The mammalian ovary has two main functions—producing mature oocytes for fertilization and secreting hormones for maintaining the ovarian endocrine functions. Both functions are vital for female reproduction. Primordial follicles are composed of flattened pre-granulosa cells and a primary oocyte, and activation of primordial follicles is the first step in follicular development and is the key factor in determining the reproductive capacity of females. The recent identification of the phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway as the key controller for follicular activation has made the study of primordial follicle activation a hot research topic in the field of reproduction. This review systematically summarizes the roles of the PI3K/PTEN signaling pathway in primordial follicle activation and discusses how the pathway interacts with various other molecular networks to control follicular activation. Studies on the activation of primordial follicles have led to the development of methods for the in vitro activation of primordial follicles as a treatment for infertility in women with premature ovarian insufficiency or poor ovarian response, and these are also discussed along with some practical applications of our current knowledge of follicular activation.

Currently, no effective treatment exists for infertility associated with premature ovarian insufficiency (POI) because affected patients lack hormone-responsive antral follicles. By screening a Food and Drug Administration (FDA)–approved drug library, we identified finerenone, a kidney disease medication, as a promising drug for restoring fertility in POI. Finerenone stimulated follicle development in aged mice and restored antral follicle development in patients with POI following oral administration, resulting in mature oocytes and embryos. Mechanistically, finerenone reduced fibrotic deposition in the ovarian stroma, alleviating collagen-mediated suppression of follicular development. Building on this insight, we identified additional FDA-approved oral antifibrotic drugs as potential treatments for POI-related infertility. Our findings highlight the ovarian stroma—rather than the follicles themselves—as the key therapeutic target and offer potential therapeutic leads for POI-related infertility.

In the present investigation, we examined whether a change in whole body energy fluxes could affect ovarian follicular development, employing mice ectopically expressing uncoupling protein 1 in skeletal muscle (UCP1-TG). Female UCP1-TG and wild-type (WT) mice were dissected at the age of 12 weeks. Energy intake and expenditure, activity, body weight and length, and body composition were measured. Plasma insulin, glucose, leptin, plasma fibroblast growth factor 21 (FGF21) and plasma insulin-like growth factor 1 (IGF1) levels were analyzed and ovarian follicle and corpus luteum numbers were counted. IGF1 signaling was analyzed by immunohistochemical staining for the activation of insulin receptor substrate 1/2 (IRS1/2) and AKT. UCP1-TG female mice had increased energy expenditure, reduced body size, maintained adiposity, and decreased IGF1 concentrations compared to their WT littermates, while preantral and antral follicle numbers were reduced by 40% and 60%, respectively. Corpora lutea were absent in 40% of the ovaries of UCP1-TG mice. Phospho-IRS1, phospho-AKT -Ser473 and -Thr308 immunostaining was present in the granulosa cells of antral follicles in WT ovaries, but faint to absent in the antral follicles of UCP1-TG mice. In conclusion, the reduction in circulating IGF1 levels due to the ectopic expression of UCP1 is associated with reduced immunostaining of the IRS1-PI3/AKT pathway, which may negatively affect ovarian follicle development and ovulation.

The lack of hormone-responsive follicles is a major challenge in treating infertility/subfertility in women with premature ovarian insufficiency or diminished ovarian reserve. In this study, we demonstrate that securinine, a neurological drug, can be repurposed to promote small follicle growth. In aged mice, intraovarian injection of securinine significantly enhances follicular development and improves fertility, yielding healthy offspring. Mechanistically, single-cell RNA sequencing reveals that securinine promotes follicular development by alleviating the negative regulation from the stromal extracellular matrix on granulosa cells. Furthermore, intraovarian injection of securinine in aged cynomolgus macaques effectively stimulates the development of small follicles into large antral follicles. Our findings highlight securinine as a promising candidate for ultrasound-guided ovarian injection for treating infertility/subfertility in women with premature ovarian insufficiency, diminished ovarian reserve, or advanced maternal age. As a small molecule drug, intraovarian securinine injection offers clinical advantages that avoid complex preparation procedures required for platelet-rich plasma or stem cell-based therapies.

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