1. Texas A&M University, Corpus Christi April 13, 2004 A Look at Thyroid Endocrinology Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston

2. This presentation is made possible by a grant entitled “Shortcourses in Endocrinology at Minority Undergraduate Institutions” from the National Institute of General Medical Sciences (NIGMS) to This presentation is made possible by a grant entitled “Shortcourses in Endocrinology at Minority Undergraduate Institutions” from the National Institute of General Medical Sciences (NIGMS) to The Minority Affairs Committee of the Endocrine Society

3. Thyroid Functions  Supports growth & development, especially in the embryo & brain  Helps regulate internal thermostasis, particularly in the young  Helps maintain metabolic energy balance; increases number & size of mitochondria, increases enzymes in the electron transport chain, increases Na + /K + ATPase activity  Generally excitatory for normal cellular functions including heart muscle

4. Thyroid Health Problems Hypothyroidism (4.1F, 0.6M/1000/y) Iodine deficiency disorders (~2x10 8 cases, 10 9 at risk; most common thyroid & endocrine illnesses) endemic goiter endemic cretinism Hashimoto’s thyroiditis (3.5F, 0.8M/1000/y) Hyperthyroidism (0.8F,<0.1M/1000/y) Grave’s disease (autoimmune thyrotoxicosis) (0.8F, 0.1M/1000/y, ≥ prevalence of diabetes mellitus) Thyrotoxicosis of pregnancy (5-10% postpartun) Toxic multinodular goiter Thyroid neoplasia (most common endocrine neoplasms) Benign enlargement Malignancies

5. Thyroid Anatomy

6. Thyroid Axis

7. http://www.addison.ac.uk/endocrine_modules/module1/lecturers_ material/html_files/END1.08/index.htm

9. T4T4 T 4 - Alb T 4 - TTR T3T3 T 4 -TBG T 3 -TBG T 3 - TTR T 3 - Alb R Thyroid Hormone Transport

10. Thyroid Hormone Transport Proteins MW kD Plasma uM T 4 cap. ug T 4 /dL K a T 4 L/M K a T 3 L/M Usual % Occ. by T 4 Turnover Rate %/d % TT 4 Bd % TT 3 Bd TBG540.27211x10 10 5x10 8 31136880 TTR544.63507x10 7 1.4x10 7 259119 Alb6664050K7x10 5 1x10 5 <0.152011 Free0.020.3 After Larsen et al., Thyroid physiology and diagnostic evaluation of patients with thyroid disorders, Ch. 10, Larsen, Kronenberg, Melmed, Polonsky (eds) Williams Textbook of Endocrinology, 10 th ed., W.B. Saunders Co.: Philadelphia, PA, 2003, 338, Table 10-3.

11. Substrate K m T 4 T 3 rT 3 D 1 - 5’ & 510 -6 10 -3 D 2 - 5’ only10 -9 10 -9 D 3 - 5 only10 -9 10 -9 Thyroxine (T 4 ) T 3 rT 3 T3ST3ST3ST3S TRIAC T2T2T2T2 T1 T1T1 T1 Thyronine Thyronine Deiodinase 2 & 1 (- 5’ I) 3,5,3’ 3,5’,3’ Deiodinase 3 & 1 (- 5 I) 40% D1, D2 (- 5’ I) D3, D1 (- 5 I) T2ST2ST2ST2S D1 (Liver) Deaminate T4ST4ST4ST4S T4GT4GT4GT4G Decarboxylate Thyroxine Catabolism

12. Direct Links to Other Endocrine Axes TRH & Somatostatin also help control PRL & GH

13. Indirect Links to Other Systems Glucocorticoid Excess  ↓ TSH, TBG, TTR, T 3, T 4, ↑rT 3 Deficiency  ↑ TSH Estrogens  TBG sialylation & serum t 1/2  T 4 requirement in hypothyroidism ↑ TSH in postmenopausal women Androgens  TBG ↓ T 4 turnover in women  T 4 requirement in hypothyroidism

14. Mechanism of T 3 4 functional intranuclear T 3 receptors:  1, β1,2,3; & 1 nonfunctional receptor, α2. Expression varies with tissue & developmental stage. http://www.addison.ac.uk/endocrine_modules/module1/lecturers_ material/html_files/END1.08/index.htm

15. Pregnancy & the Thyroid Axis Pregnancy Causes:  TBG  Plasma volume  hCG D3 expression in placenta  Renal clearance fetal T 4 synthesis in 2 nd & 3 rd trimester  O 2 consumption by fetus, placenta, uterus & mother Maternal Thyroid Axis Impacts:  T 4 production  Total [ T 4 ] & [ T 3 ]  T 4 & T 3 pool  cardiac output  Free T 4  Basal TSH  I 2 requirements  BMR

16. A population study of the thyroid axis arose during examination of the physiological determinants of fertility level in a non- Westernized population.

17. Where were the Gainj?

18. The Gainj are a natural fertility population with a low total fertility rate & an intriguing reproductive history.

20. Physiology & demography were synergistic in explaining fertility.

21. Female PRL made us question impacts on thyroid function. But no goiter?

22. Prolonged intensive nursing keeps prolactin high & ovulation suppressed.

23. [PRL] decreased during lactation, but was still clinically high implying TRH might be high, TSH should be high, & T 4 should be high unless iodine deficiency was present. Thyroid axis pathology might help explain low fertility. Was there evidence for any?

24. http://www.j3s.net/phot olog/ghana/ t.20030909_goiter.jpg Classic Highlands goiter, a clear sign of endemic iodine - deficiency hypothyroidism, was absent.

25. There were, however, at least two cretins in the Gainj community.

26. Thyroid Axis Parameters

27. Hormone levels looked pretty normal (euthyroid). What about carrier protein levels, albumin, prealbumin (= transthyretin), or TBG? MenWomen

28. Gainj men & women have high thyroid- binding globulin but normal thyroxine. Compensation for low dietary protein & I - elevates TBG when other carrier proteins decline, prolongs thryoxine life, & decreases I - needs.

29. Given the protein levels, how does T 4 /T 3 distribute across TBG,TTR, & Alb?

30. While Alb & TTR are low, particularly in women, high TBG levels might also indicate a low-binding genetic variant.

31. Biochemical characteristics of Gainj TBG & DNA sequencing of several samples by Refetoff et al. in Chicago implies Gainj TBG is a wild – type.

32. The data imply the Gainj are euthyroid with high TBG compensating for low Alb & TTR, probably prolonging T 4 circulation time, decreasing clearance & decreasing the iodine requirement. Unmet elevated demands during pregnancy & lactation may result in fetal hypothyroidism & cretinism, in more marginal thyroid status for women, & in overall depression of population fertility.

33. There is an important interplay of environmental & dietary controls on the thyroid axis & its functions as well as impact of sex steroids. Exploring this network requires evaluation of all the hormones & binding proteins involved. Summary:

34. Work on the Gainj has implications for public health control of endemic iodine deficiency: to avoid hyperthyroid rebound while supplementing dietary iodine, you must also supplement protein intake to allow binding globulins to readjust. Conclusions:

35. Support from: NSF, Umass/Boston, Sandia National Labs, Hybritech, Quidel, Monoclonal Antibodies Inc. Acknowledgements Gainj Project The Gainj People Rees Midgley Al Hermalin Lora Myers Jim Wood Pat Johnson Ila Maslar Diana Lai Sam Refetoff Peter Smouse Peter Heywood Michael Alpers Brian Davison Yan Ren Lynne Shinto Diane Drinkwater Darryl Holman Bettina Shell Related Studies Kathy O’Connor Coralie Munro Susannah Barsom Ellie Brindle Cheryl Stroud Kai Orton Jodiann Thompson Yefim Proshchitskiy Yelena Filipova Matt Lopresti Oliver Schultheiss Cheryl Frederick Steve Monfort Malcolm Potts David McClelland (dec) Turkana Project All Turkana Subjects Mike Little Paul Leslie Ben Campbell Dhanesh Dookhran Kathy Whiteman Alexandra Evindar William Lukas Sandra Gray Jeanine Quigley Christine Sekadde -Kigondu -Kigondu Leah Kirumbi (*in the lab at UMB)