Abstract
This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues. A detailed understanding of these local mechanisms will enhance our knowledge of disturbed endometrial/uterine function – including problems with excessively heavy menstrual bleeding, endometriosis and breakthrough bleeding with progestin only contraception. The development of novel strategies to manage these clinically significant problems depends on such new understanding as does the development of new contraceptives which avoid the endometrial side effect of breakthrough bleeding.
Highlights
The uterus plays a pivotal role in the key events of primate reproduction, implantation, and in the absence of pregnancy, menstruation
Preparation of the endometrium for implantation is a consequence of exposure of this steroid target tissue to estradiol and progesterone [1,2]
We propose that the unscheduled breakthrough bleeding (BTB) reported may be due in part to an intracellular "functional estrogen deficiency" caused by the elevated levels of 17βHSD2 that either directly or indirectly leads to vascular fragility. 17βHSD2 protein expression is significantly reduced following 3 months treatment, coincident with the onset in improvement in menstrual bleeding patterns. 17βHSD2 mRNA expression declines, but this occurs more slowly, becoming undetectable after 6 months of LNG-intrauterine delivery system (IUS) treatment
Summary
The uterus plays a pivotal role in the key events of primate reproduction, implantation, and in the absence of pregnancy, menstruation. ERα, PR, and AR were not detectable in either the endothelium or vascular smooth muscle cells of primate endometrial vessels but were strongly expressed in the perivascular stroma where they were increased by estrogen and suppressed by progesterone in the functional layer. One way to control this pattern of BTB in women wearing an LNG-IUS may be to treat them intermittently with a progesterone antagonist These compounds would increase endometrial estrogen receptor levels and lower 17βHSD2 expression thereby reversing any intracellular estrogen deficiency. 5. Progesterone withdrawal and up regulation of matrix metalloproteinases (MMPs) and the VEGF receptor type 2 (kinase domain receptor -KDR) During the secretory phase, the expression and activity of MMPs in endometrial stromal/decidual cells are inhibited by the circulating levels of progesterone. VEGF, KDR and MMPs are co-ordinately expressed by stromal cells in the upper functional layers of premenstrual stage endometrium at the time of progesterone withdrawal. As our knowledge increases, we will one day be able to alleviate the severe bleeding problems so many women endure
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