Estrogen has a significant role in overall brain health and cognitive function.
That’s why so many studies focused on the prevention of cognitive decline consider the effect of reduced estrogen levels during the menopause transition.
A new study suggests a cognitive benefit from a longer reproductive window complemented with hormone therapy.
Study results are published online today in Menopause.
Because women comprise two-thirds of the 5.5 million cases of Alzheimer’s disease in the United States, researchers have long suspected that sex-specific factors such as estrogen may contribute to women’s increased risk for the disease.
Multiple studies have previously suggested a role for estrogen in promoting memory and learning.
In this newest study involving more than 2,000 postmenopausal women, researchers followed participants over a 12-year period to examine the association between estrogen and cognitive decline.
More specifically, they focused on the duration of a woman’s exposure to estrogen, taking into account such factors as time of menarche to menopause, number of pregnancies, duration of breastfeeding, and use of hormone therapy.
The researchers concluded that a longer duration of estrogen exposure is associated with better cognitive status in older adult women.
The researchers concluded that a longer duration of estrogen exposure is associated with better cognitive status in older adult women.
Furthermore, they documented that these beneficial effects are extended with the use of hormone therapy, especially in the oldest women in the sample.
Women who initiated hormone therapy earlier showed higher cognitive test scores than those who started taking hormones later, providing some support for the critical window hypothesis of hormone therapy.
Study results appear in the article “Lifetime estrogen exposure and cognition in late life: The Cache County Study.”
“Although the assessment of the risk-to-benefit balance of hormone therapy use is complicated and must be individualized, this study provides additional evidence for beneficial cognitive effects of hormone therapy, particularly when initiated early after menopause.
This study also underscores the potential adverse effects of early estrogen deprivation on cognitive health in the setting of premature or early menopause without adequate estrogen replacement,” says Dr. Stephanie Faubion, NAMS medical director.
In addition to the known effects of estrogen in regulating reproductive function and bone metabolism, studies suggest that estrogen plays a role in enhancing cognitive performance1–3. Women with Turner syndrome and postmenopausal women, who are characterized by estrogen-deficiency, have cognitive deficits including altered memory and executive control, suggesting a role for estrogen in enhancing cognitive skills4–8. Similarly, use of aromatase inhibitors in breast cancer treatment to block estrogen production has been linked to impaired verbal memory (VM) and reduced information processing speed9, 10.
Brain-derived neurotrophic factor (BDNF), a nerve growth factor produced predominantly in the hippocampus, which represents the prime neural correlate of learning and memory14.
The promoter of the BDNF gene harbors an estrogen response element15, suggesting that BDNF may mediate estrogen effects on cognitive function.
Additionally, exercise increases BDNF expression, but this effect is evident in ovariectomized rats only after estrogen replacement13.
Another postulated mechanism for estrogen is via catecholamine and cholinergic pathways in the prefrontal cortex (PFC)16.
This region is important for mediating executive control, the processes that top-down regulate information processing to ensure goal achievement17.
While exercise has a positive impact on cognition22, excessive exercise can lead to low energy availability and inhibition of the hypothalamic-pituitary-gonadal axis, leading to estrogen deficiency and menstrual dysfunction (which occurs in up to 44% of female athletes23).
Although the impact of estrogen deficiency on bone has been widely studied in oligo-amenorrheic athletes (OA), its effect on cognitive domains remains to be investigated.
Further, female athletes comprise a distinctive population in that the negative impact of estrogen deficiency on cognitive performance may be counteracted by the beneficial effects of physical activity22.
Estrogen replacement in OA athletes may serve as a physiological probe to investigate the cognitive domains that may be altered in these athletes who have estrogen deficiency.
Of importance, the PFC matures through the second decade of life resulting in ongoing development of executive control during this period26.
Thus, factors affecting cognitive development during the critical teenage/young adult years of neurobehavioral development merit careful investigation.
Our primary objective was to determine whether estrogen replacement for six months could improve cognitive measures of VM and executive control in adolescent and young adult OA (irrespective of route of administration or form).
Our secondary objective was to determine whether a more physiologic form of estrogen administration, transdermal estrogen, would be more effective than oral estrogen in improving these cognitive outcomes. We hypothesized that OA randomized to estrogen replacement for six months would perform better on tasks evaluating VM and executive control compared to those randomized to no estrogen.
Further, we hypothesized that transdermal estrogen will perform better than oral estrogen for these cognitive measures.
While studies have examined the effect of estrogen replacement on cognition in other estrogen-deficient states such as postmenopausal women and women with Turner’s syndrome, OA have not been examined for cognitive deficits with respect to their estrogen status.
Our study is the first to assess the impact of estrogen replacement on cognitive measures in young female OA. Estrogen replacement is not the standard of care for athletes with functional hypothalamic amenorrhea33.
In fact, estrogen replacement is not advised until athletes fail to respond to non-pharmacological therapy for at least one year or until they develop significant fractures with low bone density33.
In our study we used estrogen as a physiological probe to investigate the cognitive domains that may be altered in athletes who have estrogen deficiency. We show that immediate free recall, a VM measure, improved significantly following estrogen replacement in OA compared to no treatment.
Female athletes in a state of relative energy deficit may develop hypothalamic amenorrhea from suppression of GnRH pulsatility subsequent to changes in hormones such as ghrelin, leptin, and cortisol34–36.
The consequence of estrogen replacement on cognitive performance of OA (who have the mitigating influence of exercise activity) has never been studied.
Additionally, a study in adult women with adolescent onset anorexia nervosa, another model of hypothalamic amenorrhea, has reported cognitive dysfunction, which improves with menstrual recovery or oral estrogen replacement, but not with weight recovery alone37.
Similar to this study, we demonstrate that athletes with hypothalamic amenorrhea have improved immediate free recall after six months of estrogen replacement compared to no treatment.
The major setback to estrogen replacement came from the NIH-initiated Women’s Health Initiative study in postmenopausal women that showed no improvement in global cognitive decline with conjugated equine estrogen administration.
Furthermore, in women >65 years, cognitive function worsened with estrogen replacement38, 39. In retrospect, the age of the participants and use of conjugated equine estrogen compared to natural estrogens such as 17-beta-estradiol used in more recent trials40 were thought to have impacted study results. With more promising results from recent studies40–42 estrogen has re-emerged as a potential positive modulator of cognitive function.
Our findings are consistent with the cognition-enhancing effects of estrogen demonstrated previously in animal and human models of estrogen deficiency. Ovariectomized rats treated with estradiol made more correct choices in the water maze test, suggesting that estrogen has a protective effect of working memory1, 11, 12.
In our analysis, VM, assessed by the CVLT-II, improved for immediate-recall scores (Trial-1 and Trial-B) after six months of estrogen replacement, even after controlling for baseline scores. Girls with Turner syndrome (similar to our population for age and estrogen-deficiency) have decreased intelligence and deficits in executive function, non-verbal memory and attention; but verbal performance is preserved4, 6.
It is unclear whether these deficits in Turner’s syndrome are consequent to the underlying genetic defect or estrogen-deficiency. However, estrogen replacement in these subjects results in improved motor speed of non-verbal processing2, 43. Of note, in our study, intelligence did not differ across treatment groups and cannot account for observed changes in memory and executive control following estrogen replacement.
In an older population, women aged 49–68 years who received 17-beta-estradiol treatment for a year demonstrated an improvement in VM40. Despite multiple positive studies3, 40–42 supporting the role of estrogen in augmenting VM, one study in 200 postmenopausal women randomized to testosterone, estrogen, or placebo found no effects of estrogen replacement on this cognitive measure44.
However, the very short duration of estrogen replacement in this study (just 4 weeks) may have resulted in these negative findings. In fact, Luine et al showed in a rodent study that only chronic estrogen replacement (3d vs. 12d) leads to improved performance in the radial maze test with a higher number of correct choices, indicating that duration of treatment may impact the cognitive effects of estrogen12.
In our study, we evaluated cognitive outcomes after six months (thus a longer duration) of estrogen replacement than in the study by Kocoska et al44. Of note, studies such as those by Asthana et al and Berent-Spillson et al have been able to demonstrate significant improvements in cognition in humans with estrogen replacement for a duration of 8 weeks and 3 months respectively3, 41.
While our data are consistent with animal studies, it is still not clear why effects are evident only after chronic use. Future studies may be necessary to determine the shortest duration of estrogen therapy that will result in changes in cognitive tests.
Another finding that merits discussion is the improvement in executive control (assessed by the inhibition-switching completion time) following estrogen replacement. Although the EST+ group performed better for inhibition-switching completion times and inhibition-switching error, this was not statistically significant even after controlling for baseline performance. Nevertheless, when adjusted for age the inhibition-switching completion time was shortened in the EST+ group. The small number of subjects in the groups and missing entries for the inhibition-switching task might have contributed to this lack of significance. Although, it is well recognized that VM is the single most common domain altered with hormonal replacement20, our study opens an interesting area of executive control to be explored in future studies. Consistent with our results, ovariectomized monkeys treated with estrogen performed better on learning to shift to a new cognitive set in the Wisconsin Card Sort Task, a measure of the cognitive flexibility feature of executive control45. Furthermore, Colzato et al demonstrated that the inhibition of return effect, which reflects the ability to delay attention from returning to a previously attended location, hence a measure of cognitive flexibility, was high in the late follicular phase in women, when estradiol levels are higher compared with luteal and menstrual phases46.
Variables known to affect results of estrogen replacement in previous studies in post-menopausal women were the type of estrogen used, timing of initiation of estrogen replacement after menopause, and duration of estrogen replacement. Studies that used 17-beta-estradiol reported better results than those using conjugated equine estrogen20, 40.
Further, the longer the duration of estrogen deficiency, the less was the response of neural tissues to estrogen replacement47–49. Our study provided estrogen replacement for a period of six months, a reasonable duration to demonstrate significant effects41, 50.
We used oral ethinyl estradiol with progesterone, or the 17-beta-estradiol transdermal patch along with progesterone to reproduce a more physiologic form of estrogen replacement.
For immediate recall and cognitive flexibility, subjects randomized to transdermal estradiol performed better than those who received no treatment after controlling for baseline scores and age.
These associations merit further investigation in a larger group of subjects. Of note, a study conducted in 9 academic centers across the US on 693 postmenopausal women using transdermal estradiol (n=211) did not show significant changes for VM (using CVLT-II) and executive control (using a Stroop color interference test) when compared with oral conjugated estradiol or placebo21.
Of note, the two modes of estrogen administration utilized different estrogen molecules. Although we attempted to minimize the difference by providing similar dose equivalents of estrogen (100 mcg of estradiol patch ~ 30 mcg of ethinyl estradiol), oral contraceptives typically have ethinyl estradiol, a synthetically derived estrogen, whereas, 17-beta estradiol used in the patch is the physiological form of estrogen.
The 30 mcg of ethinyl estradiol used in our study in the oral estrogen arm is the most common form of estrogen used in oral contraceptives, and the study was designed to use an oral estrogen preparation that is commonly use in adolescents and young adults and is also commonly prescribed by practitioners to regulate menstrual cycles in athletes51. However, there could be differences stemming from the variation in the type of estrogen molecule as well as the route of administration.
Further, for this study, we used a monophasic estrogen preparation (that does not mimic estrogen changes across a menstrual cycle), and future studies are necessary to determine whether the use of a biphasic or triphasic estrogen preparation that more closely mimics cyclic changes in estrogen levels across a menstrual cycle results in a different outcome.
Although our sample size is not large, it compares well with other studies such as that of Asthana et al, which reported a significant improvement in verbal memory in 12 postmenopausal women following estrogen replacement3.
A limitation of the study is that we do not have data for the total duration of estrogen deficiency, because athletes may have periods of amenorrhea interspersed with periods of oligo-amenorrhea or eumenorrhea depending on the training season and kind of athletic activity. Also, it was difficult to accurately assess the degree of adherence to study medications given that ethinyl estradiol (in oral pills) cannot be assessed with standard assays. However, we did use tools such as a medication calendar and returned pill packs and backings of patches to determine adherence.
Although subjects with active anorexia nervosa were excluded, subjects with a past history of anorexia nervosa or active bulimia were not excluded and we acknowledge this as a study limitation. Further, the impact on cognitive function of local estrogen produced in the brain versus estrogen produced in the ovaries remains unclear.
Estradiol is known to cross the blood-brain barrier52, and changes in systemic estradiol levels (as observed in post-menopausal women and hypogonadal conditions such as Turner syndrome known to impact cognition) may alter local estradiol production in the brain through their effect on GnRH neurons53.
Studies are needed to delineate the effects of peripheral versus locally produced estradiol on cognitive indices, and to also assess the impact of gonadal steroids on mood outcomes, as changes in mood can affect cognitive indices54.
Data regarding effects of estrogen on cognition and memory in humans have thus far been inconclusive and are lacking in adolescents and young adults with estrogen deficiency, except for a few studies in Turner’s syndrome.
Our investigation supports the cognition-enhancing role of estrogens in another population that presents with estrogen deficiency early in life.
In this study, we have used exogenous estrogen as a physiologic probe rather than as a treatment strategy. Importantly, our data provide the first clue that estrogen replacement may improve cognitive function in oligoamenorrheic athletes. However, further studies exploring the differences in cognitive indices following estrogen replacement in athletes, particularly focusing on verbal memory and executive control, are warranted.
Eileen Petridis – NAMS
The image is in the public domain.
Original Research: Closed access
“Lifetime estrogen exposure and cognition in late life: The Cache County Study”. Matyi, Joshua M.; Rattinger, Gail B.; Schwartz, Sarah; Buhusi, Mona; Tschanz, JoAnn T..