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Clinical C’hemistiy 42:1 135-139 (1996) Physiological variations in thyroid physiological and pathophysiological A. DELBERT Thyroid hormone thyrotropin (TSH) mone secretion active triiodothyronine sues via both serious the events onset of sleep noon hours. ±50%. and nadir Peak and nadir concentrations effect on circulating T4 The is not T4 significant on thyroid for variation concentrations of TSH decreased cretion ratio, and concentrations. hormone in iodine T4 production, an increased Excessive biosynthesis biosynthetic increased an ratio by inhibiting the resulting goiter, can in- All hormones in T4 secretion, conjugates, and application at the TERMS: hormone regulation Nichols July thyrotropin Institute, 3!, most of FT4. The latter variations. Other measurements TBG, and thyroglobulin. or no clinical important use include uptake and little blood. glucuronide in vitro TSH and include a direct the T3 resin include T3, free T3 is chronic. #{149} triiodothyronine . thyroxine. San Juan Capistrano, CA 92690. Fax 714-728- 4960. Received clinical and have The measurement 1995; accepted October 13, 1995. 135 VARIATIONS There are evident in all of the in vitro These variations Nonstandard Corning sulfate acid time. only in peripheral the or indirect PHYSIOLOGICAL INDEXING present thyroacetic metabolites, bioactivity. be measured triiodothyroacetic III MDI sulfoconjugated, to the Of all the for T4 also by a type deaminated of TRH, for routine (VT3), rT3, hypothyroidism can T3 tissue. be of monodeio- produces (ri’3) can manifest iodothy- II [2]. Most adipose T3 (or) acid measurements measurements thyroid involved of the II MDI derivatives. triiodothyroacetic However, se- and acid tissues, via hepatic T4 albumin by the type I and brown and The peripheral to T3 Type “reverse” and to type and tissues, conjugated, and (prealbumin) I MDI. to inactive nonhepatic prohormone in serum. is thyroxine-binding to be derived pituitary, thyropropionic T3 T3/T4 block enzymes and and iodine T3f1’4 circulating in reduced concentrations, excess with most glucuronide im- thyroid increased intake in of the is distributed appears triiodothyrespectively. proteins by deiodination in brain, is deiodinated Subthreshold associated of body T4 by type of T4 action hormone proteins whereby hypothalamic production, secretion (MDIs) T active to binding binding monodeiodinases local and pituitary loop and is secreted to stimulate TRH transthyretin roles. circulating dination no ambulatory a minimal intake. are the is of these it is metabolized ronine the geographic has increased iodine process, TSH iodine iodine goiter, or significant also intake secretion, uptake, no Nutrition of training, exercise, and size there physical by synthesis but the and (TSH) in turn (TRH) the pituitary to TSH bound (TBG), secretion system at both it is converted secondary where acts the thyrotropin by a feedback-inhibiting to inhibit important play after- (VT’4) by [1].’TSH thyroliberin vascular and circulates globulin concentra- large subjects which most at the portal stimulates T4, is a cirthe T3 TSH and differ and the weight, function, variation. except of metof little values during healthy immobilization, environmental creased In of body posture, Status because pool. impact habitus, concentrations significant extrathyroidal (T3)] gland by hypothalamic release, [where estrogens peak thyroxine is regulated pituitary pituitary TSH ronine There with iodo- the levels are pregnancy. into gland at cancer, secretion, of function the regulated in infection, during of TSH from Control differences of placental gland secretion modified gender effects Thyroid free (trauma, and for the and FISHER largely tis- of the systems. regulated illness prohor- regulation activities enzyme gonadotropin rhythm and pituitary in peripheral influencing Racial except chorionic cadian gland production is developmentally significance tions thyroid (T) diseases). if the via (T4) nonthyroidal abolic the regulated thyroxine monodeiodinase levels pact is of by metabolic thyronine production modulation hormones: considerations marked WITH variations are in hormone abbreviations: TSII, thyroxine; -F,. thyronine anonodeiodinase; ri,, and human gonadotropin. hCG, chorionic and summarized triiodothvronine; GENDER, thyroid tuG, reverse in RACE, protein Table thyrotropin; FT., Thyroid thyroliherin; globulin; FF,), age, measurements. TRH, (or AGE with 1 [3-6]. thyroxine-binding F,; AND function free T4, MDI, 14 (or jodofree T,); 136 NACB Table 1. Changes in thyroid-function Serum T4, nmol/L FT4. pmoi/L Symposium TBG, mg/I TSH, miIJ/L indicators with age.a conc rT3, nmol/L T3, nmol/I Tg, eg/L T4 utilization, per day pg/kg Fetus 12-20 weeks 5-50 0-50 1-8 2-23 21-30 weeks 35-100 5-12 1.9-8.8 8-33 0.10-0.75 31-40 weeks 70-180 12-22 3-12 15-50 0.2-1.5 22-42 0.5 - 1 - 6-230 2 2-54 5 - 1.5-7.7 Infant 1-4 days 142-277 28-68 1-39 1-4 weeks 106-221 12-30 1.7-9.1 76-210 10-23 0.8-8.2 16-36 1.6-3.8 1-12 months - 2-110 0.4-4.5 - 7 0.17-2.0 - 6 1.5-11.4 1.6-5.3 10 Child 1-5 years 94-193 10-27 0.7-5.7 12-28 1.6-4.1 0.23-1.1 2-65 5 82-171 13-27 0.7-5.7 12-28 1.4-3.7 0.26-1.2 2-65 4 years 71-151 10-26 0.7-5.7 14-30 1.3-3.3 0.29-1.3 2-36 3 years 54-152 10-26 0.7-5.7 14-30 1.2-3.2 0.39-1.2 2-36 2 21-50 years 55-161 12-32 0.4-4.2 17-36 1.1-3.1 0.46-1.2 2-25 1.5 51-80 years 55-160 12-32 0.4-4.2 17-36 0.6-2.8 0.46-1.2 2-25 1.5 clearance; androgens 6-10 years 11-15 16-20 Adult 4Data from Values refs. 3-6 Corning in the thyroid hormone weight) fetus in early all utilization and Clinical Correlations highest rates decrease Division. of progressive function, changes on tions is minimal. age after In adults in serum decreases in >50 years, subjects T4 T4 is a modest, studies general, little tion. Estrogen hancing little or no the and hormonal changes significant increases serum sialylation of in gender TBG the manifest other 20 DIETARY FT4, or Caloric restriction T3 and T4 at both the net TSH are a 2. Changes Decreased TRH secretion Decreased TSH response Decreased pituitary Decreased T4 secretion Decreased T4 disposal effect TSH of Basal and (slight) Decreased T3 disposal No change in serum (slight) aFrom ref. 7. feedback somewhat tissues are These of puberty healthy or FT4 and TSH, serum T4 T3 administration or (contra- during [5]. subjects racial varia- pregnancy which by en- reduces suppression TSH not Somatostatin reverse function with aging.a with caloric CIRCADIAN sensitivity There and in release. usually AND SEASONAL is a clear the daytime, before sleep f9-1l/. and increase Amounts of concentrations in 98 healthy 8) and decline and TRH fasting is in rats, does not [8/. T4 and FT4 in association of healthy one older in circulating in humans. studies = the deprivation significantly variation 3 summarizes n the RHYTHMS circadian in animals cohorts altered to mediating deprivation. during two as in anorexia the tone, during [8]. of the caloric contribute abolishes in TSH are not duration to caloric somatostatin decline in T4-to-T3 concentrations mechanism(s) antibody are reduction may in response levels. in peripheral restriction, The effects activities and secretion with tissue concentrations T3 prolonged secretion acute serum to the extent increased the TSH I MDI in cortisol decreased peripheral a concomitant are related of TSH suggesting type the with function, and a reduction increased clear. thyroid serum In severe nervosa, to reduce and reduced, effects trations T4 monodeiodination TBG pharma- NUTRITION tends TRH-stimulated conversion in or concentrations molecule, to TRH (negative) Decreased Decreased in thyroid circulating predominantly drug uses) hypothalamic-pituitary concentrations Table are during therapeutic INFLUENCES, reduced concentradecrease in serum indicators clinically hepatic or T4, there progressive variation thyroid-function show effects ceptive deprivation. show during concentrations cologic reduce these birth T3 concentrations. Recent [2]. However, ages thyroid 2 [7]. The thyroid There with age in Table circulating concentrations TSH are in hypothalamic-pituitary as summarized these serum modest changes metabolic of women. modestly. with [7]. In and as of rate. more but observed levels kilogram period, progressively are no changes are (per this production there utilization variety during decrease concentrations, to maximum utilization [3, 4]. T4, T3, VT4, FT5, infancy are indicators to 50 years TSH and presumably T4 utilization /6,1; other In Institute progressively matures production concentrations axis Nichols are 2 SD range. function body and TSH in the evening, decline slowly mean, adults, (67-84 children, sleep. peak serum ages 5-18 n group = concenare peak during younger years, and and nadir, one TSH concentrations years, (20-27 8) [9-11]. low shortly Table TSH and in years, TSH is Clinical Table 3. Circ adian variation TSR conc, in serum mlU/L Chemistry Mean W Children, 98 5-18 1, 1996 lutropin TSH.a (±SD) and Time Nadir Nadir Peak during 3.7 1500 2300 may 1.6 (±1.0) (±2.0) 8 1.4 (±0.4) 0.9 (±0.3) 1.94 (±0.5) 1653 0356 Adults, 67-84 8 1.01 (±0.7) 0.73 (±0.6) 1.30 (±0.9) 1611 0215 refs. Thus, and the tration [15]. of because secreted in nocturnal a pulsatile TSH quency and and basal rhythm, tyrapone TSH not increment TSH stress, of the is of the the circadian f8]. in nonthyroidal illness, syndromes states, and TSH with The serum TSH 0900 concentration. and 1600 circadian usually variation serum However, does in TSH T4 concentrations, represents (500-600 exceed has small the hourly fraction approximates the measured variation between 19-11]. The a minimal effect T4 secretion rate of the extrathyroidal change lution, but known there is There concentrations, with vs summer, variation peripheral variation in plasma concentration. winter no There values for serum significant this be on (3-5 T4 pool higher to an effect no data TSH with due to hemodi- change maintain normal increased T4 concentration in during to suggest the that be seasonally the CYCLE, is some gens reduce of -300 tg trimester. fetal T4 sex-related TSH increase TBG. are and The effects in the /8]. in when cycles tend estrogens in the production as already in phase tend excessive related to men and to have obtundation andro- estrogens there to exogenous irregular, bleeding of the in TBG during some the maternal-toT4 maternal within the some is maximal turnover normal large bioactivity. the end the time of increase a transient range produces near At is a transient (or) the placenta TSH-like it declines. and hCG of the hCG in maternal decrease first peak serum in serum TSH /15/. IMMOBILIZATION, hormonal EXERCISE, response of TRH /16, lin release, the icance cycle [13]. testing. anovulatory influence [14/. habitus, ovulatory on prolactin, AMBULATORY of the and thyroid corticotropin have thyroid in the endocrine little impact with function absence function. of TSH cortisol regard and insu- secretion. nutrition, are are secre- inhibits to training, axis aspects posture, possibly responses thyroid symnpa- corticotropin, increases The Immobilization, increased secretion is related all of the training. and epinephrine changes these involves somatotropin, vasopressin, increased and of health; exercise to exercise increased 17]. The extent state during These activity, tion The amount greater placenta concentrations concentrations the in is transient remain has which concentrations to for increase of T4, increase are pregnancy in the extrathyroidal increase However, which by the f3-endorphin, variation discussed, of the menstrual menstrual an and diurnal an magnitude reason The in STATUS is no apparent the circulating prolactin luteal and of the to reduce and increase this than pregnancy [15/. women. after The clear. concentrations of hCG, POSTURE, altered. hut there magnitude than hypothyroid, can to TRH, of TSH women than appear TSH pregnant in most lower during the (hCG) during of this degradation involved thoadrenal Additionally, responses greater menstrual that response androgens preovulatory Women, evidence difference in serum are are hypothyroidism but and transfer, probably FT4 of T4, Placental with gonadotropin an increase 14 concentrations in the T4 dosage with 12 to in serum coincident increases is not in in its after FT4 they of increase winter normative PREGNANCY the TSH utilization first concentraas a result increases concentrations. pool trimester, /8, 11, 12]. to accelerate hormone or T4 should TSH TSH may enlargement increase trimester, however, with is associated living day) Serum parallel T4 utilization concentration women trimester chorionic general, increases in women The There and necessary amounts FT4 in is minimal of cold at present the in variation T4 too, of thyroid are amount diurnal a seasonal variation, be due T4 concentration a statistically but metabolism months. in total protein may may MENSTRUAL In Serum and Serum first and fetus. per plateaus are human controls. by 2 5-50%, there the in and tg estrogen-stimulated concentrations. during rate to the [15]. first concentration and T3 nonpregnant an TBG peak Serum is the diurnal and concentrations. controlled The slightly hyperthy- poorly 10% T4 increase pg). There This not secretion since a very the [IS]. increases by an estrogen-induced and of pregnancy, first-trimester mellitus. mediated concen- iodide deficiency the in circu- TBG filtration pregnancy during of TBG of (<50 iodine concentrations on decrease, intake during increase clearance nocturnal hypercorti- gland of TBG weeks iodide are indicators change transfer iodine or relative thyroid tions total me- of in TSH concentration time of day may influence absolute synthesis can rhythm marginal sialylation night, iodothyronine of inorganic of reduced or delayed part rhythln depressive fre- of glucocorticoids diurnal hypothyroidisln, The diurnal variation ±50% (Table 3), so that tg) the manifest suprachiasmatic or early abolish cortisol is obtunded surgical diabetes and the alter central solism, late pulse the rhythm be advanced doses secretion preventing does roidism, in the and TSH in the can Pharmacologic TSH but rhythm day, increased diurnal pacemaker to light [11/. the with The circadian h by exposure inhibit is associated circadian the respectively throughout amplitude. by the nucleus, 1-2 surge pulse modulated fashion clearance glomerular and T4 effect the in of iodide areas Total transient renal increase there function cycle. the of gonadal systems, of the and women, an concentrations in because concentrations pregnant are interactions endocrine in thyroid- menstrual slightly estrogen these variations normal lating there across transient fluctuate In although hormones because 9-10. 137 surge. thyroid Peak 2.4 (±1.0) Adults, 20-27 from No. minimal Study group and age, years “Data 42, and reduced of limited by signif- to thyroid-function ambulatory significantly. Body malnutrition, also status weight are without do not and body effect 138 NACB GEOGRAPHIC The AND ENVIRONMENTAL geographic function and include earlier, the iodine detectable in large necessary to testing. also concentrations but, these again, areas in minor circulating associated iodine an increased serum T/F4 concentration concentrations, ratio, iodine-deficient in adults), there is an increased hypothyroidism, “euthyroid increased thyroid decreased total and are reduction in mean can thyroid block zymes involved effect) [19]. reduced and in the The T4 population and inversely related [18/. result hypothyroidism if the iodine likely to produce these infants are most susceptible) due to variation stuffs individual related such intake with subclinical individuals borderline iodine prevailing amount thyroid gland until phenomenon, NONTHYROIDAL Systemic are and chronic variable with are is some food- with factor and secretion, produce iodine a hyperthyroid Graves [20]. intake is not In sufficient iodine state disease such is such the increased of TBG states, referred a variety probabie of the to produce substrate in contribute The thyroid illness are the patients effects, and on the underlying infants 0-6 0-12 Children months 1-10 Adolescents/adults “From ref. be seen- or decreased these related, thyroid at least T4 have been and significantly generally pathogenetic as with secondary, euthyroid. gene glucocorticoid associated considered remain to reduce hepatic and to necrosis shown inhibit dysfunctions system in part, tumor deprivation Caloric may non- adaptive Treatment is focused disease. SURGERY, TRAUMA trauma, the ations in thyroid-function those seen excessive overt is uncommon. in dietary safe intakes illnesses, thyroid including surgery, is similar, although be rapid more the whether syndrome associated T is associated The medical illness process [20-24]. determine also indicators. in nonthyroidal is more with changes and are the recovery may studies are ongoing replacement therapy in the with trauma or surgery to pathogenesis and acute alter- similar Experimental may to low-T3 be beneficial. are References hormone 6. of iodine M, and IodIne intake, JE. Vassart Burger 2. Refetoff pg/kg per day __________ Upper HG, lism. limit S. DL. Marshall 100 WB Saunders, 15 150 Thorpe-Beeston months 7 140 function. years 3 50 4. Delange 2 30 _________ 5. regulation. JL. Loriaux 3rd ed. Philadelphia: Nicoloff In: DeGroot 30 G. Thyroid Jameson Endocrinology, iimits.a upper Recommended Age Infants secretion, [20]. Acute is provided. to as nonthyroidal alterations Dietary Infants which T4 factors thyroidal ill, diseases radiocon- (including [20J), hypersecretion [20-22]. liver can that are cytokines inhibit in areas instances that to as “Jod-Basedow,” 4. Recommended Premature suggested of interleukins 1. Dumont Table concentrations illness production expression are summarized TBG in nonthyroidal TSH in severely (amiodarone, concentrations in ILLNESSES disease associated The hypothyroidism autoimmune referred goiter, drug effects, but there availability of high-iodine deficiency of synthesis, drugs patients of T3 and certain T4 has information increased seen with there [20]. or both alterations Of amounts frequently certain serum disease concentrations, concentrations. patients serum as the is related kelp. may stimulation hyperthyroidism This and iodine effects of iodine-excess dietary and to geographic as seafood Excess of instances of T4 In TBG low and from disorder In severe and manifest is more receiving to increased Recent en- WoIff-Chaikoff is chronic. age (premature 4. Most (the the T4 [20]. high metabolism, intake inhibiting concentrations, concentrations in Table iodine a T4 illness. [20]. subjects of the disorder in TSH -30-50% serum related of the serum patients congenital and free units, low of goiter, by excess and moribund agents), Excessive TSH T4, in patients efficiency increased and trast cretinism, duration a with recover of the extent and subjects patients led to designation The rT3, in most (as to of T4 is associated in most disorder reductions care and process is reduced secretion, total intensive intake/day biosynthesis biosynthetic in amounts and be associated and a have of which FT4 related conversion clearance T4, normal syndrome.” are reduced concentrations of the illness) sick but and increased TSH. reduced TSH nature .tg of iodine hypothyroid IQ hormone can T4 and total or metabolism activity, for serum normal, serum hormone TBG total FT4 to the severity FT4 concentrations, (<50 and acute their reduced prevalence neurological transient of alter- changes areas the include degree to the prevailing iodine intake. Recommended of iodine intake are shown in Table 4 /6]. In severe normal low or I MDI of serum The (c) low, tissues, affinity a variety an increased normal peripheral (a) reduced rT; in thyroid of type in with TSH These T3 reduced in geographic ratio, ( and decreased These secretion serum [18/. areas, concentrations, T3/T4 increased to goiter geographic to include: serum changes an inhibition thyroid serum intake indicators. inorganic for in normative vs colder of iodine are uptake, It is not 20]. These increased T4; The in extent. goiter iodine are [19, (b) serum function in degree. variations FT4; As mentioned thyroid modest thyroid calibrators be minor thyroid-function tendency are concentrations of endemic on in tropical are Subthreshold hut influencing temperature. winter/summer may TSH/FT4 ations and effects develop There factors intake studies metabolism INFLUENCES environment winter/summer Symposium iT. U, F, Fisher iC, WB Saunders, HG, Endocrinology, and Jameson 3rd U, Besser et al., eds. 1995:543-59. transport M, Burger eds. Marshall hormone Besser JC, et al., Thyroid Thyroid In: DeGroot DL, ed. metabo- JL, Loriaux Philadelphia: 1995:560-82. JG, Nicolaides KH, McGregor AM. Fetal thyroid 1992;2:207-17. DA. The thyroid pediatric endocrinology, 1995:397-433. Nelson JC, Clark Si, 3rd Borut DL, gland. ed. Tomei In: Brook Oxford: RT, CGD, Blackwell Canton El. ed. Clinical Scientific, Age related Clinical changes cence. in serum I Pediatr free during F. Thyroid brain entific, hormone development. 7. Solomon DH. Effect Wu SY, ed. Thyroid 8. during childhood and 16. adoles- and iodine requirements in MF. of aging on thyroid hormone metabolism. hormone metabolism. Oxford: Blackwell Neuroendocnine LE, Utiger Braverman control RD. eds. of thyrotropin The thyroid, secretion. In: 11. secretion 1989:69:177-85. Van Cauter E, Turek In: DeGroot Marshall 12. in healthy U, FW. Besser JC, et al., eds. elderly men. Endocrine M, and Burger HG, Endocrinol other biological Jameson Loriaux 3rd ed. Philadelphia: Endocrinology, 18. Beck 14. 15. 19. Fawcett DM, phases of the Morcos F. Thyroid menstrual cycle and function studies in women receiving function. GN, Fisher N EngI DA, I Med Larsen PR. 1994;331:1072-8. Maternal and fetal thyroid Integrated endocrine M, Burger eds. responses responses and HG, lameson to IL, exercise. exercise. Loriaux De- In: DL, Marshall 3rd ed. Philadelphia: Endocrinology, Medeiros-Neto G. M, Burger Iodine deficiency HG, lameson Endocrinology, Roti 3rd E, Vagenakis WB Saunders, disorders. In: DeGroot IL, Loniaux DL, Marshall ed. 21. AG. Effect LE, Utiger JB Lippincott, Philadelphia: WB Nicoloff U, IC, et al., Saunders, 1995: iodide: clinical aspects. In: 6th ed. Philadelphia: 1991:390-402. IT, Besser LoPresti M, Burger eds. of excess RD, eds. The thyroid. II. Nonthyroidal illness Endocr Care: in press. Chopra IS. syndrome Nonthyroidal HG, lameson Endocrinology, 3rd ed. IL, or euthyroid illnesses. Loniaux Philadelphia: sick syn- In: DeGroot U, DL, Marshall WB IC, et al., Saunders, 1995: 665-75. 22. Van der mann hormone in 23. Heyden G, Physiol RP, neuroendocrine Sci 1986:8:3-17. Besser Braverman WB norethindrone with or without estrogen. Am I Obstet Gynecol 1972:112:369-73. Thomas R, Reid RL. Thyroid disease and reproductive dysfunction: a review. Obstet Gynecol 1987;70:789-98. Burrow H. U, drome. DL, Autonomic 821-33. 20. Saunders, 1995:2487-548. Konno N, Monikawa K. Seasonal variation of serum thyrotropin concentration and thyrotropin response to thyrotropin-releasing hormone in patients with primary hypothyroidism on constant replacement dosage of thyroxine. I Clin Endocninol Metab 1982; different Galbo eds. 54:1118-24. 13. I Sports 1995:2692-701. rhythms. IL, H. Scand Besser Metab 139 Galbo IC, et al., 6th ed. 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