The lack of an effective medical therapy for patients with Cushing's disease (CD) requires the search for new modalities of treatment. PPAR- receptors are abundantly expressed in adrenocorticotrophic hormone (ACTH) secreting pituitary tumors. Treatment with PPAR- agonists inhibit 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 PPAR- agonist pioglitazone would normalize the hypothalamic-pituitary-adrenal axis of patients with Cushing's disease.

We evaluated the hypothalamic pituitary adrenal axis in 5 patients with Cushing's disease in whom we measured: (1) the 24 h (24-h) urine concentration of free cortisol (UFC); (2) the 24-h profile of serum cortisol and plasma ACTH; and (3) the ACTH and cortisol response to CRH (CRH) stimulation. All measurements were taken at baseline and after low dose dexamethasone (LDD) treatment (0.5 mg dexamethasone every 6 h). The entire protocol was done before and after 30 days of treatment with 45 mg of daily oral pioglitazone.

At baseline, before LDD, all 5 patients had elevated 24-h urine free cortisol (UFC), elevated 24-h serum cortisol and plasma ACTH levels, and robust responses to CRH, consistent with their diagnosis of Cushing's disease. There was no significant change in any of the above variables after 30 days 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 days) of patients with Cushing's disease was not found to be effective at attenuating either ACTH or cortisol levels and does not appear to be an alternative to surgical therapy.