What is the pathophysiology of abnormal uterine bleeding?

Pathophysiology of Abnormal Uterine Bleeding

Abnormal uterine bleeding results from either structural abnormalities of the uterus or nonstructural disruptions in the normal endometrial hemostatic mechanisms, including aberrant angiogenesis, impaired vasoconstriction, defective vascular maturation, and dysregulated tissue breakdown.

Classification Framework: PALM-COEIN System

The pathophysiology is best understood through the PALM-COEIN classification system, which divides causes into structural and nonstructural categories 1:

Structural Causes (PALM):

• Polyp
• Adenomyosis
• Leiomyoma (submucosal or other myoma)
• Malignancy and hyperplasia

Nonstructural Causes (COEIN):

• Coagulopathy
• Ovulatory dysfunction
• Endometrial
• Iatrogenic
• Not yet classified

Core Pathophysiological Mechanisms

Ovulatory Dysfunction (AUB-O)

Ovulatory dysfunction causes heavy, irregular bleeding through unopposed estrogen stimulation leading to endometrial proliferation without adequate progesterone-mediated stabilization 1. The mechanisms include:

• Anovulation or oligo-ovulation disrupts the normal progesterone withdrawal that coordinates organized menstrual shedding
• Specific causes include: adolescence, perimenopause, lactation, pregnancy, hyperandrogenic conditions (PCOS), hypothalamic dysfunction, hyperprolactinemia, thyroid disease, primary pituitary disease, premature ovarian failure, and medications 1
• The endometrium becomes unstable with disturbed angiogenesis and fragile vessels, leading to unpredictable focal breakdown 2

Endometrial Dysfunction (AUB-E)

When no structural cause exists, primary endometrial disorders involve multiple vascular and hemostatic abnormalities 3, 2:

Aberrant Angiogenesis:

• Increased VEGF-A and its receptors (VEGFR-1 and VEGFR-2) promote excessive vessel formation 3
• Elevated angiopoietin-1:angiopoietin-2 ratio and Tie-1 expression indicate impaired vessel maturation 3
• These changes result in fragile, permeable vessels with compromised structural integrity 3

Defective Vasoconstriction:

• Decreased endometrial vasoconstriction fails to control menstrual blood volume 2
• Impaired vascular hemostatic plug formation prevents adequate vessel sealing during menstruation 2

Tissue Breakdown Dysregulation:

• Normal menstruation involves coordinated release of proteolytic lysosomal enzymes from endometrial and inflammatory cells 4
• In AUB-E, breakdown occurs in the superficial subsurface layer rather than the upper two-thirds of endometrium 4
• This can be either focal (breakthrough bleeding) or diffuse (withdrawal bleeding) 4

Iatrogenic (AUB-I)

Hormonal contraceptives cause bleeding through distinct vascular mechanisms that differ from AUB-E 3:

Short-term hormone exposure:

• Increased microvessel density (MVD) and elevated proangiogenic factors 3
• Rapid vessel proliferation without adequate maturation

Long-term hormone exposure:

• Gradual loss of increased MVD but persistent alterations in vessel maturation 3
• Impaired vessel integrity after both short and long-term exposures 3
• Chronic endometritis and microerosions may develop 4

Structural Pathology Mechanisms

Polyps, leiomyomas, and adenomyosis cause bleeding through:

• Focal chronic endometritis initiating tissue breakdown 4
• Microerosions in the endometrial surface 4
• Distorted vascular architecture with abnormal vessel distribution

Malignancy and hyperplasia involve:

• Altered estrogen and progesterone receptor expression 5
• Endometrial carcinoma shows reduced hormonal receptor expression compared to hyperplasia 5
• Disrupted normal tissue architecture and vascular support

Coagulopathy (AUB-C)

Bleeding disorders are not appreciated histologically but involve 4, 2:

• Impaired coagulation factor function
• Enhanced fibrinolysis preventing adequate clot stabilization
• Defective platelet function

Critical Pathophysiological Distinctions

Ovulatory vs. Anovulatory DUB

Ovulatory DUB: Predominantly decreased vasoconstriction and defective hemostatic plug formation leading to excessive volume loss during otherwise organized menstruation 2

Anovulatory DUB: Poorly understood but associated with disturbed angiogenesis, fragile vessels, and defective hemostatic processes 2

Normal Menstruation vs. AUB

Normal menstruation:

• Tissue necrosis confined to upper two-thirds of endometrium
• Coordinated microvasculature disruption
• Controlled inflammatory cell influx
• Effective platelet/fibrin thrombi formation 4

AUB:

• Subsurface breakdown (superficial layer)
• Uncoordinated or excessive vascular disruption
• Impaired hemostatic mechanisms
• Fragile, permeable vessels 4

Common Pitfalls in Understanding AUB Pathophysiology

Avoid assuming all AUB has the same mechanism - the pathophysiology varies dramatically between structural causes (mechanical disruption), ovulatory dysfunction (hormonal imbalance), endometrial causes (primary vascular defects), and iatrogenic causes (exogenous hormone effects) 1, 3.

Do not overlook that microvessel density differs between AUB-E and AUB-I - AUB-E typically shows normal MVD with abnormal vessel function, while AUB-I shows increased MVD especially with short-term hormone exposure 3.

Recognize that histology cannot identify all causes - ovulatory DUB and coagulopathy require clinical and laboratory assessment rather than tissue diagnosis 4.