Perimenopausal Anxiety: Why You’re Suddenly Anxious in Your 40s

The Universal Baseline (Why Perimenopause Triggers Anxiety in Everyone)

It is incredibly easy to blame yourself or assume you are simply cracking under the pressure of daily life. But the truth is that your brain and body are experiencing a complex, physical, and chemical storm, and this transitional life stage systematically lowers your body’s natural defense mechanisms against stress. 

Anxiety is one of the most prevalent and least-recognised symptoms of the perimenopause transition. Studies have found that women in perimenopause are significantly more likely to develop high anxiety symptoms than premenopausal women, with odds ratios of 1.56–1.61 even when controlling for life events, financial strain, and vasomotor symptoms — suggesting the hormonal component is independent of external stress. Global data project that the burden of anxiety disorders in perimenopausal women will rise to 1,180 per 100,000 by 2035, a 40% increase on 2021 levels.

The symptom most associated with this transition — across large survey data — is not the hot flush. It is “feeling like I can’t calm down on the inside.” That phrase is a clinical fingerprint. It describes what happens when the brain loses its primary calming system.

1. The Progesterone Shift: Losing Your Brain’s Natural Valium

In early perimenopause, your ovaries begin to skip ovulation. You may still get a regular period, but you are experiencing anovulatory cycles—months where an egg is not released. Because ovulation is what triggers your body to manufacture progesterone, your levels of this vital hormone begin a steep, erratic decline.

Progesterone is not just a reproductive hormone; it is a powerful neurosteroid. Research confirms that progesterone and its metabolites, such as allopregnanolone, bind directly to GABA receptors in the brain. GABA is your brain’s primary inhibitory neurotransmitter—essentially, your nervous system’s built-in brake pedal. It stops racing thoughts, relaxes muscles, and signals to your body that you are safe. When progesterone plummets, your brain loses its natural Valium. Without this calming buffer, your central nervous system stays idling at a dangerously high speed, making you highly susceptible to sudden hyperarousal and unprovoked dread. 

2. The Oestrogen Rollercoaster: Crashing Your Serotonin

While progesterone drops early and stays low, oestrogen behaves like a roller coaster. Instead of declining smoothly, oestrogen in early perimenopause swings wildly, spiking to sky-high levels before crashing overnight.

This matters because medical literature details how oestrogen directly acts as a primary engine behind monoamine neurotransmitter pathways. It keeps serotonin receptors sensitive and blocks the enzymes that break serotonin down. Serotonin is the chemical responsible for mood stability, impulse control, and emotional safety. When your oestrogen levels plunge during a perimenopausal dip, your serotonin levels drop right along with them. This sudden crash leaves you feeling emotionally fragile, intensely irritable, and highly vulnerable to sudden, unpredictable bouts of crying or anxiety.

3. The Iron Drain: The Hidden Cause of Panic Attacks

Early perimenopause is notorious for causing chaotic, flooding, and incredibly heavy periods. This rapid blood loss frequently leads to systemic iron deficiency and low ferritin (stored iron), a crisis that is often completely overlooked because it happens long before full-blown anemia sets in.

Clinical findings show that iron loss can cause severe anxiety and panic attacks completely on its own, independent of any other hormone. Iron is a mandatory co-factor that your brain requires to manufacture both serotonin and dopamine . When iron drops, your brain chemical production tanks. Furthermore, iron status directly modifies glutamate and GABA homeostasis. When iron stores fall, glutamate (the brain’s primary stimulating neurotransmitter) becomes hyperactive. This triggers physical survival responses that mimic a textbook panic attack—complete with heart palpitations, dizziness, and shortness of breath. 

For many women, balancing these three pillars—restoring calming pathways, smoothing out hormonal dips, and rebuilding iron stores—is enough to reclaim their calm.

But if your anxiety still feels like an explosive, unprovoked physical hijack that leaves you trapped in full fight-or-flight mode, or if your long-standing ADHD management has suddenly collapsed into severe executive dysfunction, there is a secondary, deeper layer to your puzzle. It lives directly in your DNA, in a genetic accelerator known as the COMT gene.

The COMT Genetic Accelerator – When Anxiety Turns into Panic

While the universal hormonal shifts and iron drops of early perimenopause leave every woman’s nervous system vulnerable, they do not affect everyone equally. You might look at a friend who is sailing through her early 40s with nothing more than occasional mild fatigue, while you are left battling debilitating, unprovoked panic attacks and a total collapse of your ADHD management.

Why the vast difference? The answer often lives in a single gene that controls your brain’s chemical cleaning crew: COMT.

What is COMT?

COMT stands for catechol-O-methyltransferase. It is an essential enzyme tasked with breaking down and clearing out a specific family of chemicals called catechols. These include your stress hormones (adrenaline and noradrenaline), your focus neurotransmitter (dopamine), and your oestrogen breakdown products (catechol oestrogens).

Genetic variations dictate how fast your specific COMT enzyme runs. If you carry the variant often called “Slow COMT” (the Met/Met genotype), your enzyme naturally runs at a 3-to-4-times reduced clearance capacity.

In a stable, low-stress environment, having a slow COMT enzyme is actually a massive executive asset. Because you clear dopamine slowly, your brain maintains higher baseline dopamine levels in the prefrontal cortex. This often gives Slow COMT individuals superior abstract thinking skills, excellent working memories, and high linguistic intelligence. In genetic research, this is known as the “Worrier vs. Warrior” paradigm: you are the brilliant, highly capable “Worrier” who excels at planning, deep focus, and high-level strategy—but collapses under extreme stress.

The Biological Collision

This system works beautifully until you hit early perimenopause. As we uncovered in Phase 1, early perimenopause is characterized by wild, chaotic spikes in oestrogen before it eventually declines.

Here is the biological trap: oestrogen naturally downregulates and suppresses the activity of the COMT gene.

When your ovaries pump out a massive, unpredictable surge of oestrogen, that oestrogen acts as a physical brake pad on an enzyme that was already genetically sluggish. Suddenly, your COMT enzyme is pushed into a state of severe, chronic congestion. It simply cannot keep up with the chemical workload.

The Adrenaline and Dopamine Backlog

With the COMT enzyme temporarily jammed by an oestrogen spike, a literal traffic jam occurs in your nervous system, triggering two catastrophic shifts:

• The Adrenaline Flood: Because your jammed COMT cannot clear out adrenaline and noradrenaline, these stress hormones back up into your bloodstream and tissues. This chemical accumulation is what triggers the raw physical sensations of panic: the sudden 3 AM waking, the racing heart, the icy feeling in your chest, and a baseline “internal hum” of anxiety. You are not panicking because of a bad thought; you are panicking because your body is swimming in un-cleared adrenaline.
• The ADHD Chaos (The Dopamine Overflow): For women with ADHD, this genetic bottleneck is devastating. ADHD is fundamentally a disorder of dopamine regulation. Data shows that prefrontal cortex executive functioning requires a delicate, highly specific chemical equilibrium. When slow COMT is jammed further by fluctuating oestrogen levels, baseline dopamine in the prefrontal cortex rises too high. Neurotransmitter levels follow an inverted-U curve: too little dopamine causes ADHD distraction, but too much dopamine shatters executive function entirely. Your brain enters a state of hyper-arousal, causing severe brain fog, intense irritability, and an inability to make simple decisions. Furthermore, because your baseline chemistry is already flooded, your usual ADHD stimulant medications may suddenly backfire, causing intense anxiety, jitters, and paranoia instead of calm focus. 

In short, early perimenopause creates the hormonal storm—but your COMT gene determines just how violently your nervous system floods.

The Litmus Test & The Truth About Fibroids

It is easy to confuse standard perimenopausal stress with a COMT-driven genetic hijack. Because both involve hormonal changes, they can look similar on paper, but they feel entirely different in your body.

Understanding this distinction is crucial. If your anxiety is driven by regular lifestyle factors, your path to relief will look very different than if you are dealing with a structural, genetic bottleneck. Here is how to tell the difference, followed by the specific symptoms to look out for.

Standard Perimenopause Stress vs. The COMT Hijack

• Standard Perimenopause Stress: This feels like a lower threshold for coping. You might feel easily overwhelmed by a busy schedule, more emotional than usual, or anxious about something specific—like an upcoming meeting, a relationship milestone, or your changing body. It is primarily a mental state of worry driven by low progesterone and crashing serotonin.
• The COMT Genetic Hijack: This is a purely physical, chemical event. It hits you completely out of nowhere when your mind is perfectly happy. You could be sitting on the sofa watching a favourite show, and suddenly your chest tightens, your heart races, and your body enters full fight-or-flight mode. It feels like an unprovoked adrenaline dump because that is exactly what it is: an oestrogen spike has physically jammed your COMT enzyme, trapping stress hormones in your system.

The COMT + Perimenopause Symptom Checklist

If your early perimenopausal anxiety is being accelerated by an overloaded COMT pathway, you will likely check off multiple items across both categories below:

The Cognitive & Emotional Signals

• Anxiety Without a Cause: Sudden waves of panic that hit you out of nowhere, completely detached from your actual thoughts or real-life stressors.
• The 3 AM Alertness: Waking up abruptly in the dead of night, not just awake, but feeling instantly alert, sweaty, and filled with an unprovoked sense of dread.
• ADHD Medication Backfire: Your usual ADHD stimulant medications (which used to provide calm focus) suddenly cause intense anxiety, physical jitters, or paranoia.
• Executive Function Collapse: A total shattering of your ability to make simple decisions, accompanied by a heavy, immovable brain fog.
• Perimenopausal “Rage”: Mood swings that feel less like sadness and more like an explosive, uncontrollable irritability or PMDD-like anger.

The Physical & Sensory Signals

• Caffeine Intolerance: A single cup of coffee, black tea, or dark chocolate now triggers heart palpitations, shaking, or an all-day baseline hum of anxiety.
• Paradoxical Supplement Reactions: Feeling noticeably worse, anxious, or angry after taking standard multivitamins or B-complexes containing Methyl-B12, Methylfolate, or SAMe.
• Hormonal Migraines: An escalation of severe, throbbing headaches or migraines that are tightly linked to your fluctuating menstrual cycle.
• Widespread Physical Pain: Increased sensitivity to pain, frequent jaw clenching (TMJ), a tight chest, or chronic muscle tension that refuses to release.
• Severe Oestrogen Dominance: Periods that have suddenly become heavier and more painful, accompanied by severe breast tenderness.

Fibroids and COMT

Because a slow COMT enzyme is responsible for breaking down both brain chemicals and hormones, its impact stretches far beyond your mood. When your COMT enzyme is running sluggishly, it struggles to clear out used oestrogen, allowing the hormone to pool and recirculate in your reproductive tissues.

This constant “hormonal bath” directly affects the cells in your uterus, making individuals with a slow COMT gene highly susceptible to developing uterine fibroids—benign, oestrogen-dependent tumours.

Clinical research shows a strong, undeniable link here. According to genetic data, variations in the COMT gene are significantly tied to multiple uterine fibroids. When the enzyme fails to break down oestrogen efficiently, the uterus is exposed to prolonged, unchecked hormonal stimulation, driving the proliferation of fibroid tissue.

The Genetic Disparity

This genetic link also helps explain why certain women suffer from fibroids at vastly disproportionate rates. Clinical reports demonstrate that Black women have up to three times the risk of developing uterine fibroids compared to white women, are diagnosed earlier, and suffer from larger, faster-growing tumours. This tightly mirrors the epidemiological distribution of slower, high-risk alterations in COMT enzyme function, which are found in roughly 47% of Black women, compared to 30% of Hispanic women and 19% of white women.

A Crucial Note: Anxiety is the Ultimate Litmus Test

While the connection to fibroids is clear, from a practical standpoint, you should almost never suspect a slow COMT issue if a woman has fibroids but zero anxiety.

Here is why:

• “Fast” COMT Can Drive Fibroids Too: Human biology is full of paradoxes. Women who carry the high-activity(Fast) COMT variant can also develop severe fibroids. Fast COMT breaks down protective forms of oestrogen too quickly, turning them into aggressive metabolites that can hyper-stimulate uterine tissue. However, because their enzyme clears adrenaline rapidly, these women are usually emotionally stable, calm, and highly resilient under stress.
• Non-Genetic Fibroids: Fibroids can also be caused by standard lifestyle factors, gut dysbiosis, or poor liver health—completely independent of your DNA.

The Bottom Line: If you have uterine fibroids but your mood is steady and you handle stress well, your fibroids are likely driven by a completely different hormonal pathway. For the “Slow COMT” genetic profile, neurological sensitivity and unprovoked anxiety are the mandatory red flags. You only suspect this specific bottleneck if the physical symptoms are accompanied by that signature nervous system overwhelm.

The Roadmap to Relief

When your anxiety, worsening ADHD, and physical symptoms like fibroids are driven by a biochemical traffic jam, standard “stress management” advice is rarely enough. You cannot simply breathe away a physical backlog of adrenaline and oestrogen. Instead, you must clear the bottleneck by giving your COMT enzyme the fuel it starves for while systematically reducing its workload.

You can successfully support this pathway and reclaim your calm entirely through targeted nutrient therapy, dietary adjustments, and strategic lifestyle shifts—completely without the use of Hormone Replacement Therapy (HRT).

1. Turn on the COMT Engine with Magnesium

The COMT enzyme has one absolute, non-negotiable requirement to function: it is completely magnesium-dependent. Without magnesium, the enzyme structurally locks up and cannot clear adrenaline or oestrogen, regardless of your genetics.

• The Action: Supplement with a highly bioavailable form of magnesium. Magnesium Glycinate is highly effective for calming the nervous system, releasing muscle tension, and easing anxiety. Magnesium Threonate passes the blood-brain barrier to directly target ADHD brain fog and executive dysfunction.
• The Goal: Provide the essential mechanical spark needed to keep the COMT clearance pathway moving.

2. Correct Vitamin D: Serotonin, COMT and Fibroids

Vitamin D isn’t really a vitamin—it’s a prohormone that acts directly on the brain. It switches on the TPH2 gene, the master switch your brain uses to manufacture serotonin, and its receptor sits on the very brain regions that govern mood. As oestradiol becomes erratic in perimenopause, low vitamin D pulls a second support out from under your serotonin system at exactly the wrong moment. Clinical trials show that correcting a deficiency specifically improves anxiety.

The COMT Bonus (Tissue-Specific): Here is where vitamin D becomes genuinely clever for the Slow COMT profile. Its effect on the COMT enzyme runs in opposite—and equally helpful—directions depending on where it acts. In the brain, vitamin D binds directly to the COMT gene promoter and increases COMT expression, giving your sluggish enzyme a gentle nudge to clear backed-up adrenaline faster. Yet in uterine fibroid tissue, vitamin D does the reverse—it suppresses COMT and halts the cell growth that fuels fibroids. So the same nutrient speeds up clearance where you want calm and slows growth where you want shrinkage.

• The Action: Test your 25(OH)D level rather than guessing, then supplement Vitamin D3 (ideally with vitamin K2) to bring yourself into a sufficient range. This is the one nutrient where a simple blood test genuinely changes the plan.
  
  Why This Matters More for Black Women: Melanin is a natural sunscreen—protective against the sun, but it also blocks the UVB rays your skin needs to make vitamin D. As a result, Black women carry up to a 15–20 times higher rate of severe vitamin D deficiency, a gap made worse by the UK’s weak northern-latitude winter sun. This is biology meeting geography, not a lifestyle failing.
  
  The Double Benefit: For a Black woman in perimenopause, correcting vitamin D does several jobs at once—it supports serotonin, nudges brain COMT to clear adrenaline, and simultaneously suppresses fibroid growth—directly addressing the disproportionate fibroid burden discussed earlier. It is a rare intervention that targets both the neurological and the physical symptoms at their root.

• The Goal: Move vitamin D from “deficient” to “sufficient” to fuel your serotonin machinery, support healthy COMT clearance in the brain, and remove a preventable fibroid risk factor—all at the same time.

3. Introduce Active Co-Factors

To clear stress chemicals, COMT requires a steady supply of a compound called SAMe. However, taking SAMe directly or using heavy “methyl donors” can cause erratic, sudden spikes in dopamine that trigger acute panic in slow COMT individuals. Instead, use a gentler approach to build your own fuel:

• Active Vitamin B2 (Riboflavin-5-Phosphate): B2 acts as a vital co-factor that helps your body create its own steady stream of fuel for COMT, without causing the sudden anxiety spikes associated with stronger B-vitamins.
• Vitamin B6 (as Pyridoxal-5-Phosphate / P5P): While B6 doesn’t directly speed up COMT, it is the mandatory co-factor your brain needs to convert backed-up, inflammatory stress hormones into GABA—your brain’s natural calming neurotransmitter.

4. Feed the Alternative Clearance Pathways

If your primary COMT pathway is congested by perimenopausal oestrogen spikes, you can bypass the bottleneck and fuel alternative clearance pathways in the liver using gentle, well-tolerated nutrients:

• Choline (Alpha-GPC or Phosphatidylcholine): Found naturally in egg yolks, choline acts as a slow-release fuel source for COMT. Simultaneously, it supports acetylcholine—a neurotransmitter critical for increasing brain focus and memory retention under changing neuroendocrine conditions.
• Trimethylglycine (TMG / Betaine): TMG is a direct methyl donor that operates through an alternative enzyme pathway in the liver. For individuals with a slow COMT gene, TMG is vastly better tolerated than methylated folate or B12, providing a clean way to speed up adrenaline clearance without the jitters.

5. Manage the Iron Seesaw: Test, Don’t Guess

As we uncovered in Phase 1, heavy flooding periods in early perimenopause can tank your iron (ferritin), which breaks down your backup stress-clearing enzyme (MAO).

• The Action: Request a full iron panel from your doctor that specifically includes Ferritin (stored iron), and a standard serum iron test.
• The Goal: For slow COMT individuals, the optimal ferritin range is a balanced middle ground (roughly 50–100 ng/mL) to ensure your secondary monoamine clearance enzymes retain full structural bio-availability. If your ferritin is too low, supplement with a gentle, non-constipating form like Iron Bisglycinate.

6. Stop Giving the COMT Enzyme Extra Work

Sometimes, the fastest way to speed up a sluggish pathway is to stop overloading it. Certain popular health foods and supplements contain compounds called catechols, which physically bind to COMT and block it from breaking down your internal adrenaline:

• Avoid COMT Inhibitors: Temporarily eliminate or drastically reduce caffeine, green tea extract (EGCG), dark chocolate, and quercetin supplements.
• Check Your Multivitamins: Read your supplement labels carefully and avoid high doses of Methylcobalamin (B12) and Methylfolate. Look for non-methylated alternatives (like Adenosylcobalamin/Hydroxycobalamin and Folinic Acid) to avoid triggering a paradoxical panic response.

7. Support Oestrogen Detoxification Through Your Diet

Because early perimenopause triggers wild oestrogen spikes that slow down COMT and feed physical issues like fibroids, helping your liver and gut clear out used oestrogen takes a massive burden off the enzyme.

• Eat Cruciferous Vegetables: Broccoli, Brussels sprouts, cabbage, and cauliflower contain a compound called Indole-3-Carbinol (I3C). This helps route oestrogen down a safer, cleaner clearance pathway in the liver.
• Keep Your Digestion Moving: Oestrogen is ultimately excreted through your bowels. If you are constipation-prone, bound oestrogen is reabsorbed back into your bloodstream, restarting the loop and jamming COMT all over again. Ensure adequate daily fiber and hydration.

8. Calm the Nervous System with Safe Adaptogens

Because your HPA axis (stress response) is raw and hyper-reactive, stopping the adrenaline flood before it even starts gives your COMT enzyme less work to do. But the goal is to calm the nervous system without adding to the two things already jamming your COMT pathway—catechols and oestrogen. Choose your adaptogen carefully:

• Avoid Rhodiola Rosea: Rhodiola contains active catechols that can temporarily compete for the COMT enzyme, worsen adrenaline backlogs, and trigger anxiety.
• Avoid Ashwagandha: This is the counter-intuitive one. Ashwagandha is a wonderful calming herb, but multiple perimenopausal trials show it significantly raises oestradiol—by roughly 40% in one study and even more in another—while lowering FSH and LH. Since erratic oestrogen surges are one of the very things slowing your COMT enzyme and feeding physical issues like fibroids, adding an oestrogen-raising herb can work against you in the early, spike-prone phase of perimenopause. If you are highly oestrogen-sensitive or still cycling erratically, this is one to skip.
• Choose Holy Basil (Tulsi): This is the cleaner first choice for slow COMT. It soothes the HPA axis and lowers circulating cortisol without the oestrogen-raising effect seen with ashwagandha—calming the adrenaline flood without adding fuel to the fire that jams your pathway.

Shift to Biochemical Peace

If you have spent months or years feeling like your brain and body are suddenly failing you, take a deep breath. You are not losing your mind, your ADHD routines aren’t failing because of a lack of willpower, and your sudden perimenopausal anxiety is not a personal defect.

It is a predictable biochemical event.

When you shift your perspective from “Why am I broken?” to “My body is experiencing an un-cleared backlog of adrenaline,” the psychological power of anxiety immediately begins to wither. Knowing that dropping progesterone, low iron, and an inherited “Slow COMT” gene can create a temporary chemical traffic jam puts the steering wheel firmly back in your hands.

You do not have to just “deal with” the 3:00 AM panic attacks, the sudden baseline hum of dread, or the collapse of your focus. By understanding the universal baseline of perimenopause and addressing your unique genetic blueprint, you can actively dismantle the bottleneck.

Feeding your system the magnesium it starves for, rebuilding your iron stores, choosing gentle, non-methylated co-factors, and removing the dietary blockers that jam the pathway allows your body to clear the wreckage naturally. Your genetics are not a life sentence—they are simply a highly specific manual for how to care for your unique nervous system during this transitional chapter of life. Listen to what your body is asking for, slow down the system, clear the backlog, and reclaim your calm.

References

1. Anxiety rises in perimenopause (prevalence & burden)

Bromberger, J.T., Kravitz, H.M., Chang, Y., Cyranowski, J.M., Brown, C. and Matthews, K.A. (2013) ‘Does risk for anxiety increase during the menopausal transition? Study of Women’s Health Across the Nation (SWAN)’, Menopause, 20(5), pp. 488–495.

Su, H. et al. (2025) ‘Global, regional, and national burden of anxiety disorders during the menopausal transition, 1990–2021, with projections to 2035’.

2. Progesterone / allopregnanolone as a GABA-A neurosteroid

Fan, C. et al. (2023) ‘Structural insights into the modulation of GABA-A receptors by neurosteroids’.

Rasmusson, A.M., Pineles, S.L., Brown, K.D. and Liang, J.J. (2018) ‘Allopregnanolone and pregnanolone: steroidogenesis and neurosteroid regulation’.

Locci, A. and Pinna, G. (2017) ‘Neurosteroid biosynthesis and GABA-A receptor plasticity in stress and anxiety’.

Brown, A.R., Herd, M.B., Belelli, D. and Lambert, J.J. (2011) ‘Neurosteroids and GABA-A receptor function in stress’.

3. Estrogen and the serotonin system

Jiménez-Rubio, G. et al. (2019) ‘Estradiol regulates the expression of TPH2, MAO-A/B, SERT and 5-HT1A in the serotonergic system’.

Onisiforou, A. et al. (2024) ‘Estradiol modulation of serotonin, glutamate and dopamine systems’.

Rybaczyk, L.A. et al. (2005) ‘A serotonergic mediation of the estrogen effect’.

Biegon, A. and McEwen, B.S. (1982) ‘Modulation of serotonin receptors by estradiol’.

4. Iron deficiency, low ferritin and anxiety

Kim, J. and Wessling-Resnick, M. (2014) ‘Iron and mechanisms of emotional behavior’.

Fu, Y. et al. (2024) ‘Iron status and anxiety: a Mendelian randomization study’.

Ethirajulu, A. et al. (2021) ‘Iron deficiency anemia and its relationship with anxiety and depression via monoamine synthesis’.

Berthou, C. et al. (2021) ‘Iron, neuro-bioavailability and depression’.

Daubner, S.C., Le, T. and Wang, S. (2011) ‘Tyrosine hydroxylase and regulation of dopamine synthesis’.

5. COMT biology, Val158Met, and the “Worrier vs Warrior” phenotype

Diamond, A. et al. (2020) ‘A double dissociation of the effects of the COMT Val158Met polymorphism under stress’.

Elvevåg, B. and Dickinson, D. (2009) ‘Genes, cognition and brain through a COMT lens’.

Mattay, V.S. et al. (2009) ‘COMT genotype and dopamine-degrading activity’.

Peacock, C.J. et al. (2020) ‘The “Warrior” COMT allele in mixed martial arts athletes’.

6. Estrogen downregulates COMT; catechol estrogens; the dopamine inverted-U

Salama, S.A. and Al-Hendy, A. (2008) ‘COMT expression in endometrial stroma is regulated by estrogen and progesterone’.

Ho, H.P. et al. (2013) ‘Estrogen-receptor-mediated reduction of soluble COMT expression’.

Louis, C.C. et al. (2023) ‘Estradiol × COMT interaction on working memory’.

Stutt, N. et al. (2021) ‘The inverted-U relationship between prefrontal dopamine/D1 signalling and working memory: a meta-analysis’.

Cools, R. and D’Esposito, M. (2011) ‘Inverted-U-shaped dopamine actions on human working memory and cognitive control’.

7. COMT variants, uterine fibroids, and racial disparity

Al-Hendy, A. and Salama, S.A. (2006) ‘COMT polymorphism is associated with increased uterine leiomyoma risk in different ethnic groups’, Journal of the Society for Gynecologic Investigation, 13(2), pp. 136–144.

de Oliveira, E. et al. (2008) ‘COMT Val158Met polymorphism and large uterine fibroids’, Maturitas, 60(3–4), pp. 235–238.

Zhang, H. et al. (2014) ‘COMT Val158Met polymorphism and uterine fibroids in Han Chinese women’.

Fischer, N. et al. (2016) ‘COMT Val/Val genotype and risk of multiple uterine fibroids’.

Eltoukhi, H.M. et al. (2013) ‘The burden of uterine fibroids for African-American women’.

8. Treatment roadmap (mechanistic references)

Magnesium as a COMT cofactor

Ehler, A. et al. (2012) ‘Metal substitution and enzyme activity of catechol-O-methyltransferase’.

Czarnota, S. et al. (2014) ‘Structure-based analysis of Mg²⁺ octahedral coordination in COMT’.

Jeffery, D.R. and Roth, J.A. (1987) ‘Magnesium binding kinetics of catechol-O-methyltransferase’.

Zhang, X. et al. (2021) ‘Magnesium-dependent catechol-O-methyltransferase activity’, Hypertension.

Methyl donors (SAMe) & B-vitamin cofactors

Bottiglieri, T. (2018) ‘S-adenosylmethionine (SAMe) as the methyl donor for COMT’.

FUDMA Journal of Sciences (n.d.) ‘The role of vitamin B6 (P5P) in GAD-mediated GABA synthesis’.

I3C / cruciferous vegetables & estrogen 2-hydroxylation

Michnovicz, J.J. and Bradlow, H.L. (1990) ‘Induction of estradiol 2-hydroxylation in humans by dietary indole-3-carbinol’.

Michnovicz, J.J. and Bradlow, H.L. (1991) ‘Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol’.

Estrogen enterohepatic recirculation / estrobolome

Gut Microbes (2023) ‘The estrobolome, β-glucuronidase and enterohepatic recirculation of estrogens’.

Journal of Biological Chemistry (2019) ‘Gut microbial β-glucuronidases and estrogen deconjugation’.

Adaptogens for anxiety

Smith, S.J. et al. (2023) ‘Ashwagandha (Withania somnifera) for cortisol and anxiety: a randomised controlled trial’.

Ashwagandha raises oestradiol (reason for caution in oestrogen-sensitive perimenopause)

Gopal, S. et al. (2021) ‘Effect of an ashwagandha (Withania somnifera) root extract on climacteric symptoms in women during perimenopause: a randomized, double-blind, placebo-controlled study (significant increase in serum estradiol; reduced FSH and LH)’, Journal of Obstetrics and Gynaecology Research, 47(12), pp. 4414–4425.

Smith, S.J., Lopresti, A.L. and Fairchild, T.J. (2023) ‘Exploring the efficacy and safety of a novel standardized ashwagandha (Withania somnifera) root extract in adults experiencing high stress and fatigue (≈60% rise in estradiol; ≈137% in perimenopausal subgroup)’, Journal of Psychopharmacology, 37(11), pp. 1091–1104.

Sochacka-Cwikla, A. et al. (2026) ‘Withania somnifera in women’s hormonal modulation: normalisation of gonadotropins and estradiol via the HPA/HPG axes — review’, Cureus.

Vitamin D — mood/serotonin mechanism

Camargo, A., Rodrigues, A.L.S., Kouba, B.R. and Gil-Mohapel, J. (2022) ‘Molecular basis underlying the therapeutic potential of vitamin D for the treatment of depression and anxiety’, International Journal of Molecular Sciences, 23(13), 7077.

Ceolin, G. et al. (2021) ‘Vitamin D, depressive symptoms, and Covid-19 pandemic’, Frontiers in Neuroscience, 15, 670879.

Kerr, D.C.R. et al. (2015) ‘Associations between vitamin D levels and depressive symptoms in healthy young adult women’, Psychiatry Research, 227(1), pp. 46–51.

Zhu, C. et al. (2020) ‘Vitamin D supplementation improves anxiety but not depression symptoms in patients with vitamin D deficiency’, Brain and Behavior, 10(11), e1760.

Vitamin D — tissue-specific effects on COMT

Pertile, R.A.N., Cui, X. and Eyles, D.W. (2016) ‘Vitamin D signaling and the differentiation of developing dopamine systems (1,25(OH)₂D3 upregulates COMT expression and binds the COMT promoter in neurons)’, Neuroscience, 333, pp. 193–203.

Sharan, C. et al. (2011) ‘Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase (down-regulates COMT expression and activity in fibroid cells)’, Fertility and Sterility, 95(1), pp. 247–253.

Vitamin D — deficiency in Black women / darker skin

Ames, B.N., Grant, W.B. and Willett, W.C. (2021) ‘Does the high prevalence of vitamin D deficiency in African Americans contribute to health disparities?’, Nutrients, 13(2), 499.

Cashman, K.D. et al. (2021) ‘Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude’, European Journal of Nutrition, 61, pp. 1015–1034.

Aloia, J.F. et al. (2007) ‘Dose response to vitamin D supplementation among postmenopausal African American women’, American Journal of Clinical Nutrition, 86(6), pp. 1657–1662.

Vitamin D — uterine fibroids

Eltoukhi, H.M., Modi, M.N., Weston, M., Armstrong, A.Y. and Al-Hendy, A. (2013) ‘Racial and ethnic differences in the pathogenesis and clinical manifestations of uterine leiomyoma’, Seminars in Reproductive Medicine, 31(5), pp. 335–343.

Baird, D.D. et al. (2013) ‘Vitamin D and the risk of uterine fibroids’, Epidemiology, 24(3), pp. 447–453.

Halder, S.K., Sharan, C. and Al-Hendy, A. (2015) ‘Role of vitamin D in uterine fibroid biology’, Fertility and Sterility, 104(3), pp. 698–706.

Harmon, Q.E. et al. (2022) ‘Vitamin D and uterine fibroid growth, incidence, and loss: a prospective ultrasound study’, Fertility and Sterility, 118(6), pp. 1127–1136.

Ashari, H. et al. (2020) ‘Correlation of low serum vitamin-D with uterine leiomyoma: a systematic review and meta-analysis’, Reproductive Biology and Endocrinology, 18, 85.