ACTH and Cortisol Response to Dex/CRH Testing in Women with and without Premenstrual Dysphoria during GnRH Agonist-Induced Hypogonadism and Ovarian Steroid Replacement

Abstract

During conditions of ovarian suppression, women with premenstrual dysphoria (PMD) experience abnormal behavioral responses to physiological levels of ovarian steroids. Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation frequently accompanies depression, and ovarian steroids regulate HPA axis responsivity, the role of HPA axis dysregulation in PMD is not known. We hypothesized that women with PMD would show abnormalities of HPA axis function analogous to those reported in depressive illness, and that ovarian steroids would differentially regulate HPA axis function in women with PMD compared with asymptomatic controls (AC). Our objective was to characterize the HPA axis response to physiological levels of estradiol and progesterone in women with PMD and AC. We conducted an open-label trial of the GnRH agonist depot Lupron with ovarian steroid replacement administered in a double-blind crossover design in an outpatient clinic. Forty-three women (18 with prospectively confirmed PMD and 25 AC) participated. Women received Lupron for 6 months. After 3 months of hypogonadism, women received 5 wk each of estradiol (100-μg patch daily) or progesterone (suppositories 200 mg twice daily). During each condition, combined dexamethasone-suppression/CRH-stimulation tests and 24-h urinary free cortisol levels were performed. Plasma cortisol and ACTH levels were evaluated. HPA axis function was similar in PMD compared with AC. In all, progesterone significantly increased the secretion of cortisol compared with estradiol [area under the curve (t(74) = 3.1; P < 0.01)] and urinary free cortisol (t(74) = 3.2; P < 0.01) and ACTH compared with hypogonadism [area under the curve (t(74) = 2.4; P < 0.05)]. HPA axis regulation is normal in PMD, suggesting that the pathophysiology of PMD differs from major depression. As observed previously, progesterone but not estradiol up-regulates HPA axis function in women.