The role of vascular endothelial growth factor and other cytokines in the aetiology of heavy menstrual bleeding in women with uterine fibroids

Introduction: The human endometrium undergoes cyclical changes of proliferation, differentiation and shedding. This cyclical process has been described as an inflammatory process. Menstrual abnormalities account for the morbidity of a large population of females in their reproductive age. Aberration in endometrial angiogenesis has been implicated in the mechanism of heavy menstrual bleeding (HMB). Although the precise mechanism for control the endometrial neoangionesis is not fully understood, vascular endothelial growth factor and other cytokines such as cyclooxygenases, prostaglandins, interleukin -8 and leukocytes have been implicated in both endometrial pathologies and angiogenesis dysregulation. In addition, heavy menstrual bleeding results from upregulation of the expression/synthesis of these local markers. Uterine fibroids are the most common benign tumor affecting the female reproductive tract. Heavy menstrual bleeding is the main presenting complaint of women with uterine fibroids. However, the mechanism by which uterine fibroids cause heavy menstrual bleeding has not been elicited yet. Therefore, the mechanism of action of different available treatments for this condition, including uterine artery embolisation is unclear. This thesis is based on the hypothesis that a) uterine fibroid changes the physiology of endometrium and we aimed to find out whether these markers work in a different way in heavy menstrual bleeding in those with uterine fibroids and those without., In addition I we wished to study whether uterine fibroid upregulate these local markers in heavy menstrual bleeding, whereas uterine artery emolisation down-regulates them. Methods: This thesis describes the use of endometrial samples, taken with a Pipelle sampler, collected from women with heavy menstrual bleeding both with uterine fibroids and also with normal uteri, to estimate the difference in the endometrial expression of the factors likely to be involved in the control of menstrual bleeding between the two groups. Results: The study found no differences between the expression of both either proteins or mRNA for the cytokines under investigation By using endometrium, myometrium and different types of fibroid tissue collected from women who had hysterectomies with the complaint of heavy menstrual bleeding, there was higher expression of VEGF, COX-2, PGE2 and IL8 proteins in fibroid than myometrial tissue. However, the level mRNA of expression for VEGF, COX-1, COX-2, IL8 and EP2 showed no differences between myometrial and fibroid tissue. In the same group, endometrial expression of these markers for women who had no hormonal therapy before operation compared with that for women who received gonadotropin releasing hormone agonists (GnRH), higher expression of VEGF mRNA in women who had GnRH agonists than those who had no any hormones. In fibroid tissue, GnRHdownregulated the expression of VEGF protein and other cytokines compared with those not on any hormonal therapy. In addition, the estimated serum levels of these factors, indicating a higher level of IL8 in the GnRH group than in the other group. Conclusion: It seems that theses markers play a role in HMB mechanism in both uterine fibroid and normal uteri group in same manner. In addition, they have a fundamental role in the growth of uterine fibroids as well