Hi Iwona, trust you are doing well?
Hi Iwona
Have you ever wondered if our genes affect our hormones?
Many women struggle with Estrogen Dominance issues and might not even realize it. Some of the symptoms include: Mood swings, tender breasts, PMS, heavy periods, weight gain, fatigue, depression and anxiety, sluggish metabolism, insomnia, brain fog, hypothyroidism. Estrogen Dominance might also contribute to endometriosis, migraines, menstrual cramps and low sex drive.
Estrogen dominance doesn’t necessary mean that one has got elevated estrogen levels, but rather insufficient progesterone to balance out the estrogen.
We know that genetic variants can play a role in how well someone will produce estrogens, or break them down, how well they can eliminate them from the body. Our hormones are influenced by our nutritional status and many enzymes that may be up, or down-regulated as a result of our unique single nucleotide polymorphisms (SNPs), I call them genetic variants.
What are the pathways that break down estrogen?
Those of us who can tolerate higher amount of estrogen will convert it into the metabolites at a faster rate. And we will also metabolise it probably down a safer pathway to 2-hydroxy metabolism, and then we can get rid of that through methylation, which is the COMT enzyme, glucuronidation, sulfation, or the conjugation of glutathione.
Genetically, many women are predisposed to having troubles with estrogen metabolism.
At the end of its life estrogen is converted in the liver via a series of phase 2 enzymes which prepare it for excretion through the bowel and kidneys.
To determine risk and cause of estrogen dominance we can look at the pathways that break down estrogen
COMT– Catechol-O-Methyltransferase (COMT) is the enzyme that methylates the estrogens, in other words it helps to inactivate and break them down. The genetic SNP COMT V158M is the primary SNP identified in estrogen methylation. Individuals with COMT V158M +/+ status will have decreased function of this enzyme and prone to reduced methylation of estrogens. Since COMT is most commonly known to break down the neurotransmitters dopamine, adrenaline and noradrenaline, and, is associated with anxiety, women with slow COMT find that their anxiety increases just before period.
Even thought the #COMT enzyme breaks down estrogen, it is also epigenetically slowed down by #estrogen.
Thus, the more estrogens a woman or man has, the slower their COMT system will be working.
We need to remember that all enzymes require a cofactor to work efficiently. In the case of COMT, the cofactor is Magnesium. And being a methyl transferase (Catechol-O-Methyltransferase), you need to have plenty of folate and B vitamins to make those methyl groups. Ellagic acid, a compound derived from blackberries, raspberries and blueberries, has been shown to stimulate COMT enzyme.
Cytochrome P450 Enzymes The vast amount of our natural detoxification process is done in the liver using the cytochrome P450 system. Some of the CYP450’s may be genetically coded for up-regulated function, others for down-regulated functions.
Knowing whether a certain SNP encodes for up-regulated enzyme, or downregulated enzyme function is very significant, especially with respect to estrogen metabolism
CYP17A1 hydroxylates pregnenolone and progesterone to androstenedione and testosterone, the initial step in estrogen biosynthesis. Variants cause up regulated enzymatic activity and higher circulating estrogens.
CYP19A1 encodes for aromatase enzyme which converts testosterone and androstenedione into Estrone (E1) or Estradiol (E2). Variants on CYP19A1 can cause upregulated conversion of androgens to estrogens.
Once aromatase enzymes generete E1 and E2, the hormones are then Hydroxylated by the enzymes CYP1A1, CYP1B1 and CYP3A4.
CYP1B1 SNPs can cause an up-regulation of this enzyme causing an increase in the toxic 4-hydroxyestrone intermediary metabolite. If this is combined with COMT SNPs it can increase the risk of estrogen related cancers and PMS.
CYP1A1 is important for the conversion of estradiol to 2-OH-estradiol which is considered the safer form of estrogen. Those with SNPs to this enzyme will be less able to convert estrogen to the less toxic form and also might have higher levels of estrogen.
Some variants on CYP1A1 cause up-regulated enzyme activity which is desirable for estrogen metabolism but can lead to high amounts of circulating pro-carcinogens if phase II detoxification pathways (methylation, sulphation, glucuronidation and glutathione conjugation) are not working optimally.
CYP1A1 enzyme is often used in nutritional therapy, because pulling estradiol or estrone out of circulation and through CYP1A1 will divert these estrogens from going down the less desirable CYP3A4 and CYP1B1 enzyme pathways.
There are other enzymes that are involved in the metabolism of estrogens like GSTM1, NQO1, SULT1A1 and UGT1A1. Writing this article I wanted to show that there are genetic variations that predispose both men and women to higher estrogen levels. If you can interpret genetic tests you will be able to find connections not only to increased estrogen levels but also predisposition to PCOS, low levels of testosterone in men and other hormonal imbalances.
A Trained Nutritional Therapist or Functional medicine consultant can determine in which specific aspects of the detoxification pathway the client is lacking and provide the appropriate nutritional support. Many botanicals and nutraceuticals can be helpful in restoring and maintaining healthy detoxification.
It ts important to address however, that genetics testing is not enough by itself to understand what the problems are.
Ideally, one pairs a genetics test with a urinary sex hormone test. Urinary sex hormone testing is now the industry standard, because it is providing an evaluation of estrogen metabolites.