Management of Elevated Cortisol Levels

Diagnostic Approach

The National Comprehensive Cancer Network recommends first determining the source of cortisol excess through appropriate testing, as management differs based on etiology 1, 2
Measuring ACTH levels is crucial, as elevated ACTH indicates pituitary or ectopic source, while suppressed ACTH suggests adrenal source 1, 3
24-hour urinary free cortisol is used to confirm hypercortisolism 1
Imaging studies, such as pituitary MRI and adrenal CT/MRI, are used to localize the source 4

The American College of Endocrinology recommends transsphenoidal surgery as the first-line treatment for Cushing's disease (pituitary source) 5
For persistent or recurrent Cushing's disease, radiation therapy, particularly stereotactic radiosurgery, can achieve biochemical control in approximately 80% of patients 5
For adrenal source (adenoma or carcinoma), laparoscopic adrenalectomy or open adrenalectomy with removal of adjacent lymph nodes are recommended 2
For ectopic ACTH source, surgical removal of the ectopic tumor is the first-line treatment, and bilateral laparoscopic adrenalectomy or medical management are alternatives 2

The Endocrine Society recommends adrenostatic agents, such as ketoconazole (400-1200 mg/day), as a medical management option for hypercortisolism 2, 3
Mitotane is also effective but has more side effects 2
Octreotide can be considered for ectopic Cushing syndrome if the tumor is Octreoscan-positive 2

The European Society of Endocrinology states that BLA is often considered a treatment of last resort after other options have failed, but provides immediate control of cortisol excess 5
BLA results in adrenal insufficiency requiring lifelong glucocorticoid and mineralocorticoid replacement 5
Long-term clinical improvement in BMI, diabetes, hypertension, and muscle weakness is reported in more than 80% of patients after BLA 5

The American Association of Clinical Endocrinologists recommends monitoring plasma ACTH and performing serial pituitary imaging, starting 6 months after surgery, for patients who undergo bilateral adrenalectomy 5
Lifelong monitoring for pituitary hormone deficiencies is necessary for patients treated with radiation therapy 5

The Anaesthesia society recommends perioperative management for patients with adrenal insufficiency, including hydrocortisone 100 mg IV at the start of surgery, followed by infusion of 200 mg/24h 6
Doubling the regular oral replacement dose for 48h and up to a week following major surgery is also recommended 6

The Lancet Diabetes and Endocrinology reports that hypopituitarism is the most common side effect of radiation therapy (25-50% of patients) and generally increases over time 5
Long-term clinical relapse of hypercortisolism after BLA due to adrenal rest stimulation is uncommon (<10%) 5

The Endocrine Society recommends preoperative medical therapy with adrenal steroidogenesis inhibitors only if surgery is delayed >2-3 months or in severely ill patients with life-threatening metabolic, psychiatric, infectious, or cardiovascular/thromboembolic complications 7, 8
Osilodrostat is the most effective agent based on prospective trials, starting at 2 mg twice daily, titrating every 2 weeks up to maximum 30 mg twice daily, as recommended by the European Society of Endocrinology 9, 8
Clinical monitoring should include assessing weight, blood pressure, glycemia, and quality of life at each visit, as suggested by the American Association of Clinical Endocrinologists 9, 8
Monitor ACTH levels with adrenal-targeting agents, as significant elevations may indicate tumor growth requiring MRI, according to the Endocrine Society 7, 8
Perform MRI 6-12 months after initiating treatment, then every few years, as recommended by the European Society of Endocrinology 7, 8

Change treatment if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses, as suggested by the American Association of Clinical Endocrinologists 7, 9, 8
Combine ketoconazole with metyrapone or osilodrostat to maximize adrenal blockade, according to the Endocrine Society 9, 8
Monitor for overlapping toxicities, particularly QTc prolongation, as recommended by the European Society of Endocrinology 7, 9

Do not under-dose ketoconazole due to fear of hepatotoxicity; it is often under-dosed, limiting efficacy, as warned by the American Association of Clinical Endocrinologists 9
Do not use UFC to diagnose adrenal insufficiency during treatment; it is not sensitive for this purpose, according to the Endocrine Society 8
Do not stop adrenal-targeting agents immediately if tumor growth is seen; first determine if it's due to loss of feedback or aggressive disease behavior, as recommended by the European Society of Endocrinology 7, 8