Editor’s Note: Dr. Lynnette Nieman, NIH, NICHD, Bethesda, MD chaired the task force that developed the guideline. The task force also included Beverly M.K. Biller of Massachusetts General Hospital in Boston, MA; James W. Findling of the Medical College of Wisconsin in Milwaukee, WI; M. Hassan Murad of the Mayo Clinic in Rochester, MN; John Newell-Price of the University of Sheffield in Sheffield, U.K.; Martin O. Savage of the William Harvey Research Institute at Barts and the London School of Medicine and Dentistry in London, U.K.; and Antoine Tabarin of CHU de Bordeaux and INSERM at the University of Bordeaux, Bordeaux France. The guideline was published in the August issue of the Journal of Clinical Endocrinology and Metabolism. The CSRF believes that this guideline will assist in the transfer of knowledge from experts in Cushing’s to other endocrinologists with less experience, resulting in better patient care. You might want to let your physicians know about this important guideline.

Introduction

The Guideline Committee of The Endocrine Society determined that a guideline on the treatment of Cushing’s syndrome (including pituitary, adrenal and ectopic causes) would be highly beneficial. Thus, a task force of experts was formed and following an extensive literature review process to identify evidence in the medical literature, reached a consensus on the guideline. The full guideline includes a grading system indicating whether the recommendation is strongly supported by evidence or only weakly supported. The guideline, co-sponsored by the European Society of Endocrinology, provides endocrinologists and other medical professionals with treatment recommendations based on evidence from the medical literature and expert physicians.

Why should Cushing’s be treated?

Overt (readily apparent) Cushing’s is a serious disorder that needs to be treated to prolong life. In the 1950’s, before treatments were available, the survival rate of patients with overt Cushing’s was about 4.6 years. Even today, with better treatment options for Cushing’s syndrome-related diabetes, hypertension and infections, Cushing’s patients continue to show increased mortality rates until cortisol is normalized. Cardiovascular disease, venous thrombosis (blood clots in the veins leading to stroke or pulmonary embolism) and infections are the primary causes of death during active Cushing’s. When Cushing’s is successfully treated, mortality rates greatly improve, however, there are conflicting reports in the medical literature as to whether mortality returns to that observed in the general population.

What about mild or cyclic Cushing’s?

All treatments for Cushing’s carry risks, thus the treatment risks need to be balanced with symptoms when evaluating patients with mild or cyclic Cushing’s. Evidence in the medical literature is lacking in this area. Although, Cushing’s is generally progressive over time, and early treatment may improve long term outcome, this has not been clearly demonstrated.

What about co-morbidities?

All co-morbidities (symptoms or conditions resulting from Cushing’s), such as diabetes, hypertension, osteoporosis, infections, low potassium, psychiatric issues, high cholesterol and triglycerides, and poor physical fitness, should be aggressively addressed. Interventions may include vaccinations for pneumonia, influenza, etc. since the immune system is compromised during active Cushing’s. Other interventions may include medications or referral for psychiatric help or physical therapy.

Fairly recently, it has become apparent that Cushing’s patients are at risk for venous thrombosis during active Cushing’s and also up to one year after successful treatment. This risk is particularly increased in the month immediately following surgery. Thus, clinicians should evaluate thrombosis in Cushing’s patients and consider anticoagulant therapy when needed.

First line treatment

Patients and their family/caretakers should be educated about the signs and symptoms of Cushing’s, treatment options, and what to expect during recovery. The recommended treatment is removal of the pituitary, adrenal or ectopic tumor(s) causing Cushing’s. Tumors may recur, except for patients with noncancerous adrenal adenoma and those undergoing bilateral adrenalectomy for adrenal causes. Patients should be evaluated for recurrence annually, or sooner if symptoms recur.

Pituitary tumors

Pituitary tumors (Cushing’s disease) should be removed by an experienced pituitary surgeon as successful removal is most likely when performed by an experienced pituitary neurosurgeon with a high case load of Cushing’s disease patients. Either the transsphenoidal or endoscopic procedure can be used depending on the surgeon’s preference. Most pituitary tumors causing Cushing’s are small (< 1 cm) and are seen on pituitary MRI in about 60% of adults and 55% of children with Cushing’s disease. In addition, a pituitary tumor < 6mm is visible in approximately 10% of the normal population, approximately 12% of patients with ectopic Cushing’s and in 12% of patients with surgically proven pituitary Cushing’s in whom MRI did not correctly locate the pituitary tumor. In patients with normal or elevated ACTH, inferior petrosal sinus sampling (IPSS) is highly recommended for patients without a pituitary tumor > 6mm. The IPSS procedure should be performed at a center experienced in conducting this evaluation. IPSS is highly accurate in identifying pituitary causes of Cushing’s vs ectopic causes of Cushing’s. However, it is less accurate in localizing the tumor to one side of the pituitary gland, with a correct prediction in only 56-69% of adult patients.

Diabetes insipidus, characterized by excessive urination and high serum sodium levels, is relatively common in the first few days following surgery, but is usually temporary. Low sodium values subsequently occur in 5-10% of patients, thus the guideline recommends measurement of serum sodium several times during the first 5-14 days following surgery. Patients should be informed about water balance problems following surgery, including when to seek emergency care and how to reach their endocrinologist after hours. In addition to sodium, measurement of free T4 and prolactin should be done 1-2 weeks after surgery. A drop in T4 or prolactin can indicate hypopituitarism. In most practices, a pituitary MRI done 1-3 months after surgery can serve as a baseline to watch for changes over time.

Ectopic ACTH-secreting tumors

Ectopic ACTH-secreting tumors, once identified, should be surgically removed. One paper reported that such removal results in normal cortisol values in 76% of patients without recognized metastatic disease.

Adrenal tumors

Removal of benign adrenal tumors (adenomas) involves removing the affected adrenal gland. This surgery is curative in nearly 100% of cases. This surgery is usually done laparascopically and complication rates are lower with experienced surgeons. In cases of adrenal incidentalomas, it is not clear whether adrenalectomy or intensive medical management of comorbidities is the treatment of choice. However, some studies in the literature indicate that patients with metabolic abnormalities may benefit from surgical intervention. Further discussion of adrenal incidentalomas is beyond the scope of this article.

Adrenal cancer is an aggressive cancer and total removal of the cancer should be attempted. Further discussion of adrenal cancer is beyond the scope of this article.

Bilateral Macronodular Adrenal Hyperplasia

Bilateral macronodular adrenal hyperplasia (BMAH) are disorders of the adrenal glands that affect both glands, although in some cases only one gland appears to be involved at initial diagnosis. Some BMAH have been shown to run in families and screening of seemingly unaffected family members can be recommended. In some cases, the adrenal glands respond abnormally to other hormones by making cortisol; for many of these patients, medications exist to block the cortisol secretion response. Further discussion of the testing procedures utilized in this setting and treatment are beyond the scope of this article. Usually, if both glands are affected, a bilateral adrenalectomy is the preferred treatment, however in elderly patients, some have suggested removal of only the largest gland.

Primary pigmented nodular adrenal disease

This disorder affects both adrenal glands, thus bilateral adrenalectomy is the treatment of choice. Patients should be evaluated for Carney complex and if detected, family members should be evaluated, as this condition is hereditary. Further discussion is beyond the scope of this article.

Remission and Recurrence

Following successful surgery, patients are usually not able to make cortisol and are placed on replacement glucocorticoid. There is little consensus on the measurement of remission as different studies have used different criteria. Generally, remission is defined as a post-surgery morning serum cortisol less than 5 ug/dL (138 nmol/L) or a 24 hr urine cortisol less than 28-56 nmol/dL (<10-20 ug/d) within 7 days of surgery. However, there are instances, such as in mild or cyclic Cushing’s or patients treated with medication to normalize cortisol levels prior to surgery, when remission may be achieved, but post-surgical cortisol levels are not as low as indicated above. In these patients in particular, and others with normal cortisol following surgery, measurement of late night salivary or serum cortisol is recommended to determine if the normal diurnal rhythm of low cortisol late at night is intact, indicating remission. There is some indication that patients who are able to discontinue replacement medication quickly after surgery may be at higher risk for recurrence. Adult series report remission rates following pituitary tumor removal of 73-76% for microadenomas (tumors < 1cm diameter) and approximately 43% for macroadenomas (tumors >1 cm).

Recurrence of pituitary ACTH-producing tumors is very low in children with Cushing’s. By contrast, recurrence rates in adults vary from 15-66% within 5-10 years. One series indicated a 23% recurrence rate for microadenomas and a 33% recurrence rate for macroadenomas. Patients should be tested every year for possible recurrence and sooner if symptoms of Cushing’s syndrome recur. Two recent studies demonstrated that elevated late night salivary or serum cortisol is one of the earliest indicators of recurrence and almost always occurs before elevation of 24 hr urinary cortisol. While early diagnosis of a recurrence is possible, there is no evidence in the literature to support the benefits of treatment if the patient does not have Cushing’s symptoms. However, in most cases, patients will progress and become symptomatic.

Glucocorticoid replacement and discontinuation of replacement

Following successful surgery, patients are usually not able to make cortisol and are placed on replacement glucocorticoid. After resection of pituitary or ectopic ACTH-secreting tumors, discontinuation of replacement medication is usually possible 6-12 months after successful surgery. In adrenal patients, replacement medication is usually needed for about 18 months. While on replacement medication, it is critical that patients are given written instructions about the need to increase the replacement dose during illness, the use of injectable emergency steroids and the need to wear a medical alert tag indicating adrenal insufficiency/needs stress dose glucocorticoids.

Hydrocortisone at 10-12 mg/m2/d in divided doses is suggested (e.g. 15 mg in the morning and 5 mg in the afternoon). This dose strategy appears to provide physiologic replacement and works well clinically. Hydrocortisone is recommended above longer acting steroids, however if the patient requests once daily doses, small doses of longer acting steroids can be used.

In spite of adequate replacement of glucocorticoids, many patients experience “steroid withdrawal” symptoms as the body gets used to lower cortisol levels. The reasons for this are not understood. Patients should be informed to expect lack of hunger, nausea, fatigue, flu-like aches and pains, lethargy and dry skin. Many patients feel worse after surgery than before and they should be prepared for such changes. Adult patients may experience continuing or new depression, anxiety or panic symptoms. For depression, serotonin reuptake inhibitors may be useful, but has not been well studied. Even patients who are not in remission can experience a steroid withdrawal syndrome and it can continue after glucocorticoid replacement is discontinued. During this time, patients often feel better with a temporary increase in replacement dose. However, high doses of replacement for long periods of time can delay recovery of normal cortisol secretion and cause a medication-induced Cushing’s syndrome. The “steroid withdrawal” can continue for a year or longer.

There are no standard protocols or studies regarding tapering or abrupt discontinuation of steroid replacement doses. Some physicians taper based on weight loss, the length of time after surgery, or how the patient is doing. Other physicians do not taper and rely on testing for recovery of normal cortisol section. Testing for recovery of normal cortisol section is generally done by measurement of morning cortisol before the dose of replacement medication every 3 months following surgery. Once a level of 7.4 ug/dL (200 nmol/L) is reached, ACTH stimulation testing is recommended; replacement can be discontinued once stimulated cortisol levels reach approximately 18 ug/dL (500nmol/L) or more. Patients with morning cortisol less than 5ug/dL should remain on replacement.

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