Women who are fertile for more than 38 years have a higher risk of developing dementia


Women with a longer reproductive period had an elevated risk for dementia in old age, compared with those who were fertile for a shorter period, a population-based study from the University of Gothenburg shows.

“Our results may explain why women have a higher risk of developing dementia and Alzheimer’s disease than men after age 85, and provide further support for the hypothesis that estrogen affect the risk of dementia among women”, says Jenna Najar, a medical doctor and doctoral student at Sahlgrenska Academy who also works at AgeCap, the Centre for Ageing and Health at the University of Gothenburg.

The study, now published in the journal Alzheimer’s & Dementia, covers 1,364 women who were followed between 1968 and 2012 in the population studies collectively known as the “Prospective Population-based Study of Women in Gothenburg” (PPSW) and the “Gothenburg H70 Birth Cohort Studies in Sweden” (the H70 studies).

The “reproduction period” spans the years between menarche (onset of menstruation) and menopause, when menstruation ceases.

Of the women studied with a shorter reproductive period (32.6 years or less), 16 percent (53 of 333 individuals) developed dementia.

In the group of women who were fertile a longer period (38 years or more), 24 percent (88 of 364) developed dementia. The difference was thus 8 percentage points.

The study shows that risk for dementia and Alzheimer’s disease increases successively for every additional year that the woman remains fertile.

The association was strongest for those with dementia onset after age 85, and the effect was most strongly associated with age at menopause.

These results persisted after adjustment for other factors with an influence, such as educational attainment, physical activity, BMI, smoking, and cardiovascular disease.

On the other hand, no association was found between dementia risk and age at menarche, number of pregnancies, duration of breastfeeding, or exogenous estrogen taken in the form of hormonal replacement therapy (HRT) or oral contraceptives.

Several studies have investigated how estrogen in the form of HRT affects dementia risk.

Some studies show that dementia risk falls and others that it rises, especially in women who take estrogen late in life.

In the current study Jenna Najar has, instead, investigated the long-term association between factors related to endogenous estrogen and dementia.

“What’s novel about this study, too, is that we’ve had access to information about several events in a woman’s life that can affect her estrogen levels. Examples are pregnancies, births, and breastfeeding.

Being pregnant boosts estrogen levels tremendously; then they decline once the baby is born, and if women breastfeed the levels fall to extremely low levels. The more indicators we capture, the more reliable our results are,” Najar says.

Ingmar Skoog, professor of psychiatry at Sahlgrenska Academy, University of Gothenburg and head of AgeCap, led the study.

“The varying results for estrogen may be due to it having a protective effect early in life but being potentially harmful once the disease has begun.”

At the same time, Skoog points out that the duration of women’s fertile periods is one risk factor for dementia among many.

Most women whose menopause is delayed do not develop dementia because of this factor alone.

However, the study may provide a clue as to why women are at higher risk than men for dementia after age 85, the most common age of onset. Alzheimer’s disease, on the other hand, starts developing some 20 years before symptoms of the disorder become apparent.

“Most people affected are over 80 and female,” Najar says.

“As a result of global ageing, the number of people affected by dementia will increase. To be able to implement preventive strategies, we need to identify people with an elevated risk of dementia.”

Sexual Steroids and Central Nervous System: Biologic Aspects
During their lifetime women experience dramatic fluctuations in the levels of the sexual hormones estradiol, progesterone and also androgens when going through the different stages of life, from menarche to menopause [1]. These fluctuations have a significant impact on the whole body including the central nervous system (CNS) and can be responsible for modifications in behavior, cognition and mood.

Sex steroids play a role in the brain, on both cortical and sub cortical structures, through genomic and non-genomic paths [2]. Even though most of the evidence in this field relies on non-human studies, several molecular and cellular processes are thought to be involved in determining changes in the structure and function of neural systems through both gene expression modulation and activation of signaling pathways.

Sex steroids are able to modify several functions including behavior, cognition and memory, sleep, mood, pain and coordination, amongst others. They exert their function through receptors both in the nuclei and along the membranes at synapsis, spine and mitochondria.

They have also been found in the glia providing regulation in myelin formation and a potential role in demyelinating diseases.
Steroid hormones active in the CNS are called neurosteroids.

They may be peripherally produced steroids able to cross the blood-brain barrier or synthesized in the central and peripheral nervous system by neurons and glial cells either via de novo synthesis from cholesterol or from local metabolism of intermediate steroids produced in the periphery [3].

Even if levels of steroid hormones in peripheral blood are different from those in the CNS, measurement of their plasma levels is still important for the understanding of their role in CNS activity as they can cross the blood-brain barrier.

Different hormones can provide brain regulation in a sexually specific way: neuroprotective effects of estrogens are more evident in females than males, and androgens seem to be more active in males in the recovery from demyelinating events, while progestogens seem to be more effective in the male in the reduction of apoptosis and abnormal proliferation after a trauma or a stroke [4].

In the CNS there is a wide distribution of estrogen receptors (ERs) localized in areas of the brain involved in memory and executive function. The ER isoform, ERβ, is expressed mostly in the cerebral cortex and hippocampus, whereas ERα signaling is largely represented in magnocellular cholinergic neurons of the basal forebrain [5].

In the basal forebrain and in the hippocampus, estradiol has been demonstrated to be able to induce a trophic effect fundamental for memory and executive functions [6,7]; furthermore, estrogens mediate neurotransmitter interactions in the prefrontal cortex, which is relevant to executive functions [8]. Estrogens are also associated with an increase in dentate gyrus neurogenesis [9].

Estrogens elicit their function involving many neurotransmitter systems, such as acetylcholine, serotonin, noradrenaline and glutamate. In particular, the cholinergic neurotransmitter system is relevant in memory processes [10]. The method by which estrogen exerts its action on the brain includes neurotrophic and neuroprotective actions specifically, enhancing synaptic plasticity, neurite growth and hippocampal neurogenesis and protecting against neural injury and apoptosis [11].

Furthermore, estrogen seems to improve mitochondrial function, enhancing adenosine triphosphate (ATP) production and mitochondrial respiration, which is very important in a site with high energy requirements such as the brain [12].

Other types of estrogen action in the brain are DNA repair and promotion of an antioxidant effect [13,14].

Estrogen has also been associated with increased C-reactive protein levels (an inflammatory marker), which has been linked to impaired cognitive function.
Similar to estrogen, progesterone is also a potent regulator of neurogenesis, cell survival and bioenergetic systems. They do not have synergistic action and their co-administration leads to a lower response than with the administration of a single compound [15,16].

Progesterone acts both through the classical pathway binding to its receptors (PRα and PRβ) and regulating gene transcription and, together with allopregnanolone and dihydroprogesterone (DHP), through the non-classical pathway activating different signaling cascades and the transcription of various genes.

The main effects of the two pathways are the promotion of anti-apoptotic and cell survival effects, bioenergetic regulation and a significant effect on neural cell proliferation [15].

Progesterone also exerts its action on glial cells mainly promoting oligodendrocyte proliferation and action [17,18].

Oligodendrocytes can produce progesterone and transform progesterone from the bloodstream into DHP and allopregnanolone, which regulates myelination and modulates gamma-aminobutyric acid (GABA-A) receptors [18] Progesterone, and especially allopregnanolone, is able to promote the GABAergic system inhibiting synaptic transmission, producing what is believed to be an anti-anxiety effect similar to that of benzodiazepines [19–21].

In humans, decreased levels of allopregnanolone are linked with depression and antidepressant drugs are able to determine and increase this metabolite [22].

The GABAergic role of progesterone in the hippocampus explains why exogenous administration of progestins has a negative impact on the cognitive performance of healthy women in working memory tests [23].

Progesterone and allopregnanolone are able to influence the dopaminergic systems with an observed improvement in motor sensory functions during the phases of the menstrual cycle when progesterone is higher [22].

The positive modulation of allopregnanolone on the release of dopamine can also have a possible effect on drug abuse and depression [24].
The brain is also able to locally produce the androgen dihydrotestosterone independently of the gonads [25]. Androgens in the animal model have been demonstrated to be able to induce neurogenesis and spine synapses in the hippocampus.

Moreover, like estrogens, androgens have neuroprotective effects. Considering the relationship between androgens and neurotransmitters, although there are fewer studies, it seems that testosterone in particular may increase serotonergic tone (also through its conversion to estradiol) and the effect of noradrenergic anti-depressants agents.

Even though much still remains to be understood, dehydroepiandrosterone (DHEA) appears to have antioxidant, neuroprotective and anti-glucocorticoid effects [26]. Through these mechanisms it can reduce anxiety and improve cognitive deficits and psychotic and depressive symptoms.

The Influence of Menopausal Transition and Menopause Hormone Therapy on Cognition

Menopausal Transition and Cognition
During menopausal transition many women complain of memory problems such as difficulty with words, forgetfulness and “brain fog” [27], thus suggesting that hormonal changes related to menopause may be responsible for changes in cognition. Elderly women also appear to be at greater risk than men for age-related dementia suggesting sex differences that are not fully explained by longevity [28].

However, in a recent cross-sectional study, women in their early midlife demonstrated better performance in detailed memory tasks when compared to age-matched men [29]. These sex differences were attenuated in the post-menopausal years. In the study by Rents et al., higher plasmatic estradiol levels were associated with better performance.

Another study previously reported lower cognitive impairment associated with higher levels of estradiol in women already reporting cognitive decline [30]. Other studies did not demonstrate any relationship between cognition and cognitive problems and estrogens levels [31].

Longitudinal data considering the impact of menopausal transition on memory and cognitive function are scarce. Two longitudinal studies reported subtle decrements in cognitive function: the Kinmen Women-Health Investigation (KIWI) did not evidence significant cognitive decline, with the exception of verbal fluency, in an 18-month follow-up of pre-menopausal women [32].

The Study of Women’s Health Across the Nation (SWAN) reported an impairment of cognitive performance mostly in learning abilities during menopause transition, with subsequent improvement to pre-menopausal levels in the post-menopausal period [33].

The SWAN study has been ongoing since 1996, observing 3302 women throughout the whole menopausal transition (https://www.swanstudy.org/); in the next few years we believe that this study will provide a unique insight into the long-term effects of hormonal changes in middle-aged women.

It should be noted that not only events occurring during menopausal transition but also lifelong hormonal processes seem to be significant for cognition. A recent observational study of 1315 women showed that a longer fertile period (later age at natural or surgical menopause) was associated with better verbal memory [34].

On the other hand, in another observational study of 3602 women, a longer fertile period was not associated with a reduced risk of dementia [35].

Menopause Hormone Therapy and Cognition

In Women without Dementia
Despite medical literature which highlight the deep connection between estrogen and cognitive function, data regarding the relationship between menopause hormone therapy (MHT) and its neuroprotective outcomes remains conflicting.

Although several observational studies have demonstrated a positive effect of hormone therapy on Alzheimer’s disease (AD) [36–40], MHT being associated with a 29% reduction in AD in the meta-analyses of observational studies [41], large clinical trials such as the Women’s Health Initiative (WHI) and Women’s Health Initiative Memory Study (WHIMS) did not support those findings [11].

WHIMS was a randomized, placebo-controlled clinical trial, and the first large, long-term study to address the cognitive effects of MHT (0.625 mg of conjugated equine estrogen (CEE) plus 2.5 mg of medroxyprogesterone acetate) in the prevention of AD, in 4532 post-menopausal women (over 65 years of age) enrolled in the larger WHI study. Results showed that after a mean follow-up of 4.2 years,

MHT failed to reduce general cognitive decline and was associated with a substantially and clinically important increased decline in Modified Mini-Mental State Examination (MMSE) total scores when compared with placebo [42].
Subsequent analysis of 2947 WHIMS estrogen-alone treated women (aged 65-79) showed that mean MMSE scores were significantly lower in the estrogen group compared with placebo. The adverse effect of estrogens was more pronounced in women with lower cognitive function at baseline [43].

In the analysis of data from the Nurses’ Health Study, a prospective cohort of over 13,807 women aged 70 to 81, little difference was found in cognitive decline between current hormone users and those that had never used them. Long-term users (at least 5-10 years of use) of estrogen or estro-progestin showed an increased risk of substantial decline in most cognitive tests. The impairment was more evident in women starting hormones at an advanced age [44].

Subsequent analysis showed that MHT users with apolipoprotein E (APOE) E4 allele presented worse cognitive impairment [45].
In 2008, a meta-analysis of clinical trials investigating MHT (estrogen or estrogen-progestin therapy) in post-menopausal women (over 60 years of age) concluded that MHT does not protect against cognitive function decline in normal women [46].

It should be observed that studies involving older women (the WHIMS was over 65 years of age) did not consider the so called “timing hypothesis”. In fact, further studies, similar to the cardiovascular risk, have suggested that estrogen can be neuroprotective only if commenced shortly after the onset of menopause [47,48].

Sustaining the “critical window hypothesis”, some epidemiologic studies have suggested that MHT in early post menopause is linked with a lower risk of dementia, whereas its later use is not [38,39,49,50].

Data from the Cache County Study revealed that women using MHT had a reduced risk of AD compared with non-MHT users only if treatment was started soon after menopause (within five years) [38,39]. Similarly, Whitmer et al. showed that among 5504 post-menopausal women, MHT in midlife was associated with a protective effect against cognitive impairment whereas starting MHT later in life could have a negative effect [49].

Other studies did not confirm that MHT use close to the time of menopause was clearly associated to better cognitive performance later in life or to a reduced risk of dementia [51,52].

There have also been other limited clinical trials regarding early MHT and cognitive performance later in life. The WHIMS-Young (WHIMSY) study examined 326 post-menopausal women between 50 to 55 years of age randomized for MHT (CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years) or placebo.

CEE based therapies produced no overall sustained benefit or risk to cognitive function when administered to post-menopausal women aged 50 to 55 years. Cognitive evaluation performed up to 67 years of age did not show sustained benefits of MHT over placebo [53]. Even though they do not support the theory of cognitive improvement in MHT users, these studies provide reassurance that hormone therapy does not adversely influence cognition in young post-menopausal women.

In Women with Dementia
Cognitive decline and dementia are a growing public health problem. The inability to recall information, defined as impaired episodic memory, is a potentially alarming symptom of the very early signs of AD or other forms of dementia.

AD is the most common cause of dementia and emerges more frequently in women than in men, with some authors hinting at sex-specific differences in the incidence of AD [54]. This condition is characterized by a progressive loss of episodic memory and cognitive function, subsequently causing language and visuospatial impairment, which are often accompanied by behavioral disorders such as apathy, aggressiveness and depression.

Considering the significance of this disease, research in this field has attracted considerable scientific and public interest. The role of estrogen has been assessed not only in the maintenance of cognitive function in non-demented women but also in the prevention and/or treatment of AD.

In vivo and in vitro preliminary data suggest that estrogen may play a role in the prevention of amyloid deposition. Estradiol has been shown to attenuate tau hyperphosphorylation [55] and deposition of amyloid b [56] and has also been shown to improve the inflammatory sequelae of amyloid b [57].

In the Cache County Study, a prospective study of incident dementia among 1357 men (mean age 73.2 years) and 1889 women (mean age 74.5 years), women using MHT had a reduced risk of AD when compared with non-MHT users (adjusted HR 0.59), whereas there were no apparent benefits with current MHT use unless they had been used for in excess of 10 years [38].

Other large epidemiologic studies have addressed the role of exogenous estrogens and the risk of dementia. In 2001, the first meta-analysis of these observational studies reported a reduced risk of dementia in MHT users, even with some methodological limits of the studies [58], whereas subsequent meta-analysis of prospective studies failed to show any association between MHT and all-cause dementia and AD [59].

Recently, the Kronos Early Estrogen Prevention Study (KEEPS) showed that transdermal 17-beta estradiol therapy was linked to a decrease in amyloid-beta deposition on neuroimaging studies, particularly in apolipoprotein E (APOE) E4 carriers [60].

More recently, data provided by Savolainen-Peltonen et al. showed that systemic hormone therapy users have a higher risk of AD when compared to vaginal estradiol users and that long term use of systemic hormone therapy could be burdened by a globally increased risk of AD, independent from the age at initiation of systemic hormone therapy [54].

The risk of AD was similar between estradiol-only users and oestrogen-progestogen users, and in oestrogen-progestogen users, the risk was not associated to specific progestogens (norethisterone acetate, medroxyprogesterone acetate, or other progestogens).

It should be noted that for shorter treatment the risk of AD was not increased among those who had commenced either estrogen therapy or estrogen plus progestin therapy before the age of 60.

Several small randomized clinical trials have considered the possibility of the treatment of women with Alzheimer’s with estrogen. In the largest study of 120 women, estrogen administration for one year (conjugated equine estrogens 0.625 mg or 1.25 mg vs placebo) did not slow progression of the disease nor did it improve global, cognitive or functional outcomes [61]. Subsequent meta-analysis of seven trials in reported similar results [62].

We believe that those studies should not modify our current clinical practice and decision making regarding MHT. In fact, even if some observational studies had inconsistent and mixed results, it should be remembered that several randomized clinical trials supported the safety profile of MHT on cognition in early menopause.

Overall, young menopausal women without contraindication to MHT and with impaired quality of life because of night sweats, vasomotor symptoms or disrupted sleep can benefit from MHT with several studies providing reassurance that MHT does not adversely affect cognition in these women.

On the counterpart, it should be noted that, consistently with guidelines, MHT should not be prescribed with the sole purpose of AD or memory loss prevention in women without these symptoms or in those not willing to start hormonal treatment.
Despite the amount of data already available on this topic, future research should focus on long-term risks of MHT on cognition and AD and on the different effects on cognitive outcomes of various type of molecules.

During menopausal transition women experience dramatic fluctuations in the levels of the sexual hormones estradiol, progesterone and also androgens, which are potentially responsible for modifications in behavior, cognition, mood and sleep.

The following short summary provides key concepts regarding MHT in menopause and perimenopause:
• Cognitive function and cognitive disorders: despite the deep connection between estrogen and cognition, data regarding the relationship between hormone replacement therapy and the neuroprotective outcomes still remain conflicting. Several studies have excluded any cognitive benefits of estrogen or combined estrogen-progestin therapy in women over the age of 65 without underlying dementia. Young menopausal women without contraindication to MHT and with impaired quality of life because of night sweats, vasomotor symptoms or disrupted sleep can benefit from MHT, and in several studies, MHT does not adversely affect cognition in these women.
• Sleep disturbances: the etiology of menopausal sleep disorder is not fully understood, but MHT can play a role enhancing sleep quality. MHT can improve sleep, reducing night sweats, but it can also act through other mechanisms, as disturbed sleep during perimenopause can occur independently of hot flashes. Further research is needed to determine if self-reported sleep quality in menopause is affected by different molecules, formulations and routes of administration of MHT. For example, the GABAergic sedating effects of progesterone should be considered in women with sleep issues.
• Mood and depressive symptoms: even though some data support a potential beneficial effect of MHT on mood, it should not be proposed to non-depressed peri-menopausal women to prevent mood symptoms. Estrogens can be considered in menopausal women with other concurrent conditions such as vasomotor symptoms as they may increase the response to anti-depressants.

reference link : https://www.mdpi.com/1010-660X/55/10/668/pdf

University of Gothenburg


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