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Dehydroepiandrosterone induces ovarian and uterine hyperfibrosis in female rats.


Do dehydroepiandrosterone (DHEA)-treated rats with polycystic ovary syndrome (PCOS) demonstrate a high level of fibrosis in ovarian and uterine tissues?DHEA induces ovarian and uterine hyperfibrosis in rats, probably involving a transforming growth factor-β (TGF-β)-dependent mechanism.Chronic inflammation is the typical cause of fibrosis and is involved in the pathophysiological process of PCOS. Patients with PCOS are reported to have a higher serum level of TGF-β, a well-characterized key pro-fibrotic factor. Fibrillin-3, a protein capable of interacting with TGF-β, has been reported to be partially responsible for the fetal origin of PCOS.Female Sprague-Dawley rats were treated with a vehicle control or DHEA for 35 days, with subsequent analyses of changes in morphology and gene expression in ovarian and uterine tissues. Rescue groups treated with metformin or simvastatin and their corresponding controls were also analyzed. A total of 80 rats were included.The PCOS model was induced by daily administration of DHEA s.c. to 3-week-old female rats, and the rescue groups were injected daily with either metformin or simvastatin in addition to DHEA. Serum steroid hormone levels were measured by enzyme-linked immunosorbent assay. Samples were stained with hematoxylin and eosin for histological morphology, and Sirius Red and immunohistochemistry for revealing collagens. The expression of fibrosis-related genes was analyzed both at mRNA (real-time RT-PCR) and protein (western blot) levels.DHEA-induced rats with PCOS exhibited significantly higher levels of fibrosis (collagen IV) in both ovarian and uterine tissues. In ovarian tissue, the expression of connective tissue growth factor (CTGF) increased following DHEA treatment at both mRNA and protein levels (P < 0.05, P < 0.001 versus controls, respectively). Similar results versus controls were obtained at a protein level for TGF-β (P < 0.01) and mRNA level for fibronectin (P < 0.05) and angiotensin-II (P < 0.05). Likewise, in uterine tissue, the protein levels of both CTGF and TGF-β were higher than controls following DHEA treatment (P < 0.05). Treatment with either metformin or simvastatin attenuated the fibrosis progression induced by DHEA exposure, as evidenced by a reduction of TGF-β, plus CTGF or not, in both ovarian and uterine tissues.The particular mechanism involved in the DHEA-induced fibrosis was not fully revealed.Ovarian and uterine hyperfibrosis may occur in patients with PCOS and result in anovulation or other PCOS-related phenotypes. Anti-fibrotic therapy, for example metformin treatment, may be beneficial for patients with PCOS.This study was supported by the National Natural Science Foundation of China (81170541) and the Natural Basic Research Program of China (973 program 2010CB945103). The authors declare no conflicts of interest.