What is the approach for an adult male patient with low testosterone levels but normal Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels?

Approach to Low Testosterone with Normal FSH and LH

This presentation indicates secondary (hypogonadotropic) hypogonadism, where the pituitary fails to appropriately elevate LH and FSH in response to low testosterone—the normal or low-normal gonadotropin levels are physiologically inappropriate and represent hypothalamic-pituitary dysfunction. 1, 2

Understanding the Diagnosis

This pattern—low testosterone with normal (or low-normal) FSH and LH—defines secondary hypogonadism, also called hypogonadotropic hypogonadism. 3 The key insight is that "normal" gonadotropin levels are actually abnormal in the context of low testosterone, since a functioning pituitary should respond to low testosterone by increasing LH and FSH secretion. 4, 5

Distinguish from Primary Hypogonadism

• Primary hypogonadism shows low testosterone with elevated FSH and LH (>normal range), indicating testicular failure with intact pituitary compensation 1, 3
• Secondary hypogonadism shows low testosterone with normal or low FSH and LH, indicating pituitary-hypothalamic dysfunction 1, 3

Diagnostic Workup Algorithm

Step 1: Confirm Persistent Hypogonadism

• Repeat morning total testosterone (8-10 AM) on at least two separate occasions to confirm levels consistently <300 ng/dL 1, 2
• Measure free testosterone by equilibrium dialysis if total testosterone is borderline (275-350 ng/dL) 2
• Measure sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from SHBG-related changes 2

Step 2: Investigate Secondary Causes

Once secondary hypogonadism is confirmed with normal/low LH and FSH:

• Measure serum prolactin—elevated prolactin indicates possible prolactinoma or other pituitary tumor 1, 2
• If prolactin is elevated, repeat measurement to confirm; persistently elevated prolactin requires endocrinology referral and pituitary MRI 1
• If testosterone <150 ng/dL with low/normal LH, obtain pituitary MRI regardless of prolactin level to evaluate for non-secreting adenomas 1
• Evaluate for reversible causes: obesity, diabetes, metabolic syndrome, sleep apnea, chronic opioid use, corticosteroid use, iron overload, pituitary surgery/radiation history 1, 6, 5

Step 3: Assess Fertility Intentions

This is critical before any treatment decision:

• If fertility preservation is desired: Testosterone replacement therapy is absolutely contraindicated 1, 2
• Men seeking fertility must receive gonadotropin therapy (recombinant hCG plus FSH) instead, which stimulates the testes directly and restores both testosterone production and spermatogenesis 1, 2
• Measure baseline FSH and perform testicular examination to assess reproductive health status 1

Treatment Options

For Men NOT Seeking Fertility

First-Line: Address Reversible Causes

• Weight loss through caloric restriction can improve testosterone levels in obesity-associated secondary hypogonadism—attempt this before medication 2, 6
• Optimize management of diabetes, sleep apnea, and discontinue offending medications if possible 6

Second-Line: Selective Estrogen Receptor Modulators (SERMs)

Clomiphene citrate is particularly valuable for secondary hypogonadism:

• Stimulates endogenous testosterone production without suppressing spermatogenesis 7
• Preserves fertility potential even if not actively seeking conception 7
• Lower risk of polycythemia compared to testosterone replacement 7
• Dosing: Start 25-50 mg daily or every other day, titrate based on testosterone response at 3 months 7
• Switch to testosterone replacement if no response after 3 months or if fertility preservation becomes irrelevant 7

Third-Line: Testosterone Replacement Therapy

Only if fertility is not a concern and SERMs have failed or are inappropriate:

• Transdermal testosterone gel (40.5 mg daily) is preferred first-line formulation due to stable day-to-day levels 2
• Intramuscular testosterone cypionate/enanthate (100-200 mg every 2 weeks) is more economical ($156/year vs $2,135/year for transdermal) with similar efficacy 1, 2
• Target mid-normal testosterone levels (500-600 ng/dL) 2

Expected Treatment Outcomes

Set realistic expectations:

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

Monitoring Requirements

Initial Monitoring (First 6 Months)

• Testosterone levels at 2-3 months after treatment initiation or dose change 2
• For injectable testosterone: measure levels midway between injections (days 5-7), targeting 500-600 ng/dL 2
• Hematocrit at each visit—withhold treatment if >54% and consider phlebotomy 1, 2
• PSA in men >40 years—refer to urology if increase >1.0 ng/mL in first 6 months or >0.4 ng/mL/year thereafter 2

Long-Term Monitoring

• Once stable, monitor testosterone and hematocrit every 6-12 months 2
• Reevaluate symptoms at 12 months—discontinue testosterone if no improvement in sexual function 1, 2

Absolute Contraindications to Testosterone Therapy

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

Critical Pitfalls to Avoid

• Never start testosterone without confirming fertility intentions—exogenous testosterone causes prolonged azoospermia that may take 6-18 months to reverse after discontinuation 1, 2
• Never diagnose hypogonadism based on symptoms alone—approximately 20-30% of men receiving testosterone lack documented biochemical hypogonadism 1, 2
• Never assume "normal" LH/FSH means normal pituitary function when testosterone is low—this represents inappropriate pituitary response 1, 5
• Never skip investigation for reversible causes (obesity, medications, sleep apnea)—these must be addressed first 6, 5
• Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable testosterone—measure midway between injections 2