CNPRC Incoming Director John Morrison is expanding our understanding of how estrogen affects cognitive functioning and synaptic health

The good, the bad and the ugly. Estrogen; such a familiar hormone, and such a large influence on everyone’s health, female or male, young or old. With an abundance of estrogen during women’s reproductive years, it is an invaluable component in reproductive, bone, and neurological health, but is also responsible for roller coaster emotions, insomnia, depression, anxiety, premenstrual syndrome, postpartum depression and headaches. With aging, and the associated decrease of estrogen throughout the body, women cope with hot flashes, cognitive decline, digestive problems, and bone fragility. For aging men, unbalanced estrogen levels increase the risk of stroke, coronary artery disease, and prostate enlargement or prostate cancer.

Estrogen, aging and synaptic health. Significantly expanding our understanding of how estrogen affects neuronal health during aging, Dr. John Morrison, CNPRC Incoming Director, focuses his research on the effects that estrogen has on the health and protection of neuronal synapses in the brain, the impact of prolonged postmenopausal low-estrogen states on learning and memory processes, and new therapeutic strategies to facilitate successful aging (e.g., having a low probability of disease), high cognitive and physical abilities, and active engagement in life. Taking into account that changes in the aging nervous system are subtle, he is hopeful that they can be reversed and cognitive performance may be improved by pharmacological treatments.

Longer female life expectancy has meant that women now live a third of their lives beyond the end of their ovarian function, with 150,000 American women entering menopause each month. Many women will have decades of healthy living after menopause, highlighting the importance of this research in understanding the increased vulnerability of aging women to cognitive decline and potentially, a greater susceptibility to neurodegenerative diseases, such as Alzheimer’s disease.

Throughout a woman’s lifetime, estrogen facilitates cognitive function through its effects on synapse structure and function. With aging, estrogen loss through menopause exacerbates the effects of aging on cognitive function, and is compounded by the alteration of estrogen receptors. Cognitive decline during aging is observed in memory abilities (e.g., verbal memory, attention, visual perception and verbal fluency), focusing attention efficiently, and speed of information processing.

Dr. Morrison, with colleagues Hara, Waters and McEwen, recently published an extensive review that highlights a new understanding of how estrogen affects higher cognitive functions and synaptic health, with studies in nonhuman primates, mice and humans (Hara Y, Waters EM, McEwen BS, Morrison JH. Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiol Rev. 2015 Jul;95(3):785-807. PMCID: PMC4491541).

Among the many functions estrogen has on the brain, estrogen also improves cerebral metabolic rate and blood flow, and exerts many antioxidant effects. The antioxidant effects of estrogen are noteworthy in light of strong evidence that mitochondrial dysfunction and damage accrued from oxidative stress precede, and may be causative for, neurodegenerative disorders such as Alzheimer’s disease.

At the CNPRC, a large colony of aged rhesus macaques live well past their normal lifespan, reaching their mid-30s (wild rhesus monkeys generally live to around 19 years of age). Excellent health care and nutrition, and aging in place with their extended families, results in good health and longevity, providing researchers with opportunities to understand the aging process in primates. The aged colony at the CNPRC is supported by the National Institutes of Aging, NIH.

Numerous long-term studies have confirmed that the distribution patterns of estrogen receptors and production in rhesus monkeys are similar to what is observed in humans, mimicking natural estrogen cycles. Studies in nonhuman primates also show that, similar to humans, both age and menopause are related to cognitive decline, which is highly relevant for developing interventions for post-menopausal women.

In addition to changes affecting cognitive decline, it is possible that the change in neuronal functioning from low estrogen levels renders neurons more vulnerable to degradation in neurodegenerative diseases such as Alzheimer’s disease (AD). Research over the past decade has led to a growing appreciation that the role that estrogen plays relevant to the influence of nerves on the nutrition of tissues and protection of neurons during adulthood.

There is considerable evidence suggesting that the use of estrogen therapies during the menopause and postmenopausal periods may decrease the risk of AD and other neurologic disorders, though the clinical data are inconsistent and this remains controversial. In addition, other hormones are altered with age and menopause as well (e.g., adrenal steroids) and these changes may contribute to functional decline as well. Nevertheless, the efficacy of estrogen requires that we take into account the most recent data on hormone neurobiology, in order to administer the hormone at the right time, with the right formulation and to the appropriate population of women.

Estrogen therapies to nurture and protect aging neurons. The attempt to delay or prevent the cognitive impairment occurring with aging is an important goal to protect the quality of life for women during the latter third of their lifespan. During the past two decades, researchers have tried to verify if the administration of estrogen to women at the beginning of, or during, menopause would protect against cognitive impairments that normally take place with increasing age.

Although it is not known with certainty why estrogen therapies do not protect cognitive functions and may even cause harm when administered to women over the age of 65 years, it is possible that the modifications characterizing brain aging, such as a reduction in brain volume and in neuronal size, alterations in neurotransmitter systems, and a decrease in the number of dendritic spines, form an adverse background that prevents the neuroprotective effects of exogenous estrogen on the brain. Other factors that have probably contributed to the inconsistencies of the estrogen–cognition literature include differences in the estrogen form utilized, route of administration, cyclic versus continuous regimens, whether progestins were administered concomitantly, and failure to account for age-related alterations in hormones other than estrogen.

To understand the variables and determine the safest and most effective treatment for aging women, Dr. Morrison turns to his work with the rhesus monkeys at the CNPRC. Nonhuman primate models have been shown to closely recapitulate clinically relevant hormone treatments in humans, demonstrating the efficacy, safety and unexpected side effects of hormone replacement therapies. Using a cohort of young and aged ovariectomized female monkeys the effects of estrogen were experimentally tested on pyramidal neurons (neurons found in the cerebral cortex, the hippocampus, and the amygdala, and the primary excitatory neurons in the mammalian brain).

In promising results, Dr. Morrison showed that in aged ovariectomized female monkeys, a cyclic estrogen hormone replacement therapy that closely mimics the natural fluctuations of estrogen in premenopausal monkeys, reverses age-related impairment in working memory, restoring cognitive function. Estrogen replacement also improved executive functions in middle-aged ovariectomized monkeys.

Nonhuman primate models mimicking clinically relevant hormone treatments In contrast to the cyclic estrogen regimen that produced procognitive effects in rhesus monkeys, the hormone replacement therapy used in women in a Women’s Health Initiative Memory Study trial consisted of estrogenic compounds combined with a progestin, in a daily regimen. Therefore, hormone treatments modeled after those used in clinical settings were tested in aged ovariectomized monkeys.

Treatments that included daily estrogen, daily estrogen with cyclic or continuous progesterone, or cyclic estrogen with cyclic progesterone, all failed to improve reliant working memory in aged ovariectomized monkeys. Young ovariectomized monkeys also showed parallel results; continuous estrogen with or without progesterone resulted in neuronal spine density and morphology that were indistinguishable from those receiving a control vehicle alone.

Together, these studies suggest that the specific formulation of hormones (estrogen alone versus a combination of estrogen and progesterone) and the treatment schedule (daily versus cyclic) are both key factors for estrogen to exert its positive effects on cognitive and synaptic health. These studies provide evidence that the standard forms of hormone replacement therapy commonly prescribed to women may not provide the same cognitive and synaptic benefits as formulations that mimic the natural menstrual cycle.

Further research for improved health. Among the many functions estrogen has on the brain, estrogen also improves cerebral metabolic rate and blood flow, and exerts many antioxidant effects. The antioxidant effects of estrogen are noteworthy in light of strong evidence that mitochondrial dysfunction and damage accrued from oxidative stress precede, and may be causative for, neurodegenerative disorders such as Alzheimer’s disease.

While it seems clear that a decline in circulating estrogen can affect brain regions and the cognitive processes they mediate, such effects are highly variable in women and we do not know the source of such variability. The hormone treatments that have been used thus far for women have concentrated largely on circulating estrogen and progesterone levels rather than on receptor dynamics, synaptic regulation and downstream effect of changes that result from changes in circulating estrogen.  The focus of new studies must be expanded to include these possible variables  if we are to develop more successful treatments. It is possible that the indirect effects of estrogens in terms of other hormonal changes may provide a deeper understanding of the relationship between aging and synaptic health.

In summary, the researchers note a need for a “more detailed appreciation of the signaling cascades activated by estrogen, the distinct role of classical and nonclassical actions for each receptor, and age- and menopause-related alterations of such processes which will be required to develop interventions for menopausal women that are both more effective and more easily tailored to individual variations”.