A synthetic 44-amino-acid peptide that copies the body's own growth-hormone-releasing hormone (GHRH). It tells the pituitary gland to release natural growth hormone in normal pulses, which in turn raises IGF-1 and breaks down deep abdominal (visceral) fat. Unlike most peptides in this atlas, tesamorelin is the real thing: it is FDA-approved (as EGRIFTA WR™ and Egrifta SV®) to reduce excess belly fat in people with HIV-associated lipodystrophy, backed by three large Phase III trials in more than 800 patients. It is also banned in sport by WADA (class S2). Everything below the approved-indication line — body composition in non-HIV adults, cognition, fatty-liver use, and most stacking — is hypothesis-layer content built on smaller trials and clinic practice, not validated prescribing.
Tesamorelin (TH9507; trade names EGRIFTA WR™ / Egrifta SV®, MW 5135.9 Da) is a stabilized full-length human GHRH(1-44) analog bearing an N-terminal trans-3-hexenoyl group that confers DPP-IV resistance. It agonizes pituitary GHRH-R with potency similar to native GHRH, restoring pulsatile endogenous GH secretion, elevating IGF-1/IGFBP-3, and driving preferential lipolysis of visceral adipose tissue (VAT). Two pooled Phase III RCTs (n=806) demonstrated ~15–18% VAT reduction vs. placebo at 26 weeks, maintained to 52 weeks with continued dosing and rebounding on discontinuation. Key clinical caveats: a hazard ratio of 3.3 for new-onset diabetes, mandatory IGF-1 monitoring, fluid-retention effects, and absolute contraindications in active malignancy and pregnancy.
Tesamorelin (CAS 218949-48-5, C₂₂₁H₃₆₆N₇₂O₆₇S, MW 5135.9 Da, PubChem CID 16137828, DrugBank DB08869) is an N-terminally acylated GHRH(1-44) analog. The trans-3-hexenoic acid moiety on the N-terminal tyrosine blocks dipeptidyl-peptidase-IV cleavage while preserving high-affinity GHRH-R (Gs-coupled GPCR) agonism → cAMP/PKA → CREB-driven GH gene transcription and pulsatile somatotroph exocytosis. Absolute SC bioavailability is <4%, Tmax ~9 min, and intact-peptide t½ ~11 min (FDA label, 1.28 mg) — though population-PK models report ~26 min (healthy) and ~38 min (HIV+); fixed daily dosing is justified by the absence of clinically significant PK covariates including body weight. Downstream JAK2/STAT5 hepatic IGF-1 synthesis and IGF-1R/PI3K-Akt/MAPK signaling mediate lipolytic and anabolic effects; VAT selectivity reflects higher visceral-adipocyte GH-receptor density plus GH-mediated 11β-HSD-1 inhibition. Overall GRADE for the approved indication: HIGH.
The numbers that define tesamorelin's unusual position in this atlas — it is one of the very few peptides here with a genuine, FDA-approved, RCT-grade evidence base for a specific indication. That approved core (HIV-associated lipodystrophy VAT reduction) is Grade A; everything off-label is Phase II / practice-pattern hypothesis layer. The regulatory, efficacy, and safety facts below are the ones a clinician should weigh most heavily.
Tesamorelin works one step upstream of growth hormone. Instead of injecting growth hormone directly, it copies GHRH — the natural signal your brain uses to ask the pituitary gland for growth hormone. Because it preserves the body's normal pulsing rhythm, GH rises the way it naturally would, then signals the liver to make IGF-1 and tells visceral fat cells to release their stored fat. A secondary effect on a fat-tissue enzyme (11β-HSD-1) further discourages belly-fat accumulation. The result is selective loss of deep abdominal fat, with improvements in blood triglycerides as a downstream benefit.
Six linked mechanistic arms, most directly demonstrated in pivotal trials. First — GHRH-R agonism on anterior-pituitary somatotrophs restores pulsatile GH secretion with native-GHRH-like potency. Second — GH drives hepatic IGF-1/IGFBP-3 synthesis (mean IGF-1 rose ~108 ng/mL vs. −7 with placebo). Third — preferential lipolysis of visceral over subcutaneous fat via hormone-sensitive lipase activation. Fourth — GH-mediated inhibition of adipose 11β-HSD-1, lowering local cortisol regeneration. Fifth — secondary metabolic improvement (triglycerides −37 mg/dL, adiponectin ↑), largely VAT-mediated. Sixth — hypothesized neuroendocrine/cognitive effects with mixed trial data.
Tesamorelin is a single-receptor agonist with a defined, replicated mechanism — the opposite of the pleiotropic peptides elsewhere in this atlas. GHRH-R activation (Gs-GPCR) drives adenylyl cyclase → cAMP → PKA → CREB phosphorylation → GH gene transcription and somatotroph exocytosis; the trans-3-hexenoyl cap confers DPP-IV resistance. GH binds the GH receptor (JAK2/STAT5) on hepatocytes → IGF-1 transcription → IGF-1R/PI3K-Akt and MAPK/ERK signaling across target tissues. VAT selectivity is attributed to higher visceral-adipocyte GH-receptor density, differential portal FFA flux, and GH-mediated 11β-HSD-1 suppression. The responder analysis (metabolic benefits concentrated in ≥8% VAT responders) supports a VAT-mediated, rather than direct lipid-pathway, mechanism for the metabolic co-benefits.
This is the core of the engine. Tesamorelin is unusual in this atlas because it has a real, FDA-approved, evidence-graded dosing label for one indication — alongside a wider speculative hypothesis layer for off-label uses. The two are kept rigorously separate below: Grade A protocols are taken directly from the prescribing information and pivotal trials; Grade B/D/P protocols are practice-pattern or trial-extrapolated models for off-label use and must not be read as guidelines. Each protocol is built to the same skeleton: starting dose, escalation cadence, dose ladder, maintenance target, cycle structure, reconstitution math, monitoring overlay, and explicit evidence grade. Working unit for the calculator is micrograms (µg).
1.28 mg SC once daily. No titration — fixed dose per label. Inject into the abdomen, rotating sites; avoid the navel, scar tissue, and bruised areas.1.28 mg SC daily indefinitely. Benefit requires continuous use — discontinuation produces rapid VAT rebound, so there is no planned taper or washout in the approved regimen.2 mg SC once daily, fixed. SC into the abdomen, rotating sites daily.1 mg SC (≈10 units on a U-100 syringe at 10 mg/mL) as a conservative start.1.5 mg SC (≈15 units) over weeks 2–4 if tolerated. Escalation gated on tolerability and IGF-1 staying within range.1 mg → 1.5 mg → 2 mg/day (10–20 units). The 2 mg ceiling mirrors the approved Egrifta SV dose; above 2 mg/day is unstudied and discouraged.1 mg SC once nightly — the exact SMART-trial regimen. Lower than the approved 1.28–2 mg VAT dose.~20 weeks in the SMART trial; IGF-1 rose to "young adult" levels (~117% increase) over that window. No long-term cognitive dosing data exist.2 mg SC once daily — the Phase II liver-fat trial dose.~26 weeks (6 months) in the pilot; median liver fat fell ~2.0% with tesamorelin vs. +0.9% placebo, and VAT fell −9.9% vs. +6.6%.Unlike most peptides in this atlas, tesamorelin's standard band is the FDA-approved dose. The low band reflects off-label / cognitive-trial starting doses; the high band is unstudied territory flagged grade P. Population PK found no significant weight or BMI effect on clearance — so weight-based dosing is not required and the table below is for educational completeness only.
| Band | Daily dose | µg/kg/day (70 kg ref) | Basis | Grade |
|---|---|---|---|---|
| Low | 500–1,000 µg (0.5–1 mg) | ~7–14 µg/kg | Off-label start; SMART cognitive trial used 1 mg. | B/D |
| Standard (approved) | 1,280–2,000 µg (1.28–2 mg) | ~18–29 µg/kg | FDA label — EGRIFTA WR™ 1.28 mg; Egrifta SV® 2 mg. | A |
| High (unstudied) | 2,000–4,000 µg (2–4 mg) | ~29–57 µg/kg | Not studied in RCTs; increased IGF-1/glucose risk — not recommended. | P |
| Body weight | Daily dose | µg/kg/day | Notes |
|---|---|---|---|
| 50 kg | 1,280 µg | 25.6 µg/kg | Fixed dose; lower-weight patients get higher µg/kg. |
| 60 kg | 1,280 µg | 21.3 µg/kg | Fixed dose. |
| 70 kg | 1,280 µg | 18.3 µg/kg | Reference (label basis). |
| 80 kg | 1,280 µg | 16.0 µg/kg | Fixed dose. |
| 90 kg | 1,280 µg | 14.2 µg/kg | ≈ mean trial patient weight (~88–90 kg). |
| 100 kg | 1,280 µg | 12.8 µg/kg | Fixed dose. |
| 110 kg | 1,280 µg | 11.6 µg/kg | Fixed dose. |
Weight-based adjustment is NOT required per FDA label; no dose-adjustment guidance exists for any weight range. No pediatric dosing exists — tesamorelin is contraindicated in children with open epiphyses (risk of linear-growth acceleration).
Because the approved dose is fixed, tesamorelin's "titration" is really a continue / hold / stop decision driven by IGF-1, glucose, efficacy, and hard safety stops. Grade A rules are drawn directly from the label; off-label rows are grade D.
| Trigger | Action | Rationale | Grade |
|---|---|---|---|
| IGF-1 persistently >3 SDS and poor VAT response | Hold / discontinue | Unknown long-term effects of sustained IGF-1 elevation; explicit FDA label guidance. | A |
| IGF-1 >3 SDS but robust VAT reduction | Discuss risk/benefit; consider dose reduction if off-label | Benefit may outweigh risk in the approved indication; no clear off-label guidance. | D |
| HbA1c ≥6.5% (new diabetes) without efficacy benefit | Discontinue | Hazard ratio 3.3 for new diabetes vs. placebo; FDA guidance. | A |
| Glucose intolerance with clear efficacy | Discuss risk/benefit; add glucose management | May continue with diabetes monitoring/therapy added. | D |
| Hypersensitivity (rash, urticaria, flushing, systemic) | Hard stop — discontinue | ~4% incidence; anaphylaxis risk. | A |
| Peripheral edema / carpal-tunnel symptoms | Monitor; hold if severe | Fluid retention is a GH-class effect; often self-limiting. | A |
| Active malignancy / recurrence | Hard stop — absolute contraindication | GH/IGF-1 are growth factors; potential tumor promotion. | A |
| Pregnancy | Hard stop — absolute contraindication | Hydrocephaly in rat offspring at clinical AUC multiples. | A |
| No VAT response after 6 months | Reassess; consider discontinuation | Effect is reversible; no benefit to justify continued risk exposure. | D |
Special populations — no PK data exist in renal/hepatic impairment, pediatric, or elderly groups; the approved label uses fixed dosing in adults regardless of these covariates. Acute critical illness (post-surgery, trauma, respiratory failure) is a relative contraindication extrapolated from GH-class mortality data.
Tesamorelin is one of the few peptides in this atlas with label-validated biomarkers. IGF-1 and glucose are FDA-mandated; VAT by CT is the trial gold standard; the remainder are partially validated surrogates or context-specific.
| Biomarker | Rationale | Timing | Validated? |
|---|---|---|---|
| IGF-1 (serum) | Direct PD marker; safety ceiling at >3 SDS. | Baseline + every 13–26 wk | ✅ Label |
| HbA1c / fasting glucose | Glucose-intolerance risk (HR 3.3 for new diabetes). | Baseline + every ~12 wk | ✅ Label |
| VAT (CT at L4-L5) | Primary efficacy endpoint in trials. | Baseline + 6 mo (trial setting) | ✅ Trial |
| Waist circumference | Inexpensive VAT surrogate. | Baseline + monthly | ⚠ Partial |
| Triglycerides / cholesterol / HDL | Metabolic co-benefit; tracks VAT response. | Baseline + 12–26 wk | ✅ Trial |
| IGFBP-3 | Interprets GH-axis status alongside IGF-1. | Baseline + 26 wk | ✅ Trial |
| Anti-tesamorelin antibodies | ~50% develop IgG; efficacy appears preserved. | Not standard of care | ⚠ Research |
| Fluid status / BP (edema, CTS) | GH-class fluid retention. | Each visit | ⚠ Clinical |
IGF-1 and glucose monitoring are explicitly required by the prescribing information; CT-VAT, lipids, and IGFBP-3 were trial endpoints rather than routine clinical practice. For off-label use the same bundle applies, with IGF-1 and glucose as the non-negotiable core.
For reference only. Not medical dosing advice. Tesamorelin is dosed in micrograms-to-milligrams (µg / mg). The approved doses are 1.28 mg (EGRIFTA WR™) and 2 mg (Egrifta SV®); other vial sizes reflect compounded off-label product. Verify purity, sterility, endotoxin, identity, and storage, and use only product from a licensed / verified source for any injection.
Tesamorelin is combined with other GH-axis and metabolic agents in off-label practice. No RCT has evaluated any of the combinations below in the off-label context — each is a mechanistic or clinical-reasoning model, not trial-validated. The defining engine rules: never combine two GHRH-class analogs (competitive receptor binding), watch for additive glucose intolerance and fluid retention, and suppress all combinations in the presence of active malignancy.
| Component | Primary mechanism | Evidence |
|---|---|---|
| Tesamorelin | GHRH-R agonism (pituitary) | Approved monotherapy (A) |
| Ipamorelin | GHS-R1a / ghrelin receptor (GHRP) | No human RCT (P) |
| Combination | Dual-axis GH amplification | Mechanistic only (D/P) |
| Component | Role | Added monitoring |
|---|---|---|
| Tesamorelin | VAT reduction · GH/IGF-1 axis | IGF-1 · HbA1c |
| Metformin | Insulin sensitizer | Renal function (eGFR) |
| Component | Role | Status |
|---|---|---|
| Tesamorelin | Metabolic · VAT reduction | Approved (A) |
| BPC-157 | Tissue repair · GI protection | Unapproved · preclinical (P) |
| Combination | Metabolic + recovery | No data (P) |
| Component | Mechanism | Note |
|---|---|---|
| Tesamorelin | GHRH-R agonist (44 AA) | Higher potency |
| Sermorelin | GHRH-R agonist (29 AA) | Same receptor — competes |
⛔ Absolute contraindication — malignancy & HPA-axis. Tesamorelin stimulates GH and IGF-1, both mitogenic growth factors — it is absolutely contraindicated in active malignancy, and any stacking combination is void in that setting; no co-peptide negates this risk. It also requires an intact hypothalamic-pituitary axis to work, so patients with hypopituitarism, prior pituitary surgery/tumor, head irradiation, or head trauma cannot respond appropriately and all stacks are inapplicable. Never combine tesamorelin with a second GHRH-class analog (sermorelin, CJC-1295) — competitive GHRH-R binding reduces, not increases, GH output. Additive glucose intolerance and fluid retention warrant added glucose and edema monitoring whenever a GHRP or GH-axis agent is layered on.
Tesamorelin's safety profile is unusually well-characterized for this atlas — drawn from controlled Phase III trials in ~740 treated patients rather than anecdote. The dominant signals are injection-site reactions, arthralgia, fluid retention, and a clinically important glucose-intolerance risk (hazard ratio 3.3 for new diabetes). The key unknowns are long-term: cardiovascular outcome data beyond 52 weeks were never established (a pivotal factor in the EMA rejection), and the consequences of sustained supraphysiologic IGF-1 (>3 SDS in 36% at 26 weeks) are uncharacterized.
Drawn from the FDA prescribing information — these are label-grade contraindications, not precautionary extrapolations.
| Condition / factor | Risk level | Applies to | Rationale |
|---|---|---|---|
| Active malignancy (any type) | Avoid | All use | GH/IGF-1 are growth factors with mitogenic potential — absolute contraindication. |
| Pregnancy | Avoid | All use | Hydrocephaly in rat offspring at clinical AUC multiples; fetal harm — absolute. |
| Hypothalamic-pituitary axis disruption | Avoid | All use | Hypopituitarism, pituitary surgery/tumor, head XRT/trauma — no GHRH-R signaling capacity; unpredictable effects. |
| Hypersensitivity to tesamorelin or mannitol | Avoid | All use | Anaphylaxis risk — absolute. |
| Acute critical illness | Caution | Systemic | Increased mortality in GH studies of acute critical illness — relative; consider discontinuation. |
| Poorly controlled / pre-existing diabetes | Caution | All use | Glucose-intolerance worsening; HR 3.3 for new diabetes — requires glucose monitoring and management. |
| History of malignancy (treated, stable) | Caution | All use | Risk of reactivation; individualized benefit-risk and specialist evaluation required. |
| Children / adolescents (open epiphyses) | Avoid | All use | Risk of linear-growth acceleration / excessive height — not indicated in pediatrics. |
| Competitive athlete / WADA testing pool | Avoid | All use | Banned under WADA S2 (Peptide Hormones, Growth Factors), in and out of competition — use is a doping violation. |
| Breastfeeding | Caution | All use | Unknown infant risk; HIV-transmission considerations per CDC guidance. |
IGF-1, fasting glucose / HbA1c, lipid panel; malignancy screen / history; pregnancy test if reproductive potential; confirm intact HPA axis. Baseline waist circumference ± CT-VAT in trial settings.
Fasting glucose / HbA1c (HR 3.3 for new diabetes). Fluid-status / edema / carpal-tunnel assessment each visit. Injection-site review and site rotation.
IGF-1 (± IGFBP-3). Persistent >3 SDS with poor VAT response → hold/discontinue; >3 SDS with good response → discuss risk/benefit.
Waist circumference ± CT-VAT; triglycerides / cholesterol-HDL ratio. No VAT response by 6 months → reassess continuation.
Monitor for relative adrenal insufficiency after initiation and dose changes (11β-HSD-1 interaction); increase glucocorticoid dose if symptomatic.
New malignancy or recurrence, pregnancy, systemic hypersensitivity, new diabetes without efficacy benefit, or severe fluid retention. Cancer screening per age/HIV guidelines throughout.
Tesamorelin's evidence base is among the strongest in this atlas: three Phase III RCTs totaling >800 patients underpin the FDA approval, with consistent ~15–18% VAT reduction vs. placebo and durable benefit to 52 weeks. Off-label use (NAFLD, cognition) rests on Phase II / exploratory data, and the cognitive signal is openly conflicting. The complete pivotal record, the off-label exploratory studies, and the long-term data gaps are summarized below.
Multicenter, randomized, double-blind, placebo-controlled trial in 412 HIV-infected adults with abdominal fat accumulation; tesamorelin 2 mg SC daily vs. placebo for 26 weeks. VAT fell −15.0% vs. +5% placebo by CT at L4-L5, with improved triglycerides and body image (PMID 18057338) — the foundational efficacy demonstration.
Pooled analysis of two Phase III RCTs (n=806) with 52-week extension. VAT −24 cm² (−15.4%) vs. +2 cm² placebo (P<0.001); triglycerides −37 mg/dL vs. +6; ~69% achieved ≥8% VAT reduction vs. 33% placebo. Patients re-randomized to placebo at 26 weeks showed VAT rebound — establishing that continued use is required (PMID 20554713).
Multicenter double-blind placebo-controlled RCT with safety extension (n=404); tesamorelin 2 mg SC daily vs. placebo for 26 weeks. VAT reduced ~18% from baseline vs. +2% placebo; body-image distress improved; generally well tolerated (PMID 20101189) — the companion pivotal trial.
Double-blind randomized placebo-controlled trial (n=50) in ART-treated HIV adults with abdominal fat; tesamorelin 2 mg SC daily × 26 weeks. Liver fat fell a median −2.0% vs. +0.9% placebo (MRS), and VAT −9.9% vs. +6.6% — the basis for off-label NAFLD interest (PMID 25003270).
Randomized double-blind placebo-controlled trial (n=152, ages 55–87, half MCI); tesamorelin 1 mg SC nightly × 20 weeks. Executive function improved in both groups vs. placebo and verbal memory improved in the MCI group; IGF-1 rose ~117% (PMID 22869065) — the positive cognitive signal.
Controlled study in persons with HIV and abdominal obesity. Tesamorelin reduced waist circumference but neurocognitive benefits did not significantly differ between groups; authors note no placebo arm and insufficient power as limitations (PMID 39813152) — directly tempering the SMART cognitive signal.
For the approved indication (HIV-associated lipodystrophy VAT reduction) the overall evidence grade is HIGH: three Phase III RCTs (>800 patients), consistent −15–18% VAT reduction vs. placebo, durable benefit to 52 weeks, and metabolic improvements supporting FDA approval with confidence. What remains uncertain is long-term: cardiovascular outcome data beyond 52 weeks (the EMA-rejection factor), consequences of sustained IGF-1 elevation, teratogenic/childbearing-potential data, and off-label evidence (non-HIV body composition, NAFLD, cognition) that is Phase II / exploratory at best — with cognition openly conflicting (positive Baker 2012, negative Ellis 2025). This is why the off-label protocols above are framed as a hypothesis layer while the approved protocols are grade A.
| Parameter | Tesamorelin | Sermorelin | CJC-1295 (no DAC) | Somatropin (rhGH) |
|---|---|---|---|---|
| Mechanism class | GHRH(1-44) analog + hexenoyl | GHRH(1-29) analog | GHRH(1-29) analog, modified | Recombinant GH (191 AA) — direct GHR agonist |
| Primary use | HIV lipodystrophy (VAT) | GH deficiency / off-label anti-aging | Off-label GH optimization | GH deficiency; Turner; PWS; off-label |
| Evidence tier | A (Phase III, FDA-approved) | D/C (no adult Phase III) | D/P (no Phase III) | A (multiple approved indications) |
| Pulsatility preserved? | ✅ Yes | ✅ Yes | ✅ Yes | ❌ No — flat exogenous GH |
| Half-life | ~11–38 min (SC) | ~10–20 min | ~30 min (no DAC) | ~15–20 min |
| VAT specificity | ✅ High — primary effect | Low | Low | Moderate |
| FDA status | ✅ Approved (HIV lipo) | ❌ Compounded only | ❌ Not approved | ✅ Multiple indications |
| WADA status | ❌ Banned (S2) | ❌ Banned (S2) | ❌ Banned (S2) | ❌ Banned (S2) |
| Diabetes risk | ⚠ HR 3.3 vs. placebo | Lower (pulsatile) | Lower (pulsatile) | ⚠ High (direct GH) |
| Human VAT evidence | 5+ RCTs, n=800+ | None | None | Limited specific data |