ELITE Trial Commentary

ELITE Trial Commentary

The long awaited Early versus Late Intervention Trial with Estradiol (ELITE) was published in the March issue of the New England Journal of Medicine 2016. This trial attempted to answer the question of whether hormonal replacement increases or decreases the risk of coronary heart disease, stroke, blood clots, osteoporosis, breast and colorectal cancer.

The ELITE trial was in response to the Women’s Health Initiative (WHI), the largest randomized clinical trial examining the effect of hormonal replacement therapy published in 2002. Unfortunately, the drugs used in the WHI were daily conjugated equine estrogen (0.625 mg) synthesized from pregnant mare (horse) urine combined with medroxyprogesterone acetate (2.5 mg), also a synthetic drug. Synthetic hormone replacement therapy increased the risk of coronary artery disease, stroke, and thromboembolism? the risk of breast cancer and gallbladder disease increased with longer use? and this therapy reduced the risk of osteoporotic fractures and colorectal cancer.

In the ELITE trial, women were given bioidentical estradiol and progesterone, rather than synthetic hormones, and the results were dramatically better than WHI. Atherosclerosis as measured by Carotid Intima Media Thickness vascular ultrasound imaging improved in the estrogen + progesterone group when started within 6 years of the onset of menopause. In addition ELITE also had an arm that examined cognitive performance. Hormone therapy provided metabolic benefit to women in high blood pressure and poor metabolic phenotypes, providing evidence that hormonal replacement therapy reduces the risk of mild cognitive impairment leading to dementia.

This is very reassuring since the negative impact of the WHI on women’s health continues to be perpetuated by confusing synthetic and bioidentical hormones in the same statement concerning benefit and risk. If anything, the ELITE trial clearly demonstrates that bioidentical hormones reduce CV risk, whereas the WHI demonstrates synthetic hormones increase risk.


N Engl J Med. 2016 Mar 31?374(13):122131.
doi: 10.1056/NEJMoa1505241.
Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. ELITE TRIAL
Hodis HN 1, Mack WJ 1, Henderson VW 1, Shoupe D 1, Budoff MJ 1, HwangLevine
J 1, Li Y 1, Feng M 1, Dustin L 1, Kono N 1, Stanczyk FZ 1, Selzer RH 1, Azen SP 1? ELITE Research Group .

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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 post-menopause] or ?10 years [late post-menopause]) and were randomly assigned to receive either oral  17?estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30day 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 carotidartery intimamedia 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 post-menopause 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 coronaryartery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either post-menopause 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. (Funded by the National Institute on Aging, National Institutes of Health? ELITE ClinicalTrials.gov number, NCT00114517 .). Neurobiol Aging. 2016 Apr?40:15563.doi: 10.1016/j.
Neurobiolaging.2016.01.011. Epub 2016 Jan 29.

Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical-metabolic indicators: potential for detecting an at Alzheimer’s risk metabolic phenotype. Rettberg JR 1, Dang H 2, Hodis HN 3, Henderson VW 4, St John JA 5, Mack WJ 5, Brinton RD 6.

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Detecting at-risk individuals within a healthy population is critical for preventing or delaying Alzheimer’s disease. Systems biology integration of brain and body metabolism enables peripheral metabolic biomarkers to serve as reporters of brain bioenergetic status. Using clinical metabolic data derived from healthy post-menopausal women in the Early versus Late Intervention Trial with Estradiol (ELITE), we conducted principal components and means clustering analyses of 9 biomarkers to define metabolic phenotypes. Metabolic clusters were correlated with cognitive performance and analyzed for change over 5 years. Metabolic biomarkers at baseline generated 3 clusters, representing women with healthy, high blood pressure, and poor metabolic phenotypes. Compared with healthy women, poor metabolic women had significantly lower executive, global and memory cognitive performance. Hormone therapy provided metabolic benefit to women in high blood pressure and poor metabolic phenotypes. This panel of well established clinical peripheral biomarkers represents an initial step toward developing an affordable, rapidly deployable, and clinically relevant strategy to detect an at-risk phenotype of late onset Alzheimer’s disease.

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Dr. Randy Knipping
Dr. Randy Knipping, Deerfields

Dr. Knipping has over 25 years of experience in clinical practice ranging from aerospace, emergency, forensic, occupational, preventive and integrative medicine.