thyroid dysfunction - josh gitalis · thyroid metabolism hypothalamus sends trh pituitary releases...

Thyroid Dysfunction

Advanced Clinical Focus:Hormones and Endocrinology

Thyroid Pathologies

• Hypothyroidism

• Hyperthyroidism

• Autoimmune thyroid (Hashimoto’s and Grave’s)

• Thyroid cancer


Thyroid Definitions

• Thyrotropin releasing hormone (TRH): hormone made by hypothalamus

• Thyroid Stimulating Hormone (TSH): hormone made by pituitary

• Thyroxine (T4): hormone made by thyroid

• Triiodothyronine (T3): active thyroid hormone

• Thyroid peroxidase (TPO): enzyme that makes thyroid hormone

• Thyroglobulin: protein that joins iodine to make T4

Copyright © 2015 ● Josh Gitalis Ba(H), RNCP/ROHP, CNP ● All Rights Reserved


Thyroid Metabolism

T3


Thyroid MetabolismHypothalamus

sends TRH



sends TRH

Pituitary releases TSH




sends TRH


TSH stims TPO

93% is T4

7% is T3✓



sends TRH


TSH stims TPO

93% is T4

7% is T3

60% converted to T3 in liver

✓



sends TRH


TSH stims TPO

93% is T4

7% is T3


20% goes to reverse T3 (inactive)

✓




sends TRH


TSH stims TPO

93% is T4

7% is T3



20% converted to active T3 in GI

✓✓



sends TRH


TSH stims TPO

93% is T4

7% is T3




Remaining T4 to T3 in tissues

✓

✓

✓


Thyroid Statistics (US)

• 27 million with thyroid disease

• 13 million undiagnosed

• 14 million Hashimotos

• 80% are women

American Association of Clinical Endocrinologists (AACE)



The thyroid is the ‘sentinel’ gland for the environment.

Dr. Jeffrey Bland


Loss of Thyroid Function

• No thyroid gland

• Autoimmune

• Postpartum thyroiditis

• Medications

• Toxins

• Stress

• Nutritional deficiencies or excesses

• Thyroid hormone resistance


Thyroid Symptoms (Most Common)

• Fatigue

• Weight gain

• Depression

• Constipation

• Hypersensitivity to cold water

• Poor circulation

• Muscle cramps

• ↓ Immunity

• Slow wound healing

• Excessive sleep

• Hypochlorhydria

• Itchy, dry skin

• Dry, brittle hair

• Hair loss

• ↓ Body temp

• Edema (esp. face)

• Lost of outer 1/3 of eye brow



Others Signs Indicating Thyroid Issues

• Heart palpitations

• Inward trembling

• Increased pulse rate

• Feeling nervous

• Insomnia

• Night sweats

• Difficulty gaining weight


Top 10 Symptoms: Hypothyroidism

1. Fatigue

2. Weight gain

3. Feeling cold

4. Dry hair and skin

5. Hair loss

6. Menstrual irregularities

7. Edema

8. Muscle aches and joint pain

9. Constipation

10. Depression


Hypothyroid

Shilomo, Melmed, Kenneth S. Polonsky, et .al. Williams Textbook of Endocrinology, 12th Ed. Elsevier Saunders: Philadelphia, PA. 2011.

Hypothyroidism can affect all organ systems. These manifestations are largely independent of the underlying disorder but are a function of the degree of hormone deficiency.



Assessing Thyroid Function

• Symptomatology (questionnaire)

• Basal temperature test

• Blood work

• Ultrasound

• Biopsy


Thyroid Questionnaire


Simple Test

• Basal Temperature Test

• Easy, non-invasive

• Monitor progress

• Not well validated

• Not diagnostic



Hypothyroidism

• Primary: ↑TSH, ↓FT4

• Secondary: ↓TSH, ↓ FT4

• Subclinical: ↑TSH, normal FT4

• Hashimoto’s thyroiditis: antibodies present

Dx


Dx

Hyperthyroidism

• ↓TSH, ↑FT4

• Subclinical: ↓TSH, normal FT4, high FT3

• Grave’s disease: antibodies present


Thyroid: Lab Testing

• Standard of care = TSH

• Is this enough?



Example of TSH Unreliability

• Patient with Hashimoto's getting no treatment

TSHJanuary 4.5February 0.08

March 2.3April 3.8May 8.7June 7.4July 1.6


• Can TSH reflect variations in target cell sensitivity?

• Can TSH reflect peripheral T4 to T3 conversion?

• Can TSH reflect cellular transport problems where there is faulty transport into the mitochondria?

• Can TSH reflect displacement of thyroid hormones from cellular receptors by RT3?

TSH Considerations…


What Does TSH Test?

• TSH indicates pituitary production

• Genetic and environmental factors can effect TSH secretion

• Pituitary hormone levels alone are not sufficient to measure the function of the gland they regulate



European Thyroid Association

• “…pituitary TSH secretion may not reflect what happens in other target tissues, and therefore serum TSH alone may not be a good marker for the adequacy of thyroid hormone replacement.”

Wiersinga W.M., L. Duntas. V. Fadeyev. et al. ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism.. European Thyroid Journal 2012 . Vol 1 No. 12 2012


TSH Range

Normal

0.0-0.39 mU/L

Hyperthyroid/ Grave’s

5.5+ mU/L

Hypothyroid/ Hashimotos

1-2 mU/LSymptoms Symptoms

• Standard of care for thyroid monitoring

0.4-5.5 mU/L


National Academy of Clinical Biochemistry (NACB)

• New guideline suggested in 2002

• TSH may be too wide

• People in this range = borderline thyroid disease

0.0-0.39 mU/L

1-2 mU/L

5.5+ mU/L

Normal

Symptoms Symptoms

Hyperthyroid/ Grave’s

Hypothyroid/ Hashimotos

0.4-5.5 mU/L



American College of Clinical Endocrinologists

• Clinicians should consider treatment for patients who “test outside the boundaries of a narrower margin based on a target TSH level of 0.3-3.04 mU/L.”

• “ The AACE believes the new range will result in proper diagnosis for millions of Americans who suffer from a mild thyroid disorder, but have gone untreated until now.”

ACCE Press release January 2003

TSH is normal but my patient is not well.


TSH Conclusion

• “Normal” is too wide

• Optimal should be 0.4-2.0 mU/L

Vanderpump M.P.J., W.M.G. Tunbridge, J.M. French, et al. The incidence of thyroid disorders in the community; a twenty year follow up of the Whickham survey. Clinical Endocrinology 1995; 43(1):55-68

Following an optimal range, is probably a much better approach.


What to Measure

• TSH

• Free-T4

• Free-T3

• Thyroid antibodies



“Bound” is Unavailable

Thyroid Hormone

1% Free

Free T3 Free T4

99% Bound


Why Test for T3?All had normal TSH

Medication No Meds

Gullo D, et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011; 6(8):e22552.

15.2% below normal for Free-T3

29.6% below normal FT3/FT4


Why Test for T3?


“…a subset of patients…do not reach a serum FT3/FT4 ratio within the reference range…These patients, therefore, live in chronic condition of abnormal thyroid hormone availability for the peripheral tissues, even if the administered levothyroxine dose is able to maintain the serum TSH within the normal range.”



Why Test for T3?


The insufficient T3 peripheral production cannot be appropriately corrected by increasing levothyroxine because T4 inhibits the conversion, and furthers the problem.


European Thyroid Association

• “Theoretically, thyroid hormone replacement therapy should aim not only at normalization of serum TSH but also at normalization of serum free T4, free T3 and FT4:FT3.”

Wiersinga W.M., L. Duntas, V. Fadeyev , et. al. ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. European Thyroid Journal 2012. Vol 1 No. 12 2012


Reverse T3Hypothalamus send

TRH


TSH stims TPO

93% is T4

7% is T3




Remaining T4 to T3 in tissues

✓

✓

✓




✓ ✗

Reverse T3


Reverse T3

• Converting T4 to T3 is optional

• The body determines whether it will convert T4 to T3 or RT3


Reverse T3: Contributing Factors

• Stress

• Trauma

• Low-calorie diet

• Inflammation

• Toxins

• Infections

• Liver/Kidney dysfunction

• Certain medications

Kelly GS. Peripheral metabolism of thyroid hormones: a review. Altern Med Rev. Aug 2000; 5(4):306-33.



Function of RT3

• Discovered in 1975 and found incapable of increasing metabolism

• RT3 considered “functionless”

• RT3 useful when a slower metabolism is advantageous: life-threatening illness, injury, or starvation

• Example: RT3 lets a person live longer without food and water


What Slows T4 to T3 Conversion

• Certain medications

• Se deficiency

• Protein deficiency, high carb diet

• Chronic illness

• Compromised liver/kidney

• Cd, Hg, Pb, herbicides, pesticides

• Stress (cortisol)

• Excess estrogen

• RT3

T4 T3-


Autoimmune Thyroid

• Most common AI disease

• It is not a metabolic issue

• This is an immune issue



Autoimmune Thyroid Known to Follow

• Radiation exposure

• Bacterial and viral infection

• Toxic exposure

• Other AI diseases

• Pregnancy


Thyroid Antibodies

• TPO antibodies

• Anti-TG antibodies

• Should be negative


Autoimmune Disease

Genetics

Nat Clin Prac Gastro & Hep, Sept 2005, Vol2;No.9

Gut PermeabilityEnvironmental Trigger



Leaky Gut Syndrome

“The autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function.”

Genes Environment

You

“Phenotype”Nat Clin Prac Gastro & Hep, Sept 2005, Vol2;No.9


Estrogen and Thyroid

• Estrogen can trigger Hashimoto’s

• Can cause Hashimoto’s after pregnancy

• Perimenopause also common due to fluctuations

• Thyroid symptoms can mimic PM symptoms

Amino N, Hidaka Y, Takano T, et al. Possible Induction of Graves disease in painless thyroiditis by gonasotropin-releasing hormone analogues. Thyroid 2003;13(8):815-8 Risk of subclinical hypothyroidism in pregnancy women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metal 1994;79(1):197-204Massoudi MS, Milan EN, Orchard TJ, et al. Prevalence of thyroid antibodies among healthy middle-aged women. Findings from the thyroid study in healthy women. Ann Epidemiol 1995:5(3):229-33


Reference Ranges

Source: The Gitalis System



Other Nutrients to Consider

• Selenium

• Zinc

• Iron

• Iodine

• Vitamin D and A

• Celiac screen


Factors that Affect Thyroid Function

T4/T3

RT3 T3

Factors that improve cellular sensitivity to thyroid hormones: • Vitamin A • Zinc • Exercise

+

Factors that contribute to proper production of T4/T3: • Iron • Iodine • Zinc • Selenium • Iron • Vitamin E, B2, B3, B6, C, D • Tyrosine

+

Factors that inhibit proper production of T4/T3: • Stress • Trauma • Toxins • Infections • Certain medications • Radiation • Fluoride • Hg, Cd, Pb • Pesticides • Autoimmune (celiac)

-

Factors that increase conversion of T4 to T3: • Selenium • Zinc

++Factors that increase conversion of T4 to RT3: • Stress • Trauma • Toxins • Infections • Certain medications • Low calories • Inflammation • Liver/Kidney dysfunction

JoshGitalis.com


Thyroid and Selenium

• Two enzymes involved in thyroid hormone synthesis are selenoproteins

• Thyroid contains one of the highest Se concentrations of any tissue

Zimmermann MB, Köhrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid. Oct 2002;12(10):867-78. Dickson RC and RH Tomlinson. Selenium in blood and human tissues. Clin Chim Acta 1967;16:311-321.



↑TSH, Ab

↓Selenium

• Selenium inversely correlated with TSH

• Selenium inversely correlated with TPO antibodies


Tong YJ et al. An epidemiological study on the relationship between selenium and thyroid function in areas with different iodine intake. Zhonghua Yi Xue Za Zhi. 2003 Dec 10;83(23):2036-9.




Factors that Affect Thyroid FunctionFactors that contribute to proper production of T4/T3: • Iron • Iodine • Zinc • Selenium • Iron • Vitamin E, B2, B3, B6, C, D • Tyrosine




T4/T3

RT3 T3

-

+

+

+

+

Factors that increase conversion of T4 to RT3: • Stress • Trauma • Toxins • Infections • Certain medications • Low calories • Inflammation • Liver/Kidney dysfunction



Thyroid and Zinc

• Zn deficiency lowered thyroid hormones by 30%

• Zn supplements normalized thyroid hormones

Kralik A, et al. Influence of zinc and selenium deficiency on parameters relating to thyroid hormone metabolism. Horm Metab Res. May 1996; 28(5):223-6. Nishiyama S, et al. Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency. J Am Coll Nutr. Feb 1994;13(1):62-7. Taneja SK & R. Mandal. Beneficial effect of modified egg on serum T3, T4 and dyslipidaemia following dietary Zn-supplementation in Wistar rat. Indian J Exp Biol. March 2008;46(3):171-9.






T4/T3

RT3 T3

-

+

+

+

+



Thyroid and Iron

• 15.7% of women with subclinical hypothyroidism were iron deficient compared to only 9.8% in the control group

Duntas LH, et al. Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism. Exp Clin Endocrinol Diabetes. 1999;107(6):356-60. Cinemre H, et al. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. Jan 2009; 94(1):151-6.



Thyroid and Iron

• Iron deficiency imparts thyroid hormone synthesis by reducing activity of thyroid peroxidase

• Iron supplementation normalizes thyroid hormones

Zimmermann MB, Köhrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid. Oct 2002; 12(10):867-78. Eftekhari MH, Eshraghian MR, Mozaffari-Khosravi H et al, Effect of iron repletion and correction of iron deficiency on thyroid function in iron-deficient Iranian adolescent girls. Pak J Biol Sci. 2007 Jan 5;10(2):255-60.






T4/T3

RT3 T3

-

+

+

+

+



• Diets both low and high in iodine associated with hypothyroidism

• High intake of iodine increases risk of Hashimoto’s

• “For the person with Hashimoto’s, supplementing with iodine is like throwing gasoline onto a fire.” - Datis Kharrazian

• Iodine supplementation prevents and treats Hashimoto’s and other thyroid disorder. - David Brownstein

Thyroid and Iodine

Laurberg P, et al. Environmental iodine intake affects the type of nonmalignant thyroid disease. Thyroid. May 2001; 11(5):457-69. Duarte GC, et al. Excessive iodine intake and ultrasonographic thyroid abnormalities in schoolchildren. J Pediatr Endocrinol Metab. April 2009; 22(4):327-34.







T4/T3

RT3 T3

-

+

+

+

+



Thyroid and Vitamin A

• Vitamin A deficiency results in poor thyroid hormone signalling

Feart C, et al. Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells. Eur J Endocrinol. Mar 2005; 152(3):449-58.






T4/T3

RT3 T3

-

+

+

+

+




Thyroid and Vitamin D

• Vitamin D deficiency significantly higher in those with autoimmune thyroid disease (72%) versus healthy individuals (30.6%)

Kivity S, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol. May 2011; 8(3):243-7.


Vitamin D Deficiency Causes

• Indoor/sedentary lifestyle

• Skin pigment

• Aging

• Sunscreen

• Latitude






T4/T3

RT3 T3

-

+

+

+

+




Basic Supplementation

• Selenium: 200-400 mcg

• Zinc: 15-30 mg

• Iron: 15-20 mg (confirm deficiency)

• Iodine: 150 mcg

• Vitamin D: 2000 iu

• Vitamin A: 2000 iu


Thyroid and Toxins

• 150 industrial chemicals have been shown to result in reduction of TSH and/or T4

Howdeshell KL. A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect. Jun 2002;110 Suppl 3:337-48.


Thyroid and Toxins

Alternative Medicine Review. Thorne Research, Inc. 4 November 2009; Volume 14.



Thyroid and Toxins

Alternative Medicine Review. Thorne Research, Inc. 4 November 2009; Volume 14.


Halogens







T4/T3

RT3 T3

-

+

+

+

+



Iodine Forms

Iodine Iodide Both

Breasts Prostate Stomach

Thyroid Skin

Kidneys Spleen Liver

Blood Salivary glands

Intestines


Thyroid and Gluten

• Studies confirm link between gluten and Hashimoto’s

• “Cellular mimicry”

Eur J endocrinol 1994 Feb; 103(2):137-40 Hepatogastroenterology 2003 Dec;50 Eur J Gasteroenterol Hepatol 1999 Aug;11(8):939-40 Clin Endocrinol (Oxf) 2003 Sep;59(3):396-401 Dig Dis Sci. 2001 Dec;46(12):2631-5 Physical Res 2003;52(1):79-88

=


Thyroid and Gluten

• Removing gluten is a critical step in any thyroid protocol



Non-Celiac Gluten Sensitivity (NCGS)

“Increased intestinal permeability after gliadin exposure occurs in all individuals.”

Nutrients 2015, 7, 1565-1576.



Factors that increase conversion of T4 to RT3: • Stress • Trauma • Low calories • Inflammation • Toxins • Infections • Liver/Kidney dysfunction • Certain medications




T4/T3

RT3 T3

-

+

+

+

+


Thyroid Summary

• Assess function

• Support proper hormone production:

• Essential nutrients

• Stress management

• Decrease toxins

• Address infection

• Decrease inflammation

• Heal the gut

• Remove gluten


Female Specific


Female Concerns

• PMS

• Low libido

• Fibroids

• Endometriosis

• PCOS

• Menopause


Healthy Menstrual Cycle



Healthy Menstrual Cycle

• Flow 3-6 days

• Raspberry, wine, or currant red in colour

• Flow is like a jellied fluid

• 30-125 ml

• None to mild cramping not requiring meds

• Post-ovulatory 12-16 days

• Cycle 26-35 days

• Premenstrual symptoms mild or non-existent

Source: Justisse Method


Menstrual Cycle


PMS: What is it?

• Recurrent signs and symptoms that develop during the 7-14 days prior to menstruation



PMS: What is it?

• Diagnostic criteria:

• Emotional:

• Depression

• Angry outbursts

• Irritability

• Anxiety

• Confusion

• Social withdrawal

• Physical:

• Breast tenderness

• Bloating

• Headache

• Swelling of extremities


PMS Causes

• Stress

• Hormone imbalance

• Poor diet

• Nutrient deficiency


PMS and Hormones

• No consistent pattern in all women

• Often associated with estrogen dominance

• May also result from:

• Hypothyroidism

• ↑ prolactin

• ↑ FSH

• ↑ Aldosterone

• Lower levels of neurotransmitters (i.e. serotonin)



Helpful Treatments for PMS

• Exercise


• Whole foods diet

• Detox support

• Magnesium: 400-800 mg

• Calcium: 800-1200 mg

• Zinc: 30-50 mg

• Vitamin B6: 50-200 mg

• Vitex: 20-40 mg


Chaste Tree Berry (Vitex)

• One of the top remedies for PMS

• Effective in moderate to severe PMS after 3 cycles

Dante et al., J Psychosom Obstet Gynaecol. 2011Mar;32(1):42-51 Freeman, Expert Opin Pharmacother. 2010 Dec;11(17):2879-89 Ma et al., Gynecol Endocrinol. 2010 Aug;26(8):612-6



• Reduces prolactin

• Improves Est:Proges




• Can mimic estrogen

• Proceed with caution:

• Fibroids

• Endometriosis

• Breast cancer (or high risk)

J trig. Food Chem. 2001, 49, 2472-2479



• 1-5 ml/day (1:5 tincture)

• 1-4 ml/day (1:2 extract)

• 500 mg BID

Mills Simon, Bone Kerry. Principles and Practice of Phytotherapy. Churchill Livingstone. 2009


Cimicifuga Racemosa Black cohosh

• Used since the 1950s

• Does not activate estrogen receptors

• Anti-estrogenic effects

• Can treat hot flashes

• Activity against breast cancer

Menopause: The Journal of the North American Menopause Society. Vol 9, No. 2, pp. 145-150




• 3.5-7 ml/day (1:5 tincture)

• 1.5-3 ml/day (1:2 extract)

• 40-200 mg/day

Mills Simon, Bone Kerry. Principles and Practice of Phytotherapy. Churchill Livingstone. 2009


Birth Control Pill

Before age 20

More than 5 yrs before age 35= 3x Risk of Breast Cancer


Birth Control Pill

• ↑ed risk cervical cancer

• ↑ed risk heart attack

• Yeast overgrowth

• Mask underlying issues (PCOS, endometriosis, fibroids)

• Nutrient depletions: B2, B6, B12, F.A., Vitamin C, Zn, Mg

• Immature reproductive system

• Increased risk of DVT

• Possible contributor to autism1,2

1. Medical Hypothesis. December 2014 Volume 83, Issue 6, Pages 718–725 2. Medical Hypothesis. December 2015 Volume 85, Issue 6, Pages 1006–1011



Birth Control Pill Discontinuation

• 3-6 months for body to heal

• Length of time it takes depends on:

1. Type of hormonal contraceptive used

2. Length of time on drug

3. Age of drug introduction

4. How healthy cycle was before drug

5. Basic health and nutritional statusSource: Justisse Method


Endocrine Disrupting Chemicals

• Bisphenol A

• Phthalates

• Pesticides

• Persistent organic pollutants

Gore AC, et.al. Executive Summary to EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocrine Reviews 36: 09, 2015 doi: 10.1210/er.2015-1093


• Obesity

• Diabetes

• Female reproduction

• Male reproduction

• Cancers

• Thyroid disease

• Neurodevelopment



Executive Summary to EDC-2: The EndocrineSociety’s Second Scientific Statement onEndocrine-Disrupting Chemicals

A. C. Gore, V. A. Chappell, S. E. Fenton, J. A. Flaws, A. Nadal, G. S. Prins, J. Toppari,and R. T. Zoeller

Pharmacology and Toxicology (A.C.G.), College of Pharmacy, The University of Texas at Austin, Austin, Texas 78734;Division of the National Toxicology Program (V.A.C., S.E.F.), National Institute of Environmental Health Sciences,National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Comparative Biosciences(J.A.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; Institute of Bioengineering and CIBERDEM(A.N.), Miguel Hernandez University of Elche, 03202 Elche, Alicante, Spain; Departments of Urology, Pathology andPhysiology & Biophysics (G.S.P.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612;Departments of Physiology and Pediatrics (J.T.), University of Turku and Turku University Hospital, 20520 Turku,Finland; and Biology Department (R.T.Z.), University of Massachusetts at Amherst, Amherst, Massachusetts 01003

This Executive Summary to the Endocrine Society’s second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full ScientificStatement represents a comprehensive review of the literature on seven topics for which there is strong mech-anistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity anddiabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thy-roid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides,persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxinswere emphasized because these chemicals had the greatest depth and breadth of available information. TheStatement also included thorough coverage of studies of developmental exposures to EDCs, especially in thefetus and infant, because these are critical life stages during which perturbations of hormones can increase theprobability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over thepast 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, includingnonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will proveuseful to researchers, physicians, and other healthcare providers in translating the science of endocrine dis-ruption to improved public health. (Endocrine Reviews 36: 593–602, 2015)

Introduction

In 2008, The Endocrine Society convened a group of ex-perts to review the state of the science on endocrino-

logical effects of environmental endocrine-disruptingchemicals (EDCs), leading to the landmark ScientificStatement on EDCs published in 2009, called hereafter“EDC-1” (1). EDCs are the hundreds or more “exogenouschemical(s), or mixtures of chemicals, that interfere withany aspect of hormone action” (2). In the subsequent 5years, the field has moved forward substantially. Fourlines of research have particularly influenced our knowl-edge about EDCs: 1) studies describing the consequencesof EDC exposure on development and physiology (mainly

conducted in rodent models, but with some notable ex-ceptions in sheep and nonhuman primates); 2) reports in-vestigating the mechanistic underpinnings of these disor-ders (gene expression and epigenetic changes induced incell and tissue culture, together with molecular and cellu-lar work conducted in endocrine tissues of EDC-exposedanimals); 3) work documenting associations betweenbody burdens of certain EDCs with disease propensity inhumans (mainly epidemiological work); and 4) investiga-tions of humans with known occupational or acute expo-sures to a particular chemical or group of chemicals withEDC activity. In 2015, there is far more conclusive evi-dence about whether, when, and how EDCs perturb en-

ISSN Print 0163-769X ISSN Online 1945-7189Printed in USACopyright © 2015 by the Endocrine SocietyReceived August 27, 2015. Accepted September 2, 2015.First Published Online September 28, 2015

Abbreviations: BPA, bisphenol A; DOHaD, developmental origins of health and disease;EDC, endocrine-disrupting chemical; ER, estrogen receptor; PBDE, polybrominated diethylether; PCB, polychlorinated biphenyl; PPAR, peroxisome proliferative-activated receptor.

R E V I E W

doi: 10.1210/er.2015-1093 Endocrine Reviews, December 2015, 36(6):593–602 press.endocrine.org/journal/edrv 593

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 December 2015. at 09:58 For personal use only. No other uses without permission. . All rights reserved.



• Common in household products: food storage, water bottles, health and beauty products, household products

• The BPA substitute BPS also an endocrine-disruptor

• Long-lived chemicals have life-time body burden

• Short-lived may induce permanent changes

• Transgenerational effects now observed




Chemicals

• By the time a women leaves her home, she has applied 126 different chemicals in 12 different products to her face and hair

ewg.org


Libido

• Always a downstream effect of other factors:

• Adrenals

• Thyroid

• Sex hormones

• Stress

• Sleep

• Relationship

• Mind



Female Hormonal Pathologies

• Fibroids

• Endometriosis

• PCOS


Fibroids and Endometriosis

• Similar etiology

• It’s more than estrogen dominance

Evans, JM. Fibroids and endometriosis. In Textbook of Functional Medicine (Ch. 32, Clinical Approaches to Hormonal and Neuroendocrine Imbalances). Jones DS (Ed), Institute for Functional Medicine; Gig Harbor, WA: 2005. pp. 635-638.


Estrogen Influence

• Not seen prior to puberty

• Enlarge during pregnancy

• Regress at menopause

✗ ↑ ↓



Inflammation Increases Estrogen

• PG2 stimulates aromatase

Bulun SE, et al., Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci. 2009 Feb;1155:121-31


Aromatization

Aromatase


Decrease Estrogen Formation

• Aromatase inhibitors:

• Dietary fiber and lignins (i.e. flax seed)

• Soy (genistein daidzein)

• Resveratrol (grapes)

• Grape seed extract (proanthocyanidins)

• White button mushrooms

Wang et al., J Steroid Biochem Molec Biol 1994;50:205-12. Eng et al., Ann N Y Acad Sci. 2002 Jun;963:239-46. Kijima et al., Cancer Res. 2006; 66:5960.

Eng et al., Cancer Res. 2003; 63:8516. Grube et al., J. Nutr. 2001; 131:3288. Balunas et al., Phytochem. Lett. 2008.



Estrogen Dominance

• Relatively small amounts (nanograms) of estrogen compared to larger amounts (micrograms) of other steroid hormones have powerful effects

• Regulation of estrogen is potentially much more important

Textbook of Functional Medicine. Jones DS (Ed), Institute for Functional Medicine; Gig Harbor, WA: 2005.


↑Estrogen

↓Progest.

Estrogen Dominance Symptoms

• Breast tenderness

• Fibrocystic changes

• Heavy periods

• Fat distribution on hips and thighs

• Anxiety/Depression

• Fibroid growth

• Endometriosis

• Dysmenorrhea

• Cervical dysplasia

Textbook of Functional Medicine (Ch. 32, Clinical Approaches to Hormonal and Neuroendocrine Imbalances). Jones DS (Ed), Institute for Functional Medicine; Gig Harbor, WA: 2005. pp. 623-6248.


↑Estrogen

↓Progest.

Lack or Progesterone

• Spotting

• Anxiety

• Infrequent ovulation

• Peri-menopause

• Hormone replacement

Textbook of Functional Medicine (Ch. 32, Clinical Approaches to Hormonal and Neuroendocrine Imbalances). Jones DS (Ed), Institute for Functional Medicine; Gig Harbor, WA: 2005. pp. 623-6248.



Estrogen Detoxification and Elimination

• Support liver detoxification

• Promote elimination

• Prevent recirculation


Food and Hormones

• Chemicals can have a hormonal effect

• Full fat dairy from pregnant cows contain lots of estrogen

• Inflammatory foods can increase estrogen


Therapeutic Foods

• Raspberries

• Pomegranate

• Mung beans

• Cruciferous veg.

• Fermented Soy

• Flax



Nutrients Supporting Detoxification

• Indole-3-Carbinol (I3C): 200mg BID

• Calcium D-Glucarate: 500 mg BID

• Sulforaphane: 1.1-5.5 mg/day

• Curcumin: 500 mg TID (depends on form)

• Rosemary extract: 200-300 mg/day

• Green tea extract: 50mg TID

• Milk thistle extract: 70-210 mg TID

• N-Acetyl-Cysteine: 1 gram TID


Vitamin D

Lower vitamin D levels resulted in higher risk of fibroids. Check vitamin D!


Fibroids and Endometriosis

Estrogen

Inflammation

Insulin

Fat

+

++ +

++



Stress and Endometriosis

“Endometriosis is an inflammatory disease, and stress and poor quality of

life may cause inflammation…”


PCOS

• Affects 5-10% of women of childbearing age

• Symptoms:

• Irregular menstrual cycles

• Hirsutism

• Acne

• Male pattern baldness (in women)

• Lack of ovulation


Polycystic Ovarian Syndrome (PCOS)

↑ Stress

↑ Cortisol

↑ Blood Sugar

↑ Insulin

↑ Androgens ↑ Estrone ↑ LH ↓ FSH More Androgen

Virilization Amenorrhea

Insulin Resistance

Obesity Metabolic Syndrome

Basin S, Fisher CE, Swerdcloff RS. Follicle stimulating hormone and luteinizing hormone. In: Memed S (ed). The pituitary. 2nd ed. Malden, MASS: Blackwell Publishing 2002; 216-278




↑ Stress

↑ Cortisol

↑ Blood Sugar

↑ Insulin



Insulin Resistance



Stress management



↑ Stress

↑ Cortisol

↑ Blood Sugar

↑ Insulin



Insulin Resistance



Blood sugar regulation



↑ Stress

↑ Cortisol

↑ Blood Sugar

↑ Insulin



Insulin Resistance



Decrease androgen production



Multi-Factorial Treatment

• Decrease inflammation

• Improve estrogen metabolism

• Production

• Detoxification and elimination

• Check vitamin D

• Decrease BMI

• Improve insulin sensitivity


Diet Functional Foods

SupplementsLifestyle

Menopause


Menopause

• Permanent cessation of menstruation

• Avg age: 51

• Ovaries stop making hormones

• Adrenals and adipose tissue take over



Menopause Symptoms

• Hot flashes

• Headaches

• Atrophic vaginitis

• Freq. UTIs

• Cold hands/feet

• Forgetfulness

• Inability to concentrate


Menopause and Exercise

• Women who spent 3.5 hours per week exercising had no hot flashes

Hammar M, Berg G, Lingren R. Does physical exercise influence the frequency of post-menopausal hot flushes? Acta Obstetrica et Gynecologica Scandinavica 1990;69:409-412


Menopause and Soy

• ↓s hot flashes

• Slow bone loss

• ↓s cholesterol

• ↓s blood pressure

• ↓s risk of breast cancer Dose = 2/3 cup

Dalais FS, Rice GE, Dahlqvist ML, et al. Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1998;1(2):124-129



• Key factor: ability to convert isoflavones into equol

• Healthy microbiome essential

Menopause and Soy


Microbiome and Hormones

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 2011, p. 1494–1503 Vol. 55, No. 40066-4804/11/$12.00 doi:10.1128/AAC.01664-10Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Effect of Antibiotic Treatment on the Intestinal Metabolome!

L. Caetano M. Antunes,1 Jun Han,2 Rosana B. R. Ferreira,1 Petra Lolic,1,3

Christoph H. Borchers,2 and B. Brett Finlay1,3*Michael Smith Laboratories, The University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada1; University of

Victoria Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia V8Z 7X8, Canada2; andDepartment of Microbiology and Immunology, The University of British Columbia,

Vancouver, British Columbia V6T 1Z3, Canada3

Received 1 December 2010/Returned for modification 8 January 2011/Accepted 21 January 2011

The importance of the mammalian intestinal microbiota to human health has been intensely studied over thepast few years. It is now clear that the interactions between human hosts and their associated microbialcommunities need to be characterized in molecular detail if we are to truly understand human physiology.Additionally, the study of such host-microbe interactions is likely to provide us with new strategies tomanipulate these complex systems to maintain or restore homeostasis in order to prevent or cure pathologicalstates. Here, we describe the use of high-throughput metabolomics to shed light on the interactions between theintestinal microbiota and the host. We show that antibiotic treatment disrupts intestinal homeostasis and hasa profound impact on the intestinal metabolome, affecting the levels of over 87% of all metabolites detected.Many metabolic pathways that are critical for host physiology were affected, including bile acid, eicosanoid,and steroid hormone synthesis. Dissecting the molecular mechanisms involved in the impact of beneficialmicrobes on some of these pathways will be instrumental in understanding the interplay between the host andits complex resident microbiota and may aid in the design of new therapeutic strategies that target theseinteractions.

The human body is colonized by a complex community ofmicrobes termed microbiota or microbiome (9, 17, 18, 24).Virtually every surface of the human body that is exposed tothe environment has its own microbial assemblage, with dif-ferent microbial species and distinct functions associated withthem. The intestinal tract is by far the most heavily colonizedbody site; it has been estimated that the human gut harborssome 1014 microbial cells (14, 22, 32). This microbial consor-tium is critical for human health and has been implicated in thedevelopment of the immune system, energy homeostasis, andprotection against pathogens, among other processes (18, 24).Conversely, imbalances in the intestinal microbiota have alsobeen associated with many pathological processes, includinginflammatory bowel disease, diabetes, asthma, obesity, autism,and others (18, 24).

The use of antibiotics is known to have significant effects onthe intestinal microbiota. The acquisition and spread of anti-biotic resistance genes between and within bacterial commu-nities due to antibiotic use have also been studied thoroughly(12). This has caused an increased awareness of the impor-tance of a more responsible use of antibiotics. However, it isonly recently that studies began to reveal details of the impactof these drugs on intestinal microbial communities. For in-stance, it is now well established that antibiotic treatment in-creases susceptibility to enteric infections (10, 23, 25); some ofthe members of the microbiota involved in this process arecurrently under investigation. Although these studies are in-

dispensable to our understanding of the effects of antibiotics inthe human body and the importance of the intestinal microbi-ota for human health, the mechanisms involved in these inter-actions remain mostly unknown.

Much of what we have learned about the intestinal micro-biota comes from high-throughput sequencing studies of theintestinal metagenome, which address only the microbial com-position of the samples but do not define the metabolic func-tions involved (3, 34). Recently, metabolomics has been estab-lished as a new technology whose aim is to study the complexlexicon of small molecules present in any given biological sam-ple, or the metabolome (6, 8, 19, 31). In order to expand ourunderstanding of the importance of the intestinal microbiotaas well as the disturbances elicited by antibiotic treatment, wehave used metabolomics to obtain a snapshot of the chemicalcomposition of the intestinal environment before and afterantibiotic treatment. By using Fourier transform ion cyclotronresonance mass spectrometry with direct infusion (DI-FT-ICR-MS) (6), we determined that a single, high dose of theantibiotic streptomycin can have a profound impact on thelevels of the majority of the compounds detected. Predictivemapping of these compounds to corresponding metabolicpathways showed that many crucial host metabolic functionsare disturbed. Among some of the pathways affected are thoseinvolved in sugar, amino acid, fatty acid, bile acid, steroid, andeicosanoid metabolism. Additionally, we show that clinicallyrelevant antibiotic doses can also disrupt host eicosanoid me-tabolism. Our results show that the microbiota has effects onpreviously unidentified host functions. Additionally, the criticalfunctions of all pathways affected suggest that the impact ofantibiotics on mammalian physiology extends far beyond thedevelopment of microbial drug resistance.

* Corresponding author. Mailing address: The University of BritishColumbia, 301-2185 East Mall, Vancouver, BC V6T 1Z4, Canada.Phone: (604) 822-2210. Fax: (604) 822-9830. E-mail: [email protected].

! Published ahead of print on 31 January 2011.

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Of the many metabolic pathways affected by antibiotic treatment, the metabolism of steroid hormones was the most profoundly impacted.


Menopause and Flax Seeds

• Contain lignans: matairesinol, secoisolariciresinol

• Estrogen-modulating effect

• 2 tbsp BID decreases hot flashes by 50% within 6 weeks

Haggans CJ, Hutshins AM, Olson BA, et al. Effect of flax-seed consumption on urinary estrogen metabolites in post-menopausal women. Nutrition and Cancer 1999;33(2):188-195 Pruthi SL et al. Pilot evaluation of flaxseed for the management of hot flashes. Journal of the Society for Integrative Oncology 2007;5(3):106-112




• Selective estrogen receptor-modifying activity

• Most prescribed natural treatment

• As good as estrogen replacement without the risks

Wattle W. Seilova-Wuttke D, Gorkow C. The Cimifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind study: effects on menopause symptoms and bone markers. Maturitas 2003;44:S67-S77


Other Nutrients That Can be Helpful

• Fish oil: 1000 mg/day

• Vitamin C: 500-1000 mg/day

• Vitamin E: 200-400 iu/day

• Black Cohosh: see above

• Maca: 3.5 grams/day

• Red Clover: 40-80 mg/day

• Dong Quai: 1-2 g TID

• Estrovera: 1 tablet/day

Male Specific



Male Concerns

• Andropause

• Erectile dysfunction

• Prostate enlargement (benign prostate hyperplasia)

• Prostate cancer


Does Andropause Exist?


Testosterone Decline

http://www.londonendocrinecentre.co.uk/Androgen-Deficiency.html



Prevalence of Low T In Other Conditions

• Obesity 52%

• Diabetes 50%

• AIDS/HIV 30%

• Hypertension 42%

• Hyperlipidemia 40%

• Erectile dysfunction 19%Daniel HW. J Pain. 2002: 3:377-384 Mulligan T, et al., Int J Clin Pract. 2006; 60: 762-769 Grinspoon S, et al., Ann Intern Med. 1998; 129:18-26 Dobs AS. Bailliere Clini Endocrin Metabol. 1998


Catch 22

Low testosterone

Obesity

Chen RY, et al., Diabetes Obes Metab. 2006 Jul;8(4):429-35.


Obese Teens and Testosterone

• Obese males 14-20 = 50% less testosterone

• Increases risk of impotence and infertility

Testosterone



Testosterone and Longevity

• Mortality levels 88% higher in men with low testosterone

Shores MM, et al., Arch Intern Med. 2006 Aug 14; 166(15):1660-5.


Influence of Testosterone

Bone marrow •RBC production

Male sex organs •Sperm production •Prostate growth •Erectile dysfunction

Muscle •Muscle mass and

strength

Brain •Libido •Positive feelings •Cognition and memory

Skin • Growth of facial and body hair

• Supports collagen

Bone •Bone density


Erectile Dysfunction

• Inability to maintain erection

• Prevalence:

• <59 = 12%

• 60-69 = 22%

• >69 = 30%

• Atherosclerosis cause of ED in 50% over 50

Hatzimouratidis K. Epidemiology of male sexual dysfunction. American Journal of Men’s Helath 2007 Jun;1(2):103-125



Erectile Dysfunction Causes

• 90% Organic

• Vascular insufficiency

• Drugs

• Alcohol/tobacco

• Endocrine disorders

• 10% Psychological


• Plays a critical role in erections

• Causes vasodilation

• Nutrients that increase:

• L-arginine

• L-citrulline

Nitric Oxide


Selenium and Prostate

• Selenium decreases PSA

• 200 mg/day

Zhang W, et al., Nutr Res. 2011 Feb 12.



Maca and Prostate

• Red maca reduces prostate size in rats

• Increase sperm production, motility, and semen volume

• 4:1 extract 525 mg TID

Forsch Komplementmed. 2009 Dec;16(6):373-80. Epub 2009 Dec 16.


Pygeum Africanum and Prostate

• “Pygeum Africanum extract administration improved all the urinary parameters we investigated; prostatic echography relieved reduction of peri-urethral edema.”

• 300 mg BID-TID

Arch Ital Urol Nefrol Androl. 1991 Sep;63(3):341-5.


Urtica Dioica (Nettle) and Prostate

• Decreases prostate size

• Beneficial for benign prostate hyperplasia

• 1000 mg BID-QID

J Herb Pharmacother. 2005;5(4):1-11.



Saw Palmetto and Prostate

• “The evidence suggests that serenoa repens provides mild to moderate improvement in urinary symptoms and flow measures. Serenoa repens produced similar improvement in urinary symptoms and flow compared to finasteride and is associated with fewer adverse treatment events.”

• 300-600 mg BID

Cochrane Database Syst Rev. 2002;(3):CD001423. Cochrane Database Syst Rev. 2009;(2):CD001423.


Zinc for Sexual Health

• Multiple studies on Zn for infertility and low testosterone

• 37 infertile men given 60 mg of Zn for 45-50 days

• Testosterone in 22 patients significantly increase and sperm count went from 8 to 20 million

Tikkiwal M, et al. Ind J Phys Pharm 1987 Jan-Mar; 31(1):30-34. Takihara H, et al. Urology 1987 Jun; 29(6): 638-641. Netter A, et al. Arch Androl 1981; 7(11): 69-73.


Exercise and Testosterone

• Strength training, high-intensity cycling increase testosterone

Izquierdo M, et al. J App Physiol 2001; 90(4): 1497-1507. J Strength Cond Res. 2011 Jan;25(1):23-31. Kraemer WJ, et al. J App Physiol 1999 Sep; 87(3): 982-92.



Addressing Male Hormone Imbalance

• Decrease aromatase activity

• Prevent the cortisol steal

• Improve BMI, and muscle

• Eliminate xenoestrogens

• Avoid toxins

• Low GI/GL diet

• Exercise

• Supplements




Summary

• The endocrine system autocorrects when the root cause is addressed

• Address blood sugar first, then adrenals, then thyroid, then sex hormones

• Give at least 2-3 months to begin to see changes


Summary





Current

EvidencePatient’sStory


Personalized


“Knowledge is not power, until it’s applied.”

Dale Carnegie



evidence-based clinical nutrition and integrative healthcare

Thank you!


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