Pituitary corticotrope adenomas overproduce adrenocorticotropin hormone (ACTH) resulting in Cushing’s disease and account for 10-15% of all pituitary adenomas. Transsphenoidal surgery (TSS) is recognized as the primary therapy for the majority of patients diagnosed with Cushing’s disease. Over 90% of patients who have microadenomas (tumor size < 10 mm) or no visible tumor on MRI are cured with TSS, if performed by an expert pituitary surgeon, and over 90% of these patients remain disease free at 10 years. Much is written about the challenges encountered in diagnosing and treating Cushing’s disease. This article will focus instead on what endocrinologists and patients can expect after Cushing’s disease has been cured surgically.
The normal regulation of cortisol secretion by the adrenal cortex involves a negative feedback cycle between the adrenal glands and the pituitary gland and hypothalamus. Corticotropin releasing hormone (CRH) is synthesized in the hypothalamic paraventricular nucleus and stimulates the release of ACTH from pituitary corticotrope cells. ACTH then stimulates the adrenal cortex to produce cortisol, an essential regulator of body composition and modulator of many different metabolic pathways. Cortisol indirectly regulates its own production by inhibiting hypothalamic CRH and pituitary ACTH production.
Excess production of cortisol by the adrenal glands results in the characteristic clinical features of Cushing’s disease including increased central fat deposition, muscle fatigability and weakness, facial plethora, thinning of the skin with easy bruising and violaceous stretch marks, high blood pressure, glucose intolerance, osteopenia, menstrual irregularity, impotence and neuropsychiatric disturbances.
In Cushing’s disease, the primary abnormality results from ACTH overproduction by pituitary tumor cells. Production of CRH and ACTH by the normal cells is profoundly suppressed by long-standing exposure to high cortisol levels. In a patient cured of Cushing’s by TSS, the source of ACTH is removed. Cortisol levels plummet within 24-48 hours, as evidenced by very low morning blood cortisol levels and low 24 hour urinary free cortisol levels. Post-operatively, the suppressed normal corticotropes are unable to produce ACTH for some time, resulting in temporary adrenal insufficiency. Rarely, patients cured of their Cushing’s disease may not develop adrenal insufficiency for 1-2 weeks post-operatively, exhibiting delayed evidence of cure.
After surgery for Cushing’s disease, patients collect 24-hour urine samples and have morning blood samples drawn for cortisol. Low levels, at or near the detection limit of the assay, suggest cure. In order to prevent patients from becoming symptomatic from steroid withdrawal, replacement is often given. Dexamethasone is used perioperatively because it does not cross-react with urine and blood measurements of cortisol. The ideal dose and taper depend on clinical features, including the severity of endogenous cortisol production preoperatively. The goal of post-operative steroid replacement is to titrate the patient down to a physiologic dose as possible to allow recovery from Cushing’s, but without causing severe steroid withdrawal symptoms.
After post-operative blood and urine testing is complete, patients are switched to a glucocorticoid with an intermediate half-life such as prednisone. The dose of prednisone replacement post-operatively can be guided by the degree of hypercortisolemia observed pre-operatively. A typical dose initiated approximately 5 days after surgery (following completion of testing for cure) for a patient with moderate pre-operative elevations in urine free cortisol might consist of 7.5-10 mg of prednisone daily. Doses of prednisone ³7.5 mg can be split with 2/3 to 3/4 of the dose administered in the morning, and 1/4 to 1/3 of the dose in the mid-afternoon.
Post-operative relative adrenal insufficiency is often accompanied by lightheadedness, dizziness, nausea, vomiting, abdominal pain, fatigue and weight loss. Given that patients with Cushing’s disease are accustomed to very high levels of cortisol, even a relative reduction in cortisol levels can result in symptoms of adrenal withdrawal. It is important to emphasize to the patient cured of Cushing’s disease the importance of daily glucocorticoid replacement and the potential clinical consequences of untreated adrenal insufficiency. Because adrenal mineralcorticoid secretion is typically preserved in these patients, fludrocortisone is not required. Patients should be advised to wear a medical alert bracelet until their hypothalamic-pituitary-adrenal (HPA) axis recovers. In addition, they should be advised to double their steroid dose during illness, to receive parenteral glucocorticoids if unable to use orally, and to inform all health care providers that they are taking steroids. It often takes 6 months to 2 years for patients cured of their Cushing’s to demonstrate an intact HPA axis and discontinue glucocorticoid replacement therapy. In some cases, central adrenal insufficiency may be a permanent complication from surgery and lifelong replacement may be needed. The clinical features of Cushing’s begin to improve as soon as the replacement dose is below the level of preoperative endogenous cortisol production.
After surgery, frequently contacts with the patient are advisable to optimize downward titration of glucocorticoid replacement. Patients are evaluated 4-6 weeks post-operatively for a more thorough assessment of pituitary function. As with all post-TSS patients, it is important to determine whether they have developed deficiency in adrenal, thyroid, sex steroid, or growth hormone production. Monitoring for diabetes insipidus and the Syndrome of Inappropriate Anti-Diuretic Hormone secretion is also necessary. Patients usually return several times the first 6 months and at least every 6 months thereafter in order to monitor for recurrent hypercortisolemia.
Tapering prednisone over the ensuing months can be one of the most challenging aspects in the management of Cushing’s disease. This is related to the fact that there is no lab test which can determine whether the replacement dose is correct. Each reduction in the amount of prednisone may result in increases in fatigue and lethargy. It is important for patients to anticipate that they will most likely experience an extended period of time (from several weeks to several months) during which they may feel less well before starting to feel better. Once the dose is in the physiologic range (such as 4-5 mg of prednisone), the goal is to reduce it further, often on alternate days, to allow recovery of the HPA axis. Therapy with ³5 mg or more of prednisone (or equivalent) daily may ameliorate symptoms but remains supraphysiologic for most patients and can delay recovery of the normal HPA axis.
When patients reach physiologic replacement (doses equivalent to prednisone 5 mg daily or less), additional testing may be performed to assess whether the HPA axis has returned to normal. A cortisol level greater than 18 mcg/dl in the morning or after Cortrosyn administration is generally accepted as evidence that pituitary control of the adrenal glands has recovered, provided the patient is not on medication which increases cortisol binding globulin, such as estrogen. Glucocorticoid replacement can then be discontinued. Patients need to be counseled that the typical recovery period is approximately one year, and that a healthy diet and exercise program are important. Those patients on medical therapy for hypertension or diabetes mellitus should be monitored carefully, as dose reductions may be needed whenever steroid doses are tapered. The recovery from Cushing’s can be remarkable, with many patients returning to their pre-Cushing’s physical and psychological health within 1-2 years.
Author: Dr. Wesley P. Fairfield MD (Summer, 2003) This article was reprinted from the Massachusetts General Hospital (MGH) Neuroendocrine Center Bulletin (Fall/Winter 2002) with permission.
Editor’s Note: Dr. Fairfield has specialized training and expertise treating patients with Cushing’s disease. Dr. Fairfield became interested in Cushing’s while a clinical and research fellow at Massachusetts General Hospital and junior faculty at Harvard Medical School. Dr. Fairfield attributes his compassionate, detailed and enthusiastic approach to this complicated disease to the extraordinary teachings of Dr. Beverly M. K. Biller and wrote this article while he was at MGH. Dr. Fairfield is now in private practice in Lewiston, Maine.
1. Braunwald E 2001 Harrison’s principles of internal medicine, 15th ed. McGraw-Hill, New York
2. Grinspoon SK, Biller BMK 1994 Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 79:923-931
3. Meier CA, Biller BMK 1997 Clinical and biochemical evaluation of Cushing’s syndrome. Endocrinol Metab Clin North Am 26:741-762
4. Swearingen B, Biller BMK, Barker FG, 2nd, Katznelson L, Grinspoon S, Klibanski A, Zervas NT 1999 Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Intern Med 130:821-824
5. Williams RH, Larsen PR 2002 Williams textbook of endocrinology, 10th ed. W.B. Saunders, Philadelphia