How Estrogen, Progesterone & Testosterone Impact Neurotransmitters
The Relationship Between Sex Hormones & Mental Health Conditions, COMT, MAOA, High Copper, NMDA, RCCX Theory, 21-Hydroxylase & Why Our Personalities May Change Over Our Lifetime
In previous newsletters, I’ve discussed many root causes of brain symptoms, none of which exist independently from our hormones. In this newsletter, I’ll address the impact our sex hormones - estrogen, progesterone, and testosterone - have on our neurotransmitters. I’ll also discuss how changes in our hormones can impact our personalities and mental health over our lifetime.
While there is a great deal of diversity in our hormonal states, there are obvious similarities for those born female and similarities for those born male. Hormones are an exceedingly complex topic. I will be oversimplifying.
To start, I’m providing some information on the role of specific neurotransmitters to refer back to if needed.
Review of Neurotransmitters
Serotonin (5-HT)- joy, well-being, enjoyment, pleasure, interest, restful sleep
Low activity - depressed or anxious mood, lack of enjoyment, difficulty falling and staying asleep
Dopamine (DA) - pleasure and reward
Low activity - lack of motivation, difficulty starting and finishing tasks, low-stress tolerance, social isolation, helplessness and hopelessness
High activity - worry, insomnia, brain fog, paranoia, mania, psychosis
Norepinephrine (NE) - arousal
Low activity - can contribute to depression
High activity - can contribute to nervousness and insomnia
GABA - the major inhibitory neurotransmitter involved in calming and rest
Low activity - anxiety, high inner tension, and feelings of overwhelm
Glutamate is the major excitatory neurotransmitter in the brain, and it is involved in learning, memory, and mood regulation. Excessive glutamate can cause over-excitation and cell death.
Review of COMT & MAOA
COMT codes for Catechol-O-methyltransferase - an enzyme that metabolizes catecholamines (dopamine, epinephrine, norepinephrine) and estrogen
A “Slow” COMT means a build-up of catecholamines, especially when under stress. This can cause high anxiety.
A “Fast” COMT can result in catecholamines being cleared too quickly. This can result in cravings, addictive tendencies, and excessive sleepiness.
MAOA also metabolizes catecholamines, which can be slow or fast; however, it also metabolizes serotonin and histamine, not estrogen.
Mental Health Data Across the Lifespan
We are most vulnerable to mental health conditions when sex hormones (estrogen, progesterone, and testosterone) are at their highest. Mental health conditions peak in adolescence and early adulthood and improve after 50. Half of all mental health problems are established by age 14, and 75% by age 24.
A decrease in hormones later in life is another vulnerable time. Depression and dementia are the most common, affecting 5% to 7% of the population over 60.
How Do Hormones Impact Our Neurotransmitters?
Estrogen
For females, estrogen increases during puberty (and obviously during the ovarian cycle). It is especially high during pregnancies and starts to decrease in perimenopause.
Four Ways Estrogen Impacts Neurotransmitters:
Estrogen slows the expression of the COMT gene that helps break down dopamine (DA) and norepinephrine (NE). It is also involved in breaking down estrogen
Estrogen slows the expression of MAO (breaks down DA, NE, and serotonin (5-HT).
Slowing of these enzymes can increase DA, NE, and serotonin 5-HT.
More estrogen can mean more neurotransmitters and potential problems calming down and being able to relax. This may be why, collectively, women are more susceptible to anxiety. It may also be why girls and women in high school and college are more academically engaged than their male peers. (Remember, dopamine and norepinephrine can contribute to higher motivation and focus).
Many factors can impact our estrogen state. For example, we have other genes besides COMT that affect estrogen levels. There are also environmental factors - birth control and/or pseudo-estrogens (from chemicals such as BPA’s, fire retardants, pesticides, and herbicides) that can add to estrogen dominance.
Slowing these genes by estrogen can override a fast COMT and/or MAOA variant. Estrogen dominance in a woman with a “fast” COMT and/or MAOA variant, for example, could still result in a slow COMT and a slow MAOA.
Estrogen can also impact copper levels, which impacts neurotransmitter functioning. For women and girls who have a copper regulation vulnerability, high estrogen states can mean lower dopamine and higher norepinephrine activity.
Examples of high copper :
Girls with a new onset of depression, anxiety, or attentional issues around puberty.
Any teen or woman who has a worsening of mood, increased anxiety, or decreased attention after starting oral contraceptives or hormone replacement.
Any woman with a history of postpartum depression, anxiety, or psychosis - Research by Dr. William Walsh found that 95% of women who reported having had postpartum depression had high copper. Copper levels go up during pregnancy (as estrogen levels go up) but should return to normal pre-pregnancy levels after birth. If a woman has difficulty regulating copper, it can stay high and contribute to postpartum symptoms.
Estrogen can increase activity at the NDMA receptor (a glutamate receptor) in females with relatively low progesterone. High activity at the NMDA receptor can look like getting stuck in repetitive thought patterns such as ruminations, obsessions, flashbacks from trauma, cravings for addictions, or delusions with psychosis. Other factors that can increase activity at this receptor include undermethylation, high histamine, low zinc, and low magnesium.
Progesterone
Progesterone, like estrogen, increases during puberty and then starts to decrease in perimenopause. Its impact on neurotransmitters differs from that of estrogen.
Enhances GABA transmission
Inhibits glutamate transmission (and glutamate induced dopamine release). As you can see, a woman with high estrogen relative to progesterone could be more vulnerable to the consequences of high activity at the NMDA receptor.
Enhances serotonin synaptic activity
The big picture here is calming and potential improvement in mood.
Testosterone
In males, testosterone levels start to increase in puberty and begin to drop off very gradually in the 30’s and 40’s. Relative to the decrease of estrogen and progesterone in women during menopause, testosterone levels don’t decrease below normal levels until much later in life. They drop off by one percent a year and, at 70 years of age, are 30% below the peak. There can be reasons, such as high oxidative stress or low zinc, for example, that could cause someone to have lower levels before then.
Estrogen levels increase in men with age. Progesterone levels show more variability with age in men.
Testosterone’s impacts on neurotransmitters are more complicated, though in many ways, mirror those of estrogen. While testosterone can increase dopamine in specific brain areas, it also speeds up the expression of COMT and MAOA, resulting in lower DA, NE, and 5-HT. This is the opposite of estrogen, which slows these genes down.
When we have low neurotransmitter states, we may be more inclined to do things that will increase those neurotransmitters. Being scared or excited increases our neurotransmitters. We may be more stimulation-seeking. This may be why men collectively engage in more risk-taking activities and have better stress tolerance. Being low in theses neurotransmitters can also contribute to irritability and anger.
Evolutionarily, it may make sense that women would be less risk-taking. Caregiving would benefit from less risk-taking. Hunting could benefit from more.
As with estrogen “slowing” effect overriding a fast COMT and MAOA variant, testosterone's ability to speed up MAOA appears to override a slow variant. Men with a slow MAOA (which you might expect to increase DA, NE & 5-HT) don’t feel happier the way women with a slow MAOA do.
RCCX Theory & Weakness at 21-Hydroxylase
To further complicate the story of sex hormones, many who have brain-related symptoms likely also have a vulnerability on the gene for 21-Hydroxylase - a pivotal gene in stress hormone pathways that codes for an enzyme that turns 17-hydroxyprogesterone into cortisol. A weakness, aside form impacting cortisol levels, can lead to sex hormone differences (by backup or slowing down of the pathway) that can convey strengths and vulnerabilities. For example, women could have relatively high androgens (testosterone), and men or women can have relatively high progesterone.
Thinking Differently About Our Development
Psychological developmental theories consider our cognitive, emotional, and social development across our life span. As you can see, each of these can be impacted by our hormones and their impacts on our neurotransmitters. Puberty and midlife are times of tremendous change.
Since it’s unlikely anyone reading this is going through puberty, I’ll speak to those in or heading into middle age:) We may notice changes in our personality and what we care about. We may even feel a slight sense of familiarity - a recognition of the child we once were before hormones altered our neurotransmitters.
Until next time,
CourtneySnyderMD.com
For information about my practice, visit CourtneySnyderMD.com
Medical Disclaimer:
This newsletter is for educational purposes and not intended or implied to be a substitute for professional medical advice, diagnosis or treatment for either yourself or others, including but not limited to patients that you are treating (if you are a practitioner). Consult your own physician for any medical issues that you may be having.
A follow-up question if you don't mind. Is speeding up COMT and MAOA caused by testosterone directly, or is it DHT that causes it.
Testosterone speeding up COMT and MAOA was new to me. Fascinating!