A K Jain Physiology
Henry Gallagher
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Menstruation is a phenomenon of repeated tissue injury and repair that is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration.
The endometrium is a dynamic, multicellular tissue highly responsive to sex steroids; subtle variances in the endometrial environment and, therefore, functioning, can lead to abnormal uterine bleeding (AUB).
AUB is a debilitating symptom that affects up to one third of reproductive-aged women; comprehensive knowledge of menstrual cycle physiology is crucial for understanding and progressing endometrial physiology research.
The terminology and definitions for diagnosing causes of AUB are now standardized in the International Federation of Gynecology and Obstetrics Systems 1 and 2, and should be followed for ease of clinical and research synchrony.
In this Review, we define typical menstruation using a standardized system developed by global experts and approved by the International Federation of Gynecology and Obstetrics (FIGO) Menstrual Disorders Committee (MDC). This system facilitates the definition and standardization of what constitutes abnormal uterine bleeding (AUB: FIGO Systems 1 and 2)2. We address the considerable impact of non-malignant AUB across the globe before discussing how delineating the physiology of menstruation could inform and improve the management of non-malignant AUB by optimizing diagnosis and treatment. This Review focuses on the biomedical aspects of menstruation, while acknowledging that cultural, social, environmental and political factors have a notable influence on menstrual health8. Comprehensive discussion of these important non-biomedical aspects can be found elsewhere and are therefore not discussed in detail here9.
In 2011, the FIGO MDC set out the core classification of conditions that cause AUB, with minor updates in 2018 (refs2,10). This classification is relevant for primary care physicians as well as specialists and researchers. The nine main categories are arranged in the acronym PALM-COEIN with each letter denoting a cause: Polyp, Adenomyosis, Leiomyoma (uterine fibroids), Malignancy, Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic and Not otherwise classified (Fig. 1; Table 1). Patients can therefore be said to have, for instance, AUB-P and/or AUB-I. The group of PALM causes relates to the structural causes of AUB, which are generally discrete entities that can be evaluated or measured using imaging modalities or histopathology. The COEI causes refer to the non-structural causes of AUB, that is those that cannot be evaluated or measured using imaging or histopathology. The N (not otherwise classified) group encompasses a spectrum of conditions that might or might not be evaluated or measured using imaging modalities or histopathology, and could ultimately be placed in their own unique category2,10.
The causes of abnormal uterine bleeding are classified using the acronym PALM-COEIN, with each letter denoting a cause. The structural causes (denoted by yellow letters) are discrete entities and include polyp, adenomyosis, leiomyoma (uterine fibroids) and malignancy. The non-structural causes (denoted by green letters) are depicted for the illustration; however, they cannot be measured or imaged. They include coagulopathy, ovulatory dysfunction, endometrial, iatrogenic and not otherwise classified (for example, a caesarean scar defect)2,10. Note that the figure is a schematic and is not to scale.
After assessment, patients can be diagnosed with one or more causes of AUB, which might or might not contribute to their bleeding complaint. For example, a third of women with adenomyosis might be asymptomatic12. For the purposes of this Review, we do not focus on malignancies, but on non-malignant conditions that increase the volume and/or frequency of menstruation.
On average, 30% of women globally with AUB are anaemic, and this figure increases to approximately 60% in South Asia, the eastern Mediterranean and Africa, probably due to the combination of dietary deficiencies, AUB and multiple pregnancies19. Iron deficiency is one of the commonest micronutrient deficiencies worldwide20. Anaemia is a global health issue that is under-recognized and under-reported in both low-income to middle-income countries and high-income countries21. In comparison to all other demographic groups, women of reproductive age are most likely to be affected by iron deficiency, which is responsible for approximately 51% of global cases of anaemia20. The prevalence of iron deficiency worldwide is approximately twice as high as iron deficiency anaemia (IDA)22. Iron deficiency and IDA lead to impaired oxygen transportation and enzyme reactions, which impacts almost all metabolic pathways in the body. The functional consequences of iron deficiency and IDA include fatigue, reduced exercise capacity, headaches and impaired cognition23,24. AUB therefore needs to be recognized as an important cause of iron deficiency and IDA.
The socioeconomic burden of AUB is high, with total direct and indirect costs in the UK and USA being greater than 1.2 billion and $37 billion, respectively14,25. Period poverty affects many people due to work absence and cost of additional menstrual products when experiencing AUB. Treatment costs for AUB are likely to increase due to an increase in the number of people seeking medical treatment for the condition. Additionally, the UK NICE guidance for the investigation of AUB11 changed in 2018 to promote more patients being referred for hysteroscopic investigation, which will potentially contribute to rising costs11.
There is a high cost to the individual, which could be related to the menstrual products themselves, clothes and/or bedding that are damaged by flooding accidents, loss of earnings due to missed work, missed opportunities at work or school, and also treatment costs in countries where health care is privately funded.
For society, the economic implications relate to the impact of AUB on a substantial proportion of the workforce, as well as the environmental impact of menstrual products, for example, which might have a broader economic impact.
The endometrium is a multicellular tissue forming the lining of the uterus. The function of the endometrium is to either prepare for embryonic implantation and maintain a pregnancy or, in the absence of pregnancy, to shed and repair, that is, menstruate. The uterine endometrium thus undergoes repetitive and physiological cycling of tissue injury and repair every month36. The endometrium is characterized by features of rapid repair without residual scarring or loss of function, similar to a fetus in utero37,38.
The human endometrium is composed of two layers. The upper two thirds, the functional layer, is shed during menstruation. The basal layer, the lower third of the endometrium (adjacent to the myometrium), does not shed during menses. The functional endometrium is composed of columnar surface epithelium, which covers a multicellular stroma. The stroma contains connective tissue with fibroblast-like stromal cells, a vasculature (including the specialized spiral arteries) and a population of tissue-resident endometrial immune cells, as well as a cyclical traffic of innate immune cells. The population of innate immune cells (both cyclical and tissue-resident immune cells) varies across the menstrual cycle, and these endometrial leukocytes play important roles in the breakdown and repair of endometrial tissue during menses39,40 (Fig. 2).
The endometrium is a dynamic structure that adapts to the endocrine environment in a cyclic manner, on average every 28 days. It undergoes a process of proliferation during an oestradiol-dominant phase. Following ovulation, the corpus luteum secretes progesterone, leading to a progesterone-dominant stage during which the endometrium decidualizes. In the absence of pregnancy, after the demise of the corpus luteum and progesterone withdrawal, the endometrium is shed during menstruation. This process requires the remaining cells to repair and regenerate without injury or scarring so that the menstrual cycle can repeat. As a multicellular tissue, the endometrium is highly responsive to the endocrine environment. The lower third of the endometrium, adjacent to the myometrium, is known as the basal layer and the upper two thirds, including the luminal surface, as the functional layer. Under the influence of changing levels of oestradiol and progesterone, the cellular structure of the endometrium adapts. The main cellular components within the endometrium are the epithelial cells, stromal cells, vascular cells and a variety of innate immune cells. The numbers of immune cells vary according to the cycle stage (see Figure key). The functional layer is shed during the menstrual phase, leaving behind a denuded basal endometrium. The peri-menstrual phase (also known as the luteofollicular transition) is the time after which progesterone and oestradiol levels fall, menstruation occurs and the endometrium transitions from a secretory to a proliferative state36,41,97. Note that the figure is a schematic and is not to scale.
The endometrium is dynamic and highly responsive to the varying circulating levels of the sex steroid hormones ovarian 17β-oestradiol (oestradiol) and pregn-4-ene-3,20-dione (progesterone). The endometrium is exposed to a series of hormonal changes throughout the menstrual cycle, first to systemic oestradiol, then to oestradiol and progesterone and, in the absence of pregnancy, progesterone withdrawal. As a consequence of this sequential exposure, the endometrium adapts in form and function across the menstrual cycle. Understanding this tightly regulated endocrine environment could help identify new therapeutic strategies for AUB.
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