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Chapter14 Thyroid

Chapter14 Thyroid

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REPRINTED FROMWWW.THYROIDMANAGER.ORGChapter 14 – Thyroid Regulation and Dysfunction in the Pregnant Patient
Daniel Glinoer, M.D., Ph.DProfessor of Internal Medicine & Cheif of the Endocrine DivisionUniversity Hospital Sant-Pierre - Universite Libre de Bruxelles, Brussels Belgium
Updated August 2008
INTRODUCTION
Over the past twenty years there has been a major expansion of our knowledge regardingthyroid disorders associated with pregnancy. These advances relate to the optimalmanagement of pregnant women who are on l-thyroxine therapy, the impact of iodinedeficiency on the mother and developing fetus, the adverse effects of maternalhypothyroidism on mental development in their offspring, thyroid dysfunction associated withpostpartum thyroiditis, etc. Simultaneously, a doubling of the miscarriage rate has beenreported in studies in antibody-positive euthyroid women, and an increase in pretermdelivery has been found in women with subclinical hypothyroidism and/or thyroidautoimmunity. Given the rapidity of advances in this field, it is not surprising that somecontroversy surrounds the optimal detection and management of thyroid diseases duringpregnancy, especially since pregnant women may have a variety of known or undisclosedthyroid conditions (such as hypothyroidism and hyperthyroidism), the presence of thyroidautoantibodies, thyroid nodules, or insufficient iodine nutrition.Pregnancy may affect the course of thyroid disorders and, conversely, thyroid diseases mayaffect the course of pregnancy. Moreover, thyroid disorders (and their management) mayaffect both the pregnant woman and the developing fetus. Finally, pregnant women may beunder the care of multiple health care professionals, including obstetricians, nurse midwives,family practitioners, endocrinologists and/or internists, making the development of clinicalpractice guidelines all the more urgent and critical. Accordingly, an international task forcewas created under the auspices of the American Endocrine Society to review the bestevidence in the field and develop evidence-based guidelines. Members of the task forceincluded representatives from the Endocrine Society, American Thyroid Association (ATA),Association of American Clinical Endocrinologists (AACE), European Thyroid Association(ETA), Asia & Oceania Thyroid Association (AOTA), and the Latin American Thyroid Society(LATS). The task force worked for two years to develop the guidelines that were, eventually,approved by all the above-mentioned scientific international organizations. The task forcefinished its work in 2007. The guidelines were published in the Journal of ClinicalEndocrinology and Metabolism (August 2007) as a Supplement containing the completedocument and also in a shorter version or “Executive Summary” containing the main 35recommendations agreed upon by the committee 1.
MATERNAL THYROID PHYSIOLOGY
Numerous hormonal changes and metabolic demands occur during pregnancy, resulting inprofound and complex effects on thyroid function. As thyroid diseases are, in general, muchmore prevalent in women (than in men) during the childbearing period, it is not surprisingthat thyroid disorders such as chronic thyroiditis, hypothyroidism, Graves' disease, etc. are
 
relatively common in pregnant women. To facilitate our understanding of the pathologicprocesses that affect the thyroid gland, it is important to understand first the normalphysiologic processes that take place in the pregnant state such as, for instance, changes inthyroid function tests, thyroid volume, immune modulation, thyroidal economy in relation withthe iodine nutrition status, etc. Over the past fifteen to twenty years, a profusion of relevantnew information regarding the relationships between pregnancy and the thyroid gland hasallowed to clarify many aspects of the interactions between gestation and regulation of thethyroid system in normal individuals as well as patients with thyroid disorders. Despite thesemajor new insights, many uncertainties remain and important questions remain incompletelyelucidated. Finally, it is important to consider that the expecting mother is the natural carrier of a future child. Hence, understanding better the complex maternal-fetal interrelationshipsrelated to the ongoing thyroid processes must remain our constant quest, in order to ensurethe best possible health status of mother and progeny.Regulation of the thyroid in normal pregnancyTable 14-1 summarizes the main physiologic changes that occur during a normal pregnancy,and which relate to thyroid function or thyroid function testing. Early in pregnancy there is anincrease in renal blood flow and glomerular filtration which lead to an increase in iodideclearance from plasma2-6.This results in a fall in plasma iodine concentrations and an increase in iodide requirements from the diet 2. In women with iodine sufficiency there is littlethyroid impact of the obligatory increase in renal iodine losses, because the intrathyroidaliodine stores are plentiful at the time of conception and they remain unaltered throughoutgestation. As an example, in a collaborative study between the Universities of Massachusetts (USA) and Santiago (Chili), iodine metabolism was investigated in the threetrimesters of gestation and again after delivery. Plasma inorganic iodide (PII) concentrations,urinary iodide levels, and thyroid function tests were determined in 16 pregnant women.While the results showed a wide variability in PII values and urinary iodide concentrations,there was no trend for a decrease in PII concentrations during pregnancy. The conclusionwas that pregnancy does not have a major influence on circulating iodine concentrations iniodine-sufficient regions. It should be noted, however, that the iodine excretion levels wereunusually high in this study, ranging between 459-786 µg/day 7.
Table 14-1.
Factors affecting Thyroid Physiology during normal PregnancyPhysiologic ChangeThyroid-related consequencesIncreased renal I- clearanceIncreased 24-hr RAIUDecreased plasma I- and placental I-transport to the fetusIn I- deficient women, decreased T4,increased TSH, and goiter formationIncreased O2 consumption by fetoplacentalunit, gravid uterus and mother Increased BMRFirst-trimester increase in hCGIncreased free T4 and T3Decreased basal TSH (partial blunting of thepituitary-thyroid axis)Increased serum TBGIncreased total T4 and T3Increased plasma volumeIncreased T4 and T3 pool sizeInner-ring deiodination of T4 and T3 byplacentaAccelerated rates of T4 and T3 degradationand productionIn regions where the iodine supply is borderline or low, the situation is clearly different andsignificant changes occur during pregnancy3, 4, 6.While 24-hour radioiodine uptake determinations are not usually performed in the pregnant state, past studies have shown thatthe uptake is increased 8. In addition, there is a further increment in iodine requirements,due to transplacental iodide transport necessary for iodothyronine synthesis by the fetalthyroid gland, which becomes progressively functional after the first trimester. Several
 
studies have convincingly documented the fact that, when pregnancy takes place inconditions with borderline iodine availability, significant increments in both maternal and fetalthyroid volume occur, when no supplemental iodine was given during early pregnancy9-11.This is in sharp contrast with the notion that in iodine-sufficient areas, there is little, if any,change in thyroid size during pregnancy 12, 13. Effects of human chorionic gonadotropin on thyroid functionHuman chorionic gonadotropin (hCG) is a member of the glycoprotein hormone family that iscomposed of a common -subunit and a non-covalently associated, hormone-spcific -
subunit. The -subunit of hCG consists of a polypeptide chain of 92 amino acid residues
 containing two N-linked oligosaccharide side-chains. The -subunit of hCG consists of 145
 residues with two N-linked and four O-linked oligosaccharide side-chains. The -subunit of 
 TSH is composed of 112 residues and one N-linked oligosaccharide. The -subunits of both
 molecules possess 12 half-cysteine residues at highly conserved positions. Three disulfidebonds form a cystine knot structure, which is identical in both TSH and hCG and is essentialfor binding to their receptor (LH and hCG bind to the same receptor, the LHCG receptor). Asingle gene on chromosome 6 encodes for the common -subunit, while the genes that
 encode for the -subunits are clustered on chromosome 19, with seven genes (but only
 three actively transcribed) coding for -hCG 14-16.
The structural homology between hCG and TSH provides already an indication that hCGmay act as a thyrotropic agonist, by overlap of their natural functions. Human CG possessesan intrinsic (albeit weak) thyroid-stimulating activity and perhaps even a direct thyroid-growth-promoting activity17-24. During normal pregnancy, the direct stimulatory effect of hCG on thyrocytes induces a small and transient increase in free thyroxine levels near theend of the 1st trimester (peak circulating hCG) and, in turn, a partial TSH suppression3, 6,25-31. When tested in bioassays, hCG is only about 1/104 as potent as TSH during normalpregnancy. This weak thyrotropic activity explains why, in normal conditions, the effects of hCG remain largely unnoticed and thyroid function tests mostly unaltered.The thyrotropic role of hCG in normal pregnancy is illustrated inFigure 14-1. The figureshows the inverse relationship between serum hCG and TSH concentrations, with a mirror image between the nadir of serum TSH and peak hCG levels et the end of the first trimester.The inset in the figure shows that the rise in serum free T4 is proportional to peak hCGvalues. At this period during gestation, 1/5th of otherwise euthyroid pregnant women have atransiently lowered serum TSH, even below the lower limit of the normal non pregnantreference range3, 24, 32.

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