Supporting Healthy Estrogen Metabolism During Bioidentical Hormone Replacement Therapy

by Chris D. Meletis, ND, and Kimberly Wilkes

As we grow older, an important component of any health-related regimen is the balancing of hormones to compensate for declining levels of estrogen and testosterone. Bioidentical hormone replacement therapy (BHRT) is a common and effective way to achieve this goal. However, one common mistake is to use BHRT without taking the correct dietary supplements to offset the poor metabolism of hormones. Gut health and any imbalances in the gut microbiota – the population of bacteria, fungi, and other microorganisms that inhabit the intestines – also need to be addressed to ensure the body is able to properly use estrogen and testosterone.

In this article, we will discuss the reasons why an imbalanced gut microbiota leads to dysfunctional hormone metabolism during menopause, as well as which dietary supplements are helpful in ensuring the body processes estrogen in a safe and efficient way. Finally, we will discuss why mitochondrial support is an often-neglected but critical component of bioidentical hormone replacement therapy.

The Gut as A Source Of Steroid Hormones

When considering the origin of estrogen production, the ovaries and adrenals normally come to mind. Surprisingly, however, it is now known the intestine can generate and metabolize sex hormones.1 Bioactive steroids have been identified in both the rodent and human gut.1 The cells lining the intestines (known as epithelial cells) are a cellular source of steroid production.1 In addition, intestinal epithelial cells are able to metabolize estrogen.1

17β-estradiol, a powerful estrogen made primarily by the ovaries of females and the testes of males, influences the development and function of the reproductive system. 17β-estradiol also is produced in tissues not related to reproduction where it governs a number of actions, including inflammatory responses. Lymph nodes located in a membrane that attaches the intestine to the abdominal wall and lymphatic tissue in the small intestine produce 17β-estradiol.2 In mice, these intestinal lymphatic areas contained 17β-estradiol levels significantly greater than those in blood, and there was more 17β-estradiol in lymph-related organs compared with the ovaries and testes.2

The estrogen estradiol also protects the lining of the intestines known as the epithelial barrier from damage.3 It keeps the gut walls strong and stops “leaky gut,” what scientists call intestinal permeability, where bacteria and food allergens slip through a weak intestinal lining and out into the blood stream, where they can wreak havoc in the body.3

Further evidence of a link between estrogen and the gut comes in the form of studies that show there is a relationship between estrogen and inflammatory bowel syndrome (IBS).4 Estrogen helps regulate the development of IBS in part through its ability to interact with the hormone serotonin,4 a large amount of which is produced in the gut and helps regulate intestinal function. Estrogen also reduces the effect of psychological stress on the brain and the gut.4 Some studies have found that, while in postmenopausal women, there is a significant decrease in incidence of IBS,5 symptom severity may increase following menopause.6

Estrogen and Your Gut Bacteria

The beneficial microbes in a woman’s gut are affected by age and her declining estrogen levels.7 But the relationship between the gut microbiota and estrogens is a two-way street because the gut microbiota also help regulate levels of estrogens.7

The parent estrogens estrone and estradiol are metabolized in several ways including the 2-, 4-, and 16-hydroxylation pathways. Each of these estrogen metabolites differs in how easily they are used by the body and the strength of the metabolite. And each of these estrogen metabolites has different effects on the body. In many cell culture and animal studies, a higher level of 2-hydroxylated estrogen metabolites is associated with a lower risk of postmenopausal breast cancer. The gut microbiota may play an important role in assuring that estrogen is metabolized through the safer 2-hydroxylated pathway. One group of researchers found that in 60 postmenopausal women, greater diversity of the microbiota was associated with higher ratios of 2- and 4-hydroxylated metabolites to parent estrogens such as estrone and estradiol, suggesting that gut microbes are associated with estrogen metabolism and optimal counts of beneficial bacteria may reduce postmenopausal breast cancer risk.7

Researchers also have shown that the use of conventional estrogen replacement therapy is able to boost levels of beneficial vaginal bacteria.8 In one study of 40 postmenopausal women receiving hormone replacement therapy (HRT) and 20 who were not on HRT, the probiotic species lactobacilli were present in the vagina of 95% or more of the participants in both groups.8 However, in the HRT group, Lactobacillus was more often the dominant and only beneficial species present. In addition, in the HRT group, there were significantly fewer harmful bacteria. Plus, an infection known as bacterial vaginosis occurred less often in the HRT group compared with the women not receiving HRT.

Adding to the evidence that there is a connection between steroid hormones and the gut is the fact that the probiotic organism Lactobacillus reuteri when given to mice in their drinking water, improved markers of gonadal aging.9 The study authors believe this was due to the anti-inflammatory actions of the probiotic. Even though this study was done in male mice, it provides an interesting perspective that could be applied in clinical practice to females.

The Microbiota’s Far-Reaching Role in Postmenopausal Health

Declining estrogen levels during menopause makes women more vulnerable to increased bone loss and fracture risk.10,11 The microbiota are involved in protecting against age-related bone loss. In mouse models of menopause, supplementation with the probiotic L. reuteri stopped bone loss and reduced bone breakdown related to estrogen deficiency.12

The way the gut microbiota accomplishes its bone-protecting effects is in part through raising levels of insulin-like growth factor 1 (IGF-1), which plays a role in bone health.13 Clinically, IGF-1 also serves as a marker of biological aging and growth hormone levels.14,15 The lower your IGF-1, the lower your growth hormone levels and the faster you age and suffer from effects like cognitive decline.15

Phytoestrogen Supplements and Gut Bacteria

Menopausal women commonly use phytoestrogen supplements to ease symptoms such as hot flashes. Phytoestrogens such as soy have a similar chemical structure to human estrogens, produce estrogenic activities, and cause effects similar to estrogen. Intestinal bacteria metabolize phytoestrogens into compounds that are more bioavailable and have more estrogenic/anti-estrogenic and antioxidant activity than the parent phytoestrogens themselves.16,17 These compounds also have anti-inflammatory effects, stop the multiplication of cells, which is linked to cancer, and trigger the death of unhealthy cells.17,18

Some individuals have the ability, through the actions of the intestinal microbiota, to convert phytoestrogens into these more bioavailable metabolites, which may make them less vulnerable to hormone-dependent diseases.19-21 The intestinal microbiota’s transformation of phytoestrogens into their bioavailable metabolites is critical to the reduction of menopausal symptoms and certain chronic diseases, such as cancer, cardiovascular disease, and osteoporosis.19-21

One group of researchers suggested, “the clinical effectiveness of soy protein in cardiovascular, bone, and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol” and that this transformation was dependent on intestinal bacteria.22 The researchers pointed out that past studies did not distinguish between participants who were “equol-producers” and “nonequol producers,” which could explain why studies on the health benefits of soy have yielded conflicting results.

The Importance of Blocking a Harmful Enzyme

The body processes hormones as well as drugs and environmental toxins using a sugar called glucuronic acid. In the liver, this sugar attaches itself to drugs, hormones, and toxins meant to be excreted from the body through the bile duct to the GI tract. In doing so, glucuronic acid neutralizes the potentially harmful substance. However, an enzyme called beta-glucuronidase searches for this sugar because it needs to use it as a source of carbon. Once beta-glucuronidase separates the glucuronic acid from the hormone, toxin, or drug, metabolites of these substances are  not always completely eliminated from the body.23 They can be reactivated and highly toxic to GI tissues.23 That’s why it is essential that beta-glucuronidase levels be balanced in people on BHRT, so that estrogen does not become reabsorbed.

A small number of the thousands of intestinal microbiota organisms – about 50 species, including E. coli – can release beta-glucuronidase.24 On the other hand, a number of probiotic organisms can inhibit the production of beta-glucuronidase. A study of the fecal water of 15 people who were a variety of ages (children, adults, and elderly) found that when the water was incubated with a carcinogen, the toxicity and the beta-glucuronidase activity of the water was increased.25 However, the probiotic organism Lactobacillus paracasei reduced beta-glucuronidase by 76% in the fecal water of the children and by 82% in the elderly.

Another study investigated the effects of a multispecies probiotic supplement consisting of Lactobacillus rhamnosus GG, Lactobacillus rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermanii JS, and Bifidobacterium breve on intestinal microbiota and beta-glucuronidase in patients with irritable bowel syndrome (IBS).26 In this placebo-controlled, double-blind trial, 55 IBS patients received either the multispecies probiotic or a placebo daily for six months. At the study’s conclusion, researchers observed a decline in beta-glucuronidase activity in 67% of the subjects given the probiotic compared with only 38% of participants given the placebo.

In an animal study, rodents that were exposed to one of three conditions – a chemical that causes colon cancer, atherosclerosis triggered by a high-fat diet, or an imbalance of the gut microbiota caused by antibiotic administration – were supplemented daily with Lactobacillus plantarum alone or combined with antibiotics.27 In the rats exposed to the cancer-causing chemical, the probiotic lowered beta-glucuronidase activity. In the atherosclerosis group and the imbalanced gut microbiota rodents, combining the probiotic with an antibiotic also reduced beta-glucuronidase activity.

Calcium D-Glucarate

Calcium-D-glucarate is the calcium salt of D-glucaric acid, which humans synthesize naturally in small amounts. Many fruits and vegetables, especially oranges, apples, grapefruit, and cruciferous vegetables, are also a source of glucaric acid. Oral supplementation of calcium D-glucarate blocks the beta-glucuronidase enzyme for five hours.28

Calcium-D-glucarate’s ability to suppress beta-glucuronidase helps hormones such as estrogen to be excreted before they are reabsorbed. Large oral doses of calcium-D-glucarate fed to rats resulted in a 23% drop in serum estrogen levels.28 In rats exposed to a chemical carcinogen that causes breast cancer in the animals, calcium D-glucarate blocked tumor development by over 70%.29

Scientists have also studied calcium-D-glucarate in breast, lung, colon, and liver cancers in rodent models, and the beneficial results occurred due to a variety of mechanisms including inhibiting beta-glucuronidase activity.28,30,31

Because calcium D-glucarate blocks beta-glucuronidase and therefore improves the excretion of estrogen from the body, Dr. Meletis uses it in his clinical practice in patients on estrogen replacement therapy as a precaution against estrogen re-absorption and the resulting harmful effects.

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.

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