Estrogen metabolism

Written by August 2015 Phoebe Wynne-Lewis, BHSc, Dip Nat Med, Dip Herb Med – FxMed Technical Support

Estrogen – is a hormone produced by women & men and is responsible primarily for sexual and reproductive development. There are three forms of estrogen circulating in our bloodstream: estradiol (E2), estrone (E1) and estriol (E3).

Each of these estrogens has particular functions. Estradiol (E2) (the predominant form in non-pregnant, reproductive females) primarily aids in the cyclic release of eggs from the ovaries (i.e., ovulation). E2 has beneficial effects on the heart, bone, brain & colon. Reduction in the level of E2 causes common menopausal symptoms such as hot flashes & night sweats. Estrone (E1), produced in the ovaries & fat cells, is the dominant estrogen in postmenopausal women. Estriol (E3) is secreted in large quantities by the placenta during pregnancy.
It is common however, for the ratios of these estrogens to be disrupted through a number of ways, such as: synthetic estrogens, estrogens in animal products, xenoestrogens (found in some environmental chemicals), phytoestrogens (found in plants) and production of estrogens in our body.

In women of reproductive age, the primary source of circulating estrogens is the ovaries. In postmenopausal women and prepuberty girls the main source of estrogens comes from extraglandular sites. Once estrogen is produced and released into the bloodstream, it reaches its target tissues and the liver. The estrogen that accounts for most of the tissue stimulation is called estradiol. Estrone is a little bit less potent with estriol being the weakest. In general, the most biologically active estrogens are the unconjugated ones. The level of estrogenic activity becomes important when there is a pathology present or if there is a genetic or environmental susceptibility towards certain hormone receptive diseases.

Metabolism of estrogens occurs in several areas of the body, however the main ones are liver and gastrointestinal tissues.

Liver

More than 50% of the metabolism and conjugation of estrogens takes place in the liver, therefore targeting the liver becomes central when it comes to affecting the circulating estrogen ratio. The liver metabolizes hormones & other substances using two primary Phases – 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.

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 favours 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. 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 stimulates enzymes that promote the metabolism of estrogens into milder forms, potentially reducing the risk of estrogen-dependent cancers.

During Phase II, 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. 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.
  • 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 re-absorbed 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 build up.
  • 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.
Gastrointestinal System

Another way estrogen metabolism is accomplished is by the gastrointestinal system. Approximately 50% of the estrogen conjugates, which enter or are formed in the liver, are excreted in the bile, pass into the intestine and are hydrolyzed by intestinal bacteria. Following this hydrolyzation reaction in the intestines the estrogens either are excreted in the feces or they are re-absorbed into the portal circulation. After the reabsorption takes place, the hydrolyzed estrogens are metabolized by the liver again and released into the bile or they stay in the circulation and stimulate their target tissues. The hydrolysis of estrogen-glucoronides is accomplished by the bacterial enzyme called beta-glucuronidase. This enzyme is carried in some unfavourable intestinal bacteria. However, certain nutritional supplements, diet and antibiotics can influence the level of activity of this enzyme.

Conclusion

In summary, the breakdown and excretion of estrogens is an extremely complicated process and a wide range of factors can influence it. Beneficial modulation of estrogen metabolism can be accomplished through dietary and lifestyle modifications such as increasing fiber and reducing fat, increasing phytoestrogen intake, losing weight and increasing exercise. In addition, research suggests that many nutrients effectively reduce estrogen load by supporting preferred pathways of estrogen metabolism and detoxification. The influences of these nutrients on estrogen metabolism may have profound significance for diseases and conditions in which estrogen plays a role in
clinical expression.