What is the best course of treatment for a patient with hypercortisolism, elevated Dehydroepiandrosterone sulfate (DHEAS), and hyperthyrotropinemia with normal thyroxine (T4) levels?

Management of Elevated DHEAS, Elevated Cortisol, and Elevated TSH with Normal T4

The priority is to confirm and localize the source of hypercortisolism through 24-hour urinary free cortisol and ACTH measurement, while simultaneously addressing the subclinical hypothyroidism with thyroid hormone replacement if TSH persistently exceeds 10 mIU/L or if symptoms are present. 1

Initial Diagnostic Workup for Hypercortisolism

Confirm Cushing Syndrome

• Obtain 24-hour urinary free cortisol (UFC) to confirm hypercortisolism, as elevated serum cortisol alone requires biochemical confirmation 1
• Measure morning ACTH level simultaneously with cortisol to localize the source of excess cortisol production 1

Interpret ACTH Results to Guide Further Management

If ACTH is elevated (>23 pg/mL):

• The excessive cortisol is NOT from the adrenal gland itself 1
• Consider pituitary adenoma (Cushing disease) or ectopic ACTH-producing tumors in lung, thyroid, pancreas, or bowel 1
• Pursue imaging to identify the source and surgical resection if feasible 1

If ACTH is low or suppressed:

• This indicates ACTH-independent Cushing syndrome from adrenal pathology 1
• The elevated DHEAS in this context suggests adrenal source of hyperandrogenism 2, 3
• Obtain adrenal imaging (CT chest/abdomen/pelvis) to evaluate for adrenal adenoma versus carcinoma 1

Assess for Malignancy Risk

Suspect adrenal carcinoma if the tumor demonstrates: 1

• Size >5 cm
• Irregular margins or inhomogeneous appearance
• Local invasion
• Hounsfield units >10 on unenhanced CT
• Secretion of multiple hormones (cortisol + DHEAS in this case)

Management of Confirmed Hypercortisolism

Surgical Management

For benign adrenal adenoma causing ACTH-independent Cushing syndrome:

• Laparoscopic adrenalectomy is the treatment of choice 1
• Postoperative corticosteroid supplementation is mandatory until HPA axis recovery 1

For suspected malignant disease:

• Open adrenalectomy is preferred over laparoscopic approach 1
• Complete staging with chest/abdomen/pelvis imaging 1

Medical Management

When surgery is not feasible or for symptom palliation:

• Ketoconazole 400-1200 mg/day is the first-line medical therapy due to easy availability and tolerable toxicity profile 1
• Alternative: Mitotane (though less commonly used due to toxicity) 1
• Treat associated complications: hypertension, hyperglycemia, hypokalemia, and muscle atrophy 1

Management of Elevated TSH with Normal T4

Interpretation

This presentation represents subclinical hypothyroidism 1

Critical consideration: Ensure this is primary hypothyroidism and not central hypothyroidism from hypophysitis 1

• In central hypothyroidism, TSH can remain in the normal range despite low T4 1
• However, with normal T4 and elevated TSH, primary hypothyroidism is most likely 1

Treatment Algorithm Based on TSH Level

TSH 4.5-10 mIU/L and asymptomatic:

• Monitor TSH every 4-6 weeks without immediate treatment 1
• Consider that elevated TSH may be secondary to hypothyroidism affecting cortisol metabolism 4

TSH persistently >10 mIU/L (measured 4 weeks apart) OR any symptomatic patient:

• Initiate levothyroxine replacement therapy 1
• For patients <70 years without cardiac disease: Start full replacement at approximately 1.6 mcg/kg/day based on ideal body weight 1
• For patients >70 years or with cardiac disease/multiple comorbidities: Start low at 25-50 mcg and titrate up 1
• Monitor TSH every 6-8 weeks while titrating to goal TSH within reference range 1

Critical Sequencing Consideration

If both cortisol excess and thyroid hormone replacement are needed simultaneously:

• Address hypercortisolism FIRST before initiating thyroid hormone replacement 1
• Thyroid hormone accelerates cortisol metabolism and clearance, which could precipitate adrenal crisis in the setting of impending adrenal insufficiency post-treatment 1
• Primary hypothyroidism can cause elevated cortisol levels due to decreased metabolic clearance 4

Special Consideration: DHEAS Elevation

The combination of elevated cortisol and elevated DHEAS strongly suggests:

• Adrenal source of hormone excess (85% of cases with this pattern) 2
• Low DHEAS would argue against subclinical hypercortisolism, as DHEAS <1.12 times the lower limit of normal has 99% sensitivity for excluding adrenal Cushing syndrome 5
• Elevated DHEAS with hypercortisolism may indicate adrenal carcinoma, especially if tumor >3 cm and secreting multiple hormones 1

Common Pitfalls to Avoid

• Do not start thyroid hormone replacement before confirming the patient is not developing adrenal insufficiency from treatment of hypercortisolism 1
• Do not rely on single serum cortisol measurement—confirm with 24-hour UFC 1
• Do not assume benign disease with elevated DHEAS and cortisol—carefully evaluate imaging for malignancy features 1
• Do not use laparoscopic approach if malignancy is suspected, as this increases risk of tumor rupture and peritoneal spread 1