What is the diagnostic approach and treatment for a patient suspected of having hypogonadism?

Diagnostic Approach for Hypogonadism

Diagnose hypogonadism by confirming both biochemical testosterone deficiency (morning total testosterone <300 ng/dL on two separate occasions) and persistent specific symptoms—particularly diminished libido and erectile dysfunction—while distinguishing primary from secondary hypogonadism through gonadotropin measurement. 1

Initial Laboratory Testing

• Measure morning total testosterone (8-10 AM) on two separate days to confirm persistent hypogonadism, as single measurements are insufficient due to pulsatile secretion and assay variability 2, 1
• Testosterone levels <300 ng/dL indicate hypogonadism, while levels >350 ng/dL generally exclude the diagnosis 2, 1
• For borderline values (300-350 ng/dL), measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in men with obesity, diabetes, or aging, where low SHBG may artificially lower total testosterone 2, 1

Distinguishing Primary from Secondary Hypogonadism

Once low testosterone is confirmed, measure serum LH and FSH to determine the type of hypogonadism 2, 1:

• Elevated LH/FSH with low testosterone = Primary (testicular) hypogonadism 2
• Low or low-normal LH/FSH with low testosterone = Secondary (hypothalamic-pituitary) hypogonadism 2, 1

This distinction has critical treatment implications, particularly for fertility preservation 2, 1.

Additional Workup for Secondary Hypogonadism

If secondary hypogonadism is identified:

• Measure serum prolactin to exclude hyperprolactinemia 1
• Assess for reversible causes: medications (opiates, glucocorticoids, anabolic steroids), obesity, type 2 diabetes, metabolic syndrome, chronic systemic diseases 1
• Consider pituitary imaging (MRI sella turcica) if prolactin is elevated or other pituitary dysfunction is suspected 2

Symptom Assessment

The diagnosis requires both biochemical confirmation AND specific symptoms 1:

Primary Symptoms (Strong Evidence for Treatment Benefit):

• Diminished libido and reduced frequency of sexual intercourse 1
• Erectile dysfunction 1
• Delayed ejaculation and reduced frequency of masturbation 1

Secondary Symptoms (Weaker Evidence):

• Hot flushes and decreased energy 1
• Reduced physical strength and activity 1
• Concentration or memory difficulties 1
• Sleep disturbances 1

Critical Pitfalls to Avoid

• Never test testosterone during acute illness, as levels are transiently suppressed 1
• Never rely on screening questionnaires alone, as they lack specificity 1
• Never diagnose hypogonadism based on symptoms without biochemical confirmation 2, 1
• Never start testosterone therapy without assessing fertility desires, as exogenous testosterone suppresses spermatogenesis and causes azoospermia 2, 1
• Do not attempt to diagnose the type of hypogonadism while the patient is on testosterone therapy, as exogenous testosterone suppresses gonadotropins and results will be misleading 2

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Treatment Approach for Hypogonadism

Initiate testosterone replacement therapy only when both confirmed biochemical hypogonadism and specific symptoms (particularly sexual dysfunction) are present, using transdermal testosterone gel as first-line therapy due to more stable testosterone levels and lower erythrocytosis risk. 2

Pre-Treatment Requirements

Before initiating testosterone therapy:

• Confirm the patient does not desire fertility, as testosterone therapy is absolutely contraindicated in men seeking fertility preservation 2, 1
  • For men with secondary hypogonadism desiring fertility, use gonadotropin therapy (recombinant hCG plus FSH) instead 2, 1
• Obtain baseline hematocrit/hemoglobin, as hematocrit >54% is an absolute contraindication 2, 3
• Measure baseline PSA and perform digital rectal examination in men over 40 years 2
• Exclude active breast or prostate cancer 2, 3

First-Line Treatment Selection

Transdermal testosterone gel 1.62% is the preferred first-line formulation, starting at 40.5 mg daily (2 pump actuations or one 40.5 mg packet) applied to shoulders and upper arms 2, 3:

• Provides more stable day-to-day testosterone levels compared to injections 2
• Lower risk of erythrocytosis than injectable testosterone 2
• Applied once daily in the morning to clean, dry, intact skin of shoulders and upper arms only 3
• Patients must wash hands immediately with soap and water after application 3
• Cover application sites with clothing after gel dries to prevent secondary exposure 3

Alternative Treatment Options

If cost is a concern or patient preference favors injections:

• Intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks (or 50-100 mg weekly) 2
  • Annual cost approximately $156 vs. $2,135 for transdermal gel 2
  • Higher risk of erythrocytosis (up to 44%) compared to transdermal preparations 2
  • Peak levels occur days 2-5, return to baseline by days 10-14 2

Dose Titration and Monitoring

• Check testosterone levels at 14 days and 28 days after starting treatment or dose adjustment 3
• Target mid-normal testosterone levels (500-600 ng/dL) 2
• For injectable testosterone, measure levels midway between injections (days 5-7) 2

Dose adjustment algorithm 3:

• If testosterone >750 ng/dL: Decrease dose by 20.25 mg

• If testosterone 350-750 ng/dL: Continue current dose

• If testosterone <350 ng/dL: Increase dose by 20.25 mg

• Once stable, monitor testosterone every 6-12 months 2

Ongoing Safety Monitoring

• Monitor hematocrit at each visit; withhold treatment if >54% and consider phlebotomy 2, 3
• Monitor PSA in men over 40 years; refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 2
• Perform digital rectal examination periodically to assess for prostate abnormalities 2

Expected Treatment Outcomes

Set realistic expectations with patients 2:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 2
• Modest quality of life improvements, primarily in sexual function domains 2
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition 2
• Minimal improvements in fatigue (standardized mean difference 0.17) 2

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

Absolute Contraindications

• Active desire for fertility preservation 2, 1
• Active or treated male breast cancer 2, 3
• Prostate cancer 2, 3
• Hematocrit >54% 2, 3
• Untreated severe obstructive sleep apnea 2
• Pregnancy in female partners (risk of secondary exposure) 3

Special Populations

Obesity-Associated Secondary Hypogonadism:

• Attempt weight loss through low-calorie diets and regular exercise first, as this can improve testosterone levels without medication 2

Men with Diabetes:

• Optimize diabetes management concurrently, considering GLP-1 receptor agonists or SGLT2 inhibitors for cardiovascular benefits 2
• Testosterone therapy may improve insulin resistance and reduce HbA1c by approximately 0.37% 2

Elderly Men:

• Target mid-range testosterone levels (350-600 ng/dL) 2
• Use easily titratable formulations (gel, spray, or patch) to allow dose adjustment 2

Critical Warning: Secondary Exposure Prevention

Children and women must never touch areas where testosterone has been applied 3:

• Virilization has been reported in children secondarily exposed to testosterone gel 3
• Wash application site thoroughly with soap and water before any skin-to-skin contact 3
• Accidental exposure can cause early puberty, enlarged genitals in children, and unwanted facial/body hair growth in women 2