Resistant ovary syndrome: Two case reports and a literature review of effective controlled ovarian stimulation in IVF.

INTRODUCTION: Resistant ovary syndrome (ROS) represents a rare reproductive endocrine disorder that is predominantly associated with infertility, characterized by heightened endogenous gonadotropin levels in the presence of a normal ovarian reserve. Patients with ROS typically exhibit a poor response to exogenous gonadotropins during controlled ovarian stimulation (COS). Due to the absence of a universally accepted effective COS protocol, this study aims to contribute to the existing body of literature by detailing 2 successful pregnancies achieved through conventional in vitro fertilization (c-IVF) in patients with ROS, and through retrospective analysis, seeks to elucidate the factors contributing to the successful ovarian stimulation in these cases, with the ultimate goal of establishing clinical guidelines for ROS management. PATIENT CONCERNS: The central challenge addressed in this study pertains to the effective induction of oocyte maturation during c-IVF COS in ROS patients. DIAGNOSIS: The study focuses on 2 infertile women diagnosed with ROS who sought to conceive via c-IVF. INTERVENTIONS: The patients were subjected to a COS protocol involving pituitary downregulation followed by ovarian stimulation using recombinant follicle-stimulating hormone (r-FSH) and human menopausal gonadotropin (HMG), preceded by 3 cycles of hormone replacement therapy (HRT) pretreatment. OUTCOMES: The proposed protocol elicited a favorable ovarian response, culminating in the retrieval of numerous mature oocytes and the development of multiple viable embryos via c-IVF, ultimately leading to successful live births post-embryo transfer. CONCLUSIONS: Our study suggests that the outlined COS protocol may serve as a viable treatment option for ROS patients aspiring to conceive through c-IVF, thereby potentially expanding the therapeutic repertoire for this challenging condition.

E2F2 is upregulated by the ERK pathway and regulates decidualization via MCM4.

Cell cycle modulation is an important event during decidualization. E2F2 is a transcription regulator that plays a vital role in cell cycle regulation. However, the biological role of E2F2 in decidualization has not yet been identified. In this study, estrogen (E2) and progestin (P4)-induced in vitro and in vivo decidualization models were applied. Our data showed that the expression levels of E2F2 and its downstream target MCM4 were downregulated in the uterus tissues of E2P4-treated mice compared with control mice. In hESCs, exposure to E2P4 resulted in a significant decrease in E2F2 and MCM4 expression. E2P4 treatment reduced hESC proliferation and ectopic expression of E2F2 or MCM4 elevated the viability of E2P4-treated hESCs. In addition, ectopic expression of E2F2 or MCM4 restored the expression of G1 phase-associated proteins. The ERK pathway was inactivated in E2P4-treated hESCs. Treatment with ERK agonist Ro 67-7476 restored the expression of E2F2, MCM4, and G1 phase-associated proteins that were inhibited by E2P4. Moreover, Ro 67-7476 retracted the levels of IGFBP1 and PRL that were induced by E2P4. Collectively, our results indicate that E2F2 is regulated by ERK signaling and contributes to decidualization via regulation of MCM4. Therefore, E2F2/MCM4 cascade may serve as promising targets for alleviating decidualization dysfunction.

SIRT1 knock-in mice preserve ovarian reserve resembling caloric restriction.

Previous studies have proposed that caloric restriction (CR) regulates many cell functions and prolongs the lifespan of an organism. Our previous studies proposed that CR also prevents follicular activation and preserves the ovarian reserve in mice by activating SIRT1. To test if SIRT1 preserves the ovarian reserve and prolongs the ovarian longevity, we generated SIRT1 knock-in mice that can overexpress SIRT1 in oocytes of the mouse. Ovaries of the mice at ages 35 days and 15 months were collected, and the follicular development and follicular reserve were examined. The vaginal opening and onset of estrus of transgenic female mice (both the homozygous and heterozygous for SIRT1 overexpression) were later than that of wild-type mice. Both the homozygous and heterozygous SIRT1-overexpressing mice had a larger and stronger reproductive capacity than wild-type mice. Moreover, 35-day-old and 15-month-old homozygous and heterozygous SIRT1-overexpressing mice also had a higher mean number and percentage of healthy follicles, fewer atretic follicles than wild-type mice, and the mean number and percentage of primordial follicles in both the homozygous and heterozygous SIRT1-overexpressing mice were higher than wild-type mice at the same age. However, the phenotypes of heterozygous and homozygous transgenic mice came no difference. Immunohistochemistry showed increased expression of SIRT1 and FOXO3a, and decreased expression of mTOR in both the homozygous and heterozygous SIRT1-overexpressing mice compared with wild-type mice. Thus, oocyte-specific SIRT1-overexpressing mice continuously activate FOXO3a and suppress mTOR and have a larger reproductive capacity, larger follicle reserve and longer ovarian lifespan.