What is the appropriate work‑up and management for a male with low testosterone and normal luteinizing hormone (LH) and follicle‑stimulating hormone (FSH)?

Secondary Hypogonadism: Work-up and Management

You have secondary (hypogonadotropic) hypogonadism, characterized by low testosterone with inappropriately normal or low LH/FSH, requiring systematic evaluation to identify the underlying cause before initiating treatment. 1, 2

Initial Diagnostic Work-up

Mandatory Laboratory Testing

• Measure serum prolactin immediately – this is essential in all cases of secondary hypogonadism to exclude prolactinoma, as elevated prolactin is a common and treatable cause 1, 3
• Repeat prolactin if elevated to confirm the finding is not spurious; persistently elevated levels (especially >2x upper limit of normal) strongly predict pituitary adenoma and warrant endocrinology referral 1, 3
• Obtain morning cortisol and ACTH (between 8-10 AM) to screen for concurrent adrenal insufficiency, as multiple pituitary hormone deficiencies suggest hypophysitis or pituitary mass 1, 3
• Check TSH and free T4 to evaluate for central hypothyroidism, another indicator of broader pituitary dysfunction 1, 4

Pituitary Imaging Indications

• Order pituitary MRI with and without contrast (with sellar cuts) if: 1, 3
  • Total testosterone <150 ng/dL with low/normal LH (regardless of prolactin level) 1
  • Evidence of multiple pituitary hormone deficiencies 1, 3
  • Persistently elevated prolactin levels 1
  • New severe headaches or visual changes 1

Evaluate and Address Reversible Causes

Before committing to lifelong testosterone replacement, systematically address potentially reversible factors:

Metabolic and Lifestyle Factors

• Screen for obesity and encourage weight loss – a 5-10% weight reduction can significantly increase endogenous testosterone production in obese men with secondary hypogonadism 1, 3
• Evaluate for metabolic syndrome, diabetes, and cardiovascular risk factors – these conditions commonly suppress the hypothalamic-pituitary-gonadal axis 1, 5
• Screen for obstructive sleep apnea – untreated sleep apnea is a common reversible cause of secondary hypogonadism 3

Medication Review

• Review all current medications, particularly: 3, 5
  • Opioids (cause dose-dependent suppression of gonadotropins)
  • Glucocorticoids (suppress the hypothalamic-pituitary axis)
  • Other medications affecting the HPG axis
• Consider discontinuation or dose reduction if clinically feasible 5

Treatment Approach

If Fertility is NOT a Current Goal

• Testosterone replacement therapy is appropriate once reversible causes are addressed and pathological hypogonadism is confirmed 1, 6, 5
• Confirm diagnosis with two separate morning testosterone measurements (8-10 AM) showing levels below the normal range before initiating therapy 1, 6
• Measure baseline hemoglobin/hematocrit before starting treatment; withhold if Hct >50% until etiology is investigated 1
• Start with testosterone gel 1.62% at 40.5 mg daily (applied to shoulders and upper arms), or use injectable testosterone ester as first-line treatment 6, 2
• Monitor testosterone levels at 14 and 28 days after starting treatment to adjust dosing, targeting pre-dose morning levels of 350-750 ng/dL 6

If Fertility IS a Goal

• Do NOT use testosterone replacement therapy – exogenous testosterone suppresses spermatogenesis and will worsen fertility 1, 7
• Refer to reproductive endocrinology for gonadotropin therapy (hCG plus FSH) to stimulate both testosterone production and spermatogenesis 7
• Perform baseline testicular examination and measure FSH to assess reproductive health status 1
• Consider semen analysis if FSH is elevated, as this suggests impaired spermatogenesis 1
• Gonadotropin therapy for 12-24 months promotes testicular growth in nearly all patients, spermatogenesis in ~80%, and pregnancy rates around 50% 7

Key Clinical Pitfalls

• Never assume "age-related" hypogonadism without excluding pathological causes – safety and efficacy of testosterone therapy in this setting remain unestablished 6, 5
• Always start corticosteroid replacement before thyroid hormone if both deficiencies are present, to prevent precipitating adrenal crisis 1
• Recognize that normal LH/FSH with low testosterone is abnormal – gonadotropins should be elevated in response to low testosterone; normal levels indicate hypothalamic-pituitary dysfunction 2, 8
• Monitor hematocrit on testosterone therapy – intervention is warranted if Hct >54% (dose reduction or temporary discontinuation) 1

Expected Benefits of Treatment

Testosterone therapy may improve: 1

• Erectile function and libido
• Anemia
• Bone mineral density
• Lean body mass
• Depressive symptoms
• Overall sense of well-being 2

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