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

Management of Normal FSH/LH with Low Total Testosterone

This presentation indicates secondary (central) hypogonadism, and the first critical step is confirming the diagnosis with a second morning testosterone measurement while simultaneously measuring LH, FSH, and prolactin to establish the etiology and rule out reversible causes. 1, 2

Diagnostic Confirmation Required

Before any treatment decisions, you must establish persistent biochemical hypogonadism:

• Repeat morning total testosterone (8-10 AM) on a separate day using the same laboratory and methodology, as single measurements are insufficient due to assay variability and diurnal fluctuation 1, 3, 2
• Diagnosis requires TWO measurements <300 ng/dL combined with consistent clinical symptoms of hypogonadism 1, 2, 4
• Measure free testosterone by equilibrium dialysis if total testosterone is borderline (275-350 ng/dL) or if obesity is present, as low SHBG can artificially lower total testosterone while free testosterone remains normal 1, 3, 2

Essential Workup for Secondary Hypogonadism

The normal FSH/LH with low testosterone defines this as secondary (hypothalamic-pituitary) hypogonadism, which has critical treatment implications:

• Measure serum prolactin immediately to screen for hyperprolactinemia, a reversible cause of secondary hypogonadism 1, 2, 5, 4
• If prolactin is elevated, obtain pituitary MRI and measure other pituitary hormones (TSH, free T4, cortisol, IGH-1) to evaluate for pituitary adenoma or other sellar masses 1, 5
• Check iron saturation to exclude hemochromatosis as a cause 1
• Assess thyroid function (TSH, free T4), as thyroid dysfunction can cause or contribute to hypogonadism 5

Critical Fertility Assessment

Before initiating ANY treatment, you must determine fertility intentions:

• Testosterone therapy is absolutely contraindicated in men seeking fertility preservation, as it suppresses spermatogenesis and causes prolonged azoospermia 1, 3, 4, 6
• For men desiring fertility, gonadotropin therapy (recombinant hCG plus FSH) is mandatory and represents first-line treatment for secondary hypogonadism with fertility concerns 1, 3, 4
• This distinction is critical because men with secondary hypogonadism can achieve both fertility restoration AND normal testosterone levels with gonadotropin therapy, whereas testosterone permanently compromises fertility 1, 3

Symptom Assessment for Treatment Justification

Testosterone therapy requires BOTH low testosterone AND specific symptoms:

Primary symptoms with proven benefit:

• Diminished libido and erectile dysfunction (standardized mean difference 0.35 for improvement) 1, 3, 2, 4
• Reduced energy and endurance 1

Symptoms with minimal or NO proven benefit (do not justify treatment alone):

• Fatigue, low energy, or sluggishness (SMD only 0.17) 1, 3
• Depressed mood (SMD only -0.19) 1, 3
• Physical functioning, muscle strength, or cognition (little to no effect) 1, 3, 4

Lifestyle Modifications (First-Line for Obesity-Related Secondary Hypogonadism)

If the patient has BMI >25 kg/m² or obesity:

• Attempt weight loss through low-calorie diets BEFORE initiating testosterone, as this can improve testosterone levels without medication 1, 3, 2, 4
• Regular physical activity provides similar benefits, though testosterone increases are typically modest (1-2 nmol/L) 1, 2
• Excessive aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion, explaining the secondary hypogonadism 1

Treatment Algorithm

If Fertility is NOT a Concern and Hypogonadism is Confirmed:

First-line testosterone formulation:

• Transdermal testosterone gel 1.62% at 40.5 mg daily is preferred due to stable day-to-day testosterone levels and lower erythrocytosis risk compared to injectable formulations 1, 3, 7
• Target mid-normal testosterone levels (450-600 ng/dL) during treatment 1, 3, 2, 4

Alternative formulations:

• Testosterone cypionate or enanthate 100-200 mg IM every 2 weeks if cost is a concern (annual cost $156 vs. $2,135 for gel), though this carries 43.8% risk of elevated hematocrit >52% 1, 3
• Testosterone undecanoate 750 mg IM initially, repeat at 4 weeks, then every 10 weeks as third-line option for fewer yearly injections 1

If Fertility IS a Concern:

• Gonadotropin therapy with recombinant hCG plus FSH is the only appropriate treatment 1, 3, 4, 8
• This directly stimulates the testes and can restore both testosterone production and spermatogenesis 1, 3

Absolute Contraindications to Testosterone Therapy

Do not initiate testosterone if ANY of the following are present:

• Active desire for fertility preservation 1, 3, 4, 6
• Breast or prostate cancer 1, 3, 4, 6
• PSA >4 ng/mL (or >3 ng/mL in high-risk men) without urological evaluation 1, 4, 6
• Hematocrit >50% 1, 4, 6
• Untreated severe obstructive sleep apnea 1, 4, 6
• Uncontrolled heart failure or MI/stroke within past 6 months 1, 4, 6

Baseline Testing Before Initiating Testosterone

• Hemoglobin/hematocrit (withhold if >50%) 1, 2, 4
• PSA in men >40 years (obtain second PSA if elevated to rule out spurious elevation) 1, 2, 4
• Digital rectal examination to assess for palpable prostate nodules 1, 4
• Lipid profile, blood pressure, and diabetes screening as modifiable cardiovascular risk factors 1

Monitoring During Treatment

First 3-6 months (most intensive monitoring period):

• Testosterone levels at 2-3 months, then every 6-12 months once stable 1, 3, 2, 4
• Hematocrit every 3-6 months initially (most changes occur in first 3 months), then less frequently once stable 1, 4
• Withhold treatment if hematocrit >54% and consider therapeutic phlebotomy 1, 3, 4
• PSA monitoring in men >40 years (urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter) 1, 4

Expected Treatment Outcomes

Set realistic expectations with the patient:

• Small but significant improvements in sexual function and libido (SMD 0.35) 1, 3, 4
• Modest quality of life improvements, primarily in sexual function domains 1, 3
• Little to no effect on physical functioning, energy, vitality, or cognition even with confirmed hypogonadism 1, 3, 4
• Potential improvements in metabolic parameters including fasting glucose, insulin resistance, triglycerides, and HDL cholesterol 3

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility, as this causes irreversible azoospermia 1, 3
• Never diagnose hypogonadism based on symptoms alone without two confirmed low testosterone measurements 1, 2
• Never assume age-related decline justifies treatment in the absence of true biochemical hypogonadism 1, 3
• Never skip investigation for secondary causes (prolactinoma, hemochromatosis, pituitary dysfunction) in secondary hypogonadism, as these may be reversible 1, 5
• Reevaluate at 12 months and discontinue testosterone if no improvement in sexual function, to prevent unnecessary long-term exposure without benefit 1, 3