Endometrial vascular changes and bleeding disturbances with long-acting progestins

Abstract

Unscheduled disturbances of bleeding with long-acting progestogen-only methods continue to be a major social inconvenience, and the most common reason for premature discontinuation of use. The patterns of bleeding with different methods are now well characterised, but in spite of a substantial amount of recent research we still do not clearly understand the actual mechanisms underlying these disturbances. The major changes occur locally within the endometrium, although these are influenced substantially by different dosages and regimens of contraceptive steroids. Hysteroscopic studies have demonstrated major changes in the extent of superficial endometrial vascularization, disturbances in superficial vascular morphology, and increased endometrial vascular and epithelial fragility in progestogen-only users. There may also be alterations in endometrial perfusion and vasomotion. Laboratory studies of cellular and molecular mechanisms have shown changes in vascular basement membranes, pericytes, migratory leukocytes, cellular architecture, cell adhesion molecules, and intercellular matrix breakdown systems, such as matrix metalloproteinases. It appears that continuous exposure to progestogen, in the presence of low to moderate levels of estrogen, results in an endometrium that histologically demonstrates ‘suppressed secretory’ changes, associated with disturbed angiogenesis, and a tendency to release molecules capable of causing focal endometrial epithelial and endothelial damage and bleeding.

Introduction

Disturbances of the menstrual bleeding pattern are an inevitable consequence of use of long-acting progestogen-only contraceptive methods [1]. These disturbances may range from amenorrhea, irregular and unpredictable spotting or light bleeding [2] to episodes of prolonged and frequent bleeding or spotting [3], [4]. Heavy bleeding is rare, although prolonged episodes of light bleeding may occasionally add up to a greater volume of total blood loss per month than the woman may have experienced in her normal menstrual cycles [5]. The great majority of women using these methods experience bleeding that is lighter in volume than their usual cycles. Nevertheless, a minority of women experience unpredictable, inconvenient bleeding of sufficient degree that they discontinue use of this method. Discontinuation rates vary greatly between methods and ethnic groups, and are greatly influenced by pretreatment counseling [1].

The mechanisms underlying these disturbances are still poorly understood; a better understanding of the mechanisms ought to help in the development of techniques to treat or prevent the unpredictable bleeding. Over the past 20 years, there has been a gradually escalating research effort to study all aspects of this clinical problem. A series of important publications by the World Health Organization and the National Institutes of Health describe the research [6], [7], [8], [9], [10].

This research has confirmed that activity and expression of a number of molecular systems are altered in endometrium exposed to long-acting progestogen-only methods, although it is far from clear how the changes in these systems link together. Some of these changes could lead to a loss of integrity in parts of the tissue or an increase in fragility of epithelium or vessels [11].

It has been known for many years that abnormal vessels may develop in the endometria of women exposed to contraceptive steroids, whether oral or injected [12]; however, only recently have researchers begun to fully comprehend the structural and functional changes of endometrial microvessels in women exposed to progestogens [13], [14].