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How Recent Findings in Iodothyronine Deiodinase Physiology Impact Womens Health Issues Denis Wilson, MD Slide 2 2 Hypothyroid symptoms 5 to 10 times more common in women than in men Includes infertility, chronic fatigue, insomnia, weight gain, mood disorders and many other issues that affect countless women Research confirms people can suffer from reversible low thyroid symptoms even when TSH is normal Millions of women with low thyroid function are being overlooked because of normal thyroid tests The need is vast and some doctors have built entire practices around the tools well discuss New York Thyroid Center, Thyroid disease in women, Columbia University: 2003 Gullo D, Latina A. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLOS One. 2011;6(8):e22552. Slide 3 Mainstream medicine and thyroid blood tests focus on what happens upstream from the deiodinase enzyme when ten times more people are suffering because of what happens downstream from that enzyme We are missing the forest for the trees Much research shows signs (like body temperature) and symptoms are still the most reliable indicators of thyroid status in the tissues Lowe JC, Garrison RL, Reichman AJ, Yellin J, Thompson M, Kaufman D. Effectiveness and safety of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double-blind placebo-controlled response-driven crossover study. Clin Bulletin Myofascial Therapy 1997;2(2/3):3157 Slide 4 Hypothermia can cause mental dullness, forgetfulness Hypothyroidism must be ruled out before a diagnosis of PMS can be made. What does that tell us? In one study, 75% of the women with PMS had subclinical hypothyroidism. There was complete resolution in over 60% of them when treated with T4 Irwin B. A case report of hypothermia in the wilderness. Wilderness & Environmental Medicine. 2002;13(2):125128. Moline M, Zendall S. Evaluating and managing premenstrual syndrome. Medscape Womens Health, 2000;5(2):1. Mainstream Medical Research Shows: Slide 5 Thyroid function should be checked in patients with Panic Disorder and Generalized Anxiety Disorder Hypothyroidism often presents with obesity Hypothyroidism can cause low libido, sexual dysfunction Women with hypothyroidism tend to have edema that should be treated with thyroid medicine. Fluid retention causes fibromyalgia-like symptoms Simon N, Blacker D. Hypothyroidism and hyperthyroidism in anxiety disorders revisited: New data and literature review. Journal of Affective Disorders. 2002;69(1):209217. Kokkoris P, Pi-Sunyer F. Obesity and endocrine disease. Endocrinology and Metaboloism Clinics of North America. 2003;32(4):895914. Viera A. Managing hypoactive sexual desire in women. Medical Aspects Hum Sex. 2001;1:713 Wheatley T, Edwards O. Mild hypothyroidism and oedema: Evidence for increased capillary permeability to protein. Clinical Endocrinology. 1983;18(6):627635. Deodhar A, Fisher A. Fluid retention syndrome and fibromyalgia. Rheumatology. 1994;33(6):576582 Slide 6 Hypothyroidism causes headaches. Hypothyroidism is a treatable cause of secondary headaches. Subclinical hypothyroidism is an exacerbating factor for migraine headache! Carpal tunnel syndrome is common in patients with hypo- thyroidism, even when medicine makes their tests normal In Irritable bowel syndrome, tests should be done if there is even a hint of hypothyroidism. Whats that tell us? Moreau T, Manceau E. Headache in hypothyroidism. Prevalence and outcome under thyroid hormone therapy. Cephalalgia. 1998;18(10):687689. Fallah R, Mirouliaei M. Frequency of subclinical hypothyroidism in 5- to 15-year-old children with migraine headache. J Ped End Met. 2012;25(9-10):859-862. Cakir M, Samanci N. Musculoskeletal manifestations in patients; with thyroid disease. Clinical Endocrinology. 2003;59(2):162167. Olden K. Diagnosis of irritable bowel syndrome. Gastroenterology. 2002;122(6):1701 1714 Slide 7 Hypothyroidism can cause insomnia First consideration for telogen (non-pigmented bulb) hair loss is hypothyroidism. Triggered by stress, surgery T3 can correct up to 50% of treatment-resistant depression Goldacre M. Use of large medical databases to study associations between diseases. QJM. 2000;93(10);669675. Kales A. Sleep disorders: Recent findings in the diagnosis and treatment of disturbed sleep. NEJM. 1974;290(9):487499. Harrison S. Diffuse hair loss: Its triggers and management. Cleveland Clinic Journal of Medicine. 2009;76(6):361367. Slide 8 Why is TSH an unreliable indicator of thyroid stimulation in the cells of the body? Slide 9 9 Slide 10 10 RXR = retinoid X receptor; THR = thyroid hormone receptor Gereben B, Zavacki A, Ribich S. Cellular and molecular basis of deiodinase- regulated thyroid hormone signaling. Endocrine Reviews. 2008;29(7):898938. T3 in the nucleus determines the rate of DNA transcription (which determines the functioning of all known living organisms) Slide 11 Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 2006;116(10):25719. 80% of T3 is produced and regulated intracellularly in a time-specific and tissue-specific fashion This regulation and control is invisible to blood tests Slide 12 A great deal of the T3 stimulation of the nucleus depends on the intracellular conversion of T4 to T3, and thats regulated. Bianco A, Kim B. Deiodinases: Implications of the local control of thyroid hormone action. J Clin Invest. 2006;116(10):25712579. Slide 13 Ubiquitin Proteasome Pathway Key regulatory system for protein levels Ubiquitin is found in every cell E1 activates ubiquitin for attachment to E2 E2 transports ubiquitin to E3 for attachment to targeted protein Process repeats until chain of at least 4 ubiquitin Targeted and tagged protein is recognized and digested by proteosome and amino acids are recycled This is the key pathway that regulates the activity of D2 which converts T4 to T3 Slide 14 T4 and rT3 both accelerate the destruction of type II deiodinase (D2), decreasing the half-life of D2 by as much as 50%, slowing the conversion of T4 to T3 This can explain why many patients dont feel well on T4-containing medicine T4 can actually bog down the system Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews 2002;23(1):3889 Slide 15 Kaiser C, Goumaz M. In Vivo inhibition of the 5 -deiodinase type II in brain cortex and pituitary by reverse triiodothyronine. Endocrinology. 1986;119(2):762770. Elliot D, Goldberg L. Sustained depression of the resting metabolic rate after massive weight loss. Am J Clin Nutr. 1989;49(1):9396 Stressful lifestyle and excessive dieting are well known to impair T4 to T3 conversion People can experience sustained depression of the metabolic rate after massive, and even moderate weight loss Possible vicious cycle that bogs the system Slide 16 In giving T4-containing medicine theres a serious question how much will go to T3 vs. rT3 This can explain why some patients feel worse and worse when their T4-containing medicine is increased Slide 17 Also: Dieting Anxiety Aging Chronic Fatigue Syndrome Fibromyalgia Migraines Stress Inflammation and chronic disease Research: Conditions impair T4 transport into cell Much research shows that TSH is especially poor indicator of thyroid sufficiency with these conditions Slide 18 Insulin resistance Diabetes Metabolic Syndrome Obesity Inflammation and chronic disease Excessive exercise Inflammation Heart disease Chronic infection Menopause Autoimmune disease (lupus, multiple sclerosis, etc) Environmental toxins (POPs) Numerous studies show the following to reduce T4 to T3 conversion: Slide 19 Thyroid purpose = Set the speed of the metabolism the faster particles are moving the higher the temperature thermometer is literally a thermometer looking at thyroid tests to see how fast the metabolism is going is like looking at the gas gauge to see how fast youre driving your car looking at the body temperature is like looking at the speedometer instead body temperature correlates with low thyroid symptoms far better than thyroid blood tests Just have your patients check their temperatures when they feel their best and when they feel their worst Slide 20 Body Temperature Thyroid physiology and body temperature go together Increased body temperature in mice in one day with T3 PubMed Health lists low body temperature as a symptom of myxedema If very low thyroid can cause very low temps, then maybe low temps can be a sign of low thyroid function even when thyroid blood tests are normal Wikstrom L, Johansson C. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO Journal 1998;17(2):455-461 Johansson C, Thoren P. The effects of triiodothyronine on heart rate, temperature and ECG measured with telemetry in freely moving mice. Acta Physiologica Scandinavica.1997;160(2);133138. Slide 21 People dont have hypothyroid symptoms without having a low body temperature Slide 22 Sheep Body Temperature by Radio Telemetry -- 24 7 365 days Slide 23 Body Temperature Seriously, should be checked first, not last It can affect every bodily function Its easy to check Its usually easy to correct The symptoms can remain improved even after the treatments been discontinued. Body temperature is the parameter that is most similar among us. Theres a reason for that. Slide 24 Workup for low thyroid symptoms and low body temperature TSH can rule out primary hypothyroidism Multichemistry blood tests can rule out kidney disease, diabetes, liver problems, etc. Complete blood counts can rule out anemia, infection, leukemia, and so on. Consider adrenal fatigue EKG, good baseline to have If no better explanation for the symptoms and temperature, consider impaired transport/conversion/resistance of thyroid hormones Slide 25 Lifestyle measures for low body temperature Stress-reduction, declutter, simplify Regular, moderate exercise, especially short sprints Detoxification, sauna Organic foods (to avoid pesticides and toxins) Avoid gluten, aspartame, excess alcohol Get adequate rest, good multi-vitamin and nutrition Iodine Selenium, Zinc Iron Tyrosine Certain thyroid and adrenal support botanicals Slide 26 Iodine Some practitioners report that the majority of their patients with low temperatures and normal thyroid tests will feel better and respond with higher temps when given 248 mg/day for a number of months. RDA is 150 g/day. T3 can sometimes go up significantly just by adding iodine. Probably, Commiphora Myrrha > source of myrrh resin. Contains ketosteroids that support iodine uptake and T4 to T3 conversion. Supports healthy cholesterol levels. Decreases total serum lipids, cholesterol, triglycerides, and beta lipoproteins and increases all thyroid functions. Guggul Tripathi YB, Malhotra OP, Tripathi SN. Thyroid stimulating action of Z-guggulsterone obtained from Commiphora mukul. Planta Med. 1984;50(1):7880. Panda S, Kar A. Gugulu (Commiphora mukul) induces triiodothyronine production: possible involvement of lipid peroxidation. Life Sci. 1999;65(12):PL137PL141. Slide 32 Iris Versicolor Used extensively from 18301940 to treat thyroid disorders Late 1800s made into a pharmaceutical called Iridin for hypothyroidism Traditionally used to move sluggish body fluids Commercially used to detoxify toxic land Blue Flag Slide 33 15 year old boy Hashimoto s Thyroiditis Slide 34 27 year old female Hashimoto s Thyroiditis Slide 35 Very important in thyroid disorders and treatment Help normalize endocrine function, resistance to stress Support for stamina as well as mental and immune function Thyroid and Adrenal go together like two players on the same team. When one struggles the other is taxed as well Adrenal support can often help people tolerate T3 therapy Botanical Adrenal Support Slide 36 Siberian Ginseng (Eleutherococcus senticocus) helps optimize adrenal response. Excellent for stress-related exhaustion and emotional disturbances. Holy Basil (Ocimum sanctum) helps to normalize hyperglycemia, corticosterones, and adrenal hypertrophy from chronic stress. Rose Root (Rhodiola rosea) adaptogen and anti-stress herb Adrenal Support Herbs Slide 37 More than 50% of people with low temperatures and normal thyroid blood tests can recover using the foregoing lifestyle measures alone More severe cases will need T3-only therapy Some people will need T3, botanicals, and nutrients to get their temperatures up Slide 38 A relatively easy way to make a huge difference in the lives of many of your patients Similar to OCPs for irregular menstrual cycles Diagnosed clinically Therapeutic trial Wean off to see if symptoms remain improved Has the potential of lasting correction of hypometabolic symptoms in patients with normal thyroid blood tests (whether taking T4-containing medicine or not) T3-only Therapy I was first diagnosed about 10 yrs ago and successfully treated [with T3]. Since then it reoccurred again about 4-5 yrs later and treated with success. -L.G. I have successfully completed your T3 protocol twice over the last twenty years with excellent results. -A.M. Slide 39 Antidepressants are given as therapeutic trials because depression does not show up on blood tests. Antidepressants have recently become the most widely- prescribed class of medicine in the United States. There is no blood test that can determine that a patient will or will not respond well to T3. Sometimes, even a patient with low TSH, high T3, and low rT3 levels can still respond well to T3. Therapeutic trial is the most common basis for medical treatment Olfson, M, Marcus, SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009,66(8):848856. Slide 40 Hypothyroid patients switched from T4 to T3 for 6 weeks at N.I.H Patients lost an average of 4.5 pounds on T3 as compared to T4. Cholesterol and LDL went down. No change in heart rate, blood pressure, or exercise tolerance. Celi F, Zemskova M. Metabolic effects of liothyronine therapy in hypothyroidism: A randomized, double-blind, crossover trial of liothyronine versus levothyroxine. The Journal of Clinical Endocrinology & Metabolism. 2011;96(11):34663474. Slide 41 T4 Add Desiccated Add T3 T3 RT3 T4 T3 RT3 T4RT3 vs. Clearing the imbalance by clearing the pathways T3 Start Effect on T4, RT3, and T3 levels Slide 42 Why not use T4 when TSH is normal and body temperature is low? If symptoms do improve with T4-containing medicine, they tend to recur when the T4 is discontinued T4 can sometimes make the symptoms worse because if a person is already having trouble utilizing T4 then giving them more T4 can sometimes push them even further in the wrong direction with the wrong medicine Classic story: Better for 23 months, then worse again, or worse right off the bat Dessicated has T4 and instant-release T3 Slide 43 The object of cyclic sustained-release T3 therapy in euthyroid patients is to eliminate symptoms of slow metabolism by resetting the oral body temperature to 98.6F by replacing some or all of the T4 in the body with T3 Slide 44 Cycling patients on and off T3 for one or more cycles as needed appears to be what normalizes the body temperature Slide 45 Slide 46 Essential concepts for T3 therapy T4 is 4 times weaker and 3 times longer- acting. Consequently, T4 tends to have a weaker, more steady effect on the thyroid hormone receptors. Also, T4 provides a steady supply of T3 as it is slowly converted to T3 by the body. Thus, doctors and patients must understand that T4 has a very stabilizing influence on the thyroid hormone system. Slide 47 Symptomatic patients with low body temperatures and normal thyroid blood tests (reversible hypometabolism) are in a very stable situation because they have plenty of T4 in their systems, BUT they still have low body temperatures and symptoms of slow metabolism. Slide 48 When T4 levels go down and T3 levels go up with treatment, the weaker and more steady effect of the T4 is replaced with the stronger and more unsteady effect of the T3. Slide 49 The stronger effect of the T3 will hopefully normalize the temperature and eliminate the symptoms of slow metabolism, but every effort must be made to minimize the unsteady effect of the T3 in order to minimize the chance of side effects such as fluid retention, shakiness, irritability, and palpitations Slide 50 One way to minimize the unsteady effect of T3 is to make the most of the steady effect of the endogenous T4 by increasing the T3 doses quickly (every 24 hours, and sometimes every 12 hours). That way, patients are able to get the stronger effect of the T3 while the steady effect of the T4 is still present but decreasing. Slide 51 Schor JM, Nigalay A. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose. 1983 US Patent 4389393. Another way to keep T3 levels as steady as possible is to use compounded sustained- release T3 Slide 52 The higher the dose of T3 the more unsteady the effect it has on the thyroid hormone receptors Slide 53 One benefit of weaning a cycle of T3 is that it allows the thyroid system to steady down again. It is important for people to steady down between cycles. Otherwise, people might start the next cycle unsteady and stay unsteady for the whole cycle. That is why it is usually best for patients to wean off the T3 entirely between cycles. Slide 54 Weaning off the T3 slowly (decreasing the dose every 26 days) gives the thyroid system and pathways more of a chance to come back on line and maintain any progress in temperature and symptoms that has been obtained from the cycle of T3. Slide 55 Thus, to keep T3 levels as steady as possible patients should: use well-made sustained-release T3 designed to be taken every 12 hours take the T3 every 12 hours on time, not even 3 minutes late increase the T3 doses quickly, wean off the T3 doses more slowly make sure they are off the T3 long enough between cycles for their systems to steady down. Slide 56 Childbirth (No. 1 cause) Divorce Death of a loved one Job or family stress Surgery or Accidents Heavy metal toxicity (e.g., mercury) Bromine, Fluorine, Chlorine; especially a mixture of compounds that contain these Typical stressors that can lower the body temperature Slide 57 Simplified T3 protocol (quick and easy version) Doctors and patients want it to be simple. Quick and easy version will help about 80% of patients. Important to know the principles in the book to help manage harder cases. But this is a simplified version many doctors and patients ask for. Slide 58 Getting started Doctors have their patients check their temperatures 3 times a day for a couple of days to see if they average below 98.6F (women are usually low almost all month regardless of their time of ovulation). Their body temps are usually 97.8F or lower. Can review with them the big potential benefit of T3 therapy and that there is some cardiac risk. Slide 59 Evaluate whether the patient can tolerate T3 Can you run around the block, and do you feel OK when your pulse rate goes up? Usually, yes. Ever had any cardiac problems (e.g., MI within the past 2 months) or blood pressure issues? Herbs can help some non-candidates (hypertension, arrhythmias) become candidates. Low magnesium levels may interfere with a person tolerating T3 therapy well. Slide 60 Adrenal support can help people tolerate T3 If low adrenal function (e.g., orthostatic hypotension, never sweats, or cortisol is low on a saliva test) then consider hydrocortisone 5 mg BID (8 am and noon) and/or adrenal support herbs for a couple of weeks before treatment (can really help). Otherwise, people may feel worse on the T3 instead of better. Some doctors do not like to give T3 without supporting the adrenals first. Slide 61 Cycling up on the T3 Have them program their timers or phones with alarms that are 12 hours apart. Start on 7.5 mcg / dose every 12 hours Slide 62 Cycling up on the T3 Increase dose by 7.5 mcg/dose/day Day 1 > 7.5 mcg (am), 7.5 mcg (pm) Day 2 > 15 mcg, 15 mcg Day 3 > 22.5 mcg, 22.5 mcg Day 4 > 30 mcg, 30 mcg Day 10 > 75 mcg, 75 mcg no higher on this cycle, just to be cautious Slide 63 Patient instructions Take the T3, and take it exactly on time. If a few hours late with a dose, go ahead and take the dose and keep following the directions. Write down your pulse every day. Stop increasing T3 and call the doctor if: Pulse is above 100 b.p.m., or Feeling palpitations. Slide 64 To manage side effects: Can take certain cardiac herbs (like Lily of the Valley, Night blooming Cereus, Hawthorne, Motherwort) and/or 0.0125 mg T4 if having a lot of palpitations or feeling unsteady and uncomfortable (this is a T4 test dose). Can repeat the dose of T4 an hour later if needed. Some people (those 10 % of people that really do not tolerate the treatment well) can continue taking the levothyroxine 12.525 mcg T4 every day if it helps them tolerate the protocol better, even if it might hinder their progress. Slide 65 Continuing the protocol: If no issues, keep going up on the T3 (notice that this is irrespective of body temperature)you cannot really overdo the temperature. Once on 75 mcg BIDstay there for about 3 days and then cycle down every 23 days (or slower). Thus, the first cycle is only up to 75 mcg BID and lasts about a month. Ask the patient to check their body temperatures about 23 times/day for a couple of days to see if and how it has changed; and then return for a visit. Slide 66 At 1-month visit How did you feel? Any palpitations? Were they severe or not? If the temperature does not go up as much as you want (which is typical) and they did not have any heart palpitations, then you can have them go up on another cycle, going all the way to 90 mcg BID this time (if no rapid pulse or palpitations). Then they can cycle back down slowly (min every 2 days or slower) and check their temperatures. Can continue more cycles as needed. Slide 67 Wrapping it up As they are going up on the next cycle, if they find a dose that they feel really good on and their temperatures are in the 98.198.5F range then they can stay on that dose for 1 month. Then cycle down and come for another visit. And that usually takes care of most patients. This is one way of using T3 to clear the problem Other patients will need more careful temperature titrating protocol in the book (free eManual and eBook on website). Slide 68 Three most important instructions for patients Take the T3 on time. Write down pulse rate every morning. Pay attention to any disagreeable awareness of the heartbeat. Slide 69 Most common side effects of T3 therapy Fluid retention Achiness Jitteriness Irritability Dull headache Increased awareness of heart beat Usually due to unsteady T3 levels from not taking the medicine on time Slide 70 Use a reliable compounding pharmacist There have been times when patients were not getting good results with the T3 therapy until they switched to another pharmacy and then they began getting better results Slide 71 Though the goal is for the temperature and symptoms to remain improved even after the T3 has been discontinued, some people may benefit staying on some T3 on a continual basis. T3 is very well tolerated long-term. A review of 28 studies showed no increase in osteoporosis in premenopausal women on suppressive doses of T3. Murphy E, Williams GR. The thyroid and the skeleton. Clin Endocrinol. 2004;61:285298. Slide 72 DWILSON.WTS@GMAIL.COM