Understanding your hormones and how your body detoxes them can help protect your breast tissue. Whether you have hormone imbalance or a concern for breast cancer, understanding your biochemistry can help protect you and your breasts. 

Know Your Biochemistry 

There are many hormones that play a role with breast health and cancer, but the most important is estrogen, specifically when estrogen is in excess. Estrogen dominance refers to this exact state in which estrogen activity is disproportionately high relative to other sex hormones, particularly progesterone. This is clinically relevant because elevated estrogen exposure is a well-established driver of breast cancer risk, especially for estrogen receptor–positive (ER+) subtypes.^[1-3] When we think about hormone testing: many options are available, from serum to saliva, but most valuable testing in this scenario is dry urine testing. Dry urine testing allows for measurement of not only estrogens, but also their metabolites, which is not available in serum or saliva. Moreover, it allows us to assess estrogen exposure over a period of time rather than a single time point, which is a limitation of serum and saliva testing.^[9] 

Know Your Estrogens 

In the context of evaluating estrogen dominance and breast cancer risk, dry urine testing can provide a comprehensive profile of estrogens (estrone, estradiol, estriol) and their metabolites, including those produced via different metabolic pathways (e.g., 2-hydroxylation, 4-hydroxylation, 16α-hydroxylation).^[9-13)  These profiles are relevant because higher urinary excretion of estrogens and certain metabolites—particularly in postmenopausal women—has been associated with increased breast cancer risk.^[9][11-13] 

By assessing the full picture and context of estrogens and their metabolites, we see how someone has unseen risks for breast cancer as well as simple solutions to modify this risk. Estrogen is a collective term for a group of steroid hormones, primarily including estradiol, estrone, and estriol, which exert their effects via estrogen receptors and play central roles in breast cancer pathophysiology. Estradiol is the predominant estrogen in premenopausal women, while estrone becomes the major circulating estrogen after menopause due to peripheral conversion in adipose tissue. Estriol is a weaker estrogen, mainly produced during pregnancy, and is present at low levels otherwise. 

Estrone is strongly associated with increased risk of postmenopausal, estrogen receptor–positive (ER+) breast cancer. Elevated urinary estrone levels correlate with higher risk, and estrone-driven signaling promotes pro-inflammatory and pro-metastatic gene expression in breast tissue, especially in the context of obesity and menopause.^[14-20] Estrone binding to ERα stimulates epithelial-to-mesenchymal transition and tumor progression, whereas estradiol has more anti-inflammatory effects and in some studies is less associated with postmenopausal breast cancer progression.^[14-15] 

Estriol is a weak estrogen with lower affinity for estrogen receptors. While it can stimulate breast cancer cell growth in vitro, its mitogenic potency is much less than estradiol or estrone, and its role in breast cancer risk outside of pregnancy is considered minor. Estriol can activate estrogen-responsive genes and promote proliferation at high concentrations, but clinical data do not support a protective or antiestrogenic effect in breast cancer.^[21-22] 

In summary, estrone is the major postmenopausal estrogen and is most strongly linked to increased breast cancer risk and progression, while estriol is a weak estrogen with limited impact on breast cancer risk. The overall burden of estrogen exposure, especially from estrone and estradiol, is a key driver of ER+ breast cancer pathophysiology.^[14-20] 

Modify Your Risk 

By a large margin, lifestyle modifications are the most effective strategies at improving estrogen levels. Healthy body composition/weight loss, reduced caloric intake, and regular exercise have consistently demonstrated reductions in estrone and other estrogen levels in randomized controlled trials, with combined interventions yielding the greatest effect. For example, a meta-analysis of RCTs in postmenopausal women found that a combined diet and exercise intervention reduced estrone by approximately 10% compared to controls, as well as reductions in estradiol and free testosterone.^[25] Adopting a Mediterranean-style, low-fat, high-fiber diet further supports estrone reduction; controlled feeding studies show that very low fat (10% of calories) and high fiber (35–45 g/day) diets can significantly lower serum estrone and estradiol without disrupting ovulatory function. Alcohol reduction is also recommended, as alcohol intake increases circulating estrogen levels, including estrone.^[23][26] 

Among natural therapies and dietary supplements, soy isoflavones (genistein, daidzein) and lignans (flaxseed) have the most evidence for modulating estrone metabolism and potentially reducing breast cancer risk.  Soy isoflavones act as selective estrogen receptor modulators (SERMs), preferentially binding ERβ and exerting antiestrogenic effects in breast tissue. Clinical trials and preclinical models demonstrate that dietary soy isoflavones can lower serum estrone and estradiol, with doses ranging from 40 mg/day (dietary intake) to 240 mg/day (supplementation) showing reductions in breast proliferation and estrone concentrations, especially in high-estrogen environments.^[26-29] Flaxseed lignans also exhibit antiestrogenic effects by competing for estrogen receptor binding and inhibiting estrone synthesis, with epidemiologic data suggesting lower breast cancer incidence in populations with high flaxseed intake.^[22] 

Black cohosh (Actaea racemosa) has been shown in vitro to inhibit the conversion of estrone sulfate to estradiol in breast cancer cells, potentially reducing the pool of bioactive estrogens available for tumor growth.^[30] However, clinical data are limited and inconsistent, and some studies have found no substantial effect on serum estrogen measures in premenopausal women.^[31] Though black cohosh may lack robust research, given the safety profile and other benefits it may be beneficial to consider for patient treatment plans. 

Given the many tools and resources, we have available to improve estrogen balance and reduce estrogen dominance, anyone with concern about breast health should understand their estrogens. 

Know Your Metabolites 

Another risk factor that is easily gleaned from a dry urine test and just as easily modifiable is the estrogen metabolites: aptly named the “good” (2-hydroxy), the “bad” (4-hydroxy) and the “ugly” (16alpha-hydroxy). The significance of the 2-hydroxy, 4-hydroxy, and 16-alpha-hydroxy estrogen metabolites lies in their distinct biological activities and associations with breast cancer risk. 

2-hydroxy estrogen metabolites are considered less estrogenic and less genotoxic. Extensive metabolism of estrogens via the 2-hydroxylation pathway is consistently associated with a lower risk of postmenopausal breast cancer. Higher ratios of 2-hydroxylation to estrogens, or to 16-hydroxylation metabolites, are inversely associated with risk, suggesting a protective effect.^[32-37] 2-hydroxylation reduces estrogen receptor activation and downstream proliferative signaling in breast tissue.^[38] 

4-hydroxy estrogen metabolites are catechol estrogens with strong genotoxic potential. They can form quinones that react with DNA, leading to mutations and cellular transformation. Less extensive methylation of 4-hydroxylation pathway catechols is associated with a higher risk of breast cancer, as these metabolites are more likely to induce DNA damage and oxidative stress.^[32][39-43] 

16-alpha-hydroxy estrogen metabolites are highly estrogenic and can covalently bind to estrogen receptors, resulting in persistent proliferative signaling. Greater metabolism via the 16α-hydroxylation pathway is associated with a higher risk of breast cancer, as these metabolites promote cell proliferation and may contribute to tumorigenesis.^{[33][37][39-41]} 

In summary, greater 2-hydroxylation is associated with lower breast cancer risk, while greater 4-hydroxylation and 16α-hydroxylation are associated with higher risk. The good news is that balance of these metabolic pathways is a very modifiable factor in breast cancer prevention.^{[32-37][39-41]} 

As complicated as the metabolites can sound, the solutions to create an optional ratio between 2-hydroxy and 16-hydroxy is simple. All of the previously outlined dietary and lifestyle modifications that improve estrone levels, also improve metabolites.^(44-46) 

Additionally, a nutrient from broccoli and cabbage (the cruciferous vegetables) has substantial research supporting its ability to improve the estrogen metabolite ratios. Glucobrassin and myrosinase combine to create indole-3-carbinol, a relatively unstable byproduct of chewing up your broccoli that then easily converts to 3,3-diindolymethane (DIM). DIM works to improve estrogen metabolite ratios by promoting CYP450 enzymes (specifically CYP1A1) to favor 2-hydroxylation.^(47-48) Flavonoids and stilbenes, found in foods like soy, berries, and tea, can inhibit CYP1B1, reducing formation of genotoxic 4-hydroxy metabolites.^(47-48) Given their strong safety profile and additional health benefits, these nutrients are an easy addition to a breast cancer prevention plan. 

Know Your Risk and Your Plan 

Testing urinary hormone metabolites gives a wealth of information about risk factors for breast cancer and helps target imbalances in hormones that can create a personalized, targeted, informed and motivating treatment plan. 

Learn more about how the DUTCH Test can help you and your patients create a personalized treatment plan by becoming a DUTCH Provider today.

References 

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