Reporter: Aviva Lev-Ari, PhD, RN
Hormone therapy may actually help the heart in some respects for newly menopausal women, a randomized trial showed, although the impact on hard outcomes like stroke and breast cancer still remains to be seen.
Oral estrogen plus progesterone improved lipid levels, while a transdermal patch improved insulin sensitivity in the KEEPS trial, according to researchers led by S. Mitchell Harman, MD, PhD, of the nonprofit Kronos Longevity Research Institute, which sponsored the trial.
Neither combination hormone treatment altered atherosclerosis progression or raised blood pressure, according to a Kronos press release summarizing a report to be presented Wednesday at the North American Menopause Society meeting in Orlando.
“The results provide reassurance for women who are recently menopausal and taking hormone therapy for short-term treatment of menopausal symptoms,” the group concluded in the release.
The need for reassurance stems from results released a decade ago from the Women’s Health Initiative (WHI), which showed an elevated risk of cardiovascular disease, stroke, and thromboembolic events as well as breast cancer with estrogen plus progestin.
Subsequent studies largely affirmed those risks and pointed to others, including ovarian cancer, lung cancer mortality, and probable dementia.
Menopause organizations largely recommended “the lowest dose for the shortest time” but have started backing away from that stance, instead endorsing a more flexible approach based on type and timing of hormone therapy.
Contradiction or Clarification?
The new study didn’t show significant differences in adverse events between women taking oral or transdermal estrogen with progesterone and those on placebo, including:
- Breast cancer
- Endometrial cancer
- Myocardial infarction
- Transient ischemic attack
- Stroke
- Venous thromboembolic disease
“However, the absolute numbers of such events were extremely small in all three treatment groups, making definitive conclusions impossible,” the researchers acknowledged.
Nor is the KEEPS study ever likely to definitively determine safety, because it was too small to assess clinical events, session moderator and presenter JoAnn E. Manson, MD, DrPH, commented in an email to ABC News and MedPage Today.
But that wasn’t the point of the trial, said Manson, who serves as chief of preventive medicine at Brigham and Women’s Hospital in Boston and is outgoing president of the menopause society.
“The KEEPS trial does not challenge the conclusions of WHI about the risks of clinical events with hormone therapy,” she wrote. “KEEPS and WHI were addressing entirely different questions.”
The earlier study tested hormone therapy as it was in clinical use at the time, for cardiovascular prevention based on epidemiologic suggestion of benefit.
The evidence has clearly come down against hormone therapy for that use, Manson noted.
The question that KEEPS is now answering is how perimenopausal women should approach management of menopausal symptoms — if relatively short periods of hormone therapy are safe, noted Sharonne N. Hayes MD, of the Women’s Heart Clinic at the Mayo Clinic in Rochester, Minn.
So it may be enough that these risks weren’t substantially elevated in the trial, several experts contacted by ABC and MedPage Today agreed.
“The safety of HRT in this newly menopausal population is very reassuring and will likely increase usage as well as demand for HRT in women suffering with vasomotor symptoms,” commented neurologist Cynthia L. Harden, MD, of the North Shore-Long Island Jewish Health System in Great Neck, N.Y., who said the KEEPS data adds nuance rather than contradiction.
The results don’t change the post-WHI clinical approach of yearly reassessment targeting discontinuation after a few years of hormone therapy, added Wendy Vitek, MD, an ob/gyn at the University of Rochester Medical Center in Rochester, N.Y.
Different Populations, Different Drugs
There were some differences between the Women’s Health Initiative and the KEEPS trial that may lead to real differences in outcome, though, researchers suggested.
The KEEPS trial included 727 healthy women ages 42 to 58 who were all within 3 years of the onset of menopause at baseline.
The mean age was 52, whereas the vast majority of women in the nine hormone therapy trials done to date, including the WHI, were in their 60s.
KEEPS randomized its newly-menopausal population to double-blind treatment with cyclical micronized progesterone (Prometrium) plus one of the following:
-
Oral conjugated equine estrogen (Premarin) given at 0.45 mg/day, which was lower than the 0.625 mg/d used in the WHI
-
Transdermal estradiol (Climara) at 50 µg/day, an option not available in the WHI
- Placebo
Even the two different estrogen administration routes showed some differential effects on cardiovascular risk factors, the investigators pointed out.
HDL cholesterol and triglycerides rose while LDL fell with the oral estrogen.
The patch didn’t affect any lipid levels, but it did lower insulin resistance, which the oral form did not.
Neither drug boosted systolic or diastolic blood pressure, unlike the blood pressure increases seen with oral estrogen in the WHI.
Atherosclerosis neither accelerated nor reversed with 48 months of either treatment as monitored by carotid ultrasound, although there was a nonsignificant trend for less coronary artery calcium accumulation compared with placebo, noted Harman, who also practices at the Phoenix VA Medical System.
But that’s not necessarily reassuring with regard to cardiovascular outcomes for this younger group of women, Jacques Rossouw, MBChB, MD, chief of the WHI Branch of the National Heart, Lung and Blood Institute, noted in an email to ABC and MedPage Today.
“Changes in arteries in younger women have little relation to risk of stroke,” he explained. “Estrogen/progestin have [effects] on clotting mechanisms, on inflammation mechanisms. Those are things that trigger acute heart attack or stroke [in younger women]. Perfectly healthy young women can have strokes but have completely normal arteries. ”
Really, “the lack of effect on atherosclerosis reinforces the results of the WHI that hormone therapy is not good preventive therapy for heart disease,” added Lewis H. Kuller, MD, DrPH, of the University of Pittsburgh.
As expected, hormone therapy cut down on hot flashes and night sweats while raising bone density and mood, co-investigator Sanjay Asthana, MD, of the University of Wisconsin in Madison, said in the Kronos press release.
Sexual function also improved compared with placebo, in accord with the reduction in vaginal dryness although not the lack of improvement in sex drive seen in prior studies.
“KEEPS also highlights the need for individualized decision making about hormone therapy, given that oral conjugated equine estrogen and transdermal estradiol may have different profiles of effects, and different women have different symptom profiles and priorities for treatment,” the researchers noted in the press release.
KEEPS Sponsor Biased?
Kronos has long had an openly declared interest in countering the 2002 WHI findings of increased health risks from postmenopausal hormone therapy. In 2007, it issued a series of press releases attacking the WHI conclusions and touting KEEPS — one of which included a synopsis describing the nascent trial as “one of the studies to refute the WHI.”
The money behind Kronos comes from the Aurora Foundation. The latter was established by John Sperling, the billionaire founder of the University of Phoenix and other for-profit education ventures.
About 90% of Kronos’ $5.3 million in funding in 2010, the last year for which public records are available, came from Aurora. The $4.8 million given to Kronos that year was more than half of Aurora’s total giving.
Sperling, who is the foundation’s sole trustee, has a long history of involvement in sometimes controversial biological research involving life extension. He funded a successful, multimillion-dollar effort to clone his girlfriend’s dog in 2007, and later a similar cloning project for house cats.
Previously, he had bankrolled a medical clinic in a Phoenix suburb called the Kronos Group — not related to the Kronos Longevity Research Institute — that offered anti-aging remedies to older patients. It has since morphed into Kronos Optimal Health, which markets relatively conventional health and wellness programs to employers and individuals.
A 2004 article in Wired magazine reported that Sperling had also invested in a group of biotechnology companies seeking to develop anti-aging technologies based on cloning and stem cells.
The study was sponsored by the Kronos Longevity Research Institute with funding from the National Institutes of Health for the ancillary cognitive and affective portion.
The presentation was supported by grant funding from Noven Pharmaceuticals.
This article was developed in collaboration with ABC News. 
Primary source: North American Menopause Society
Source reference:
Manson JE, et al “New findings from the Kronos early estrogen prevention study (keeps) Randomized trial” NAMS2012.
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