Critical Function of SIK3 in Androgen-Producing Ovarian Theca Cells for Female Reproductive Competence

Infertility affects over 10% of women of reproductive age, with ovulatory dysfunction being the leading cause. Despite its widespread prevalence, the mechanisms behind infertility and anovulation are not fully understood. Recently, we reported infertility, ovulation failure, and severe ovarian abnormalities in mice lacking salt-inducible kinase 3 (SIK3). However, this phenotype was not fully replicated in mice in which SIK3 was deleted in granulosa cells. Since SIK3 is also expressed in theca cells, we generated SIK3 knockout mice specifically targeting SIK3 loss in androgen-producing theca cells (SIK3C17TCKO). These mice are infertile, have irregular estrous cycles, and produce fewer oocytes after gonadotropin treatment compared to controls. Histological examination revealed enlarged, cystic ovaries with hemorrhagic follicles and a significant increase in multinucleated giant cells, indicating inflammation and ovarian aging. Additionally, SIK3C17TCKO ovaries exhibited increased CYP17A1 expression, an enzyme crucial for androgen synthesis, resulting in higher serum testosterone levels. Consistent with in vivo results, knocking down SIK3 in primary mouse theca-interstitial cells in vitro significantly raised Cyp17a1 expression and testosterone production. This suggests that androgen excess may contribute to the severe ovarian dysfunction observed in SIK3C17TCKO mice. Overall, this study further highlights the vital role of SIK3 in ovarian function and identifies theca cells as key targets of this kinase. The phenotype of SIK3C17TCKO mice closely resembles many features of polycystic ovary syndrome (PCOS), making it a valuable model for studying PCOS pathophysiology and potential treatments for ovulatory disorders.