Bleeding with menopausal hormone therapy: physiological or pathological?

Abnormal bleeding is a common reason for discontinuation of hormone replacement therapy. There is little consensus regarding when to investigate abnormal bleeding, what to do about persistent bleeding or when reinvestigation is indicated. Transvaginal ultrasound, endometrial biopsy and hysteroscopy are discussed. The mechanisms of this bleeding are poorly understood and do not correlate well with endometrial histology or the type or dose of hormone therapy used. Endometrial bleeding requires breakdown of endometrial vessels and their overlying epithelium. Endometrial vascular breakdown appears to be largely locally regulated. Potential mechanisms involved in endometrial bleeding include: changes in the ratio of vascular endothelial growth factor (pro-angiogenic) to thrombospondin-1 (anti-angiogenic); alterations in matrix metalloproteinases and their tissue inhibitors; changes in endometrial haemostasis due to tissue factor; and increased endometrial leucocytes.