Diagnosis and Treatment of Hypogonadism

Diagnostic Confirmation Required

Hypogonadism diagnosis requires both biochemical confirmation with morning total testosterone <300 ng/dL measured on two separate occasions between 8-10 AM, plus specific symptoms such as decreased libido, erectile dysfunction, or diminished sense of vitality. 1

Essential Laboratory Testing

Measure morning total testosterone (8-10 AM) on two separate days to confirm persistent low levels, as single measurements are insufficient due to assay variability and diurnal fluctuation 1, 2
In men with obesity, diabetes, or borderline total testosterone (231-346 ng/dL), measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), as low SHBG can artificially lower total testosterone while free testosterone remains normal 1, 2, 3
Measure serum LH and FSH after confirming low testosterone to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 1, 3
- Elevated LH/FSH with low testosterone = primary hypogonadism
- Low or inappropriately normal LH/FSH with low testosterone = secondary hypogonadism 1, 3

Additional Workup for Secondary Hypogonadism

Measure serum prolactin to exclude hyperprolactinemia 1, 3
Check iron saturation to evaluate for hemochromatosis 3
Consider pituitary MRI if prolactin is elevated or other pituitary dysfunction is suspected 1, 3
Avoid testosterone testing during acute illness, as this can artificially suppress levels 1

Critical Treatment Decision: Fertility Preservation

Before initiating any treatment, you MUST determine if the patient desires current or future fertility, as this fundamentally changes the treatment approach. 1, 4

For Men Seeking Fertility (Secondary Hypogonadism Only)

Testosterone therapy is absolutely contraindicated in men seeking fertility, as it suppresses spermatogenesis and causes azoospermia that may persist for months to years after discontinuation 1, 4
First-line treatment: Gonadotropin therapy with recombinant human chorionic gonadotropin (hCG) 500-2500 IU subcutaneously or intramuscularly 2-3 times weekly 1, 4, 5
After testosterone levels normalize on hCG monotherapy, add FSH (recombinant or highly purified urinary) if needed to optimize spermatogenesis 1, 4, 5
Combined hCG + FSH therapy for 12-24 months promotes testicular growth in nearly all patients, spermatogenesis in ~80%, and pregnancy rates of ~50% 5
Primary hypogonadism patients cannot benefit from gonadotropin therapy and require surgical sperm extraction with assisted reproductive technologies 1

For Men NOT Seeking Fertility

Proceed to testosterone replacement therapy as outlined below.

First-Line Testosterone Replacement Therapy

For confirmed hypogonadism without fertility concerns, transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation due to stable day-to-day testosterone levels and lower erythrocytosis risk compared to injectable preparations. 1, 2, 3

Alternative Formulations Based on Patient Factors

Intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks (or 50-100 mg weekly for more stable levels) if cost is a primary concern (annual cost ~$156 vs ~$2,135 for gel) 2, 6
- Peak levels occur days 2-5 after injection, return to baseline by days 10-14 2, 6
- Monitor testosterone levels midway between injections (days 5-7), targeting mid-normal range 500-600 ng/dL 2, 3
- Higher risk of erythrocytosis compared to transdermal preparations 1, 2
Testosterone undecanoate 750 mg initially, repeat at 4 weeks, then every 10 weeks for patients preferring fewer injections 2
Transdermal patches or topical solutions for patients preferring non-gel transdermal options 1, 2

Lifestyle Modifications as Adjunctive Therapy

For men with obesity-associated secondary hypogonadism, weight loss through low-calorie diets and regular physical activity can improve testosterone levels by 1-2 nmol/L, though combining lifestyle changes with testosterone therapy yields better outcomes than lifestyle changes alone. 1

Target weight loss through hypocaloric diet and regular exercise, which improves testosterone by reducing excessive aromatization of testosterone to estradiol in adipose tissue 1, 2
Smoking cessation and avoiding excess alcohol also improve testosterone levels and sexual function 2

Expected Treatment Outcomes: Setting Realistic Expectations

Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference 0.35), with modest quality of life improvements primarily in sexual function domains. 1, 2, 3

Proven Benefits

Sexual function and libido: Small but significant improvement (SMD 0.35) 1, 2, 3
Metabolic improvements: Reduced fasting glucose, improved insulin resistance, decreased triglycerides, increased HDL cholesterol 2
Bone mineral density: Potential improvement, particularly relevant for long-term bone health 2, 3
Body composition: Increased lean body mass, decreased body fat 2

Minimal or No Benefits

Physical functioning: Little to no effect (SMD 0.17 for energy/fatigue) 1, 2, 3
Depressive symptoms: Less-than-small improvement (SMD -0.19) 2, 3
Energy and vitality: Minimal improvements, effect sizes too small to be clinically meaningful 1, 2, 3
Cognition: No demonstrated benefit 1, 2, 3

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, to prevent unnecessary long-term exposure to potential risks without benefit. 2, 3

Monitoring Requirements During Treatment

Initial Monitoring (First 3-6 Months)

Check testosterone levels at 2-3 months after initiation or dose adjustment 1, 2, 3
- For transdermal preparations: measure any time of day once steady-state is achieved
- For injectable testosterone: measure midway between injections (days 5-7 for cypionate/enanthate) 2, 3
- Target mid-normal range: 500-600 ng/dL 2, 3
Monitor hematocrit/hemoglobin at each visit 1, 2, 3
- Withhold treatment if hematocrit >54% 1, 2, 3
- Consider phlebotomy in high-risk cases with persistent erythrocytosis 1, 2
In men over 40 years: measure PSA and perform digital rectal examination 1, 2, 3
- Refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 2, 3

Long-Term Monitoring (After Stabilization)

Once stable testosterone levels are confirmed, monitor every 6-12 months 1, 2, 3
Continue hematocrit and PSA monitoring at each visit 1, 2, 3
Assess symptomatic response, particularly sexual function 2, 3

Absolute Contraindications to Testosterone Therapy

Never initiate testosterone therapy in the following situations: 1, 2, 3

Active desire for fertility preservation (use gonadotropin therapy instead) 1, 3, 4
Active or treated male breast cancer 1, 2, 3
Hematocrit >54% 1, 2, 3
Untreated severe obstructive sleep apnea 2, 3
Recent cardiovascular events (myocardial infarction, stroke) within past 3-6 months 2, 6

Relative Contraindications Requiring Caution

Prostate cancer (evolving evidence; discuss with oncologist) 2
Congestive heart failure (risk of fluid retention; target mid-range testosterone levels) 2, 6
Severe benign prostatic hyperplasia with urinary symptoms 1, 6

Critical Pitfalls to Avoid

Never diagnose hypogonadism based on symptoms alone without biochemical confirmation on two separate morning measurements 1, 2, 3
Never start testosterone without confirming the patient does not desire fertility, as this causes prolonged azoospermia that may be irreversible 1, 3
Never attempt to diagnose primary vs. secondary hypogonadism while the patient is already on testosterone therapy, as exogenous testosterone suppresses LH/FSH and results will be misleading 2, 3
Never prescribe testosterone to eugonadal men (normal testosterone levels) for weight loss, athletic performance, energy, or cognitive enhancement, as this violates evidence-based guidelines and provides no benefit 1, 2, 3
Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable preparations, as this leads to inappropriate dose adjustments 2
Never skip the workup for secondary causes of hypogonadism in young men, as reversible conditions (hyperprolactinemia, hemochromatosis, medications) must be addressed first 1, 2, 3

Special Populations

Men with Diabetes

Optimize diabetes management concurrently with testosterone therapy; consider adding GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 2
Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c by ~0.37% in hypogonadal men with type 2 diabetes 2
Continue statin therapy as indicated, as testosterone may improve lipid profile 2

Elderly Men (Age-Related Hypogonadism)

The primary indication for testosterone therapy in elderly men is diminished libido and sexual dysfunction, not energy, vitality, or physical function 1, 2, 3
Use easily titratable formulations (gel, patch) and target mid-range testosterone levels (350-600 ng/dL) 2
Be particularly vigilant for cardiovascular events and erythrocytosis in this population 2, 6

Men with Cirrhosis

Transdermal testosterone can be given to hypogonadal men with cirrhosis only after discussing theoretical risks of hepatocellular carcinoma 2
Use free testosterone index (total testosterone/SHBG ratio <0.3) to define hypogonadism in this population 2

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