Optimizing Thyroid Function

The Thyroid Foundation of American reports that about 13 million Americans have thyroid disorders, of which nearly 11 million are women and more than half are undiagnosed 1.

In his book, Thyroid Power, Dr. Richard L. Shamus concurs with the above and writes, “Although extremely common, low thyroid is an unsuspected illness. Even when suspected, it is frequently undiagnosed. When it is diagnosed, it often goes untreated. When it is treated, it is seldom treated optimally” 2. How true are his words. Like many of you, almost everyone who walks into my office complains of fatigue, low energy, depression, weight gain or the inability to lose unwanted weight—all symptoms of suboptimal thyroid function. Many times I have found myself scratching my head and seriously asking myself “what is going on here?” and “why is it that almost every patient I’ve seen in seven years of practice has something going on with his or her thyroid function?”

Thyroid Hormones 101
Thyroid Stimulating Hormone (TSH) measurement is the blood test most commonly used by conventional doctors to screen for thyroid dysfunction. The “normal” range varies from lab to lab; the most common ranges are 0.3 to 5.5 with some labs using the newer values of 0.3 to 3.0 established by the American Association of Clinical Endocrinologists (AACE) in 2002 3. However, if we focus only on TSH we may be missing vital clues in the patient’s thyroid hormone function. Unfortunately, too often, if TSH measures within the “normal” range, the patient’s complaints are dismissed and left untreated. TSH is a very poor indicator of thyroid hormone function and should never be used alone to evaluate or monitor thyroid function. Comprehensive testing that includes free levels of thyroid hormones, free thyroxine (fT4) and free triiodothyronine (fT3) to evaluate peripheral conversion problems (T4 into T3) should be performed. Anti-thyroperoxidase (TPO) antibodies should be measured to rule in/out autoimmune thyroid disease (i.e., Hashimoto’s). Many patients come to me saying that their doctor said their thyroid tests were all normal; however, upon further scrutiny of their labs and with comprehensive testing I have seldom found this to be the case.

The first mistake some physicians make upon finding that their patient is hypothyroid is to immediately put them on thyroid hormone replacement therapy. Thyroid hormone, be it synthetic Synthroid (T4), or natural porcine USP Armour (T4, T3), will increase the patients’ metabolic rate and some will initially report feeling better with increases in energy and less fatigue. However, in many patients this is often a transient effect, and the benefits they initially reported may begin to fade. This most likely occurs when doctors only treat the symptoms with medication and do not address the underlying cause. I have witnessed time and time again that, when medication for hypothyroidism is the sole therapy, many patients will eventually complain that they no longer feel well. The old symptoms of hypothyroidism tend to creep back in and they feel they are back where they started, or even worse off than before they were given the medication.
When adrenal function has been weakened by chronic stress, poor diet, and environmental toxins, thyroid medication, by accelerating the metabolic rate, may further stress the system, causing the patient to feel even more fatigue and exhaustion. I believe that it is a mistake to prematurely rush in and give thyroid hormone if you find your patients are hypothyroid, as you may cause them to crash and burn. Before treating with thyroid hormone, it is absolutely necessary to get a clearer picture of your patient and ask yourself how and why your patient got here in the first place.

Address the Underlying Cause
As with most chronic disease, thyroid dysfunction tends to be multi-factorial; very seldom is there one single initiating cause. Stress 4, aging 5, cigarette smoking 6,7, insulin resistance 8, genetics 9.10, nutritional deficiencies/imbalances 11,12,13,14, extreme dieting and/or starvation 15, iodine (excess and/or deficiency) 16, goitrogens 17, poor digestion/absorption and dybiosis 18 are all contributing factors. Toxins from the environment, such as pesticides, herbicides, PCBs, dioxins and heavy metals such as mercury, are known to disrupt the delicate balance of thyroid hormone 19,20. Perchlorate 31 and thiocyanates 31,32 have been shown to block the sodium-iodide symporter (NIS) and prevent the uptake of iodine into the thyroid gland 21,22. Exogenous hormones such as xenoestrogens, birth control pills, and hormone replacement therapy have also been shown to interfere with thyroid function 23. Halogens such as bromine, chlorine and fluoride may interfere with the NIS and also prevent iodine uptake into the thyroid gland 24,27 29, 30. More recently plastics (i.e., phthalates, bisphenol-A) have also been in the news and are being implicated in hormone disruption (xenoestrogens) and thyroid dysfunction 33, 34, 35.

Environmental Effects on the Thyroid Function
Various environmental chemicals easily disrupt the delicate balance of the thyroid gland and its function 25. It is the additive effects, or bioaccumulation, of these chemicals over the years in our tissues that create hormone disruption and imbalance.

The European Journal of Endocrinology reported in 2006:

“Several groups of chemicals have potential for thyroid disruption. There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis. Similarly, flame-retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce. Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals. Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic-pituitary-thyroid axis at different levels. Mechanisms of action may involve the sodium-iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms. The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes. Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable” 26.

Every man, woman, and child on planet earth has been found to harbor these toxins in their tissues. Even more disturbing is the fact that cord blood of newborn babies was found to contain these harmful compounds exposing neonates to their damaging effects even before they are born 27, 28. 29, 30.

Environmental Toxins: Disruption of Thyroid Hormone Synthesis
Chemical: Perchlorate (ClO4)
Effect: Blocks iodine uptake by the NIS; displaces T4 from thyroid-hormone binding
Sources: Contaminated drinking water (propellant found in rocket fuel), found in milk, human breast milk,vegetables(contaminated irrigation water)

Chemical: Thiocyanate
Effect: Blocks iodine uptake by the NIS; displaces T4 from thyroid-hormone binding, serum proteins (causes transient elevation in free T4)
Sources: Cigarettes, brassica vegetables(i.,e., broccoli, cauliflower, etc).

Chemical: Phthalates
Effect: Thyroid disruptor (exact mechanism unknown)
Sources: Plastics (polyvinyl chloride), children's toys, IV tubing, cosmetics, nail polish,perfumes,detergents, solvents.

Chemical: Bisphenol A (BPA)
Effect: Binds thyroxine receptor(antagonist); increases serum thyroxine (T4)
Sources: Polycarbonates (plastics) #7, water bottles, liners in cans, baby bottles,dental fillings, sealants, electronics, paints, adhesives, varnishes.

Chemical: Mercury
Effect: Blocks conversion of T4 into T3 (5’ deiodinase) inhibits TPO enzyme.
Sources: Thimerosol (i.e. flu vaccines), dental amalgams, mercury thermometers,agriculture, medications (i.e.,nasal spray, opthalamic solutions, antibiotics, and the new Compact Fluorescent energy-saving light bulbs)

Chemical:Perfluoro-octanoic acid (PFOA)
Effect: Possible thyroid disruptor
Sources: Teflon coatings, coating for food packaging, stain-resistant coatings for carpets, fabrics, and clothing. Scotchguard, Gore-Tex,coatings on microwave popcorn bags, fast food containers.

Chemical: Bromide
Effect: Displaces iodine; increases plasma TSH. Inhibitory effect on thyroid activity
Sources: Flame retardants found in plastics,paints, electronic parts and fabrics. Bromated flour, bromated vegetable oils (i.e., Gatorade®,Powerade®, Squirt®, Fresca®, and MountainDew®), contaminated drinking water.

Chemical: Fluoride
Effect: Suppresses thyroid hormone(mechanism unknown);increases plasma TSH
Sources: Sodium fluoride in treated drinking water, fluoride toothpaste, fluoride dental treatments, beverages made with fluoridated water (i.e., soda, juice, tea)

Chemical:Chlorine
Effect: Inhibits iodide trapping;Decreases serum thyroxine(T4)
Sources: Chlorinated tap water, swimming pools, bleach, household chemicals

Chemical: Polychlorinated Biphenyls (PCBs)
Effect: May reduce thyroid hormone levels by decreasing synthesis; displacing T4 from binding proteins; may mimic thyroid hormones’ effect on expression of genes.
Sources: Persistent, ubiquitous environmental contaminants. Banned in 1977;found in old fluorescent lighting fixtures, electrical devices; enter the environment through open burning of plastics, paints, etc.

Dietary Compounds: Disruption of Thyroid Hormone Synthesis

Compound: Isothiocyanates
Effect: Goitrogenic; interferes with iodine uptake in the thyroid gland; inhibition of thyroid peroxidase(TPO) activity Produces goiter & hypothyroidism in lab animals.
Sources: Brassica (cruciferae): cabbage, broccoli, kale, cauliflower, kohlrabi,turnip, rutabaga, mustard,horseradish and rapeseed.Cassava, sorghum, maize, millet

Compound: Isoflavones
Effect: Inhibits thyroid peroxidase (TPO); goitrogenicInhibits thyroid peroxidase (TPO);Inhibits type I deiodinase activity.
Sources: Soy protein(i.e.,genestin, daidzen), peas, beans Flavonoids: Fruits and vegetables (i.e.,quercetin, catechin, rutin).

Compound: Gluten (Gliadins)
Effect: Associated with autoimmune thyroid disease (i.e., Hashimoto’s); may increase anti-thyroperoxidase antibody levels (anti-TPO) in gluten-sensitive individuals.
Sources: Wheat, rye, barley, spelt,and non-gluten-free oats,
may be hidden in processed foods as natural flavorings

Compound: Epigenin and luteolin
Effect: Thyroid disruptors
Sources: Millet

Medications that Disrupt Thyroid Synthesis

Drug: Sulfonamides
Effect: Antithyroid activity, prevents intrathyroidal iodide binding
Sources: Acetazoleamide (Diamox)

Drug: Sulfonylureas
Effect: Inhibits the synthesis of thyroid hormone; goiter (rats); inhibit iodide binding, block binding of T4 to the carrier proteins in serum
Sources: Carbutamide, tolbutamide,methahexamide, and possibly
chlorpropamide

Drug: Lithium
Effect: Inhibits thyroid hormone release; and coupling reactions; associated with the development of goiterinhibits thyroglobulin iodination
Sources: Bipolar medication

Drug: Estrogen (ERT)
Effect: Increases thyroid binding globulin, possible elevation of TSH
Sources: Hormone replacement, PCBs, (TBG), xenoestrogens

Drug: Androgens
Effect:Decrease thyroid binding globulin
Sources: Testosterone replacement,anabolic steroids, Danazol

I have often pondered that what we may consider dysfunction may not be dysfunction at all, and that the slowing down of the metabolic rate in hypothyroidism may actually be an important mechanism that protects the body from undue harm posed by chronic exposure to harmful substances in our environment. Down-regulation of the hypothalamus-pituitary-thyroid (HPT) axis may be a protective mechanism to conserve energy in times of stress. Chronic, low-dose exposure to environmental chemicals most certainly must be considered a stressor to all life upon this planet. One just has to glance at the list provided above to get an idea of the magnitude of the problem. Based upon this evidence, metabolism most likely slows down to protect the organism from the toxic effects of its internal and external environment. It is interesting to note, that hyperthyroidism often precedes the hypothyroid state. A common trigger of hyperthyroidism is excessive stress. When you ask a hyperthyroid patient what was occurring in his or her life before they were diagnosed with hyperthyroidism, many of them will tell you a tragic event or that a period of severe stress precipitated their diagnosis. In hyperthyroidism the metabolic rate accelerates and metabolism is upregulated. At this rate the cells are rapidly metabolizing toxins. I propose it is reasonable to consider that if the liver (phase II) is unable to keep up with detoxifying this large metabolic load, toxic metabolites will build up in the bloodstream and begin to interfere with metabolic functions. Therefore, the metabolic rate slows down in an attempt to reduce the rate of toxic metabolites that are building up, therefore leading to a hypothyroid (low metabolic) state in order to protect itself. Obviously, this scenario is theoretical; nevertheless, the body in its own mysterious wisdom ALWAYS strives to do the right thing. Could this so-called disease actually be the body’s way of attempting to correct the problem? It is our job, as naturopathic physicians, to identify and remove the barriers to healing.

Uncovering the Underlying Cause
It is most important to not just treat symptoms with thyroid hormone medication and/or supplements without addressing the underlying cause(s). It is our job as doctors to identify and remove the barriers to healing. Ask yourself, why does your patient have thyroid dysfunction in the first place? Evaluate his/her lifestyle; help your patient build a solid foundation on which they can begin to heal. Look at their diet and nutritional status and work with them to optimize it; find out if they are getting enough high quality sleep, and if they are not, help them to achieve it. Ask questions to find out how they are coping with the stressors in their lives. What is upsetting the balance, what are the barriers to healing? Ask yourself not “are they toxic?” but “how toxic are they?” and develop a comprehensive detoxification plan based on their biochemical individuality.

As you can see, cleaning up the thyroid patient’s internal and external environment becomes a very important matter in helping them to improve thyroid function and begin to heal. There are simple things you can teach your patient to do, such as avoiding polycarbonate plastics (i.e., phthalates, Bisphenol-A), and drinking reverse osmosis purified water instead of tap water to avoid contaminants such as perchlorates, fluoride, bromide, chlorides and mercury.

Other important steps should include evaluating the patient’s total body burden. Look for sources of exposure to heavy metals such as mercury (i.e., silver amalgams, fish, vaccines) and exogenous estrogen (xenoestrogens) exposure such as hormone replacement therapy, birth control pills, excessive exposure to estrogen mimics (pesticides, plastics, cosmetics, hormones in animal products, etc).

Detoxification
This makes detoxification a very important matter. However, placing someone on a “cleanse” or “water fast” is not necessarily the best step to take. There is evidence that when someone loses weight, the toxins that are stored in the body fat (adipose tissue) will be released into the bloodstream. The circulating toxins disrupt endocrine function and interfere with thyroid function. Proper and safe methods of detoxification are essential for the patient and should include nutrients (i.e., glutathione, sulfur amino acids, etc.) that have been shown to support phase I and phase II liver detoxification of toxins. Detoxification powders, such as UltraClear or MediClear, may be used and are appropriate for detoxifying most patients. Use of saunas and hydrotherapy may also be appropriate for the patient to enhance the detoxification process. It is important to evaluate your patients’ needs and create a program just for them.

Diet & Nutrition
Encourage an organic, whole foods diet, rich in plant foods (i.e., phytochemicals and minerals). Optimizing nutrition through diet and nutritional supplements is necessary to lay down the foundation for healing. It has been found that certain foods may interfere with thyroid function--especially gluten found in wheat, rye and barley.

Goitrogenic properties found in the brassica (cruciferae) family of vegetables (i.e., broccoli, collard greens, mustard greens, arugula, Brussels sprouts and kale) have been shown to impede thyroid function. Nevertheless, it is not advised to avoid these foods, because they are shown to help the body to detoxify; simply do not eat too many in their raw state. Cooking has been shown to deactivate the goitrogenic properties associated with this family of vegetables. Isoflavones, found in beans, especially soy, have been shown to impede thyroid function. However, studies have found that soy did not cause problems in individuals with adequate iodine intake 37, 38.

Vitamin D status should be evaluated in individuals with thyroid dysfunction as it is involved in helping T3 bind to nuclear receptors 39. It has been suggested that optimal 25-hydroxy vitamin D3 levels should be between 50 and 75 ng/ml in the blood 40. Food sources of vitamin D are wild-caught, cold-water fish such as salmon, mackerel, sardines and herring.

Other important nutrients such as selenium 12, zinc 12,13 and vitamin A 11 are also important for thyroid health.

Sleep, Exercise, and Stress Management
Address sleep quantity and quality, amount of exercise (too little, too much), and stress levels and coping skills in all thyroid patients. It is interesting to note that the thyroid and adrenal glands cannot function without each other, and to address only the thyroid without addressing adrenal health is not good medicine.

Steps to Begin Optimizing Thyroid Function
• Drink and bathe in filtered water only (reverse osmosis)
• Avoid swimming in chlorinated pools, chlorine bleach
• Avoid fluoride toothpaste
• Avoid bromated flours, flame-retardants (i.e., clothing, furniture, electronics, etc)
• Purchase and use environmentally-friendly cleaning products
• Optimize nutrition
• Avoid pesticides
• Avoid plastics that contain phthalates, and bisphenol-A (BPA)
• Purchase and eat organic foods whenever possible
• Cook cruciferous vegetables and don’t eat too many in their raw state
• Avoid gluten (especially with Hashimoto’s autoimmune thyroiditis) and/or gluten sensitivity or Celiac Disease
• Evaluate vitamin D status by 25-OH vitamin D3 testing
• Evaluate halogens (iodine, bromide, fluoride) status – Doctor’s Data
• Consider and address adrenal function
• Consider and address sex hormone status
• Identify and avoid food sensitivities
• Consider and address inflammation
• Address blood sugar and insulin levels
• Individualized detoxification program
• Comprehensive thyroid panel: TSH, Free T3, Free T4, anti-TPO antibodies
• If indicated, use thyroid medication wisely along with addressing the cause

As you can see, there is not one simple answer that fully corrects the thyroid epidemic we are seeing in this country. Nevertheless, addressing the underlying causes and removing the barriers to healing provides the best opportunity for healing patients with thyroid disorders.

References
1. Prevalence and Prevention of Thyroid Disease in the USA. The Thyroid Foundation of America. 2004. http://www.tsh.org/media/prevalence.html

2. Shames, R., Shames, K. Thyroid Power: Ten Steps to Total Health. 2002. Harper Collins, New York, NY.

3. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism. 2006 Amended Version. Endocrine Practice Vol 8 No.6 November/December 2002.

4. Helmreich DL, Crouch M, Dorr NP, Parfitt DB. Peripheral triiodothyronine (T(3)) levels during escapable and inescapable footshock. Physiol Behav. 2006 Jan 30;87(1):114-9. Epub 2005 Oct 26.

5. Peeters RP. Thyroid hormones and aging. Hormones (Athens). 2008 Jan-Mar;7(1):28-35.

6. Bufalo NE, Santos RB, et al. Genetic polymorphisms associated with cigarette smoking and the risk of Graves' disease. Clin Endocrinol (Oxf). 2008 Jun;68(6):982-7. Epub 2007 Nov

7. Steinmaus C, Miller MD, Howd R. Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001-2002 national health and nutrition examination survey. Environ Health Perspect. 2007 Sep;115(9):1333-8.

8. Rezzonico J, Rezzonico M, Pusiol E, Pitoia F, Niepomniszcze H
Introducing the thyroid gland as another victim of the insulin resistance syndrome. Thyroid. 2008 Apr;18(4):461-4.

9. Panicker V, Cluett C, et al. A Common variation in Deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triidothyronine. J Clin Endocrinol Metab. 2008 May 20. [Epub ahead of print]

10. Ban Y, Tomer Y. Genetic susceptibility in thyroid autoimmunity. Pediatr Endocrinol Rev. 2005 Sep;3(1):20-32.

11. Zimmermann MB. Interactions of vitamin A and iodine deficiencies: effects on the pituitary-thyroid axis. Int J Vitam Nutr Res. 2007 May;77(3):236-40.

12. Moncayo R, Kroiss A, et al. The role of selenium, vitamin C, and zinc in benign thyroid diseases and of selenium in malignant thyroid diseases: Low selenium levels are found in subacute and silent thyroiditis and in papillary and follicular carcinoma. BMC Endocr Disord. 2008 Jan 25;8:2.

13. Kucharzewski M, Braziewicz J, et al. Copper, zinc, and selenium in whole blood and thyroid tissue of people with various thyroid diseases. Biol Trace Elem Res. 2003 Summer;93(1-3):9-18.

14. Gärtner R, Gasnier BC, et al. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002 Apr;87(4):1687-91.

15. Boelen A, Wiersinga WM, Fliers E. Fasting-induced changes in the hypothalamus-pituitary-thyroid axis. Thyroid. 2008 Feb;18(2):123-9.

16 Markou KB, et al. Treating iodine deficiency: long-term effects of iodine repletion on growth and pubertal development in school-age children. Thyroid. 2008 Apr;18(4):449-54.

17 Rao PS et al. Role of goitrogens in iodine deficiency disorders & brain development. R Indian J Med Res. 1995 Nov;102:223-6.

18 Lauritano EC et al. Association between hypothyroidism and small intestinal bacterial overgrowth.J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. Epub 2007 Aug 14.

19.. Abdelouahab N, Mergler D, et al. Gender differences in the effects of organochlorines, mercury, and lead on thyroid hormone levels in lakeside communities of Quebec (Canada). Environ Res. 2008 Feb 27. [Epub ahead of print]

20. Köhrle J. Environment and endocrinology: The case of thyroidology. Ann Endocrinol (Paris). 2008 Apr;69(2):116-22. Epub 2008 Apr 28.

21. De Groef B, Decallonne BR, et al. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur J Endocrinol. 2006 Jul;155(1):17-25.

22. Hershman JM. Perchlorate and thyroid function: what are the environmental issues? Thyroid. 2005 May;15(5):427-31.

23. Gray LE Jr. Tiered screening and testing strategy for xenoestrogens and antiandrogens. Toxicol Lett. 1998 Dec 28;102-103:677-80.

24. Darnerud PO. Brominated flame retardants as possible endocrine disrupters. Int J Androl. 2008 Apr;31(2):152-60.

25. Disrupting a Delicate Balance: Environmental Effects on the Thyroid. Environmental Health Perspectives. Vol 111, no 12, Sept 2003

26, Boas M, Feldt-Rasmussen U, et al. Environmental chemicals and thyroid function. Eur J Endocrinol. 2006 May;154(5):599-611.

27. Maervoet J, Vermeir G, et al. Association of thyroid hormone concentrations with levels of organochlorine compounds in cord blood of neonates. Environ Health Perspect. 2007 Dec;115(12):1780-6.

28. Iijima K, Otake T, et. al. Cadmium, lead, and selenium in cord blood and thyroid hormone status of newborns. Biol Trace Elem Res. 2007 Oct;119(1):10-8.

29. Pathak R, Suke SG, et al. Endosulfan and Other Organochlorine Pesticide Residues in Maternal and Cord Blood in North Indian Population. Bull Environ Contam Toxicol. 2008 May 17. [Epub ahead of print]

30. Antignac JP, Cariou R, et al. Exposure assessment of fetus and newborn to brominated flame retardants in France: preliminary data. Mol Nutr Food Res. 2008 Feb;52(2):258-65.

31. Sanchez CA, Blount BC, et al. Perchlorate, thiocyanate, and nitrate in edible cole crops (Brassica sp.) produced in the lower Colorado River region.Bull Environ Contam Toxicol. 2007 Dec;79(6):655-9. Epub 2007 Oct 26.

32. Laurberg P, Andersen S, et al. Thiocyanate in food and iodine in milk: from domestic animal feeding to improved understanding of cretinism.Thyroid. 2002 Oct;12(10):897-902.

33. Huang PC, Kuo PL, et al. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod. 2007 Oct;22(10):2715-22. Epub 2007 Aug 17.

34. Meeker JD, Calafat AM, et al. Di(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ Health Perspect. 2007 Jul;115(7):1029-34.

35. Kaneko M, Okada R, et al. Bisphenol A acts differently from and independently of thyroid hormone in suppressing thyrotropin release from the bullfrog pituitary. Gen Comp Endocrinol. 2008 Feb 1;155(3):574-80. Epub 2007 Sep 19.

36. Zoeller RT. Mol Cell Environmental chemicals as thyroid hormone analogues: new studies indicate that thyroid hormone receptors are targets of industrial chemicals? Endocrinol. 2005 Oct 20;242(1-2):10-5.

37. Bruce B, Messina M, et al. Isoflavone supplements do not affect thyroid function in iodine-replete postmenopausal women. J Med food. 2003 Winter;6(4):309-16.

38. Messina M, Redmond G. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid. 2006 Mar;16(3):249-58.

39. DS Darling, JS Beebe, et al. 3,5,3’-triiodothyronine (T3) receptor-auxiliary protein (TRAP) binds DNA and forms heterodimers with the T3 receptor. Molecular Endocrinology 1991 Vol 5, 73-84.

40. Dawson-Hughes B, Heaney R, et al. Estimates of optimal vitamin D status. International Osteoporosis Foundation and National Osteoporosis Foundation 2005. 10.1007/s00198-005-1867-7.