In vitro and in vivo treatment with propranolol influences the number of early preantral follicles in mice†

Stimulating follicle growth could have utility for fertility preservation before follicular culture or as part of ovarian stimulation protocol therapies for women with a limited ovarian reserve. Propranolol is a clinically approved beta-blocker. Beyond its beta-adrenergic receptors, recent investigations have suggested an alternative role in activating mTOR. Therefore, this study aimed to evaluate the efficacy of propranolol treatment on early follicle growth, both in vitro and in vivo. For in vitro studies, neonatal mouse ovaries were cultured for up to 3 days in the presence or absence of propranolol and then processed for histological analysis, quantitative PCR (qPCR), RNA in situ hybridization, and Western Blot (WB). For in vivo experiments, mice were treated with a low or a high dose of propranolol or no drug for 15 days. Then, analyses were performed, including body and ovarian weight measurements, histological analyses, WB, and qPCR. In vitro experiments demonstrated that treatment decreased primordial follicles and increased transitional, primary, and secondary follicles. Consistent with this, propranolol treatment resulted in the downregulation of PTEN and an increased presence of Cpeb1, a novel biomarker of follicle activation, in primordial follicles. In our in vivo studies, propranolol promoted follicle activation, increased PI3K-p110 levels, and decreased PTEN expression. In summary, propranolol increases the transition of primordial follicles to more advanced stages of development. These findings highlight propranolol as a potential drug to induce, in vivo and in vitro, early preantral follicle growth, potentially improving fertility preservation techniques and studies.

Cpeb1; PI3K; follicle activation; primordial follicle; propranolol.