Progesterone and medroxyprogesterone acetate differentially regulate alpha4 subunit expression of GABA(A) receptors in the CA1 hippocampus of female rats

Abstract

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 alpha4 subunit of GABA(a) receptors in the CA1 hippocampus of female rats. Prior research has shown that P4, acting through its reduced metabolite allopregnanolone (AP), can mediate alpha4 subunit expression, thereby altering GABA(A) 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 alpha4 mRNA in the CA1 hippocampus. At 12 h but not 24 h, alpha4 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.

Fig. 1

Levels of α4 mRNA expression in hippocampal CA1 neurons at 12 h and at 24 h among subjects treated with vehicle, P4 or MPA. Results of the ANCOVA at 12 h indicate there was a significant difference in receptor sub-unit expression across treatment conditions (P = 0.002), but there was no significant difference at 24 h (P = 0.482).

Fig. 2

Film radiograms illustrating mRNA expression of the α4 subunit in hippocampal CA1 neurons at 12 h following treatment with vehicle, P4 or MPA. Subjects treated with P4 showed lower levels of mRNA expression in comparison to subjects treated with vehicle (P = 0.005), and especially in comparison to subjects treated with MPA (P = 0.001).