Remission in Cushing disease with cabergoline

To The Editor: Transsphenoidal surgery (TSS) is the first-line treatment of Cushing disease (CD) with remission rates between 60% and 80% (<15% for macroadenomas) with a relapse rate of up to 20%.¹ Pituitary radiotherapy (RT) and total bilateral adrenalectomy (BA) are second line treatments in patients not cured by surgery. Patients undergoing BA need lifelong treatment with glucocorticoids and mineralocorticoids with a risk of Nelson syndrome, while RT is associated with risk of hypopituitarism. Medical treatment usually consists of use of adrenal-blocking drugs and neuromodulatory drugs acting at the pituitary level.^2,3

We describe a 12-year-boy with persistent CD after TSS and RT, in whom short-term cabergoline treatment was effective in inducing a remission. The patient presented in October 2005 with history of progressive weight gain and short stature for the past 3 years. Persistent uncontrolled hypertension had been documented for 2 years previously. He had classical clinical features of CD, including obesity (BMI 34 kg/m²), moon facies, facial plethora vellous hypertrichosis, acanthosis nigricans (axilla, neck and knuckle) and pink striae. He was prepubertal. Investigations were suggestive of adrenocorticotrophin (ACTH)-dependent CD: a basal cortisol (BC) of 35 μg/dL, a basal ACTH of 25.4 pg/mL and a low-dose dexamethasone suppression (LDDS) cortisol of 21.8 μg/dL; MRI of the abdomen showed an adrenal hyperplasia and an MRI of the pituitary was normal. Corticotrophin releasing hormone stimulated IPSS (inferior petrosal sinus sampling) showed a central to peripheral ratio of 46 and lateralization to the right side with a ratio of 1.5. The patient underwent TSS in January 2006. Histopathology confirmed pituitary adenoma (immunohistochemistry by ACTH stain was positive). Postoperatively, he continued to have evidence of persistent CD. One year post-surgery he was still uncured (BC of 22.2 μg/dL, basal ACTH of 59.6 pg/ml and post-LDDS cortisol of 20.9 μg/dL). He received conventional fractionated RT, with a total dose of 45Gy over 38 days beginning in March 2007. In May 2007 he was started on cabergoline 1 mg/week for 1 month which was progressively increased to 3 mg/week. At the end of 3 months, marked clinical and biochemical remission was achieved (decrease in pigmentation of skin and hair growth, weight loss of 7 kilograms, BC of 3.26 μg/dL and basal ACTH of 38.5 pg/mL). The patient omitted cabergoline for 2 months following which he had recurrence of CD (BC of 19.3 μg/dL, basal ACTH of 45.12 pg/mL and LDDS of 5.3 mcg/dL). The patient was restarted on cabergoline and is due for follow-up. Neuromodulatory drugs (sodium valproate, cyproheptadine, rosiglitazone^4,5 and dopamine agonists with pharmacological action at the level of the hypothalamus and pituitary) have been tried in patients with uncured CD.^6,7 Dopamine agonists have been tried in CD because of their established efficacy in prolactinomas. Dopamine receptors are expressed in normal adrenals, adrenal tumors (adenomas and carcinomas), ⁷ 80% of corticotroph pituitary tumors and ectopic corticotroph tumors. There are various case reports of remission of CD with dopamine agonists with tumor shrinkage in some cases.^2,3 Cabergoline is likely to be superior in efficacy as compared with bromocriptine.⁸ Our patient improved with short-term treatment with cabergoline. This is the first documented case report from India with cabergoline showing a response in uncured CD. Although our patient received RT, the time interval between RT and clinical and biochemical remission was very short suggesting that this remission was unlikely due to RT. A mean interval of 11.2 months has been reported in children and adolescents with uncured CD before any benefit from RT was observed.⁹ Since our patient had an initial remission and recurrence on discontinuing the drug, this suggests that the observed benefit is likely due to cabergoline. Thus cabergoline could be a useful option for inducing remission in uncured CD patients who have undergone TSS and radiotherapy.