What are the treatment options for a man with hypogonadism and erectile dysfunction who cannot receive testosterone replacement because of contraindications such as active prostate cancer, elevated hematocrit, need to preserve fertility, or severe untreated obstructive sleep apnea?

Treatment Options When Testosterone Replacement Therapy is Contraindicated

When testosterone replacement therapy (TRT) cannot be used due to contraindications such as active prostate cancer, elevated hematocrit, need to preserve fertility, or severe untreated obstructive sleep apnea, the primary alternative is gonadotropin therapy with human chorionic gonadotropin (hCG) plus follicle-stimulating hormone (FSH) for men with secondary hypogonadism who desire fertility preservation, as this directly stimulates testicular testosterone production and spermatogenesis without suppressing the hypothalamic-pituitary axis. 1

Algorithm for Treatment Selection Based on Contraindication Type

For Men Requiring Fertility Preservation

Gonadotropin therapy is mandatory and TRT is absolutely contraindicated because exogenous testosterone suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 1, 2

Primary Treatment Protocol:

• Start recombinant hCG 500 IU subcutaneously 3 times weekly (total 1,500 IU/week) to maintain intratesticular testosterone in the normal range 2
• Add recombinant FSH 75-150 IU subcutaneously 2-3 times weekly after 3-6 months if sperm counts remain low 1, 2, 3
• Combined hCG plus FSH therapy provides optimal outcomes for both testosterone restoration and fertility preservation 1
• This approach is FDA-approved for induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism 4, 3

Monitoring Schedule:

• Check testosterone levels at 2-3 months to assess testicular response 2
• Measure LH and FSH to confirm they remain suppressed initially, then gradually recover 2
• Perform semen analysis at 3-4 months if fertility is the goal 5
• Approximately 67-90% of men eventually recover spermatogenesis, but this can take 6-24 months 2

Alternative for Secondary Hypogonadism:

• Clomiphene citrate 25-50 mg daily or enclomiphene 12.5-25 mg daily can be used off-label to stimulate endogenous LH/FSH production rather than replacing it 2, 6
• Clomiphene is indicated when both morning total testosterone measurements are below 300 ng/dL and LH/FSH levels are low or low-normal, confirming secondary hypogonadotropic hypogonadism 5
• However, data supporting efficacy on hypogonadal symptoms are insufficient, so clomiphene should not be used in routine clinical practice to treat sexual symptoms 6

For Men with Active Prostate Cancer

TRT is absolutely contraindicated in men with breast or prostate cancer. 1 There is no new level 1 evidence to support a connection between TRT in men with previously treated or active prostate cancer to support a change in recommendations. 1

Management Options:

• Address reversible causes first: Treat obesity through hypocaloric diet (500-750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2-3 times/week), as 5-10% weight loss can significantly increase endogenous testosterone production 5
• Optimize metabolic control if diabetes or metabolic syndrome is present 5
• Treat underlying conditions such as hyperthyroidism, hepatic disease, or medication-induced hypogonadism 5
• Consider PDE5 inhibitors (sildenafil, tadalafil) as first-line treatment for erectile dysfunction without testosterone 5, 7

For Men with Elevated Hematocrit (>54%)

Testosterone therapy must be withheld if hematocrit exceeds 54% and therapeutic phlebotomy should be considered in high-risk cases. 1, 5, 8

Management Strategy:

• Discontinue TRT immediately until hematocrit falls below 52% 5
• Therapeutic phlebotomy protocol: Remove 500 mL blood every 1-2 weeks until hematocrit <52%, monitoring iron studies to avoid iron deficiency 5
• Address underlying causes: Evaluate for sleep apnea, smoking, chronic hypoxia, or polycythemia vera 5
• If TRT must be resumed: Switch from injectable to transdermal formulations (15.4% erythrocytosis risk vs. 43.8% with injectables), target mid-normal testosterone levels (450-600 ng/dL), and monitor hematocrit every 3-6 months 5

For Men with Severe Untreated Obstructive Sleep Apnea

Untreated sleep apnea and severe lower urinary tract symptoms may not be absolute contraindications to TRT based on recent level 1 evidence. 1 However, severe untreated OSA remains a relative contraindication requiring careful consideration. 9

Treatment Algorithm:

1. First-line: Initiate CPAP therapy for OSA before considering any hormonal intervention 10, 9

2. Reassess testosterone levels 3 months after adequate CPAP therapy, as treatment of OSA alone may normalize testosterone in some men 10, 9

3. If hypogonadism persists despite adequate OSA treatment:

   • Consider TRT with close monitoring, preferably using transdermal formulations at lower doses 9
   • Short-term high-dose TRT might worsen OSA, whereas long-term lower doses could eventually improve symptoms 9
   • Perform polysomnography to assess patients who develop signs and symptoms of OSA during TRT 9

4. For men with OSA, ED, and documented hypogonadism: All patients need testosterone replacement therapy if levels persist low despite adequate therapy of OSA 10

Non-Pharmacological Interventions (First-Line for All Patients)

Before considering any pharmacological alternative, address reversible causes:

Weight Loss and Lifestyle Modification

• Implement hypocaloric diet with 500-750 kcal/day deficit below maintenance requirements 5
• Prescribe structured physical activity: minimum 150 minutes/week of moderate-intensity aerobic exercise plus resistance training 2-3 times weekly 5
• Weight loss of 5-10% can significantly increase endogenous testosterone production in obese men with secondary hypogonadism 5
• Weight loss, smoking cessation, increased physical activity, and avoiding excess alcohol improve sexual function and testosterone levels 5

Treat Underlying Medical Conditions

• Optimize diabetes management with intensified therapy including GLP-1 receptor agonists or SGLT2 inhibitors 5
• Treat hyperthyroidism with antithyroid drugs, radioiodine, or surgery 5
• Address hepatic disease and optimize liver function 5
• Screen for and treat hyperprolactinemia (measure serum prolactin; if >1.5× upper limit of normal, obtain pituitary MRI) 5
• Evaluate for hemochromatosis with iron studies 5

Medication Review

• Discontinue or substitute SHBG-elevating drugs when feasible (anticonvulsants, estrogens, thyroid hormone) 5
• Review chronic narcotic use and chronic corticosteroid therapy as potential contributors 5

Expected Outcomes and Realistic Expectations

With Gonadotropin Therapy:

• Testosterone levels reach mid-normal range (500-600 ng/dL) within 6 weeks in obese secondary hypogonadal men 5
• Small but statistically significant improvements in sexual function and libido (standardized mean difference ≈0.35), comparable to TRT 5
• Preserves or improves spermatogenesis, making it the preferred option for men seeking fertility 5

With Lifestyle Modification Alone:

• Modest improvements in testosterone levels without medication in obesity-associated secondary hypogonadism 5
• Improvements in metabolic syndrome markers including insulin sensitivity, triglycerides, and HDL cholesterol 5

Limitations Across All Alternatives:

• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition even when testosterone levels normalize 5
• Minimal improvement in fatigue or energy (standardized mean difference ≈0.17), well below clinical significance 5
• Primary therapeutic benefit is confined to sexual function domains (libido and erectile function) 5

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis 5
• Never use testosterone therapy for weight loss, energy improvement, or athletic performance in men with contraindications—these are not evidence-based indications 5
• Do not assume age-related decline requires treatment; approximately 20-30% of men over 60 have testosterone levels in the low-normal range, which does not constitute a disease requiring treatment 5
• Do not omit LH/FSH testing after confirming low testosterone, because the primary vs. secondary distinction guides therapy and fertility counseling 5
• For men with elevated hematocrit, do not continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy 5
• In men with OSA, do not initiate TRT without first attempting CPAP therapy and reassessing testosterone levels after adequate OSA treatment 10, 9