What are the potential causes of cold intolerance and weight gain in a woman over 50, besides hypothyroidism (Thyroid Stimulating Hormone (TSH) and free T4 abnormalities)?

Other Causes of Cold Intolerance and Weight Gain (Besides Hypothyroidism)

The most important alternative diagnosis to consider in a woman over 50 with cold intolerance and weight gain is Cushing's syndrome, which presents with rapid weight gain (especially central distribution), proximal muscle weakness, depression, and hyperglycemia. 1

Primary Differential Diagnoses

Cushing's Syndrome

• Screen with overnight 1-mg dexamethasone suppression test as the initial diagnostic step 1
• Confirm diagnosis with 24-hour urinary free cortisol excretion (preferably multiple collections) or midnight salivary cortisol 1
• Key clinical features include central obesity, "moon face," dorsal and supraclavicular fat pads, wide (≥1 cm) violaceous striae, and hirsutism 1, 2
• Prevalence is <0.1%, but the morbidity from undiagnosed disease is substantial 1

Metabolic Adaptation from Recent Weight Loss

• Rapid weight loss causes decreased metabolic rate and reduced heat production, directly causing cold intolerance 3
• Loss of insulating subcutaneous fat mass contributes to cold sensitivity 3
• Weight loss typically plateaus after 6 months due to metabolic adaptation, with symptoms gradually improving as weight stabilizes 3
• Critical pitfall: If the patient recently lost weight and then regained it, the cold intolerance may reflect the metabolic adaptation phase rather than an endocrine disorder 3

Drug-Induced Causes

• Multiple medications can cause weight gain and metabolic changes mimicking endocrine disorders 1
• Key offenders include: oral contraceptives, cyclosporine, tacrolimus, neuropsychiatric agents (antidepressants, antipsychotics), and clonidine withdrawal 1
• Obtain a comprehensive medication history including over-the-counter agents and herbal supplements 1

Uncommon but Important Endocrine Causes

Hypopituitarism/Hypophysitis

• Can present with both adrenal insufficiency (causing cold intolerance) and secondary hypothyroidism (even with normal TSH) 1
• In the presence of both adrenal insufficiency and hypothyroidism, steroids must always be started prior to thyroid hormone to avoid adrenal crisis 1
• Diagnostic criteria include ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or ≥2 pituitary hormone deficiencies 1
• Consider this diagnosis particularly in patients with history of immune checkpoint inhibitor therapy 1

Acromegaly

• Rare cause but presents with weight gain, enlarging shoe/glove/hat size, acral features, large hands/feet, and frontal bossing 1, 2
• Screen with serum growth hormone ≥1 ng/mL during oral glucose load 1, 2
• Confirm with elevated age- and sex-matched IGF-1 level and pituitary MRI 1, 2

Diagnostic Algorithm for Women Over 50

Initial Laboratory Evaluation

1. TSH and free T4 (to definitively rule out hypothyroidism) 1, 2
2. Overnight 1-mg dexamethasone suppression test (for Cushing's syndrome) 1
3. Complete metabolic panel and complete blood count 3
4. Fasting glucose or HbA1c (hyperglycemia suggests Cushing's) 1

Physical Examination Priorities

• Look for central obesity with "moon face," dorsal/supraclavicular fat pads, and wide violaceous striae (Cushing's syndrome) 1, 2
• Assess for proximal muscle weakness (Cushing's or hypopituitarism) 1
• Examine for acral enlargement, frontal bossing, and enlarged hands/feet (acromegaly) 1, 2
• Check blood pressure in all four extremities (coarctation, though rare in this age group) 1

History-Taking Essentials

• Document all medications including recent changes (drug-induced causes are 2-4% of cases) 1
• Assess for recent weight loss followed by regain (metabolic adaptation) 3
• Screen for depression, sleep disturbances, and headaches (Cushing's or hypopituitarism) 1
• Inquire about heat versus cold intolerance specifically (helps differentiate from hyperthyroidism) 1

Critical Pitfalls to Avoid

• Do not rely on single cortisol measurements—they are unreliable and require serial testing 2
• Do not assume normal TSH rules out all thyroid-related causes—secondary hypothyroidism from hypopituitarism can present with normal or low-normal TSH 1
• Do not overlook medication review—drug-induced causes represent 2-4% of cases and are completely reversible 1
• Do not attribute symptoms to "normal aging" without biochemical confirmation—the symptoms are nonspecific but treatable causes exist 4, 5
• Do not start thyroid hormone replacement in hypopituitarism before addressing adrenal insufficiency—this can precipitate adrenal crisis 1

When Endocrinology Referral is Mandatory

• All cases of suspected or confirmed Cushing's syndrome 1
• Any patient with suspected hypopituitarism or hypophysitis 1
• Suspected acromegaly 1, 2
• Persistent symptoms despite normal thyroid function tests and negative initial workup 4, 5