Activation of dormant follicles: a new treatment for premature ovarian failure?

Abstract

Purpose of review: Premature ovarian failure (POF) is diagnosed by amenorrhea before 40 years of age. Owing to exhaustion of follicles in POF ovaries, egg donation is the only option. Although menstrual cycles cease in POF patients, some of them still contain residual dormant follicles in ovaries. Recently, we developed a new infertility treatment and named it as in-vitro activation (IVA), which enables POF patients to conceive using their own eggs by activation of residual dormant follicles. Here, we summarize data showing the potential of IVA as a new infertility treatment for POF patients.

Recent findings: Transgenic mouse studies revealed that the stimulation of phosphatidylinositol-3-kinase-AKT-forkhead box O3 pathway activated dormant primordial follicles. In murine and human ovaries, the phosphatase and tensin homolog inhibitors and phosphatidylinositol-3-kinase activators were demonstrated to activate dormant primordial follicles in in-vitro cultures. Subsequent studies showed that ovarian fragmentation suppressed Hippo signaling pathway, leading to ovarian follicle growth. Combining these two methods in an IVA approach followed by ovarian tissue autotransplantation, successful follicle growth, and pregnancies were reported in POF patients. Currently, two healthy babies were delivered, together with two additional pregnancies.

Summary: IVA treatment is a potential infertility therapy for POF patients who have residual follicles.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1

A scheme for in-vitro activation. Under laparoscopic surgery, one or both ovaries from POF patients were removed and cut into cortical strips before vitrification. Using small portion of ovarian cortices, histological analyses were performed to detect residual follicles. After thawing of cryopreserved ovarian tissues, the ovarian strips were fragmented into 1–2 mm cubes and cultured with PI3K stimulators for 2 days. After cultures, cubes were washed and autografted beneath serosa of Fallopian tubes under laparoscopic surgery. Follicle growth was promoted by FSH treatment. When antral follicles reached preovulatory stage, mature oocytes were retrieved and fertilized with husbands’ sperm in vitro followed by embryo transfer. Modified from [19▪]. hCG, human chorionic gonadotropin; PI3K, phosphatidylinositol-3-kinase; POF, premature ovarian failure.