Abstract and Introduction
Abstract
Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.
Introduction
Progesterone (P) is a sex steroid essential for pregnancy and lactation produced almost entirely by the ovarian corpus luteum (CL) and the placenta. Normal endometrial function requires both estrogen (E), which mediates cell growth and induction of progesterone receptors (PR), and P, which counteracts E stimulation and downregulates the receptors for E and P. The normal balance achieved by sequential actions of E and P is essential to the normal cyclic functions of human endometrium, and disruption of this balance is a significant factor in the pathogenesis and/or pathophysiology of many clinical problems, including endometriosis, infertility, abnormal bleeding, pregnancy loss, and cancer.
The mechanisms governing P action on endometrium are complex, involving at least two receptor subtypes (PR-A and PR-B), with distinct expression patterns and functional profiles as well as other putative P receptors, whose identity and function remain an active area of research. The effects of PR-A and PR-B are further modulated by differential expression and activation of coregulators such as SRC1-3. Furthermore, many of P's important effects on endometrium are indirect, via paracrine and autocrine factors.
Although mechanistically complex, P is essential for successful embryo implantation and pregnancy maintenance. Therefore, levels of circulating P below some undefined threshold or resistance of endometrium to otherwise adequate P will result in infertility or pregnancy loss. This concept of insufficiency of P action on endometrium comprises the pathophysiological concept of luteal phase deficiency. However, whether sufficiently low P or sufficiently resistant endometrium is encountered clinically remains to be demonstrated definitively. In this article, we focus on the role of sex steroids in endometrial function in women and review the evidence for P insufficiency versus P resistance, using clinical examples that illustrate the importance of appropriate P action.