Improving precision in the treatment of heavy menstrual bleeding

Heavy menstrual bleeding (HMB) is a common and debilitating symptom that affects 1 in 4 women during their reproductive lifetime [1]. This negatively impacts quality of life and is also a major socio-economic burden to individuals, families and health services [2]. In up to half of women, no structural cause for HMB is found (fibroids/adenomyosis) and these cases are designated "of endometrial origin" (HMB-E). The mechanisms underpinning HMB-E are not fully delineated but include excessive endometrial inflammation and defective hypoxia at menstruation [3]. Current treatment options are mostly hormonal and can be ineffective with adverse side effects, meaning up to 60% of women seeking risky fertility-ending surgical procedures [4]. There is a clear unmet clinical need for improved precision in the treatment of HMB. Therefore, we aim to identify novel therapeutic targets for HMB and develop pre-clinical models in which to test potential therapeutics.
Using carefully characterised human endometrial tissue from women with objectively measured HMB (>80ml blood per cycle; n=4) and normal menstrual bleeding (<80ml/cycle, n=4), we will perform an unbiased comparison using single-cell RNA sequencing alongside spatial transcriptomics. Findings will be validated using our bioresource of human endometrium collected from women with measured menstrual blood loss (n=83).
Mice do not usually menstruate. A mouse model of simulated menstruation is established in our laboratory. We have also optimised a pre-clinical mouse model of HMB due to defective uterine hypoxia. A model of HMB due to excessive inflammation is also required to test therapeutic compounds for HMB. We will develop and optimise this model by adapting methods used in other tissue sites (e.g. lung/liver) and compare histological and molecular changes to ensure analogy with those found in the human endometrium of women with HMB.
This unbiased transcriptomic screen of human menstrual endometrium will allow us to detect differential gene expression and pathways in women with HMB-E. These results will be used to identify potential therapeutic targets. Our collaboration with AstraZeneca Open Innovations will facilitate the identification of novel therapeutic compounds which we can test in our pre-clinical models of HMB. In this way, our project has the potential to develop specific, non-hormonal, fertility sparing medical treatments for women experiencing HMB-E.

[1] Shapley M., et al. (2004) An epidemiological survey of symptoms of menstrual loss in the community. Br J Gen Pract. 54(502): 359-363.
[2] Critchley H.O.D., et al. (2020) Menstruation: science and society. Am J Obstet Gynecol. 223(5): 624-664.
[3] Whitaker L. & Critchley H.O.D. (2016) Abnormal uterine bleeding. Best Pract Res Clin Obstet Gynaecol. 34: 54-65.
[4] RCOG. National Heavy Menstrual Bleeding Audit: Final Report. 2014.