A Look at Thyroid EndocrinologyKenneth L. CampbellProfessor of BiologyUniversity of Massachusetts at Boston
Supports growth & development, especially in the embryo & brainHelps regulate internal thermostasis, particularly in the youngHelps maintain metabolic energy balance; increases number & size of mitochondria, increases enzymes in the electron transport chain, increases Na+/K+ATPase activityGenerally excitatory for normal cellular functions including heart muscle
Thyroid Health Problems
Hypothyroidism(4.1F, 0.6M/1000/y)Iodine deficiency disorders(~2x108cases, 109at risk; most common thyroid & endocrine illnesses)endemic goiterendemic cretinismHashimoto’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 goiterThyroid neoplasia(most common endocrine neoplasms)Benign enlargementMalignancies
Thyroid Hormone Transport
Thyroid Hormone Transport Proteins
After Larsenet al., Thyroid physiology and diagnostic evaluation of patients with thyroid disorders, Ch. 10, Larsen, Kronenberg, Melmed, Polonsky (eds)Williams Textbook of Endocrinology, 10thed., W.B. Saunders Co.: Philadelphia, PA, 2003, 338, Table 10-3.
Substrate KmT4T3rT3D 1 - 5’ & 510-610-3D 2 - 5’ only10-910-9D 3 - 5 only10-910-9
Deiodinase2& 1 (-5’ I)
Deiodinase3& 1 (-5 I)
D1, D2 (-5’ I)
D3, D1 (-5 I)
Direct Links to Other Endocrine Axes
TRH & Somatostatin also help control PRL & GH
Indirect Links to Other Systems
GlucocorticoidExcess↓TSH, TBG, TTR, T3, T4,↑rT3Deficiency ↑ TSHEstrogensTBG sialylation & serum t1/2T4requirement in hypothyroidism↑ TSH in postmenopausal womenAndrogensTBG↓ T4turnover in womenT4requirement in hypothyroidism
Mechanism of T3
4 functional intra-nuclear T3receptors:α1,β1,2,3; & 1 non-functional receptor,α2. Expression varies with tissue & developmental stage.
Pregnancy & the Thyroid Axis
Pregnancy Causes:TBGPlasma volumehCGD3 expression in placentaRenal clearancefetal T4synthesis in 2nd& 3rdtrimesterO2consumption by fetus, placenta, uterus & mother
Maternal Thyroid Axis Impacts:T4productionTotal [ T4] & [ T3]T4& T3poolcardiac outputFree T4Basal TSHI2requirementsBMR
A population study of the thyroid axis arose during examination of the physiological determinants of fertility level in a non-Westernized population.
Where were the Gainj?
The Gainj are a natural fertility population with a low total fertility rate & an intriguing reproductive history.
Physiology & demography were synergistic in explaining fertility.
Female PRL made us question impacts on thyroid function.
But no goiter?
Prolonged intensive nursing keeps prolactin high & ovulation suppressed.
[PRL] decreased during lactation, but was still clinically high implying TRH might be high, TSH should be high, & T4should be high unless iodine deficiency was present. Thyroid axis pathology might help explain low fertility. Was there evidence for any?
Classic Highlands goiter, a clear sign of endemic iodine - deficiency hypothyroidism, was absent.
There were, however, at least two cretins in the Gainj community.
Thyroid Axis Parameters
Hormone levels looked pretty normal (euthyroid).What about carrier protein levels, albumin, prealbumin (= transthyretin), or TBG?
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.
Given the protein levels, how does T4/T3distribute across TBG,TTR, & Alb?
While Alb & TTR are low, particularly in women, high TBG levels might also indicate a low-binding genetic variant.
Biochemical characteristics of Gainj TBG & DNA sequencing of several samples by Refetoffet al.in Chicago implies Gainj TBG is a wild – type.
The data imply the Gainj areeuthyroidwithhigh TBG compensating for low Alb & TTR, probably prolonging T4circulation 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.
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.
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.
Support from: NSF, Umass/Boston, Sandia National Labs, Hybritech, Quidel, Monoclonal Antibodies Inc.
Gainj ProjectThe Gainj PeopleRees MidgleyAl HermalinLora MyersJim WoodPat JohnsonIla MaslarDiana LaiSam RefetoffPeter SmousePeter HeywoodMichael AlpersBrian DavisonYan RenLynne ShintoDiane DrinkwaterDarryl HolmanBettina Shell
Related StudiesKathy O’ConnorCoralie MunroSusannah BarsomEllie BrindleCheryl StroudKai OrtonJodiann ThompsonYefim ProshchitskiyYelena FilipovaMatt LoprestiOliver SchultheissCheryl FrederickSteve MonfortMalcolm PottsDavid McClelland (dec)
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(*in the lab at UMB)