How do you treat hypogonadism?

Treatment of Hypogonadism

Yes, you should treat low testosterone levels when hypogonadism is confirmed biochemically with persistently low morning testosterone levels AND the patient has specific symptoms such as decreased libido, erectile dysfunction, or diminished vitality. 1

Diagnostic Confirmation Required Before Treatment

Before initiating any therapy, you must confirm the diagnosis properly:

• Measure morning total testosterone (between 8-10 AM) on at least two separate occasions to confirm persistently low levels 1
• If testosterone is subnormal, measure serum LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 1
• Free testosterone by equilibrium dialysis and sex hormone-binding globulin should be measured, especially in obese men 1
• In men with total testosterone near the lower limit, free or bioavailable testosterone levels are essential given expected decreases in SHBG with diabetes 2

A critical pitfall: Do not treat based on a single testosterone measurement, as levels vary significantly between assays and over time 1

Treatment Selection Based on Fertility Goals

For Men NOT Seeking Fertility

Testosterone replacement therapy (TRT) is first-line treatment 1:

• Transdermal testosterone gel (40.5 mg daily) is the preferred initial formulation due to more stable day-to-day testosterone levels 1
• Intramuscular testosterone injections (cypionate or enanthate every 2-3 weeks) are an alternative, particularly when cost is a concern (annual cost $156 vs $2,135 for transdermal) 1
• Peak serum levels with injections occur 2-5 days after administration, with return to baseline at 10-14 days 1

Critical contraindication: Never prescribe exogenous testosterone to men interested in current or future fertility, as it suppresses spermatogenesis through negative feedback on the hypothalamus and pituitary 2, 3, 4

For Men Seeking Fertility Preservation

Gonadotropin therapy is mandatory; testosterone is absolutely contraindicated 1:

• Use recombinant human chorionic gonadotropin (hCG) 500-2500 IU, 2-3 times weekly as first-line treatment 2, 5
• Add FSH injections when indicated after testosterone levels normalize on hCG 2
• The degree of response correlates with baseline testicular size 2
• Recovery of spermatogenesis after stopping testosterone can take months or rarely years 2

Expected Treatment Outcomes

Sexual Function and Quality of Life

• TRT improves sexual function and libido in hypogonadal men 2, 1
• Small but significant improvements in quality of life occur, particularly in vitality, social functioning, and mental health domains 2
• Effect sizes are modest—do not oversell the benefits 1

Metabolic Benefits

• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol can be expected 1
• Increases in lean body mass and decreases in visceral adiposity occur 6
• Bone mineral density improves with treatment 6

Limited or No Benefits

• Little to no effect on physical functioning, depressive symptoms, energy/vitality, or cognition in older men 1
• In men with major depression refractory to SSRIs, TRT does not improve depressive symptoms or overall quality of life, though sexual function may improve 2

Monitoring Requirements

Initial Monitoring

• Check testosterone levels 2-3 months after treatment initiation or any dose change 1
• For injectable testosterone, measure levels midway between injections, targeting mid-normal values (500-600 ng/dL) 1
• Once stable on a given dose, monitor every 6-12 months 1

Ongoing Safety Monitoring

• Hematocrit periodically—withhold treatment if >54% and consider phlebotomy in high-risk cases (erythrocytosis risk is higher with injectable forms) 1, 3
• PSA levels in men over 40 years—adjust treatment if significant increases occur 1, 3
• Prostate examination to assess for benign prostatic hyperplasia symptoms 1, 4
• Serum calcium in cancer patients at risk of hypercalcemia 3

Absolute Contraindications to Testosterone Therapy

• Men actively seeking fertility (use gonadotropins instead) 1
• Active or treated male breast cancer 1
• Prostate cancer (though evidence is evolving) 2, 3

Important warning: The European Association of Urology strongly recommends against testosterone therapy in eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men 1

Special Populations

Hypogonadal Women (Premenopausal)

• Estrogen replacement with progesterone is first-line therapy 2, 1
• Transdermal HRT for premenopausal or postmenopausal women (estrogen only if no uterus, otherwise combined/sequential or combined/continuous HRT) 2
• The oral contraceptive pill can be given to premenopausal women who also need contraception 2

Men with Diabetes

• In men with diabetes who have symptoms or signs of hypogonadism (decreased libido, erectile dysfunction), measure morning total testosterone using an accurate assay 2
• Free or bioavailable testosterone levels should also be measured in diabetic men with total testosterone near the lower limit 2

Potential Risks and Side Effects

• Erythrocytosis (most common with injectable forms) 1, 3
• Fluid retention, which may worsen congestive heart failure in susceptible patients 3, 4
• Potential worsening of benign prostatic hyperplasia 1, 3
• Sleep apnea may be potentiated, especially in obese patients or those with chronic lung disease 3, 4
• Gynecomastia may develop and persist 3, 4
• Testicular atrophy and infertility with exogenous testosterone 3
• Cardiovascular risk remains inconclusive—some studies report increased MACE risk, though data are conflicting 3

Critical safety note: Long-term cardiovascular safety trials have not been conducted; patients must be informed of possible cardiovascular risks when deciding whether to initiate or continue therapy 3