Improving precision in the treatment of heavy menstrual bleeding

月经大量出血（HMB）是一种常见的衰弱症状，影响四分之一的女性在其生殖寿命[1]。这对生活质量产生了负面影响，也是个人、家庭和卫生服务的主要社会经济负担[2]。在多达一半的女性中，没有发现HMB的结构性原因（肌瘤/子宫腺肌病），这些病例被称为“子宫内膜起源”（HMB-E）。HMB-E的基础机制尚未完全阐明，但包括过度的子宫内膜炎症和月经时的缺陷性缺氧[3]。目前的治疗选择大多是激素，可能无效，并有不良副作用，这意味着高达60%的女性寻求危险的终止生育的外科手术[4]。在HMB治疗中存在明显的未满足的临床需求，即提高精确度。因此，我们的目标是确定HMB的新的治疗靶点，并开发临床前模型来测试潜在的治疗方法。使用来自客观测量HMB（> 80 ml/周期; n=4）和正常月经出血（<80 ml/周期，n=4）的女性的仔细表征的人类子宫内膜组织，我们将使用单细胞RNA测序和空间转录组学进行无偏比较。研究结果将使用我们的人类子宫内膜生物资源进行验证，这些子宫内膜是从测量月经失血量的女性（n=83）中收集的。本实验室建立了小鼠模拟月经模型。我们还优化了由于子宫缺氧缺陷的HMB临床前小鼠模型。还需要由于过度炎症的HMB模型来测试HMB的治疗化合物。我们将通过调整用于其他组织部位（例如肺/肝）的方法来开发和优化该模型，并比较组织学和分子变化，以确保与HMB女性的人类子宫内膜中发现的相似性。人类月经期子宫内膜的这种无偏见的转录组学筛选将使我们能够检测HMB-E女性的差异基因表达和途径。这些结果将用于确定潜在的治疗靶点。我们与阿斯利康开放创新公司的合作将有助于识别新型治疗化合物，我们可以在HMB的临床前模型中进行测试。通过这种方式，我们的项目有可能为经历HMB-E的女性开发特定的，非激素的，生育保留的药物治疗。[1]Shapley M.，等人（2004年）社区月经减少症状的流行病学调查。Br J Gen Pract.54（502）：359-363。[2]克里奇利总部（2020）月经：科学与社会。美国妇产科杂志。223（5）：624-664。[3]惠特克湖& Critchley H.O.D.（2016）异常子宫出血。最佳临床妇产科实践研究。34：54-65。[4]RCOG。全国重度月经出血审计：最终报告。2014.

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.