MON-159 A Critical Role of an ESR2-to-ESR1 Switch in the Female Reproductive Axis

Abstract Disclosure: M.A. Bunnell: None. P.P. Lin: None. J. Oh: None. C. Park: None. S. Zhou: None. C.J. Ko: None. Most actions of estradiol (E2) are exerted by two distinct nuclear receptors, estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2). Despite being activated by the same ligand, ESR1 and ESR2 exhibit distinct expression patterns and elicit different physiological outcomes. Typically, ESR1 mediates E2-driven actions in regulating reproductive functions. ESR2 modulates or attenuates these effects. Global ESR1 knockout mice are infertile, underscoring ESR1’s essential role in regulating fertility. In this study, we tested a novel hypothesis that a switch from ESR2 to ESR1 in specific cell lineages is critical for female fertility and health. To test this, we generated a transgenic mouse model in which ESR1 expression is specifically ablated in the ESR2-expressing cell lineage using the Cre-LoxP system (Esr1 flox/flox Esr2 iCre/WT; Esr2-Esr1KO). Female Esr2-Esr1KO mice did not produce any litters (0% vs. 100% in WT controls; p < 0.0001) when paired with proven male breeders. Their ovaries were smaller than WT, and had follicular cysts, disrupted cumulus oocyte complexes, atretic follicles, and lacked corpus luteum (CL), indicating impaired folliculogenesis and ovulation. These ovarian phenotypes were indicatives of an inadequate supply of gonadotropins. To determine if the GnRH-gonadotroph axis was impaired in the Esr2-Esr1KO mice, we measured LH secretion before and 30 minutes after kisspeptin (KP-10, 50 nmol) stimulation in adult female mice. WT mice exhibited a significant increase in LH concentration (0.88 to 2.88 ng/mL, p=0.003), whereas Esr2-Esr1KO mice did not (0.37 to 0.35 ng/mL, p=0.9), indicating an impaired GnRH-gonadotroph axis. Thus, inadequate LH secretion contributed to the anovulatory phenotype in the ovaries of Esr2-Esr1KO mice. To determine ovarian responsiveness to gonadotropins, mice were treated with gonadotropins following the superovulation protocol. Although fewer than WT, Esr2-Esr1KO mice ovulated oocytes (p =0.0008) and formed CL, suggesting that follicular atresia was primarily caused by an inadequate supply of endogenous gonadotropins. In conclusion, ESR1 deletion in ESR2-expressing lineages results in female infertility due to impaired gonadotropin secretion, revealing a previously unknown requirement for ESR2-to-ESR1 switch in the hypothalamic-pituitary-ovarian axis. These findings highlight the significance of estrogen receptor plasticity in reproductive organs and their functions. Presentation: Monday, July 14, 2025