Cellular and molecular mechanisms underlying abnormal fluid formation in the female reproductive tract and its adverse effects on reproduction.

摘要

In the female reproductive tract, fluid microenvironment is of physiological importance for a number of reproductive events. However, abnormal fluid is probably responsible for the reduced fertilization, implantation and pregnancy rates seen in women with pathological conditions. Therefore, the present study was done to elucidate the cellular and molecular mechanisms underlying abnormal fluid formation and accumulation in the female reproductive tract such as hydrosalpinx and ovarian hyperstimulation (OHSS) and its adverse effect on reproductive outcome using histological and electron microscopic techniques, immunofluorescence staining and immunohistochemistry, molecular biology and electrophysiological techniques.;Pathological characterization of whole hydrosalpinx showed that muscle fibers were atrophic and occasionally replaced by fibrous tissues, or separated by areas of severe edema. Inflammatory cells could be found in residual hydrosalpinx fluid (HF) in the lumen in areas with flattened to no epithelial cells, without epithelial lining as well as in dilated blood vessels and/or lymph vessels. Scanning electron microscopy of the epithelial surface revealed epithelial denudation and stomata exuding globular bodies on eroded ampulla surface. Severe chronic inflammation and damage to the epithelial lining and musculature of Fallopian tubes and the presence of inflammatory cells provides explanations for HF formation, and thus the detrimental effects of HF on reproductive processes and in vitro fertilization (IVF) outcome.;Further studies were conducted to characterize cultured hydrosalpinx epithelial cells using electron microscopy and examine the adverse effects of its conditioned medium (CM) on sperm motility and acrosome reaction as well as early embryo development. The percent of human motile sperm (MOT), incubated in hydrosalpinx conditioned medium (CM) was significantly different from those in normal Fallopian tube (NFT) Conditioned medium and modified human tubal fluid medium (hTF) (control), with alteration in movement characteristic, mean linearity 24 hours after incubation in hydrosalpinx CM. Reduced acrosome reaction and poor mouse embryo development were also observed in hydrosalpinx CM but not in NFT CM and hTF. The results suggest that hydrosalpinx epithelial cells may be producing a fluid milieu hostile to sperm and early embryo development.;This possible involvement of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent chloride channel, in the pathogenesis of hydrosalpinx was also investigated.;The present findings revealed that CFTR, a cAMP activated chloride channel expressed in many epithelial cells, plays a central role in the pathogenesis of abnormal fluid formation in the female reproductive tract. Upregulation of CFTR by infection and elevated estrogen levels during ovarian hyperstimulation leads to hydrosalpinx and OHSS respectively. The results of the present study may provide grounds for better treatment strategy for infertile patients with hydrosalpinx, patients at risk of developing OHSS and improving IVF outcome. (Abstract shortened by UMI.)