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Uterine bleeding: how understanding endometrial physiology underpins menstrual health

Nature Reviews Endocrinology volume 18, pages 290–308 (2022)Cite this article

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Abstract

Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person’s physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues.

Key points

  • 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.

  • There is a high prevalence of iron deficiency and iron deficiency anaemia in those with AUB, on a global scale, and this is often under-recognized and under-reported.

  • 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.

  • Treatments for AUB are not specific and a third of patients resort to a hysterectomy for resolution of symptoms, highlighting a clinically unmet need for more targeted and personalized treatments.

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Fig. 1: FIGO System 2: the PALM-COEIN classification system.
Fig. 2: Menstrual cycle and ovarian cycle physiology with highlighted aspects of the structure of the endometrium.
Fig. 3: Major biosynthetic pathways in steroidogenesis.
Fig. 4: The impact of the presence of uterine fibroids (leiomyoma) or adenomyosis on endometrial bleeding.
Fig. 5: Diagnostic pathway for abnormal uterine bleeding, and iron deficiency and/or iron deficiency anaemia.

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Acknowledgements

The authors acknowledge the support of MRC Centre Grants G1002033 and MR/N022556/1, and MRC Research Grants: G0000066, G0500047, G0600048, MR/J003611/1 and MRC/NIHR 12/206/52 (H.O.D.C.); Wellcome Trust 209589/Z/17/Z, 100646/Z/12/Z, Wellbeing of Women RG1820 and Academy of Medical Sciences AMS-SGCL13 (J.A.M.); and Wellbeing of Women (RTF902) (V.J.). The authors acknowledge M. Munro (UCLA, Los Angeles, USA), I. Mason (University of Edinburgh) and A. Williams (University of Edinburgh) for their valuable contributions during preparation of the manuscript figures.

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Authors and Affiliations

  1. MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK

    Varsha Jain, Rohan R. Chodankar, Jacqueline A. Maybin & Hilary O. D. Critchley

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  1. Varsha Jain
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  2. Rohan R. Chodankar
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V.J., H.O.D.C., R.R.C. and J.A.M. researched data for article, contributed substantially to discussion of content, wrote the manuscript and reviewed and edited the manuscript before submission.

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Correspondence to Hilary O. D. Critchley.

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Competing interests

H.O.D.C. has received clinical research support for laboratory consumables and staff from Bayer AG, and provides consultancy advice (but with no personal remuneration) to Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc. and Myovant Sciences GmbH. H.O.D.C. receives royalties from UpToDate for an article on abnormal uterine bleeding. V.J. receives salary and research consumables support from Wellbeing of Women (WoW). R.R.C. has been supported as a clinical research fellow by Bayer AG. J.A.M. receives salary and research consumables support from The Wellcome Trust.

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Peer review information

Nature Reviews Endocrinology thanks C. Gargett, who co-reviewed with F. Cousins; M. Hickey; and L. Salamonsen for their contribution to the peer review of this work.

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Glossary

Amenorrhoea

Absence or cessation of menstruation.

Menstrual health

A state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity, in relation to the menstrual cycle.

Polyp

A growth or mass protruding from a mucous membrane.

Adenomyosis

A benign invasion of the myometrium by the endometrium.

Leiomyoma

A usually benign tumour arising from smooth muscle cells of the uterus; <1% of leiomyomas are malignant.

Coagulopathy

A disorder of blood coagulation.

Ovulatory dysfunction

Abnormal, irregular or absent ovulation.

Iatrogenic

Resulting from the activity of a health-care provider or institution.

Health-related quality of life score

An individual’s or group’s perceived physical or mental health over time.

Period poverty

Being unable to access products needed for menstruation, and/or having poor knowledge about menstruation, often due to financial constraints.

Progesterone receptor modulator-associated endometrial change

Histological endometrial changes, which are benign and reversible, found after selective progesterone receptor modulator use.

Fibrinolysis

The dissolution of fibrin by enzymatic action.

Mesenchymal to epithelial transition

The reverse of epithelial-to-mesenchymal transition, whereby a mesenchymal cell undergoes biochemical changes to enable it to assume the phenotype of an epithelial cell.

Epithelial to mesenchymal transition

A biological process whereby a polarized epithelial cell, which normally interacts with the basement membrane via its basal surface, undergoes multiple biochemical changes that enable it to assume the phenotype of a mesenchymal cell.

Secondary endometrial disorder

A disorder in the phenotype of the endometrium as a result of the presence of a structural cause of abnormal uterine bleeding in the myometrium; for example, fibroids or adenomyosis.

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Jain, V., Chodankar, R.R., Maybin, J.A. et al. Uterine bleeding: how understanding endometrial physiology underpins menstrual health. Nat Rev Endocrinol 18, 290–308 (2022). https://doi.org/10.1038/s41574-021-00629-4

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