title: A low-testosterone state associated with endometrioma leads to the apoptosis of granulosa cells.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Yoshihiro J
authors.initials: YJ
authors.lastname: Ono
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanabe
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Terai
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
mesh_terms: D000328:Adult; D017209:Apoptosis; D045744:Cell Line, Tumor; D004715:Endometriosis / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015571:Follicular Fluid / Q000378:metabolism; D006107:Granulosa Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013739:Testosterone / Q000032:analysis / Q000097:blood*
chemical_list: D013739:Testosterone; D019869:Phosphatidylinositol 3-Kinases