What is the appropriate workup for a patient with unintended weight loss, shivering and cold sensitivity, fatigue, reduced appetite, and chronic gastritis without bleeding, who has a history of hypogonadism and denies night sweats?

Workup of Unintended Weight Loss with Cold Sensitivity and Fatigue in a Patient with Known Hypogonadism

Immediate Priority: Rule Out Secondary Hypophysitis/Hypopituitarism

The combination of unintended weight loss, morning cold sensitivity/shivering that improves with eating, fatigue, and reduced appetite in a patient with known hypogonadism strongly suggests secondary adrenal insufficiency and/or hypothyroidism from hypopituitarism, which requires urgent evaluation before these conditions become life-threatening. 1

Critical First-Line Laboratory Tests (Morning, 8 AM)

• Thyroid function: TSH and free T4 to detect central hypothyroidism (low free T4 with low/normal TSH) 1
• Adrenal function: Morning cortisol (8 AM) and ACTH, or perform 1 mcg cosyntropin stimulation test 1
• Confirm hypogonadism status: Morning total testosterone (8-10 AM), free testosterone by equilibrium dialysis, LH, and FSH 1, 2, 3
• Prolactin level: To evaluate for hyperprolactinemia causing secondary hypogonadism 3, 4

The morning cold sensitivity that resolves after eating is particularly concerning for adrenal insufficiency, where hypoglycemia and impaired thermogenesis occur during fasting states. 1

Secondary Diagnostic Studies

• MRI of the sella turcica with pituitary cuts: Essential if biochemical testing confirms ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) 1
• Sex hormone-binding globulin (SHBG): To calculate free androgen index if total testosterone is borderline 2, 3

Critical Diagnostic Criteria for Hypophysitis

Confirmation requires either:

• ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, OR
• ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) in the presence of headache and other symptoms 1

Differential Diagnosis Considerations

Why This Presentation Suggests Hypopituitarism Over Other Causes

• Against malignancy: Patient denies night sweats, which are typically present in lymphoma and other malignancies causing weight loss 1
• Against primary hypothyroidism: Primary hypothyroidism would show high TSH with low free T4, not the low/normal TSH pattern of central hypothyroidism 1
• Against isolated hypogonadism: The constellation of weight loss, cold intolerance, and fatigue suggests multiple pituitary hormone deficiencies beyond just gonadotropins 1

Evaluate for Reversible Causes of Secondary Hypogonadism

• Obesity assessment: Measure BMI and waist circumference, as obesity-associated secondary hypogonadism can cause similar symptoms 3, 4
• Metabolic screening: Fasting glucose, HbA1c, lipid panel to assess for metabolic syndrome 3, 4
• Medication review: Identify drugs affecting the hypothalamic-pituitary-gonadal axis, including opioids 3, 4
• Iron studies and ferritin: To exclude hemochromatosis causing pituitary dysfunction 4

Management Algorithm Based on Test Results

If Central Hypothyroidism AND Adrenal Insufficiency Confirmed

CRITICAL: Always start physiologic-dose hydrocortisone (15-25 mg daily in divided doses) BEFORE initiating levothyroxine to avoid precipitating adrenal crisis 1

• Start hydrocortisone 15-20 mg in morning, 5 mg in afternoon 1
• Wait 1-2 weeks, then start levothyroxine 50-75 mcg daily 1
• Provide medical alert bracelet and stress-dose steroid education 1
• Both conditions typically require lifelong replacement 1

If Only Central Hypothyroidism Confirmed

• Start levothyroxine 50-75 mcg daily (can start immediately if adrenal function normal) 1
• Recheck TSH and free T4 in 6-8 weeks 1

If Hypogonadism Confirmed Without Other Pituitary Deficiencies

Do NOT start testosterone therapy until:

• Adrenal insufficiency and hypothyroidism are definitively ruled out or adequately treated 1
• Patient confirms he does NOT desire fertility preservation (testosterone causes azoospermia) 2, 4

If fertility is desired, use gonadotropin therapy (hCG plus FSH) instead of testosterone 2, 4

Additional Workup for Weight Loss

Rule Out Gastrointestinal Causes

• Chronic gastritis evaluation: Upper endoscopy if not recently performed, H. pylori testing, vitamin B12 level 1
• Celiac disease screening: Tissue transglutaminase IgA with total IgA 1
• Inflammatory markers: ESR, CRP to assess for inflammatory conditions 1

Malignancy Screening (Age-Appropriate)

• Chest radiograph: Baseline imaging given weight loss, though absence of night sweats makes lymphoma less likely 1
• Complete blood count: To evaluate for anemia, leukemia, or other hematologic abnormalities 1
• Age-appropriate cancer screening: Colonoscopy if due, PSA if indicated 1

Common Pitfalls to Avoid

• Never start thyroid hormone replacement before confirming adequate adrenal function or starting steroid replacement - this can precipitate life-threatening adrenal crisis 1
• Never diagnose hypogonadism based on single testosterone measurement - always confirm with repeat morning testing 2, 3
• Never assume the patient's known hypogonadism explains all symptoms - new-onset weight loss and cold intolerance suggest evolving pituitary disease 1
• Never start testosterone therapy without confirming the patient does not desire fertility - testosterone causes prolonged, potentially irreversible azoospermia 2, 4
• Never test testosterone during acute illness - results may be transiently suppressed and misleading 3

Expected Timeline for Diagnosis

• Urgent (within 24-48 hours): Morning cortisol, ACTH, TSH, free T4 1
• Within 1 week: MRI sella if biochemical abnormalities confirmed 1
• Within 2-4 weeks: Complete metabolic and malignancy workup 1

The morning timing of cold sensitivity that improves with eating is a red flag for cortisol deficiency with fasting hypoglycemia, making adrenal insufficiency the most urgent diagnosis to confirm or exclude. 1