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 wid ely used effective contraceptive, has a high rate of discontinuation d ue to unacceptable menstrual bleeding disturbances. Endothelin (ET), a potent vasoconstrictor, varies across the menstrual cycle in normal e ndometrium. It has been proposed that ET has a potential paracrine rol e in the regulation of uterine blood how Neutral endopeptidase (NEP), a membrane-bound ectoenzyme, can inactivate ET and is localized princi pally in endometrial stroma. We have compared the immuno-localization of ET and NEP in endometrial biopsies from Indonesian women using Norp lant(R) with normal controls. Differences were observed in the glandul ar and luminal epithelium of Norplant(R)-treated subjects, where ET im munostaining was low while NEP immunoreactivity was increased. The lat ter may represent a local increase in enzyme activity, potentially exp laining the reduced ET immunoreactivity. There was no correlation of E T immuno-reactivity with the duration of implant use or total number o f bleeding days. The marked differences in the ET immunostaining patte rn in Norplant(R) users, with their increased risk of abnormal uterine bleeding, suggest that ET may be important in controlling menstrual b leeding. Whether endometrial epithelial cell ET has a role as a mitoge n in endometrial repair and regeneration, or as a vasoconstrictor impo rtant in the cessation of bleeding following menstruation, remains to be determined.