Exploring estrogen’s effects on the brain
By: Natalie Osborne
In biology class you probably learned that estrogen is responsible for developing secondary sexual characteristics and regulating the menstrual cycle. But did you know that it also plays a key role in brain health and cognition? Understanding exactly how estrogen influences brain function could help researchers better understand disparities in brain diseases and mental health, such as why women are two to three times more likely to get Alzheimer’s disease than men1.
Investigating the effects that hormones have on the brain is one of Dr. Gillian Einstein’s many specialties. Professor in the Department of Psychology, IMS member, and founder of the University of Toronto’s Collaborative Specialization in Women’s Health, Dr. Einstein is a trailblazing expert on women’s brain health and cognition. Her lab combines structural and functional brain imaging with neurocognitive and qualitative assessments to investigate how attributes like age, sex, gender, and hormones influence cognition. And the hormone they’re particularly interested in is estrogen.
Or more correctly, estrogens—a family of hormones including 17-beta estradiol, estrone and estriol. They are expressed in different quantities at different times throughout a woman’s life, with 17-beta estradiol being the most prominent until menopause.
Estrogen receptors can be found throughout the brains of both women and men. Two areas where they are particularly abundant are the hippocampus (a structure that’s integral for memory) and the prefrontal cortex, which is important for executive functions such as planning and decision-making. When estrogens bind to these receptors they can act like a growth factor, promoting the generation of new neurons and the sprouting of dendritic spines (the tiny branches that help neurons to communicate and make connections with each other). Estrogens can also influence the release of neurotransmitters, such as dopamine and serotonin, and even up- or down-regulate the expression of certain genes. But what does this mean for brain function?
“The effects of estrogens on synapses and the growth of synaptic connections is a form of brain plasticity—it is through this plasticity that circuits for learning and memory are established,” explains Dr. Einstein. “So, in the field of aging and dementia research, ultimately the loss of estrogen is linked with the loss of the ability of certain neurons to make new connections.”
A woman’s estrogen levels fluctuate across the menstrual cycle, as can her performance on certain cognitive tasks. One example is mental rotation, the ability to recognize a 3D object that has been rotated from its previous position. Men typically outperform women on these tasks. However, Dr. Einstein’s lab found this to be true only when women were tested in the luteal phase of their cycle, when estrogen levels are relatively high. When tested in the follicular phase (characterized by lower 17-beta estradiol), women performed equally to men.
Much of what we know about estrogens’ role in the brain comes from animal studies, where researchers can directly manipulate the location and concentration of estrogens and observe how they affect cognitive abilities such as spatial navigation and memory. Studying estrogens’ effects on cognition in humans is a bit trickier. Therefore, Dr. Einstein and her lab look for opportunities where women’s estrogen levels are naturally or medically altered.
One example is oral contraceptives, or “the pill”, used by over 100 million women worldwide. The pill’s exogenous supply of synthetic estrogen and/or progesterone hormones suppresses the monthly fluctuations of their endogenous counterparts. Some studies have examined the pill’s effects on mood, particularly its link to increased depression. But very few have considered how it may be influencing cognition.
Einstein lab member Laura Gravelsins began addressing this serious knowledge gap in her Masters project. She asked whether the pill affects short term memory—the ability to maintain information in your mind and manipulate it in order to accomplish a goal. Work by another lab had previously shown that women with high circulating 17-beta estradiol levels performed better on a spatial memory task than women with low levels.2 Laura wanted to know how synthetic estradiol would interact with memory. She was particularly interested in the pill’s pharmacokinetics: a large spike in estrogen that occurs one to two hours after taking a pill, followed by a gradual decline in estrogen over the next 20 or so hours.
Women taking oral contraceptives came into the lab and performed a classic working memory task on two separate occasions: once within one to two hours of taking their pill, and once about 24 hours after taking it (when their synthetic estrogen levels would be lowest). Naturally-cycling women did the same experiment during both the early and late follicular phase of their menstrual cycle, representing low and relatively high 17-beta estradiol levels, respectively.
Somewhat surprisingly, Laura did not find a difference in task performance between high and low estrogen states in either the naturally cycling women or those taking the pill. In addition, both groups of women performed similarly on the task.
“One positive thing that came out of this study was the finding that the pill’s pharmacokinetics did not influence cognition, at least in the task we looked at, which is something very surprising that had not been looked at before,” explains Laura. “There’s very limited knowledge right now on how contraception affects the brain, so I think its extremely important as women to advocate for more research on how contraception might influence a wide variety of cognitive abilities.”
Now a first year PhD student in Psychology, Laura hopes to continue exploring this question. She has also joined Psychology Masters student Alana Brown in studying women positive for the BRAC1 or BRAC2 mutation who have had oophorectomies (surgery to remove their ovaries) to reduce their risk of developing ovarian and breast cancer. The ovaries are the primary producers of 17-beta estradiol. Consequently, these women experience a “surgically induced” menopause, although some choose to take hormone replacement therapy (HRT) to restore their estrogen levels.
This surgically induced menopause differs from natural menopause in two important ways. First, the drop in 17-beta estradiol from removing the ovaries is rapid compared to the slow decline in estrogens that occurs over several years in natural menopause. Second, the women undergoing oophorectomies are on average 10 years younger than the age when menopause would typically occur.
“Importantly, it seems that women who have had oophorectomies may have an increased risk for developing Alzheimer’s disease” explains Alana. “So, we’re using brain imaging and neurocognitive assessments and following these women over time to try and understand what might be contributing to this increased risk.”
To parse out the effects of estrogen and age, they are studying four groups of women: (1) those who had oophorectomies and are on HRT; (2) those who also had oophorectomies but are not on HRT; (3) age-matched healthy control participants; and (4) older, naturally menopausal women.
Alana is using functional magnetic resonance imaging (fMRI) to study associative memory—the ability to tie previously unrelated items of information together. In the MRI scanner women are shown a series of faces with names attached and are asked to judge whether it is a “good name” or a “bad name” for the face. After the scan, they are shown the faces again, this time accompanied by two names, and are asked to remember which name was previously linked with that face.
Alana looks at the brain activity while the women are making the associative links between faces and names in the scanner and compares the brain response to face-name pairs that are later correctly recalled versus those that aren’t. This gives her a pattern of brain activity that is associated with “successful” versus “unsuccessful” associative memory encoding.
The research team is particularly interested in prefrontal areas, the fronto-parietal attention network, and the anterior hippocampus. Some studies show reduced activity in the anterior hippocampus of people who have a greater risk of Alzheimers, while other studies have found spikes in activity. Alana hopes to understand how the anterior hippocampus functions in post-oophorectomy women early on, and then track its activity over several years to investigate what role it has in any signs of cognitive decline that may appear.
“Its very important to understand the role of estrogens in aging and dementia as well as in the presentation of other conditions such as schizophrenia, depression, and even autoimmune disorders,” says Dr. Einstein. “All of these clinical syndromes are influenced—both negatively and positively—by estrogens, and ultimately estrogens may be seen as key players in the etiology and treatment of these disorders.”
- Alzheimer’s A. 2015 Alzheimer’s disease facts and figures. Alzheimer’s & dementia: the journal of the Alzheimer’s Association. 2015 Mar;11(3):332.
- Hampson E, Morley EE. Estradiol concentrations and working memory performance in women of reproductive age. Psychoneuroendocrinology. 2013 Dec 1;38(12):2897-904.