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 (HPA) activation in FHA and we wondered, therefore, 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. Cross-sectional comparison.

Setting. General clinical research center in an academic medical center.

Participants. 15 women with FHA of normal body weight and 14 EW.

Intervention. Blood samples were collected at 15-min intervals for 24-h followed by procurement of 25 mL of CSF.

Main outcome measures. Cortisol, CBG, and SHBG levels in blood and CSF.

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. Since CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound.

Conclusions. The HPA 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.