What is the differential diagnosis for a male patient with secondary hypogonadism, presenting with complete loss of libido, erectile dysfunction, and loss of penile sensation, with normal total testosterone, low free testosterone, inappropriately normal Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels, and fluctuating prolactin levels?

Differential Diagnosis and Workup for Secondary Hypogonadism with Inappropriately Normal Gonadotropins

This patient has functional hypogonadism—a form of secondary hypogonadism where LH/FSH levels appear "normal" but are inappropriately low relative to the reduced free testosterone, indicating subtle hypothalamic-pituitary axis dysfunction rather than complete failure. 1, 2

Understanding the Biochemical Pattern

The key diagnostic feature here is inappropriately normal LH (6.87 mIU/mL) despite low free testosterone (0.295 nmol/L)—in true eugonadism, low free testosterone should trigger compensatory LH elevation, but this patient's pituitary response is blunted. 1, 3 This distinguishes functional hypogonadism from:

• Primary hypogonadism: Would show elevated LH/FSH (>12-15 mIU/mL) as the pituitary attempts compensation 1, 4
• Classical secondary hypogonadism: Would show frankly low LH/FSH (<2 mIU/mL) 1, 3
• Functional hypogonadism: Shows low-normal gonadotropins that are inadequate for the testosterone level 2

The fluctuating prolactin (69.4 to 9.5 ng/mL) is particularly concerning—the initial elevation suggests intermittent hyperprolactinemia, which directly suppresses GnRH pulsatility. 5

Differential Diagnosis (Prioritized by Likelihood)

Drug-Induced Causes (Most Common—Always Exclude First)

• Opioid medications: Directly suppress GnRH neurons, causing this exact pattern 5, 3
• Glucocorticoids: Suppress hypothalamic-pituitary function 5, 4
• Hyperprolactinemia-inducing drugs: Antipsychotics, metoclopramide, SSRIs 5
• Anabolic steroids or testosterone: Even remote use can cause prolonged axis suppression 5

Pituitary/Hypothalamic Structural Lesions

• Prolactinoma or microprolactinoma: The fluctuating prolactin (peak 69.4 ng/mL) strongly suggests this—even microadenomas cause gonadotropin suppression 5, 3
• Non-functioning pituitary adenoma: Can cause partial gonadotropin deficiency with "normal" but inadequate LH 5, 3
• Hypothalamic tumors: Germinomas, craniopharyngiomas 5, 6
• Traumatic brain injury: Even remote head trauma can cause delayed pituitary dysfunction 5
• Prior pituitary surgery or cranial radiation: Iatrogenic causes 5

Systemic Diseases Causing Functional Hypogonadism

• Metabolic syndrome/Type 2 diabetes: Obesity and insulin resistance suppress GnRH pulsatility 5, 2
• Chronic systemic diseases: HIV, chronic kidney disease, liver disease 5
• Sleep apnea: Causes intermittent hypoxia affecting hypothalamic function 2
• Chronic inflammatory conditions: Rheumatoid arthritis, inflammatory bowel disease 5

Infiltrative/Inflammatory Disorders

• Lymphocytic hypophysitis: Autoimmune pituitary inflammation 5
• Sarcoidosis or granulomatous disease: Can infiltrate hypothalamus/pituitary 5
• Hemochromatosis: Iron deposition in pituitary 5, 3
• Langerhans cell histiocytosis 5

Congenital Disorders (Less Likely Given Adult Onset)

• Adult-onset idiopathic hypogonadotropic hypogonadism: Can present later in life 5, 3
• Kallmann syndrome variants: Usually presents earlier but mild forms can be delayed 5

Recommended Workup Algorithm

Step 1: Repeat and Expand Hormonal Assessment

• Repeat morning prolactin (8-10 AM) on 2-3 separate occasions: Single elevated value may be spurious; persistent elevation >25 ng/mL warrants imaging 4, 3
• Measure SHBG: Calculate free testosterone index (total testosterone/SHBG <0.3 confirms hypogonadism) 4
• Thyroid function (TSH, free T4): Thyroid disorders alter SHBG and can cause secondary hypogonadism 4
• Morning cortisol and ACTH: Screen for Cushing syndrome or adrenal insufficiency 5, 4
• IGF-1: Screen for growth hormone deficiency (often accompanies gonadotropin deficiency in pituitary disease) 3

Step 2: Pituitary MRI with Gadolinium Contrast

Obtain MRI regardless of prolactin level given the clinical picture—even with normal prolactin, structural lesions can cause selective gonadotropin deficiency. 5, 3 Look specifically for:

• Microadenomas (especially in pituitary stalk region)
• Macroadenomas compressing normal pituitary
• Empty sella syndrome
• Hypothalamic masses
• Pituitary stalk thickening (infiltrative disease)

Step 3: Comprehensive Medication and Substance Review

• Document all current and recent medications (past 6-12 months), specifically asking about: 5, 4
  • Opioid analgesics (even intermittent use)
  • Glucocorticoids (including topical, inhaled, intra-articular)
  • Psychotropic medications
  • Anabolic steroids or "supplements"
  • Marijuana (suppresses GnRH)

Step 4: Screen for Systemic Conditions

• Metabolic assessment: Fasting glucose, HbA1c, lipid panel, BMI, waist circumference 4, 2
• Complete blood count: Anemia suggests chronic disease or hemochromatosis 4
• Comprehensive metabolic panel: Liver and kidney function 4
• Iron studies (ferritin, transferrin saturation): Screen for hemochromatosis if family history or elevated ferritin 3
• Sleep study: If symptoms of sleep apnea (snoring, daytime somnolence) 2

Step 5: Additional Testing Based on Initial Findings

If prolactin remains elevated (>25 ng/mL):

• Macroprolactin assay: Exclude laboratory artifact 3
• Visual field testing: If macroadenoma found on MRI 3

If MRI shows pituitary mass:

• Complete pituitary hormone panel: ACTH, cortisol, TSH, free T4, IGF-1 to assess for hypopituitarism 3, 6

If no structural lesion and no medications identified:

• GnRH stimulation test: Can differentiate hypothalamic from pituitary dysfunction (though rarely changes management) 6
• Consider genetic testing: If young age (<30) or family history suggests congenital hypogonadotropic hypogonadism 5

Critical Pitfalls to Avoid

• Do not dismiss "normal" LH as excluding secondary hypogonadism—inappropriately normal gonadotropins in the setting of low testosterone IS secondary hypogonadism (functional type). 1, 2
• Do not attribute symptoms to "aging" without full workup—this patient is symptomatic with objective biochemical abnormalities requiring investigation. 7
• Do not start testosterone therapy before completing workup—testosterone will suppress the axis further, masking underlying pathology and eliminating fertility potential. 1, 4
• Do not ignore fluctuating prolactin—the peak of 69.4 ng/mL is significant and warrants MRI even if subsequent values normalize. 5
• Do not overlook medication history—drug-induced hypogonadism is the most common reversible cause and must be systematically excluded. 5, 4

Loss of Penile Sensation: Additional Consideration

The complete loss of penile sensation for 3 years is unusual and suggests possible peripheral neuropathy (diabetic, alcoholic, or other metabolic causes) or neurological pathology independent of hypogonadism. Consider:

• Neurological examination and nerve conduction studies if metabolic workup negative
• Spinal MRI if any lower extremity symptoms present
• This symptom may not resolve with testosterone normalization alone