Progesterone and medroxyprogesterone acetate differentially regulate α4 subunit expression of GABAA 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 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.

Expression of Steroid Receptor Coactivator-1 Was Regulated by Postnatal Development but Not Ovariectomy in the Hippocampus of Rats

“…Because estrogens and progestins have been shown to regulate the structure and function of the hippocampus [1,23,24,25,33,34,35], in our studies the postnatal temporal profile of hippocampal SRC-1 provided a possibility that the age-related decrease of hippocampal SRC-1 may be caused by changes in circulating female hormones with aging. To test whether the aging-related changes of SRC-1 expression were related to dysfunction of the aging ovary, we used ovariectomy to mimic circulating estrogen deficiency.…”

“…The hippocampus is one of the most important targets of ovarian hormones; hippocampal synaptic plasticity can be regulated by estrogen [3,4,8] and progestins [23,24,25]. In the hippocampus, the mRNAs and proteins of steroid receptors such as estrogen receptor α and β (ERα and ERβ) and progestin receptor [23] are present, and these nuclear receptors function to regulate hippocampal neuronal excitability, synaptogenesis and plasticity redundancy as well as hippocampus-associated learning and memory [6,8,26].…”

Long-term replacement of estrogen in combination with medroxyprogesterone acetate improves acquisition of an alternation task in middle-aged female rats.

“…It is unknown if progesterone and MPA have similar neural effects because few studies have directly compared them. Braden et al (2010) found that chronic MPA significantly and progesterone marginally decreased levels of glutamic acid decarboxylase in the hippocampus when administered via osmotic pumps However, a single injection of progesterone transiently down regulated mRNA expression of GABA a subunits, where as MPA did not (Pazol, Northcutt, Patisaul, Wallen, & Wilson, 2009). If MPA and progesterone result in different neural outcomes, they may differentially affect cognition.…”

“…Chronic long-term treatment with E 2 down-regulates estrogen receptors (Brown, Scherz, Hochberg, & MacLusky, 1996), and levels of choline acetyltransferase increase after acute E 2 treatment but return to normal after chronic treatment in the basal forebrain (Gibbs, 1997). Furthermore, acute treatment with estrogen and progesterone resulted in decreases in GABA receptor subunit expression 12 hours, but not 24 hours after treatment (Pazol et al, 2009). Therefore long term chronic hormone treatment during aging might lead to a down regulation of estrogen receptors in cognitive brain regions and different behavioral outcomes than short term treatments.…”

The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory

“…For example, our laboratory and others have shown that progesterone decreased GAD65 + 67 protein levels in the hippocampus and increased GAD65 + 67 protein levels in the entorhinal cortex (Braden et al, 2010) as well as decreased GAD activity in several brain regions, including the dorsal hippocampus, as measured by kinetic studies (Wallis and Luttge, 1980). Furthermore, an in situ hybridization study revealed that 12 h after treatment, progesterone, but not MPA, reduced hippocampal mRNA expression of the α4 subunit of the GABA(A) receptor (Pazol et al, 2009), suggesting that different progestogens can have variable impacts on the GABAergic system. We recently showed that in a middle-age Ovx rat model, progesterone administration resulted in transient working memory impairments on a spatial memory task, but concomitant delivery of bicuculline, a GABA(A) receptor antagonist, obviated these memory impairments (Braden et al, 2015).…”