Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea

Context: The proximate cause of functional hypothalamic amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated. Objective: We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW). Design: The study is a cross-sectional comparison. Setting: The study was set in a general clinical research center at an academic medical center. Participants: Fifteen women with FHA who were of normal body weight and 14 EW participated. Intervention: Blood samples were collected at 15-min intervals for 24 h, followed by procurement of 25 ml CSF. Main Outcome Measures: Cortisol, cortisol-binding globulin (CBG), and SHBG levels in blood and CSF were the main outcome measures. Results: CSF cortisol concentrations were 30% greater when serum cortisol was 16% higher in FHA compared with EW. Circulating CBG, but not SHBG, was increased in FHA and, thus, the circulating free cortisol index was similar in FHA and EW. Because CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound. Conclusions: The hypothalamic-pituitary-adrenal axis is activated in FHA. The maintenance of CRH drive despite increased CSF cortisol indicates resistance to cortisol feedback inhibition. The mechanisms mediating feedback resistance likely involve altered hippocampal corticosteroid reception and serotonergic and GABAergic neuromodulation.