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Testosterone Replacement Therapy

Testosterone replacement therapy (TRT) is the standard treatment for symptomatic men with confirmed testosterone deficiency (TD). For AndroGel 1.62%, the FDA label indicates replacement therapy in males with primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism (congenital or acquired), including gonadotropin/LHRH deficiency or pituitary-hypothalamic injury.[1][2][9] In TRAVERSE (2023), daily testosterone gel was noninferior to placebo for major adverse cardiovascular events over a mean 33.0 months in 5,246 men aged 45–80 with symptoms, two low testosterone tests, and established or high cardiovascular risk; pulmonary embolism and atrial fibrillation were observed more often with gel.[2] A 2025 review weighs benefits for libido, body composition, bone density, and anemia against risks including erythrocytosis and clinical fractures.[1][3][15][54]

For related classes, see PDE5 inhibitors, Intracavernosal injection agents, and Androgen adjuncts.

Diagnosis — confirm the biochemical defect before prescribing​

The AUA uses compatible symptoms and signs plus two early-morning total testosterone (TT) measurements, with <300 ng/dL as a reasonable diagnostic threshold; it does not require fasting. The Endocrine Society recommends two fasting morning measurements showing consistently low testosterone. The 264 ng/dL limit applies to CDC-standardized assays in healthy, nonobese young men; other assays and clinical settings require separate interpretation.[1][4]

The 300 ng/dL cutoff was derived from older men. A NHANES-based analysis of men 20–44 years old found age-specific middle-tertile cutoffs of 350–413 ng/dL depending on 5-year age band, all above 300 ng/dL, and a single-center retrospective series linked hypogonadal symptoms in men under 40 to a threshold nearer 400 ng/dL. Neither study establishes a treatment-response cutoff. The ICSM 2024 consensus says evidence is insufficient to adopt age-stratified total-T reference intervals; in symptomatic young men with borderline TT, repeat morning testing and assess SHBG/free T when indicated while applying the relevant guideline threshold.[41][42][51]

For men with borderline total T (roughly 300–350 ng/dL), the Lisbon 2018 International Consultation for Sexual Medicine frames treatment as a clinical judgment weighing benefits and risks rather than a binary threshold call, and describes a six-month empirical TRT trial for strongly suggestive symptoms despite values above its proposed threshold, with discontinuation at six months if symptoms do not improve. This is an expert-consensus position.[43]

Interpret SHBG correctly: low SHBG can produce low TT with normal free T, whereas high SHBG can conceal low free T behind normal or high TT. When TT is borderline or SHBG is altered, use equilibrium dialysis or a validated free-T calculation with TT, SHBG and albumin; do not use an inaccurate direct analog free-T assay.[1]

Core diagnostic workup​

TestPurpose
Total testosterone (morning; fasting per Endocrine Society)Confirm on a separate morning with a reliable assay[1][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 FSHPrimary (elevated) vs secondary (low / normal) hypogonadism[5]
ProlactinIf LH is low or low-normal, measure prolactin to evaluate a central cause; repeat a mild elevation before further evaluation for a pituitary lesion.[5][4]
EstradiolAUA : measure before TRT if breast symptoms or gynecomastia are present; for symptoms developing during treatment, Appendix C calls estradiol measurement optional while Table 7 recommends it.[4]
Secondary-cause workupPituitary MRI (hyperprolactinemia, panhypopituitarism), iron studies (hemochromatosis), karyotype (Klinefelter)[6]

In secondary hypogonadism, obtain pituitary MRI for total T <150 ng/dL with low or low-normal LH, persistent hyperprolactinemia, panhypopituitarism, or symptoms or signs of a sellar mass (such as new headache or visual-field loss).[1][4]

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]

Reasons to defer treatment or obtain specialist assessment[1][4]​

CategorySpecific
OncologicBreast cancer or known/suspected prostate cancer per product labels; distinguish this from individualized specialist discussion after definitive treatment[29][31]
Prostate evaluation pendingPalpable prostate nodule or induration without urologic evaluation; PSA >4 ng/mL (>3 ng/mL in high-risk men) without urologic evaluation
HematologicAUA: with baseline hematocrit >50%, clinicians should consider withholding treatment until the cause is investigated.[4] Endocrine Society identifies >48% (>50% at altitude) as a relative contraindication and recommends against starting with elevated hematocrit or thrombophilia .[1]
RespiratoryUntreated severe OSA; among 599 T4DM posttrial survey respondents, new OSA diagnosis during 2 years of IM testosterone undecanoate or placebo was reported by 10/316 (3%) versus 1/283 (0.4%).[50]
LUTSEndocrine Society recommends against starting testosterone therapy in men with severe LUTS ; evaluate and manage the cause of the symptoms before reconsidering treatment.[1]
CardiovascularEndocrine Society: uncontrolled heart failure or MI/stroke within 6 months. AUA 2018: defer starting for 3–6 months after a cardiovascular event . Follow product-specific blood-pressure warnings.[1][4]
FertilityCurrent or future fertility interest — exogenous testosterone should not be prescribed under AUA/ASRM guidance (see below). The AUA testosterone-deficiency guideline states it should not be prescribed to men currently trying to conceive and that its long-term effect on spermatogenesis should be discussed with men who want future fertility.[8][4]

Formulations — detailed comparison​

FormulationTypical doseKey features
Testosterone cypionate / enanthate (IM, short-acting)Endocrine Society starting regimens: 75–100 mg IM weekly or 150–200 mg every 2 weeks. Generic labels state a wider range for hypogonadal replacement: 50–400 mg every 2–4 weeks (enanthate: total doses above 400 mg/month generally not required)[52]Inexpensive, widely available; supraphysiologic peaks and symptom troughs; monitor mid-interval TT and titrate to response. Deep gluteal IM injection per label[1][37]
Testosterone enanthate autoinjector (SC — Xyosted)75 mg SC weekly into the abdomen; measure the 7-day trough after 6 weeks of dosing and again 6 weeks after each dose change; adjust in 25 mg steps (target trough 350–650 ng/dL; reduce if ≥650, increase if <350)Avoid IM or intravascular delivery. The former boxed blood-pressure warning was removed in 2025; blood pressure remains a Warnings and Precautions item (not recommended in uncontrolled hypertension). The Xyosted label reports depression and suicidal ideation or behavior, including completed suicide, during clinical trials and advises patients and caregivers to seek medical attention for new or worsening depression, anxiety, other mood changes, or suicidal thoughts or behavior.[38]
Testosterone undecanoate (IM, long-acting — Aveed)750 mg IM, repeat at 4 wk, then every 10 wk10-week maintenance interval after loading; Boxed warning for POME and anaphylaxis; the Aveed label specifies deep gluteus medius injection and aspiration for several seconds; if blood appears, discard the syringe and prepare a new dose, otherwise inject over 60–90 seconds; 30-minute observation after each injection and Aveed REMS enrollment remain required[29]
Testosterone gel 1.62% (AndroGel)40.5 mg (2 pumps) to shoulders / upper arms daily; range 20.25–81 mgSteady-state levels; boxed warning for secondary exposure (virilization of children); women and children should avoid contact with unwashed or unclothed application sites, and the gel is contraindicated in pregnant women. Apply to shoulders/upper arms only, wash hands, cover the site once dry[9]
Other gels / solutionsUse the individual product labelConcentrations, application sites, starting doses and titration tests are not interchangeable.[9]
Subcutaneous pellets (Testopel)Label: 150–450 mg SC every 3–6 months (2–6 pellets, 75 mg each); individualized higher regimens described in guidelines are off-label for TestopelLess easily adjusted than daily treatment; infection/extrusion and possible pellet removal require counseling. In a retrospective single-institution comparison of 281 implantation procedures (40 standard and 241 V) in 168 patients, the two-channel "V" technique had lower per-procedure extrusion (7.5% standard versus 0.8% V), infection (5% versus 1.2%) and significant pain without discontinuation (5% versus 1.2%) than the single-channel standard technique, with hematoma in 0% versus 1.2%.[1][33][44]
Oral undecanoate (Jatenzo)Start 237 mg BID with food; titrate 158–396 mg BID using product-specific testingLabel lists blood-pressure increases under Warnings and Precautions; the former boxed warning for blood-pressure increases was removed in 2025. Check testosterone 6 hours after the morning dose, at least 7 days after a change[28][30]
Other oral undecanoate — Tlando / KyzatrexFormulations are not dose-interchangeable. Tlando: fixed 225 mg (two 112.5 mg capsules) BID with food, no titration; check testosterone 3–4 weeks after starting (8–9 h after the morning dose) and stop if <300 or >1080 ng/dL. Kyzatrex: start 200 mg BID with food; range 100 mg each morning to 400 mg BID; measure serum testosterone at least 7 days after starting or changing dose, 3–5 h after the morning dose, and titrate by the product tableSame 2025 blood-pressure labeling as Jatenzo (boxed warning removed; Warnings and Precautions entry). For Tlando, check hematocrit approximately every 3 months in year 1 and every 6 months thereafter; check prolactin before treatment and at 3–4 months, and discontinue if it remains elevated.[32][39]
Nasal gel (Natesto)5.5 mg per nostril (11 mg total per dose), three times dailyOne actuation per nostril; 33 mg/day total. Nasal adverse effects; spermatogenesis may be suppressed[31]

Selection principles: injection for cost and efficacy; gel for steady physiology (watch transfer); pellets for adherence-challenged men; IM undecanoate for long dosing intervals with POME and anaphylaxis precautions; oral products require daily product-specific dosing and BP monitoring.[8][28]

FDA’s February 2025 class-wide labeling change added TRAVERSE results to all testosterone products, removed adverse-cardiovascular-outcome language from the boxed warning, retained the limitation of use for age-related hypogonadism, and added or strengthened blood-pressure warnings. Individual labels updated in 2025 (Xyosted, Jatenzo, Tlando, Kyzatrex) no longer carry a boxed blood-pressure warning, and current labels include a venous thromboembolism warning. Aveed’s POME and anaphylaxis boxed warning and the gel secondary-exposure boxed warning remain. Check BP before and during treatment.[28][29][37][38] For patients taking warfarin, monitor INR/PT more often when testosterone is started or stopped; diabetic patients may need less insulin, and concomitant corticosteroids can increase fluid retention.[9][38]

Treatment goals and monitoring​

Target: AUA recommends the minimum dose needed to reach approximately 450–600 ng/dL, with symptom improvement.[4] The Endocrine Society suggests the mid-normal range during treatment with any approved formulation, not a blanket target of 300–900 ng/dL. Apply the individual product's sampling and titration instructions.[1][4]

Monitoring — distinguish guideline and product instructions[1][4]​

ParameterTimingAction thresholds
Serum testosteroneProduct-specific titration, then reassessment at 3–6 mo; AUA every 6–12 mo once stableSampling timing varies by formulation; AUA : discuss stopping at 3–6 months if total testosterone normalizes without symptom or sign improvement; continuation may be considered for documented BMD loss or unexplained anemia that improves during treatment.[4] Endocrine Society 2018: for enanthate or cypionate, measure midway between injections and adjust the dose or interval if the level is above 600 or below 350 ng/dL; for undecanoate injection, measure just before the next dose.[1]
HematocritGeneral guidelines: baseline, 3–6 mo, then annually; use stricter product-label intervals when applicable (Xyosted, Jatenzo, Kyzatrex: about every 3 mo; Tlando: about every 3 mo in year 1, then every 6 mo).[30][32][38][39]AUA: ≥54% requires intervention, with dose adjustment first when on-treatment T is high. Endocrine Society: >54%, stop until safe, investigate hypoxia/OSA, then restart at reduced dose.[1][4]
PSAAUA: baseline in men over 40. Endocrine Society: shared prostate-monitoring decisions at 55–69 with >10-year life expectancy, or 40–69 with increased risk; if chosen, baseline and 3–12 moConfirm a rise before acting. Endocrine Society: urologic evaluation for confirmed increase >1.4 ng/mL above baseline during the first 12 mo, confirmed PSA >4 ng/mL, or abnormal examination.
DRE / prostate monitoringAccording to the chosen guideline and shared screening planInvestigate abnormality or substantial LUTS worsening; thereafter follow routine screening guidance.
BMD (DXA)After 1–2 y in men with osteoporosis who are not at high fracture riskAssess response and need for approved osteoporosis treatment; high-risk men receive osteoporosis pharmacotherapy alongside testosterone.[1]
Symptoms and AEsEvery visitClinical response and formulation-specific effects

The 2025 Eur Urol review recommends follow-up at 3 months and every 6–12 months thereafter.[10]

EAU 2026 (Limited Update March 2026). The EAU differs from the US guidelines in several practical thresholds. It diagnoses late-onset hypogonadism from symptoms plus total testosterone below 12 nmol/L (3.5 ng/mL, about 346 ng/dL; strong), measured in the morning and fasting on two occasions, and screens only symptomatic men . It recommends against testosterone therapy in eugonadal men, for infertility or in men wishing to father children, and to improve cognition, vitality or strength in aging men (all strong). For monitoring it asks for testosterone and hematocrit at 3, 6 and 12 months then annually , with a hematocrit above 54% requiring dose adjustment or withdrawal, venesection if needed, and restart at a lower dose or with a topical preparation. It advises cautious use, with hematocrit not exceeding 54%, in men with cardiovascular disease, venous thromboembolism or heart failure , and excluding a family history of venous thromboembolism first . After surgery for localized prostate cancer it limits therapy to low-risk men and suggests starting only after at least one year of follow-up with PSA below 0.01 ng/mL and no recurrence , with PSA at 3, 6 and 12 months then annually . It treats active prostate or breast cancer as contraindications and suggests gels rather than long-acting depots when starting therapy in high-risk men .[40]

Benefits​

Sexual function​

Randomized trials show improved sexual desire and activity in selected hypogonadal men. In the TRAVERSE sexual-function substudy (1,161 men with low libido and testosterone <300 ng/dL), testosterone gel improved sexual activity through 24 months and desire, but did not significantly improve erectile-function scores versus placebo.[53] Earlier pooled trials found a small average improvement in erectile-function scores (SMD 0.16–0.27).[1][11] In a 2023 individual-participant meta-analysis of men with baseline testosterone <12 nmol/L, testosterone improved IIEF erectile-function scores by a mean 2.14 points versus placebo at 12 months (95% CI 1.40–2.89; n = 1,436 for this outcome), reaching that study's minimal clinically important difference for mild ED.[55] The 2025 NEJM review is explicit: TRT may not be effective if the main symptom is ED.[3] In men aged 40 years or older with sexual dysfunction but without primary or secondary hypogonadism, Lee 2024 found little to no clinically important erectile-function benefit from testosterone versus placebo over up to 12 months.[12] EAU 2026 is more permissive on ED: it recommends testosterone therapy as first-line treatment for hypogonadal men with mild ED and a PDE5 inhibitor with testosterone for more severe ED with hypogonadism .[40] For men with ED and confirmed deficiency, the AUA ED guideline advises that a PDE5 inhibitor may be more effective combined with testosterone (Moderate Recommendation, Grade C; five small, mostly low-quality trials, four comparing combination treatment with PDE5 inhibitor alone (pooled IIEF-EF difference 2.69 points)), and that testosterone is not an effective monotherapy for ED.[36] Evidence that testosterone adds benefit to an already optimized PDE5i regimen is limited.[1][36] Two of the underlying placebo-controlled trials enrolled men specifically documented as unresponsive to PDE5 inhibitor monotherapy: adding testosterone gel improved erectile function in the TADTEST study, with benefit reaching significance only in the subgroup with baseline total T ≤300 ng/dL (the overall population, whose mean baseline T was 337 ng/dL, showed no added effect), and a separate sildenafil-adjunct trial in hypogonadal nonresponders (T ≤400 ng/dL) found a similar early benefit.[45][46] Effects in men without an adequate PDE5i trial were not assessed.[45][46] See PDE5 inhibitors.

Body composition​

Earlier randomized trials in older men consistently increased lean mass and decreased fat mass.[1] In Buratto's 16-RCT meta-analysis (1,728 men; mean age 77), hip BMD and total lean mass increased versus placebo at 6 months, but the total-fat-mass difference was not statistically significant; no musculoskeletal outcome differed significantly at 12 months.[13]

Bone mineral density​

Increases areal and volumetric BMD at spine and hip; improves cortical density and thickness.[1][14]

TRAVERSE fracture substudy: Snyder 2024 reported more clinical fractures with testosterone (91/2,601 [3.50%] versus 64/2,603 [2.46%]; HR 1.43, 95% CI 1.04–1.97) over a median 3.19 years. BMD improvement has not demonstrated fracture prevention.[15]

Anemia​

In the TRAVERSE anemia substudy, 143/349 (41.0%) testosterone-treated and 103/375 (27.5%) placebo-treated anemic men reached hemoglobin ≥12.7 g/dL at 6 months; the difference persisted through 36 months among those assessed.[54] The earlier Testosterone Trials found greater hemoglobin increments >1 g/dL with treatment in men with unexplained anemia.[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; 1,007 randomized). Men with central obesity and either impaired glucose tolerance or newly diagnosed type 2 diabetes, without pathological hypogonadism, received a structured lifestyle program plus testosterone undecanoate or placebo. At 2 years, the OGTT diabetes-range endpoint occurred in 55/443 (12%) versus 87/413 (21%) with available data (RR 0.59, 95% CI 0.43–0.80); the effect was independent of baseline testosterone.[16]
  • 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[17]
  • Interpretation: these trials differ in population, formulation and co-intervention. In a post-trial T4DM survey a median 5.1 years after the last injection, no between-group difference in self-reported new diabetes was detected among 599 survey completers (59% of 1,007 randomized men); durability of the OGTT difference remains uncertain. Do not prescribe TRT as established diabetes prevention or glucose-lowering therapy.[1][16][17][50]

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. Eligible men reported at least one symptom of hypogonadism and had two fasting morning testosterone values below 300 ng/dL (central laboratory, liquid chromatography–tandem mass spectrometry). Cardiovascular disease was defined as coronary, cerebrovascular or peripheral arterial disease; increased risk required three or more of hypertension, dyslipidemia, current smoking, stage 3 chronic kidney disease, diabetes, elevated high-sensitivity C-reactive protein, age 65 or older, or a coronary calcium score above the 75th percentile. Exclusions included testosterone below 100 ng/dL, a history of prostate cancer or prostate nodules, elevated screening PSA, thrombophilia, uncontrolled heart failure, and an acute coronary syndrome, stroke or revascularization within 4 months. Men were randomized 1:1 to daily 1.62% transdermal gel or matching placebo, dose-adjusted by a central algorithm to keep testosterone at 350–750 ng/dL. The mean daily dose was 65 ± 22 mg. Study drug was stopped for testosterone above 750 ng/dL or hematocrit above 54% despite the lowest dose, a new prostate cancer diagnosis, or suicide risk. Mean treatment was 21.7 months and mean follow-up 33.0 months (safety population 5,198; 61% of each group discontinued study drug), so the results apply to that formulation and duration:[2]

EndpointTestosteronePlaceboInterpretation
MACE (primary)7.0%7.3%Non-inferior; HR 0.96 (95% CI 0.78–1.17; p < 0.001 for non-inferiority)
Secondary composite (MACE plus coronary revascularization)10.4%10.1%HR 1.02 (0.86–1.21)
Cardiovascular death3.4%4.0%HR 0.84 (0.63–1.12)
Nonfatal myocardial infarction2.6%2.4%HR 1.10 (0.78–1.56)
Nonfatal stroke1.4%1.5%HR 0.94 (0.60–1.49)
Coronary revascularization5.5%4.6%HR 1.20 (0.95–1.53)
Venous thromboembolism (composite)1.7%1.2%HR 1.46 (0.92–2.32)
Pulmonary embolism0.9% (24)0.5% (12)Higher on testosterone; no hazard ratio was prespecified for components
Atrial fibrillation3.5%2.4%Higher on testosterone (investigator-reported, p = 0.02)
Acute kidney injury2.3%1.5%Higher on testosterone (investigator-reported, p = 0.04)
Nonfatal arrhythmia needing intervention5.2%3.3%Higher on testosterone (p = 0.001)[2]
Clinical fractures3.50% (91/2,601)2.46% (64/2,603)Higher on testosterone[15]
Prostate cancer12 (0.5%)11 (0.4%)p = 0.87. Men with prior prostate cancer, prostate nodules or elevated screening PSA were excluded, and follow-up was short.[2]

The Androgen Society 2024 position paper interprets the cardiovascular evidence as reassuring.[18]

The paper reports the arrhythmia, atrial fibrillation, acute kidney injury and pulmonary embolism differences without correction for multiplicity, and describes the arrhythmia, atrial fibrillation and kidney findings as unexpected. Mean PSA rose more with testosterone (0.20 versus 0.08 ng/mL), and mean systolic blood pressure changed by +0.3 versus −1.5 mm Hg over 6 months. Men could not enter the trial within 4 months of an acute coronary syndrome, stroke or revascularization, and retention was limited (outcome data covered about 82% of possible follow-up time).[2]

Residual safety signals: TRAVERSE reported more pulmonary emboli and atrial fibrillation, and its fracture substudy found more clinical fractures. A 2025 meta-analysis of 23 randomized trials in 9,280 men aged ≥40 years with low or low-normal testosterone and at least 12 months of follow-up found more cardiac arrhythmias with testosterone (RR 1.53, 95% CI 1.20–1.97).[2][15][49]

A UK population-based case-control study (19,215 men with VTE vs 909,530 matched controls) found the VTE rate ratio was 1.63 (95% CI 1.12–2.37) specifically in the first 6 months of testosterone treatment (about 26 versus 16 events per 10,000 patient-years), and not significantly elevated either overall (rate ratio 1.25) or after 6 months (rate ratio 1.00). In the first six months, the VTE rate ratio was 1.41 (95% CI 0.82–2.41) in men with a known risk factor and 1.91 (95% CI 1.13–3.23) in men without one. This is a more actionable counseling point than TRAVERSE's single aggregate hazard ratio: the highest-risk period is the first several months after starting treatment.[48]

Prostate safety​

Prostate cancer risk​

AUA 2018 : clinicians should inform patients of the absence of evidence linking TRT to prostate cancer development.[4]

  • TRAVERSE prostate substudy (Bhasin 2023). High-grade PCa occurred in 5/2,596 versus 3/2,602 men (HR 1.62, 95% CI 0.39–6.77)[19]
  • Baik 2025 Medicare cohort (n = 546,964). TRT was associated with 16% reduction in PCa hazard (HR 0.84)[20]
  • García-Becerra 2026 meta-analysis of 41 RCTs (n = 11,161). No statistically significant increase in PCa events (OR 0.88, 95% CI 0.52–1.51)[21]

TRT after prostate cancer​

The AUA states there is inadequate evidence to quantify the risk-benefit ratio in men with PCa history .[4]

SPIRIT 2026 randomized 136 men with symptomatic low testosterone, organ-confined Gleason 3+3 or 3+4 disease treated by radical prostatectomy, and undetectable PSA for at least 2 years, to testosterone cypionate 100 mg IM weekly or placebo for 12 weeks.[34] Sexual activity and desire improved; erectile function did not. No biochemical recurrence was observed. A subsequent correction concerned baseline testosterone units, not the reported treatment outcomes.[34][35]

The saturation model offers a biological hypothesis.[22][25]

BPH / LUTS​

Trials have not shown significant LUTS worsening in their selected populations, but severe LUTS was generally excluded. Continue symptom monitoring. In TRAVERSE, investigator-reported benign prostatic hyperplasia occurred in 45 versus 46 men and urinary retention in 50 versus 34 (1.9% versus 1.3%, p = 0.08).[2] In Baik's propensity-matched Medicare analysis of 412,782 men, TRT use was associated with more BPH diagnoses than nonuse (HR 1.13, 95% CI 1.11–1.14).[20]

Erythrocytosis — the most common dose-limiting AE​

Highest risk with injectable formulations and in older men.[1][6] An unadjusted retrospective comparison of 57 injection, 74 pellet, and 47 gel users reported hematocrit ≥50% in 66.7%, 35.1%, and 12.8%, respectively, during up to three years of follow-up, a roughly fivefold unadjusted spread between injections and gel. The nonrandomized groups differed in baseline hematocrit, limiting causal interpretation.[47] In T4DM, hematocrit >54% was triggered in 22% of testosterone-treated men (vs 1% placebo).[16] TRAVERSE used the same 54% threshold as a stop rule after dose reduction to the lowest dose; the mean baseline hematocrit was 42%.[2]

AUA: hematocrit ≥54% requires intervention; reduce dose when on-treatment T is high. If T is low or normal, reassess SHBG/free T and investigate other causes, with hematology input when indicated. Endocrine Society: if hematocrit >54%, stop until safe, evaluate hypoxia or OSA, then restart at reduced dose. Routine phlebotomy is not an automatic substitute for reassessing the dose and cause. Oral formulations do not eliminate erythrocytosis risk.[1][4][30]

Fertility — exogenous TRT suppresses spermatogenesis​

AUA / ASRM Male Infertility Guideline : exogenous testosterone should not be prescribed to men interested in current or future fertility.[8]

Recovery after discontinuation is variable and can take months or longer. Men uncertain about future conception may consider sperm banking before TRT if sperm are present.[1] Recovery estimates come from healthy-men contraceptive studies; some men do not recover adequately.[4]

AUA/ASRM allows selected use of hCG, SERMs or aromatase inhibitors for infertile men with low testosterone .[8] Selection depends on the endocrine defect and fertility evaluation. The Habous 2018 trial (282 men) compared short-term testosterone and symptom outcomes, not demonstrated preservation of spermatogenesis.[8][26]

See the Androgen adjuncts hub for agents, label and off-label distinctions and dosing considerations.

Special populations​

Older men — age-related decline vs pathologic hypogonadism​

In the 2025 NEJM review, benefit is most likely in men with unequivocal hypogonadism (TT <200 ng/dL with classic symptoms) and marginal in age-related decline without consistent symptoms.[3] The EMAS position statement 2023 advises offering TRT in symptomatic older men with confirmed low testosterone only after explaining uncertainties about long-term safety, and preferring short-acting transdermal preparations for initiation.[7]

Obesity​

The most common cause of functional hypogonadism. Weight loss through lifestyle modification is first-line and raises endogenous testosterone. T4DM showed testosterone augmented a structured lifestyle program, but TRT for diabetes prevention in men without pathologic hypogonadism is premature.[7][10][16]

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.[27]

Evidence Summary​

DomainEffectStrengthKey source
Libido / sexual desireConsistently improvedStrongMultiple RCTs; Endocrine Society 2018[1]
Erectile functionSmall average improvement in men aged 40 years or older with sexual dysfunctionModerate for the Cochrane population, which excluded primary or secondary hypogonadismLee 2024; Bhasin and Snyder 2025[12][3]
Body compositionEarlier RCTs: ↑ lean mass, ↓ fat mass; 16-RCT meta-analysis: ↑ total lean mass but no significant total-fat-mass difference at 6 moMixed for fat mass; time-limited pooled evidenceEndocrine Society 2018; Buratto 2023[1][13]
Bone mineral densityIncreased at spine and hipStrongNg Tang Fui 2021[14]
Clinical fracturesUnexpectedly increased (43%)Moderate (single large RCT)Snyder 2024 TRAVERSE[15]
AnemiaHemoglobin normalized at 6 mo in 143/349 (41.0%) testosterone versus 103/375 (27.5%) placebo participants with baseline anemia in TRAVERSEStrong (randomized evidence)TTrials / Endocrine Society; Pencina 2023[1][54]
Mood / depressionSlight improvementLow–Moderate2025 NEJM review[3]
MACENon-inferior in TRAVERSE over mean 33.0 months; HR 0.96 (95% CI 0.78–1.17)Strong for the studied population, gel, and follow-upTRAVERSE 2023[2]
Pulmonary embolismHigher observed incidence with testosterone gel (24 versus 12 events)Low to Moderate (exploratory safety signal)TRAVERSE[2]
Atrial fibrillationPossibly increasedLow–ModerateTRAVERSE[2]
Prostate cancerNo significant excess in selected short–mid-term trials; long-term and post-cancer uncertainty remainsLimited for rare events and cancer survivorsTRAVERSE; SPIRIT 2026[19][34]
ErythrocytosisDose-dependent; most common AEStrongMultiple sources[1][16]
Fertility (spermatogenesis)SuppressedStrongAUA/ASRM 2024[8]

Clinical Positioning​

  • Confirm symptoms plus consistently low testosterone on two mornings; fasting is the Endocrine Society recommendation, not an AUA requirement. Interpret assay limits and altered SHBG.[1][4]
  • TRAVERSE established MACE non-inferiority within its studied population and follow-up.[2][18]
  • 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][15]
  • For ED as the chief complaint, confirm testosterone deficiency and assess severity. Testosterone can improve libido in hypogonadal men; in a Cochrane sensitivity analysis of six randomized trials of men with sexual dysfunction (n = 2,016; primary or secondary hypogonadism was excluded, and confirmed testosterone deficiency was not required), testosterone improved erectile-function scores by a mean 2.37 IIEF-EF points more than placebo at 3–12 months (IIEF-EF and converted IIEF-5 pooled), below the 4-point threshold specified in the review’s abstract.[12] EAU 2026 strongly recommends testosterone first-line for hypogonadal men with mild ED and weakly recommends combining it with a PDE5 inhibitor for more severe ED. AUA advises that a PDE5 inhibitor may be more effective with testosterone in men with ED and confirmed deficiency .[3][12][36][40]
  • Monitor hematocrit. Separate the AUA baseline >50% investigation threshold from its on-treatment ≥54% intervention threshold; follow the guideline-specific actions above.[1][4]
  • Do not prescribe exogenous testosterone for men interested in current or future fertility. Refer to the androgen-adjuncts hub and select alternatives after endocrine and fertility assessment.[8]
  • Nasal testosterone remains exogenous testosterone. Limited short-term semen studies do not establish long-term reproductive safety or override fertility counseling.[8][31]
  • Known or suspected prostate cancer remains a product-label contraindication.[29] Evidence after prostate-cancer treatment consists largely of observational studies, with one 12-week randomized trial in 136 selected men after radical prostatectomy[34]; active-surveillance data remain observational. Use remains outside routine label-approved care and requires specialist selection and discussion of uncertainty.[22][23][24][34]
  • Obesity first. In men with functional hypogonadism from obesity, lifestyle modification is first-line before TRT; T4DM shows TRT can augment a structured program.[10][16]
  • In symptomatic older men with confirmed low testosterone, EMAS 2023 favors short-acting transdermal treatment at initiation and reassessment at 3, 6 and 12 months, then at least annually; treatment may continue while benefits outweigh risks.[7]
  • Confirm PSA changes. A confirmed rise >1.4 ng/mL above baseline during the first treatment year is an Endocrine Society trigger for urologic evaluation, alongside absolute PSA and examination findings.[1]
  • Prevent gel transfer: wash hands immediately, cover the site after drying, and wash the application site before anticipated skin contact. Drying alone does not eliminate transfer risk.[9]

See Also​

References​

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