Estrogen receptors α and β have different roles in the induction and trafficking of progesterone receptors in hypothalamic ventromedial neurons

Abstract

Progesterone receptor (PR) activation in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl) is essential for promoting female sexual behavior. Estrogen receptor (ER) a, in contrast to ERb, has been implicated in the induction of PRs. The simultaneous activation of ERa and ERb, although not increasing the number of PR-immunoreactive neurons in the VMNvl, facilitates lordosis, which suggests that ERb and/or the ERa-ERb interaction might play a role in PR dynamics and/or PR expression by individual neurons. To address this question, we used western blot and immunohistochemical studies to determine the amounts and subcellular distributions of both PR isoforms in VMNvl neurons of ovariectomized rats injected with estradiol benzoate or with specific agonists of ERa and ERb, alone or in association. The present data show that ERa activation does not change PR expression in individual neurons, but increases the number of PRs in the VMNvl, because it increases the number of neurons expressing PRs. Conversely, ERb activation does not change the total number of PRs in the VMNvl, but increases the labeling intensity of the perikaryal cytoplasm, which suggests that it promotes the transport of PRs from neurites into cell bodies. In addition, the simultaneous activation of ERa and ERb increases the expression of PRs by individual neurons and, consequently, increases the total number of PRs in the VMNvl. Our findings reveal that individual and simultaneous activation of ERa and ERb have different effects on the levels and subcellular location of PRs in VMNvl neurons. IntroductionEndogenous progesterone plays a critical role in the regulation of female reproductive functions, including sexual behavior. By acting through its cognate receptors, progesterone modulates sexual behavior [1][2][3] and, according to the phase of the estrous cycle, activates or inhibits the sexual response [4][5][6]. These actions require previous estrogen priming [7,8] for the induction of progesterone receptors (PRs) in the brain areas that are involved in the modulation of sexual behavior [8][9][10]. This is the case for the hypothalamic ventromedial nucleus (VMN), particularly its ventrolateral division (VMNvl). Neurons located in this divi-0 ,6-diamidino-2-phenylindole; DPN, diaryl-propionitrile; EB, estradiol benzoate; ER, estrogen receptor; PPT, propyl-pyrazole triol; PR, progesterone receptor; VMN, hypothalamic ventromedial nucleus; VMNvl, ventrolateral division of the hypothalamic ventromedial nucleus.

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

“…Our findings corroborate the results of previous studies showing that the activation of ERα but not that of ERβ results in increased uterine weight 24, 25 . Uncontrolled uterine epithelial cell proliferation may lead to a pathological condition such as endometrial hyperplasia, which is a premalignant lesion of endometrial cancer 28 .…”

“…However, recent data suggest a possible tumour-suppressive role of ERβ 19–23 . Moreover, some studies indicate that activation of ERβ alone does not result in increased uterine weight 24, 25 . Therefore, selective activation of ERβ may be a safer approach to HRT than the common use of oestrogen, with respect to the risk of developing endometrial hyperplasia and cancer 26 .…”

Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction

“…Although estradiol priming through ERα is sufficient for upregulation of PGR and facilitation of lordosis [62], there is evidence that ERα and ERβ both have a role PGR induction [80]. However, simultaneous ERα and ERβ activation does not replicate estradiol treatment, pointing to the involvement of an additional ER, such as GPER, which induces enough PRG for progesterone for a moderate level lordosis [81].…”

Cooperation of Genomic and Rapid Nongenomic Actions of Estrogens in Synaptic Plasticity

“…The differential local distribution of ERs most likely indicates the different effects of local E2 administration in the brain [60]. Evidence has revealed that the individual or simultaneous activation of ERα and ERβ has different effects [61]. These findings suggest the intriguing hypothesis that the interactions between the two ERs and the consequences of transcriptional modulation are complicated and delicately balanced.…”