Hormone Therapy and Cognitive Preservation – Now A Distant Memory!
By Jonathan Raymond
Of all the proven negative consequences that result from long-term hormone therapy (HT) use, surely one of the most shocking is an increased risk of both dementia and mild cognitive impairment.1 What’s most troubling is that, while a few observational studies have pointed to HT’s potential benefit in preserving cognitive function and preventing dementia, proponents of HT promoted this unproven benefit to almost the same degree as HT’s unproven heart disease prevention benefits. The negative and unexpected side effects of HT on brain functioning were confirmed by the results of the two hormone therapy trials in the Women’s Health Initiative Memory Study (reported in 2003 and 2004) that explored HT’s impact on women’s cognitive functioning.
The idea that hormones might positively benefit brain functioning was suggested by laboratory data that hinted estrogen might aid post-menopausal women through processes that improved neuronal growth, nerve cell branching, and glucose use. The issue was complicated by the fact that the observational studies on this possible link often attempted to gauge HT’s cognitive effects on women who suffered from bothersome menopausal symptoms. It’s long been known that hormones relieve hot flashes and night sweats, thereby making it easier to sleep well - which helps people function better in general. So, there was no way to assess whether the perceived cognitive benefit resulted from a direct effect on women’s brain function, or just from symptom relief and better rest.
Thus, a clear-cut benefit from estrogen on cognitive function in perimenopausal and postmenopausal women remained undetermined. And, while some observational studies showed a reduced risk of dementia among HT users, other studies did not – in fact, some studies indicated that HT worsened dementia. Two such studies were the Harvard-based Nurses’ Health Study (NHS) and the Kaiser-Permanente-based Cache County Memory Study.2 The NHS included over 120,000 women, making it one of the biggest and most-referenced of all observational studies on HT and overall health. The NHS showed declines in several cognitive domains that were associated with long-term hormone use. The Cache County Memory Study, which included approximately 1,300 women, used pharmacy records to track participants’ prescription histories. That study showed a slight increase in total dementia among long-term users of both estrogen alone and of estrogen/progestin.
The Women’s Health Initiative Memory Study
These data highlighted the need for randomized trials to assess what role, if any, estrogen plays in the brain health of post-menopausal women. That trial, the Women’s Health Initiative Memory Study (WHIMS), began in 1997 and included over 7,400 women. WHIMS examined the effects of taking estrogen/ progestin hormone therapy (Prempro) in approximately 4,500 women with an intact uterus, and of taking estrogen hormone therapy alone (Premarin) in over 2,900 women who had had a hysterectomy.
The WHIMS results were released in May 2003 and June 2004 and immediately overturned the notion that HT prevented either dementia or overall cognitive decline.3 Participants aged 65 and over who used HT experienced higher rates of dementia when compared to women who took a placebo instead of HT. WHIMS specifically found that combined estrogen/progestin led to a doubled risk of dementia and had no effect on mild cognitive impairment. Women taking estrogen alone experienced slight increases in both dementia and mild cognitive impairment compared with placebo (93 cases vs. 69 when both outcomes were combined). Global cognitive function, as determined by The Mini-Mental Status Examination (MMSE), also decreased in both hormone groups, but showed no change among the placebo group. While no specific numbers were given regarding the change experienced over time by the women who received the placebo, HT users were found to be at much higher risk of experiencing a significant decrease in their MMSE test scores throughout the trial’s course.
What puzzled scientists was how HT increased the risks for dementia and cognitive impairment. The WHIMS investigators logically believed that, since estrogen significantly raises women’s risk of stroke, the cognitive problems might have stemmed from cerebrovascular disease in the form of silent/mini-strokes that were never diagnosed. (Note: WHIMS initial results stated that Alzheimer’s disease was the most frequently diagnosed type of dementia, seen in over 50% of cases.) To assess this possibility, the WHI funded an ancillary study, WHIMS-MRI, to examine MRI scans of over 1,400 WHIMS participants in order to track microvascular brain changes and assess HT’s role in causing strokes. Scientists hypothesized that the MRIs would indicate that strokes had occurred by revealing evidence of small, previously undiagnosed cerebrovascular lesions. The lesions, if present, could at least partially explain the increased cognitive problems experienced by women taking HT.
Unfortunately, this theory didn’t pan out - and the investigation raised more questions than it answered. WHIMS-MRI did not find significant differences in the cerebro- vascular disease in women taking HT when compared to women taking a placebo. While the HT users had a greater loss of brain tissue volume in two brain regions that are critical for learning and memory (the hippocampus and the frontal lobe), the women did not have a higher incidence of mini-strokes. (Women taking HT also had slightly smaller total brain volumes.) Because the total stroke risk was identical in the hormone and the placebo groups in WHIMS participants, it appeared that strokes were not the reason for the increased risk of dementia and brain decay observed in the WHIMS participants. The WHI results showed that the risks of having a stroke and of experiencing dementia and brain tissue loss among HT users are, actually, two separate brain diseases. (WHIMS-MRI also noted that brain tissue loss, regardless of HT use, was increased in women who smoked, had hypertension, and were diabetic.)
What Does it Mean?
What are the implications of these findings for menopausal and post-menopausal women who are already using HT or are considering HT? First, scientists were not able to determine why HT increased the risk of dementia. And, unfortunately, the cause of women’s increased loss of brain tissue also remains elusive. We just don’t know why HT users risk these negative outcomes, so we aren’t sure how to prevent them among women taking HT. Second, a woman who has been on HT for many years should note that the claims about HT’s benefits for brain health are unproven. Taking HT is not, in fact, a guarantee of good brain health in the future, and it actually increases the risks of having a stroke. In fact, the Black Box warning label required by the Food and Drug Administration for HT explicitly states that dementia and stroke are potential risks in older women. Third, the WHIMS findings are limited in scope because the data apply only to the WHIMS participants, all of whom were over age 65. While the WHI is planning to conduct brain MRIs on women under age 65 in order to assess the risk in a younger population, these results will not be available for some time.
Right now, the available trial data on younger women are quite worrisome. As seen in the WHI, HT increases the risk of stroke among women in their 50s. In August, researchers at the University of Illinois reported the effects of two botanicals, Prempro and a placebo, in a small clinical trial on cognition among women with hot flashes. The year-long study examined 66 women with an average age of 53; it found that Prempro caused a significant, although slight, decrease in verbal memory, despite a 94% improvement in hot flashes.4 In 2007, the same researchers had reported similar results in the Cognitive Complaints in Early Menopause (COGENT) trial. COGENT, a six-month study of 180 women aged 45-55, found that Prempro (while it relieved hot flashes and night sweats, and increased sexual interest) had a small negative effect on both short- and long-term verbal memory.5 The significance of HT’s negative effects on women who are not experiencing hot flashes is not known at this time.
Younger, recently menopausal women who do experience hot flashes should continue to follow the national guidelines issued for HT products: use the lowest dose for the shortest time possible. Women over 65 who are still having symptoms should probably consider alternatives. They should also be leery of any headlines proclaiming that HT prevents dementia if they “start early enough.” As with heart disease, any timing hypothesis about hormone use and brain function must be supported by solid clinical data and, right now, those data do not exist. As a whole, the WHI results do not even come close to hinting at an age-specific effect of hormones on brain function. Keep that in mind when you sift through what is actual science and what is just mere hype.
Until we have data on brain function that includes “younger” women (under 65), we at the NWHN believe that it is important that hormone proponents stop making claims for brain benefits from taking these drugs. The FDA has made it clear that they pose risks to postmenopausal women’s brain health. We call on them to reemphasize these data and, if necessary, to incorporate these new findings from the WHIMS-MRI Study into their warning labels.
Jonathan Raymond is a long-time supporter of NWHN and hormone therapy critic.
1. Dementia is “a broad term referring to a decline in cognitive [brain] function to the extent that it interferes with daily life and activities”; mild cognitive impairment is “a condition in which a person has memory problems greater than those expected for his or her age, but not the personality or cognitive problems that characterize AD” (Alzheimer’s Disease). See National Institutes of Health (NIH), National Institute on Aging, Alzheimer’s Disease Education and Referral Center (ADEAR), Alzheimer’s Disease: Unraveling the Mystery — Glossary, Silver Spring, MD: ADEAR, November 2008. Accessed 6/29/09 from http://www.nia.nih.gov/Alzheimers/Publications/Unraveling/Glossary.
2. Kang, J H, Weuve J, and F Grodstein, “Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women,” Neurology 2004; 63:101-107; and Petitti D B, Crooks V C, Chiu, V et al, “Incidence of Dementia in Long-term Hormone Users,” American Journal of Epidemiology, published online on 1/23/08; doi:10.1093/aje/kwm362. Available online at: http://aje.oxfordjournals.org/cgi/content/full/kwm362v1
3. Shumaker S A, Legault C, Rapp S R, et al., “Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women,” JAMA . 2003; 289(20):2651-2662; and Shumaker S A, Legault C, Kuller L, et al. “Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women,” JAMA 2004; 291(24):2947-2958.
4. Maki PM, Rubin LH, Fornelli D, et al, “Effects of botanicals and combined hormone therapy on cognition in postmenopausal women,” Menopause 2009; epub ahead of print available online at: http://www.ncbi.nlm.nih.gov/pubmed/19590458.
5. Maki PM, Gast J, Vieweg A J, et. al., “Hormone therapy in menopausal women with cognitive complaints: A randomized, double-blind trial,” Neurology 2007; 69:1322-1330.
6. H. Coker, PhD, P. E. Hogan, MS, N. R. Bryan, MD, et. al., “Postmenopausal hormone therapy and subclinical cerebrovascular disease — The WHIMS-MRI Study,” Neurology 2009; 72:125-134; and Resnick S M, Espeland M A, Jaramillo S A, et. al., “Postmenopausal hormone therapy and regional brain volumes — The WHIMS-MRI Study,” Neurology 2009; 72:135-142.