Research is Changing Our Beliefs About Menstruation

The past decade has seen a major shift in our understanding of how menstruation occurs. The focus of interest has moved from the concept of menstruation as a process generated primarily by vascular events to one in which tissue destruction is a key feature. Although the onset of bleeding is the first outward sign of menstruation, it is clearly not the first important event in the process. During the late luteal phase of the cycle, there is widespread degeneration of the basal lamina that support the decidualized endometrial cells and the endothelium of blood vessels. Electron microscopy has revealed small lesions in the luminal epithelium on the 28th day of the normal cycle and has shown that these are followed by very rapid, although incomplete, degeneration of the functionalis layer, exposing open blood vessels and glands. Thus, it can be argued that the primary event that initiates menstruation is the destruction of tissue.

If menstruation begins with tissue destruction, how is this destruction caused? Recent research has examined the actions of a group of enzymes, known as matrix metalloproteinases or MMPs, in the endometrium. These enzymes are stimulated as the result of a process of inflammation, which in turn is a response to the withdrawal of progesterone. A number of the MMPs are capable of degrading both the interstitial matrix and basement membrane components, leading fairly rapidly to the bleeding that is characteristic of menstruation. They have been localized to the endometrium immediately before and during menstruation and they appear to be locally produced and activated. Indeed, the pattern of expression of MMPs during the normal menstrual cycle seems to indicate that they play an important role in the process. They are, for instance, found specifically at points where tissue destruction occurs. Progesterone has long been recognized as capable of regulating the activity of collagenase (MMP-1), and the falling levels of progesterone and estrogen during the late phase of the cycle could be directly responsible for the sudden steep rise in the production of MMPs at menstruation.

Research has pointed to the close temporal relationship between MMPs production and activation and cells of the immune system. Since the mid-1980s it has been argued that menstruation could be regarded as a process of inflammation, and various studies have reported the dramatic increase in lymphomyeloid cells (specifically eosinophils, neutrophils and macrophages) in the endometrium immediately before menstruation. Although mast cells do not increase in number during the cycle there is a sharp rise in mast cell activation before and during menstruation. Studies indicate numerous cellular interactions between these cells and the endometrial stromal and epithelial cells that may be relevant to the expression of MMPs and the degradation of tissue at menstruation. Each of these leukocytes produces a range of regulatory molecules, including cytokines and proteases which are known to regulate MMPs. Many of these regulatory molecules are released only when the cell is activated.

Research indicates that the presence of large numbers of leukocytes in perimenstrual tissue is due to the influence—or rather lack of it—of ovarian steroids. Experiments with animal endometrium show that the numbers of leukocytes are regulated negatively by progesterone, and the influx of cells into the human endometrium coincides with the fall in progesterone. Steroid hormones could control the influx of migratory cells via their influence on chemokines (chemoattractive molecules) which attract cells. In the uterus, chemokines exist that are known to attract neutrophils and eosinophils and that increase in the late secretory phase of the cycle.

Steroid hormones may also affect the differentiation and activation of leukocytes in the human uterus. Both estrogen and progesterone are known to have a strong influence on uterine leukocytes in a number of species, particularly with regard to their production of certain pro-inflammatory molecules. In mast cells in the mouse uterus, for example, estrogen promotes and progesterone inhibits certain substances (nitric oxide synthase, for instance), while experiments on macrophages in the rodent uterus show that estrogen has no effect but progesterone inhibits the same substances. Since neither estrogen receptors nor progesterone receptors have been found in leukocytes in the human endometrium, the effects of estrogen and progesterone on leukocytes may be indirect.

While a complete detailed explanation of how menstruation occurs is not yet available, it is clear that research into the actions of MMPs is leading the scientific community towards a fuller understanding of the physiological processes that are involved in this event that affects women monthly during much of their lives. This fuller understanding will contribute not only to a clearer picture of how steroid hormone contraception works, but will help researchers to devise methods of making these contraceptives more acceptable to their users.

Source: Salamonsen LA. Current concepts of the mechanisms of menstruation: a normal process of tissue destruction. Trends in endocrinology and metabolism, 1998, 9(8):305-309.

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