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In a small number of case reportssubstantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogensIn a largerandomizedplacebo-controlled clinical triala generalized effect of estrogen therapy on blood pressure was not seen.

Breakthrough bleeding and spotting may occur during the first months of treatmentIf break-through bleeding or spotting appears after some time on therapyor continues after treatment has been discontinuedthe reason should be investigatedwhich may include endometrial biopsy to exclude endometrial malignancy.

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Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRTwhich becomes apparent within 5 years of use and diminishes over time after stopping.

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