How do cortisol excess (Cushing's syndrome) and cortisol deficiency (adrenal insufficiency) affect libido, erectile function, and loss of morning erections in adults, and what is the recommended hormonal work‑up and management?

Cortisol Disorders and Sexual Dysfunction: Diagnostic and Management Approach

Direct Answer

Both cortisol excess (Cushing's syndrome) and cortisol deficiency (adrenal insufficiency) cause reversible sexual dysfunction in men, including loss of libido, erectile dysfunction, and loss of morning erections—all of which improve with appropriate hormonal correction. 1, 2

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Cortisol Excess (Cushing's Syndrome) and Sexual Function

Sexual Manifestations

Cushing's syndrome causes reversible amenorrhea in women and impotence in men through direct suppression of the hypothalamic-pituitary-gonadal axis by hypercortisolemia. 1

• Male patients present with:

  • Erectile dysfunction 1
  • Loss of libido 1
  • Low plasma testosterone levels 1
  • Mild virilization may occur in ACTH-dependent subtypes due to elevated adrenal androgens 1

• Mechanism: Hypercortisolemia suppresses the hypothalamic-pituitary-gonadal axis at multiple sites, leading to hypogonadotropic hypogonadism 1

• Cortisol acts as an antagonist of the normal sexual response cycle in adult males 3

Hormonal Work-Up for Cushing's Syndrome

Initial screening requires demonstration of chronic hypercortisolism using one of three first-line tests: 4, 5, 6

1. 24-hour urinary free cortisol (UFC) – markedly elevated in clinically apparent Cushing's syndrome 5, 6
2. 1 mg overnight dexamethasone suppression test (DST) – failure to suppress morning cortisol to <1.8 μg/dL (50 nmol/L) 4, 5
3. Late-night salivary cortisol – demonstrates loss of normal circadian rhythm 4, 6

After confirming hypercortisolism, measure morning (08:00-09:00h) plasma ACTH to determine etiology: 4

• ACTH >5 ng/L → ACTH-dependent Cushing's (pituitary or ectopic source) 4
• ACTH >29 ng/L → 70% sensitivity and 100% specificity for Cushing's disease (pituitary adenoma) 4
• Low or undetectable ACTH → ACTH-independent Cushing's (adrenal source) 4, 6

Further Localization for ACTH-Dependent Disease

For ACTH-dependent Cushing's, obtain high-resolution 3-Tesla pituitary MRI with thin slices and gadolinium contrast: 4

• Adenoma ≥10 mm → proceed directly to transsphenoidal surgery 4
• Adenoma 6-9 mm → perform CRH or desmopressin stimulation test; cortisol rise >38 nmol/L at 15 minutes supports pituitary source 4
• No adenoma or <6 mm lesion → bilateral inferior petrosal sinus sampling (BIPSS) is mandatory 4

BIPSS diagnostic criteria (gold standard with 96-100% sensitivity and near-100% specificity): 4

• Central-to-peripheral ACTH ratio ≥2:1 at baseline OR ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 4
• Must be performed in specialized centers by experienced interventional radiologists 4

Management of Cushing's Syndrome

Definitive treatment is surgical removal of the causative lesion: 7, 6

• Cushing's disease: transsphenoidal resection of pituitary adenoma 6
• Adrenal adenoma: laparoscopic adrenalectomy 7
• Adrenal carcinoma: open adrenalectomy with possible adjuvant therapy 7

Sexual dysfunction typically resolves after successful treatment and normalization of cortisol levels. 1

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Cortisol Deficiency (Adrenal Insufficiency) and Sexual Function

Sexual Manifestations

Autoimmune Addison's disease in males causes multiple sexual dysfunctions that are completely reversible with appropriate glucocorticoid and mineralocorticoid replacement: 2

• Erectile dysfunction – improves significantly within 2 months of hormone replacement 2
• Reduced orgasmic function 2
• Loss of sexual desire/libido 2
• Decreased intercourse satisfaction 2
• Reduced overall sexual satisfaction 2

The variation in erectile function correlates significantly with: 2

• Serum cortisol levels (positive correlation) 2
• Urinary free cortisol (positive correlation) 2
• Upright plasma renin activity (inverse correlation) 2

Both cortisol and aldosterone deficiency play important roles in the genesis of erectile dysfunction, though the exact mechanism remains unclear. 2

Hormonal Work-Up for Adrenal Insufficiency

Initial diagnostic approach requires morning (08:00-09:00h) paired measurement of serum cortisol and plasma ACTH: 8

Primary adrenal insufficiency (Addison's disease):

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH (often >300 pg/mL) is diagnostic 8
• Hyponatremia present in 90% of cases 8
• Hyperkalemia present in only ~50% of cases (absence does NOT rule out diagnosis) 8

Secondary adrenal insufficiency:

• Low cortisol with low or inappropriately normal ACTH 8
• Consider evaluating LH and testosterone in males with fatigue, loss of libido, and mood changes 7

Confirmatory Testing

When morning cortisol is indeterminate (5-18 μg/dL), perform cosyntropin stimulation test: 8

Protocol: 8

1. Administer 0.25 mg (250 mcg) cosyntropin IV or IM
2. Measure serum cortisol at baseline, 30 minutes, and 60 minutes

Interpretation: 8

• Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 8
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 8

Etiologic Work-Up for Primary Adrenal Insufficiency

Measure 21-hydroxylase autoantibodies (positive in ~85% of autoimmune Addison's disease in Western populations): 8

If autoantibodies are negative, obtain adrenal CT to evaluate for: 8

• Adrenal hemorrhage
• Tuberculosis or fungal infections
• Tumors
• Other structural abnormalities

In males with negative autoantibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy. 8

Management of Adrenal Insufficiency

Glucocorticoid replacement (required for all patients): 8

• Hydrocortisone 15-25 mg daily in divided doses (preferred regimen) 8
  • Typical schedule: 10 mg at 07:00,5 mg at 12:00,2.5-5 mg at 16:00 8
  • Allows recreation of diurnal cortisol rhythm 7
• Alternative: Cortisone acetate 25-37.5 mg daily or prednisone 4-5 mg daily 8

Mineralocorticoid replacement (required ONLY for primary adrenal insufficiency): 8

• Fludrocortisone 50-200 µg daily 8
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 8
• Unrestricted sodium salt intake is essential 8

DHEA replacement (controversial but consider in specific cases): 7

• Test DHEA deficiency in women with low libido and/or energy who are otherwise well-replaced 7
• Consider replacement if deficiency is documented 7

Critical Patient Education

All patients with adrenal insufficiency require: 8

1. Stress-dosing education:

   • Double or triple usual dose during illness, fever, or physical stress 8
   • Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 8

2. Medical alert identification:

   • Wear medical alert bracelet or necklace indicating adrenal insufficiency 8
   • Carry steroid emergency card at all times 8

3. Warning signs of impending adrenal crisis:

   • Severe vomiting, diarrhea, inability to take oral medications 8
   • Marked weakness, confusion, hypotension 8

4. Mandatory endocrine consultation for:

   • Pre-operative planning 7
   • High-stress treatments 7
   • Any patient with recurrent adrenal crises 8

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Expected Timeline for Sexual Function Recovery

In males with autoimmune Addison's disease, significant improvement in erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall sexual satisfaction occurs within 2 months of initiating appropriate hormone replacement therapy. 2

In Cushing's syndrome, sexual dysfunction typically resolves after successful surgical treatment and normalization of cortisol levels. 1

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Common Pitfalls to Avoid

1. Never delay treatment of suspected acute adrenal crisis for diagnostic procedures – immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion 8

2. Do not rely on electrolyte abnormalities alone – hyperkalemia is present in only ~50% of primary adrenal insufficiency cases 8

3. Do not attempt diagnostic testing while patient is on corticosteroids – exogenous steroids suppress the HPA axis and confound results 8

4. In patients with both adrenal insufficiency and hypothyroidism, start corticosteroids several days before initiating thyroid hormone to prevent precipitating adrenal crisis 8

5. For secondary adrenal insufficiency from hypophysitis, consider evaluating sex hormones (LH, testosterone in males; FSH, estrogen in premenopausal females) when patients present with fatigue, loss of libido, and mood changes 7

6. Testosterone or estrogen therapy may be needed in those without contraindications (e.g., prostate cancer, breast cancer, or history of DVT) after adrenal replacement is stabilized 7