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The extent to which testosterone and other androgens might affect cognitive skills in women is not yet well understood. In this chapter, Sherwin reviews changes in endogenous androgens over a woman's lifespan and research findings germane to androgens and cognitive skills in women. For younger women, there is evidence that cyclical changes during the menstrual cycle affect cognitive performance, although it is not possible to tease out effects of testosterone from those of estradiol. In older women, the relation between testosterone levels and cognitive test scores is inconsistent. The ratio of estradiol to testosterone may be important in modulating sex-advantaged cognitive functions in women, with a lower ratio leading to relatively impaired performance on cognitive tasks in which women typically excel.
This chapter explains why two meta-analyses of treatment studies only found time-limited positive effects of estradiol in both women with and without dementia. The findings in women with dementia do not substantiate the “window of opportunity” theory. Negative effects of longer term treatment (>1 year) have also been reported in both women with and without dementia.
The meta-analyses reported that the most substantial effects of estradiol on cognition were seen in women who had undergone surgical menopause. Another large observational study found an increased risk for dementia when women had undergone surgical menopause. This chapter attempts to explain these findings by speculating that some women who are more at risk for medical indications for surgical menopause have particular genotypes implicated in sex steroid metabolism and synthesis. These genotypes expose these women to high estradiol levels. This may explain why these women show such strong responses to undergoing surgical menopause, as this induces a very sharp decline in their previously high estradiol levels. If these women also have genetic polymorphisms that predispose them to high levels of toxic estrogenic metabolites (such as catecholestrogens) this could lead to DNA damage. In the first instance that could lead to medical indications for surgical menopause, such as ovarian or endometrial cancer, endometriosis, cysts, etc. If these women are given estrogens at a later time in their lives, they might also be more susceptible to dementia, which has previously also been associated with DNA damage. The brain is apparently less able to compensate for this type of damage in later life, which could explain the more substantial negative effects on cognition and dementia risk found in the older women. Future genetic screening for these polymorphisms might allow more targeted treatment for those women who are not genetically at risk.
Estrogen-based therapies often include a progestin to antagonize tumorigenic effects of estrogens in the uterus. While much has been learned about the functional and neuroprotective effects of estrogens in the brain, far less is known about the effects of progestins, particularly specific progestins like progesterone and medroxy-progesterone acetate, used either alone or in combination with estrogenic therapies. In this chapter, Pike and Carroll review many of the effects on cell survival and function, first of estrogens, and then of progestins. While not all progestins are alike, the authors find that prolonged exposure to progestins often will decrease the protective effects of estradiol on cell survival and function. Evidence suggests that a cyclical regimen of estradiol and progesterone may be most efficacious. Ultimately, the development of neural selective estrogen receptor modulators (SERMs) with the potential to circumvent the need for, and hence the negative neural consequences of, progesterone will be an important advance to estrogen-based therapies.
Casadesus and colleagues make a case that hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause are implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this postulate has come from studies demonstrating an increase in amyloid-β (Aβ) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, decrements in sex steroids result in a proportionate increase in gonadotropins. They provide a review of the basic science relevant to luteinizing hormone (LH) and its receptor as a background for considering LH regulation of cognitive behaviors and AD pathology. Results of their analyses suggest that marked increases in serum LH following menopause/andropause is a physiologically relevant signal that could increase Aβ secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents, such as leuprolide, is proposed as a novel therapeutic strategy for AD.
A decade ago, oestrogen-containing hormone therapy was viewed as a promising strategy for the prevention and treatment of dementia and age-related cognitive decline. However, treatment trials in women with Alzheimer's disease showed that oestrogens did not reverse cognitive impairment, and clinical trials in healthy older women indicated that oestrogens did not prevent cognitive decline. The Women's Health Initiative Memory Study trial even suggested an increased risk of dementia with treatment late in life. What happened? How are we to understand these findings? What are the implications for middle-aged and older women? What about testosterone, and what about men? And where do we go from here? This book brings together world-renowned experts in basic and clinical research on sex steroids, aging, and cognition to integrate existing findings with emerging new data, and offer challenging hypotheses on these key issues.
Gibbs reviews the basic science, animal and neurochemical data, regarding estrogens and cognitive function. Importantly, estrogenic regulation of cognitive function is selective and does not affect all types of cognitive function but instead selectively affects specific types of behaviors. He goes on to review the impact of combination hormone therapy (HT) on cognitive performance and basic science investigations of the critical period of hormone intervention hypothesis. These findings indicate that estradiol enhancement of cognitive performance is lost over time following ovariectomy, which is consistent with Gibbs's cholinergic hypothesis and the critical window of therapeutic opportunity hypothesis (see Chapter 4). Results derived largely from rodent studies suggest that estradiol regulation of basal forebrain cholinergic neurons plays an important role in the regulation of select types of cognitive function, and may provide a mechanistic foundation for the critical period hypothesis. Gibbs proposes that identifying the specific neural circuits that account for the task-selective effects of estradiol, as well as the mechanisms by which these effects are mediated by basal forebrain cholinergic neurons, will aid in the proper use and timing of HT in postmenopausal women to sustain cognitive performance and prevent age-related cognitive decline and dementia.
The landmark Women's Health Initiative Memory Study (WHIMS) program has had an enormous impact on our understanding of how estrogens and estrogen-containing hormone therapy affect cognitive outcomes in postmenopausal women. It is the starting point and touchstone for any discussion on cognition and dementia in women. As reviewed in this chapter by principal WHIMS program investigators, the WHIMS comprised two large randomized placebo-controlled trials of conjugated equine estrogens with and without medroxyprogesterone acetate in women aged 65 years and older. In this study, the two hormone therapy formulations were associated with increased risk for probable dementia (hazard ratio 1.77, 95% confidence interval 1.22 to 2.58). They were also associated with a small adverse mean difference of 0.21 (0.06 to 0.37) points on the 100-point Modified Mini-Mental State examination. Adverse findings were similar for both hormone therapy formulations and for women with and without histories of prior hormone therapy use. The Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Magnetic Resonance Imaging Study were conducted on subsets of WHIMS participants. The former found little evidence that conjugated equine estrogens with medroxyprogesterone acetate had a positive effect on cognitive aging. The latter found that the hormone therapy formulations were associated with decreased brain volumes, particularly among women with lower levels of cognitive function at baseline, but mean effects on ischemic lesions were not significant. No subgroups of WHIMS participants have been identified for which initiating hormone therapy appears to convey cognitive benefit.
Few comparisons of the efficacy of different estrogenic formulations on brain function have been carried out. While most basic science studies have evaluated effects of estradiol, many of the clinical studies that have evaluated effects of hormone therapies (HT) in healthy older women have used conjugated equine estrogens (CEE). In this chapter, Gleason, Wharton, Carlsson, and Asthana review some of the cellular mechanisms by which estrogens are thought to protect the brain from age-related cognitive decline and Alzheimer's disease (AD), and discuss the pros and cons of oral vs. transdermal therapies and of estradiol vs. CEE. Their analysis identifies numerous advantages of transdermal estradiol vs. oral estrogenic therapies, primarily related to effects on liver enzymes, venus thromboembolic events, and inflammatory cytokines. Collectively, the analysis provides compelling arguments in favor of transdermal estradiol as the therapy of choice. Nevertheless, it is clear that the benefits of estradiol vs. CEE have yet to be proven, as has the efficacy of estrogenic therapies (ET) in the prevention of AD. These issues will be addressed in the recently initiated Kronos Early Estrogen Prevention Study (KEEPS) trial and the ancillary KEEPS study of cognitive aging. Details of the trial including its design and primary goals are discussed.
Research over the past 30 years has demonstrated that the brain is an important target organ for estrogen effects. Studies using sensitive autoradiographic and immunohistochemical techniques have documented the presence of estrogen receptors throughout the brain (Brown et al., 1995; Österlund et al., 1998; Pfaff, 1968; Rainbow et al., 1982). The highest levels of receptors are often detected in brain areas involved in gonadal regulation, physiologic homeostasis, and reproductive behavior. Receptors have also been detected throughout the neocortex, hippocampus, and amygdala – regions of the brain long known to be associated with higher cognitive functions such as learning, memory, and attention. Some of the effects of estrogen recently described include changes in neurotransmitter production and release, changes in the number and frequency of synaptic contacts, and changes in the expression and regulation of second messengers and transcription factors, as well as effects on cell survival and growth.
Given the variety of estrogen effects throughout the brain, it is not surprising that estrogen should affect cognitive processes or that the loss of estrogen would play a role in the biology of brain aging in women. Consider that women in the United States reach menopause at approximately 51 years of age, and that the average lifespan for women in the United States is 79 years. This means that approximately 28 years of a woman's life are postmenopausal and reflect a hypoestrogenic state.
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