HRT’s cardio-protective effect is time-sensitive

Hormone replacement therapy can have added health benefits if started within six years of menopause

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Hormone replacement therapy affords women cardiovascular protection if begun within six years of menopause, but not if started later than 10 years after menopause, a NEJM study shows

The study found that oral oestradiol therapy 1mg daily, with or without progesterone, was associated with less progression of subclinical atherosclerosis, as measured by carotid artery intima thickness, than was placebo if begun in early menopause.

The findings confirm the so-called timing hypothesis, the authors said, which “posits that the effects of hormone therapy on atherosclerosis and coronary heart disease depend on the time of the initiation of hormone therapy relative to menopause, age or both”.

Previous data had suggested the beneficial cardiovascular effects of post-menopausal HRT varied with the timing of therapy initiation, they said, however the theory had not been specifically tested in an RCT.

For the study, 643 healthy postmenopausal women were stratified according to time since menopause – those who were in the first six years of menopause (early menopause) and those who had been in menopause for a decade or more (late menopause).

Women in each group were randomly assigned to receive oestradiol or placebo, plus progesterone or a placebo vaginal gel in the case of women with a uterus.

The rate of progression of atherosclerosis was determined using ultrasound measurements of carotid-artery intima-media thickness (CIMT) every six months.

After five years, the mean CIMT for early-postmenopausal women receiving oestradiol was around half that of those in the placebo group.

However, this did not hold for late-postmenopausal women, with the annual increases in CIMT for those taking the drug and those on placebo being similar.

As such, the researchers concluded that “the effects of oestradiol, with or without progesterone, on the progression of atherosclerosis, assessed by CIMT, differed according to the time of initiation of therapy, with benefit noted when it was initiated in women who were less than six years past menopause but not when it was initiated in women who were 10 or more years past menopause”.

However, no effect of timing of oestradiol treatment relative to menopause was found with regard to CT measures of coronary atherosclerosis, which was a secondary outcome measure. This was possibly due to sample size, but was also consistent with some previous trials, the authors said.

“Studies in animals have shown the effectiveness of hormone therapy in preventing arterial lesion formation but not in reversing established lesions”, they said.

Dr Sonia Davison, endocrinologist at the Jean Hailes foundation, said the study fitted the ‘window of opportunity’ or ‘timing’ hypothesis, that postulated that HRT given close to the time of menopause had a cardio-protective effect.

“It is also a good news story for women who have bothersome symptoms around the time of menopause, and would benefit from HRT but are worried about the risks,” Dr Davison added. 

The study was also “unique in that it gives us information on HRT in the form of oestradiol, which is the main oestrogen women produce before menopause, and the link with early measures of cardiovascular disease”, she said.

“We need further studies like this, that aim to carefully re-examine the problems with previous studies linking HRT use and risk.”