What is the diagnosis and treatment for primary hypogonadism?

Diagnosis and Treatment of Primary Hypogonadism

Diagnostic Confirmation

Primary hypogonadism is definitively diagnosed by demonstrating low morning testosterone (<300 ng/dL or <10.5 nmol/L) on two separate occasions combined with elevated LH and FSH levels above the normal range, indicating testicular failure with compensatory pituitary response. 1, 2

Biochemical Testing Algorithm

• Obtain two fasting morning total testosterone measurements (between 8-10 AM) on separate days to confirm low testosterone, as diurnal variation makes single measurements unreliable 2, 3
• Measure LH and FSH after confirming low testosterone to distinguish primary from secondary hypogonadism 2, 3
• Elevated LH and FSH with low testosterone confirms primary (hypergonadotropic) hypogonadism, indicating testicular dysfunction 1, 2
• Add free testosterone by equilibrium dialysis if total testosterone is borderline (200-400 ng/dL) or if the patient is obese, as SHBG alterations affect total testosterone interpretation 2, 3
• Measure SHBG levels to calculate free testosterone index (total testosterone/SHBG ratio <0.3 indicates hypogonadism) 2

Additional Diagnostic Workup

• Screen for thyroid disorders with TSH and free T4, as these affect SHBG and testosterone metabolism 2
• Perform bone density assessment (DXA scan of lumbar spine and femoral neck) if osteoporosis risk factors are present 2
• Check corrected serum calcium, phosphate, and 25-OH vitamin D levels if the patient is housebound, has malabsorption, or is hypocalcemic 2
• Review medications for drugs that interfere with testosterone production (glucocorticoids, opioids) 2

Critical Diagnostic Pitfalls to Avoid

• Do not measure testosterone during acute illness, as levels are artificially suppressed and unreliable 2
• Do not rely on screening questionnaires alone, as they lack specificity for systematic diagnosis 2
• Do not initiate testosterone therapy without confirming elevated gonadotropins, as normal or low LH/FSH indicates secondary hypogonadism requiring different management 2

Treatment Approach

Testosterone replacement therapy is the definitive treatment for primary hypogonadism, as these patients cannot achieve fertility restoration through gonadotropin therapy due to testicular failure. 1, 4, 5, 4

First-Line Testosterone Formulation

• Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied to shoulders and upper arms is the preferred first-line formulation due to stable day-to-day testosterone levels 2, 4
• The dose can be adjusted between 20.25 mg (minimum) and 81 mg (maximum) based on pre-dose morning testosterone levels 4

Alternative Testosterone Formulations

• Intramuscular testosterone cypionate or enanthate 50-400 mg every 2-4 weeks is a more economical option ($156.24 annually vs. $2,135.32 for transdermal) 3, 5
• Injectable testosterone has higher risk of erythrocytosis compared to transdermal preparations 3
• Peak serum levels occur 2-5 days after injection, with return to baseline by days 10-14 3

Dose Titration Protocol

• Check testosterone levels at 2-3 months after treatment initiation or dose adjustment 3, 4
• For transdermal gel: if pre-dose morning testosterone >750 ng/dL, decrease by 20.25 mg; if 350-750 ng/dL, continue current dose; if <350 ng/dL, increase by 20.25 mg 4
• For injectable testosterone: measure levels midway between injections, targeting mid-normal value (500-600 ng/dL) 3
• Once stable levels are confirmed, monitor every 6-12 months 3

Monitoring Requirements During Treatment

• Check hematocrit periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases 2, 3
• Monitor PSA levels in men over 40 years and adjust treatment if significant increases occur 2
• Assess for benign prostatic hyperplasia symptoms through prostate examination 2

Expected Treatment Outcomes

• Testosterone therapy improves sexual function and libido in hypogonadal men, with small but significant improvements in quality of life 3
• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol can be expected 3
• Little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition should be anticipated 3
• Modest improvements in bone mineral density may occur 3

Absolute Contraindications to Testosterone Therapy

Men actively seeking fertility are absolutely contraindicated from receiving testosterone therapy, as it suppresses spermatogenesis and causes azoospermia; however, in primary hypogonadism, fertility is already compromised due to testicular failure. 1, 2

• Active or treated male breast cancer is an absolute contraindication 2
• Active prostate cancer is an absolute contraindication, though evidence is evolving 3
• Untreated severe obstructive sleep apnea is a contraindication 2

Critical Treatment Caveats

• Testosterone therapy is absolutely contraindicated in eugonadal men (normal testosterone levels), even if symptomatic, and should not be used for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men 2, 3
• In primary hypogonadism, gonadotropin therapy (hCG plus FSH) will not restore fertility because the testicular failure is at the gonadal level, not hypothalamic-pituitary 1
• Testosterone therapy produces only small improvements in sexual function and quality of life, with limited effects on other domains 2
• For men with primary hypogonadism seeking biological children, assisted reproductive techniques (testicular sperm extraction, testicular microdissection) may be necessary if any viable sperm can be retrieved 6