Aetiology

AUB can be caused by uterine pathologies, systemic conditions, and ovulatory dysfunction.[11] The International Federation of Gynecology and Obstetrics (FIGO) classification system can be used to identify the nine main causes of AUB, which are arranged according to the acronym PALM-COEIN (pronounced pahm-koin).[1]

  • Polyp[12][13]

  • Adenomyosis[14][15]

  • Leiomyoma[16][17]

  • Malignancy and hyperplasia[18]

  • Coagulopathy[19][20][21]

  • Ovulatory dysfunction, Endometrial, Iatrogenic[22][23][24][25][26][27][28][29]

  • Not otherwise classified (changed from 'not yet classified' in the 2018 FIGO update).[30][31][32][33]

Pathophysiology

A series of complex, orchestrated interactions between endocrine, paracrine, immunological, and haemostatic factors on the endometrium results in normal menstrual bleeding. Aberrations of each of these characteristics may result in AUB/heavy menstrual bleeding.[34]

During the follicular phase of the menstrual cycle, follicle-stimulating hormone (FSH) causes the ovarian follicles to produce oestrogen from granulosa cells. A dominant follicle emerges on days 5 to 7, leading to another rise in the oestrogen level and further growth of the endometrium.

The rise in oestrogen triggers negative feedback to FSH at the same time that it stimulates a surge in luteinizing hormone, triggering ovulation. The remaining corpus luteum produces progesterone, stimulating a secretory endometrium. If fertilisation does not occur, progesterone and oestrogen levels fall rapidly, leading to synchronous shedding of the endometrial lining approximately 14 ±1 days after ovulation has occurred.

Menstruation is an inflammatory process. Progesterone withdrawal secondary to the demise of the corpus luteum heralds the onset of menstruation. A key role is played by endometrial stromal cells, as they retain responsiveness to progesterone throughout the secretory phase. Progesterone withdrawal is responsible for increased levels of cytokines (IL-1, IL-6, chemokines) and prostaglandins into the endometrium; and consequently, an influx of neutrophils, the activation of matrix metalloproteinases, and the destruction of the extracellular matrix. Macrophages also increase peri-menstrually and are involved in tissue remodelling and debris removal.[35][36]

Menstruation has been proposed to occur also as a result of ischaemia and reperfusion. Markers for hypoxia have been detected in the human endometrium during menstruation.[37] Evidence now suggests that transient, physiological hypoxia occurs in the menstrual endometrium to stabilise hypoxia inducible factor 1 (HIF-1) and drive endometrial repair.[38]

Endothelins (ET-1, vasoconstrictor), prostaglandins PGF2 alpha (vasoconstrictor), and PGE2 (vasodilator) have an important role to play in menstrual pathophysiology. An imbalance in these factors affects the uterine spiral arterioles, which in turn affects the volume of menstrual blood loss. Drugs like NSAIDs help by acting on this pathway to improve menstrual blood loss.[39]

Endometrial endothelial injury initiates platelets plug formation. The subsequent stage of haemostasis involves the formation of fibrin via the coagulation cascade. Tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA) drive the production of plasmin, and plasminogen activator inhibitor (PAI) inhibits fibrinolytic activity. A disturbance in this mechanism may result in AUB and prevent timely cessation of menstruation.

Classification

Abnormal uterine bleeding[1][2]

  • Acute AUB is an episode of non-gestational uterine bleeding in a woman of reproductive age that is of sufficient quantity to require immediate intervention to prevent further blood loss.

  • Chronic AUB is bleeding from the uterine body (or corpus) that is abnormal in frequency, regularity, duration, and/or volume, and has been present for most of the past 6 months.

  • Inter-menstrual bleeding (IMB) occurs between well-defined cyclical menses. This symptom may be virtually impossible to discern if the woman has irregular and/or very frequent menses.

    • Cyclic mid-cycle IMB is a small quantity of frank vaginal bleeding or discharge around mid cycle, corresponding with ovulation due to a fall in estradiol levels, and is physiological.

    • Cyclic pre- or post-menstrual IMB predictably occurs either early in the cycle (follicular phase) or late in the cycle (luteal phase), and typically presents as very light vaginal bleeding for one or more days.

    • Acyclic IMB is not cyclical or predictable.

  • Heavy menstrual bleeding is excessive menstrual blood loss that interferes with the physical, social, emotional, and/or material quality of life.[1][3]​​​​[4]

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