What are the diagnostic steps and treatment options for secondary hypogonadism?

Secondary Hypogonadism Diagnosis

Diagnose secondary hypogonadism by confirming low morning testosterone (<10.5 nmol/L or ~300 ng/dL) on at least two separate occasions combined with low or inappropriately normal LH/FSH levels, along with specific symptoms of testosterone deficiency. 1

Diagnostic Algorithm

Step 1: Clinical Assessment

Symptom Evaluation - Look for these specific manifestations:

• Sexual symptoms: Reduced frequency of sexual intercourse, decreased masturbation, delayed ejaculation 1
• Physical symptoms: Hot flushes, decreased energy, reduced physical strength/function/activity 1
• Cognitive symptoms: Concentration difficulties, memory problems, sleep disturbances 1

Critical History Elements:

• Evaluate for pituitary disorders (tumors, hemochromatosis) 2
• Document surgical history affecting the hypothalamic-pituitary axis 1
• Identify medications that suppress gonadotropins: opiates, GnRH agonists/antagonists, glucocorticoids, estrogens, progestogens 3
• Assess for obesity and metabolic syndrome (major causes of functional secondary hypogonadism) 3
• Determine fertility desires immediately - this fundamentally changes treatment approach 1, 3

Step 2: Physical Examination

Measure and document:

• Body mass index (BMI) and waist circumference (obesity causes secondary hypogonadism via increased aromatization of testosterone to estradiol, suppressing LH) 3, 2

Step 3: Laboratory Confirmation

Initial Testing:

• Morning total testosterone (8-10 AM) on at least two separate days - this is mandatory 1, 2, 4
• Avoid testing during acute illness (results transiently suppressed) 1, 2

Confirmatory Testing (if initial testosterone is low):

• LH and FSH levels - the defining test for secondary hypogonadism 3, 2
  • Secondary hypogonadism: Low or inappropriately normal LH/FSH with low testosterone 3
  • Primary hypogonadism: Elevated LH/FSH with low testosterone 3
• Free testosterone by equilibrium dialysis - especially critical in obese patients where SHBG is altered 3, 2
• Sex hormone-binding globulin (SHBG) - low levels in obesity affect total testosterone interpretation 3
• Prolactin - measure when testosterone is low with low/normal LH to exclude prolactinoma 2

Step 4: Imaging for Structural Lesions

MRI of hypothalamic-pituitary region is indicated when:

• Total testosterone ≤6.1 nmol/L (~176 ng/dL) 5
• OR LH ≤1.9 U/L 5

These thresholds are more sensitive than the older Endocrine Society recommendation of testosterone <5.2 nmol/L and better predict structural abnormalities like pituitary tumors or hypothalamic lesions. 5

Treatment Options

For Men NOT Seeking Fertility

Testosterone Therapy (TTh) is first-line:

• Starting dose: 50 mg testosterone gel applied topically once daily to shoulders/upper arms 4
• Check morning pre-dose testosterone at 14 days 4
• Target range: 300-1,000 ng/dL 4
• Increase to 100 mg daily if levels remain <300 ng/dL (maximum dose) 4

Lifestyle modifications should be combined with TTh:

• Weight loss through low-calorie diets can reverse obesity-associated secondary hypogonadism 1
• Physical activity provides benefits correlating with exercise duration 1
• However, testosterone increases from lifestyle alone are modest (1-2 nmol/L), so combining with TTh yields better outcomes 1

For Men Seeking Fertility

Gonadotropin therapy is mandatory - testosterone therapy is absolutely contraindicated as it suppresses spermatogenesis:

• Combined hCG and FSH therapy provides optimal outcomes 1
• This maintains testosterone levels while preserving fertility 1, 3
• Recombinant formulations are comparable to urinary-derived preparations 1

Absolute Contraindications to Testosterone Therapy

• Men desiring fertility 1, 3
• Active or treated male breast cancer 1

Specific Treatment Recommendations by Indication

Use TTh as first-line for:

• Mild erectile dysfunction (strong recommendation) 1

Combine PDE5 inhibitors with TTh for:

• Severe erectile dysfunction (weak recommendation) 1

Do NOT use TTh for:

• Eugonadal men (strong recommendation) 1
• Weight reduction or cardiometabolic improvement as primary goal (weak recommendation) 1
• Improving cognition, vitality, or physical strength in aging men (strong recommendation) 1

Critical Pitfalls to Avoid

• Never prescribe testosterone to men wanting fertility - it will suppress spermatogenesis and worsen their condition 3
• Do not test testosterone during acute illness - results are unreliable 1, 2
• Do not rely on single testosterone measurement - at least two morning samples required 1, 2
• Do not skip LH/FSH testing - this distinguishes primary from secondary hypogonadism and fundamentally changes management 3, 2
• In obese patients, measure free testosterone - total testosterone is less reliable due to altered SHBG 3, 2
• Consider MRI with very low testosterone (≤6.1 nmol/L) or LH (≤1.9 U/L) - may indicate pituitary tumor requiring different management 5