Estrogen Balance and Mental Health: Depression, Anxiety and Stress (2023)

Estrogen levels in the brain and body affect our brain’s levels of dopamine and norepinephrine, two neurotransmitters that are implicated in mood disorders like depression, psychosis and anxiety.

Our brain has several built-in recycling processes to keep us level-headed. When neurotransmitters (brain chemicals that have mood-regulating effects) are finished with their tasks, enzymes recycle them, breaking them down into their chemical parts to be reused again at a later date. This process controls the level of chemical nervous system stimulation in our brains and keeps our moods regulated.

You’re at home, late a night, working on an important assignment, driven by the excitement of the topic at hand. Your brain is flooded with dopamine, a brain chemical that is connected to positive mood and motivation, pleasure and reward; dopamine pathways are activated when we’re engaged in a task that is pleasurable and rewarding, when our lives are flooded with meaning and we’re working towards a goal. Dopamine, however can also be connected to psychosis, conditions like schizophrenia and bipolar disorder, and also be linked to impulsive behaviour, aggression and irritability, when over-expressed.

Typing happily, you near the end of your assignment. Suddenly, your computer screen goes dark. Your heart begins to race, your skin prickles and you’re overtaken by anxiety, panic and fear. Your body is releasing norepinephrine, a chemical connected to stress, anxiety and the “Fight or Flight” response, but that also allows us to feel alert and energized. Your heart pounds as your reboot your computer. You are hyperaware of the sounds and smells around you. Your skin prickles and your breathing is loud and rapid.

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You exhale with relief as your computer screen lights up again, revealing that your assignment is unharmed. Stress drains out of your body, and your norepinephrine levels fall. You begin to tire; it’s time for bed. You add some finishing touches to your work, hit “save” and turn in for the night. The stress and motivation you felt only hours before dwindle, as the neurotransmitters responsible for these responses are swept out of your synaptic clefts and recycled.

When our brains have had enough stimulation of dopamine (mood, reward, pleasure, but also aggression, irritability, impulsivity and psychosis) and norepinephrine (stress and anxiety, “Fight or Flight”, but also alertness and energy), both get recycled through COMT, which pulls them out of circulation, breaks them down into their chemical parts, and reassembles them for later use.

We all have variability in how fast our COMT enzyme works, based on the expression of the COMT genes in our DNA. Some of us have slower COMT genes, meaning that our brain levels of dopamine and norepinephrine tend to be higher than other people’s, as our ability to clean up and recycle these hormones is slowed. This might result in an individual (depending on other genetic and lifestyle factors) who is at a higher risk of mental health conditions like psychosis or bipolar disorder, or someone who is more irritable, prone to aggression, or stress intolerant.

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Others have more COMT gene expression, resulting in a faster enzyme that clears dopamine and norepinephrine more quickly, resulting in lower brain levels of these neurotransmitters. If other factors are present, these individuals may be more at risk for mental health conditions such as depression, low mood, lack of motivation, or susceptible to addictions.

Beyond genetics, there are several environmental and biological factors that may affect the speed of the COMT enzyme. One of these factors is estrogen. Estrogen slows the COMT enzyme down by as much as 30%. This means that when estrogen levels are high (seen in many women around ovulation or premenstrually, or in women with generally high estrogen levels, termed “Estrogen Dominance”, COMT performs more slowly and dopamine and norepinephrine levels remain elevated.

Depending on the extent of the problem, women with high estrogen often experience anxiety and irritability and a low tolerance for stress. On the more severe end of the spectrum, some women experience conditions such as PMDD (Premenstrual Dysphoria Disorder) or PMS-induced psychosis, resulting from abnormally high brain levels of dopamine and norepinephrine due to high estrogen. These conditions probably result from a combination of high estrogen, slowed COMT and other genetic and lifestyle factors. Xenoestrogens from environmental toxins, or birth control pills may also slow COMT and further exacerbate some of the symptoms of estrogen dominance.

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Conversely, women with lowered levels of estrogen, such as those with amenorrhea (missed menstrual cycles) from various causes—PCOS is one, so is the birth control pill, especially progestin-only pills, or hormonal IUDs—or women who are peri-menopausal or menopausal, will have a faster COMT enzyme. This means that dopamine and norepinephrine will be cleared from the brain more quickly. Low levels of these neurotransmitters may result in depression: low mood, low energy and lack of motivation. On the extreme end, low levels of dopamine in the brain may result in conditions like Parkinson’s. Currently, research is being done on estrogen-replacement therapy as a treatment for Parkinson’s because of its ability to increase brain dopamine levels through slowing COMT.

When it comes to birth control pills, which are combination of synthetic estrogen and synthetic progesterone (“progestins”), or just straight progestin, either in pill-form or in a hormonal IUD, effects can be unpredictable. There is evidence that oral contraceptive use, especially progestin-only contraception, can exacerbate anxiety and depression, especially in teens. The pill acts by suppressing ovulation and suppressing natural hormone production, which may result in low levels of naturally-occurring progesterone and estrogen, which can slow COMT. However, the synthetic estrogens from the pill may interact with COMT, speeding it up in some women. Therefore the effects of specific forms of birth control on individual women is hard to predict; if functional medicine and genetic research tells us anything, it’s that there is no one-size-fits-all when it comes to striking the right hormonal balance.

Estrogen also has effects on another enzyme, called MAO-A, that recycles serotonin, the “Happy Hormone”, often implicated in depression and anxiety. Like COMT, estrogen slows down MAO, reducing the speed at which the body breaks down serotonin, resulting in higher brain serotonin levels. Drops in estrogen around and before a woman’s period, or low estrogen levels, may result in feelings of depression. Many women report feeling depressed and craving carbs and sugar around their periods. This is often related to a drop in serotonin as estrogen levels fall right before menses. Drops in serotonin levels due to drops in estrogen levels after childbirth may explain postpartum depression, according to some researchers.

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The link between estrogen and its effects on COMT and MAO hint at the complexities of the body and brain’s hormonal milieu and its implications for hormonal regulation and mental health. Mental wellness is a complex state involving a variety of factors: hormones, enzymes and neurochemical pathways that are affected by our environment, our genetics and our hormonal predispositions. This is why I believe in taking a functional approach to mental health, seeing our mental health symptoms for what they are: symptoms, and making efforts to uncover underlying causes rooted in lifestyle, genetics and our environment. I believe the way to address symptoms is to trace them back to their source.

For many women, treating depression, anxiety and stress-intolerance may involve balancing estrogen levels and healing the menstrual cycle. For others it may involve supporting genetic susceptibilities with lifestyle changes, finding a birth control method that balances (or coming off entirely), and reducing exposure to xenoestrogens, supporting estrogen detoxification pathways, and addressing women’s health conditions such as irregular menses, and conditions like PMS, fibroids, endometriosis and PCOS.

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