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Catechol-O-methyltransferase Features

Catechol-O-Methyltransferase (COMT) is one of the several enzymes that degrade dopamine, epinephrine, and norepinephrine. COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive or executive function (prefrontal cortex).

COMT helps break down estrogen byproducts that have the potential to cause DNA mutations and cause cancer. 

If you have higher COMT levels:

  • Mucuna  to increase dopamine,
  • Tyrosine to increase dopamine,
  • EGCG/Tea (COMT inhibitor),
  • Epicatechins/Chocolate (COMT inhibitor),
  • Luteolin 

If you have lower levels of COMT, the following may counteract some of the effects of the gene:

  • SAM-e – however, this can increase dopamine levels in people who already have high dopamine.
  • Methyl Guard Plus to ensure adequate B6, B12, folate and betaine to support the formation of S-adenosylmethionine and prevent elevated homocysteine; S-adenosylhomocysteine inhibits COMT activity.
  • Ensure adequate anti-oxidants to prevent oxidation of dopamine and pro-carcinogenic 4-hydroxyestrogens,
  • Magnesium Citrate (magnesium is a cofactor)
  • Be careful of the following supplements that are the targets of COMT: quercetin, rutin, luteolin, EGCG, catechins, Epicatechins, Fisetin, Ferulic acid, Hydroxytyrosol
  • Avoid excessive alcohol consumption.  Since alcohol-induced euphoria is associated with the rapid release of dopamine in limbic areas, low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of alcohol dependence.
  • Avoid stimulants, especially amphetamines.  Amphetamines may do worse with people who are AA, but later studies did not replicate this.  It could be differences in study design.
  • Avoid chronic stress (stress hormones require COMT for degradation and compete with estrogens),

Catechol Estrogens, Cancer and Autoimmunity

Catechol estrogens form from CYP enzymes breaking down Estradiol and Estrones. Catechol estrogens can break DNA and cause cancer and autoimmune conditions. COMT methylates (using SAM) and inactivates these catechol estrogens (2- and 4-hydroxycatechols). The products of COMT methylation are 2- and 4-o-methylethers, which are less harmful and excreted in the urine (they have anti-estrogen properties). However, if COMT is inhibited too much either because of genetics or dietary inhibition, it should result in higher levels of catechol estrogens, especially if glucuronidation and sulphation pathways are not working. 4-Hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumour model, whereas 2-hydroxylated metabolites were without activity. 4-Hydroxyestrogen can be oxidized to quinone intermediates that react with purine base of DNA, resulting in depurination adduct that generates cancerous mutations. Quinones derived from 2-hydroxyestrogens are less toxic to our DNA. Estrone and estradiol are oxidized to a lesser amount to 2-hydroxycatechols by CYP3A4 in the liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a larger extent .

It has been observed that tissue concentration of 4-hydroxyestradiol is highest in malignant cancer tissue, out of all the estrogens. The concentration of these Catechol Estrogens in the hypothalamus and pituitary are at least ten times higher than parent estrogens. Catechol Estrogens have potent endocrine effects and play an important role in hormonal regulation (those produced by hypothalamus and pituitary).

Increased availability of estrogen and estradiol for binding and hypothalamic sites would facilitate the formation of Catechol Estrogens. These estrogens affect Luteinizing Hormone (LH) and maybe follicle-stimulating hormone (FSH) and prolactin. Catecholestradiol competes with estradiol for estrogen binding sites in the anterior pituitary gland and hypothalamus and dopamine binding sites on anterior pituitary membranes.

Other possible mechanisms of inactivation of these catechol estrogens include conjugation by glucuronidation and sulphation. High concentration of 4-hydroxylated metabolites caused insufficient production of methyl, glucuronide or sulfate conjugate which in turn results in catechol estrogen toxicity in cells and oxidation to semiquinone and quinone, which may reduce glutathione (GSH). These oxidation products could lead to DNA mutations. The quinone/semiquinone redox system produces superoxide ions (O2¯ ) which can react with NO to form peroxynitrite, which could cause DNA damage. In summary, CEs lead to the production of potent ROS, capable of causing DNA damage, thus playing an important role not only in causing cancer but also in systemic lupus erythematosus (SLE) and Rheumatoid Arthritis. The abilities of the estrogens to induce DNA mutations were ranked as follows: 4-hydroxyestrone (most damaging) > 2-hydroxyestrone > 4-hydroxyestradiol >2-hydroxyestradiol > > Estradiol, Estrone.

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RELATED

Nutrient Correlation Wheel on Estrogen

SpectraCell Labs

Choline – Estrogen stimulates the breakdown of phosphatidylcholine (cell membrane) so those with low estrogen (postmenopausal women) require more choline; Detoxifies excess estrogen via methylation pathway.1,32,33

Folate –  Deficiency reduces estrogen levels; Excess folate is linked to some types of estrogen-related breast cancer; Detoxifies excess estrogen via methylation pathway; Regulates estrogen’s effect on genes.1,2,3

Vitamin B6 – Protects genes from estrogen-induced damage thus lowering risk of hormone related cancers; Detoxifies excess estrogen via methylation pathway; Estrogen-based oral contraceptives cause B6 deficiency.4,5,6,7

Vitamin D – Regulates synthesis of estradiol and estrone; Enhances estrogen’s protective effect on bones.8,9,10

Vitamin C – Increases the most potent estrogen (estradiol) in women on hormone therapy; Lowers aromatase (enzyme that converts testosterone to estrogen) in ovaries.11.12.13

Vitamin K – Inhibits estrogen activity by binding to estrogen receptors; Lowers the ratio of estradiol (strong estrogen) to estrone (weaker estrogen).14,15

Vitamin E – Deficiency impairs estrogen detoxification pathway; Some forms of vitamin E inhibit estrogen action, especially in breast tissue; Low levels linked to higher estrogen.1,16,17

Vitamin A – Helps metabolize the biologically active estrogen (estradiol) to an inactive form (estrone).18,19

Calcium –  Calcium-D-glucarate lowers estradiol levels; Helps breakdown estrogen in the liver and convert it to a less toxic form.1,20,21

Selenium – Estrogen levels affect how selenium is distributed to various tissues in the body.22,23

Magnesium – Cofactor for the enzyme that removes toxic forms of estrogen (catechol-O-methyltransferase); Estrogen alters magnesium levels throughout menstrual cycle.1,24,25,26

Zinc – Estrogen lowers risk of zinc deficiency; Zinc dependent proteins metabolize estrogen.26,27,28

Cysteine –  Prevents oxidation of estrogen into a dangerous form that causes breast cancer.29,30,31

Estrogen and female anxiety

The Harvard Gazette

Low estrogen levels can make women more vulnerable to trauma at some points in their menstrual cycles, while high levels of the female sex hormone can partially protect them from emotional disturbance, according to new research.

…Low estrogen levels can make women more vulnerable to trauma at some points in their menstrual cycles, while high levels of the female sex hormone can partially protect them from emotional disturbance, the research suggests. 

Depression and anxiety disorders are twice as common in women as in men, but the reason for this gender difference is unclear. The new work, reviewed by Harvard’s Mohammed Milad and colleagues in a commentary, suggests that women are most at risk for symptoms of post-traumatic stress disorder (PTSD) when their estrogen is low during the menstrual cycle.

…Estrogen calms the fear response in healthy women and female rats, according to the Harvard researchers, who were led by Kelimer Lebron-Milad, an HMS instructor of psychiatry. The Emory researchers, led by postdoctoral researcher Ebony Glover, showed that the same is true for women suffering from PTSD. The higher the estrogen was in their blood when they trained on a fear-extinction task, the less likely women were to startle.

…PTSD is common in women after a trauma such as rape or sexual assault, which studies say are experienced by 25 to 30 percent of women in their lifetimes, and the symptoms last on average four times as long in women as in men after trauma. This new research suggests the reason for this susceptibility may be the monthly menstrual change in estrogen.

Tank Estradiol and Lose Metabolic Flexibility: Pitfalls of Lupron and Oophorectomy

Hormones Matter

Steroid hormones regulate metabolic flexibility at the level of the mitochondria. Estradiol, the most frequently studied among the steroid hormones, plays a pivotal role in determining how food fuel is converted into cellular fuel or ATP. 

When we eliminate estradiol with medications such Lupron and other GnRH agonists or antagonists, or when we remove a woman’s ovaries, depleting her primary source for estrogen synthesis, metabolic flexibility diminishes significantly.*  

With the lack of metabolic flexibility comes a number of health issues, some noticeable, like weight gain, and others less noticeable, at least initially, like cardiac and neurodegenerative diseases.

READ MORE

Chronic pain:antidepressants not painkillers recommended

BBC

Doctors are being advised not to prescribe common painkillers, including paracetamol and ibuprofen, for patients with chronic pain not caused by an injury or other medical condition.

The National Institute of Health and Care Excellence (NICE) said there was little evidence they help.

And it suggests there is evidence long-term use can be harmful.

Its draft guidance recommends antidepressants, acupuncture or psychological therapy instead.

… They could also consider recommending a course of cognitive therapy, aimed at helping patients accept their condition or change the way they thought about it.

… The guidelines acknowledged there is a lot of uncertainty in this diagnosis, and “normal or negative test results can be communicated in a way that is perceived as being dismissive of pain”.

When it comes to chronic pain more broadly – defined as pain that “persists or recurs” for more than three months, no matter the cause – NICE advises using these new guidelines alongside existing guidance on the management of specific conditions.

That includes headaches, back pain, arthritis and endometriosis.

Tapering strips

Tapering Strip

The reduction or discontinuation of psychiatric medications such as antidepressants, antipsychotics or anxiolytics can cause physical and psychological withdrawal and rebound symptoms. Withdrawal symptoms may be so severe that patients are unable to continue reducing the dose, regardless of the medication’s efficacy.


In 2010, the Tapering Project was started to address these problems through the development of tapered doses of medication provided in strip packaging: tapering strips.

Tapering strips allow patients to regulate the tempo of their dose reduction over time and enable them to taper more gradually, conveniently and safely than is possible using currently available standard medication, thereby preventing withdrawal symptoms.

What

In a tapering strip, medication is packaged in a roll or strip of small daily pouches. Each pouch is numbered and has the same or slightly lower dose than the package before it.p

How

Strips come in series covering 28 days and patients can use one or more strips to regulate the tempo of their dose reduction over time. Dose and day information printed on each pouch allow patients to precisely record and monitor the progress of their reduction.

For whom?

Tapering strips are developed for medication in cases where doing so improves the medical care available and meets an unmet need. See the list with available tapering strips.

Researchers Provide Guidance for Reducing and Stopping Psychiatric Drugs

Mad in America

In a new article in European Neuropsychopharmacology, researchers Mark Horowitz and David Taylor provide guidance for tapering psychiatric drugs, whether for full discontinuation or to reduce the dose. They suggest a slow, individualized taper to minimize withdrawal effects.

“The general principle when reducing or stopping psychiatric medications is as follows. Make a small reduction, monitor for withdrawal effects or destabilization of the patient, then ensure stability before making further reductions. Reductions should probably be made in smaller and smaller increments because of the pharmacology of the drugs; the final dose before completely stopping will need to be very small.”

Horowitz and Taylor have previously written about this approach for antidepressants in Lancet Psychiatry and for antipsychotics in JAMA Psychiatry (with Sir Robin Murray).

…Some people may require months or even years to slowly decrease their dose before eventually stopping the drug. The researchers write:

“Withdrawal effects (and relapse) might be minimized by stopping psychiatric drugs over a period long enough for underlying adaptations to the drug to resolve.”

According to the researchers, based on studies of the drugs’ effects on the brain, psychiatric drugs impact the brain along with a hyperbolic relationship. That is, at low doses, small adjustments have huge impacts—but at high doses, even large adjustments have less of an impact.

“The relationship between dose of a psychiatric drug and its effects is hyperbolic,” they write. “This is a consequence of the law of mass action: when there are few molecules of a drug present at the site of action, every additional molecule has a large incremental effect, but when higher concentrations are present each additional molecule has less and less effect, as receptors become saturated.”

This means that dose reductions should not be linear (reduced by the same amount each time, e.g., 40, 30, 20, 10, 0 mg). Instead, one strategy is to reduce the current dose by 10% each time, especially ensuring that the last adjustment—to full discontinuation—is very small.

Endometriosis pathogenesis : role played by the oxidative stress due to MTHFR mutations

FertStert

Endometriosis can be explained by MTHFR mutations.

On the one hand, polymorphisms of MTHFR induces oxidative stress through the increased homocysteine level (Guo, 2016).

On the other hand, the oxidative stress is implicated in the pathophysiology of endometriosis by causing a general inflammatory response in the peritoneal cavity (Augoulea, 2009) and therefore impairs the fertility of the female patients.

To our knowledge, these preliminary results are the first in the literature showing the role played by MTHFR in the endometriosis genesis of infertile patients.

Therefore, by improving the methylation and decreasing the oxidative stress of the endometriosis patients, treating MTHFR mutation carriers improves the quality of the gametes and their ART (Assisted Reproductive Technologies) outcomes.

Moody Bitches: The Truth About the Drugs You’re Taking, the Sleep You’re Missing, the Sex You’re Not Having and What’s Really Making You Crazy

AMAZON

Overworked? Exhausted? Powering between career, family and friends and frazzled and libido-less as a result? No wonder you’re moody! But as New York psychiatrist Julie Holland explains in her radical and eye-opening new book, the first step to overcoming the lows is to accept that being testy is in our nature – we were made to be Moody Bitches.

Being a successful modern woman is hard, and for so many of us the constant flux in our hormones and the dip and dives our mood swings take makes it that much harder. For over 17 years, women have visited celebrated psychopharmacologist Dr Julie Holland looking for the miracle cure to eradicate these feelings. Now, in her illuminating and honest Moody Bitches, she details the invaluable advice she shares with her patients, revealing how suppressing our natural emotions is actually damaging. Instead she offers tried and tested alternatives to help keep the moods under control, making exhaustion and low sex-drive a thing of the past.

From the meds you can trust to those you can’t; from the foods you should be eating, the healthy behaviours you should be practising and the herbal remedies that actually work, Dr Julie imparts wisdom from years of not only professional but personal experience too. Simple yet revolutionary, Moody Bitches is the life-changing self-help book for women and those who love them.

Gut microbial metabolites in depression: understanding the biochemical mechanisms

Microbial Cell

Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products.

Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism.

This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules – neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins – play in the context of emotional behaviour.

The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behaviour.

We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behaviour: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation.

Elucidating these mechanisms is essential to expand our understanding of the aetiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules.

Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder.

 

Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers

Psychopharmacology

There is now compelling evidence for a link between enteric microbiota and brain function. The ingestion of probiotics modulates the processing of information that is strongly linked to anxiety and depression, and influences the neuroendocrine stress response. 

This study found that taking a prebiotic called galactooligosaccharides for three weeks significantly reduced the amount of cortisol, a primary stress hormone in the body.

Catechol-O-methyltransferase polymorphism is associated with increased uterine fibroid risk in different ethnic groups.

J Soc Gynecol Investig

Fibroids – uterine leiomyomas (ULMs) – are estrogen-dependent tumors that are more common in African American women. The aetiology for such ethnic disparity is currently unknown. Catechol-O-methyltransferase (COMT) is an essential enzyme in estrogen metabolism.

Women with the high-activity COMT genotype are 2.5 times more likely to develop ULMs than women with other genotypes. The prevalence of this genotype was significantly higher in African American women (47%) compared with white (19%) or Hispanic (30%) women. Myometrial cell lines expressing the Val/Val genotype exhibited significantly enhanced responses to estrogen in proliferation and in estrogen-responsive element reporter assays. COMT-specific inhibitors reversed such a response and induced apoptosis. Myometrial specimens from Val/Val women demonstrated distinct estrogen-regulated gene expression that was consistent with enhanced proliferation and decreased apoptosis.

The results provide a possible explanation for the higher prevalence of ULMs among African American women and offer a potential new target for nonsurgical treatment using COMT inhibitors.

Why We Can’t Sleep: Women’s New Midlife Crisis

Amazon

‘I look at the clock… it’s 3am’: Why can’t women sleep?

…A new book from the US … appears at first glance to be more of a feminist manifesto for Generation Xers than a self-help manual for insomniacs. On closer inspection, though, a picture starts to form that’s recognisable to any woman who is knee-deep in the mothering, marriage and career years. Disregarding the generational focus of the book’s premise, it offers, not a cure, but insight and some unpalatable news about the lives of women today. Every right we’ve earned, every advance we’ve made, every career we are now free to embark on continues to co-exist with our near full-time engagement in the oldest job in the world: keeping hearth and home.

Despite a century of emancipation, women still do most of the backstage work that keeps the show on the road. Scratch the surface of this national insomnia pandemic and you discover that inequality is at the heart of the malaise. Aside from sexual politics and headline grabbers, such as #MeToo, most women’s lives aren’t improving quantifiably, they’re just different from 50 years ago.

“It’s great that men and women are equals in the workplace, but what this means in reality is that women are effectively taking on twice the load,” says Dr Elle Boag, associate professor in social psychology at Birmingham City University. “Only too often we do the work, the domestic labour and the childcare (to be fair, sometimes these chores are shared). We’ve adopted this multitasking role and it’s become normative.” So, it’s no surprise that when we go to bed we find we can’t switch off.

5 Breathing Techniques to Help Reduce Stress

Dr Chattergee

Breathing is information. The more stressed you feel, the faster you breathe, and your brain will notice this and read it as a signal that things are not going well. That fast, shallow breathing which happens when you’re stressed is effectively telling your brain that you’re running from a lion. But the reverse of this rule is also true: if you breathe slowly, you’re giving your brain a signal that you’re in a place of calm. You will start to feel less stressed. Studies have even shown that the right kind of breathing can reduce our perception of pain. Both the pace at which you breathe and how deeply you breathe change your stress response. If all you do for one minute is slow your breathing down and aim for six breaths (one breath is in and out) in that minute, it will reduce the stress state and stimulate the thrive state.

A daily practice of breathing – Breathing practice is especially worth considering if you’re the kind of person who finds meditation difficult. You don’t have to stick to the same practice each time. Play around. Listen to your body. Experiment. I’m sure that, within a few days, you’ll find a technique that works for you. Aim to do at least one of these practices every day. Even one minute per day of focused, intentional breathing can make a big difference.

Gut Microbes linked to estrogen breakdown in menopause

MedScape

Postmenopausal women with a more diverse population of gut bacteria may be more efficient at breaking down estrogen, a new study suggests. Because estrogen plays a role in causing breast cancer, researchers speculate a healthy bacterial population may lower the risk for cancer.

“The composition and diversity of the intestinal microbiota were associated with patterns of estrogen metabolism that are predictive of the risk of breast cancer in postmenopausal women,”

Estrogen is metabolized in the liver and in other tissues such as the breast, yielding fragments that are excreted in urine or, through bile, into the gut. Gut microbes can degrade these metabolites, allowing them to be reabsorbed into the bloodstream and further recycled in the liver. Dr. Fuhrman and colleagues suggest that women whose gut bacteria more efficiently process estrogen may have a lowered risk for breast cancer.

Get better now

I have had a drastic improvement since following my plan to manage my endometriosis. My pain and nausea have massively reduced.
- P. G.
Not only totally cured, full of energy and healthy, but also PREGNANT, which I didn’t think would be possible!!
- I. W.
I have lost 2 stone, and haven’t had a migraine for 11 weeks! That has not happened since I was 15.
A. L
I could finally sleep, my hair was growing back, my hormones began to calm down and my long Covid symptoms eased!
- J C.
A change of diet and some short term supplements have completely resolved issues I thought would never go away.
- R. E.
Today I’m completely free of pre-menstrual anxiety and antidepressants.
- E. W.
I was amazed at how quickly my weight started dropping and soon my migraines all but disappeared.
- K. C.
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Sandra Ishkanes
Functional Medicine Practitioner
BSc MA DipION

sandra@gynecologic.dream.press
Brighton, UK

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Connecting women, science and spirit, the Gynelogic Sunday Supplement delivers a bi-monthly dose of  news, views and reviews, as seen through my lady lens.