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.