What is the cause of dark skin discoloration (hyperpigmentation) on the underarms and inner thighs in a patient without insulin resistance or metabolic disorders?

Dark Underarms and Inner Thighs Without Insulin Resistance

The most common cause of hyperpigmentation in the underarms and inner thighs without insulin resistance is friction-induced postinflammatory hyperpigmentation, though other causes including drug-induced hyperpigmentation, genetic insulin receptor defects, autoimmune conditions, and endocrine disorders must be systematically excluded.

Primary Differential Diagnosis

Friction and Mechanical Causes

• Postinflammatory hyperpigmentation from chronic friction is the leading cause when metabolic disorders are excluded, occurring from repetitive skin-to-skin contact or clothing irritation in intertriginous areas 1
• This mechanism can affect persons of any age and typically presents symmetrically in areas of mechanical stress 1

Genetic Insulin Receptor Defects (Without Overt Insulin Resistance)

• Insulin receptor mutations can cause acanthosis nigricans with hyperpigmentation even before frank insulin resistance develops, ranging from hyperinsulinemia with modest hyperglycemia to more severe presentations 2, 3
• Women with these mutations may present with virilization and enlarged cystic ovaries, previously termed type A insulin resistance 2, 3
• These genetic defects should be suspected in younger patients with family history or associated features like polycystic ovary syndrome 2

Autoimmune Causes

• Anti-insulin receptor antibodies (type B insulin resistance) can cause hyperpigmentation and acanthosis nigricans, occasionally found in systemic lupus erythematosus and other autoimmune diseases 2, 3
• This condition may present with skin changes before glucose intolerance becomes apparent 4
• Resolution of skin lesions can occur with treatment of the underlying autoimmune condition and disappearance of insulin receptor antibodies 4

Drug-Induced Hyperpigmentation

• Multiple medications cause hyperpigmentation in photoexposed and intertriginous areas, including NSAIDs (25% of cases), antihypertensives (18.75%), antimalarials (12.5%), and antibiotics 5
• Drug-induced hyperpigmentation affects 1.31% of dermatology patients and is particularly common in those taking multiple medications 5
• A thorough medication review is essential, as this is a frequently overlooked but reversible cause 5

Endocrine Disorders

• Cushing's syndrome, acromegaly, and other hormone excess states can cause hyperpigmentation through mechanisms independent of insulin resistance 2, 3
• These conditions antagonize insulin action but may present with skin changes before metabolic derangements are detected 2

Diagnostic Approach

Essential Clinical Evaluation

• Examine for texture changes: True acanthosis nigricans has velvety thickening, while pure hyperpigmentation from friction or drugs lacks this texture 1, 6
• Assess distribution pattern: Symmetric involvement of axillae and inner thighs suggests friction or systemic cause; asymmetric suggests localized process 1
• Document all current and recent medications, including over-the-counter NSAIDs and supplements 5

Laboratory Investigation

• Screen for occult insulin resistance with fasting insulin levels and HOMA-IR, as standard glucose testing may miss early receptor defects 2, 3
• Consider anti-insulin receptor antibody testing if autoimmune features present (arthritis, rash, cytopenias) 2, 4
• Evaluate for endocrinopathies with morning cortisol, IGF-1, and thyroid function if clinical suspicion exists 2

Critical Pitfalls to Avoid

• Do not assume absence of insulin resistance based solely on normal fasting glucose or HbA1c, as genetic receptor defects and early compensatory hyperinsulinemia may precede glucose abnormalities 2, 3
• Do not overlook polypharmacy as a cause, particularly in patients seeing multiple specialists who may not communicate medication lists 5
• Do not dismiss the diagnosis in non-obese patients, as abdominal fat distribution and genetic factors can cause metabolic changes at normal BMI 2

Management Considerations

When Friction is Confirmed

• Weight reduction if overweight, use of moisture-wicking fabrics, and application of barrier creams to reduce mechanical irritation 1
• Topical treatments including hydroquinone combinations may improve appearance but do not address underlying cause 1

When Systemic Cause Suspected

• Discontinue potentially causative medications when safe alternatives exist, as drug-induced changes often resolve with cessation 5, 4
• Treat underlying endocrine or autoimmune disorders, as skin manifestations may improve with disease control 4
• Refer to endocrinology for suspected genetic insulin receptor defects requiring specialized evaluation 2, 3