7411 Hypothalamic Estrogenic Signal Regulates Prolactin Homeostasis and Reproduction in Female

Disclosure: M. Yu: None. C. Wang: None. Both 17β-estradiol (E2) and prolactin (PRL) are important reproductive hormones. It has been well established that E2 can act on estrogen receptor-α (ERα) in the lactotroph cells in the pituitary to upregulate PRL level. This mechanism may explain the high PRL and high E2 during proestrus phase or pregnancy, however, it could not explain high PRL but low E2 singling during lactation. We found that central supplement of E2 reduced PRL level in lactating dams, suggesting a novel inhibitory role of E2 on lactational hyperprolactinemia. To explore the mechanism and the relationship with reproductive regulation, firstly we compared the activity of ERα-expressing neurons in the hypothalamus during virgin and lactation. We found that ERα neurons in the ventrolateral subdivision of the ventromedial hypothalamus (ERαvlVMH) were inhibited during lactation. Further, we specifically deleted ERα from vlVMH in virgin females. These mice with deletion of ERαvlVMH showed dramatic changes: 1) lactation-like hyperprolactinemia and prolactinoma, 2) developed mammary gland and amenorrhea, and 3) disrupted reproduction including enlarged uterus and reduced fertility. Consistently, we specifically activated ERαvlVMH neurons in lactating mice and found that these lactating mice showed attenuated lactational hyperprolactinemia and impaired maternal cares. Together, we revealed a novel neuroendocrine mechanism that hypothalamic E2-ERα signaling regulate PRL homeostasis, which is important to maintain reproduction in females. Our study also supports that lactational suppression of hypothalamic E2-ERα signaling is required to maintain normal lactation which may contribute to reduced fertility during lactation. Presentation: 6/1/2024