27 - 30 May 2005

LOCAL MECHANISMS REGULATING MENSTRUAL BLOOD LOSS Hilary OD Critchley Reproductive and Developmental Sciences University of Edinburgh Scotland

Regular menstrual bleeding is the outward manifestation of cyclical ovarian function. Woman today in developed countries expect to menstruate over 400 times until the ovaries fail at the time of menopause.

Menstruation is initiated by the fall in concentration of progesterone that follows luteal regression. The molecular mechanisms by which steroids induce these changes involve interactions between the endocrine and immune system. The epithelial, stromal, and endothelial cells that participate in cyclic proliferation, differentiation, and desquamation, and a dynamic population of leukocytes within the endometrium all play important roles in the menstrual breakdown process.

In the immediate pro-menstrual phase, progesterone (P) withdrawal induces a unique cascade of events including, expression of uterine cytokines that attract leukocytes into the uterine environment, expression of matrix metalloproteinases (MMPs) by both endometrial and leukocytic cells, and a complex set of interactions between these cells and their products that ultimately result in the tissue sloughing and bleeding characteristic of the menstrual process (Critchley et al, 2001). Due to the leukocytic invasion and subsequent production of inflammatory mediators, menstruation has been likened to an inflammatory event. The endometrium is thus a site of physiological injury and repair. As such, information pertaining to this normal monthly process can provide valuable insights into injury and repair mechanisms (often pathological) elsewhere in the body.

It is highly probable that the characteristics of menstruation are programmed within the endometrium in the days immediately prior to the onset of menses (the premenstrual phase). We have preliminary data that premenstrual endometrium, at the time of physiological progesterone withdrawal, displays a coordinated programme of gene expression changes also identifiable as a specific signature. Several genes identified as up-regulated in the signature are consistent with the literature as being key players in the process of menstruation (MMP-10, MMP-7, TIMP-2, -3; endometrial bleeding associated factor (ebaf); endothelin (ET)-1 and ETB receptor). This signature in premenstrual tissue was evident despite collection of endometrial samples from a heterogenous population and a heterogenous tissue with a mixed cell population. Abnormal uterine bleeding (AUB) experienced by women with fibroids may be the consequence of dysregulation of local endometrial factors that regulate angiogenesis with consequent vascular abnormality (Smith and Nowak, 1996; Smith, 2001).

Novel strategies for management of AUB include selective progesterone receptor modulators (SPRMs) such as Asoprisnil (J867). Asoprisnil exhibits a direct inhibitory effect on both the endometrium and leiomyoma. Early clinical studies of asoprisnil have demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation. Further, studies in subjects with uterine fibroids demonstrate that asoprisnil induced amenorrhea and reduced the volume of the dominant leiomyoma in a dose-dependent manner (Chwalisz et al, 2004). It is thus essential to have a detailed knowledge of the local mechanisms regulating endometrial events involved in menstruation if we are to understand the mechanisms responsible for aberrations of menstrual bleeding. Indeed through a better understanding of these crucial local mechanisms, there will be an ability to modulate sex steroid interactions with far reaching applications for the management of female reproductive health, including the medical management of heavy bleeding.

References:

Critchley, HOD, Kelly RW, Brenner RM, Baird DT (2001. The endocrinology of menstruation – a role for the immune system. Clin Endocrinol 55: 701 – 10.

Chwalisz K, DeManno D, Garg R, Larsen L, Mattia-Goldberg C, Stickler T (2004). Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med: 22: 113-9.

Smith SK (2001). Regulation of angiogenesis in the endometrium. Trends Endocrinol Metab. 12: 147 – 51
Stewart EA und Nowak RA (1996) Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era. Human Reproduction Update 2: 295-306

List of abstracts from the 3rd International Conference on the Female Reproductive Tract