Increased cortisol responsivity to adrenocorticotropic hormone and low plasma levels of interleukin-1 receptor antagonist in women with functional hypothalamic amenorrhea

Objective: To assess the hypothalamic-pituitary-adrenal (HPA) axis at all levels,to determine the origin of the, previously reported hypercortisolism in patients with functional, hypothalamic amenorrhea. A secondary-aim was to evaluate factors outside the central nervous-system which are known to affect the HPA axis, i.e., circulating levels of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and fat,mass-adjusted leptin levels, in patients with functional hypothalamic amenorrhea and healthy controls. Design: Cross-sectional study. Setting: Umea University Hospital, Umea, Sweden. Patients: Fifteen subjects with hypothalamic amenorrhea, and 14 age- and weight-matched controls. Interventions: None. Main Outcome Measures: We collected blood samples four times during a 24-hour interval for analysis of cortisol, leptin, IL-1Ra, and IL-6 levels. We performed a low-dose oral dexamethasone test and a low-dose ACTH test. We measured body-fat percentage using a dual-energy X-ray absorptiometer. Results: Patients with hypothalamic amenorrhea had increased diurnal cortisol levels (P <.001). The cortisol response to intravenous low-dose ACTH was increased in functional hypothalamic amenorrhea patients compared to control subjects (P <.01), but they had similar rates of dexamethasone suppression. Patients with hypothalamic amenorrhea also had decreased diurnal leptin (P <.05), and decreased diurnal IL-1Ra levels (P <.05), compared to controls. Body-fat percentage was the main predictor of leptin levels. Conclusion: The present study suggests novel links for the development of functional hypothalamic amenorrhea, including increased adrenal responsiveness and impairments in proinflammatory cytokine pathways.