3 · 52 weeks · 2010

  Confirmed visceral adipose tissue reduction across both registration trials with 26-week safety extension data. Per the EGRIFTA SV label, mean VAT change was -18 percent versus +2 percent on placebo in study 1, and -14 percent versus -2 percent in study 2.

• Stanley et al., effects of tesamorelin on non-alcoholic fatty liver disease in HIV - randomised, double-blind, multicentre trial 2 · 52 weeks · 2019

  Reduction in hepatic fat fraction in HIV-associated NAFLD. Published in Lancet HIV in 2019. This is the strongest evidence for the liver-fat effect and it is a proper randomised controlled trial, not an observational extrapolation.

• Baker et al., controlled trial of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults 2 · 20 weeks · 2012

  Improved executive function on GHRH administration in both mild cognitive impairment and healthy older adults. Published in Archives of Neurology in 2012. A companion study in JAMA Neurology in 2013 showed corresponding increases in brain GABA levels by magnetic resonance spectroscopy.

Peak plasma concentration is reached in about nine minutes and the drug is essentially gone within the hour - the label reports an elimination half-life of 8 minutes in healthy subjects, which is shorter than most people assume. Injection-site erythema and itching, the most common adverse event, appear immediately and usually settle over the first few weeks with site rotation. Arthralgia, myalgia and peripheral oedema, when they occur, are early - first two to six weeks - and dose-related. Visceral fat reduction is measurable by 12 weeks and near-maximal at 26 weeks, which is the interval every trial used. Hepatic fat changes ran over 12 months in the Lancet HIV trial. After discontinuation, visceral fat returns over roughly six months.

The pairing that has actually become popular is tesamorelin with a GLP-1 receptor agonist: semaglutide or tirzepatide for total mass and appetite, tesamorelin for the visceral compartment specifically. Mechanistically this is coherent and the side-effect profiles do not overlap much, but there is no trial data on the combination and no reason to assume the visceral effect size holds during aggressive weight loss. The interaction the label actually flags is with corticosteroids: GH alters 11-beta-hydroxysteroid dehydrogenase type 1 activity, which converts cortisone to cortisol, so anyone on cortisone or prednisone may need their steroid dose reviewed. The same enzyme effect is why GH can unmask previously compensated adrenal insufficiency. The label also flags CYP substrates, because GH can suppress CYP-mediated metabolism - relevant for narrow-therapeutic-index drugs. Do not stack with another GHRH-receptor agonist: CJC-1295 in either form, or sermorelin, is the same receptor and adds nothing. Stacking with a GHRP is pharmacologically sensible - it is the same GHRH-plus-GHRP logic as everywhere else in this class - but it takes you off the protocol every efficacy number was generated on, and it adds the GHRP's own glucose burden to a drug that already has a labelled diabetes warning.

Against everything else in this class, tesamorelin's distinguishing feature is that it has phase 3 data and an FDA approval for a specific measurable outcome, and that outcome is regional rather than general. Against CJC-1295 with DAC: same receptor, but tesamorelin preserves pulsatility and keeps IGF-1 largely in range, whereas DAC drives sustained supraphysiological IGF-1. Tesamorelin is daily and expensive; DAC is weekly and cheap and unstudied. Against sermorelin and Mod GRF 1-29: same receptor, ten to twenty times the dose, and an actual evidence base. Against a GLP-1 agonist for fat loss: they do different jobs. GLP-1s produce far larger total weight loss including lean mass; tesamorelin produces a modest total change concentrated in the visceral compartment with lean mass preserved or slightly increased. Against exogenous GH for visceral fat: GH does reduce visceral fat but with far more insulin resistance, fluid retention and IGF-1 elevation, and without the regional selectivity being as clean.

$120–$8000/month. The range here is not a mistake. Branded EGRIFTA SV in the US runs into the thousands of dollars a month at cash price and is generally only accessible through insurance for the HIV lipodystrophy indication. Grey-market lyophilised tesamorelin, typically sold in 10 mg vials at roughly 60 to 130 USD, works out to roughly 120 to 300 USD a month at 1 to 2 mg daily. These are two entirely different products in terms of quality assurance and should not be price-compared as if they were the same thing. Figures are approximate and volatile.

• ?The label reports an elimination half-life of 8 minutes in healthy subjects for EGRIFTA SV 1.4 mg, whereas the Core record and most secondary sources quote 26 to 38 minutes. The discrepancy probably reflects different formulations, doses and populations across label versions, but it is not resolved here and the shorter figure is the one that appears in the current label.
• ?The 412 participant figure for the 2007 NEJM phase 3 trial is the commonly cited enrolment and was not confirmed from the primary abstract in this session.
• ?No protein binding, systemic clearance or metabolism data exists - the label states explicitly that no formal metabolism studies have been done in humans.
• ?All efficacy data comes from HIV-infected patients with lipodystrophy. Whether the 15 to 18 percent visceral fat reduction transfers to metabolically healthy people using it off-label for body composition has not been tested.
• ?The cognition evidence used GHRH administration in older adults, not tesamorelin specifically at its labelled dose, and the trials were small. Treating this as an established nootropic indication overstates it considerably.
• ?The long-term consequence of anti-tesamorelin antibodies cross-reacting with endogenous GHRH is not known beyond 52 weeks.
• ?Grey-market tesamorelin identity and potency are unverified, and at 1 to 2 mg daily the cost pressure to cut product is higher than for microgram-dosed peptides.

• Metabolic effects of a growth hormone-releasing factor in patients with HIV Falutz J, Allas S, Blot K, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S, New England Journal of Medicine, 2007 · PMID 18057338

  The pivotal phase 3 trial and the basis of the FDA approval.

• Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in HIV-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data Falutz J, Mamputu JC, Potvin D, Moyle G, Soulban G, Loughrey H, Marsolais C, Turner R, Grinspoon S, Journal of Clinical Endocrinology and Metabolism, 2010 · PMID 20554713

  The pooled registration dataset with extension safety data - the best single source for the effect size and its durability.

• Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, Pan CS, Aepfelbacher J, Buckless C, Tsao A, Kellogg A, Branch K, Lee H, Liu CY, Corey KE, Chung RT, Torriani M, Kleiner DE, Hadigan CM, Grinspoon SK, Lancet HIV, 2019 · PMID 31611038

  Randomised controlled evidence for the hepatic fat effect, which is the main reason tesamorelin is interesting outside its labelled indication.

• Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD Fourman LT, Billingsley JM, Agyapong G, Ho Sui SJ, Feldpausch MN, Purdy J, Zheng I, Pan CS, Corey KE, Torriani M, Kleiner DE, Hadigan CM, Stanley TL, Chung RT, Grinspoon SK, JCI Insight, 2020 · PMID 32701508

  Mechanistic corroboration at the level of hepatic gene expression, from paired liver biopsies in a randomised trial. Unusually strong for anything in this class.

• Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin Stanley TL, Falutz J, Marsolais C, Morin J, Soulban G, Mamputu JC, Assaad H, Turner R, Grinspoon SK, Clinical Infectious Diseases, 2012 · PMID 22495074

  Links the visceral fat reduction to actual metabolic marker improvement rather than just an imaging endpoint.

• Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial Baker LD, Barsness SM, Borson S, Merriam GR, Friedman SD, Craft S, Vitiello MV, Archives of Neurology, 2012 · PMID 22869065

  The controlled trial behind the cognition claim. Note that this used GHRH administration in older adults, not tesamorelin in its labelled population.

• Growth hormone-releasing hormone effects on brain gamma-aminobutyric acid levels in mild cognitive impairment and healthy aging Friedman SD, Baker LD, Borson S, Jensen JE, Barsness SM, Craft S, Merriam GR, Otto RK, Novotny EJ, Vitiello MV, JAMA Neurology, 2013 · PMID 23689947

  The proposed neurochemical mechanism for the cognition finding - increased brain GABA on magnetic resonance spectroscopy.

• EGRIFTA SV (tesamorelin for injection) US prescribing information DailyMed, Theratechnologies Inc

  Source of every pharmacokinetic number here: absolute bioavailability under 4 percent, tmax 0.15 hours, volume of distribution 4.8 L/kg, elimination half-life 8 minutes in healthy subjects, and the 50 percent anti-tesamorelin antibody rate at 26 weeks with roughly 60 percent cross-reactivity to endogenous GHRH.

• Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation Falutz J, Allas S, Mamputu JC, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S, AIDS, 2008 · PMID 18690162

  The 52-week extension data, including the observation that visceral fat returns after discontinuation - the reason this is maintenance therapy rather than a cycle.