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The effect on blood pressure of oral ‘replacement’ doses of exogenous oestrogen may depend on the type and dose of oestrogen administered. This study was designed to compare with placebo the effect of once daily treatment with a ‘natural’ oestrogen, piperazine oestrone sulphate, in two different doses and a semisynthetic oestrogen, ethinyloestradiol, on clinic and ambulatory blood pressure and the renin–angiotensin system in postmenopausal women.Twenty-four normotensive postmenopausal women (median age 54 years, range 47–60 years) participated in the study which used a double-blind crossover design. For each subject there were four randomized treatment phases, each lasting 4 weeks. The separate treatments administered once daily were 0.625 mg oestrone sulphate, 2.5 mg oestrone sulphate, 0.02 mg ethinyloestradiol and matching placebo. Clinic blood pressure, heart rate and weight were measured weekly with the mean values of weeks three and four of each phase used for analysis. Ambulatory blood pressure and biochemical measurements were performed in the final week of each phase.Twenty-four subjects entered and 22 completed the randomized phases of the study. Compared with the placebo phase, end-of-phase mean clinic diastolic blood pressure was reduced in subjects taking the semisynthetic oestrogen (P < 0.01) but was unchanged in those taking the ‘low’ and ‘high’ dose natural oestrogen. Mean clinic systolic blood pressure was also unchanged by any of the oestrogen treatments. Ambulatory night-time systolic, diastolic and mean arterial blood pressures were reduced with the low-dose natural and semisynthetic oestrogen treatments compared with placebo (P < 0.01), whereas there was no significant effect of the oestrogen treatments on ambulatory daytime blood pressures. A reduction in clinic and ambulatory heart rate was observed with the high-dose oestrone and semisynthetic oestrogen treatments. There was a dose-dependent increase in plasma renin substrate and decrease in plasma renin concentration with all active treatments; however, there was no change in plasma renin activity or plasma aldosterone concentration.In normotensive postmenopausal women, replacement doses of natural and semisynthetic oestrogen reduce night-time ambulatory blood pressure with either no change or a small reduction in clinic blood pressure. Reduction in blood pressure is not explained by reduced activity of the renin–angiotensin system but could have a component of reduced central sympathetic drive consistent with the decreased heart rate.