4-Methoxyestrone is a metabolite of estrone, a form of estrogen, and is produced through the methoxylation process. This metabolite is considered to be a less active form of estrogen, having weaker estrogenic effects compared to other metabolites like 16a-Hydroxyestrone. The presence and levels of 4-Methoxyestrone in a pre-menopausal woman can offer insights into her estrogen detoxification pathways, specifically indicating the activity of methylation processes in the body. Efficient methylation is important for the neutralization and elimination of estrogen and its metabolites, reducing the risk of estrogen-dominant conditions.

Most recent studies find an increased breast cancer risk associated with the ratio of 4-pathway cetechols to 4-pathway methylated catechols.

Most recent studies find an increased breast cancer risk associated with the ratio of 4-pathway cetechols to 4-pathway methylated catechols.

Since 4-methylhippuric acid (4-MHA) is a metabolite of p-xylene, the measurement of 4-MHA in urine may be correlated to a subject's level of xylene exposure.

4-Nonylphenols are used in manufacturing antioxidants, lubricating oil additives, laundry and dish detergents, emulsiers, and solubilizers. These compounds are also precursors used to produce paints, pesticides, cosmetics, and plastics. Nonylphenol persists in aquatic environments and is moderately bioaccumulative. It is not readily biodegradable, and it can take months or longer to degrade in surface waters, soils, and sediments. It has a potential role as an endocrine disruptor and xenoestrogen due to its ability to act with estrogen-like activity. Nonylphenol exposure has also been associated with breast cancer.

4-OHE1and 4-OH-E2 are referred to as the “bad” estrogens, along with 16a-OHE1. They are primarily produced by CYP1B1 and CYP34A, respectively, enzymes localized in tissues, including breast and prostate as well as liver. Some have suggested that increased expression of CYP1B1 and 4-hydroxylation of estradiol are biomarkers of tumorigenesis.

Human breast cancer tissue produces much higher levels of 4-OH than 2-OH, while normal breast tissue produces approximately equal amounts of the two metabolites. Women taking hormone therapy with a polymorphism in CYP1B1 had twice the risk of developing breast cancer compared to other HRT users.

The hydroxylation of estradiol is one of the major routes of metabolism of the estrogen steroid hormone estradiol. It is hydroxylated into the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol and into estriol (16α-hydroxyestradiol). 4-hydroxyestradiol (4-OH-E2), like 2-OH-E2, can be physiologically active as well as tumorigenic. 4-OH-E2 is capable of binding estrogen receptors with a reduced dissociation rate and prolonged activation, thereby inducing cellular growth and proliferation, adenohypophyseal hormone secretion, and prostaglandin production.

- The 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA.

- Estrone is hydroxylated through Phase 1 detox to form 4-OH-E1. In Phase 2 it is methylation to form 4-MeE1. When 4-OH-E1 is properly methylated to 4-MeE1 it is relatively benign as the 4-MeE1 is easily eliminated and risks are low.

- When it is not methylated 4-OH-E1 builds up. Then it converts to 3,4-Quinones which are carcinogenic similarly to the 16 pathway. Women with uterine fibroids may have increased levels of 4-OH-E1. High levels of estrogen across the board are associated with heavy cycles.

- The 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA.

- Estrone is hydroxylated through Phase 1 detox to form 4-OH-E1. In Phase 2 it is methylation to form 4-MeE1. When 4-OH-E1 is properly methylated to 4-MeE1 it is relatively benign as the 4-MeE1 is easily eliminated and risks are low.

- When it is not methylated 4-OH-E1 builds up. Then it converts to 3,4-Quinones which are carcinogenic similarly to the 16 pathway. Women with uterine fibroids may have increased levels of 4-OH-E1. High levels of estrogen across the board are associated with heavy cycles.

Percentages of 2-OH-E1, 4-OH-E1, and 16-OH-E1

When evaluating phase I metabolism, it can be helpful to compare the percentages of 2, 4, and 16 OH-E1 metabolites. Most individuals metabolize the majority of their estrogens down the 2-OH-E1 pathway which is generally considered the “safer pathway”. This is followed by 16-OH-E1 and 4-OH-E1 respectively, both of which are deemed more reactive and potentially genotoxic.

In a Hormone Metabolite Assessment Panel (HUMAP) designed for pre-menopausal women, the percentage of 4-Hydroxyestrone (4-OH-E1) plays a crucial role in understanding estrogen metabolism and its associated risks. 4-OH-E1 is one of the metabolites of estrogen produced through the 4-hydroxylation pathway, which is significant due to its potent biological activity. This metabolite is known for its strong estrogenic effects and has been linked to an increased risk of estrogen-related cancers, particularly breast cancer.

In the body, 4-OH-E1 can be further metabolized to form catechol estrogen quinones, which have the potential to damage DNA and cause mutations. The percentage of 4-OH-E1 in the overall estrogen metabolite profile is a critical marker; higher percentages can indicate a greater reliance on the 4-hydroxylation pathway, suggesting a potential increase in the risk for estrogen-driven conditions. Factors influencing the proportion of 4-OH-E1 include genetics, liver health, diet, lifestyle, and exposure to environmental toxins.

A very carcinogenic estrogen metabolite, levels low in the reference range are desirable. Additional magnesium, liver support, and methylation support may help decrease 4-OH-E1 levels.

- The 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA.

- Estrone is hydroxylated through Phase 1 detox to form 4-OH-E1. In Phase 2 it is methylation to form 4-MeE1. When 4-OH-E1 is properly methylated to 4-MeE1 it is relatively benign as the 4-MeE1 is easily eliminated and risks are low.

- When it is not methylated 4-OH-E1 builds up. Then it converts to 3,4-Quinones which are carcinogenic similarly to the 16 pathway. Women with uterine fibroids may have increased levels of 4-OH-E1. High levels of estrogen across the board are associated with heavy cycles.