Response to Neurotransmitter Modulating Drugs in Patients With Cushing's Disease

Abstract

We designed a systematic study of patients with Cushing's disease to compare the results of acute experiments with cyproheptadine, sodium valproate and bromocriptine with the results of chronic treatment with sodium valproate. In 13 patients the plasma cortisol response to single doses of 2.5 mg bromocriptine, 6 mg cyproheptadine and 300 mg sodium valproate was assessed over 4-8 h. All patients were then treated with sodium valproate 200 mg three times a day for a period of 3 months. Subjects were classified as responders when there was a reduction in plasma cortisol by at least 50% below the basal level in two consecutive plasma samples during one of these tests, and/or clinical remission and normalization of cortisol production rate during sodium valproate treatment. Four patients responded significantly to at least one of the agents (group I) and 9 did not (group II). In group I three patients were bromocriptine responsive and one of these responded also to cyproheptadine; in this patient both sodium valproate and cyproheptadine were able to induce a remission during chronic treatment. In the one patient of the responder group who was bromocriptine insensitive, sodium valproate treatment also induced a remission. In two patients of the responder group sodium valproate treatment was ineffective. However, in both patients chronic treatment with bromocriptine induced a marked clinical improvement associated with a decrease of cortisol production rate. There was no difference between the groups in sex, age, clinical presentation, duration or severity of hypercortisolism. In one patient in group I a macroadenoma with suprasellar extension was present, while a microadenoma was detected in four patients in group II.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Cushing's disease: a mechanistic update

“…Valproate blocks GABA reuptake enhancing GABA inhibition of hypothalamic CRH release. Clinical reports of valproate-responsive patients with CD have emerged (Cavagnini et al 1984, Koppeschaar et al 1986, Colao et al 1997. However, chronic administration and placebo-controlled studies failed to confirm the ACTHlowering effects of valproate , Colao et al 1997.…”

The effect of sodium valproate in Cushing's disease, Nelson's syndrome and Addison's disease

“…[3]. However, clinical remission in Cushing's disease induced by sodium valproate has been reported occasionally [4,10,11] but these cases appear to be very rare. These inconsistend results may be explained by the fact that in Cushing's disease the underlying dis order appears to be heterogenous.…”

“…In recent years sodium valproate, an anticonvulsant, has been shown to decrease plasma ACTH levels in Nelson's syndrome [5,6,9]. However, the efficacy of sodium valproate Abbreviations: ACTH = Adrenocorticotrophic hormone; CRF = Corticotropin releasing factor in pituitary dependent Cushing's syndrome remains controversial [1,3,4,6,10,11,13]. This study evaluates the effectiveness of sodium valproate in different ACTH hypersecreting states and investigates the site of its action.…”

Bromocriptine-Responsive Cushing's Disease; Clinical and Biochemical Remission Accompanied by Amelioration of Impaired Ocular Movement

“…However, trials in series of consecutive patients revealed that only fewer than 25% of unselected patients respond to bromocriptine. A clinical response to low-dose (less than 10 mg) bromocriptine in 15 cases has been reported thus far (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), while tumor shrinkage has been reported in only 3 cases (9,16,18) (Table 2).…”