Response to flumazenil in the late luteal phase and follicular phase of the menstrual cycle in healthy control females

Rationale. Animal studies of short-term progesterone administration and withdrawal model the natural increase and abrupt decrease in progesterone levels which occur in the late luteal phase (LP) of the human menstrual cycle (MC). Previously, studies in animals have shown that abrupt cessation of chronic or short-term progesterone administration results in pharmacological changes at the GABA(A) receptor, resulting in altered sensitivity to GABA(A) receptor neuromodulators such as benzodiazepines and flumazenil, a GABA(A) receptor antagonist. Objectives. This study's goal was to compare the response to flumazenil in the follicular phase (FP) and late LP in female healthy controls (HCs). We postulated that HC females would exhibit a greater psychological and somatic response to flumazenil in the late LP, a period of progesterone withdrawal, compared to the FP. Methods. Twelve healthy females, without history of psychiatric disorder, were randomized to receive two injections of a 2 mg bolus injection of flumazenil (one in the late LP and one in the FP) and two injections of placebo (one in the late LP and one in the FP). Following injection, subjects were asked to rate the occurrence and intensity of panic symptoms on the panic symptom scale (PSS). Results. A main treatment effect was detected for the PSS score response after flumazenil injection (P=0.008). However, there was no significant treatment-by-phase interaction observed (P=0.449). Conclusions. These findings indicate that MC phase did not affect the response to flumazenil in HC females. This result is contrary to our hypothesis of altered sensitivity to flumazenil in the late LP.