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  • Title: Immunolocalization of endothelin and neutral endopeptidase in the endometrium of users of subdermally implanted levonorgestrel (Norplant).
    Author: Marsh MM, Butt AR, Riley SC, Rogers PA, Susil B, Affandi B, Findlay JK, Salamonsen LA.
    Journal: Hum Reprod; 1995 Oct; 10(10):2584-9. PubMed ID: 8567775.
    Abstract:
    Subdermally implanted slow-release levonorgestrel (Norplant), a widely used effective contraceptive, has a high rate of discontinuation due to unacceptable menstrual bleeding disturbances. Endothelin (ET), a potent vasoconstrictor, varies across the menstrual cycle in normal endometrium. It has been proposed that ET has a potential paracrine role in the regulation of uterine blood flow. Neutral endopeptidase (NEP), a membrane-bound ecto-enzyme, can inactivate ET and is localized principally in endometrial stroma. We have compared the immuno-localization of ET and NEP in endometrial biopsies from Indonesian women using Norplant with normal controls. Differences were observed in the glandular and luminal epithelium of Norplant-treated subjects, where ET immunostaining was low while NEP immunoreactivity was increased. The latter may represent a local increase in enzyme activity, potentially explaining the reduced ET immunoreactivity. There was no correlation of ET immuno-reactivity with the duration of implant use or total number of bleeding days. The marked differences in the ET immunostaining pattern in Norplant users, with their increased risk of abnormal uterine bleeding, suggest that ET may be important in controlling menstrual bleeding. Whether endometrial epithelial cell ET has a role as a mitogen in endometrial repair and regeneration, or as a vasoconstrictor important in the cessation of bleeding following menstruation, remains to be determined. In Indonesia, 107 women requesting insertion of the contraceptive implant system Norplant at the Klinik Raden Saleh in Jakarta kept a daily menstrual diary for 90 days before endometrial biopsy and allowed venous blood samples to be taken six times in the two-week period also before endometrial biopsy so researchers could examine the roles of endothelin (ET) and neutral endopeptidase (NEP) in menstrual bleeding changes in women using Norplant. They compared the degree of immunostaining in the endometrial biopsy samples of these women with those of 55 controls, most of which came from women in Melbourne, Australia. The endometrium of the Norplant group exhibited low glandular and luminal epithelial ET immunostaining as did the normal endometrium during the proliferative phase. Glandular epithelial ET immunostaining in the Norplant group fell considerably during the secretory or menstrual phases, however. NEP immunoreactivity was greater in the endometrium of Norplant users than in that of controls, suggesting that enzyme activity may have been increased locally among Norplant users. This increase may have accounted for the low ET reactivity. ET immunoreactivity was not related to duration of implant use or total number of bleeding days. These findings indicate that, since Norplant users are at an increased risk of abnormal uterine bleeding, ET may control menstrual bleeding. It is not known whether ET acts as a mitogen in endometrial repair and regeneration or as a vasoconstrictor to stop bleeding after menstruation.
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