No abstract

One of the characteristics of polycystic ovary syndrome (PCOS) is the presence of cystic follicles in various stages of growth and atresia, the latter of which is known to be the result of apoptosis and tissue remodeling. To further investigate the process of follicular atresia, we compared ovarian expression and localization of Fas, Fas ligand (FasL), casapse-8 and membrane-type1 matrix metalloproteinase (MT1-MMP) in rats treated with dehydroepiandrosterone (DHEA) as a model of PCOS, and in control rats. We found that the numbers of TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive follicles were significantly higher in ovaries from PCOS rats than in those from control rats (P < 0.05), as were ovarian levels of FasL mRNA and protein, processed caspase-8 protein and MT1-MMP mRNA. Correspondingly, we also observed an increase in the level of MTI-MMP catalytic activity and a decrease in the level of pro-caspase-8 protein. In addition, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TUNEL-positive apoptotic granulosa cells within atretic follicles of PCOS ovaries. Our results suggest that under the PCOS-like conditions induced by DHEA, the Fas/FasL/Caspase-8 (death receptor dependent) pathway is pivotal for follicular atresia, and that increased levels of MT1-MMP likely play an important role in tissue remodeling during structural luteolysis.

Gonadotropin-releasing hormone (GnRH) and its agonist analog (GnRHa) are well known to have luteolytic effects. We previously reported that prolactin (PRL) stimulated matrix metalloproteinase (MMP)-2 activity to degrade collagen type IV as a mechanism of structural luteolysis. The effects of GnRHa treatment on developed corpora lutea are unknown. In this study we assessed the effect of GnRH on MMP expression and induction of structural involution of developed corpora lutea of superovulated rats using GnRHa.Pregnant mare serum gonadotropin-human chorionic gonadotropin (hCG)-synchronized ovulation and luteinization were induced in immature female rats, followed by daily treatment with GnRHa from 5 days after hCG treatment. GnRHa-induced involution of corpora lutea was evident 3 days after the treatment, as shown by their markedly smaller size (60% of the control weight). Nine days after hCG injection, serum progesterone and 20 -dihydroprogesterone concentrations were as low as those associated with structural luteolysis. These findings revealed that GnRHa has the ability to induce structural luteolysis in superovulated rats in the same way that PRL does. To gain information on mechanisms of luteal involution induced by GnRHa, we performed gelatin zymography. This showed a significant increase in the active form of MMP-2 in the luteal extract of GnRHatreated rats (more than twofold that of the control). Activation of pro-MMP-2 by membrane type-MMP (MT-MMP) is reported to be a rate-limiting step for catalytic function. Another function of MT-MMP is to degrade collagen types I and III. The plasma membrane fraction of corpora lutea of GnRHa-treated rats activated pro-MMP-2 of fetal calf serum, resulting in a marked shift of the 68-kDa band to the 62-kDa band in the zymogram. A Northern hybridization study also revealed simultaneous significant increases in expression of MMP-2 mRNA and MT1-MMP mRNA in corpora lutea of GnRHa-treated rats (more than threefold the control level).In summary, hormonal and histological features of corpora lutea of GnRHa-treated superovulated rats correspond to those of structural luteolysis. GnRHa stimulated the expression of MMP-2 and MT1-MMP in developed corpora lutea associated with involution. These findings support the conclusion that MMP-2, activated by MT1-MMP, and MT1-MMP itself, remodel the extracellular matrix during structural luteolysis induced by GnRHa.

The expression of membrane type 1 (MT1) matrix metalloproteinase (MMP), MMP-2, and tissue inhibitors of MMP-1 and -2 during structural involution of the human corpus luteum was examined using immunohistochemistry, Northern blotting, Western blotting, gelatin zymography and in-situ hybridization techniques. The corpora lutea of 20 patients were investigated at the time of total hysterectomy and were obtained from five patients each in the early, mid- and late luteal phases and during gestation. Immunohistochemistry for MT1-MMP in corpus luteum showed that the protein appeared in granulosa lutein cells in the late luteal phase. Both the expression of MT1-MMP mRNA and the amount of the protein increased in the late luteal phase. In-situ hybridization showed that MT1-MMP mRNA was localized mainly in the cytoplasm of granulosa lutein cells. These results suggest that increased expression of MT1-MMP may be a major factor in remodelling of the human corpus luteum during structural luteolysis.

Purpose To evaluate the efficacy of silicone sheet as a new type of barrier for preventing adhesion reformation following hysteroscopic adhesiolysis of intrauterine adhesions (IUAs). Methods Hysteroscopic adhesiolysis was performed for 36 patients with IUAs. The adhesion reformation rate was retrospectively compared between 26 patients treated with silicone sheet (group 1) and 10 patients treated with an intrauterine device wrapped in oxidized regenerated cellulose as a barrier (group 2). For patients in group 1, a 1‐mm‐thick silicone sheet was cut to fit the size and shape of the individual uterine cavity as a personalized barrier. Results The size and shape of each silicone sheet used for patients in group 1 differed significantly. The adhesion reformation rate was significantly lower in group 1 (4/26, 15.4%) than in group 2 (4/10, 40.0%; P = 0.03), although the pregnancy rate (14/20, 70.0% vs. 5/10, 50.0%; P = 0.28) and miscarriage rate (2/14, 14.3% vs. 1/5, 20.0%; P = 0.72) were not significantly different. Conclusion Use of silicone sheets appears to be effective for preventing adhesion reformation following hysteroscopic adhesiolysis of IUAs. This is the first study to investigate the efficacy of silicone sheet used as a personalized barrier for preventing IUAs.