Page 1, 2
Funneling Estrogen Through the Safest Pathway
As we mentioned earlier, there are several ways in which estrogens are metabolized in the body, including the 2-, 4-, and 16-hydroxylation pathways. A type of estrogen produced in the body known as 17beta-estradiol can be converted into 16alpha-hydroxyestrone (16alphaOHE1) or 2-hydroxyestrone (2OHE1). Compared with 2OHE1, which can act as an anti-estrogen, 16alphaOHE1 is extremely estrogenic; and in cell culture studies, it caused estrogen-sensitive breast cancer cells to multiply.32 Consequently, researchers have hypothesized that changing the way 17beta-estradiol is metabolized from the 16alphaOHE1 pathway toward the 2OHE1 pathway could lower the risk of estrogen-sensitive cancers, including breast cancer.33,34
However, the scientific community is debating the extent to which the urinary 2OHE1:16OHE1 ratios can protect against breast cancer risk, based on conflicting results among studies. A trial of 272 women with breast cancer and 291 controls concluded that the ratio of 2-OHE1 to 16alpha-OHE1 did not predict breast cancer risk.35 In another study of 66 breast cancer patients and 76 control patients, the mean level of urinary 2-OHE1, which is thought to be protective against breast cancer, was actually higher in the women with breast cancer compared with controls.36
Evidence to the contrary includes one study of 65 women with breast cancer, in which the ratio of 2OHE1 to 16OHE1 significantly predicted whether the women would develop breast cancer or not.37 In another study of 42 postmenopausal breast cancer patients and 64 women who visited the hospital for a routine mammogram, 16OHE1 was a strong risk factor for breast cancer as was a higher level of 16OHE1 compared with 2OHE1.38 Another group of researchers studied 10 normal women and 33 breast cancer patients. The scientists found that there was greater 16 alpha-hydroxylation in the women with breast cancer.39
A recent trial offered one explanation as to why not all studies show that higher levels of 2-hydroxylation are associated with breast cancer risk. In this trial, researchers measured levels of the estrogens estradiol, estrone, and 13 metabolites in 1,298 postmenopausal women with breast cancer and 1,524 matched controls.40 There was a strong link between total estrogen levels and an increased risk of breast cancer. When the researchers normalized estrogen levels in the women, they observed that both a relative increase in levels of 2-hydroxylation and an increase in the ratio of 2-hydroxylation to 16-hydroxylation resulted in a lower risk of breast cancer. The greatest risk of breast cancer occurred in women who had the highest estrogen levels accompanied by lower levels of 2-hydroxylation or a lower ratio of 2-hydroxylation to 16-hydroxylation. Past studies finding that the 2OHE1:16OHE1 ratio is not associated with breast cancer risk did not determine how total estrogen levels impacted the risk associated with the 2OHE1:16OHE1 ratio.
It is also interesting to note that mutations in the catechol-O-methyltransferase (COMT) gene can lead to the body processing estrogen metabolites differently compared to women who don't have this mutation. If a person has a defect in the COMT gene, it can lead to altered levels of 2OHE1 and 16OHE1.41 Tests are available to detect COMT genetic mutations.
Nutrients That Encourage the Safe Metabolism of Estrogen
Cruciferous vegetables such as broccoli, cauliflower, kale, and Brussels sprouts contain the phytochemical indole-3-carbinol (I3C). In the body, I3C is broken down to 3,3-diindolylmethane – DIM, for short. Studies in animals and humans have shown that supplementation with I3C or DIM or eating a lot of cruciferous vegetables can change the way the body metabolizes estrogen from the possibly harmful 16-hydroxylation pathway to the safer 2-hydroxylation pathway.34
Increased urinary 2OHE1 levels or urinary 2OHE1:16αOHE1 ratios have occurred in a number of controlled clinical trials using oral supplementation with 300-400 mg/day of I3C in women. In one of those studies, 400 mg/day of I3C daily for three months resulted in a significant mean increase in the 2OHE1:16alphaOHE1 ratio in all but three of 20 women.42 In another study of both men and women, I3C significantly increased 2-hydroxylation and lowered levels of nearly all other estrogen metabolites, including estradiol, estrone, estriol, and 16alpha-hydroxyestrone.43 In a trial of 60 women who had an increased risk of breast cancer, 300 mg/day of I3C improved the urinary estrogen metabolite ratio of 2OHE1 to 16alphaOHE1.44
DIM works similarly to I3C. Supplementation with 108 mg/day of DIM in postmenopausal women with a history of early stage breast cancer increased urinary 2OHE1 levels.45 In women with thyroid proliferative disease, 300 mg of DIM per day led to an increase in the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone.46 In a randomized, controlled clinical trial, 2 mg/kg/day of DIM was shown to cause a high rate of improvement in cervical dysplasia,47 a precancerous condition where cells grow abnormally on the outside of the cervix or in the opening between the uterus and the vagina.
Supporting Mitochondria During Hormone Therapy
All hormones originate in the mitochondria, where the conversion of cholesterol to pregnenolone – the precursor to all steroid hormones – occurs.48,49 Additionally, the electron transport chain of mitochondria plays a role in testosterone production and altering this pathway increases production of testosterone.50
More evidence that hormones are involved in mitochondrial function is that receptors for estrogens, androgens, and thyroid hormones are located in the mitochondria of many cell types.51,52 Scientists have found estrogen receptors in mitochondria of rat uterine and ovarian cells, breast cancer cells, cultured human lens epithelial cells, and rat hippocampus and neuronal cells. Moreover, estrogen receptors were found in mitochondria of heart cells, liver cancer cells, osteosarcoma cells, human sperm cells, and in human ligament cells of the gums.51 Estrogens and male hormones play a role in shielding the mitochondria from damage.53 Plus, estrogen controls many aspects of mitochondrial function as well as the generation of new mitochondria.54,55
Because of the relationship between estrogen and mitochondrial health, Dr. Meletis often includes a mitochondrial-supporting supplement in the regimen of patients on hormone replacement therapy. Coenzyme Q10 (CoQ10), alpha-lipoic acid, acetyl-L-carnitine, and quercetin can all be used to support mitochondrial function.
CoQ10 is one of the best-known mitochondria-supporting nutrients. Human studies have shown that giving CoQ10 to patients before cardiac surgery raises levels of this nutrient in the mitochondria of the heart and makes the mitochondria more efficient.56 It also protects the mitochondria from the stress that occurs when blood vessels are deprived of oxygen during surgery and then reoxygenated.56 In people with mitochondrial diseases known as mitochondrial cytopathies, taking 150 mg of CoQ10/day for six months improved brain health and enhanced mitochondrial function in the skeletal muscle of the CoQ10 group compared with controls.57
In animal models of aging, alpha-lipoic acid and/or acetyl-L-carnitine block the generation of harmful oxidants and improve mitochondrial function.58 In humans with coronary artery disease, alpha-lipoic acid and acetyl-L-carnitine lowered blood pressure and improved vascular function, probably in part through enhancing mitochondrial function.59
Quercetin has also emerged as a mitochondrial rejuvenating nutrient. In untrained men, 1,000 mg/day of quercetin led to a small but significant improvement in 12-minute treadmill time trial performance and a modest improvement in mitochondrial function and genes related to the creation of new mitochondria.60 Quercetin improved mitochondrial function and/or stimulated the production of new mitochondria in models of traumatic brain injury,61 the muscle atrophy that occurs after disuse,62 and aluminum-caused free radical damage.63
Conclusion
When implementing a bioidentical hormone replacement therapy regimen, it is essential to support the safe metabolism of estrogen. The gut is an important source of steroid hormones such as estrogen, and probiotic organisms play a role in how the gut metabolizes estrogens. A balanced gut microbiota also increases the effectiveness of phytoestrogen supplements such as soy. I3C and DIM are important supplements that ensure that estrogen is escorted out of the body through the safest possible pathway. Calcium-D-glucarate also assists with estrogen metabolism as it blocks an enzyme known as beta-glucuronidase, which interferes with the body's ability to safely process estrogen and potentially harmful substances such as drugs and toxins. Additionally, mitochondrial support also is recommended during hormone replacement therapy, as all hormones originate in the mitochondria, which possess steroid hormone receptors.
Page 1, 2
References .pdf
Dr. Chris D. Meletis is an educator, international author, and lecturer. His personal mission is "Changing America's Health One Person at a Time." He believes that when people become educated about their bodies, that is the moment when true change and wellness begins. Dr. Meletis served as dean of naturopathic medicine and chief medical officer for 7 years at National College of Natural Medicine (NCNM) and was awarded the 2003 Physician of the Year award by the American Association of Naturopathic Physicians.
www.DrMeletis.com
Kimberly Wilkes is a freelance writer specializing in health, science, nutrition, and complementary medicine. She has written more than 300 articles covering a variety of topics from the dangers of homocysteine to sugar's damaging effects on the heart. She is the editor of Complementary Prescriptions Journal and enjoys scouring the medical literature to find the latest health-related science. |
