September 17, 2007

Early Start
By Jennifer Wider, MD
For The Record
Vol. 19 No. 19 P. 40

Researchers uncovered several interesting findings when they revisited an aborted 2002 study.

Five years ago this summer, the National Institutes of Health (NIH) prematurely stopped a major portion of the Women’s Health Initiative (WHI), a large and ambitious study to address the most common causes of death, disability, and impaired quality of life in postmenopausal women.

One part of the WHI sought to determine whether hormone therapy has a positive or negative impact on cardiovascular disease, cancer, and osteoporosis. The estrogen-plus-progestin hormone therapy trial for women with intact uteruses was stopped in July 2002 after investigators found that the associated health risks of the combination hormone therapy outweighed the benefits.

Less than two years later, in March 2004, the NIH announced that it had stopped another portion of the WHI—the estrogen-alone hormone therapy study for women who have had a hysterectomy—in the interest of safety after careful consideration of preliminary data and an average follow-up of nearly seven years.

The studies’ abrupt end and the news stories that followed left many patients confused or scared. Questions still remained about the safety and efficacy of hormone therapy, who could take it, and for what purpose and what duration.

More information was needed about the risks and benefits of estrogen-alone hormone therapy, long-term risks for short-term hormone therapy use, the appropriate timing of hormone therapy use in relation to a woman’s onset of menopause, and the effects for women who take hormone therapy well after menopause.

The medical community has learned more about hormone therapy since the WHI trials were stopped. A study published in the July 11 issue of the British Medical Journal (BMJ) confirmed that hormone replacement therapy should not be prescribed for the purpose of preventing chronic conditions, such as heart disease, in older women well past menopause. That same study, however, concluded that hormone therapy may be a safe, short-term option for younger women in early menopause to relieve symptoms and improve quality of life.

“If the woman is healthy and has no risk factors, low-dose hormone replacement therapy use for a short period of time should confer a small risk to her health,” says Helen Roberts, MD, MPH, a senior lecturer of women’s health issues at the University of Auckland in New Zealand. Roberts, who wrote an accompanying editorial to the BMJ study, also says women with risk factors such as a previous heart attack, stroke, blood clots, or breast cancer or a high risk of cardiovascular disease should not use hormone therapy.

Although confusion about hormone therapy persists, this study solidifies some thinking about the issue. Short-term use of hormones in healthy women going through early menopause may not pose serious health risks. Long-term use of hormone therapy to prevent chronic diseases in older women who begin the therapy many years after menopause may actually increase their risk of blood clots and heart disease and should be discouraged.

A limitation of the WHI is that it primarily studied women who began taking hormone therapy long after they had passed menopause. Researchers are still trying to determine the effects of taking hormone therapy for long periods of time if the treatment begins in the early stages of menopause. Some data suggest the health risks are lower for these women, but more studies are needed.

“There has been mounting evidence that a woman’s age and the amount of time since onset of menopause influence her health outcomes on estrogen, particularly her risk of heart disease,” says JoAnn Manson, MD, DrPH, chief of preventative medicine at Brigham and Women’s Hospital in Boston, professor of medicine at Harvard Medical School, and one of the principal investigators of the WHI. “We’ve recently reported in April of 2007 that when you combine the findings from the estrogen-plus-progesterone trial and the estrogen-alone trial, there is a suggestion of a lower risk of heart disease in the women who were less than 10 years since onset of menopause.”

By contrast, Manson’s analysis shows an increased risk of heart disease for women who were more than 20 years past menopause.

Manson’s research team reported in the June 21 issue of The New England Journal of Medicine that women who were in their 50s in the estrogen-alone trial tended to have less coronary artery calcium if they received estrogen compared with placebo.

“Coronary artery calcium is a marker for plaque build up in the arteries, hardening of the arteries, and it’s a strong predictor of future risk of cardiovascular, of coronary heart disease,” Manson says. “So these results lend support to the theory that estrogen may slow early stages of atherosclerosis.”

As research continues, taking hormone replacement therapy is an individual decision for women and depends on many factors. Women should speak with their healthcare providers about the potential benefits and risks that may be relevant to them as individuals.

— Jennifer Wider, MD, wrote this article for the Society for Women’s Health Research.

Estrogen Therapy Gives Aging Brain Cells a Boost
Cyclical, long-term estrogen injections protected brain cells from age-related deterioration, according to a new study conducted at Mount Sinai School of Medicine. The study suggests that age is a factor in estrogen treatment and sheds light on the intricate relationship between mind, age, and hormones. The study was recently published in the online edition of Proceedings of the National Academy of Sciences.

In a multicenter study comparing older rhesus monkeys with younger female monkeys, researchers found that estrogen significantly improved cognitive function in older animals but not in young monkeys. The study was led by Jiandong Hao, MD, PhD, assistant professor of neuroscience; and senior coauthor John H. Morrison, PhD, dean of basic sciences and the graduate school of biological sciences, and the W.T.C. Johnson Professor of Geriatrics and Adult Development (Neurobiology of Aging). Peter Rapp, PhD, interim chair of the department of neuroscience and associate professor of neuroscience, geriatrics, and adult development, led the behavioral phase of the study. Patrick Hof, MD, the Irving and Dorothy Regenstreif Research Professor Neuroscience, and William Janssen, a researcher in Neurobiology of Aging, also contributed to the research.

Working with colleagues from the University of Toronto and the University of California-Davis, Morrison, Rapp, and Hao compared the outcomes of four groups of female monkeys that were ovariectomized, which induced menopause: older monkeys that received estrogen, older monkeys that did not receive estrogen, younger monkeys that received estrogen, and younger monkeys that did not receive estrogen. The treated animals received pure estradiol injections every 21 days while being tested on a series of cognitive tasks over the course of more than two years.

Cognitive performance tests showed the older treated animals performed nearly as well as the younger animals, whereas older untreated animals displayed dramatic cognitive decline. Surprisingly, the younger animals performed equally well with or without estrogen treatments. The aged animals had their ovaries removed around the time of perimenopause—before the onset of full menopause—and began treatment within months of their ovariectomy.

Microscopic studies conducted after the cognitive testing was completed revealed that in the prefrontal cortex—a region of the brain associated with cognitive tasks that Rapp used to test the monkeys—the older estrogen-treated animals showed a greater density of synaptic spines—tentaclelike structures that link brain cells to one another and aid in brain cell communication—while the older untreated animals showed no such neuronal growth. These spines are critically important for learning and memory.

The findings indicate that the debate on the potential benefits of postmenopausal hormone therapy is not yet over, says Morrison. “There’s been a great deal of confusion as to whether estrogen helps or harms postmenopausal women, and our findings tell us is that there is a very critical window of opportunity in which estrogen therapy may be helpful,” he says.

Morrison notes that this critical window may be around the time of perimenopause, in which cyclical estrogen treatments as used in this study may be particularly effective in protecting the brain from age-related decline.

“We found that this increase in synaptic spines in the prefrontal cortex in the older estrogen-treated monkeys appears to have prevented age-related cognitive decline,” Morrison explains. “Importantly, the increase was most pronounced among the small spines that are highly plastic and particularly important for learning and memory. Young monkeys retain a high number of these small spines even without estrogen, which explains their ability to perform well on the cognitive tasks. Estrogen levels decline in old age, so the brain may need a certain amount of circulating estrogen to remain supple. Timing may be everything.

“The increase we observed in small, thin spines suggests that estrogen allows for greater neuroplasticity,” says Morrison. “Synaptic spines are lost during aging, and interestingly, it is the dynamic nature of the small-headed spines that are critical to the formation of new memories.”

The younger animals retain neural plasticity in the absence of estrogen, Morrison explains, “but what’s happening with the older animals is this double hit of both age and estrogen decline. These particular brain cells are not resilient enough anymore to endure this kind of double hit.”

Rhesus monkeys undergo menstrual cycles and a menopause that closely mimic those of humans. Although it is well known that estrogen affects brain function, what is unclear is what form of estrogen works best, when estrogen should be given, and how much is needed to be effective. It is possible, the researchers note, that administering the same cyclical estradiol treatments to much older monkeys would result in less benefit.

“It’s possible a middle-aged brain reacts differently to estrogen than a young brain and that a very old brain might not react to estrogen at all,” Morrison explains, “so this window of opportunity may be fairly narrow—we just don’t know yet. If the brain is too old, then age-related decline may be difficult to reverse. However, our study suggests that if we jump before it’s too late, we may possibly prevent memory loss.” What is also unclear, Morrison adds, is at what point the natural course of aging trumps the effects of any estrogen treatment.

Rapp and Morrison plan to extend their research through similar behavioral and microscopic studies in monkeys that have not been ovariectomized, so the aging process is more natural and not acutely induced.

— Source: Mount Sinai Medical Center