Hormone therapy and cognitive function: Is there a critical period for benefit?

The large majority of women receiving hormone therapy initiate therapy early in life for the treatment of menopausal symptoms. However, the Women's Health Initiative Memory Study, the only randomized clinical trial to date on hormone therapy and dementia, was carried out in women age 65 and older. That trial provided important insights into the detrimental effects of hormone therapy on dementia in women initiating later in life. The generalizability of those findings to the typical hormone therapy user who initiates earlier in life is unknown. To address this important issue, this review focuses on observational trials of hormone therapy and dementia risk, randomized clinical trials of hormone therapy and cognitive function, and basic science studies. These lines of research provide suggestive, but not definitive, evidence that early initiation of hormone therapy may provide cognitive benefits, particularly to verbal memory and other hippocampally mediated functions. Other forms of hormone therapy, other cognitive domains, and cyclic hormone regimens may not conform to this "critical period hypothesis." Further research is needed to test the validity and limits of this hypothesis.     

Effects of ovarian hormones on cognitive function in nonhuman primates

Several studies have suggested that estrogen benefits verbal memory and lowers the risk of Alzheimer's disease in women, and improves cognitive function in animal models. However, the negative outcome of the Women's Health Initiative Memory Study has challenged the rationale for using estrogen as a protective agent against age-related cognitive decline. In view of the limitations of the Women's Health Initiative Memory Study, it is clear that our understanding of estrogen effects would greatly benefit from further interactions between clinical and basic science. Animal models of menopause can provide crucial information regarding the consequences of estrogen loss and replacement on several systems, including cognition. In this paper, I review the evidence that nonhuman primates, who share numerous cognitive and physiological characteristics with humans, can substantially contribute to our understanding of estrogen influences on the brain and cognition. Studies in young adult females suggest that some aspects of cognition fluctuate with the menstrual cycle, but that ovariectomy and estrogen replacement have only modest effects on cognitive function. In contrast, data in aged, naturally or surgically menopausal monkeys indicate that estrogen modulates a broad range of cognitive domains. Neurobiological data are consistent with the cognitive findings and demonstrate an array of morphological and physiological changes in brain areas important for cognition following ovariectomy and/or estrogen replacement. It is concluded that nonhuman primates, by providing a bridge between rodent and human data, constitute invaluable models to further our understanding of hormonal actions on the brain and cognition and to develop effective hormonal interventions against brain and cognitive aging.     

Estrogen and cognitive aging in women

Although several randomized controlled trials of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the Women's Health Initiative Memory Study, have failed to confirm these findings. One critical difference between studies that found a protective effect of estrogen on memory and those that did not is that, in the former studies, treatment with estrogen began at the time of menopause and in the latter studies, it was first administered many years after the menopause had occurred. Recent evidence from rodent, nonhuman primate, and human studies consistently suggests that the timing of the initiation of estrogen treatment with regard to the menopause may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy, provides a window of opportunity for the protection of memory in females whereas the administration of the hormone following a considerable delay in time after ovariectomy or following a natural menopause has little or no beneficial effect on cognition.     

Postmenopausal hormone therapy: new questions and the case for new clinical trials

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Women's Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.     

Interactions between melatonin and estrogen may regulate cerebrovascular function in women: clinical implications for the effective use of HRT during menopause and aging

A number of clinical trials associated with the Women's Health Initiative (WHI) have assessed the potential benefits of hormone replacement therapy (HRT) for protection against the development of cardiovascular disease and memory loss in menopausal women. The results of the WHI Memory Study suggest that HRT increases the risk of stroke and dementia in menopausal women. This finding has called into question the results of hundreds of basic science studies that have suggested that estrogen could protect brain cells from damage and improve cognition. A number of researchers have argued that inappropriate formulation, improper dosing, a limited study population, and poor timing of administration likely contributed to the reported findings from the clinical trial. Regarding appropriate formulation, it has been suggested that interactions between estrogen and other hormones should be considered for further investigation. A review of the literature has led us to conclude that a thorough investigation into such hormonal interactions is warranted. We hypothesize that the increased risk of cerebrovascular disease observed in menopausal women may, in part, be due to changes in the circulating levels of melatonin and estrogen and their modulatory affects on many relevant endothelial cell biological activities, such as regulation of vascular tone, adhesion to leukocytes, and angiogenesis, among others. Our hypothesis is supported by numerous studies demonstrating the reciprocal inhibitory effects of melatonin and estrogen on vascular tone, neuroprotection, and receptor expression. We believe that a thorough analysis of the distribution, localization, expression, quantification, and characterization of hormonal receptor subtypes, as well as changes in structural morphology in diseased and normal, healthy cerebrovascular tissue, will substantially aid in our understanding of the effects of HRT on the cerebrovascular circulation. The application of new molecular biological techniques such as tissue microarray analysis, gene and protein arrays, and multi-photon confocal microscopy may be of tremendous benefit in this regard.     

Lessons to be learned from animal studies on hormones and the breast

The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women's Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.     

Depression, estrogen, and the Women's Health Initiative

This clinical observation report compares hormone use and clinical presentation in a series of middle-aged depressed women before and after publication of the Women's Health Initiative. Depressed women over age 40 seen at a general hospital academic women's affective disorders practice 6 months before and after publication of the Women's Health Initiative were compared for medication changes, hormone therapy, lifetime depressive episodes, time since last episode, time to depression recurrence after hormone cessation, symptoms, and treatment response. More women stopped hormone therapy and reported onset of depression within 3 weeks of hormone discontinuation after than before publication of the Women's Health Initiative. Depression in most women responded to reinstitution of estrogen or initiation or increase in antidepressant dose. Discontinuation of hormone therapy appears to be associated with the rapid recurrence of depression in some women with a history of depression. Randomized controlled trials in middle-aged depressed women of estrogen or a selective estrogen receptor modulator as monotherapy or as an augmentation agent are urgently needed.     

Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757

OBJECTIVES: At present the Women's Health Initiative trial is the only reported randomised controlled trial studying the effects of hormone therapy among healthy postmenopausal women. The Women's Health Initiative reports have been criticized for lacking in generalisability, due to the characteristics of the trial population. We aimed to compare the health effects of oral continuous combined hormone therapy with a placebo and non-treatment among healthy Estonian women. METHODS: Eligible women were randomised into a blind group of hormone therapy versus placebo and into a non-blind group of open label hormone therapy versus non-treatment. One thousand seven hundred and seventy-eight postmenopausal women aged 50-64 at the time of sampling were recruited in 1999-2001 at three clinical centers in Estonia. Participants received conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5mg/d, or conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 5mg/d, if less than 3 years had passed since menopause at recruitment, or matched placebo or non-treatment. Trial treatment was stopped gradually from 1 January 2004 to 31 May 2004. RESULTS: After a follow-up period from 2.0 to 5.0 years the combined hazard ratio, stratified by blinding and adjusted for age at recruitment and former oral contraceptive use was 1.12 (95% confidence interval [CI]: 0.90-1.40) for coronary heart disease, 1.24 (95% CI: 0.85-1.82) for cerebrovascular disease, 1.36 (95% CI: 0.73-2.52) for total cancer, and 0.61 (95% CI: 0.42 to 0.89) for bone fractures. CONCLUSIONS: The results from the Estonian Postmenopausal Hormone Therapy randomised trial are consistent with the Women's Health Initiative findings.     

Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy

The risks of low bone mineral density, osteoporosis and fractures, are major concerns in postmenopausal women. Although postmenopausal hormone therapy is effective for reducing these risks, safety issues have been raised by the results of studies such as the Women's Health Initiative. Although there are scientifically valid reasons to be wary of the general applicability of the Women's Health Initiative findings, the study has underscored the continuing need for research into new forms of menopausal hormone therapy. Low-dose transdermal estrogen monotherapy can preserve bone density while relieving vasomotor symptoms. Transdermal administration may offer advantages, including lack of first-pass liver metabolism, which permits the use of lower doses and avoids a negative impact on the lipid profile. Moreover, a recently published 2-year study of ultra-low-dose transdermal estrogen monotherapy in an older population similar to that of the WHI reported significant increases in bone mineral density, accompanied by significant reductions in markers of bone turnover, with no increased risk of endometrial hyperplasia or other side effects. Additional studies are warranted to shed further light on the possible benefits of low-dose estrogen monotherapy for the prevention of bone loss in postmenopausal women.     

New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.     

Autoimmune hepatitis associated with the use of black cohosh: a case study

Herbal remedies generate more than 1.8 billion dollars in annual sales in the United States. Herbal products have been associated with a wide spectrum of hepatic toxicities. With the recent Women's Health Initiative Study demonstrating increased risk of breast cancer and cardiovascular events associated with hormone therapy, many women may resort to herbal remedies for persistent menopause symptoms. We report a case of autoimmune hepatitis likely triggered by the use of black cohosh (Actaea racemosa), an agent marketed to treat menopause symptoms. Given this case report, we recommend close monitoring of women using this herbal preparation.     

Coronary heart disease in menopausal women: implications of primary and secondary prevention trials of hormones

In direct contrast to the observational studies, both primary and secondary prevention trials of female reproductive hormones have found no benefit for coronary heart disease (CHD). Basic science studies have elucidated several mechanisms by which estrogen may improve coronary arterial physiology and prevent pathology, but have also found mechanisms by which estrogen might increase coagulation or inflammation, or might trigger coronary events in advanced lesions. Animal studies suggest that hormones may retard early atherosclerosis, while both animal studies and human angiographic trials are conclusive that hormones do not retard progression of raised lesions. Hormone use in the primary prevention observational studies would mostly have started at the age of menopause, in women whose arteries on average would be closer to normal than those of women in the clinical trials. One hypothesis worthy of further study is that estrogen may have a beneficial effect in normal or near-normal arteries, but the opposite effect in the presence of established atherosclerosis. However, at the average age of menopause, a substantial proportion of women has raised lesions, and a smaller proportion already has advanced lesions. Also, the apparent benefit of hormone use was found in secondary prevention observational studies, i.e., in women with compromised arteries. It is likely that uncorrected biases in the observational studies lead to an overestimation of any benefit of hormone use. On the other hand, endogenous estradiol may be responsible for the later onset of coronary disease in women compared to men; if so, then the appropriate test of the estrogen hypothesis would employ transdermal estradiol in a young population of menopausal women. Hormones are not indicated for the prevention of CHD, particularly in the light of the increased risk for stroke and venous thrombosis. Their use for other indications (menopausal symptoms, osteoporosis) needs to be tempered by the risk for cardiovascular disease (CVD).     

Memory functioning among midlife women: observations from the Seattle Midlife Women's Health Study

OBJECTIVE: As the number of midlife women increases, there is an increased interest in women's experiences of the perimenopause. Because of the evidence linking estrogen with cholinergic and serotonergic activity in the brain and with central nervous system development of dendritic arborization, and mixed evidence of estrogen use with incidence of Alzheimer's disease, the effects of the perimenopause on memory functioning are of interest. The purpose of these analyses, part of the Seattle Midlife Women's Health Study, was to describe changes in women's perceived memory functioning according to their perimenopausal group, age, perceived stress, health status, and mood. DESIGN: Memory functioning was assessed with the Memory Functioning Questionnaire as part of a questionnaire mailed to study participants annually. Perimenopausal group was assessed using Mitchell's rating schema. RESULTS: Age was unrelated to any of the Memory Functioning Questionnaire indicators except for retrospective memory; younger women reported more memory problems than older women. Perimenopausal groups were unrelated to most memory functioning ratings with few exceptions. Memory functioning ratings of current memory compared with the past were worse for women who were in early and middle transition and for those who were using hormone therapy than for those who were in late transition and postmenopause. Women reported more current memory problems compared with 10 and 20 years ago and at age 18. Health ratings were negatively correlated with memory functioning ratings, and depressed mood positively correlated with nearly every indicator of memory functioning (frequency of memory problems, ratings of current memory, past memory, and memory change). Greater perceived stress levels were associated with more memory problems. CONCLUSIONS: Perceived memory functioning seems more closely related to perceived health, depressed mood, and perceived stress than to perimenopausal stage or age. Further work is needed to determine whether these ratings provided by the Seattle cohort will change over time as women age and as they make the transition to menopause and beyond.     

Timing of the vascular actions of estrogens in experimental and human studies: Why protective early,and not when delayed?

Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes including the cardiovascular system. Although epidemiological studies and Nurses' Health Study suggested, and all animal models of early atheroma clearly demonstrated a vasculoprotective action of both endogenous and exogenous estrogens, the Women's Health Initiative did not confirm the preventive action of estrogens against coronary heart disease (CHD). However, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with increased CHD risk among women more distant from menopause. Thus, it is now mandatory to try to understand the mechanisms that could have influenced the actions of estrogens at various stages of atherosclerosis and/or of life. In this current review, we will summarize our understanding of the potential cellular targets and mechanisms of the vasculoprotective actions of estrogens, as well as of the lack of action of estrogens when administered after a period of hormonal deprivation. The mechanisms of the aggravating role of progestogens such as medroxyprogesterone acetate will be considered. Finally, we will analyze the possibilities to uncouple some beneficial from other undesirable actions following the partial/selective activation of estrogen receptors.     

A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life

The results of several observational studies suggest that the use of estrogen replacement is associated with better mood, cognitive function and quality of life. Such findings are consistent with those of laboratory-based research showing that estrogen promotes neuronal sprouting, enhances cholinergic activity in the brain, decreases brain and plasma levels of beta-amyloid, increases serotonin postsynaptic responsivity and the turnover of noradrenaline, and inhibits monoamine oxidase activity. However, the findings from the Women's Health Initiative controlled trial showed that hormone replacement (estrogen plus progestin) not only failed to improve mood, cognition and quality of life but also increased the risk of dementia. At present, there is limited information about the effect of unopposed estradiol replacement therapy (ERT) on the mental health outcomes of women at increased risk of cognitive decline (aged 70 years and over). We designed the present randomized, double-blind, placebo-controlled trial to clarify this issue. One hundred and fifteen women were randomized to treatment with estradiol (n=58; 2mg per day) or placebo for a total period of 20 weeks. The outcomes of interest in this study included changes in the Beck Depression Inventory (BDI) scores between baseline and week 20, as well as changes in quality of life scores (as measured by the SF-36) and cognitive function (CAMCOG, Block Design, Memory for Faces, California Verbal Learning Test (CVLT) and verbal fluency (VF)). Nineteen women treated with estradiol and 10 of those treated with placebo discontinued the use of the medication during trial, most frequently due to adverse reactions (OR=4.11, 95% CI=1.29-15.37). Intention-to-treat analysis showed that the active and placebo groups did not differ in their response to treatment in any of the outcome measures (p>0.05). A separate analysis restricted to women who completed the 20-week-trial produced similar negative results. The results of this trial indicate that the use of a relatively high dosage of unopposed estrogen replacement for 20 weeks is not associated with significant changes in cognitive function, mood and quality of life. Other more efficacious and safer interventions need to be devised with the aim of improving the mental state and quality of life of older women.     

Potential age-dependent effects of estrogen on neural injury

In 2000, approximately 10 million women were receiving hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies suggested that HRT may be neuroprotective and cardioprotective. Then, in 2003, reports from the Women's Health Initiative (WHI) indicated that long-term estrogen/progestin supplementation led to increased incidence of stroke. A second branch of the WHI in women with prior hysterectomy found an even stronger correlation between estrogen supplementation alone and stroke incidence. Follow-up analyses of the data, as well as data from other smaller clinical trials, have also demonstrated increased stroke severity in women receiving HRT or estrogen alone. This review examines the studies indicating that estrogen is neuroprotectant in animal models and explores potential reasons why this may not be true in postmenopausal women. Specifically, age-related differences in estrogen receptors and estrogenic actions in the brain are discussed, with the conclusion that animal models of disease must closely mimic human disease to produce clinically relevant results.     

A Cross-sectional Survey of Menopausal Status, Symptoms and Psychological Distress in a Community Sample of Australian Women

While many researchers assume the menopause to be an endocrine deficiency disease, others argue that menopause is normally non-traumatic, associated with few and minor symptoms. An Australian sample of 304 female volunteers (128 pre-menopausal, 35 peri-menopausal, 80 post- menopausal and not taking hormone replacement therapy, 61 post-menopausal and taking hormone replacement therapy) completed the Women's Health Questionnaire and the Profile of Mood States. There were differences among the groups on some symptoms, although the only difference between the post-menopausal groups was on vasomotor symptoms. There were no between-group differences in depression, anxiety or mood states, nor did demographic variables affect these measures. There was no evidence that post-menopausal women experienced increased psychological distress, supporting the hypothesis that menopause is not particularly distressing for normal women.