Effect of pioglitazone on adrenocorticotropic hormone and cortisol secretion in Cushing's disease

The lack of an effective medical therapy for patients with Cushing's disease (CD) requires the search for new modalities of treatment. Peroxisomal proliferator-activated receptors (PPAR)-gamma are abundantly expressed in ACTH-secreting pituitary tumors. Treatment with PPARgamma agonists inhibits ACTH-secreting pituitary tumor growth, proliferation, and ACTH secretion in vitro in human and murine models and in vivo in murine corticotroph tumors. It was hypothesized that treatment with the PPARgamma agonist pioglitazone would normalize the hypothalamic-pituitary-adrenal axis of patients with CD. We evaluated the hypothalamic pituitary adrenal axis in five patients with CD in whom we measured: 1) the 24-h urine concentration of free cortisol; 2) the 24-h profile of serum cortisol and plasma ACTH; and 3) the ACTH and cortisol response to CRH stimulation. All measurements were taken at baseline and after low-dose dexamethasone treatment (0.5 mg dexamethasone every 6 h). The entire protocol was done before and after 30 d of treatment with 45 mg of daily oral pioglitazone. At baseline, before low-dose dexamethasone, all five patients had elevated 24-h urine free cortisol, elevated 24-h serum cortisol and plasma ACTH levels, and robust responses to CRH, consistent with their diagnosis of CD. There was no significant change in any of the above variables after 30 d of treatment with pioglitazone. Furthermore, there was no significant difference in the number of cortisol or ACTH spikes or in their diurnal rhythms. In summary, pioglitazone treatment (45 mg daily for 30 d) of patients with CD was not found to be effective at attenuating either ACTH or cortisol levels and does not appear to be an alternative to surgical therapy.