Regulation of human endometrial function: mechanisms relevant to uterine bleeding

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This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues.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.

Figure 1

Endometrial changes after insertion of an LNG-IUS; the effects of intermittent antiprogestin therapy on bleeding. A working hypothesis. A Insertion of an LNG-IUS induces a process of decidualisation (grey colour) in the endometrium. During the first 3 months bleeding is high then slowly improves. During this time, 17βHSD-2 is elevated and therefore estrone, E₁ (a less potent estrogen) is high and estradiol, E₂ (the more potent estrogen) is low; steroid receptors are suppressed. After 6 months, when decidualisation is extensive, bleeding is reduced, 17βHSD-2 is low, E₂ is high and E₁ is low. Steroid receptors remain low, (though ERβ is likely to be present in the vascular endothelium). This balance of steroids at 6 months is associated with reduced bleeding. B. Intermittent antiprogestin treatment during the first 3 months will suppress 17βHSD-2 and thereby lower E₁, elevate the more potent E₂and elevate steroid receptors. This balance of steroids is similar to the balance at 6 months, but would allow E₂ to interact with higher levels of receptors in all cell types and should suppress BTB. In addition, the spiral arteries would be strongly inhibited by antiprogestins, which should also suppress BTB. This periodic "putting on the brakes" on bleeding may help women through the most difficult period of adjustment to an LNG-IUS, after which antiprogestin treatment could be stopped.

Figure 2

Coincident events of progesterone withdrawal and hypoxia. Progesterone withdrawal results in an up-regulation of inflammatory mediators, production of MMPs, a leukocyte influx and expression of stromal KDR in the upper endometrial zones. There is coincident hypoxia and an up-regulation of VEGF. VEGF binds to its type 2 receptor, KDR and there is a paracrine/autocrine action on the up-regulation of MMP production in the same endometrial upper zone stromal cells. Menstrual sloughing takes place from the superficial regions of the endometrium. Reproduced with permission.