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The Liver’s Role in Hormone Balance

Everything we breathe, ingest, or absorb through the skin gets into the blood stream and eventually passes through the liver. Because the liver is the body’s primary detoxifier, keeping it healthy is critical to your overall health, including proper metabolism and function of your hormones.

Liver Function

As unglamorous as it sounds, the liver operates somewhat like a sewage treatment plant. The liver takes everything we put into our bodies—whether it is swallowed, inhaled or absorbed through the skin—and filters it. The liver’s filtration process separates the nutrients that the body needs for energy and all of its other functions and prepares to dispose of that which the body does not need, such as metabolic waste, toxins and excess substances.

Specific liver functions include:

  • Converting fats, proteins and carbohydrates to energy and nutrients
  • Creating bile to break down fats and eliminate fat-soluble toxins and excess substances, including excess hormones
  • Removing harmful chemicals, bacteria, and excesses
  • Metabolizing drugs and breaking down alcohol
  • Storing vitamins and minerals, such as iron
  • Storing sugars as fuel (glycogen) for future use
  • Helping to maintain fluid and electrolyte balance
  • Creating serum proteins that act as hormone carriers
  • Creating immune substances, such as gamma globulin
  • Filtering blood, regulating blood clotting, and storing extra blood for quick release
  • Manufacturing testosterone and the estrogen hormones
  • Regulating sex hormone levels and eliminating excess hormones.

Health problems can arise when we put things into our body, both consciously and unconsciously, that are toxic or build up an excess or toxicity over time, such as:

  • Oily, processed foods
  • Man-made chemicals including preservatives, pesticides, and lead from paints or gasoline
  • Alcohol and drugs (therapeutic or otherwise)
  • Excess hormones.

Health problems can also occur if the nutrients that the liver needs to process toxins or excesses are in limited supply. Like a sewage treatment plant that is
short staffed, if these nutrients are in short supply, the liver cannot process as quickly or as thoroughly as needed. If the liver becomes overburdened because of insufficient nutrients, the toxins or waste build up and the excess can escape back into the body, leading to serious health concerns.

Hormone Metabolism

The liver plays a vital role in the body’s use of hormones, both those that are produced naturally in our bodies as well as those hormones that are “introduced” via hormone therapies. It acts as a hormone processor, manufacturing and/or regulating some hormone levels, and directing various hormones to perform their proper function in other parts of the body. But when the body experiences a hormone excess (whether produced by the body or introduced by hormone therapy), the liver may not be able to process the hormone(s) as quickly or efficiently, causing a hormone imbalance.

Estrogen Hormones

Of primary concern for women’s health is the liver’s role in regulating the sex hormones, primarily the estrogen hormones. This is a consideration for women undergoing hormone therapy, whether it is conventional hormone replacement therapy (HRT), typically consisting of synthetic hormones that are not biologically identical to human hormones, or a biologically-identical hormone therapy (BHT).

Researchers are gaining new insight into how estrogens are metabolized and the effects of that metabolism. They found that estrogens break down into estrogen metabolites that have varying levels of estrogenic activity, and that the stronger the estrogenic effect, the greater the risk of developing estrogen related cancer.

Phase I and Phase II Pathways

The liver metabolizes hormones and other substances using two primary phases known as the Phase I and Phase II pathways.

During Phase I, some hormones or substances are metabolized directly, but often they are converted into intermediate forms, which are then further metabolized in Phase II.

Cumulatively, these two phases of biological transformation are how the liver provides the body with nutrients and supports the excretion of excess or toxic substances in the urine, liver bile, perspiration and exhaled air.

The pathways depend on a large number of nutrients, including enzymes and amino acids, and their availability (or lack thereof) seems to have a significant influence on the
metabolic outcome. For example, the Phase I pathway is the main metabolic pathway for the estrogen hormones. In premenopausal women, the ovaries produce estrogen, primarily estradiol, most of which the body converts to estrone, and eventually estriol. The liver then metabolizes the remaining estradiol and the converted estrone, breaking it down further, and excreting the excess from the body.

Some researchers and practitioners now believe that the liver’s ability to metabolize estrone is the key to understanding estrogen-related cancer risk. During Phase I metabolism, estrone is converted into various metabolites including 2-hydroxyestrone, a very weak estrogen, and 16-alphahydroxyestrone, a very potent estrogen. If the conversion process favors the stronger form(s) rather than the weaker form(s), then tissue that has an abundance of estrogen receptors, such as the breasts and uterus, may be more vulnerable to excessive estrogen activity, potentially leading to the formation of fibroids or the stimulation of estrogen-sensitive cancers.

Phase I processing can be affected by many factors, including extreme overload, the effects of alcohol or drugs, a lack of nutrients, or interference from other substances. For example, grapefruit juice can slow down the enzymes in Phase I, potentially altering hormone balance. And, many prescription drugs are metabolized in Phase I, which can also interfere with the liver’s ability to handle the estrogen hormones. On the other hand, Indole-3-carbinol (I3C), a phytonutrient derived from cruciferous vegetables (e.g., broccoli, cauliflower, cabbage and brussels sprouts), stimulates enzymes that promote the metabolism of estrogens into milder forms, potentially reducing the risk of
estrogen-dependent cancers.

During Phase II, a process known as conjugation begins, in which nutrients such as amino acids are combined with hormones and other substances, to convert them to water-soluble compounds that can be excreted efficiently in the urine or stool.

Of the various types of conjugation that may occur in Phase II, the following are most relevant to hormone metabolism:

  • Methylation, also known as methyl metabolism, is the process in which small parts of molecules, called methyl groups, are passed from one molecule to another. Once estrogens are methylated, they can be easily excreted. In order for the liver to have an adequate supply of methyl groups available, an adequate intake of vitamins B6 (e.g., whole grains and legumes) and B12 (primarily from animal products), and folic acid (such as from green leafy vegetables) are necessary. An over-the-counter dietary supplement known as SAMe (s-adenylmethionine) is also a rich source of methyl groups and sulfur.
  • Sulfation is the process in which sulfur groups are added to estrogen or other molecules to prepare them for easy excretion. Adequate amounts of foods containing sulfur should be in the diet, including egg yolks, garlic, onions and brussels sprouts. Animal protein is another important source of sulfur.

Free Radicals

Each reaction in the Phase I pathway produces an intermediate form called a free radical.
As you have probably heard, free radicals can be very damaging to body tissues if they are
not quickly neutralized by antioxidants. Nutrients such as vitamins C and E, minerals such as
selenium, and other substances such as lipoic acid and glutathione are antioxidants that help protect against free radicals. The intermediate forms produced in Phase I are in a highly reactive state until they are fully converted in Phase II.

  • Glucuronidation is another process by which estrogens can be conjugated. This type of conjugation may be affected by the condition of the intestines. If the intestines have an abundance of abnormal bacteria, an enzyme produced by these bacteria may cut off the conjugated part from the estrogen. The estrogen that would have been excreted is then reabsorbed back into the body, allowing even estrogens produced by the body to build up to excessive levels. The supplement calcium D glucarate (also found in fruits and vegetables) can render the enzyme inactive and prevent this buildup.
  • Gluthathione conjugation is the process in which glutathione, another sulfur-containing molecule, is added to estrogen for easy excretion. Foods such as avocado, walnuts and asparagus are rich in glutathione, and vitamin C stimulates the body to produce more of it. Glutathione depletion can be due to a lack of the essential nutrients and amino acids (found in fresh fruits, vegetables, fish and meats) that are needed to synthesize it.

Glutathione deserves special mention as a crucial detoxifier because it also behaves as an antioxidant in Phase I. Glutathione neutralizes the free radicals produced in the Phase I reactions, and combines with them to produce water-soluble compounds that can be excreted.

Glutathione is also needed for the detoxification of alcohol. Studies have shown that even a small amount of alcohol intake can increase estrogen levels in the blood because alcohol competes for the available glutathione, preventing estrogen excretion.

Smoking is also known to deplete glutathione levels, as do chronically stressful conditions such as infections or inflammatory disorders.

Sex Hormone- Binding Globulin

To regulate sex hormones, the liver also produces special proteins (binding globulins) that “chaperone” the hormone molecules throughout the body. If the hormone level is too high, the protein also inactivates the body’s own hormone production as part of its chaperoning duty.

Sex hormone-binding globulin (SHBG) is stimulated by estrogen in the blood stream. However, as the body produces more SHBG, it is more attracted to testosterone than it is to estrogens. In the case of women who have been treated only with estrogens after a hysterectomy, it is therefore predictable that testosterone activity is limited due to the increase in SHBG stimulated by this overbalance of estrogen. A consequence of this is a decrease in sexual interest, mental zest, and the body’s ability to maintain muscle mass.

Hormone Delivery

As mentioned earlier, most drugs are metabolized during Phase I. However, the delivery method is key. Orally administered drugs, including birth control pills and other hormones, are absorbed through the digestive tract and at least partially metabolized by the liver and excreted before they can be made available to the rest of the body. This is known as “first-pass effect.” Avoiding the first-pass effect is not intended to protect the liver, but to provide greater absorption of the hormones.

Liver Bile

Bile is a complex fluid secreted by the liver for the digestion and absorption of fats and fat-soluble substances. Bile is stored in the gall bladder (see figure above), where it then flows through the bile duct to the small intestine, from which it is eventually eliminated in stool.

Many fat-soluble toxins, including excess estrogen hormones, are eliminated from the body into the intestines with the aid of bile. However, some women, such as those on birth control pills, may have difficulty eliminating excess estrogens, and this may be linked to an inhibited bile flow. Methionine, found in an over-the-counter dietary supplement called SAMe, has been shown to improve bile flow, thereby helping to reduce excess estrogen levels.

Delivery methods that avoid the first-pass effect include creams or gels applied to the skin, suppositories or inserts administered in the rectum or vagina, and lozenges or drops delivered under the tongue in the mouth (not swallowed).

In addition, oral gelatin capsules that contain micronized powdered hormones mixed with edible oils also avoid the first-pass effect because the fat is taken up directly into the lymphatic system. To illustrate the difference that the delivery mechanism can make, refer back to the role of SHBG in hormone balance and consider this: a study showed that orally administered conjugated estrogens (not in edible oil) transfer to the liver quickly, triggering the liver to release SHBG, whereas a skin patch containing estradiol did not trigger the SHBG release, primarily because the patch released the hormone more slowly. From that study we can infer that the influx of estrogen and resulting SHBG spike from conjugated estrogens (not in edible oil) can have a negative effect on other hormones, whereas estradiol absorbed through a skin patch would not have that same effect.

Maintaining a Healthy Liver

The liver is responsible for literally hundreds of functions that affect the entire body, including regulating hormones. Maintaining a healthy liver is central to maintaining hormone balance, which in turn helps to maintain overall health.

Liver function and hormone balance are intimately connected. Liver function has a critical effect on hormones and, at the same time, is affected by hormones—the ones produced in the body as well as those used as therapy. The liver can be protected by using bioidentical hormones, by not taking excessive levels of hormones, by ensuring that the liver has adequate nutrients available for processing hormones, and by avoiding other chemicals that compete for liver function. Healthy liver function is the underpinning of hormone balance.

One of the best ways to achieve and maintain good overall health is to be kind to your liver. This includes reducing the burden on the liver whenever possible, and providing adequate supplies of nutrients to assist with detoxification.

Liver stress can be reduced by avoiding overeating and heavy alcohol use. Other ways to reduce liver burden are to eliminate processed foods, high-fat foods, and those with preservatives or other additives from your diet, and to drink plenty of water to facilitate elimination of toxic and excess substances. Reducing exposure to toxic chemicals such as pesticides and herbicides in your home, yard and workplace will also reduce the burden on the liver and promote liver health.

As discussed previously, the liver is dependent upon many nutrients to complete its job of breaking down and detoxifying any excess and toxins. To promote healthy liver function, we must ensure that those nutrients are available with a proper diet and/or supplementation, when necessary or appropriate.

If you are wondering if your liver function is up to par, ask yourself the following questions:

  • Are you overweight?
  • Do you engage in heavy alcohol or tobacco use?
  • Do you have high exposure to chemicals such as herbicides or pesticides?
  • Are you on hormone therapy, or other prescription drugs?
  • Have you been diagnosed with gallstones?
  • Have you been diagnosed with a liver disease?

If you answered yes to any of these questions, discuss your liver health with your healthcare practitioner. We are fortunate in that the liver is quick to heal itself, if we give it the chance to do so.

Connections is a publication of Women’s International Pharmacy, which is dedicated to the education and management of PMS, menopause, infertility, postpartum depression, and other hormone-related conditions and therapies.

This publication is distributed with the understanding that it does not constitute medical advice for individual problems. Although material is intended to be accurate, proper medical advice should be sought from a competent healthcare professional.

Publisher: Constance Kindschi Hegerfeld, Executive VP, Women’s International Pharmacy
Co-Editors: Julie Johnson and Carol Petersen, RPh, CNP; Women’s International Pharmacy
Writer: Kathleen McCormick, McCormick Communications
Illustrator: Amelia Janes, Midwest Educational Graphics

Copyright © Women’s International Pharmacy. This newsletter may be printed and photocopied for educational purposes, provided that your copy(s) include full copyright and contact information.

For more information, please visit or call 800.279.5708.

Women’s International Pharmacy | Madison, WI 53718 | Youngtown, AZ 85363

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