What are the next steps for a patient with a low cortisol level found incidentally during a Polycystic Ovary Syndrome (PCOS) workup?

Management of Incidentally Low Cortisol During PCOS Workup

For a patient with incidentally discovered low cortisol during PCOS evaluation, immediate referral to endocrinology is required while conducting further testing to determine if this represents primary or secondary adrenal insufficiency. 1

Initial Assessment

• Evaluate for symptoms of adrenal insufficiency (even if mild or absent): fatigue, weakness, weight loss, nausea, vomiting, abdominal pain, hypotension, or hyperpigmentation 1
• Check electrolytes for hyponatremia and hyperkalemia, which are present in approximately 90% and 50% of new adrenal insufficiency cases, respectively 1
• Order morning paired ACTH and cortisol levels to differentiate between primary and secondary adrenal insufficiency 1
• Consider standard-dose ACTH stimulation testing (250 μg) if morning cortisol results are indeterminate (between 3-15 μg/dL) 1

Diagnostic Workup

For Primary Adrenal Insufficiency Suspicion (High ACTH, Low Cortisol)

• Measure 21-hydroxylase (anti-adrenal) autoantibodies to assess for autoimmune etiology 1
• Order adrenal CT scan to evaluate for adrenal hemorrhage, metastasis, or other structural abnormalities 1
• In males, consider very long-chain fatty acid testing for adrenoleukodystrophy 1

For Secondary Adrenal Insufficiency Suspicion (Low ACTH, Low Cortisol)

• Evaluate additional pituitary hormones: TSH, free T4, LH, FSH, and in males, testosterone 1
• Consider MRI of brain with pituitary/sellar cuts to assess for hypophysitis or other pituitary abnormalities 1

Treatment Approach

For Mild Symptoms (Grade 1)

• Initiate replacement therapy with hydrocortisone 15-20 mg daily in divided doses (typically 2/3 in morning, 1/3 in early afternoon) 1
• For primary adrenal insufficiency, add fludrocortisone 0.05-0.1 mg daily 1
• Provide education on stress dosing for illness, emergency injections, and medical alert identification 1

For Moderate Symptoms (Grade 2)

• Consider higher initial dosing of hydrocortisone (30-50 mg total daily dose) or prednisone 20 mg daily 1
• Assess need for hydration and supportive care 1
• Taper to maintenance doses after symptoms improve 1

For Severe Symptoms (Grade 3-4)

• Immediate hospitalization for IV hydrocortisone 50-100 mg every 6-8 hours 1
• IV normal saline (at least 2L) for volume repletion 1
• Taper stress-dose corticosteroids to oral maintenance doses over 5-7 days 1

Important Considerations

• When replacing multiple hormones, always start corticosteroids first before thyroid hormone replacement to avoid precipitating an adrenal crisis 1
• Be aware that oral contraceptives used in PCOS treatment can affect cortisol levels by increasing cortisol-binding globulin, which may complicate interpretation of total cortisol measurements 2, 3
• Some PCOS patients may have altered cortisol metabolism with increased cortisol clearance, which can affect interpretation of cortisol levels 4, 5
• ACTH stimulation testing may give false-negative results early in secondary adrenal insufficiency as adrenal reserve declines gradually after loss of pituitary stimulation 1

Follow-up

• Endocrinology consultation should be part of planning before any surgery or high-stress treatments 1
• Patients require ongoing monitoring to adjust maintenance therapy based on clinical response 1
• For patients with secondary adrenal insufficiency, reassess the hypothalamic-pituitary-adrenal axis after 3 months of maintenance therapy to determine if recovery has occurred 1