Critical Considerations for Successful Bioidentical Hormone Therapy

Critical Considerations for Successful Bioidentical Hormone Therapy 

by Chris D. Meletis, N.D.

As healthcare practitioners, bioidentical hormone therapy is an important part of many of our clinical practices. Based on the results we’ve seen in our patients, we are all aware that bioidentical hormones are safe and more effective than conventional hormone therapy.

Research has confirmed the results we've seen in clinical practice. One group of researchers who conducted a review of the medical literature concluded, "Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT."1

Yet, there is an aspect of bioidentical hormone therapy that is critical to its success. All hormones - even those naturally produced in the body and bioidentical hormones given during therapy - must be metabolized and detoxified properly in order to be effective.

Ensuring Hormone Therapy Success

There are two organs in the body that play a particularly important role in metabolizing hormones. It's critical to enhance the health of these organs during or even before implementing bioidentical hormone therapy. The pathway through which the body metabolizes estrogen and the method of delivery also are involved in the effectiveness of bioidentical hormone replacement therapy.

In this article, I'm going to discuss the importance of hormone metabolism in relation to bioidentical hormone therapy, the two organs most important in hormone metabolism, substances that affect the metabolism of hormones, as well as supplements for ensuring the body processes bioidentical hormones effectively. I'm also going to touch upon the form of treatment - oral or transderma - that many functional medicine providers believe is most effective.

The Many Faces of Estrogen

The three major endogenous estrogens found in humans include estradiol, estriol and estrone. Ovaries mostly produce 17 beta-estradiol and estrone, whereas estriol is formed from estrone and estradiol. Prior to menopause, 17 beta-estradiol is the primary estrogen in circulation. After menopause, estrone is the estrogen found in the highest concentration. It is converted in adipose tissue from estradiol and adrenal androstenedione.

Estriol is not as potent as the other endogenous estrogens and is short acting. In the serum of non-pregnant women, it is found in very low concentrations (10 pg/ mL). In pregnant women, estriol is produced in high concentrations by the placenta. Unlike estrone, it is not converted to estradiol.

Estriol is considered the safest of the three estrogens according to reviews from the 1970s to modern day.2-5 In Europe and Asia, it has been used extensively for the treatment of menopausal symptoms6- 9 because unlike 17 beta-estradiol, it causes minimal uterine endometrial proliferation.10-12 Estriol is being investigated for its potential to help people with multiple sclerosis. In a pilot trial, relapsing remitting MS patients treated with oral estriol (8 mg/day) experienced decreased gadolinium enhancing lesion numbers and volumes on an MRI. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels. When researchers reinstated the estriol treatment, enhancing lesions again significantly decreased. Estriol treatment also significantly increased cognitive function.13 Several Phase II trials of estriol in MS patients are underway.13

Estrogens bind to and activate estrogen receptors that are widely distributed throughout the body including the brain, heart, breast, bone and genital tract.

There are two types of estrogen receptors, ER-alpha and ER-beta. The activity of all three forms of estrogen depends in part upon their affinity for either of these two estrogen receptors, which are found in different tissues. For example, the estrogen receptor alpha is located in the endometrium, breast cancer cells and the ovary, whereas the beta receptor is found in bone, kidney, lung and endothelial cells, as well as in several other tissues. 17 beta-estradiol has the highest affinity for both alpha and beta receptors. Estrone is midrange in affinity but predominantly binds to estrogen receptor alpha. Estriol has the weakest binding affinity for either receptor.14

Preventing Testosterone Conversion to Estrogen

The steroid hormone testosterone, although primarily secreted in the testicles of males and the ovaries of females, can also be secreted in the adrenal glands.Testosterone is metabolized by way of two primary pathways:

  1. The aromatization of testosterone to estradiol in brain, breast, liver, fat cells and other tissues and
  2. The peripheral conversion of testosterone via 5-alpha-reductase activity to the more potent dihydrotestosterone (DHT), which can be involved in male pattern baldness and benign prostatic hyperplasia but can also have beneficial effects in chronic heartdisease.15

The conversion of testosterone to estrogen has been shown to produce the proinflammatory 16-hydroxylated estrogens, which is an estrogen-metabolism pathway related to cancer development and other detrimental effects.16

Aromatase inhibitor drugs such as Arimidex® are used to inhibit the conversion of testosterone to estradiol. However, this approach can backfire since men need some estrogen to support bone density, cognitive health and the endothelium of the arteries. Reducing estrogen levels too low, therefore, can have negative effects.

For example, in one study of 793 men with no history of hip fracture, researchers analyzed blood levels for:

  1. Estradiol only
  2. Testosterone only and
  3. Estradiol and testosterone together.

In men who had low estradiol (2.0-18.1 pg/mL of blood), hip fractures were more than three times higher compared with men who had estradiol levels of 18.2- 34.2 pg/mL.

Men who had estradiol levels greater than 34.3 pg/mL had a slightly higher risk of hip fracture compared with those who had levels between 18.2-34.2 pg/mL.

The researchers in this study also found that in the group of men whose blood was measured for estradiol and testosterone, the subjects who had low levels of both these hormones had 6.5 times greater incidence of hip fractures compared to men whose levels were optimal.17

The study authors concluded, "Men with low estradiol levels are at an increased risk for future hip fracture. Men with both low estradiol and low testosterone levels seem to be at greatest risk for hip fracture."

This confirms the key is to achieve balanced levels of both testosterone and estrogen in men and that bioidentical hormone therapy in men should not just focus on optimal testosterone levels.

Sometimes, balancing estradiol levels in men simply requires lifestyle changes. As men age, much of the estradiol synthesis occurs in abdominal adipose tissues.18 Therefore, losing weight can result in reduced estrogen levels. Naturally restoring testosterone levels while at the same time inhibiting aromatase through the use of Eurycoma longifolia Jack19 may in and of itself reduce belly fat while simultaneously balancing estrogen levels.

Proinflammatory cytokines also stimulate aromatase activity.16 This means that inflammation can cause conversion of testosterone to estrogens. Encouraging our patients to adopt an anti-inflammatory lifestyle by going to bed early, finding stress-reduction measures and reducing or eliminating intake of sugar and refined carbohydrates may reduce the conversion of testosterone to estradiol.

Specific receptors in target tissues such as the brain (especially in the hypothalamus and hippocampus) and, to a lesser extent, the bone (osteoblasts) respond to testosterone. These receptors are even more likely to respond to DHT, which has a much greater affinity for the  androgen receptor than testosterone. Additionally, DHT does not go through aromatization, meaning its androgenic activity is magnified. Because of this, another variable to consider when implementing testosterone therapy is the patient's ability to convert testosterone to DHT.

Progesterone: A Powerful Neurosteroid

Progesterone is formed during the conversion of cholesterol to estrogens and androgens. Endogenous progesterone, like estrogen, is mainly metabolized in the liver, with the metabolites being conjugated, secreted in the bile, and excreted in the feces. I'll touch upon the liver's role in hormone metabolism more in a little while and how certain hormone delivery systems avoid processing by the liver.

Endogenous progesterone also can be metabolized in the brain, where it acts as a neurosteroid. One of progesterone's brain metabolites, allopregnanolone, has an affinity for and activates the gammaaminobutyric acid (GABA) receptor, resulting in varying degrees of sedation.20 Unlike endogenous progesterone, the synthetic progestogens are unlikely to be converted into neurosteroids and may, in some instances, actually intensify mood disorders.20

Hormone Therapy Saboteurs

One of the biggest factors compromising the success of bioidentical hormone therapy is inefficient metabolism of the hormone used in treatment. That is why it's critical to support the health of the liver, which plays an important part in making sure excessive amounts of hormones aren't reabsorbed into the body. Orally administered hormones are absorbed through the digestive tract and at least partially metabolized by the liver and excreted. Estrogen is stored in fat, and when a patient's bile is so contaminated with toxins that it can't properly emulsify fat, an imbalance in estrogen metabolism can occur. This is because as a fat-soluble waste, estrogen can't be cleared from the body. The result is that the estrogen is reabsorbed, causing high levels of estrogen, which can increase the growth of abnormal cells and ultimately lead to cancer. A good detoxification supplement is therefore a must to clear environmental toxins.

Liver's Role in Estrogen Metabolism

Metabolism of hormones and other substances occurs in the liver using two primary pathways known as Phase I and Phase II.

During Phase I, some hormones are metabolized directly. Often, however, hormones are converted into intermediate forms, which are further metabolized in Phase II.

Estrogens are metabolized mainly through the Phase I pathway. In premenopausal women, estradiol is converted primarily to estrone, and eventually to estriol. The liver then metabolizes the remaining estradiol and the converted estrone, breaking it down further, and excreting the excess from the body.

Many factors can interfere with Phase I metabolism. This happens when the liver is overwhelmed when processing an overload of toxic substances or is exposed to alcohol or drugs. Grapefruit juice also has the potential to alter hormone balance by slowing down the enzymes involved in Phase I. Many prescription drugs are metabolized in Phase I, which can disrupt estrogen hormone metabolism.

The cruciferous-vegetable-derived supplements indole-3-carbinol (I3C) and diindolylmethane (DIM) can help the liver metabolize estrogen more efficiently I3C and DIM stimulate enzymes that promote the metabolism of estrogens through the more beneficial 2-hydroxyestrone pathway, potentially reducing the risk of estrogen-dependent cancers.21

Phase II's Role in Hormone Metabolism

In Phase II of the liver detoxification pathway, conjugation begins. This is where nutrients such as amino acids combine with hormones and other substances in order to convert them into water-soluble compounds which help escort hormones out of the body in the urine or stool. Four types of conjugation play an important role in hormone metabolism: methylation, sulfation, glucuronidation and glutathione conjugation.

Methylation is the process where methyl groups are exchanged between one molecule to another. When estrogens are methylated, they are more easily excreted from the body. Therefore, it's important to ensure the liver has enough methyl groups available for its use. This can be achieved through supplementation with vitamins B6, B12, SAMe (s-adenylmethionine) and folic acid (especially the more bioavailable form of folate known as 5-methyltetrahydrofolate (5-MTHF)).

Sulfation combines sulfur groups with estrogen or other molecules to make them easier to excrete. Optimal sulfur intake can be achieved through eating sulfur-containing foods such as egg yolks, garlic, onions, grassfed and organic animal protein and cruciferous vegetables as well as by supplementing with methylsulfonylmethane (MSM).

Glucuronidation is another type of conjugation. I'll discuss this process in more detail in a little while when I delve into colon health and its impact on hormone metabolism.

In gluthathione conjugation, another sulfur-containing molecule combines with estrogen. Glutathione also acts as an antioxidant in Phase I, neutralizing free radicals produced in Phase I reactions.

Interfering with Testosterone Metabolism

The liver also produces proteins called sex hormone-binding globulin (SHBG). These proteins help regulate sex hormones by shuttling the hormone molecules around the body. When a level of a hormone is too high, SHBG helps mitigate the impact of the excess hormone.

Estrogen stimulates SHBG. As the body produces more SHBG, the SHBG becomes more attracted to testosterone than to estrogens. That's why women treated only with estrogen after a hysterectomy have a reduced amount of bioavailable testosterone. The increased estrogen levels stimulate SHBG, which in turn leads to low bioavailable testosterone levels. This causes decreased libido, mental vitality and muscle mass.

The Gut and Hormones

Intestinal health affects the liver conjugation pathway known as glucuronidation. Glucuronidation is the normal process in the liver of attaching a glucuronic acid molecule to substances for detoxification and elimination from the body. During Phase II liver detoxification, steroid hormones and other fat-soluble toxins undergo glucuronidation and are then excreted through the bile or urine.

An overabundance of pathogenic bacteria in the intestines produce an enzyme called beta-glucuronidase that deconjugates estrogens, blocking estrogen excretion and causing the hormone to be reabsorbed into the body. This allows estrogens - both those given as oral hormone therapy and endogenous hormones - to accumulate to excessive levels. Elevated beta-glucuronidase activity has been linked to an increased risk for various cancers, especially hormone-dependent cancers such as breast, prostate and colon cancers.22

Oral supplementation of calcium-Dglucarate has been shown to increase glucuronidation and inhibit beta-glucuronidase. Calcium D-glucarate's ability to inhibit beta-glucuronidase helps the body excrete environmental toxins23 as well as excessive amounts of estrogens before they can become reabsorbed. Oral administration of large doses of calcium-D-glucarate have lowered serum estrogen levels in rats by 23 percent.22

Additionally, high-fiber diets and/or taking a fiber supplement can decrease estrogen reabsorption by speeding up intestinal transit time.24

High-fiber intake can help ensure two to three bowel movements per day, essential for not only eliminating environmental toxins, but also preventing reabsorption of hormones.

Another important consideration in regards to hormone reabsorption is intestinal permeability, otherwise known as leaky gut. Intestinal permeability can increase the reabsorption of estrogens and other hormones.

Estrogen receptor-beta (ERB) is the most abundant estrogen receptor in the colon. A complete absence of ERB expression is associated with disrupted tight-junction formation. In fact, estrogen receptor-beta signaling is involved in controlling intestinal permeability. There is reduced ERB mRNA in animal models of colitis and in the colon of patients with inflammatory bowel disease.25

Two of the most effective supplements for reducing intestinal permeability are probiotics and butyrate. Lactobacillus has reduced intestinal permeability in both animals and humans.26-27

The short-chain fatty acid butyrate enhances the intestinal barrier by regulating the assembly of tight junctions between epithelial cells. It accomplishes this by activating AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis.28

Butyrate supplementation has been found to reduce intestinal permeability in chemotherapy patients suffering from mucositis29 and in animal models of colitis.30

Substances That Alter Hormone Metabolism

When implementing bioidentical hormone therapy, it's helpful to keep in mind there are other factors that might influence hormone metabolism. Even a small amount of alcohol intake can elevate estrogen levels in the blood, especially in postmenopausal women, because alcohol competes for the available glutathione.31-33 Since glutathione conjugates estrogen, the reduced glutathione levels prevent the excretion of estrogen.

Smoking, infections and inflammatory disorders also deplete glutathione levels. Smoking also decreases hormone therapy estrogen concentrations and has a greater effect with oral products.34

Aspirin and non-steroidal anti-inflammatory drugs have the ability to influence 2-hydroxy and 16-hydroxy estrogen metabolism.35 Non-aspirin NSAID use is associated with 17-epiestriol, a powerful estrogen linked to factors in the prevention of heart disease.35

Furthermore, other drugs can alter estrogen metabolism. For example, phenytoin increases the metabolism of conjugated estrogens.

Is Topical the Answer?

The type of delivery system of hormone therapy dictates where and how the hormone is metabolized. Oral undergoes first pass liver clearance whereas topicals and troches (oral lozenges) are absorbed in many sites throughout the body and can impact tissues without first having to go through the liver. Therefore, oral estrogens have minimal systemic bioavailability (2 to 10 percent) due to gut and liver first-pass metabolism. It should be noted that since troches do mix with saliva and saliva is swallowed, this does offer some potential additional burden on the liver metabolism compared to topicals.

High concentrations of estrone are achieved with oral administration, whereas higher concentrations of estradiol are generally achieved after transdermal absorption. Vaginal products also achieve high serum concentrations while at the same time avoiding the first-pass effect.

In addition, there is some evidence that the use of oral gelatin capsules that contain micronized powdered hormones mixed with edible oils can help lessen the first-pass effect because the fat is taken up directly into the lymphatic system.34 I would like to see additional research on this subject.

Because transdermal products bypass the first-pass effect, they are generally considered safer and more effective than oral varieties. When using these products, the concerns over liver and gut reabsorption are reduced.

In a study published in the Journal of The American Menopause Society, participants receiving estradiol transdermally had a significantly lower incidence of venous thromboembolism than participants receiving oral estrogen-only hormone therapy.36

In addition, oral testosterone is linked to increased risk of liver cancer.37 However, when testosterone is applied topically this is not the case because the body uses most of the testosterone before it reaches the liver.


The effectiveness of bioidentical hormone therapy is ultimately dependent upon how the hormones are metabolized. Oral hormones are metabolized differently than topical hormones while certain drugs and other substances also will influence the way a hormone is processed by the body. The liver and colon play critical roles in this process and it's important to nourish the health of each of these organs when implementing a bioidentical hormone regimen.


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