Estrogen Metabolism and Breast Health: Treatment Approaches for Functional Medicine Providers

Ruth Hobson, ND | July 27, 2022

Achieving optimal hormone balance is the goal of many treatment protocols. Evaluating hormones via testing plays an important role in this process. Different testing modalities can serve different roles toward the goal of hormone balance. Measuring tissue levels in saliva is essential for understanding physiology and how it plays into a patient’s symptom picture. For a deeper understanding of hormone metabolism and how it impacts breast health, the metabolism and excretion of hormones measured in urine should also be considered.

Elevated endogenous levels of estrone (E1) and estradiol (E2) have been implicated as risk factors in breast cancer. It is well established that the metabolites of E1 and E2 can exert proliferative effects in breast tissue. This is due to the way in which these hormones are metabolized as well as the activity of the metabolite intermediates. The liver is responsible for most of this metabolism first through phase I. During phase I metabolism, E1 and E2 are metabolized to the intermediary hydroxy estrogens, 2-OH, 4-OH, and 16-OH, via CYP1A1, CYP1B1, and CYP3A4 respectively. Each of these metabolites carries known risk as they relate to breast health; 2-OH is generally considered the safer metabolite, while 4-OH is considered to be the most carcinogenic, followed by 16-OH E1, which has also been shown to have a negative impact on breast tissue health.

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 favorable treatment strategy. Research has found these natural products can boost CYP1A1.

  • DIM (diindolylmethane) – phytonutrient found in cruciferous vegetables
  • I3C (requires stomach acid to convert to DIM) 
  • Coffee
  • Resveratrol 
  • Andrographolide, from the Andrographis paniculata plant 
  • Astaxanthin (antioxidant found in shrimp and some algae)
  • Fish oil and garlic oil
  • Green and black tea 
  • Hops 

Phase I metabolism in and of itself can generate free radicals. Because of this, the following antioxidants are a consideration to help further reduce additional harm to the tissues:

  • Vitamins A, C, E
  • Carotenoids
  • Selenium
  • Copper
  • Zinc
  • Manganese
  • CoQ10
  • Alpha lipoic acid
  • Thiols (garlic, onions, cruciferous vegetables)
  • Bioflavonoids
  • Silymarin
  • Oligomeric proanthocyanins
  • Glutathione
  • Melatonin

Phase II metabolism involves methylation of phase I metabolites into more water-soluble versions that can be excreted and for the most part rendered inactive, via the COMT enzyme. This is an extremely important step. If 4-OH metabolites are not inactivated, they have the potential to form quinones and or semiquinones, which are highly carcinogenic and genotoxic, capable of inducing and potentiating breast cancer.  Quinones and semiquinones can also increase the risk of hormone responsive breast cancer. To decrease this risk, it is critical to optimize the function of COMT. The following have been shown to increase COMT:

  • Nutrient cofactors: cruciferous vegetables, soy foods, resveratrol, citrus food, teas (rooibos, dandelion), and spices (rosemary, curcumin)
  • Methyl donors: methionine, methylcobalamin, 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.

Doctor’s Data now offers the Hormone and Urinary Metabolites Assessment Profile (HuMAP™) which directly measures metabolite levels, offering providers a tool for a targeted approach for breast health risk reduction.

 

References


  1. Cavalieri E, Rogan E. The 3,4-quinones of estrone and estradiol are the initiators of cancer whereas resveratrol and N-acetylcysteine are the preventers. International Journal of Molecular Sciences. 2021;22(15):8238. doi:10.3390/ijms22158238
  2. Chen HW, Tsai CW, Yang JJ, Liu CT, Kuo WW, Lii CK. The combined effects of garlic oil and fish oil on the hepatic antioxidant and drug-metabolizing enzymes of rats. Br J Nutr. 2003;89(2):189-200. doi:10.1079/BJN2002766
  3. Hodges RE, Minich DM. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab. 2015;2015:760689. doi:10.1155/2015/760689
  4. Horn TL, Reichert MA, Bliss RL, Malejka-Giganti D. Modulations of P450 mRNA in liver and mammary gland and P450 activities and metabolism of estrogen in liver by treatment of rats with indole-3-carbinol. Biochem Pharmacol. 2002;64(3):393-404. doi:10.1016/s0006-2952(02)01190-5
  5. Jaruchotikamol A, Jarukamjorn K, Sirisangtrakul W, Sakuma T, Kawasaki Y, Nemoto N. Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes. Toxicol Appl Pharmacol. 2007;224(2):156-162. doi:10.1016/j.taap.2007.07.008
  6. Ohno M, Darwish WS, Ikenaka Y, Miki W, Ishizuka M. Astaxanthin can alter CYP1A-dependent activities via two different mechanisms: induction of protein expression and inhibition of NADPH P450 reductase dependent electron transfer. Food Chem Toxicol. 2011;49(6):1285-1291. doi:10.1016/j.fct.2011.03.009
  7. Romilly E. Hodges, Deanna M. Minich, "Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application", Journal of Nutrition and Metabolism, vol. 2015, Article ID 760689, 23 pages, 2015. https://doi.org/10.1155/2015/760689
  8. Sisti JS, Hankinson SE, Caporaso NE, et al. Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women. Cancer Epidemiol Biomarkers Prev. 2015;24(8):1174-1183. doi:10.1158/1055-9965.EPI-15-02
  9. Thomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3'-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutr Rev. 2016;74(7):432-443. doi:10.1093/nutrit/nuw010
  10. Yager JD. Mechanisms of estrogen carcinogenesis: The role of E2/E1–quinone metabolites suggests new approaches to preventive intervention – A Review. Steroids. 2015;99:56-60. doi:10.1016/j.steroids.2014.08.006
  11. Yao HT, Hsu YR, Lii CK, Lin AH, Chang KH, Yang HT. Effect of commercially available green and black tea beverages on drug-metabolizing enzymes and oxidative stress in Wistar rats. Food Chem Toxicol. 2014;70:120-127. doi:10.1016/j.fct.2014.04.043

Hormone Testing and Prescribing: Practical Applications for Clinical Cases

Lylen Ferris, ND

July 27, 2022 at 12 PM Pacific

Approximately 60 minutes with Q&A

Doctor's Data is excited to announce the HuMap™ is now available! In this webinar, attendees will gain an understanding of the HuMap™, including when to consider testing urinary metabolites, how to read the reports, what hormones and metabolites are tested, and how to analyze metabolic pathways and enzymatic key relationships. This concise introduction to the HuMap™ will also address collection instructions and best practices, saliva vs urine testing for BHRT monitoring, as well as the benefits of Doctor's Data test methodology and available complementary test profiles. Attendees will have the opportunity to send in questions prior to the webinar and participate in a live Q&A session with our clinicians and account representatives.

Immune Rejuvenation

Heather Zwickey, PhD

August 3, 2022 at 9:30 AM and 12 PM Pacific

Approximately 60 minutes with Q&A

Regardless of whether you experienced an infectious disease, your immune system has suffered in the past couple of years. As we work to restore immunity in our post pandemic world, we must be aware of how our immune systems have been affected by SARS-CoV2 infection, social isolation, insomnia, and anxiety. We know diets and nutritional habits changed; work/life balance changed; and stress increased beyond our wildest projections. This seminar will discuss immune health in the context of our individualized microbial ecosystems, our hormones, and environmental exposures. We will highlight our current understanding of how the gut microbiome and immune system interact to achieve health, as well as how the microbiome is affected when we reconnect with each other. Finally, we will discuss a strategy to support immune rejuvenation in yourself and your patients.

Disclaimer: All information given about health conditions, treatment, products, and dosages are for educational purposes only and do not constitute medical advice.

FOLLOW US

FacebookTwitterInstagram

800.323.2784 (US and Canada)

+1.630.377.8139 (Global)