What Urinary Hormone Metabolite Testing Tells Us about Estrogen Metabolism and Breast Cancer Risk

Estrogen is a life-giving hormone with which modern humans have a complicated relationship. Over two decades ago, The Women’s Health Initiative (WHI) findings reported that combined estrogen and progestin hormone therapy increased the risk of breast cancer, coronary heart disease, stroke, and venous thromboembolism in postmenopausal women. This led to a pervasive vilification of estrogen therapy that has affected generations of women.

 

The lasting impact of a misinterpreted study on estrogen therapy and women’s health

However, a reevaluation of the WHI data by the original researchers, published in 2019  indicates that the initial published findings focused on estrogen when it was actually the progestins (synthetic progestogens given in combination with estrogen therapies) that were the culprit in increasing the risk of cardiovascular disease and breast cancer. The estrogen-only arm of the WHI actually showed a 23% reduced occurrence of breast cancer.

It is now clear that often, estrogen protects women’s hearts, brains, bones, and breasts. There are many risk factors for  breast cancer, but when it comes to estrogen, it doesn’t seem to be estrogen alone that is driving breast cancer risk. So what is it?

 

Science-backed risk factors for breast cancer

The GENICA study provides some clues. This trial evaluated established phenotypic risk factors (i.e., age, having a first-degree relative with breast cancer, menopausal status, oral contraception use, hormone replacement use, and BMI) in conjunction with an evaluation of estrogen metabolism via CYP1A1 (2 OH E1/E2) and CYP1B1 (4OH E1/E2) pathways. The researchers found that premenopausal women with elevated 4-OH E2 levels (in the 90^th percentile) had a higher odds risk of breast cancer than women in the 10^th percentile. The relative risk for premenopausal women favoring CYP1B1 metabolism was 2.3 times higher than that of women at the 10^th percentile and 1.89 times higher in postmenopausal women. The GENICA model combines phenotypic factors with genotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure as a more thorough predictor of breast cancer risk.

Urinary hormone metabolite testing, like the HuMap^TM Profile from Doctor’s Data, gives insight into how the pathways of estrogen metabolism can influence the safety of this important hormone, as various metabolites can contribute to the promotion of or protection against pathologies like breast cancer.

 

The role of estrogen metabolism and detoxification pathways in breast cancer

Estrogens are metabolized through multiple pathways, primarily via Phase 1 and Phase 2 detoxification, which render these fatty molecules water soluble and ready for excretion in urine and stool. The balance between these pathways influences the risk of estrogen-related cancers.

Phase 1 hydroxylation is driven by the cytochrome P450 family  of enzymes. The CYP1A1 gene regulates metabolism in the liver while the CYP1B1 gene does so outside the liver, mainly in the breasts, ovaries, and uterus. In phase 2 metabolism, these metabolites are conjugated through sulfation via steroid sulfotransferases, or methylation and glucuronidation, requiring catechol-O-methyltransferase (COMT) and glutathione S-transferase (GST) enzymes.

Phase I hydroxylation yields three estrogen metabolites that vary greatly in biologic activity: 2-hydroxyestrone/estradiol (2-OH), 16-hydroxyestrone/estradiol (16α-OH), and 4-hydroxyestrone/estradiol (4-OH). The 2-OH metabolite is generally termed the “good” estrogen metabolite because it generates weaker and potentially less harmful estrogenic activity. In contrast, the 16α-OH and 4-OH metabolites show persistent estrogenic activity, which could promote dangerous tissue growth if left unchecked. Women who metabolize a larger proportion of estrogen via the 16α-OH E1 and 4-OH metabolites may be at significantly higher risk of developing breast cancer.

The literature supports the evaluation of phase 1 metabolites as a component of risk reduction:

• 2-OHE1, a product of CYP1A1 metabolism, is considered protective and associated with reduced breast cancer risk.
• 4-OHE1, a product of CYP1B1, has a higher potential for DNA damage, increasing breast cancer risk.
• 16-OHE1, converted via CYP3A4, has estrogenic activity and has been linked to increased risk of hormone-related cancers.

In phase 2 metabolism, the 2-OH and 4-OH estrogen metabolites are further detoxified via methylation by the COMT enzyme. This is an important pathway because it renders the harmful 4-OH metabolites significantly less active and activates the protective 2-OH into the stable 2-methoxyestrone (2-M-E1). If the 2-OH and 4-OH estrogens are not methylated, they can become reactive quinones and semi-quinones which are highly carcinogenic and genotoxic, capable of inducing and potentiating breast cancer.

Some of the most potent agents for supporting methylation and the enzymes that support healthy estrogen metabolism come from plants. According to the 2015 Behavioral Risk Factor Surveillance System, only 9% of American adults met the recommendations for vegetable consumption and only 12% for fruit. Dietary modifications and appropriate  supplementation (if needed) provide important support for healthy estrogen metabolism.

 

Nutritional strategies for healthy estrogen metabolism

It is well established that having a relative increase of 2-OH metabolites compared to 4-OH metabolites is favorable. For this reason, increasing 2-OH metabolism via CYP1A1 is a beneficial treatment strategy. Research has found that these nutritional compounds can boost CYP1A1.

• DIM (diindolylmethane) – phytonutrient found in cruciferous vegetables
• I3C (indole 3 carbinol) – a precursor to DIM, I3C requires stomach acid to convert to DIM.
• Andrographolide, from the Andrographis paniculata plant
• Astaxanthin – an antioxidant found in shrimp and some algae
• Fish oil and garlic oil
• Hops

Phase 2 metabolism involves the methylation of phase 1 metabolites into more water-soluble versions that can be excreted and, for the most part, rendered inactive via the COMT enzyme. The following have been shown to increase COMT activity:

• Nutrient cofactors: cruciferous vegetables, organic non-GMO soy, resveratrol, citrus fruits, teas (rooibos, dandelion), and spices (rosemary, curcumin)
• Methyl donors: methionine, methylcobalamin (B12), SAMe, pyridoxyl-5-phosphate, betaine, folate, and magnesium

For those who have lower COMT activity and thus greater potential for quinone activity, two supplements may offer some additional protection:

Resveratrol

• Can reduce catechol estrogen semiquinones back to catechol estrogens
• Can induce the estrogen-protective enzyme quinone reductase
• Modulates CYP1B1, thereby reducing its activity and minimizing the potential for the formation of 4-OH metabolites

NAC

• Can reduce estrogen semiquinones back to catechol estrogens
• Primary effect is to react with quinones to form conjugates, preventing the formation of estrogen-DNA adducts.

 

Lab testing for assessing estrogen metabolism

Urinary hormone metabolite testing, like the Doctor’s Data HuMap^TM Profile, provides a non-invasive and comprehensive assessment of estrogen metabolism, allowing clinicians to identify potential risk factors for breast cancer and personalize therapeutic interventions. By addressing hormonal imbalances through targeted lifestyle, dietary, and nutraceutical strategies, providers can support optimal breast health and long-term wellness.

 

About the HuMap^TM Profile

The Hormone & Urinary Metabolites Assessment Profile (HuMap^TM) provides a comprehensive overview of steroid hormones, their metabolites, and the efficiency of the enzymes that metabolize these hormones. This non-invasive test requires only 4 or 5 separate urine collections. Because the breakdown of hormones relies so heavily on processes within the liver, this test can also elucidate areas of interest as it pertains to conjugation of each metabolite. Additionally, testing urinary hormone metabolites can contribute to a further understanding of endogenous hormone secretion, supplemental hormone utilization, enzyme activity, oxidative stress, and insight into how the body is metabolizing hormones.

To gain a deeper understanding of utilizing estrogen metabolism information to optimize breast health, please join us for a webinar presented by Ruth Hobson, ND, staff physician at Doctor’s Data. Click here to register for this webinar on May 20, where Dr. Hobson will present Rethinking Estrogen: Understanding Metabolism, the Estrobolome, and the Path to Hormonal Balance. By bridging the gap between fear and science, this presentation delivers a balanced perspective on estrogen, equipping attendees with the knowledge needed to support hormonal health with confidence.

Further Resources:

HuMap Collection Instructions

HuMap Resource Guide

HuMap Sample Report

Best Practices for Specimen Collection

HuMap Clinical and Therapeutic Considerations

How to Read the HuMap Webinar

Intro to HuMap Webinar

Hormone Metabolism 101 Webinar

Townsend Letter article, “Clinical Utility of Salivary and Urinary Hormone testing”