Estradiol, the most potent of the three primary estrogens (estradiol, estrone, and estriol), plays an essential role in maintaining the health of nearly every tissue in the body, in particular the reproductive tissues, brain, skin, bone, liver, and cardiovascular system. Physiological levels of estradiol formed cyclically with natural progesterone throughout a woman’s premenopausal years maintain the health and youthfulness of these tissues.
Menopause results in the loss of ovarian estrogen production and a consequent drop in circulating levels of estradiol. If, during menopause, estradiol drops well below the lower end seen in premenopausal women, this can be associated with adverse effects in the reproductive tissues (incontinence, vaginal dryness), brain (lowered neurotransmitters, increased hot flashes and night sweats), skin (more rapid aging), bone (accelerated loss and greater risk for osteoporosis and fracture), liver (compromised hormone metabolism and reduced synthesis of hormone binding globulins, reducing the circulating half-lives of hormones that are bound to them), and cardiovascular system (increased risk for insulin resistance, diabetes, and cardiovascular disease).
Needless to say, estrogens, and specifically estradiol, are essential for maintaining health in both premenopausal and postmenopausal women.
While estradiol plays this significant role in maintaining health, it can also have the opposite effect when certain catechol metabolites are formed in excess and not eliminated properly. Two separate enzymes are involved in converting estradiol and estrone to their respective 2- and 4-catechol derivatives. 2-catechol estrogens are formed by the interaction of the cytochrome enzyme designated CYP1A1. 4-catechol estrogens are formed from CYP1B1. If methylated, both 2- and 4-catechols are essentially rendered inert (harmless), and are excreted in urine. In a healthy individual the formation of estrogens, their beneficial utilization by tissues, and their subsequent elimination in urine and feces are biochemically well coordinated and balanced. However, estradiol and estrone can turn bad in the same way as beneficial oils can go rancid. In fact, the process is very similar and involves oxidation of the estrogens to highly reactive and potentially dangerous metabolites. If these metabolites are not properly channeled down safe pathways of elimination, this could be damaging to some tissues in a way that may eventually be expressed as cancer, most notably breast cancer.
In the presence of excessive reactive oxygen species (ROS) such as peroxylipids, formed mostly from transfats consumed in the diet, the catechol estrogens are further co-oxidized to highly reactive 2- and 4-estrogen quinones. In fact, the reason for avoiding trans-fats to protect the cardiovascular system against damage is the same reason to avoid them to protect the breasts from damage that may lead to breast cancer. ROS such as peroxylipids are very electrophilic (electron hungry) molecules that, under normal circumstances, are inactivated rapidly by interaction with glutathione (the most abundant nucleophilic molecule in tissues, which donates electrons to reactive electrophiles to inactivate them) and glutathione transferase. However, if ROS are in abundance and glutathione levels are low, the highly reactive catechol quinones can bind to DNA, causing mutations that can lead to cancer. 4-quinone estrogens are considered much more dangerous than 2-quinone estrogens because the former cause DNA damage that leads to more permanent (unfixable) mutations (2) that can produce aberrant cancer cells, and given the right circumstances (e.g., a compromised immune system) eventually a breast tumor.
General guide to interpretation:
Lower levels of estradiol and estrone, and higher relative levels of 16-hydroxyestrone and estriol are associated with lower breast cancer risk in postmenopausal women not supplementing with exogenous estrogens (i.e., estrogen replacement therapy). However, this is also dependent on the level of catechol estrogens present, their relative levels (2 vs 4), and how well they are methylated.
If estrogens (estradiol and estrone) are low, as are the catechol estrogens, this would portend a lower risk for breast cancer, but possibly a higher risk for symptoms (e.g., hot flashes), conditions (e.g., bone loss), and diseases (e.g., cardiovascular disease) associated with estrogen deficiency. When estradiol, estrone, and estriol are low, the methylated estrogens would be expected to be low also because of low levels of precursor catechol estrogens. If, however, catechol estrogens are elevated, regardless of the estradiol or estrone level, and methylated estrogens are low, this could indicate higher risk. Keep in mind that the catechol estrogens are not dangerous per se, unless converted to more reactive quinone estrogens. Whether the quinone estrogens damage DNA, or are rapidly inactivated will depend on many factors that are modifiable through diet and nutritional supplements. Excessive dietary consumption of unhealthy trans-fats oxidizes catechol estrogens to more dangerous quinone estrogens, and if glutathione is not present in adequate amounts the quinone estrogens are more likely to damage DNA, and lead to mutations that could be eventually expressed as breast cancer.
1) Prevention strategies begin with reducing the overall burden of excessive estradiol and estrone in the absence of diminished levels of progesterone, which often occurs in the early phases of menopause (perimenopause-ages 35-55). Progesterone supplementation helps reduce the estrogen burden by increasing the conversion of E2 to E1 (activates 17-beta-hydroxysteroid dehydrogenase), and E1 to E1-sulfate (E1-SO4), an inert form of estrogen that will not enter target cells. 2) 2-hydroxy catechol estrogens are safer than 4-hydroxy catechol estrogens; these are created from the cytochrome enzyme CYP1A1, which is activated by phytochemicals found in cruciferous vegetables (cauliflower, broccoli, cabbage), and by iodine, progesterone, and Vitamin D. If 2-hydroxy catechol estrogens are low, or are low relative to the 4-hydroxy catechol estrogens, consider lowering consumption of meats and increasing consumption of green leafy and cruciferous vegetables.
3) 4-hydroxy catechol estrogens are created from the cytochrome enzyme CYP1B1, which is induced by man-made petrochemical toxins (some drugs, oils, plastics, pesticides, household chemicals, etc.) that contaminate our food, water, and air. If 4-hydroxy catechol estrogens are elevated, consider identifying and avoiding exposure to these petrochemical products as much as possible.
4) As the good (2-OH-catechols) and bad (4-OHcatechols) are both rendered inactive by COMTmediated methylation, it is important to maintain adequate substrates for COMT. These include vitamins B6, B12, and folate, as well as betaine. Excessive estrogens tend to deplete these vitamins, so supplementation during times of estrogen excess (often at perimenopause) is vital to clearing catechol estrogens such that they are less likely to spill over into the highly reactive and mutagenic 4-estrogen quinones.
5) Prevent the conversion of the 2- and 4-catechol estrogens into their respective quinones, and provide adequate substrate to inactivate them if they do. The 2- and 4-catechol estrogens are activated to their quinones by oxidized fats and some heavy metals such as arsenic and mercury. Removal of bad (trans) fats from the diet and countering the heavy metals with adequate beneficial elements such as iodine and selenium are important for preventing further oxidation of estrogen catechols to estrogen quinones.
6) Iodine, progesterone (only when estrogens are within normal to high physiological range of a premenopausal woman), and Vitamin D have all been shown to increase formation of 2-hydroxy catechol estrogens, and decrease the relative concentration of the more dangerous 4-hydroxy catechol estrogens. Consider supplementation if any of these is found to be low by testing.
7) Glutathione is important as the last step in detoxification of quinone estrogens. Excessive medications, hormone therapy, and exposure to environmental toxins such as heavy metals, cigarette smoke and excessive industrial air pollution results in high utilization and lower levels of glutathione. Cysteine is the most limiting amino acid as regards glutathione synthesis, and vitamin C is an essential nutrient for reactivation of oxidized glutathione. Selenium also plays an important role in glutathione’s effectiveness as an anti-oxidant, and low levels of selenium have been associated with higher risks for cancers of the breasts and prostate. If quinone estrogens are elevated, particularly if the methylated catechol estrogens are low, consider foods high in sulfur containing amino acids (allium foods like garlic and onions) and/or supplementation with N-acetylcysteine and Vitamin C. Also consider supplementation with selenium, an essential element in many anti-oxidant enzymes, if it is found to be low.
8) Inadequate production of melatonin has been linked with breast cancer. Melatonin has antiestrogenic actions, acting as a selective estrogen receptor modulator in breast tumor cells, and also downregulating aromatase, thus reducing local estrogen synthesis from androgenic precursors.
Because of the oncostatic effects of melatonin, breast cancer risk can be reduced by getting adequate sleep and/ or reducing exposure to light at night.
Lee JR, Zava D, Hopkins V. What your doctor may not tell you about breast cancer. How hormone balance may save your life. Warner Books, Inc., New York, NY, 2002. Chapter 6.
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Falk RT, Brinton LA, Dorgan JF, Fuhrman BJ, Veenstra TD, Xu X, Gierach GL. Relationship of serum estrogens and estrogen metabolites to postmenopausal breast cancer risk: a nested casecontrol study. Breast Cancer Res. 2013;15:R34.
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Cos S, Gonzalez A, Martínez-Campa C, et al. Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev. 2006;30:118-28.
Low estradiol in premenopausal women is unusual unless they experience an anovulatory cycle (no ovulation) or are supplementing with birth control pills, which can suppress endogenous (made in the body) production of estrogens by the ovaries. A low estradiol level is much more common in postmenopausal women or in women of any age who have had their ovaries surgically removed (oophorectomy) and/or those who have not been treated with hormone replacement. Symptoms and conditions commonly associated with estrogen deficiency include hot flashes, night sweats, sleep disturbances, foggy thinking, vaginal dryness, incontinence, thinning skin, bone loss, and heart palpitations.
High estradiol in premenopausal women is usually caused by excessive production of androgens (testosterone and DHEA) by the ovaries and adrenal glands, which are converted to estrogens by the ‘aromatase’ enzyme found in adipose (fat) tissue. When estrogen levels are high in postmenopausal women, this is usually due to estrogen supplementation or slow clearance from the body (sluggish liver function). Excess estrogen levels, especially in combination with low progesterone, may lead to the symptoms of “estrogen dominance,” including: mood swings, irritability, anxiety, water retention, fibrocystic breasts, weight gain in the hips, bleeding changes (due to overgrowth of the uterine lining and uterine fibroids) and thyroid deficiency. Estradiol, even at normal, premenopausal levels, can cause estrogen dominance symptoms if not balanced by adequate progesterone. Diet, exercise, nutritional supplements, cruciferous vegetable extracts, herbs and foods that are natural aromatase inhibitors and bioidentical progesterone can help to reduce the estrogen burden and symptoms, naturally.
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