Abstract
Although endometriosis is suspected to be a cause of premature ovarian insufficiency (POI), the mechanism(s) underlying this process have not been elucidated. Recently, androgens were shown to promote oocyte maturation and to play a role in folliculogenesis. In addition, several reports have documented low testosterone levels in the follicular fluid obtained from endometriosis patients. We therefore examined whether the low levels of serum testosterone are associated with the apoptosis of granulosa cells in follicles obtained from endometriosis patients. Serum samples were collected from 46 patients with endometriosis and from 62 patients without endometriosis who received assisted reproductive therapy. Specimens of the ovaries obtained from 10 patients with endometrioma were collected using laparoscopy. The mean serum testosterone concentration in the patients with endometriosis was significantly lower than that observed in the patients without endometriosis. Furthermore, high expression of a pro-apoptotic Bcl-2 member, BimEL, in the follicles was found to be associated with a low serum testosterone level. We clarified the underlying mechanisms using a basic approach employing human immortalized granulosa cells derived from a primary human granulosa cell tumor, the COV434 cell line. The in vitro examination demonstrated that testosterone inhibited apoptosis induced by sex steroids depletion via the PI3K/Akt-FoxO3a pathway in the COV434 cells. In conclusion, we elucidated the mechanism underlying the anti-apoptotic effects of testosterone on granulosa cells, and found that a low-testosterone status is a potentially important step in the development of premature ovarian insufficiency in patients with endometriosis.
Highlights
Endometriosis is a chronic benign disease characterized by the presence of endometrium-like tissue outside the uterine cavity, primarily on the ovaries
According to data generated from different genetic models, the Bim extra-long (BimEL) expression presumptively determines the rate of granulosa cell apoptosis [28,29,30]
Immunoreactive BimEL staining in granulosa cells was performed to evaluate whether the BimEL expression is related to the serum testosterone level in endometriosis patients
Summary
Endometriosis is a chronic benign disease characterized by the presence of endometrium-like tissue outside the uterine cavity, primarily on the ovaries. It is a major cause of symptoms, such as pelvic pain, dysmenorrhea, dyspareunia and infertility, affecting 6–10% of females of reproductive age and at least one-third of those with infertility and often relapsing after surgery [1,2,3]. The aim of most medical treatments for endometriosis is to alleviate pain and other symptoms, reduce the size of the endometriotic lesions and improve the patient’s quality of life without causing problems with infertility; there are limited therapeutic options for infertile patients. Endometriosis is suspected to be a cause of premature ovarian insufficiency (POI), no effective treatment has been established to prevent POI in individuals with endometriosis [7]
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