Metformin reduces androgen receptor and upregulates homeobox A10 expression in uterine endometrium in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) causes anovulation and is associated with a reduced clinical pregnancy rate. Metformin, which is widely used for treating PCOS, can lead to successful pregnancy by restoring the ovulation cycle and possibly improving endometrial abnormality during the implantation period. However, the mechanism by which metformin improves endometrial abnormality remains unknown. Women with PCOS have an aberrant expression of steroid hormone receptors and homeobox A10 (HOXA10), which is essential for embryo implantation in the endometrium. METHODS: In this study, we examined whether metformin affects androgen receptor (AR) and HOXA10 expression in PCOS endometrium in vivo and in human endometrial cell lines in vitro. Expression of AR and HOXA10 was evaluated by immunohistochemistry, fluorescent immunocytochemistry, and western blot analysis. RESULTS: AR expression was localized in both epithelial and stromal cells; however, HOXA10 expression was limited to only stromal cells in this study. In women with PCOS, 3 months after metformin treatment, the expression of AR was reduced in epithelial and stromal cells in comparison to their levels before treatment. In contrast, HOXA10 expression in the stromal cells with metformin treatment increased in comparison to its level before treatment. Further, we showed that metformin counteracted the testosterone-induced AR expression in both Ishikawa cells and human endometrial stromal cells (HESCs); whereas, metformin partly restored the testosterone-reduced HOXA10 expression in HESCs in vitro. CONCLUSIONS: Our results suggest that metformin may have a direct effect on the abnormal endometrial environment of androgen excess in women with PCOS. TRIAL REGISTRATION: The study was approved by the Ethical Committee of Fukushima Medical University (approval no. 504, approval date. July 6, 2006), and written informed consent was obtained from all patients. https://www.fmu.ac.jp/univ/sangaku/rinri.html.

Double-Filtration Plasmapheresis and High-Dose Intravenous Immunoglobulin Therapy in a Case of Anti-M Alloimmunization.

Hemolytic disease is a common cause of fetal morbidity and mortality. The anti-M blood cell alloantibodies are one of the most severe causes of fetal anemia and intrauterine death. Since no standard treatment method has been established for pregnant women, the management of this pathology is through conventional methods used for treating Rh blood-type alloimmunization. For the first time, we report a unique case wherein a pregnant woman who had intrauterine fetal death in two previous pregnancies with very low titers of anti-M antibodies had negative effects during very early pregnancy, which were successfully managed in her third pregnancy with a novel protocol. We aggressively managed the blood type (anti-M antibody) and blood platelet incompatibilities (anti-HPA-4b antibody) through combination therapy twice a week (46 cycles between 12 and 34 weeks) of double filtration plasmapheresis (DFPP) and high-dose γ-globulin (20-40 g/wk). An elective cesarean section was performed at 34 weeks, and a healthy neonate was born without detection of alloantibodies in the umbilical cord blood. Our report suggests that the combination of DFPP and intravenous immunoglobulin should be considered for the treatment of anti-M alloimmunization in pregnant women.