Background: Premature ovarian insufficiency (POI) is characterized by a reduction in primary follicle count along with abnormal follicle development. This study aims to explore the impact of combined oral contraceptives (COCs) on the apoptosis of ovarian granulosa cells, which are instrumental for follicular development, in POI and the underlying mechanisms, to provide theoretical guidance for the treatment of POI.

Methods: A rat model of POI was established using tripterygium glycoside tablets. After treatment with COCs, the therapeutic effect of the animals was verified by means of hematoxylin-eosin staining, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Flow cytometry, cell counting kit-8 (CCK-8), quantitative polymerase chain reaction, and Western blotting were utilized to investigate the impact of COCs on granulosa cell apoptosis, as well as the function of the interleukin (IL)-11/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Further experiments were also conducted to verify whether COCs could inhibit granulosa cell apoptosis through this pathway.

Results: COCs treatment was effective in improving ovarian granulosa cell status, reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and increasing estradiol levels in the POI rats (p < 0.01). IL-11 silencing promoted apoptosis in POI granulosa cells by inhibiting the PI3K/AKT pathway. COCs treatment partially reversed these effects by upregulating IL-11 expression and restoring PI3K/AKT pathway activity. This resulted in increased levels of B-cell lymphoma 2 (Bcl-2) (p < 0.05) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) (p < 0.01), while suppressing the expression of Bax and cleaved-cysteine-aspartic acid protease 3 (cleaved-caspase 3) (p < 0.001).

Conclusions: Our findings demonstrated that COCs protect ovarian granulosa cells from apoptosis in rats with POI, an effect mediated through the IL-11/PI3K/AKT signaling cascade.