Testosterone Formulations: Special-Populations Summary for Prescribers

Why Special-Population Prescribing Differs from Standard TRT

Standard testosterone replacement targets a serum total testosterone of 450-600 ng/dL in otherwise healthy hypogonadal men. Special populations force departures from this framework because altered pharmacokinetics, competing comorbidities, or unique treatment goals shift the therapeutic window.

Pharmacokinetic Variability Across Populations

Body composition directly changes testosterone distribution. In men with BMI ≥35, the volume of distribution for lipophilic testosterone esters expands substantially, which blunts peak concentrations after intramuscular injection and may lengthen the time to steady state 6. Hepatic first-pass metabolism eliminates conventional oral testosterone entirely, which is why oral testosterone undecanoate (Jatenzo) was engineered for lymphatic absorption. Patients with portal hypertension or cirrhosis lose this advantage.

Risk Stratification Before Formulation Selection

The 2018 Endocrine Society Clinical Practice Guideline states: "We recommend against testosterone therapy in men who are planning fertility in the near term, have breast or prostate cancer, a palpable prostate nodule, PSA >4 ng/mL, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia" 2. This contraindication list applies regardless of formulation. Population-specific adjustments layer on top of these absolute restrictions.

Older Adults (Age 65 and Above)

Testosterone prescribing in men over 65 requires balancing modest, domain-specific benefits against erythrocytosis risk and the residual uncertainty around long-term cardiovascular outcomes.

Evidence from the TTrials

The Testosterone Trials (TTrials) enrolled 790 men aged 65 or older with serum testosterone <275 ng/dL. After 12 months of daily 1% testosterone gel (AndroGel), participants showed statistically significant improvements in sexual desire (P<0.001) and erectile function, along with increased volumetric bone mineral density by quantitative CT 3. Physical function (measured by 6-minute walk distance) improved modestly. Vitality scores and cognitive function did not separate from placebo.

Formulation Considerations in Geriatric Patients

Transdermal gels offer the most titratable option for this population. Dose adjustments in 10-20 mg/day increments allow clinicians to target the lower end of the physiologic range (400-500 ng/dL) while monitoring hematocrit every 3-6 months. Injectable cypionate, while effective, produces supraphysiologic peaks that can push hematocrit above 54% more readily in older men 7. The nasal formulation (Natesto, 11 mg per nostril three times daily) avoids sustained serum elevations entirely but requires strict dosing adherence, which may be problematic in patients with cognitive decline.

Polypharmacy and Drug Interactions

Warfarin sensitivity increases with testosterone co-administration. INR monitoring frequency should increase to weekly for the first month after testosterone initiation in anticoagulated patients 8. Insulin and sulfonylurea doses may need reduction as testosterone improves insulin sensitivity, particularly in men with type 2 diabetes 9.

Cardiovascular Risk: What TRAVERSE Settled and What It Did Not

The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men) provided the first adequately powered cardiovascular safety data for testosterone therapy.

Primary Endpoint Results

Among 5,246 men aged 45-80 with hypogonadism and either established cardiovascular disease or high cardiovascular risk, 1% transdermal testosterone gel did not increase the incidence of major adverse cardiovascular events (MACE) compared to placebo over a mean follow-up of 33 months. The hazard ratio for the primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke) was 0.99 (95% CI, 0.81-1.21) 1.

Residual Concerns

TRAVERSE did reveal a higher incidence of atrial fibrillation (HR 1.26, 95% CI 0.94-1.69), pulmonary embolism (HR 1.92, 95% CI 1.11-3.32), and acute kidney injury in the testosterone arm 1. Dr. Shalender Bhasin, a principal investigator, noted: "The increased risk of pulmonary embolism and the signal for atrial fibrillation require careful patient selection, particularly in men with pre-existing arrhythmia or VTE history" 10.

Formulation Implications for High-CV-Risk Patients

Transdermal gels produce more stable pharmacokinetics than intramuscular injections, avoiding the supraphysiologic peaks associated with cypionate or enanthate. For patients with established atrial fibrillation or prior VTE, the lowest effective dose of a transdermal formulation is preferred. Oral testosterone undecanoate (Jatenzo) carries an FDA boxed warning for increased blood pressure and should be used cautiously in patients with uncontrolled hypertension 11.

Hepatic Impairment

Liver disease alters testosterone metabolism, protein binding, and formulation suitability in ways that demand careful formulation matching.

Altered SHBG and Free Testosterone

Cirrhosis increases sex hormone-binding globulin (SHBG) production in early-stage disease but decreases it in decompensated liver failure. This paradox means total testosterone levels may appear normal in compensated cirrhosis while free testosterone is already low 12. Equilibrium dialysis or calculated free testosterone (Vermeulen equation) is necessary for accurate assessment.

Formulation Restrictions

Oral testosterone undecanoate relies on intestinal lymphatic uptake to bypass hepatic first-pass metabolism. In patients with portal hypertension, lymphatic drainage is compromised, and absorption becomes unpredictable. The 17-alpha-alkylated androgens (methyltestosterone, fluoxymesterone), which are rarely prescribed today, are explicitly hepatotoxic and contraindicated 13. Injectable testosterone cypionate or enanthate, administered intramuscularly or subcutaneously, bypasses the portal circulation entirely. Transdermal gels are also acceptable. Both routes avoid first-pass hepatotoxicity.

For patients with Child-Pugh class A or B cirrhosis, start injectable cypionate at 50-75 mg weekly (half the standard dose) and titrate based on trough serum testosterone and hematocrit at 6-week intervals. Avoid oral formulations. Monitor LFTs monthly for the first 3 months.

Renal Impairment

Chronic kidney disease (CKD) causes hypogonadism in 40-60% of men on hemodialysis, driven by uremic suppression of hypothalamic GnRH pulsatility and elevated prolactin 14.

Fluid Retention Risk

Testosterone promotes sodium and water retention through mineralocorticoid receptor cross-reactivity. In patients with eGFR <30 mL/min/1.73 m², this effect can worsen peripheral edema and exacerbate heart failure. The 2018 Endocrine Society guideline recommends against testosterone therapy in men with NYHA class III-IV heart failure regardless of renal function 2.

Dose Adjustment and Monitoring

No formal renal dose adjustment exists for injectable testosterone esters because they are metabolized hepatically and do not undergo significant renal clearance. The clinical adjustment is monitoring-driven: check serum testosterone (trough), hematocrit, and potassium every 4-6 weeks during titration. Erythrocytosis risk is compounded in CKD patients already receiving erythropoiesis-stimulating agents (ESAs). If hematocrit exceeds 52%, hold testosterone and reduce ESA dose before restarting at a lower testosterone dose 15.

Dialysis Timing

For men on hemodialysis receiving intramuscular testosterone cypionate, administer the injection on non-dialysis days. Testosterone is highly protein-bound (98% to SHBG and albumin) and is not significantly removed by standard hemodialysis membranes.

Obesity and Metabolic Syndrome

Obesity-associated hypogonadism is functionally distinct from primary or classical secondary hypogonadism. Adipose tissue aromatase converts testosterone to estradiol, suppressing gonadotropin secretion through negative feedback.

Diagnostic Challenges

Total testosterone falls by approximately 2.4 ng/dL for every 1 kg/m² increase in BMI above 25, according to data from the European Male Ageing Study (EMAS, N=3,369) 6. SHBG also declines in obesity, so total testosterone underestimates the degree of androgen deficiency less than expected. Free testosterone calculated by the Vermeulen method or measured by equilibrium dialysis is the preferred diagnostic metric in men with BMI ≥30.

Weight Loss as First-Line Therapy

The Endocrine Society recommends weight loss as the primary intervention for obesity-associated hypogonadism, with testosterone therapy reserved for men who remain symptomatic and biochemically hypogonadal after weight management 2. GLP-1 receptor agonists have emerged as a practical adjunct: in STEP-1 (N=1,961), semaglutide 2.4 mg produced 14.9% mean weight loss at 68 weeks vs. 2.4% with placebo 16, and this magnitude of weight reduction can increase total testosterone by 50-100 ng/dL in obese men.

Formulation Selection in Obesity

Transdermal gels have reduced bioavailability in men with thick subcutaneous adipose tissue overlying application sites. If gel is chosen, apply to the shoulders or upper arms (not the abdomen) and verify serum levels at 2-4 weeks. Intramuscular injections into the ventrogluteal site, using a 1.5-inch needle, remain reliable regardless of BMI. Subcutaneous testosterone cypionate (typically 50-80 mg twice weekly) is gaining traction as an alternative that patients can self-administer, though it remains off-label for most testosterone products 17.

Transgender Men (Female-to-Male Hormone Therapy)

Masculinizing hormone therapy follows a distinct prescribing framework from hypogonadism treatment, with different target ranges, timelines, and monitoring priorities.

Recommended Regimens

The Endocrine Society Guideline on Gender-Affirming Hormone Treatment recommends testosterone cypionate or enanthate 20-100 mg subcutaneously weekly, or 50-200 mg intramuscularly every 2 weeks, titrated to male-range serum testosterone (320-1,000 ng/dL) 4. Transdermal testosterone (50-100 mg/day gel) is an alternative for patients who prefer non-injectable routes, though adherence tends to be lower. Testosterone undecanoate (Aveed) 750 mg intramuscularly every 10 weeks after a loading schedule offers the longest injection interval.

Timeline of Virilization

Voice deepening begins at 3-12 months. Cessation of menses typically occurs within 2-6 months at adequate doses. Facial hair growth plateaus at 3-5 years. Clitoromegaly develops within 3-6 months and is largely irreversible 4.

Fertility Preservation

Testosterone therapy suppresses ovulation, but this effect is not reliable as contraception. Patients should be counseled that pregnancy can occur during testosterone therapy and that oocyte cryopreservation should be completed before starting testosterone if future biological parenthood is desired 18.

Monitoring Differences

In transgender men, monitor serum testosterone (target trough 400-700 ng/dL), hematocrit, lipid panel, and hepatic function at baseline, 3 months, 6 months, and then every 6-12 months. Cervical cancer screening continues per USPSTF guidelines if the cervix is retained. Erythrocytosis thresholds are the same as for cisgender men (hold if hematocrit >54%) 4.

Adolescents with Delayed Puberty

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty in boys, affecting approximately 2% of the adolescent male population.

Induction Protocols

Low-dose testosterone enanthate 50 mg intramuscularly once monthly for 3-6 months is the standard induction regimen 5. If pubertal progression does not occur spontaneously after discontinuation, a second 3-6 month course at 100 mg monthly can be administered. Full replacement doses (200 mg every 2 weeks or equivalent) are reserved for confirmed hypogonadism, not CDGP.

Monitoring Growth Plates

Exogenous testosterone accelerates epiphyseal maturation. Bone age radiographs (left hand and wrist) should be obtained before initiation and every 6 months during treatment. The goal is to stimulate pubertal onset without prematurely fusing growth plates and compromising adult height. Height velocity should be tracked alongside bone age advancement 19.

Distinguishing CDGP from Permanent Hypogonadism

If a boy fails to progress through puberty after two induction courses, serum gonadotropins (LH and FSH), inhibin B, and anti-Mullerian hormone should be reassessed. An LH <0.3 IU/L with absent pubertal response suggests hypogonadotropic hypogonadism requiring long-term testosterone replacement or potential GnRH pump therapy if fertility is a future consideration 5.

Formulation Selection Decision Framework

Matching the right testosterone product to the right patient requires weighing absorption reliability, monitoring burden, adherence patterns, and population-specific risks.

Injectable Esters (Cypionate, Enanthate, Undecanoate)

Best for: hepatic impairment, obesity (IM route), transgender men, patients who prefer infrequent dosing (undecanoate). Avoid in: patients with bleeding disorders requiring anticoagulation at high INR targets (consider transdermal instead to avoid IM injection site hematomas).

Transdermal Systems (Gels, Patches)

Best for: older adults needing fine-dose titration, cardiovascular-risk patients who benefit from stable pharmacokinetics, patients with needle phobia. Avoid in: men with extensive psoriasis or dermatitis at application sites, households with children or pregnant women due to transfer risk 8.

Nasal Testosterone (Natesto)

Best for: men who want to preserve spermatogenesis (nasal testosterone may suppress the HPG axis less than other formulations, though data remain limited). Avoid in: patients with chronic sinusitis, nasal polyps, or those who cannot adhere to three-times-daily dosing 20.

Oral Testosterone Undecanoate (Jatenzo)

Best for: patients who refuse both injections and topicals. Requires twice-daily dosing with a fat-containing meal. Carries an FDA boxed warning for blood pressure increases (systolic rise of 3-5 mmHg on average). Avoid in: uncontrolled hypertension, severe hepatic disease 11.

For all formulations across all populations, measure trough testosterone, hematocrit, and PSA (in men over 40) at 3 and 6 months, then annually. Adjust the dose to the lowest level that resolves symptoms while keeping hematocrit <54% and PSA velocity <0.75 ng/mL/year.