Cellular localization of membrane metalloendopeptidase (enkephalinase) in human endometrium during the ovarian cycle

Previously, we found that membrane metalloendopeptidase (MMEP; enkephalinase) is present in human endometrium where it may inactivate certain bioactive peptides such as endothelin. The specific activity of MMEP in endometrium is correlated positively with the level of plasma progesterone. In the present study, we determined the cellular distribution of MMEP immunoreactivity (IR) in samples of endometrium from 31 ovulatory women at different phases of the menstrual cycle and from 5 postmenopausal women. At all times, MMEP-IR was localized in the endometrial stromal cells and was absent from myometrium, epithelia, and vessels. The presence of the enzyme on the stromal cell plasma membrane was demonstrated by immunostaining of freshly isolated endometrial stromal cells. During the endometrial cycle, there were dramatic changes in MMEP-IR in the zona functionalis: In the proliferative phase when plasma progesterone levels were low, MMEP-IR was weak; but after ovulation, during the early and midsecretory phases, when progesterone levels were increasing or high, MMEP-IR was strong. During the late secretory phase, in the stromal areas that were decidualized, contiguous with spiral arterioles and beneath the surface epithelium, most of the MMEP-IR was lost, whereas MMEP in the other stromal areas remained strong. In the premenstrual phase, there was a more generalized decline in MMEP-IR in the stromal cells. MMEP-IR in the zona basalis was weak to moderate and was relatively unchanged during the ovarian cycle; the findings in postmenopausal tissues were similar to those of proliferative phase tissues. These results are consistent with the previous findings of increased MMEP mRNA, protein, and activity in endometrial tissue of midsecretory phase and in cultured endometrial stromal cells in response to progestin. Furthermore, in this study, we demonstrate that in the late secretory phase in decidualizing stroma, MMEP-IR is decreased considerably compared with midsecretory stromal cells. These changes in MMEP-IR are consistent with the possibility that endothelin, also produced in endometrium, is spared inactivation in the premenstrual phase and may act on the spiral arterioles. These findings are supportive of a role for MMEP in paracrine interactions affecting vascular homeostasis in the endometrium.