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BHuman cohort / observational

Testosterone Undecanoate

Nebido · Aveed · Andriol

Testosterone undecanoate (TU) is a long-chain fatty-acid ester of the natural androgen testosterone, marketed as long-acting intramuscular depot injections (Nebido, 1000 mg/4 mL in the EU; Aveed, 750 mg/3 mL in the US) and as oral capsules (Andriol). It is a bioidentical testosterone prodrug used clinically for testosterone-replacement therapy in men with diagnosed hypogonadism; it is also misused non-medically as an anabolic-androgenic steroid. The main risks are not liver toxicity (TU is not 17-alpha-alkylated) but rather: (1) erythrocytosis/polycythemia — a hematocrit rise driving blood viscosity and thrombotic risk, which is the most common treatment-limiting effect; (2) a rare but acute injection-specific reaction, pulmonary oil microembolism (POME) and anaphylaxis, from the oily vehicle entering the circulation; (3) profound, sometimes prolonged suppression of the body's own testosterone production and fertility (azoospermia); and (4) cardiovascular signals (atrial fibrillation, pulmonary embolism, acute kidney injury) seen in the large TRAVERSE trial even though overall major adverse cardiac events were non-inferior to placebo. This monograph leads with risk and monitoring. Any use should be under a physician with baseline and periodic bloodwork; self-directed use without clinical oversight carries meaningful, sometimes life-threatening risk. This is reference information, not medical advice or an endorsement of use.

Clinical readoutAAS · testosterone
Hepatic strainLow
CardiovascularNone
HPTA suppressionVery high
Half-life
4.8 wk
Route
Intramuscular deep inje…
Evidence
B
Active
Long-acting by design
4.8 wk9.6 wk14.4 wk19.1 wk23.9 wk
Illustrative single-compartment washout · each mark = one half-life · t½ ≈ Injectable depot: apparent terminal half-life is long due to slow release from the oily intramuscular depot — approximately 33-34 days for the 1000 mg (Nebido) formulation; the rate-limiting step is depot dissolution, not ester hydrolysis. Oral TU has a short effective half-life (a few hours) requiring multiple daily doses.
Pharmacology

Mechanism of action

Testosterone undecanoate is a prodrug: the undecanoic (C11) fatty-acid ester at the 17-beta position is cleaved by serum and tissue esterases to release free testosterone, the endogenous androgen. Testosterone binds the intracellular androgen receptor (AR), and the receptor-ligand complex translocates to the nucleus to modulate androgen-responsive gene transcription, driving anabolic effects on skeletal muscle and bone and androgenic effects on secondary sex characteristics. Testosterone is also a substrate for two amplifying/diversifying pathways: 5-alpha-reductase converts it to the more potent AR agonist dihydrotestosterone (DHT), and aromatase (CYP19) converts it to estradiol, which acts on estrogen receptors and mediates several downstream effects including bone maintenance and some feedback. Circulating testosterone exerts negative feedback on the hypothalamic-pituitary-testicular axis, suppressing GnRH, LH and FSH, which shuts down endogenous testicular testosterone production and spermatogenesis. The long undecanoate ester and oily depot vehicle slow release from the injection site, giving the prolonged pharmacokinetics.
Kinetics

Pharmacokinetics

Half-life

Injectable depot: apparent terminal half-life is long due to slow release from the oily intramuscular depot — approximately 33-34 days for the 1000 mg (Nebido) formulation; the rate-limiting step is depot dissolution, not ester hydrolysis. Oral TU has a short effective half-life (a few hours) requiring multiple daily doses.

Active duration

Long-acting by design. In hypogonadal men, a single 750 mg (Aveed) injection maintains serum testosterone in the physiologic range across roughly a 10-week interval; Nebido 1000 mg regimens are typically dosed at intervals of about 10-14 weeks after a loading dose (per the reviewed labeled regimens, always risk-attached and clinician-set). Reported clinical injection schedules: loading at week 0 and week 4-6, then maintenance every ~10-14 weeks.

Route

Intramuscular deep injection (gluteal) of an oily depot for Nebido/Aveed; also available as oral capsules (Andriol) absorbed largely via intestinal lymphatics, partly bypassing hepatic first-pass metabolism. This monograph focuses on the injectable depot.

Metabolism & clearance

After esterase cleavage, liberated testosterone follows normal androgen metabolism: 5-alpha-reduction to DHT, aromatization to estradiol, and hepatic oxidation/conjugation to inactive metabolites (androsterone, etiocholanolone, glucuronide/sulfate conjugates) excreted predominantly renally in urine. Note on monitoring/washout: because of the multi-week depot half-life, serum testosterone and hematocrit remain elevated for weeks to months after the last injection, so any adverse effect (e.g., high hematocrit) cannot be rapidly reversed by stopping — this is a safety consideration, not guidance for evading detection.

For monitoring and washout planning, not drug-test evasion.

Reported effects

Physiological & performance effects

  • Raises serum testosterone from hypogonadal into the physiologic young-adult male range with a single injection maintained across a multi-week interval (750 mg Aveed regimen; 1000 mg Nebido/T4DM regimen)
  • Improves sexual function (libido, erectile parameters) in hypogonadal men in pooled randomized-trial meta-analysis of testosterone therapy
  • Favorable changes in body composition: increased lean/muscle mass and decreased fat mass
  • Increases bone mineral density and improves skeletal microarchitecture in at-risk older men
  • Increased hand-grip strength in the T4DM randomized trial
  • Reduced progression to type 2 diabetes over 2 years versus placebo when added to a lifestyle program (T4DM), in men with impaired glucose tolerance and low-normal testosterone
  • Suppresses endogenous LH/FSH and testicular testosterone output and spermatogenesis (an intended pharmacologic consequence that is also an adverse/fertility effect)
Safety

Adverse effects by system

Cardiovascular

In the large TRAVERSE RCT (transdermal testosterone in hypogonadal men at high cardiovascular risk), overall major adverse cardiac events were non-inferior to placebo, but higher incidences of atrial fibrillation, pulmonary embolism, and acute kidney injury were observed in the testosterone arm. The injectable-TU RCT (T4DM) reported no clear cardiovascular signal but was not powered for cardiovascular outcomes. Testosterone-induced erythrocytosis raises blood viscosity and is a plausible contributor to thrombotic risk.

Hepatic

Injectable testosterone undecanoate is an ester of bioidentical testosterone and is not 17-alpha-alkylated, so it does not carry the cholestatic/hepatocellular hepatotoxicity characteristic of oral 17-alpha-alkylated anabolic steroids. Clinically significant hepatotoxicity is not a recognized feature of injectable TU in the human literature reviewed.

Endocrine / HPTA

Marked suppression of the hypothalamic-pituitary-testicular axis: LH and FSH fall, endogenous testosterone production is shut down, and spermatogenesis is impaired, ranging from oligospermia to azoospermia. Testicular atrophy can occur. Recovery after cessation is variable and can be slow.

Reproductive

Infertility from suppressed spermatogenesis (oligospermia to azoospermia) via HPTA shutdown; documented in men receiving testosterone replacement, with cases of hypogonadotropic hypogonadism and impaired semen parameters. Testicular volume reduction can occur. Fertility recovery after stopping is variable.

Neuropsychiatric

Testosterone therapy can affect mood and irritability; supraphysiologic androgen exposure is associated with mood disturbance/aggression in the broader AAS literature. No adequate TU-specific human trial data on serious neuropsychiatric outcomes was identified, so this is stated conservatively.

Renal

Acute kidney injury was reported more frequently in the testosterone arm of the TRAVERSE trial. No established chronic direct nephrotoxicity of TU itself is documented in the reviewed human literature; the AKI signal warrants monitoring and clinician attention.

Hematologic

Erythrocytosis/polycythemia is the most common and often treatment-limiting adverse effect: hematocrit and hemoglobin rise dose- and time-dependently. In the T4DM RCT a hematocrit >54% safety trigger occurred in ~22% of the testosterone group versus ~1% of placebo; a long-term observational cohort reported ~40% of TU-treated patients experienced polycythemia over extended follow-up. Elevated hematocrit increases blood viscosity and thrombotic risk.

Dermatologic

Androgenic skin effects consistent with the drug class — acne and oily skin — occur; injection-site pain/reactions are reported with the intramuscular depot. Class-based male-pattern hair changes are expected via DHT but were not quantified in the TU-specific sources retrieved.

Recovery

HPTA suppression & recovery

Suppression: Severe

Exogenous TU strongly suppresses LH/FSH and endogenous testosterone via negative feedback, commonly producing oligospermia or azoospermia. Recovery of the hypothalamic-pituitary-testicular axis and spermatogenesis after stopping is variable and can be slow — sometimes months and occasionally longer, prolonged further by the multi-week depot half-life. TU is contraindicated in men who wish to preserve fertility. Any HPTA-recovery or fertility-preservation plan must be individualized and directed by an endocrinologist or reproductive specialist; where pharmacologic assistance is used, published cases describe clinician-supervised single-agent approaches (e.g., a single selective estrogen receptor modulator such as clomiphene, or hCG), but these are off-label, must not be self-directed, and are outside the scope of this reference. This monograph does not describe multi-agent or dual-SERM protocols. Defer all recovery decisions to a physician.

Bloodwork & vitals

Monitoring

Recommended labs & checks
Serum total testosterone (trough/interval level to confirm physiologic range, not supraphysiologic)Hematocrit and hemoglobin (the key safety lab — at baseline, ~3-6 months, then periodically; act on hematocrit >54%)Prostate-specific antigen (PSA) and digital rectal exam per age-appropriate prostate surveillanceEstradiol if gynecomastia or symptomsLipid panelLiver and renal function panel (baseline and periodic)LH/FSH and semen analysis if fertility is a concern

Cadence: Baseline before starting; reassess at approximately 3 and 6 months (including a trough testosterone and hematocrit), then at least annually once stable. Hematocrit should be checked whenever dose or interval changes and if symptoms of hyperviscosity appear. Because of the long depot half-life, elevations resolve slowly, so proactive monitoring matters.

Warning signs — seek care
  • Symptoms of pulmonary oil microembolism during or right after injection: cough, urge to cough, shortness of breath, throat tightening, chest pain, dizziness, sweating, fainting — seek emergency care
  • Signs of anaphylaxis after injection: hives, swelling, difficulty breathing — emergency
  • Signs of thrombosis/high hematocrit: severe headache, visual changes, chest pain, leg swelling/pain, sudden breathlessness (possible pulmonary embolism), stroke symptoms
  • Palpitations or irregular heartbeat (atrial fibrillation)
  • Reduced urine output or swelling (possible acute kidney injury)
  • New or worsening urinary obstruction; breast lumps or tenderness
  • Marked mood change, aggression, or worsening sleep apnea
Do not use if

Contraindications

  • Known or suspected prostate cancer or male breast cancer (androgen-sensitive malignancies)
  • Men desiring current or near-term fertility (suppresses spermatogenesis, can cause azoospermia)
  • Pre-existing erythrocytosis / elevated hematocrit (e.g., hematocrit above ~50-54%) until corrected
  • History of hypersensitivity to testosterone undecanoate or to the oily vehicle (castor oil/benzyl benzoate)
  • Untreated severe obstructive sleep apnea, severe untreated lower-urinary-tract symptoms/BPH
  • Pregnancy and women (contraindicated; risk of virilization; teratogenic)
  • Uncontrolled or poorly managed heart failure; caution with recent cardiovascular or thromboembolic events given AF/PE/AKI signals
  • Severe hepatic, renal, or cardiac insufficiency (general labeled caution)
Combinations

Interaction profile

  • MajorWith another anabolic steroid: Additive cardiovascular strain
  • MajorWith a thermogenic stimulant: Additive cardiovascular strain
  • ModerateWith thyroid hormone: Additive cardiovascular strain
  • ModerateWith growth hormone: Additive cardiovascular strain
  • MajorWith another anabolic steroid: Blood / clotting
  • MajorWith a clot-promoting SERM: Blood / clotting
  • ModerateWith an aromatase inhibitor: Hormonal
  • ModerateWith an anabolic steroid: Hormonal
  • ContraindicatedWith DNP: Additive cardiovascular strain

Check a specific combination in the interaction checker.

Harm reduction

Reducing harm & when to stop

  • This information is educational and not an endorsement of use or medical advice; testosterone therapy should be undertaken only under a physician who has confirmed a genuine clinical indication.
  • Get baseline bloodwork before starting and periodically thereafter — at minimum hematocrit/hemoglobin, total testosterone, PSA, lipids, and liver/renal panels; the single most important routine lab is hematocrit.
  • If hematocrit rises above ~54%, stop and seek medical review — options a clinician may use include dose reduction, lengthening the interval, or therapeutic phlebotomy; do not self-manage.
  • The intramuscular depot must be injected slowly and deeply by a trained person; POME and anaphylaxis can occur during or immediately after injection. Injections should be given where the patient can be observed and emergency care is available, and the patient should be watched for cough, breathlessness, chest tightness, dizziness or fainting for a period afterward.
  • Because of the multi-week half-life, adverse effects (high hematocrit, mood, blood pressure) resolve slowly after stopping — you cannot quickly reverse them, so prevention and monitoring matter more than with short-acting agents.
  • Do not use if you want to father children in the near term — TU suppresses sperm production and can cause azoospermia; discuss fertility preservation with a specialist beforehand.
  • Seek emergency care for: sudden breathlessness or chest pain (possible pulmonary embolism), stroke symptoms, fainting or severe cough during/after an injection, or palpitations.
  • Any plan to stop and recover natural testosterone or fertility must be directed by an endocrinologist; do not attempt self-directed recovery protocols.
  • Men with heart disease, prior clots, prostate concerns, or sleep apnea should have these evaluated and monitored, given the atrial-fibrillation, pulmonary-embolism, AKI, and prostate signals.
Evidence

Citations (11)

Every clinical claim above is tied to a primary source. Overall evidence grade B — graded to the best available evidence for its core claims.

  1. 01

    Testosterone undecanoate is a long-acting injectable testosterone ester (Nebido) for male hypogonadism with a long depot terminal half-life (~33-34 days for the 1000 mg formulation) and slow release from the oily depot.

    ReviewNebido: a long-acting injectable testosterone for the treatment of male hypogonadism.PMID 16086661 ↗

  2. 02

    TU is a long-acting injectable that can be administered about four times per year to produce stable physiologic testosterone levels; convenient dosing and favorable PK/safety profile.

    ReviewTestosterone undecanoate in the treatment of male hypogonadism.PMID 20642374 ↗

  3. 03

    A 750 mg intramuscular TU regimen (weeks 0, 4, 14) maintains serum testosterone in the normal young-adult male range over an ~10-week interval; hematocrit, hemoglobin and PSA rose from baseline over 24 weeks.

    CohortLong acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study.PMID 18930255 ↗

  4. 04

    Injectable TU 1000 mg every 3 months over 2 years reduced progression to type 2 diabetes vs placebo (RR 0.59) and improved 2-h glucose; a hematocrit >54% safety trigger occurred in ~22% of the testosterone group vs ~1% of placebo.

    RCTTestosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.PMID 33338415 ↗

  5. 05

    Long-term TU treatment raises hematocrit over time; ~40% of TU-treated patients experienced polycythemia during extended follow-up in an observational cohort.

    CohortLong-term testosterone undecanoate treatment in the elderly testosterone deficient male: An observational cohort study.PMID 34743411 ↗

  6. 06

    Testosterone therapy improves sexual function and body composition in hypogonadal men (pooled randomized-trial meta-analysis), with effects evident for injectable and transdermal preparations.

    Meta-analysisPharmacological management of late-onset hypogonadism.PMID 29505313 ↗

  7. 07

    Testosterone-replacement therapy was non-inferior to placebo for major adverse cardiac events (HR 0.96, 95% CI 0.78-1.17) in high-CV-risk hypogonadal men, but atrial fibrillation, pulmonary embolism, and acute kidney injury were more frequent with testosterone.

    RCTCardiovascular Safety of Testosterone-Replacement Therapy.PMID 37326322 ↗

  8. 08

    Pulmonary oil microembolism (POME) and anaphylaxis are recognized injection-specific risks of intramuscular TU (Aveed); postmarketing analysis found a spontaneously reported POME rate of <0.1% per injection, most events resolving quickly, with injection technique a contributing factor.

    Case seriesOccurrence of Pulmonary Oil Microembolism After Testosterone Undecanoate Injection: A Postmarketing Safety Analysis.PMID 32184081 ↗

  9. 09

    Exogenous testosterone suppresses the HPT axis and spermatogenesis, causing oligospermia to azoospermia and infertility; testosterone is contraindicated in men wishing to preserve fertility, and recovery of spermatogenesis after cessation is variable.

    Case series[Risk of Male Infertility Due to Testosterone Replacement Therapy for Late-Onset Hypogonadism (LOH)].PMID 33271659 ↗

  10. 10

    Testosterone modulates erythrocytosis and cardiovascular endothelial/smooth-muscle function; injectable TU raises hematocrit and is associated with slow recovery of the hypothalamo-pituitary-testicular axis.

    ReviewTestosterone and type 2 diabetes prevention: translational lessons from the T4DM study.PMID 37227171 ↗

  11. 11

    In the T4DM trial, 2-year injectable testosterone undecanoate treatment was associated with favourable changes in body composition, hand-grip strength, bone mineral density, and skeletal microarchitecture in at-risk older men, alongside reduced progression to type 2 diabetes.

    ReviewTestosterone and type 2 diabetes prevention: translational lessons from the T4DM study.PMID 37227171 ↗

Last reviewed 2026-07-06 · Verified against PubMed · Educational, not medical advice