Starting oestradiol therapy soon after menopause may slow atherosclerosis

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Taking oestradiol within six years after the onset of menopause may help prevent atherosclerosis, plaque build-up in artery walls, from progressing; however, starting oestradiol therapy 10 years after menopause did not have similar benefits, according to preliminary research presented at the American Heart Association’s Epidemiology and Prevention | Lifestyle and Cardiometabolic Health Scientific Sessions 2020.

Oestradiol is a female sex hormone and a form of oestrogen that is often prescribed to treat the symptoms of menopause and to prevent osteoporosis. “Atherosclerosis is a major cause of heart disease, and cholesterol accumulation in the arterial wall is the predominant characteristic of atherosclerosis,” said lead study author Dr Roksana Karim, an associate professor of clinical preventive medicine at the Keck School of Medicine at the University of Southern California in Los Angeles. “Our results show that oestradiol initiated earlier in menopause reduces atherosclerosis and appears to do so by directly reducing cholesterol accumulation in the arterial wall.”

Karim and colleagues analysed findings from the Early versus Late Intervention Trial with Oestradiol (ELITE), a study of 643 healthy, post-menopausal women who were divided into 4 groups: participants in group 1 and 2 were randomised to 1 mg daily of oestradiol or to a placebo pill within six years after the onset of menopause; and those in groups 3 and 4 were randomized to oestradiol or to placebo more than a decade after menopause. All study participants took oestradiol or placebo daily for an average of five years. The study’s initial findings, published in 2016, indicated that women starting hormone therapy earlier in menopause experienced less progression of artery wall thickening, compared to those who started the hormone therapy later or who received the placebo.

When the researchers looked further into oestradiol’s impact on heart health by analysing cholesterol, or lipids, in the arterial wall, they found the rate of atherosclerosis progression among early oestradiol users was less than half, compared to the women taking placebo who had gone through menopause within the last six years. Oestradiol did not have this benefit among the women who started the hormone therapy 10 years or more after the onset of menopause. Cholesterol in the arterial wall and atherosclerosis progressed similarly for both the women in the placebo group and those who started oestradiol therapy a decade after menopause.

“Our results show that starting oestradiol soon after the onset of menopause may result in fewer cholesterol deposits in the arteries, compared to women starting oestradiol much later,” said Karim.

“The American Heart Association does not recommend hormone replacement therapy after the onset of menopause to prevent heart disease. Although some studies, like this one, show benefits, we are still seeing other trials with different outcomes. Because of that, oestrogen replacement therapy should be used only to alleviate the symptoms of menopause,” said Dr Suzanne Steinbaum, an American Heart Association volunteer expert, an attending cardiologist and director of Women’s Heart Health of Northwell Lenox Hill Hospital, and senior faculty at Mount Sinai Hospital in New York City.

The National Institute of Aging of the National Institutes of Health funded the study.

Abstract 1
Objective: The effect of estradiol therapy (ET) has been evaluated on atherosclerosis progression measured by carotid artery wall thickness. Echogenicity of the arterial wall, a measure of lipid deposition, has not been investigated in relation to ET.
Methods: This is a secondary analysis from ELITE. A total of 643 healthy postmenopausal women were randomized within time-since-menopause strata (early (<6 years) and late (>10 years) postmenopause) to daily 1 mg estradiol or placebo. The atherosclerosis outcome for the current analysis is grey scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high resolution ultrasonography of the common carotid arterial wall. Lower GSM values indicate more lipid deposition. GSM and serum concentrations of estradiol (E2) were assessed every 6 months over a median 5-year trial period. Linear mixed effects regression models were used to compare the rate of GSM progression between the randomized groups within time-since-menopause strata. The association of mean on-trial serum E2 levels with GSM progression was also tested using similar mixed effects model.

Results: The effect of ET on the annual rate of GSM progression significantly differed between early and late postmenopause strata (p-value for interaction = 0.006). Annual GSM progression rate (95% confidence interval) among women in early postmenopause decreased by -0.30 (-0.63, 0.04) per year among women taking ET compared to -1.41 (-1.77, -1.06) per year among the placebo group (p<0.0001). In contrast, the annual GSM progression rate was not significantly different between ET and placebo among the late postmenopausal women (p=0.37). The positive association between mean on-trial E2 level (pg/ml) and GSM progression rate was stronger and significant among early postmenopausal women (0.008 (0.0007, 0.016)) compared to women in the late postmenopause group (0.003 (-0.006, 0.01)). However, this differential association between E2 level and GSM progression rate was not statistically significant (p-value for interaction = 0.33).
Conclusion: Compared to placebo, oral ET significantly reduced progression of lipid deposition in the carotid arterial wall among women in early postmenopause. ET had no such beneficial effect in late postmenopause. Associations between serum estradiol levels and lipid deposition validated those findings. Qualitative assessment of subclinical atherosclerosis (GSM) complements the anatomic assessment by carotid artery intima-media thickness.

Roksana Karim, Wenrui Xu, Howard N Hodis, Naoko Kono, Intira Sriprasert, Yanji Li, Mingzhu Yan, Frank Stanczyk, Wendy Mac

Abstract 2 (2016)
Background: Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.

Methods: A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima–media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.
Results: After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.
Conclusions: Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum.

Howard N Hodis, Wendy J Mack, Victor W Henderson, Donna Shoupe, Matthew J Budoff, Juliana Hwang-Levine, Yanjie Li, Mei Feng, Laurie Dustin, Naoko Kono, Frank Z Stanczyk, Robert H Selzer

Heart Organisation material

Epi/Lifestyle 2020 abstract

New England Journal of Medicine (2016) abstract

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