Testosterone Replacement Therapy
Testosterone replacement therapy (TRT) is the standard treatment for symptomatic men with confirmed testosterone deficiency (TD). FDA-approved indications are limited to primary hypogonadism (testicular failure) and hypogonadotropic hypogonadism from established hypothalamic-pituitary disease.[1][2] The safety landscape has been fundamentally reshaped by the TRAVERSE trial (2023, NEJM, n = 5,246) establishing cardiovascular non-inferiority, and by the 2025 NEJM review that reframes the benefit–risk conversation around consistent benefit for libido, body composition, bone density, and anemia alongside a narrower list of genuine concerns — erythrocytosis, pulmonary embolism, atrial fibrillation, and (unexpectedly) clinical fractures.[2][3]
For related classes, see PDE5 inhibitors, Intracavernosal injection agents, and Androgen adjuncts.
Diagnosis — confirm the biochemical defect before prescribing
Both the AUA and Endocrine Society define testosterone deficiency as total testosterone (TT) <300 ng/dL (AUA) or <264 ng/dL (Endocrine Society) on two separate morning fasting measurements, combined with compatible clinical symptoms.[1][4]
Core diagnostic workup
| Test | Purpose |
|---|---|
| Total testosterone (fasting, morning, same lab / method) | Initial screen[4] |
| Free testosterone (equilibrium dialysis or calculated) | Confirmatory when TT is borderline or when SHBG-altering conditions are present (obesity, aging, liver disease, thyroid disorders)[1] |
| LH and FSH | Primary (elevated) vs secondary (low / normal) hypogonadism[5] |
| Prolactin | If LH is low or low-normal — evaluate for pituitary adenoma[5] |
| Secondary-cause workup | Pituitary MRI (hyperprolactinemia, panhypopituitarism), iron studies (hemochromatosis), karyotype (Klinefelter)[6] |
When to measure testosterone even without classic sexual symptoms[4]
Unexplained anemia, low bone density, type 2 diabetes, chemotherapy or radiation exposure, HIV/AIDS, chronic opioid use, infertility, pituitary dysfunction, chronic corticosteroids.
Validated symptom questionnaires (ADAM, AMS) are NOT recommended as screening tools or as surrogates for laboratory testing.[4]
Indications and contraindications
Indication: symptomatic men with confirmed low TT, after shared decision-making regarding benefits and risks.[1]
Absolute and near-absolute contraindications[1][6][7]
| Category | Specific |
|---|---|
| Oncologic | Breast cancer; metastatic prostate cancer |
| Prostate evaluation pending | Palpable prostate nodule or induration without urologic evaluation; PSA >4 ng/mL (>3 ng/mL in high-risk men) without urologic evaluation |
| Hematologic | Hematocrit >48% (>50% at high altitude) — relative; thrombophilia, active VTE |
| Respiratory | Untreated severe OSA |
| LUTS | IPSS >19 (severe) |
| Cardiovascular | Uncontrolled heart failure; MI or stroke within the last 6 months (EMAS extends to 4 months)[7] |
| Fertility | Near-term fertility desire — TRT suppresses spermatogenesis (see below)[1][8] |
Formulations — detailed comparison
| Formulation | Typical dose | Key features |
|---|---|---|
| Testosterone cypionate / enanthate (IM, short-acting) | 50–100 mg IM q1–2 wk (or 100–200 mg q2 wk) | Inexpensive, widely available; supraphysiologic peaks and symptom troughs; monitor mid-interval TT[5][6] |
| Testosterone undecanoate (IM, long-acting — Aveed) | 750 mg IM, repeat at 4 wk, then every 10 wk | Only 4–5 injections/year; FDA boxed warnings for pulmonary oil microembolism (POME), anaphylaxis, and MACE; requires 30-min post-injection observation in a healthcare setting[5] |
| Testosterone gel 1.62% (AndroGel) | 40.5 mg (2 pumps) to shoulders / upper arms daily; range 20.25–81 mg | Steady-state levels; secondary transfer risk to women and children — wash hands, cover application site[9] |
| Other gels | 1% gel 50–100 mg; 2% gel 40–70 mg; axillary solution 60 mg | Similar transfer-risk considerations[6] |
| Transdermal patch | 2.5 or 5 mg nightly | Recreates circadian rhythm; skin irritation is the dominant discontinuation driver[5] |
| Subcutaneous pellets (Testopel) | 600–900 mg in-office implantation q3–6 mo | Stable levels, no daily maintenance; extrusion 5–10%, infection, difficult removal[5][10] |
| Oral undecanoate (Jatenzo) | 237–396 mg PO BID with food | First U.S.-approved oral (2019); self-emulsifying delivery bypasses hepatic first-pass; MACE boxed warning; can raise BP[5][6] |
| Oral — Tlando (225 mg BID), Kyzatrex (100–200 mg BID) | Per product | Additional oral options[6] |
| Nasal gel (Natesto) | 11 mg per nostril, 2–3×/day | Less suppression of spermatogenesis than other routes (pulsatile delivery, rapid clearance); nasal irritation, frequent dosing[6][10] |
| Buccal (Striant) | 30 mg bioadhesive tablet BID to the gum above incisor | Gum-related AEs in ~16%[6] |
Selection principles: injection for cost and efficacy; gel for steady physiology (watch transfer); pellets for adherence-challenged men; undecanoate oral / IM for infrequent dosing at the cost of boxed warnings; Natesto when fertility preservation matters alongside TRT.
Treatment goals and monitoring
Target range: mid-normal (450–600 ng/dL) per the 2025 Eur Urol review, or 300–900 ng/dL per Endocrine Society.[1][11]
Endocrine Society monitoring protocol[1]
| Parameter | Timing | Action thresholds |
|---|---|---|
| Serum testosterone | 3–6 mo, then annually | Adjust to mid-normal; sampling timing varies by formulation |
| Hematocrit | Baseline, 3–6 mo, then annually | If >54%, stop therapy; evaluate for hypoxia / OSA; restart at reduced dose |
| PSA | Baseline (age ≥40), 3–12 mo, then per screening guideline | Urology referral if PSA increase >1.4 ng/mL in 12 mo, confirmed PSA >4 ng/mL, or prostatic abnormality |
| DRE | Baseline, 3–12 mo, then per screening guideline | Refer for abnormality |
| BMD (DXA) | After 1–2 y in men with osteoporosis | Assess response |
| Symptoms and AEs | Every visit | Clinical response and formulation-specific effects |
The 2025 Eur Urol review recommends follow-up at 3 months and every 6–12 months thereafter.[11]
Benefits
Sexual function
Consistent improvement in libido and sexual activity. Effect on erectile function is small but statistically significant (SMD 0.16–0.27).[1][12] The 2025 NEJM review is explicit: TRT may not be effective if the main symptom is ED.[3] The Cochrane review (Lee 2024) concluded TRT produces little to no clinically important difference in erectile function vs placebo.[13] Adding testosterone to an optimized PDE5i regimen has not been shown to further improve erectile function in RCTs.[1] See PDE5 inhibitors.
Body composition
Consistently increases lean mass and decreases fat mass. Buratto 2023 meta-analysis (16 RCTs) — significant gains in hip BMD and total lean mass at 6 months; effects less clear at 12 months.[14]
Bone mineral density
Increases areal and volumetric BMD at spine and hip; improves cortical density and thickness.[1][15]
The TRAVERSE fracture substudy paradox: Snyder 2024 reported a 43% increase in clinical fractures with testosterone (3.8% vs 2.8% over 3 years) — predominantly ankle, wrist, and rib fractures, plausibly related to increased physical activity rather than bone deterioration.[16] This result is unexplained by BMD data and counsels caution in framing TRT as a bone-health intervention.
Anemia
TRT corrects unexplained anemia in hypogonadal men; significantly greater proportion achieved hemoglobin increments >1 g/dL in the TTrials.[1]
Mood and energy
Slight improvements in depressive symptoms, mood, and energy; effect sizes are small and not consistently significant across trials.[1][3]
Glycemic outcomes — the T4DM / TRAVERSE contrast
- T4DM (Wittert 2021, n = 1,007) — 2 years of testosterone undecanoate + a structured lifestyle program reduced progression to T2D by 40% (RR 0.59) in overweight men with IGT, independent of baseline testosterone[17]
- TRAVERSE diabetes substudy (Bhasin 2024) — testosterone gel without a structured lifestyle program showed no significant difference in prediabetes-to-diabetes progression and no glycemic improvement in established T2D[18]
- Interpretation: the metabolic benefits of testosterone appear to require a concurrent lifestyle intervention — TRT is not a diabetes drug on its own[19]
Cardiovascular safety — TRAVERSE
TRAVERSE 2023 (Lincoff, NEJM, n = 5,246 men 45–80 y with hypogonadism and established or high CV risk) is the first adequately powered RCT of CV safety:[2]
| Endpoint | Testosterone | Placebo | Interpretation |
|---|---|---|---|
| MACE (primary) | 7.0% | 7.3% | Non-inferior; HR 0.96 (95% CI 0.78–1.17; p < 0.001 for non-inferiority) |
| Pulmonary embolism | 0.9% | 0.5% | Higher on testosterone |
| Atrial fibrillation | 3.5% | 2.4% | Higher on testosterone |
| Acute kidney injury | 2.3% | 1.5% | Higher on testosterone[5] |
| Clinical fractures | 3.8% | 2.8% | Higher on testosterone[16] |
| CV death, MI, stroke, prostate cancer, LUTS | No increase | — | — |
The Androgen Society 2024 position paper concluded that it has been "conclusively determined" that TRT does not increase heart attack, stroke, or CV death, based on TRAVERSE plus 2 additional large RCTs, multiple smaller RCTs, several large observational studies, and 19 meta-analyses.[20]
Genuine residual signals: pulmonary embolism, atrial fibrillation, and the unexplained fracture signal. Counsel accordingly.
Prostate safety
Prostate cancer risk
AUA 2018 — Strong Recommendation, Grade B: clinicians should inform patients of the absence of evidence linking TRT to prostate cancer development.[4]
- TRAVERSE prostate substudy (Bhasin 2023) — PCa incidence 0.46% (T) vs 0.42% (placebo); high-grade PCa rare in both arms[21]
- Baik 2025 Medicare cohort (n = 546,964) — TRT was associated with 16% reduction in PCa hazard (HR 0.84)[22]
- García-Becerra 2026 meta-analysis of 41 RCTs (n = 11,161) — no statistically significant increase in PCa events (OR 0.88)[23]
TRT after prostate cancer
The AUA states there is inadequate evidence to quantify the risk-benefit ratio in men with PCa history (Expert Opinion).[4] Retrospective evidence increasingly supports cautious use in selected men with low-to-intermediate-risk disease on active surveillance or after definitive treatment (RP or radiation) with stable PSA.[24][25][26]
Saturation model rationale: androgen-receptor-mediated prostate growth plateaus at relatively low testosterone concentrations, so raising testosterone from hypogonadal to mid-normal ranges should not drive incremental tumor growth.[24][27]
BPH / LUTS
TRT has not been shown to worsen LUTS in RCTs; a large retrospective study found a modest 13% increase in BPH-diagnosis hazard — likely detection bias from intensified follow-up.[3][22]
Erythrocytosis — the most common dose-limiting AE
Highest risk with injectable formulations and in older men.[1][6] In T4DM, hematocrit >54% was triggered in 22% of testosterone-treated men (vs 1% placebo).[17]
Endocrine Society protocol: if hematocrit >54%, stop therapy, evaluate for hypoxia and OSA, and reinitiate at a reduced dose once hematocrit is safe.[1] Switching from injectable to transdermal or to Jatenzo reliably lowers the erythrocytosis signal when therapy must be continued.
Fertility — exogenous TRT suppresses spermatogenesis
AUA / ASRM Male Infertility Guideline — Clinical Principle: exogenous testosterone should not be prescribed to men interested in current or future fertility.[8]
Recovery after discontinuation: two-thirds recover sperm within 6 months; ~10% may not recover until the second year; recovery is not guaranteed in previously infertile men.[4]
Fertility-preserving alternatives[28][29][30][10]
| Agent | Mechanism | Typical dosing | Key features |
|---|---|---|---|
| Clomiphene citrate | SERM — blocks estrogen negative feedback → ↑ GnRH/LH/FSH → ↑ endogenous testosterone | 25–50 mg PO daily or every other day | Off-label; preserves spermatogenesis; inexpensive; oral |
| hCG | LH analog → stimulates Leydig cells | 1,000–3,000 IU SC 2–3×/week | Maintains intratesticular testosterone; combine with FSH analog for hypogonadotropic hypogonadism |
| Enclomiphene | Pure trans-isomer of clomiphene | Under investigation | Potentially fewer estrogenic AEs than clomiphene |
| Nasal testosterone (Natesto) | Pulsatile delivery + rapid clearance | 11 mg per nostril 2–3×/day | May have less HPT suppression than other TRT routes; limited fertility data |
Habous 2018 RCT (n = 282 hypogonadal men) — clomiphene, hCG, and combination therapy were equally effective at restoring testosterone (~223% increase), with combination producing the greatest symptom improvement.[30]
See Androgen adjuncts for the full fertility-preserving armamentarium.
Special populations
Older men — age-related decline vs pathologic hypogonadism
The 2025 NEJM review — benefit most likely in men with unequivocal hypogonadism (TT <200 ng/dL with classic symptoms); marginal in age-related decline without consistent symptoms.[3] EMAS position statement 2023 — offer TRT in symptomatic older men with confirmed low testosterone only after explaining uncertainties about long-term safety, and prefer short-acting transdermal preparations for initiation.[7]
Obesity
The most common cause of functional hypogonadism. Weight loss through lifestyle modification is first-line — it raises endogenous testosterone. T4DM showed testosterone augmented a structured lifestyle program, but TRT for diabetes prevention in men without pathologic hypogonadism is premature.[7][11][17]
Cancer survivors (non-prostate)
Per the NCCN Survivorship Guidelines, survivors of non-prostate malignancies who develop hypogonadism after radiation, chemotherapy, or surgery should be evaluated and treated for hormone-related symptoms.[31]
Evidence Summary
| Domain | Effect | Strength | Key source |
|---|---|---|---|
| Libido / sexual desire | Consistently improved | Strong | Multiple RCTs; Endocrine Society 2018[1] |
| Erectile function | Small improvement; inadequate if ED is dominant | Moderate (Cochrane-moderate) | Lee 2024[13] |
| Body composition | ↑ Lean mass, ↓ fat mass | Strong | Buratto 2023[14] |
| Bone mineral density | Increased at spine and hip | Strong | Ng Tang Fui 2021[15] |
| Clinical fractures | Unexpectedly increased (43%) | Moderate (single large RCT) | Snyder 2024 TRAVERSE[16] |
| Anemia | Corrected | Strong | TTrials / Endocrine Society[1] |
| Mood / depression | Slight improvement | Low–Moderate | 2025 NEJM review[3] |
| MACE | No increase (non-inferiority established) | Strong | TRAVERSE 2023[2] |
| Pulmonary embolism | Increased | Moderate | TRAVERSE[2] |
| Atrial fibrillation | Possibly increased | Low–Moderate | TRAVERSE[2] |
| Prostate cancer | No increase short–mid term | Strong | TRAVERSE; García-Becerra 2026[21][23] |
| Erythrocytosis | Dose-dependent; most common AE | Strong | Multiple sources[1][17] |
| Fertility (spermatogenesis) | Suppressed | Strong | AUA/ASRM 2024[8] |
Clinical Positioning
- Confirm TD biochemically before prescribing — two morning fasting TT values below threshold, with symptoms. Do not rely on ADAM / AMS questionnaires.[4]
- TRAVERSE has resolved the MACE question. TRT does not increase heart attack, stroke, or CV death in hypogonadal men with elevated CV risk.[2][20]
- Pulmonary embolism, atrial fibrillation, and the unexplained fracture signal remain genuine — counsel patients on these, particularly men with prior VTE, paroxysmal AF, or falls risk.[2][16]
- For isolated ED as the chief complaint, TRT is not the answer. Libido responds; erectile function does not meaningfully improve on its own, and adding T to PDE5i has not improved ED in RCTs.[3][13]
- Hematocrit is the dose-limiting lab. Monitor at 3–6 mo then annually; stop at >54%, investigate OSA, and either switch formulation or re-initiate at a lower dose.[1]
- Do not give TRT to men pursuing near-term fertility. Offer clomiphene 25–50 mg or hCG 1,000–3,000 IU 2–3×/wk instead, or combine — Habous 2018 showed equivalent testosterone recovery with preserved spermatogenesis.[30]
- Nasal testosterone (Natesto) is the one TRT formulation with a fertility-sparing argument — the pulsatile delivery and rapid clearance spare the HPT axis more than continuous routes.[10]
- Prostate cancer is not a contraindication to TRT in selected men with low/intermediate-risk disease on AS or post-definitive treatment with stable PSA — the saturation-model rationale, combined with Kaplan, Gibson 2025, and Santucci 2025 retrospective series, supports cautious use with explicit informed consent.[24][25][26]
- Obesity first — in men with functional hypogonadism from obesity, lifestyle modification is first-line before TRT; T4DM shows TRT can augment a structured program but does not replace it.[11][17]
- For older men with age-related decline and mild symptoms, prefer transdermal formulations and short courses with explicit reassessment windows — EMAS 2023 framing.[7]
- PSA increase >1.4 ng/mL in 12 months on TRT triggers urology referral regardless of absolute value; this is the most operationally useful monitoring rule.[1]
- Secondary transfer from gels is a real issue — patients must wash hands, cover the site, and avoid skin-to-skin contact with women and children until absorbed.[9]
See Also
- Androgen adjuncts — clomiphene, hCG, AI
- PDE5 inhibitors
- Intracavernosal injection agents
- Intraurethral alprostadil
References
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2. Lincoff AM, Bhasin S, Flevaris P, et al. "Cardiovascular safety of testosterone-replacement therapy (TRAVERSE)." N Engl J Med. 2023;389(2):107–117. doi:10.1056/NEJMoa2215025
3. Bhasin S, Snyder PJ. "Testosterone treatment in middle-aged and older men with hypogonadism." N Engl J Med. 2025;393(6):581–591. doi:10.1056/NEJMra2404637
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17. Wittert G, Bracken K, Robledo KP, et al. "Testosterone 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." Lancet Diabetes Endocrinol. 2021;9(1):32–45. doi:10.1016/S2213-8587(20)30367-3
18. Bhasin S, Lincoff AM, Nissen SE, et al. "Effect of testosterone on progression from prediabetes to diabetes in men with hypogonadism: a substudy of the TRAVERSE randomized clinical trial." JAMA Intern Med. 2024;184(4):353–362. doi:10.1001/jamainternmed.2023.7862
19. Grossmann M, Wittert GA. "Testosterone in prevention and treatment of type 2 diabetes in men: focus on recent randomized controlled trials." Ann N Y Acad Sci. 2024;1538(1):45–55. doi:10.1111/nyas.15188
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23. García-Becerra CA, Arias-Gallardo MI, Juárez-García JE, et al. "Cardiovascular and prostate cancer risk associated to testosterone replacement therapy — a systematic review and meta-analysis of 41 randomized controlled trials." Int J Impot Res. 2026. doi:10.1038/s41443-026-01237-4
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29. American Society for Reproductive Medicine. "Management of nonobstructive azoospermia: a committee opinion." Fertil Steril. 2018;110(7):1239–1245. doi:10.1016/j.fertnstert.2018.09.012
30. Habous M, Giona S, Tealab A, et al. "Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study." BJU Int. 2018;122(5):889–897. doi:10.1111/bju.14401
31. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: survivorship. Updated 2026-04-08.