Low estrogen leads to loss of brain function
Growing up, I remember hearing about “the change.” This mysterious process was the reason that my mother acted more forgetful after she turned 50. In college and medical school, my friends and I learned about menopause as a situation of low estrogen. We watched our mothers adjust to living without it. We learned there was "nothing to do" about the change.
Now that I am in my forties, I think about my approaching menopause. As a functional medicine doctor, I think about preventing dementia. I’ve learned a lot about the important role that estrogen plays in cognition. Postmenopausal women have a greater risk of getting Alzheimer’s dementia compared to men. Most people living with dementia are women. Over a very short time period, women lose estrogen. Low estrogen sets them up for memory loss. Unfortunately, many people are unaware of the relationship between low estrogen and memory loss. Practitioners can overlook it. Basic science research, also called bench science, clearly shows that estrogen is vital for the brain. Here is an introduction to those research findings. Estrogen does many important things for the brain.
Low estrogen equals fewer brain connections
The brain is a complex network. This is a basic overview.
- The main building block of the brain is the neuron. This is where the electricity of the brain is.
- Neurons send signals down a special highway, called the axon. Axons have a special insulator called myelin. The result is speedy signal transmission. The song “Greased Lightning” from the musical Grease! might as well be about axons.
The signals power every movement we make and every thought we have. Neurons and axons are high maintenance. They need the right support to work well. This is where astrocytes and microglia come in.
- Astrocytes make sure the neurons have enough materials to build connections to other neurons. Astrocytes also help maintain the connections, like a gardener who prunes plants. The pruning helps the neuron networks grow and use resources efficiently.
- Microglia guard the neurons and respond to disturbances by activating inflammation pathways.
It turns out that estrogen interacts with all of these different cells. Estrogen increases the number of astrocytes. It directly influences the health of neurons. If something damages axons, estrogen stimulates repair and growth of new axons. This is a super efficient version of highway repair. Think about how awful interstate travel would be if we never fixed aging highways. The same is true for signals traveling in the brain. Estrogen also balances the inflammatory influence of microglia. This is important because when these cells get going, they can injure neurons by mistake. With low estrogen, there is less management of all these cells. Over time neural connections break down. Memories and skills disappear.
MORE BRAIN CONNECTIONS=NEUROPLASTICITY
There are many receptors for estrogen in the brain. Most receptors are in places that have a role in making memories. The main places are:
- the hippocampus
- the amygdala
- the posterior cingulate gyrus.
All the estrogen receptors suggest that these regions are actively looking for estrogen. Estrogen fits the receptors like a lock into a key. When this happens, estrogen influences the actual creation of memory. Low estrogen leads to less activity in these areas.
Estrogen creates neuroplasticity. Neuroplasticity is the ability of the brain to change in response to stimuli like hormones or experiences. In lab experiments, estrogen promotes the formation of more neuron cells. An increase in the parent cells leads to more potential brain connections. Estrogen also makes neuron connection points stronger. Think about the scene of an action movie, where a character has fallen over a cliff, and someone is holding their hand to keep them from falling. Most of the time they fall anyway, right? Now imagine that two people are holding their arm, and another three people are holding the opposite hand and arm. That connection is strong, and that person will not fall. When estrogen is present, it makes all of those extra contact points possible. Researchers call the arms holding the person “spines.” All the spines create neuron networks that stay together more easily. Memories and abilities remain intact longer. Neuroplasticity also means faster information processing and recall of information. That can mean the difference between slamming on the brakes in time when another car runs a red light, and hitting that car head on. It can also mean the difference between instantly knowing an acquaintance you have not seen in months and having to ask for their name. The presence of estrogen-related spines correlates with higher brain performance. When you have low estrogen, brain connections are more fragile. Performance suffers.
The hippocampus is part of the limbic system. It creates emotions and reactions to what is going on around us. The hippocampus helps us process and retrieve declarative and spatial memories. Declarative memories involve facts, like learning the provinces in Canada. Spatial memories involve pathways, like knowing the best roads to take to your friend’s house. The hippocampus turns short term information into long term memories when needed. Estrogen does a lot of work in the hippocampus. It strengthens the communication between the hippocampus and the prefrontal cortex. The prefrontal cortex is the center of executive function. This refers to working memory, flexible thinking and self-control. If the connections between the hippocampus and prefrontal cortex are strong, it makes a big difference to everyday function. When the connections are weak, we have trouble with focusing, following directions and handling emotions. This is probably why so many women entering menopause complain about brain fog and mood swings. Low estrogen is the reason.
Low estrogen compromises mitochondria function
Neuroplasticity requires the brain to have a lot of energy lying around. Estrogen makes that possible. It helps to feed the mitochondria more effectively. Mitochondria are the energy producers of cells. They turn glucose and ketones into adenosine triphosphate, or ATP. This powers every single process in our bodies.
- When mitochondria do not have an adequate supply of glucose or ketones, they cannot work as well. They make less ATP.
- This leads to slowed thinking and poor memory.
When the brain has high estrogen levels, receptors for glucose move from the inside of neurons to the cell surface. This means that glucose has a lot more doorways to get inside the cell and act as an energy source.
Estrogen also increases the amount of ATP that mitochondria produce. It does this by enhancing the machinery involved. Enzymes can put together or break apart molecules. Many enzymes support the process of making ATP. Estrogen increases the presence of those enzymes. It’s like having a hundred people working on an assembly line instead of one. In the later part of the process, proteins generate energy which they package as ATP. When there is enough estrogen, there are more proteins working together. Think of a large warehouse in wintertime. If there is only one heater, it will take a long time to generate enough heat to warm up the whole building. When you have many generators working together, the energy production (in the form of heat) happens more quickly. Low estrogen interrupts this cooperation.
Mitochondria are delicate. They need protection from dangerous intermediates and waste that comes from basic cell processes. Antioxidants are one of the main ways that our body protects mitochondria. Antioxidants act like paper towels that mop up reactive chemicals. Estrogen increases the production of important antioxidants like peroxiredoxin 5 and manganese superoxide dismutase. These antioxidants keep energy production going smoothly. Estrogen has a special role in protecting mitochondria from amyloid beta. If this name sounds familiar to you, it is because this material is what causes the symptoms of Alzheimer’s dementia. It gathers in what researchers call “plaques and tangles.” You can see these changes in the brains of people who die with Alzheimer’s. The amyloid beta chokes off mitochondria, so neurons have less energy to survive. As neurons die, so does memory. Animal studies show that when estrogen is present, the mitochondria continue to work well. They are more resistant to the damaging presence of amyloid beta. To learn more about what causes this build-up of amyloid beta, check out my article Reversing Memory Loss with the Bredesen Protocol: An Overview.
Low estrogen damages blood vessels
Many people with cognitive decline and dementia have problems with blood flow to and inside their brain. This means less oxygen for neurons. Over time this contributes to the decay of brain connections. By now, you should not be surprised to learn that estrogen has a role in keeping blood vessels healthy so that the brain (as well as other parts of the body) can get the necessary nutrients and resources to thrive. Blood vessels consist of several layers. There is a smooth muscle layer that controls how wide the vessels are. Make a fist and look at your hand from the side. The “passageway” through your fingers is very narrow. This is what a vessel looks like when the smooth muscle layer tightens. Vessels can also be narrow when they have blockages from fatty deposits called plaques. If the fatty deposits are too big, you can have a heart attack or a brain attack (also called stroke). Researchers have shown that there are specific receptors for estrogen on our blood vessels. When estrogen is present, it helps the smooth muscle layer to relax. This happens because the level of nitric oxide increases. Nitric oxide acts like a massage therapist for blood vessels. Low estrogen impacts this pathway.
Estrogen also prevents blockages in the vessels. The reason why plaques form in the first place is oxidation of cholesterol particles. Think about what happens to a bicycle when it stays outside in the rain. Eventually the metal body rusts. Oxidation refers to the “rusting” of cholesterol particles. The particles can more easily stick to the blood vessel wall. This creates inflammation and leads to plaque formation. When estrogen is present, cholesterol particles do not rust. Estrogen inserts itself into the particle. This interrupts the rusting. Low estrogen leads to more heart attacks and strokes.
Caveats to bench science
Laboratory science has shown over the last twenty years that without question, low estrogen is bad for to the brain. But what is true in a dish or in animal experiments does not always remain true for humans. We have to ask if estrogen improves brain health and prevents cognitive decline in clinical research, which focuses on actual people. Does brain function actually improve with more estrogen? Would my mother have forgotten less with estrogen replacement? Should you and I be on estrogen replacement when we are in menopause? Be on the lookout for my next article summarizing the research looking at estrogen replacement in women.
Learn more about the Bredsen protocol and where low estrogen fits in here.
Sujuan G. et al. The Relationships Between Age, Sex, and the Incidence of Dementia and Alzheimer Disease. Arch Genl Psychiatry 1998. 55:808-815
Brinton RD et al., Estrogen induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Science 2009 April: 30 (4) 212-222
Rettberg, et al., Estrogen: a master regulator of bioenergetic systems in the brain and body. 2014.Front. Neuro- endoc. 35, 8–30
Nilsen J. et al., Estradiol In Vivo Regulation of Brain Mitochondrial Proteome. J of Neuroscience, December 19, 2007 • 27(51):14069–14077 • 14069
McCullough LD and Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab 2003; 14: 228-235
Guo X. et al., Estrogen Induces Vascular Wall Dilation mediation through kinase signaling to nitric oxide and estrogen receptors α and β. J of Biol Chem 2005. 280(20) May 20, pp. 19704 –10