What is the diagnostic approach and treatment for a patient with suspected late onset hypogonadism (low testosterone levels)?

Diagnosis of Late-Onset Hypogonadism

The diagnosis of late-onset hypogonadism requires both persistent specific symptoms (particularly diminished libido and erectile dysfunction) AND confirmed biochemical testosterone deficiency with morning total testosterone below 300 ng/dL measured on at least two separate occasions between 8-10 AM. 1, 2

Diagnostic Algorithm

Step 1: Identify Specific Symptoms

The cornerstone of diagnosis requires hypogonadism-consistent symptoms, not just screening questionnaires which lack specificity 1. The most specific symptoms warranting testosterone measurement include:

• Diminished libido (most specific symptom associated with low testosterone) 1, 3
• Erectile dysfunction 1, 2
• Decreased sense of vitality 1, 4
• Reduced muscle mass and strength 5
• Increased adiposity 5
• Depressive mood 4, 5

Critical pitfall to avoid: Never diagnose hypogonadism based on symptoms alone without biochemical confirmation, and screening questionnaires have clinical value but lack specificity for systematic screening 1, 2.

Step 2: Obtain Morning Testosterone Measurements

Measure morning total testosterone between 8-10 AM on two separate days to confirm levels are consistently below 300 ng/dL 1, 2, 6. Single measurements are insufficient due to assay variability and diurnal fluctuation 2, 7.

• Total testosterone <200 ng/dL indicates clear hypogonadism 4
• Total testosterone 200-300 ng/dL requires repeat measurement plus free testosterone assessment 4
• Avoid testing during acute illness, as this interferes with accurate assessment 1

Step 3: Measure Free Testosterone in Borderline Cases

In men with total testosterone between 200-400 ng/dL or those with obesity (which lowers SHBG), measure free testosterone by equilibrium dialysis or calculate free testosterone index using total testosterone, SHBG, and albumin 1, 2, 4.

Step 4: Distinguish Primary from Secondary Hypogonadism

Measure serum LH and FSH levels to determine the type of hypogonadism 2, 6:

• Primary (hypergonadotropic): Low testosterone with elevated LH/FSH indicates testicular dysfunction 1, 2
• Secondary (hypogonadotropic): Low testosterone with low or inappropriately normal LH/FSH indicates hypothalamic-pituitary dysfunction 1, 2

This distinction is critical because secondary hypogonadism patients can potentially achieve both fertility and normal testosterone levels with gonadotropin therapy, while primary hypogonadism patients can only receive testosterone therapy, which compromises fertility by suppressing the HPG axis 1.

Step 5: Exclude Classical Organic Causes

LOH diagnosis is based on exclusion of classical (organic) etiology 1. Check for:

Drugs and substances interfering with testosterone production:

• Opioids, glucocorticoids, anabolic steroids 1
• Anticonvulsants, estrogens 1

Comorbid conditions:

• Obesity/metabolic syndrome/type 2 diabetes 1
• Hypothyroidism or hyperthyroidism 1
• Cushing's disease, acromegaly 1
• Nonalcoholic fatty liver disease 1
• HIV/AIDS 1

Pituitary disorders (if secondary hypogonadism):

• Measure serum prolactin to evaluate for hyperprolactinemia 2
• Consider pituitary MRI if prolactin is elevated or other pituitary dysfunction is suspected 2
• Assess iron saturation to evaluate for hemochromatosis 2

Step 6: Assess for Contraindications Before Treatment

Before initiating testosterone therapy, evaluate for absolute contraindications 1, 2:

• Active desire for fertility preservation (testosterone is absolutely contraindicated; use gonadotropin therapy instead) 1, 2
• Active or treated male breast cancer 1, 2
• Hematocrit >54% 1, 2
• Untreated severe obstructive sleep apnea 2
• Recent cardiovascular events within 3-6 months 2

Perform baseline assessments 2, 8:

• Digital rectal examination and PSA level in men over 40 years 2
• Baseline hematocrit or hemoglobin 2
• BMI and waist circumference 1

Treatment Considerations

Lifestyle Modifications First

For obesity-associated secondary hypogonadism, weight loss through low-calorie diets can reverse the condition by improving testosterone levels and normalizing gonadotropins, though increases are modest (1-2 nmol). 1 Physical activity shows similar benefits, with results correlating to exercise duration and weight loss 1. While lifestyle changes are essential, evidence suggests combining these with testosterone therapy may yield better outcomes in symptomatic patients 1.

Testosterone Replacement Therapy

Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation for men with confirmed hypogonadism not seeking fertility 2. Alternative options include:

• Intramuscular testosterone cypionate or enanthate: 50-400 mg every 2-4 weeks 8, 6
• Target mid-normal testosterone levels (500-600 ng/dL) when monitoring therapy 2

Expected outcomes with testosterone therapy:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 2, 5
• Modest quality of life improvements 2
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition 1, 2

Monitoring During Treatment

Check testosterone levels at 14 and 28 days after initiation or dose adjustment, then every 6-12 months 2. Monitor hematocrit periodically and withhold treatment if >54% 1, 2. Monitor PSA levels in men over 40 years 1, 2. Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen 2.

Fertility Preservation

For men with secondary hypogonadism seeking fertility, gonadotropin therapy with recombinant hCG plus FSH is mandatory, and testosterone therapy is absolutely contraindicated because exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia 1, 2.