Endometrial bleeding during hormone therapy: the effect of progestogens

Postmenopausal women using continuous combined estrogen/progestin therapy (ccEPT) are likely to have irregular bleeding or spotting. The use of estrogen with 12-14 days of a progestin is called cyclic (scEPT). This method results in regular endometrial bleeding at a scheduled time. The mechanism(s) involved in this regimen that result in bleeding could be similar to a spontaneous menstrual bleeding episode in a menachal woman, but there are no data in this regard. This aspect of regular scheduled bleeding in postmenopausal women will not be addressed in this article due to the paucity of information. The effect of cyclic progestogen with continuous estrogen on the endometrium could result in similar local mechanisms for endometrial bleeding as seen wth ccEPT. The mechanism(s) involved in endometrial bleeding is unknown. Several reports have highlighted a number of potential pathophysiologic mechanisms. Most of the investigation into the mechanisms involved in endometrial bleeding has been in women using progestin only contraceptive methods not ccEPT. The use of ccEPT could be construed as similar but not identical to that of a continuous progestin only contraceptive since the progestin in ccEPT is delivered daily. The potential mechanism(s) involved in endometrial bleeding includes the following: changes in the ratio of vascular endothelial growth factor to Thrombospondin-1 (pro- versus anti-angiogenic factors); alterations in metalloproteinases and tissue inhibitor of metalloproteinases (TIMP); changes in tissue factor a known haemostasis mediator in the endometrium; and increased endometrial leukocytes with a particular emphasis on uterine natural killer (uNK) cells. Each of these potential causes has been the subject of both in vivo and in vitro investigations. There is no clear linkage between any of these hypotheses and the onset or cessation of uterine bleeding in ccEPT users. No good therapeutic option to control the bleeding or spotting exists at this time. Evaluation and monitoring of the patient regarding endometrial safety is of paramount importance.