American Thyroid AssociationCorporate Leadership Council

May 14, 2010Minneapolis, Minnesota

"..I have seen societies come and go..I recognize a harmonious and understanding

attitude between those who are interested in almost pure science, bordering on its relation to clinical medicine, and the rest of us...Even

if we often do not possess the fundamental training and experience to understand them

fully, we listened with profit to these scientific papers that have been presented to us..."

1. Mayo Clinic, Rochester, Minn.3. Johns Hopkins Hospital, Baltimore7. Brigham and Women's Hospital, Boston10. Hospital of the University of Pennsylvania14. University of Chicago16. Washington Hospital Center17. University of Michigan19. Cedars-Sinai Hospital23. Baystate Medical Center24. Methodist Hospital

• National Academy of Sciences-1• Institute of Medicine-2• Medical School Deans and Associate Deans-

Northwestern, UCLA, Georgetown, Harvard, former-Yale, Univ of Alabama, UC San Diego

• Scientific Director NIDDK (Natl Institutes of Health)• Department Chairs; Medicine, Pediatrics, Surgery,

ENT, Genetics-12• University/Major Medical Center Division Chiefs-20• NIH Molecular and Cellular Endocrinology Study

Section-3 of 15 regular members, current chair and 2 past chairs

Condition Reported Prevalence in Adult Population (%)

Hypothyroidism 2Mild (subclinical) hypothyroidism

5-17

Hyperthyroidism 0.2Mild (subclinical) hyperthyroidism

0.1-6

Prevalence of Mild Thyroid Failure Prevalence of Mild Thyroid Failure Across Studies: Women by DecadeAcross Studies: Women by Decade

1. Tunbridge W, et al. Clin Endocrinol. 1977;7:481-493. 2. Canaris G. Arch Intern Med. 2000;160:526-534. 3. Hollowell J. J Clin Endocr Metab. 2002;87:489-499.

0

5

10

15

20

25

30s 50s 80s

% o

f Wom

en

Colorado2 (N=25,862) NHANES3 (N=17,353)

Whickham1 (N=2779)

Decade of Age

http://seer.cancer.gov/cgi-bin/csr/1975_2006

Smith, et al., J Clin Oncol 2009

• Thyroid autoimmunity -prevalent disease, familial, identify triggers, genetic susceptibility, antigen-antibody interactions, antagonists, application to other autoimmune conditions (eg. Type 1 diabetes).

• Thyroid hormone action -development in mammals and amphibians, tissue specificity, analogs, metabolic regulation, neural development, adult brain function, bone growth and remodeling, crystal structure-function, central regulation of TRH/TSH, environmental toxicants.

• Thyroid hormone metabolism -developmental role, deiodinase enzyme structure/function/regulation, regulation in tissues (tumors, skeletal muscle, brain), interface with adrenergic system, role in metabolic regulation.

• Thyroid cancer-mechanism of onset, mechanism of spread, iodine transport and regulation, molecular diagnostics, targeted therapy.

• Thyroid and the heart-mechanism of action, role in atrial fibrillation and heart failure, therapy for heart failure, vascular action to reduce resistance.

• Thyroid Clinical-thyroid disease in pregnancy, iodine intake and influence on thyroid function, thyroid and brain development, psychiatric disease, cardiovascular effects, bone effects, thyroid nodule evaluation, impact of mild thyroid disease, epidemiology, thyroid and aging (bone loss, frailty), thyroid function testing, .

• “Related” Areas-Sodium/iodide symporter (NIS) regulation in tumors and NIS gene therapy, pharmacological treatment in psychiatric disease, interaction with feeding behavior, sleep, circadian rhythms.

Potential Applications of Thyroid Hormone Analogs

Brenta G et al, Nature Clin Pract Endocrin Metab 3:632, 2007

Thyroid hormones T4 and T3

Thyroid hormone analogs

Pituitary GlandCardiovascular System

Liver

All Organ Systems

TSH suppression(negative regulation of

TSH -subunit

Cardiac OutputHeart Rate (HCN2)

Contractility (SERCA2, MHCs)Systemic Vascular Resistance

Cholesterol Metabolism(SERBP-2 sterol regulatoryelement binding protein-stimulatesLDL-R gene, CYP7A-cholesterol7 hydroxylase-bile acid syn/cholesterolClearance, CETP-cholesterol estertransfer protein)

Thermogenesis and V02

(ATP turnover, muscle mass,facultative thermogenesis)

100%

87%

DBD Hinge LDB

TR1

TR1

N-terminal

410

461

P448H

P398H

cofactor interaction interface

Activation

Thyroid Hormone Receptors and Functional Domains

Liu and Brent Trends Endo Metab 2010; 21:166

SERBP-2 sterol regulatory element binding proteinCYP7A-cholesterol 7 hydroxylaseCETP-cholesterol ester transfer protein

Rulon Rawson, MDPresident, American Goiter Association

Presidential Address, 1956

Side effects

• Cardiac

• CNS

• Bone

• Muscle

Metabolic effects

• Metabolic rate

• Cholesterol

• Triglycerides

• Lipoprotein(a)

• Reverse cholesterol transport

Metabolic effects

• Metabolic rate

• Cholesterol

• Triglycerides

•

•

Selective Thyromimetics

Baxter and Webb Nature Drug Discovery 8:308, 2009

Cable et al Hepatology 49:407, 2009

Liver-Activated Thyroid Hormone Receptor Analog

MB07811 is a phosphonate containing derivative of MB07344with high first-pass extraction in the liver and activated byCytochrome P450 3A

Cable et al Hepatology 49:407, 2009

Vehicle MB07811 10mg MB07811 30mg

Baxter and Webb Nature Drug Discovery 8:308, 2009

Ladenson et al N Engl J Med 2010 362:906

Lichtenbelt N Engl J Med 360:1500, 2009

LeanHighBAT

LeanModBAT

Obese

2 hoursExposure16ºC

Brown Adipose Tissue in Humans

Klein I, Danzi S. Circulation 2007; 116:1725

Thyroid Hormone Actions on the Cardiovascular System

Goldman et al Circulation 119:3093, 2009

End Diastolic Diameter Cardiac Index

DITPA

Thyroid Hormone Analogs

Thyroid Hormone Synthesis

Coupling ReactionsDIT+DIT=T4MIT+DIT=T3

NIS-Sodium Iodide Symporter, TPO-thyroid peroxidase, D1/D2-5’-deiodinase 1 and 2

Coupling ReactionsMIT+DIT=T3DIT+DIT=T4

Kondo, et al., Nat Rev Cancer 2006

Neumann et al Endocrinology 149:5945, 2008

Neumann et al Endocrinology 149:5945, 2008

Low Molecular Weight Compound 52 Antagonizes TSHStimulation of the TSH-Receptor

Thyroid Salivary Gland

Stomach Lactating Breast

Transactions of the American Goiter Association 1951

Xing, et al., J Clin Oncol, 2009

Bauer et al J Clin Endocrinol Metab 94:2922, 2009PCC-posterior cingulate cortexACC-anterior cingulate cortex

P13, ~ onset of hearing

P0, birth P20, weaning

Dio2 activating

amplify hormone

conception

Thyroid hormone and the senses: the example of hearing

Multiple genes determine the nature, cell-specificity and timing of the response to T3

• Adequate amounts of thyroid hormone in the circulation are necessary

• The cochlea auto-regulates its hormonal response: Dio2 and Dio3, double control over timing

• “Critical period” of maturation of auditory function, depends upon T3

Dio3 inactivating

limit hormone

TR~ E12

“critical period”

MCT8-Thyroid Hormone Transporter

Hierarchy of ligand preference T3>T4>rT3~T2

Visser et al Best Prac Res Clin Endo Metab 21:223, 2007

Model of the role of astrocytes expressing D2 to convert

T4 to T3 and neurons expressing the MCT8

transporter to take up T3.

• Mutations in the monocarboxylase transporter 8 (MCT8) gene located on X chromosome.

• Neurologic and thyroid function test abnormalities in males carrying the mutation

• Neurologic abnormalities include dystonia, developmental delay, and progressing to quadriplegia

• Inactivating mutations of the MCT8 gene identified

Alan-Herndon-Dudley Syndrome-X Linked Mental Retardation

Schwartz and Stevenons, Best Prac Res Clin Endo Metab 21:307, 2007

DITPA

Thyroid Hormone Analogs