Question: I was diagnosed with a large prolactinoma, started cabergoline and am now experiencing some symptoms that make me wonder if I could also have Cushing’s. Is it possible for a pituitary tumor to secrete both prolactin and ACTH? If so, what effect, if any, will the cabergoline have on testing for Cushing’s? Could these be side effects of the cabergoline?

Answer: Pituitary gland benign tumors called adenomas are rare and found in approximately 200 per million individuals. Many do not produce excess pituitary hormones but approximately 45% produce excess prolactin (prolactinomas), which is the most frequent hormone secreted in excess. Pituitary adenomas producing ACTH and resulting in excess cortisol production (Cushing’s disease) are less frequent and represent approximately 12% of pituitary tumors. The vast majority of pituitary adenomas are single tumors as more than one adenoma occurring in the same pituitary occurs in less than 1% of cases. Single pituitary adenomas may be silent and secrete no significant amount of hormones (chromophobe adenomas) or secrete hormones such as prolactin (prolactinoma), FSH, LH or part of these hormones (gonadotropinas), growth hormone (acromegaly-gigantism), ACTH (Cushing’s disease), or TSH (hyperththyroidism). Most hormone secreting adenomas secrete only one hormone, but a small proportion secrete two hormones, the most frequent combination being growth hormone and prolactin and less frequently other combinations; a few cases of combined prolactin and ACTH have been reported in the literature. Even less frequently (only a handful of cases), two distinct adenomas one secreting prolactin and one secreting ACTH (or another hormone) can occur concurrently or sequentially over a few years in the same patient. Cushing’s syndrome can also occur in individuals who have single tumors producing excess cortisol from one adrenal gland (adenoma or adrenocortical carcinoma) or over function of both adrenal glands (micro or macronodular adrenal hyperplasia) which result in suppressed ACTH levels. In the rare genetic syndrome of multiple endocrine neoplasia type 1, there can be a combination of prolactinoma (or other pituitary adenoma) and adrenal tumor usually non secreting, but rare cases of adrenal Cushing’s can occur; this is usually in a familial context with the presence of concomitant primary hyperparathyroidism and pancreatic and gut tumors such as gastrinomas or insulinomas.

The vast majority of patients with prolactinomas are treated with drugs (bromocryptine, cabergoline, quinagolide) which act trough dopamine receptors and are effective to restore normal prolactin levels and reduce prolactinoma size in approximately 80% of cases. Pituitary surgery is necessary only in patients with usually larger tumors not responding or intolerant to medical treatment or experiencing local tumor complications such as visual field defects or acute hemorrhage. The most common side effects of cabergoline or bromocryptine are nausea, headaches, dizziness when standing up, nasal congestion, fatigue, anxiety or depression. The symptoms resulting from excess ACTH and cortisol are quite different and include mainly weight gain (central distribution), high blood pressure, fatigue, excess hair growth and menstrual irregularities in woman, skin thinning, easy bruising/ecchymosis, sleep disturbance, lack of concentration, mood changes, proximal muscle weakness and diabetes.

Treatment of Cushing’s disease is usually performed by surgical removal of the pituitary ACTH-secreting adenoma. Unfortunately the surgery is unable to remove the tumor completely in 10-15 % of cases and recurrence of tumors believed to be cured occurs in up to 20-30% of cases within 10 years of follow-up. Other treatment options have included a second pituitary surgery, pituitary radiotherapy, drugs which inhibit adrenal production of cortisol or bilateral adrenalectomy. Recently, new studies have identified that in patients with Cushing’s disease drugs such as cabergoline or somatostatin receptor acting pasireotide can inhibit ACTH and cortisol production in a significant proportion of cases. Cabergoline was found to be able to maintain normal cortisol secretion in 24 hour urine collections in 40% of patients studied over 2 years in one study and in 30% treated as long as 5 years. Even if cabergoline could restore normal 24-hour cortisol production and disappearance of Cushing’s symptoms, there were no detailed studies as to whether diurnal fluctuations of cortisol, or normal suppression of cortisol by dexamethasone are also normalised by cabergoline.

Returning to your question, it would be necessary for your physician to obtain more precise details about the symptoms which you believe may be compatible with excess cortisol production. Is your excess prolactin efficiently controlled with cabergoline and are your other pituitary functions normalized? Do you experience any side effects from cabergoline? If any of those or physical findings did evoke the possibility of Cushing’s syndrome, the investigation according to recent guidelines could include testing blood cortisol levels following administration of dexamethasone 1 mg at bedtime, salivary cortisol level at bedtime or urinary free cortisol levels. The likelihood of combined prolactinoma and Cushing’s disease is as you have understood very remote.

References

Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA; Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab. 96:273-88, 2011

Meij BP, Lopes MB, Vance ML, Thorner MO, Laws ER Jr. Double pituitary lesions in three patients with Cushing’s disease. Pituitary 3: 159-168, 2000

Andrioli M, Pecori Giraldi F, Losa M, Terreni M, Invitti C, Cavagnini F. Cushing’s disease due to double pituitary ACTH-secreting adenomas: the first case report. Endocr J. 57: 833-7, 2010

Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93:1526–1540, 2008

Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SWJ & Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. Journal of Clinical Endocrinology and Metabolism 94: 223-230, 2009.

Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 163: 1-9, 2010

By André Lacroix MD (Spring, 2011)