RECENT STUDIES QUESTION HORMONE THERAPY EFFECTIVENESS
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NEWS RELEASE NR-28-06 (10/16/06). For more information, please contact Sara Harris at (202) 962-4000 or sharris@sfn.org.
RECENT STUDIES QUESTION HORMONE THERAPY EFFECTIVENESS
ATLANTA, October 16, 2006 - Scientists are sorting out the conflicting messages from recent studies about estrogen's effect on the aging female brain. They're discovering, for example, that such factors as the type of estrogen prescribed, the age at which estrogen therapy is begun, and the health of brain cells at the start of the therapy may explain why past studies have failed to agree on whether estrogen helps or hinders women's brains as they age.
For years physicians routinely prescribed hormone therapy (HT) -- either estrogen plus progesterone or estrogen alone -- to women. They relied primarily on laboratory and observational studies that suggested HT, particularly estrogen therapy, protected postmenopausal women from a host of illnesses, including dementia associated with Alzheimer's disease. Some evidence suggested that postmenopausal women on estrogen therapy were 30 percent less likely to develop dementia than women not treated with the hormone.
However, recent clinical studies -- most notably the randomized, placebo-controlled trials sponsored by the Women's Health Initiative (WHI) -- have questioned such findings. The WHI found no improvement in cognition in older, postmenopausal women taking HT compared with a placebo. In fact, it observed an increased risk of dementia among those treated with HT.
"The findings were quite surprising," says Peter Schmidt, MD, of the National Institute of Mental Health, who will participate in the symposium on the aging female brain at this year's meeting. "The evidence regarding postmenopausal hormone therapy's effects on the brain went from positive to negative almost overnight."
Perplexed by this scientific turn of events, researchers took a closer look at the effects that ovarian steroids, particularly estrogen, have on brain function and behavior. They found that timing, in particular, may play a major role in whether or not estrogen therapy is effective in keeping the brain's neurons healthy.
"Studies of the effects of estrogen on brain function and behavior need to consider the changing patterns of hormone secretion that occur across the menopause transition, and not treat the menopause as a single hormonal event," says Schmidt.
Scientists have recently discovered, for example, that women who start estrogen therapy either late in their transition through menopause or soon after menopause has occurred are at lower risk of developing dementia than women who start the therapy several years after menopause. In addition, estrogen therapy has been found to be effective in relieving depression among women who are approaching menopause (perimenopausal) but not among those who are postmenopausal.
"Most women do not develop depression as a result of the menopausal transition," says Schmidt. "But some do, particularly during the perimenopausal phase. And for these women, estrogen therapy may be beneficial."
Past research into the process of menopause in women has focused primarily on the role of declining ovarian follicles, the group of cells in the ovaries that release eggs during monthly ovulation. Scientists now believe, however, that menopause occurs as the result of complex interactions between the aging ovary and the aging brain that involve all three levels of the reproductive axis: the hypothalamus (located at the base of the brain), the pituitary gland, as well as the ovary. Each undergoes age-related changes, both independently and inter-dependently, that contribute to reproductive failure.
At the University of Texas at Austin, Andrea Gore, PhD, and her colleagues have been studying the specific role of the hypothalamus and its key neurotransmitter, gonadotropin-releasing hormone (GnRH), during the menopausal transition. The secretion of GnRH from the hypothalamus is known to be the primary signal controlling reproductive function during a woman's childbearing years. The role of GnRH in menopause, however, is not so well understood.
GnRH, which is released from about 1,000 neurons in the hypothalamus in 60- to 90-minute pulses throughout the menstrual cycle, induces the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones enable ovarian follicles to grow, setting the stage for ovulation. As the follicles develop in the ovary, they produce estrogens, which, through a complex feedback system, return to the brain where the hormones help regulate the release of GnRH.
In recent studies involving female rats, Gore and her colleagues have found that GnRH function is suppressed by key brain circuits during the animals' transition to acyclicity (in women, menopause) at middle age. "This loss of hypothalamic drive appears to be a critical mechanism underlying the failure to ovulate," says Gore.
The drop in GnRH production by the hypothalamus causes further loss of ovarian output, which in turn disrupts the feedback onto GnRH cells. "These two interdependent processes -- the loss of GnRH output and the dysregulation of feedback regulation of GnRH by estrogens from the ovaries -- play a crucial role in menopause," says Gore.
This research on rodents by Gore's laboratory and others has provided unexpected insights into menopause in women. "The loss of ovarian estrogens in women may mask other changes in the reproductive axis, particularly the hypothalamic GnRH system," says Gore. "Rats do not undergo such dramatic ovarian changes as humans, yet rats still become acyclic at middle age, indicating a non-ovarian, presumably hypothalamic, process. This experimental model enables us to reveal the neurobiological contribution to reproductive aging."
The prefrontal cortex of aged rhesus monkeys is highly responsive to estrogen, a hormone that aids cognition in older animals, says John Morrison, PhD, of Mount Sinai School of Medicine. Morrison organized the symposium on the aging female brain and hormone therapy at this year's meeting.
The prefrontal cortex mediates the highest levels of cognitive function, such as goal-directed learning, attention, and planning. This cortical region and these functions suffer in normal aging and are devastated in Alzheimer's disease. He has found that.
In earlier studies involving both rats and non-human primates, Morrison and his colleagues showed that estrogen therapy increases the number of dendritic spines, the small knob-like extensions that protrude from the surface of dendrites, the branched projections of neurons that receive information from other neurons. Such increases may explain behavioral studies in women that suggest the prefrontal cortex is a key target for estrogens, perhaps even more so than the hippocampus.
"Our latest behavioral testing of aged rhesus monkeys supports this view," says Morrison. "We found that when given estrogen therapy, the animals were able to perform as well as younger animals in a learning task that requires the use of the prefrontal cortex. These same monkeys displayed a dramatic increase in spines and synapses in the prefrontal cortex that likely led to the enhanced behavior. The ability of estrogen to reverse the pattern of aging in this cortical area is remarkable."
Morrison believes the conflict between these findings and those of the WHI studies, which found that estrogen did not improve memory, may be partially explained by the fact that his studies used pure estradiol rather than conjugated equine estrogen. "Also, our monkeys were premenopausal or perimenopausal-more like women in their early to mid-fifties than women in their mid-sixties, the age when treatment was initiated in the WHI trial," he says. "At those older ages, women may not receive the optimal neuronal response from estrogen therapy."
Morrison now plans to do experiments that will test different hormone treatments, particularly those most suitable for women, to determine which approaches are most suitable to promote healthy cognitive aging.
HT's effect on the cortex may alter how older women respond to and remember past events, according to new reports from Oregon Health & Science University in Portland. Earlier studies have shown that people tend to remember emotionally evocative information better than emotionally neutral information, an effect called "emotional enhancement." In addition, research has shown that as people age, they remember positive stimuli better than negative or neutral stimuli. This loss of emotional enhancement may be one of the mechanisms that limit memory in the elderly.
To examine whether HT affects older women's perception and memory for emotional stimuli, Jeri Janowsky, PhD, and her colleagues tested the emotional memory of two groups of elderly women aged 65 to 85. Some were on long-term HT; others were not taking any hormones. Also tested were a group of younger, premenopausal women, aged 24 to 40.
During the test, the women were asked to rate their feelings about various emotionally "positive," "negative," and "neutral" photographs. "We found that the older women who were taking hormones responded to the negative scenes much more strongly than to the neutral or positive ones, while the older women not on the hormones responded more strongly to the positive scenes" says Janowsky. The younger women in the study did not demonstrate any differences in their reactions.
Despite increased arousal for negative scenes and events, HT did not impact memory. Nor, as has been found in younger people, did heightened arousal translate into better memory for negative events.
"These findings suggest that with aging there is a disconnection between the arousing nature of negative information and the memory system," says Janowsky. "Normally, very arousing negative things boost memory. But in the elderly, despite estrogen's effect of increasing this arousal, memory is not boosted."
At the University of Southern California, researchers have found that the protective effects of estrogen on the brain may depend on how much of the drug is administered and whether treatment starts before or after Alzheimer's disease has already begun to destroy neurons. Using in vitro (neurons in culture) models of perimenopause, Roberta Brinton, PhD, and her colleagues have discovered that low levels of estradiol protected against neurodegeneration caused by beta-amyloid, a protein that forms "sticky" plaque deposits in the brains of AD patients. By contrast, high levels of estradiol were ineffective at protecting neurons from beta-amyloid.
Brinton and her team also discovered that the therapeutic effect of low levels of estradiol occurred only when the drug was administered before rather than after beta-amyloid induced neurodegeneration.
"Our findings suggest that estrogen has a 'healthy cell bias,'" says Brinton. "In other words, it appears to have a protective, preventive effect on healthy neurons, but it doesn't appear to benefit unhealthy ones. Nor does it seem that increasing the dose increases the likelihood of a positive effect. In fact, you may get a better response by decreasing the dose."
Brinton and her team are developing what they call neuroSERMs -- selective estrogen receptor modulators -- that will promote estrogen action in the cerebral cortex and hypothalamus while not promoting similar action in the breast or uterus. "Such agents could help prevent age-associated neurodegenerative disease such as Alzheimer's without the risk of possibly promoting breast or uterine cancer," she says.
