Role of membrane estrogen receptor alpha on the positive feedback of estrogens on LH secretion

Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ER) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling is unclear. To address this question, we used two complementary approaches: estetrol (E4) a natural estrogen described to act as an agonist of nuclear ER and a mER antagonist and the C451A-ER mouse lacking mER. E4 dose-dependently blocks ovulation in female rats, but the mechanism underlying this effect is unknown. To determine whether E4 acts centrally to control ovulation, we tested its effect on the positive feedback of estradiol (E2) on LH secretion. In ovariectomized females chronically exposed to a low dose of E2, estradiol benzoate (EB) alone or combined with progesterone (P) induced a LH surge and the associated increase in the number of activated kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons. However, E4 blocked these effects of EB when provided alone, but not when combined to P. These results indicate that E4 blocked the induction of the positive feedback and the associated neuronal activation in the absence of P, suggesting an antagonistic effect of E4 on mER as shown in peripheral tissues. In parallel, C451A-ER females do not show a pre-ovulatory LH surge and the associated activation of Kp and GnRH neurons in response to EB unless they are treated with P. The similarity of the responses of C451A-ER mice and wild-type females treated with E4 supports a role for membrane-initiated estrogen signaling in the EB-induced LH surge.