What endocrine disorders could cause combined cognitive impairment and sleep disturbances, and what initial laboratory work‑up and treatment options should be considered?

Endocrine Disorders Causing Combined Cognitive Impairment and Sleep Disturbances

The most critical endocrine disorders to evaluate are hypothyroidism, hyperthyroidism, adrenal insufficiency (both primary and secondary), hyperprolactinemia, and diabetes mellitus, as these directly impair both cognitive function and sleep architecture through distinct hormonal mechanisms. 1

Initial Laboratory Work-Up

Begin with a focused endocrine panel that includes morning cortisol (collected simultaneously with ACTH), TSH, free T4, electrolytes, HbA1c, prolactin, calcium, and vitamin B12. 1, 2, 3

Critical Timing Considerations

• Morning cortisol and ACTH must be collected together between 8-9 AM for accurate interpretation, as the relationship between these values distinguishes primary from secondary adrenal insufficiency 1, 2, 3
• If morning cortisol is indeterminate (3-15 mg/dL), proceed with standard-dose ACTH stimulation testing 1, 3
• In women of reproductive age, include FSH, LH, estradiol, and progesterone to assess for hypogonadism 1, 2

Additional Baseline Testing

• Complete metabolic panel to assess renal function and electrolyte abnormalities that may contribute to cognitive symptoms 1, 4
• Urine albumin:creatinine ratio to evaluate for diabetic nephropathy or other renal pathology 1, 4
• Consider MRI brain with pituitary/sellar cuts if multiple hormonal deficiencies are identified or if severe headaches or vision changes are present 1, 2

Specific Endocrine Disorders and Their Mechanisms

Hypothyroidism

Hypothyroidism causes cognitive slowing, memory impairment, and disrupted sleep architecture through reduced cerebral metabolism and altered neurotransmitter function. 1, 5, 6

• Presents with fatigue, cold intolerance, weight gain, and depressed mood alongside cognitive symptoms 1
• Sleep disturbances include increased sleep latency and reduced sleep efficiency 1
• Thyroid function should be assessed annually in at-risk populations 1

Hyperthyroidism

Hyperthyroidism produces anxiety, restlessness, cognitive dysfunction, and severe insomnia through excessive sympathetic activation. 1, 5, 6

• Associated with premature ejaculation in men and can cause erectile dysfunction 6
• Physical examination reveals tachycardia, tremor, and hyperreflexia 1
• Hypothyroidism is a specific risk factor for obstructive sleep apnea in women 1

Adrenal Insufficiency (Primary and Secondary)

Adrenal insufficiency is life-threatening and presents with profound fatigue, cognitive slowing, depression, and disrupted sleep-wake cycles. 1, 2, 3

• Low ACTH with low cortisol indicates secondary (central) adrenal insufficiency from hypopituitarism 1, 2, 3
• High ACTH with low cortisol indicates primary adrenal insufficiency 1, 3
• Symptoms include orthostatic hypotension, hyponatremia, and hypoglycemia 1, 3
• A critical pitfall is attributing all fatigue to depression or menopause when ACTH is critically low, as this can precipitate adrenal crisis 2

Hyperprolactinemia

Elevated prolactin suppresses gonadotropin secretion, causing hypogonadism with resultant cognitive impairment, mood disturbance, and sleep disruption. 1, 6, 7

• Only severe hyperprolactinemia (>35 ng/mL or 735 mU/L) significantly impacts sexual and cognitive function 6
• Associated symptoms include galactorrhea, menstrual irregularities, and decreased libido 1, 6
• Pituitary MRI is indicated when prolactin is elevated to exclude prolactinoma 1

Diabetes Mellitus

Diabetes causes cognitive impairment through vascular damage, chronic inflammation, and direct neurotoxic effects of hyperglycemia, while also increasing risk of obstructive sleep apnea. 1, 8, 7

• Diabetes is the most common endocrine cause of erectile dysfunction due to vascular and neurological complications 8
• Associated with increased insulin resistance and metabolic syndrome 1
• Screen with HbA1c and fasting glucose 1, 4

Hypogonadism

Low testosterone in men and estrogen deficiency in women impair memory consolidation, executive function, and sleep quality through reduced neuroprotective steroid effects. 1, 2, 5, 7

• Estradiol and progesterone regulate oxidative metabolism in brain mitochondria and promote dendritic spine formation critical for memory 1
• In men, testosterone deficiency reduces nocturnal erections, sexual desire, and ejaculate volume 5, 7
• Primary hypothyroidism is associated with reversible hypogonadotropic hypogonadism 5

Treatment Algorithm

Step 1: Address Life-Threatening Conditions First

If adrenal insufficiency is confirmed, initiate hydrocortisone 15-25 mg daily in divided doses immediately (typically 2/3 in morning, 1/3 early afternoon) before addressing any other hormonal deficiencies. 1, 2, 3

• For Grade 1 (mild) symptoms: hydrocortisone 15-20 mg daily in divided doses 1, 3
• For Grade 2 (moderate) symptoms: hydrocortisone 30-50 mg daily or prednisone 20 mg daily 3
• For Grade 3-4 (severe) symptoms: hospitalize and give stress-dose steroids (hydrocortisone 50-100 mg every 6-8 hours initially) 1
• Wait at least 1 week after initiating cortisol replacement before starting thyroid hormone or estrogen therapy to avoid precipitating adrenal crisis 1, 3

Step 2: Initiate Thyroid Hormone Replacement

For confirmed hypothyroidism, start levothyroxine with goal free T4 in upper half of reference range. 1

• In secondary hypothyroidism from hypopituitarism, TSH is not accurate for monitoring; use free T4 instead 1
• Reassess symptoms after 4-6 weeks of adequate replacement 2

Step 3: Address Gonadal Hormone Deficiency

For postmenopausal women with confirmed estrogen deficiency, initiate estrogen therapy alone (if no uterus) or combined with progesterone (if uterus intact) after ensuring pituitary pathology is excluded and adrenal function is addressed. 2

• Estrogen therapy is first-line for vasomotor symptoms and can improve mood and cognitive function 2
• Contraindicated in women with history of breast cancer or other hormone-sensitive malignancies 2

For men with confirmed hypogonadism, testosterone supplementation improves sexual desire, nocturnal erections, and may benefit cognitive function. 5, 6, 7

• Contraindicated in men with prostate cancer 1

Step 4: Treat Persistent Mood and Sleep Symptoms

If depression persists despite adequate hormone replacement, add SSRI/SNRI such as venlafaxine or citalopram. 2

• Screen for obstructive sleep apnea using STOP-BANG questionnaire if snoring, witnessed apneas, or excessive daytime sleepiness persist 1, 4
• Polysomnography is required to confirm OSA diagnosis and for insurance reimbursement of CPAP therapy 1

Step 5: Consider DHEA Replacement

In women with persistent low libido and/or energy despite adequate cortisol and estrogen replacement, test DHEA levels and consider replacement. 1, 3

Patient Education and Safety

All patients with adrenal insufficiency require education on stress dosing (doubling or tripling usual dose during illness), emergency injectable hydrocortisone, and medical alert identification. 1, 3

• Early endocrinology consultation is appropriate for all patients with confirmed adrenal insufficiency 1, 3
• Endocrine consultation should be part of planning before surgery or high-stress treatments 1

Common Pitfalls to Avoid

Do not attribute all cognitive and sleep symptoms to psychiatric causes without excluding reversible endocrine disorders, particularly hypothyroidism, adrenal insufficiency, and vitamin B12 deficiency. 1

• Single abnormal laboratory findings without symptoms may not constitute clinically relevant endocrine disorder, but require monitoring 1
• Do not start hormone therapy until pituitary pathology is excluded 2
• Avoid interpreting hormones from single time-point measurements; morning cortisol and ACTH must be collected simultaneously 1, 2, 3
• Long-acting steroids like prednisone carry higher risk of over-replacement than hydrocortisone (hydrocortisone 20 mg = prednisone 5 mg) 1, 3
• Monitor for iatrogenic Cushing's syndrome with excessive cortisol replacement (bruising, thin skin, edema, weight gain, hypertension, hyperglycemia) 3

Differential Diagnosis Considerations

Distinguish endocrine-mediated cognitive impairment from delirium, medication effects, sleep deprivation, and primary neurodegenerative disease. 1

• Delirium presents with acute alterations in arousal and attention 1
• Review all medications including over-the-counter products for sedating effects, anticholinergics, and drugs causing xerostomia 1, 4
• Screen for depression using validated tools, as poststroke depression affects one-third of patients and may mimic cognitive impairment 1
• Workup for delirium should include assessment of electrolytes, liver and renal function, infection, constipation, and pain 1