What is the primary treatment for hypogonadism (low sex hormone production)?

Primary Treatment for Hypogonadism

The primary treatment for hypogonadism is testosterone replacement therapy (TRT) for men not seeking fertility, while gonadotropin therapy (hCG with or without FSH) is the treatment of choice for men with secondary hypogonadism who wish to preserve fertility. 1, 2

Diagnostic Requirements Before Treatment

Diagnosis must include both persistent specific symptoms (diminished libido, erectile dysfunction, reduced vitality) AND confirmed biochemical testosterone deficiency through repeated morning total testosterone measurements between 8 AM and 10 AM. 1, 2, 3

Measure LH and FSH levels to distinguish primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low/normal LH/FSH), as this classification determines the treatment approach. 2, 3

Treatment Algorithm Based on Hypogonadism Type and Fertility Goals

For Secondary Hypogonadism WITH Fertility Concerns:

• Gonadotropin therapy is mandatory and TRT is absolutely contraindicated in men seeking fertility. 1, 2
• Start with recombinant human chorionic gonadotropin (hCG) at 500-2500 IU administered 2-3 times weekly subcutaneously or intramuscularly. 2, 4
• Add FSH (recombinant or highly purified urinary preparations) after testosterone levels normalize on hCG if spermatogenesis does not adequately respond. 1, 2, 4
• Combined hCG and FSH therapy for 12-24 months promotes testicular growth in nearly all patients, induces spermatogenesis in approximately 80%, and achieves pregnancy rates around 50%. 4

For Primary or Secondary Hypogonadism WITHOUT Fertility Concerns:

Transdermal testosterone gel at 40.5 mg daily is the preferred first-line formulation due to more stable day-to-day testosterone levels. 1, 3

Alternative formulations include:

• Intramuscular testosterone cypionate or enanthate every 2-3 weeks if cost is a primary concern (annual cost $156 vs $2,135 for transdermal). 3, 5, 6
• Injectable testosterone undecanoate for depot formulations if patients prefer less frequent dosing. 7

Critical Contraindications to Testosterone Therapy

• Men actively seeking current or future fertility (TRT suppresses the hypothalamic-pituitary-gonadal axis and spermatogenesis; recovery can take months to years after cessation). 1, 2
• Active or treated male breast cancer (absolute contraindication due to testosterone conversion to estradiol). 1
• The European Association of Urology specifically recommends against TRT in eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength. 1, 3

Lifestyle Modifications as Adjunctive Treatment

For obese patients with functional secondary hypogonadism, weight loss through low-calorie diets can reverse obesity-associated hypogonadism by improving testosterone levels and normalizing gonadotropins, though increases are modest (1-2 nmol/L). 1, 3

Physical activity shows similar benefits, with results correlating to exercise duration and weight loss achieved. 1, 3

While lifestyle changes are essential, combining these with TRT yields better outcomes in symptomatic patients than lifestyle modifications alone. 1

Monitoring Requirements During Treatment

• Check testosterone levels 2-3 months after treatment initiation or dose changes; once stable, monitor every 6-12 months. 3
• For injectable testosterone, measure levels midway between injections targeting mid-normal values (500-600 ng/dL). 3
• Monitor hematocrit periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases (erythrocytosis risk is higher with injectable forms than transdermal preparations). 3
• Monitor PSA levels in men over 40 years and adjust treatment if significant increases occur. 3

Expected Treatment Outcomes

TRT produces small but significant improvements in sexual function and quality of life. 2, 3

TRT shows little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition, particularly in older men. 3

Additional benefits may include improvements in fasting plasma glucose, insulin resistance, triglyceride levels, HDL cholesterol, bone mineral density, and mild anemia correction. 3

If no improvement in sexual function occurs after 12 months of treatment, discontinue TRT. 3

Common Pitfalls to Avoid

• Never prescribe TRT without first assessing fertility desires, as exogenous testosterone suppresses spermatogenesis. 1, 2
• Avoid testosterone testing during acute illness, as results will be unreliable. 1
• Do not use screening questionnaires alone for diagnosis, as they lack specificity. 1
• Recognize that gynecomastia is the most common side effect of gonadotropin therapy due to hCG-stimulated aromatase activity increasing estradiol secretion. 4