Immunocytochemistry was used to localize endothelial (eNOS) and inducible (iNOS) nitric oxide synthase in human uterine tissues collected at various stages of the menstrual cycle, after exposure to exogenous progestagens, and in early pregnancy. Endothelial NOS-like immunoreactivity was detected in all specimens in endothelial cells lining blood vessels in the myometrium and endometrium, and in endometrial glandular epithelial cells. Inducible NOS-like immunoreactivity was also demonstrated in glandular epithelial cells. For both eNOS and iNOS there was considerable variation in the intensity of epithelial cell staining between samples, which was not related to the stage of the menstrual cycle at which the tissue was collected. Messenger RNA for eNOS and iNOS was detected by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA purified from isolated endometrial gland fragments. Immunoreactivity for eNOS and iNOS was not present in endometrial stroma throughout the menstrual cycle, but iNOS-like immunoreactivity was seen in decidualized stromal cells both following treatment with exogenous progestagen (intrauterine L-norgestrel) and in tissues obtained in the first trimester of pregnancy. The detection of protein and mRNA for eNOS and iNOS in normal human endometrium suggests that NO may play a role in the local control of endometrial function.

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The endothelins are signalling peptides that act via two receptors, ET(A) and ET(B). In the human endometrium, endothelin receptors have been demonstrated in glands and stroma and have been shown to vary during the course of the menstrual cycle. The present study was undertaken to determine whether or not expression of endothelin receptors changes during pregnancy or after administration of exogenous progestagens. The expression of the receptors was correlated with the appearance of basement membrane components during decidualization of the endometrial stroma. Decidual specimens (n = 15) were obtained during the first trimester of pregnancy and 10 at term. Sixteen pairs of endometrial biopsies were obtained from women with menorrhagia before and after exposure to exogenous progestagens. A total of 15 hysterectomy specimens were used as controls for the expression of stromal basement membrane proteins in the absence of decidualization. Autoradiography was carried out with selective ligands for ET(A) ([125I]-PD 151242) and ET(B) ([125I]-BQ3020). The distribution of ligand binding was then compared with the distribution of laminin alpha2 light chain and collagen IV. ET(A), ET(B), laminin alpha2 light chain, and collagen IV were expressed in stromal decidual cells in the first trimester of pregnancy. ET(B) was also found on endometrial glandular epithelium. Quantitative macro-autoradiography and multiple regression analysis demonstrated a highly significant positive correlation (P < 0.001) between expression of ET(B) and laminin alpha2 light chain. In the third trimester qualitative examination suggested a reduction of ET(A) in the stroma. Progestagen-induced decidua exhibited a similar pattern to that found in first trimester decidua. This study has demonstrated up-regulation of ET(B) during the progesterone-dependent process of decidualization and suggests a paracrine or autocrine role for endothelins in the decidua.

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