Progesterone and medroxyprogesterone acetate differentially regulate α4 subunit expression of GABAA receptors in the CA1 hippocampus of female rats

The Women's Health Initiative trials – in which more extreme adverse outcomes were observed in the medroxyprogesterone acetate (MPA) + conjugated equine estrogen (CEE) arm, as compared to the CEE only arm – suggest that the addition of MPA to estrogen treatment has undesirable consequences. An important question raised by these results is whether the adverse outcomes observed in the progestin arm can be attributed to effects that are unique to MPA or are common to all progestins. In this study we explored the potential for MPA and progesterone (P4) to differentially impact neuroendocrine function by comparing their effects on mRNA expression for the α4 subunit of GABAa receptors in the CA1 hippocampus of female rats. Prior research has shown that P4, acting through its reduced metabolite allopregnanolone (AP), can mediate α4 subunit expression, thereby altering GABAA receptor gated currents. By contrast, MPA competitively inhibits the enzymes necessary for the synthesis of AP. In this study, ovariectomized females were primed with estradiol benzoate and then treated with P4, MPA, or vehicle. Subjects were sacrificed 12 h or 24 h later and in situ hybridization was used to measure α4 mRNA in the CA1 hippocampus. At 12 h but not 24 h, α4 mRNA was reduced in the P4 group as compared to the MPA group, and as compared to the vehicle group. These results suggest that MPA, while progestational in terms of its effects in the uterus, is not a simple substitute for P4 in other systems. The relative impact of these two progestins on neuroendocrine function must be carefully explored.