OR19-03 SIK2 Regulates Granulosa Cell Response to Exogenous Gonadotropins

Abstract

Abstract Disclosure: E. Hayes: None. O. Lakomy: None. M. Hassan: None. R. Filzen: None. M. Rodriguez Esquivel: None. M. Foretz: None. C.O. Stocco: Grant Recipient; Self; NIH R01HD097202. Forty percent of cases of infertility are attributed to ovulatory defects. Successful ovulation requires the coordinated development of the ovarian follicle, the functional unit of the ovary that is composed of the oocyte surrounded by steroidogenic granulosa cells. However, the mechanisms that govern follicle development remain incompletely understood. Previously, our group showed that loss of salt-inducible kinase 2 (SIK2) in a murine knockout model resulted in a significantly increased number of ovulated oocytes in response to an ovarian hyperstimulation protocol. Here, we aimed to further characterize the reproductive phenotype of SIK2 knockout mice, as well as to understand the role of SIK2 in granulosa cells by creating and characterizing a granulosa cell-specific knockdown of SIK2 using the Cre-Lox system. Loss of SIK2 resulted in no changes in the number of litters or litter size as well as a normal estrus cycle. Interestingly, granulosa cell-specific knockdown of SIK2 resulted in a significantly increased number of ovulated oocytes in response to ovarian hyperstimulation. However, SIK2 knockout mice do not ovulate more oocytes under physiologic conditions. Furthermore, knockdown of SIK2 in granulosa cells resulted in significantly increased Cyp19a1 gene expression and serum estradiol concentration. The data reveal that SIK2 plays an important role in the regulation of the response of granulosa cells to gonadotropins. These data support the potential of SIK2 as a pharmacologic target for improving oocyte yield for women receiving gonadotropins during in vitro fertilization as a treatment to trigger follicular maturation and ovulation. SIK2-regulated mechanisms could reveal new targets for the development of innovative methods of contraception. Presentation Date: Saturday, June 17, 2023