A Look at Thyroid Endocrinology Kenneth L. Campbell Professor of Biology

1. A Look at Thyroid Endocrinology Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston

2. 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

3. Thyroid Health Problems Hypothyroidism(4.1F, 0.6M/1000/y) Iodine deficiency disorders (~2x108 cases, 109 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

4. Thyroid Anatomy

5. Thyroid Axis

6. http://www.addison.ac.uk/endocrine_modules/module1/lecturers_material/html_files/END1.08/index.htmhttp://www.addison.ac.uk/endocrine_modules/module1/lecturers_material/html_files/END1.08/index.htm

8. Thyroid Hormone Transport T3-TBG R T3- Alb T3 T4- TTR T4 T3- TTR T4-TBG T4- Alb

9. Thyroid Hormone Transport Proteins 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, 10th ed., W.B. Saunders Co.: Philadelphia, PA, 2003, 338, Table 10-3.

10. Deaminate T4G Thyroxine (T4) T4S Decarboxylate Deiodinase 2 & 1 (- 5’ I) Deiodinase 3 & 1 (- 5 I) 40% TRIAC 40% T3 rT3 3,5,3’ 3,5’,3’ (Liver) T3S D1, D2 (- 5’ I) D3, D1 (- 5 I) T2 D1 T2S T1 Thyronine Substrate Km T4 T3 rT3 D 1 - 5’ & 5 10-6 10-3 D 2 - 5’ only 10-9 10-9 D 3 - 5 only 10-9 10-9 Thyroxine Catabolism

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

12. Indirect Links to Other Systems Glucocorticoid Excess  ↓ TSH, TBG, TTR, T3, T4, ↑rT3 Deficiency  ↑ TSH Estrogens  TBG sialylation & serum t1/2  T4 requirement in hypothyroidism ↑ TSH in postmenopausal women Androgens  TBG ↓ T4 turnover in women  T4 requirement in hypothyroidism

13. Mechanism of T3 4 functional intra-nuclear T3 receptors: α1, β1,2,3; & 1 non-functional receptor, α2. Expression varies with tissue & developmental stage. http://www.addison.ac.uk/endocrine_modules/module1/lecturers_material/html_files/END1.08/index.htm

14. Pregnancy & the Thyroid Axis Pregnancy Causes:  TBG  Plasma volume  hCG D3 expression in placenta  Renal clearance fetal T4 synthesis in 2nd & 3rd trimester  O2 consumption by fetus, placenta, uterus & mother Maternal Thyroid Axis Impacts:  T4 production  Total [ T4 ] & [ T3 ]  T4 & T3 pool  cardiac output  Free T4  Basal TSH  I2 requirements  BMR

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

16. Where were the Gainj?

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

19. Physiology & demography were synergistic in explaining fertility.

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

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

22. [PRL] decreased during lactation, but was still clinically high implying TRH might be high, TSH should be high, & T4 should be high unless iodine deficiency was present. Thyroid axis pathology might help explain low fertility. Was there evidence for any?

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

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

25. Thyroid Axis Parameters

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

27. 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.

28. Given the protein levels, how does T4/T3 distribute across TBG,TTR, & Alb?

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

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

31. The data imply the Gainj are euthyroid with high TBG compensating for low Alb & TTR, probably prolonging T4 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.

32. 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:

33. 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:

34. 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 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 Leah Kirumbi 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) Support from: NSF, Umass/Boston, Sandia National Labs, Hybritech, Quidel, Monoclonal Antibodies Inc. (*in the lab at UMB)