Menstruation: science and society

Abstract

Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation-a fast, scarless healing process in healthy individuals-will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, "Menstruation: Science and Society" with an aim to "identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field." Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration-and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids-to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent "menstrual equity" and "period poverty" movements spreading across high-income countries.

Keywords: abnormal uterine bleeding; adenomyosis; endometrium; fibroids; menstrual health; microbiome; pelvic health menstrual effluent; period poverty; stem cells; tissue engineering; uterus.

Figure 1

PubMed publications, 1941–2018 A, Search term “Menstruation.” B, Search term “Menstrual Blood.”. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 2

Phylogenetic distribution of menstruating species among eutherian mammals Lineages in black are from menstruating species, and lineages in white from nonmenstruating species. The lineages with red outline are the lineages where menstruation originated. Note that there are at least 4 independent originations of menstruation. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 3

Schematic outline of the experiment by Rudolph et al testing the idea that menstruation is a secondary consequence of spontaneous decidualization The experiment is conducted with the laboratory mouse, which is a species that under normal conditions is neither decidualizing nor menstruating. In this species, clitoral or vaginal stimulation during copulation leads to the maintenance of the corpus luteum even if no pregnancy ensued, leading to pseudopregnancy, as is the case by copulation with a vasectomized male. Furthermore, it is known that injection of a small droplet of oil into the uterine lumen causes decidualization. The experiment starts with mating a female to a vasectomized male to induce a pseudopregnancy. At the morning of the following day, the females are checked for a copulatory plug to verify that copulation has taken place. Then at day 4 after copulation, a small droplet of oil is injected into the uterus to induce decidualization. Day 4 is the normal day of implantation in mice. Then the mice are monitored for their level of progesterone and signs of vaginal bleeding. Progesterone starts to decrease after day 7, and bleeding ensues at about day 9. This experiment shows that differentiation of the endometrium (decidualization) is sufficient to cause menstruation-like symptoms in a species that normally does not menstruate. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 4

The modern effect of menstruation Previously, women experienced menstruation approximately 40 times in their lifetime, owing to pregnancy and lactational amenorrhea. Women may now expect to have more than 400 episodes of menstruation, mainly as a result of fertility management. Therefore, AUB is increasingly common. Women may experience significant anemia resulting in a poor physical quality of life. A negative financial effect occurs because of the cost of managing their blood loss and an inability to work outside the home. These costs, alongside a loss of caring ability, will have a negative effect on the wider family. The cost to society through loss of work days and healthcare costs is significant. AUB, abnormal uterine bleeding. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 5

The PALM-COEIN classification for abnormal uterine bleeding in the reproductive years illustrating the structural (PALM) and nonstructural causes (COEIN) and as described in Munro et al^, Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 6

Potential mechanisms of “primary” and “secondary” endometrial AUB As the corpus luteum regresses in the absence of pregnancy, progesterone levels fall. This occurs irregularly in those with ovulatory or iatrogenic AUB. Progesterone withdrawal causes a local inflammatory response in the endometrium and may be increased in those with primary endometrial AUB. An increase in vasoactive factors results in intense vasoconstriction of spiral arterioles to limit blood loss; this may be decreased in primary endometrial AUB. Vasoconstriction may induce transient tissue hypoxia and stabilization of HIF-1, the master regulator of the cellular response to hypoxia, to coordinate endometrial repair. There is evidence that this is less intense in those with endometrial AUB. Efficient hemostasis limits menstrual blood loss at menstruation and this is defective in women with coagulopathy AUB. Structural and nonstructural pathologies have the potential to disrupt endometrial physiology at menstruation, leading to abnormal uterine bleeding; these mechanisms remain undefined. AUB, abnormal uterine bleeding; HIF-1, hypoxia-inducible factor 1. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 7

The estrobolome plays a central role in health and disease through the gut microbiota-estrogen axis Dysbiosis of gut microbiota may induce systemic inflammation and interferes with estrogen metabolism and receptor activation in estrogen-regulated organs, influencing neurocognition, metabolism, and the onset of gynecologic diseases and infertility. Reprinted from Baker et al. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 8

The vaginal microbiome during the life cycle Bacterial populations inhabiting the vagina change in response to estrogen levels, modulating glycogen availability in the vaginal epithelium and subsequently the growth of bacteria based on the physicochemical features of the niche at each phase of the lifecycle. Reprinted from Muhleisen et al. Mod, moderate. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.

Figure 9

Potential mechanisms of interaction between endometrial cells and the uterine microbiome Reprinted from Baker et al. AMP, adenosine monophosphate; ROS, reactive oxygen species; SCFA, short-chain fatty acid; TLR, toll-like receptor. Critchley. Menstruation: science and society. Am J Obstet Gynecol 2020.