HRT Benefits Newly Menopausal Women

No Heart Disease Risk Was Found

October 3, 2012 (Updated October 4, 2012) — Hormone replacement therapy (HRT) with low-dose oral or transdermal estrogen and cyclic monthly progesterone started soon after the start of menopause improves depression, anxiety, and cognitive function in healthy women, researchers said here at the 23rd annual meeting of the North American Menopause Society (NAMS).

But, perhaps most importantly, HRT does this without posing any cardiovascular disease risk, according to results of the Kronos Early Estrogen Prevention Study (KEEPS).

The data of KEEPS are being closely guarded and nothing was released to the press or to NAMS officials, as of press time. But the study is generating a lot of buzz here at the meeting.

KEEPS was a 4-year, randomized, double-blind, placebo-controlled clinical trial involving healthy women aged 42 to 58 years (mean age, 52) who were within 3 years after menopause at the time of randomization.

The women were randomly assigned to 1 of the following 3 groups, and all also received cyclical micronized progesterone (Prometrium):

• Oral conjugated equine estrogens given as Premarin, 0.45 mg/day, which was a lower dose than the 0.625 mg/day used in the Women’s Health Initiative (WHI) trial
• Transdermal estradiol (Climara patch) 50 μg /day
• Placebo

To assess cardiovascular harm, the researchers assessed carotid artery intima media thickness (CIMT) and coronary artery calcium (CAC).

In addition, 662 women agreed to participate in the cognitive part of KEEPS, which assessed the effect of HRT on their cognitive function and mood over the 4 years of the KEEPS trial.

The trial was carried out at 9 centers in the United States. Besides studying CIMT and CAC as surrogate markers of cardiovascular disease and cognitive function, the study also assessed symptoms of menopausal hormone deficiency and sexual function for the 4 years that the women received HRT.

“Once you start designing a study like this, you try to get as many relevant measurements as you can, because you know you are not going to get another chance,” S. Mitchell Harman, MD, PhD, Director and President of Kronos Longevity Research Institute, and Chief of the endocrinology division in the department of internal medicine, Phoenix VA Health Care System, Arizona, told Medscape Medical News.

Among the cardiovascular findings, KEEPS showed that neither type of estrogen replacement therapy used significantly affected systolic or diastolic blood pressure, in contrast to the higher dose of oral conjugated equine estrogens (CEE) that were used in WHI. “Those higher doses increased blood pressure levels,” Dr. Harman pointed out.

The researchers also report that oral CEE, but not the transdermal patch, was associated with an increase in HDL cholesterol levels. However, CEE also increased triglyceride levels. The transdermal patch had neutral effects on these biomarkers, the researchers said.

Transdermal estrogen appeared to improve insulin sensitivity as calculated from glucose and insulin levels as HOMA-IR (homeostasis model assessment of insulin resistance).

During 48 months of treatment with either type of HRT vs placebo, there were no apparent effects, either beneficial or deleterious, on atherosclerosis progression assessed by carotid ultrasound, and a nonsignificant trend toward less accumulation of CAC.

“KEEPS provides evidence that combined hormone therapy in recently menopausal women shows no evidence for cardiovascular harm in terms of either imaging of the arteries or known biomarkers or risk factors for cardiovascular disease,” Dr. Harman said.

“That’s a reassuring take away. It goes along with what the breakdown of the WHI found, that when you looked at the younger, more recently menopausal women, that there was no evidence of an increase in progression of atherosclerosis when you treat women with estrogen plus progesterone,” he said.

“Significant Improvement” in Depression, Anxiety, Tension

In the portion of the study that assessed cognitive function and mood, the results were similarly positive.

“At the 4-year point, the women using the oral estrogen or estrogen patch showed no evidence of adverse effects on memory compared to the placebo group,” said Sanjay Asthana, MD, Duncan G. and Lottie H. Ballantine Endowed Chair in Geriatrics and Head of the Division of Geriatrics and Gerontology at the University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

“The WHI memory study showed that in fact hormone therapy in older postmenopausal women would increase the risk for dementia and also worsen memory,” Dr. Asthana told Medscape Medical News.

“The key finding here is that in fact there is no adverse effect of hormone therapy when you started in early menopausal women in KEEP. In contrast, there is significant improvement in measures of symptoms of depression, anxiety, and tension,” Dr. Asthana said.

The cognitive portion of KEEPS was sponsored by the National Institute on Aging, he added.

Dr. Asthana also pointed out that women in the KEEPS study got a different form of estrogen than women in the WHI study, and this factor may have made a difference in the KEEPS results.

“One of the theories is that the form of progesterone used in WHI, medroxyprogesterone is very different than the form that KEEPS used, which is micronized progesterone, the more natural form of progesterone. We certainly did not see any adverse effects with this type of progesterone, and it was used in a cyclical fashion, not given every day as was Provera in the WHI,” he said.

JoAnn E. Manson, MD, MPH, DrPH, professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School and chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, Massachusetts, who presented an overview of the KEEPS rationale, design, and study population, told Medscape Medical News that the KEEPS key findings ‘highlight a favorable benefit-risk profile of hormone therapy in newly menopausal women.”

She stressed that HRT should be used only for the treatment of menopausal symptoms.

“We certainly would not say at this point in time to initiate hormone therapy for the express purpose of trying to prevent heart disease or cognitive decline; the evidence is not to that point. But for women who have menopausal symptoms and who are considering hormone replacement therapy to reduce their symptoms and improve their quality of life related to these symptoms, there were many favorable effects seen of taking hormone therapy for 4 years,” Dr. Manson said.

North American Menopause Society (NAMS) 23rd Annual Meeting. Presented October 3, 2012.