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Estrogen Metabolism Tara Scott, MD

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Estrogen Metabolism Tara Scott, MD 7/15/2020 Estrogen Metabolism Tara Scott, MD. FACOG, FAAFM, ABOIM 1 Webinar Technical Issues & Clinical Questions •Please type any technical issue or clinical question into either the “Chat” or “Questions” boxes, making sure to send them to “Organizer” at any time during the webinar. •We will be compiling your clinical questions and answering as many as we can the final 15 minutes of the webinar. All rights reserved © 2020 Precision Analytical Inc. 2 1 7/15/2020 Need more resources? Ensure you have an account! • Contact Customer Service at 503.687.2050 or go to https://dutchtest.com/providers/ to open your account today! All rights reserved © 2020 Precision Analytical Inc. 3 WHO Am I? • Tara Scott, MD • Board certifications in: OB/GYN, Integrative Medicine, and Anti‐Aging, Functional and Regenerative Medicine • Lecture around the world teaching doctors a functional approach to women’s health • Medical Director of Integrative Medicine at Summa Health in Akron, OH Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 4 2 7/15/2020 Objectives Review the basics of estrogen metabolism Define SNPs and how they affect metabolism Discuss which SNPs affect the risk of breast cancer Review a case and demonstrate the information the DUTCH test provides 5 Why is it so important to check estrogen metabolism? • Is it really possible to have a randomized placebo controlled trial with hormone therapy? • You need to consider: • Weight, age, oophorectomy status • Pharmacokinetics‐ what the body does to the drug • Pharmacodynamics‐ what the drug does to the body 6 3 7/15/2020 Suppose I tell all my patients to drink 2 liters of water Marathon Runner in 80 degree weather Dialysis Patient 7 Menstrual Cycle • Developing egg makes Estrogen‐ causes growth • After its released, progesterone balances estrogen 8 4 7/15/2020 What do we Know? This was our Endocrinology Bible in residency!! 9 Menstrual Cycle • Developing egg makes Estrogen‐ causes growth • After its released, progesterone balances estrogen 10 5 7/15/2020 Estrogen causes proliferation Page 126 Progesterone Inhibits proliferation, decline in DNA synthesis, interferes with the estrogen receptor Page 128 Estrogen stimulates many oncogenes that mediate estrogen induced growth. Progesterone antagonizes this action‐ suppresses transcription of oncogene mRNA Page 128 Pearls from Dr. Speroff 11 STEROIDOGENIC PATHWAY 12 6 7/15/2020 Estrogen‐ Functions • Promotes growth • Body development • Slows bone loss • Three main types • Estradiol‐ good for heart and bones • Estriol ‐ good for skin • Estrone‐ goes to breast‐ sort of the bad one 13 Estrone (E1) Predominant estrogen in postmenopausal women. Estradiol (E2) Predominant estrogen in premenopausal women. Most biologically active estrogen in women Estriol (E3) Predominant estrogen in pregnant women. Most abundant estrogen in urine. Samavat & Kurzer, 2015 14 7 7/15/2020 Estrone (E1) Primarily synthesized from androstenedione by aromatase conversion in the ovaries. Reversibly converted into estradiol by enzyme, 17β‐hydroxysteroid dehydrogenase Type II. Estradiol (E2) Primarily synthesized by developing follicle in the ovaries. Reversibly converted into estrone by enzyme, 17β-hydroxysteroid dehydrogenase Type I. Estriol (E3) Synthesized from estrone, which can be converted from the hydroxylation of estradiol or 16-Hydroxyestrone. Samavat & Kurzer, 2015 15 I think of Estrogen like three sisters 16 8 7/15/2020 Boothby, Lisa A., et Al. “Bio identical hormone therapy: a review” in Menopause, 2004, vol 11, No. 3, pp.356‐367 Estrogen Receptor‐ Alpha Estrogen Receptor‐ Beta 17‐ Beta‐estradiol 100 100 17‐ alpha‐estradiol 58 11 Estriol 14 21 Estrone 60 37 4‐OH‐Estradiol 13 7 2‐OH‐Estrone 2 0.2 Tamoxifen 4 3 Raloxifene 69 16 17 Other sources of Estrogens 18 9 7/15/2020 PHASES OF DETOXIFICATION Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 19 20 Healthy Estrogen Metabolism Specific Phytonutrients Specific Supplements Specific Vitamins Specific Diet Healthy Intestine Minerals Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP Correct Insulin Resistance 20 10 7/15/2020 Estrogen Metabolism Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 21 Estrone Metabolism Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 22 11 7/15/2020 Estrogen Metabolism More simplified . Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 23 The “Good” Estrogens 2-HYDROXYESTROGENS: Estrogen • Considerable weak with overall low hormonal Metabolites potency and low binding affinity to estrogen receptors1. • 2-hydroxyestrogen have anti-proliferative effects in breast tissue1,2. 1. Samavat & Kurzer, 2015 2. Gupta et al., 1998 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 24 12 7/15/2020 The “Good” Estrogens METHOXYESTROGENS: • Methoxyestrogens are deactivated forms of estrogen Estrogen formed from methylation of catechol estrogens. Metabolites • This methylation conjugation prevents the biotransformation of hydroxyestrogens into quinone-DNA adducts (DNA damage) and the byproduct formation of reactive oxygen species. • Methoxyestrogens also inhibits cell proliferation by 1. Dawling et al., 2003 1,2.3 2. Lakhani et al., 2003 inhibiting mitosis . 3. Lottering et al., 1992 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 25 The “Bad” Estrogens 4-HYDROXYESTROGEN QUINONE METABOLITES Estrogen • Lead to the formation of depurinating adducts1. Metabolites • Women with or at high risk for breast cancer had high levels of adducts in their urine2. • In cellular preparations of adenocarcinoma, 4- hydroxyestradiol was 4x higher than 2- hydroxyestradiol3. 1. Cavalieri et al., 1997 2. Cavalieri & Rogan, 2010 3. Liehr & Ricci, 1996 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 26 13 7/15/2020 The “Bad” Estrogens 16α-HYDROXYESTRONE • 16α-Hydroxyestrone is the intermediate between estrone and estriol. • Higher urinary concentrations of 16α-Hydroxyestrone were associated Estrogen with mammary cell proliferation in animals1. Metabolites • 16α-Hydroxyestrone has been found to be higher cancer breast tissue relative to normal breast tissue2. • 16α-Hydroxyestrone is inversely proportional to 2-hydroxyestrone. • Recent evidence has drawn into question the significance in the 16α- Hydroxyestrone breast cancer relation3,4. 1. Telang et al., 1992 2. Castagnetta et al., 2002 3. Obi et al., 2011 4. Huang et al., 2012 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 27 Preventing INSECTICIDES (e.g., endosulfan) has been Negative found to inhibit the expression of CYP-1A1, Estrogen resulting in reduced Burden activity of the 2- hydroxyE pathway1. 1. Coumoul et al., 2001 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 28 14 7/15/2020 RESVERATROL prevents the formation of Preventing depurinating estrogen DNA adducts in human breast Negative cells treated with E1. Estrogen Resveratrol inhibits peroxidase activity, Burden reducing the formation of catechol estrogen quinones1. Resveratrol also increases NDPH quinone reductase activity2. 1. Cavalieri & Rogan, 2010 2. Zahid et al., 2008 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 29 Preventing N-ACETYLCYSTEINE prevents electrophilic Negative damage to DNA by inhibiting the formation Estrogen electrophilic quinones. Burden It has been found that the consumption of N- acetylcysteine for a 1- month period resulted in 55% reduction in urinary levels of estrogen DNA adducts1. 1. Cavalieri & Rogan, 2010 2. Zahid et al., 2008 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 30 15 7/15/2020 IODINE plays a critical Preventing role in the maintenance and functioning of Negative mammary gland tissue. Estrogen There exists high rates of breast cancer among women with thyroid Burden abnormalities1,2. Women with breast cancer tend to have larger thyroid volumes than controls, indicating an association between iodine deficiency and breast cancer1,2. 1. Smyth et al., 1996 2. Vassilopoulou-Sellin et al., 1999 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 31 IODINE supplementation is effective at diminishing Preventing ductal hyperplasia in rats1. Patients with benign breast Negative disease that received iodine treatment experienced Estrogen significant bilateral breast reduction2. Burden Japanese communities that consume high amounts of seaweed (high [I]) have reported lower incidences of benign and malignant tissue3. Iodine is thought to exhibit its beneficial effects by modulating estrogen 1. Eskin et al., 1995 2. Ghent et al., 1993 3. Cann et al., 2000 4,5 4. Snyth, 2003 metabolism . 5. Stoddard II et al., 2008 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 32 16 7/15/2020 Preventing Negative Estrogen Increase Reduce 2-HydroxyE 4-HydroxyE Burden Pathway Pathway Activity Activity Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 33 Preventing • Increase CYP 1A1 • Reduce CYP- 1B1 Negative • Increase COMT • Reduce • Increase quinone Estrogen Peroxidase reductase Burden • Decrease β- • Increase glucuronidase glutathione activity conjugation Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 34 17 7/15/2020 BIFIDOBACTERIUM Preventing significantly decreases Negative glucuronidase Estrogen activity1. Burden CALCIUM-D- GLUCARATE is a potent beta- glucuronidase inhibitor that has been shown to exert anticarcinogenic 1 1. Bouhnik et al., 1996 effects . 2. Walaszek et al., 1997 Tara Scott, MD, FACOG, FAAFM, ABOIM, CNMP 35 Estrogens & Estrogen Metabolites Urinary Hormone Results Patient information – Permission for use granted by T. Scott, MD, FACOG, FAAFM, ABOIM, NCMP Laboratory Results – Adapted from Genova Diagnostics. Permission for use granted by A.L. Peace-Brewer, PhD, D(ABMLI), Lab Director at Genova Diagnostics. Genova Diagnostics is not involved in the teachings, opinions, or the diagnostic and treatment
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