IMMUNOLOCALIZATION OF ENDOTHELIN AND NEUTRAL ENDOPEPTIDASE IN THE ENDOMETRIUM OF USERS OF SUBDERMALLY IMPLANTED LEVONORGESTREL (NORPLANT(R))

Subdermally implanted slow-release levonorgestrel (Norplant(R)), 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 how Neutral endopeptidase (NEP), a membrane-bound ectoenzyme, 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(R) with normal controls. Differences were observed in the glandular and luminal epithelium of Norplant(R)-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(R) 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.