The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta.

Endothelin-1 (ET-1), a potent vasoconstrictor, and parathyroid hormone-related protein (PTH-rP), a potent vasorelaxant, are present and synthesized in human endometrium. The production of these vasoactive peptides in stromal cells of the human endometrium is modulated by sex steroid hormones. In addition, neutral endopeptidase 24.11 (also called enkephalinase), which degrades ET-1, is expressed in the stromal cells of the endometrium, and the levels of this enzyme (mRNA, protein and specific activity) are increased in response to progesterone/progestin. The sex steroid hormone-mediated regulation of vasoactive peptide formation and action in the human endometrium is believed to serve a key role in modulating spiral artery tone/blood flow, and thus endometrial bleeding, whether progestin induced or naturally occurring. Moreover, the expression of ET-1, PTH-rP and enkephalinase is modulated by transforming growth factor-beta. We hypothesize that the inappropriate expression of ET-1, enkephalinase and PTH-rP in endometrial stromal cells during synthetic progestin administration may be one cause of abnormal endometrial development and erratic endometrial bleeding.