Medicinski glasnik 43 - sve.indd

Jelica Bjeki -Macut *,1Božo Trbojevi

U ESTALOST DRUGIH ENDOKRINIH POREME AJA U HIPOTIROIDIZMU

Sažetak: Hipotiroidizam predstavlja stanje snižene proizvodnje, po-reme ene raspodele ili izostanka dejstva tiroidnih hormona. Klini ka dijagnoza hipotiroidizma nije uvek jednostavna zbog nespeci nosti klini kih manifestacija. Odre ivanje TSH u serumu predstavlja test prve linije za dijagnozu hipotiroidizma. Cilj rada je bio da se utvrdi prisustvo drugih endokrinih oboljenja i poreme aja u bolesnika sa supklini kom (nivo TSH od 5 do 10 mIU/l) ili klini kom (TSH ve i od 10 mIU/l) formom hipotiroidizma. Analizirano je 50 bolesnika (35 sa klini kom hipotireozom i 15 sa supklini kom formom bolesti). Kod svih bolesnika su utvr eni antropometrijski podaci (starost, pol, telesna težina i visina, indeks telesne mase, arterijski krvni pritisak i puls) i klini ki znaci hi-potireoze (kožne promene, poreme aj menstrualnog ciklusa). Iz uzorka krvi na tašte odre ivani su FT4, sTSH, glikemija, lipidi, jonizovani kalcijum, PTH, kortizol, ACTH, prolaktin, gonadotropini, estradiol u žena u reproduktivnom periodu i testosteron kod muškaraca. Kožne promene bile su retko zastupljene. Oligomenoreja je bila eš e prisutna u supklini koj hipotireozi, a menopauza u klini koj formi bolesti. Vrednosti krvnog pritiska su bile normalne kod svih bolesnika. Kod bolesnika sa klini kom hipotireozom u odnosu na bolesnike sa supklini kom formom bile su više vrednosti TSH (19.5 ± 5.7 vs. 5.9 ± 0.3 mIU/l) i viša doza primenjivanog L-tiroksina (81.2 ± 4.6 vs. 21.4 ± 3.5 mg/dan). Poreme aj glikoregulacije bio je prisutan kod 18% bolesnika. Ukupni holesterol i LDL je bio statisti ki nezna ajno viši kod bolesnika sa hipotiroidizmom u odnosu na supklini ku formu bolesti, dok se vrednosti FT4, kalcijuma, PTH, kortizola, ACTH, gonadotropina, estradiola i testosterona nisu ra-zlikovale me u grupama. Ukazano je na proaterogenu povezanost nivoa estradiola i triglicedira kod žena sa klini kom formom bolesti.Klju ne re i: hipotireoza, supklini ka hipotireoza, TSH, FT4, endokrini poreme aji.

* Mr sc. med dr Jelica Bjeki -Macut, endokrinolog, KBC „Bežanijska kosa“, Autoput bb, 11080 Beograd; e-mail: [email protected]

30 MEDICINSKI GLASNIK / str. 29-41

Uvod

Hipotiroidizam je stanje nastalo zbog snižene proizvodnje, poreme ene raspo-dele ili izostanka dejstva tiroidnih hormona (1). Hipotiroidizam se može pojaviti od intrauterinog perioda pa do dubokog senijuma, i to kao supklini ki ili blagi, i klini ki ili manifestni hipotiroidizam (1, 2). Nedavne skandinavske studije su ukazale da se incidenca manifestnog hipotiroidizma kre e od 32 do 156/100.000 bolesnika-godina u zavisnosti od zemlje i starosne dobi ispitanika (3). Za razliku od klini ki mani-festnog hipotiroidizma, prevalenca supklini kog hipotiroidizma iznosi 4 do 8.5%, sa porastom do 20% kod žena starijih od 60 godina (4). Studija Dieza i Iglesiasa je analizirala tok supklini kog hipotiroidizma i pokazala da kod 26.8% bolesnika dolazi do razvoja manifestnog hipotiroidizma, dok je kod 37.4% bolesnika došlo do normalizacije TSH (5).

Hroni ni autoimunski tiroiditis ili Hashimotov tiroiditis predstavlja danas naj-eš i uzrok ste enog hipotiroidizma. Bolest je preko sedam puta eš a u žena nego u

muškaraca, i sa incidencom koja raste sa staroš u. Bolest ima nasledni karakter ija priroda još uvek nije rasvetljena (6).

Dok u klini koj hipotireozi, pored postojanja znakova i simptoma bolesti, postoji pove an TSH i sniženi tiroksin (T4) i trijodtironin (T3), supklini ka hi-potireoza se karakteriše pove anom koncentracijom TSH uz normalan ukupni ili slobodni T4 i T3. Zbog toga jasno proisti e da TSH predstavlja osnovu za dija-gnozu supklini ke hipotireoze. Populacione studije su pokazale da se uobi ajeni referentni opseg za TSH kre e od 0.4 do 4 mU/l (7), dok neki autori smatraju da gornja granica referentne koncentracije serumskog TSH ne treba da prelazi 2.5 mU/l (8).

Poreme aji metabolizma lipida predstavljaju zna ajnu posledicu hipotireoze. Pokazano je da u supklini koj hipotireozi supstitucija tiroksinom smanjuje ukupan holesterol i LDL holesterol, a da ne uti e na HDL holesterol i trigliceride. Smatra se da je nivo TSH ve i od 10 mU/l udružen sa neželjenim efektima na metabolizam lipida, što nije jasno pokazano za nivo TSH izme u 4 i 10 mU/l (4, 9). Poreme aji elektrolita u hipotiroidizmu su esti ali obi no blagi. Naj eš e zapaženi poreme aj elektrolita u hipotiroidizmu je hiponatremija u kojoj poreme aj ekskrecije vode ispoljava primarne efekte nedostatka tiroidnih hormona na bubrežnu i hipo znu funkciju (2). Poznato je da kod bolesnika sa hipotiroidizmom postoji ošte en odgovor kortizola tokom testa insulinske hipoglikemije (10). Kod žena hipotiroidizam može biti udružen sa ovula-tornom disfunkcijom (11), a kod muškaraca može da uzrokuje erektilnu disfunkciju i gubitak libida (12).

Uzimaju i u obzir navedene injenice o važnosti tiroidnih hormona u metabo-li kim procesima i ulozi u funkcionisanju endokrinih osovina, cilj ovog rada je bio da se utvrdi prisustvo drugih endokrinih poreme aja u bolesnika sa supklini kom ili klini kom formom hipotiroidizma.

31U ESTALOST DRUGIH ENDOKRINIH POREME AJA U HIPOTIROIDIZMU

Materijal i metode

Klini ke karakteristike grupe ispitanika

Studijom je obuhva eno 50 bolesnika koji su se javili na ambulantni endokrino-loški pregled u Klini ko-bolni ki centar „Bežanijska kosa”. Bolesnici su upu ivani na pregled zbog sumnje na postojanje supklini kog ili klini kog hipotiroidizma, ili zbog potrebe redovne kontrole i uskla ivanja terapije ve postoje eg supklini kog ili klini kog hipotiroidizma.

Za de nisanje supklini kog hipotiroidizma je, uz prisustvo klini kih znakova i simptoma, koriš en nivo TSH od 5 do 10 mIU/l. U de nisanju klini kog hipotiroid-izma služio je nivo TSH ve i od 10 mIU/l.

Kod svih ispitanika su utvr ivani podaci o polu, starosti, telesnoj težini, telesnoj visini, izra unavan indeks telesne mase (ITM), odre ivane vrednosti sistolnog i dija-stolnog arterijskog krvnog pritiska (sistolni KP i dijastolni KP) u sede em položaju na nivou kubitalne fose, i odre ivan puls. Od klini kih karakteristika hipotiroidizma, pra eno je da li su prisutne promene na koži (suvo a, promena turgora ili elasticite-ta), a kod žena izmene u menstrualnoj regularnosti (oligomenoreja ili amenoreja) ili menopauza.

Odre ivanje biohemijskih i hormonskih parametara

Kod svih bolesnika su iz uzorka krvi na tašte odre ivani biohemijski i hormon-ski parametri. Glikemija (mmol/l) je odre ivana enzimskim UV testom (metod sa heksokinazom), proizvo a a Beckman, SAD. Holesterol (mmol/l), HDL holesterol (mmol/l) i trigliceridi (mmol/l) su odre ivani enzimskim kolor testom proizvo a a Beckman, SAD. LDL holesterol (mmol/l) je odre ivan kalkulacijskom metodom po Friedwald-u. Jonizovani kalcijum (mmol/l) je odre ivan upotrebom jon se-lektivne elektrode, AVL 9180 Electrolyte Analyzer proizvo a a Roche-Diamond Diagnostics, Nema ka. FT4 (pmol/l), antimikrozomalna antitela (anti TPO At, IU/l), antitireoglobulinska antitela (anti Tg At, IU/l), PTH (pg/ml) i testosteron (ng/ml) su odre ivani metodom elektrohemiluminiscencije proizvo a a Roche, Nema ka. TSH (mIU/l), kortizol (nmol/l), ACTH (pg/ml), FSH (mIU/l), LH (mIU/l), prolaktin (mIU/l), C-peptid (ng/ml), insulin (IU/ml) i estradiol (pg/ml) su odre ivani metodom elektrohemiluminiscencije proizvo a a DPC-Siemens, Germany. Antiovarijalna antitela (IU/ml) su odre ivana ELISA metodom proizvo a a Bioserv Diagnostics, Nema ka.

U proceni glikemijskog statusa u injena je kategorizacija glikemije na vrednosti izme u 6.0 i 6.9 mmol/l, i preko 7.0 mmol/l. U proceni insulinske osetljivosti koriš en je homeostatski model ili HOMA indeks, koji je izra unavan iz vrednosti insulina i glikemije (13).


Statisti ka analiza

Sva izra unavanja su ura ena uz pomo standardnog programskog paketa SPSS (v.10.0.1) na personalnom ra unaru. Kontinuirane varijable su prezentovane kao srednja vrednost ± standardna greška (standard error, SE) u tekstu i u tabelama. U statisti koj analizi podataka koriš en je t-test, ANOVA i Spearman-ov koe cijent korelacije za kvanti kovanje korelacija me u varijablama. Statisti ki zna ajnom je smatrana vrednost P < 0.05.

Table 1. Biochemical and hormonal characteristics of the whole group of patients and related to the type of hypothyroidism

Whole groupSubclinical

hypothyreosis (n=15)

Clinical hypothyreosis

(n=35)

P (subclinical vs. clinical

hypothyreosis)

Age (years) 53.4 ± 2.2 48.2 ± 5.0 55.7 ± 2.2 0.114

Weight (kg) 79.2 ± 2.6 79.3 ± 6.3 79.2 ± 2.7 0.982

BMI (kg/m2) 28.8 ± 0.8 28.0 ± 1.9 29.2 ± 0.9 0.569

Systolic BP(mmHg) 127.2 ± 2.4 125.0 ± 5.8 128.0 ± 2.5 0.581

Diastolic BP(mmHg) 80.9 ± 1.1 79.6 ± 2.3 81.4 ± 1.3 0.482

Puls (heart beats per min) 68.6 ± 1.7 71.1 ± 3.6 67.6 ± 1.9 0.363

Dose L-thyroxin ( g/day) 70.8 ± 5.3 21.4 ± 3.5 81.2 ± 4.6 <0.0001





(n=35)

P (subclinical vs. clinical hypothyreosis)

Glucose 5.7 ± 0.2 5.6 ± 0.3 5.8 ± 0.3 0.716Cholesterol 6.1 ± 0.2 5.4 ± 0.3 6.5 ± 0.3 0.077HDL cholesterol 1.3 ± 0.05 1.3 ± 0.08 1.3 ± 0.07 0.720LDL cholesterol 4.0 ± 0.2 3.5 ± 0.3 4.3 ± 0.3 0.107Triglycerides 1.6 ± 0.1 1.5 ± 0.2 1.6 ± 0.1 0.718Ionized calcium 1.18 ± 0.007 1.16 ± 0.01 1.19 ± 0.007 0.103FT4 13.7 ± 0.7 14.2 ± 0.6 13.4 ± 1.0 0.640sTSH 15.2 ± 4.0 5.9 ± 0.3 19.5 ± 5.7 0.118Anti TPO At 522.4 ± 123.4 346.8 ± 88.3 596.9 ± 171.0 0.360Anti Tg At 1067.9 ± 345.8 702.4 ± 362.8 1250.7 ± 486.8 0.462Cortisol 462.5 ± 20.7 481.8 ± 47.2 454.5 ± 22.3 0.556





(n=35)

P (subclinical vs. clinical hypothyreosis)

ACTH 28.0 ± 2.2 35.0 ± 6.0 25.4 ± 1.9 0.057FSH 6.7 ± 1.1 6.7 ± 2.0 6.7 ± 1.3 0.993LH 6.4 ± 1.4 7.9 ± 2.8 4.9 ± 0.9 0.332PTH 48.1 ± 2.5 41.7 ± 3.6 51.2 ± 3.1 0.073Prolactin 273.2 ± 15.5 310.5 ± 33.2 255.2 ± 15.9 0.096Insulin 9.2 ± 1.1 12.7 ± 3.2 7.7 ± 0.7 0.044C-peptid 0.9 ± 0.08 0.9 ± 0.09 1.0 ± 0.1 0.766HOMA 2.6 ± 0.3 3.3 ± 0.9 2.2 ± 0.3 0.203Estradiol 18.4 ± 3.3 13.4 ± 11.5 20.9 ± 0.3 0.351Testosterone 5.7 ± 1.0 5.5 ± 2.5 5.9 ± 0.3 0.873Antiovarian At 0.8 ± 0.1 0.6 ± 0.2 0.8 ± 0.1 0.368

Rezultati

Klini ke karakteristike ispitivane grupe bolesnika

Od 50 ispitanika u studiji, 6 (12%) su bili muškarci, a 44 (88%) žene. Kod 15 (30%) bolesnika je postojao supklini ki hipotireoidizam, a kod 35 (70%) je bio ispoljen klini ki hipotiroidizam. Od svih analiziranih bolesnika sa hipotiroidizmom, 7 (20%) je bilo klini ki novodijagnostikovanih, a 12 (34.2%) su bili bolesnici sa hipotiroidizmom nakon u injene totalne tiroidektomije.

Od ukupnog broja analiziranih bolesnika, kod 10 (20%) su postojale promene na koži tipi ne za hipotiroidizam. Od ukupnog broja žena, uredan menstrualni ciklus je imalo 7 (14%), neurednost menstrualnog ciklusa 5 (10%), dok su 32 žene (64%) bile u menopauzi. Kada je izvršena analiza ispitivane grupe prema tipu distiroidiz-ma, promene na koži su na ene kod jednog bolesnika (6.7%) u podgrupi bolesnika sa supklini kom hipotireozom i kod 9 bolesnika (25.7%) u podgrupi bolesnika sa hipotiroidizmom. Kada je analizirana izmenjenost menstrualnog ciklusa, u pod-grupi žena sa supklini kim hipotiroidizmom, dve bolesnice (13.3%) su ispoljile neurednost menstrualnog ciklusa (oligomenoreja), a 6 (40%) je bilo u menopauzi, dok je u podgrupi sa klini kim hipotiroidizmom kod dve bolesnice (5.7%) postojala neurednost menstrualnog ciklusa (oligomenoreja), a da je 26 bolesnica (74.3%) bilo u menopauzi.

Antropometrijske karakteristike cele grupe bolesnika, kao i u odnosu na tip hipotiroidizma, prikazane su na tabeli 1. Prikazane doze L-tiroksina u tabeli se kod bolesnika sa supklini kom hipotireozom odnose na dozu leka pri uvo enju terapije, dok je za bolesnike sa klini kom formom bolesti to bila trenutna doza leka. Kod supklini ke forme bolesti inicijalni terapijski pristup je podrazumevao samo pra enje bolesnika ili primenu malih doza L-tiroksina (12.5 do 25 mg). Odluka o jednom ili


drugom terapijskom pristupu je donošena individualno. Kod klini ke forme bolesti raspon terapijskih doza primenjenog L-tiroksina se kretao od 25 do 150 mg.

Metaboli ke karakteristike ispitivanih bolesnika

Biohemijske i hormonske karakteristike cele grupe bolesnika, i u odnosu na tip hipotiroidizma, prikazane su na tabeli 2. Podaci za FSH, LH i estradiol se odnose na žene u reproduktivnom periodu.

Prema u injenoj kategorizaciji vrednosti glikemije, u celoj grupi bolesnika njih pet (10%) je imalo vrednosti glikemije izme u 6.0 i 6.9 mmol/l, dok je etvoro (8%) imalo vrednosti glikemije preko 7.0 mmol/l, odnosno vrednosti koje se mogu karak-terisati kao glukozna intolerancija ili dijabetes; kod jednog pacijenta zabeležena je vrednost glikemije na tašte od 11.7 mmol/l.

Korelacije u podgrupama bolesnika prema tipu hipotiroidizma

U podgrupi bolesnika sa supklini kim hipotiroidizmom dobijena je zna ajna pozitivna korelacija izme u starosti bolesnika i ukupnog holesterola (r=0.58, p=0.029) i ACTH (r=0.58, p=0.048); ITM i HOMA (r=0.64, p=0.023); dijastolnog KP i PTH (r=0.64, p=0.032); glikemije i ACTH (r=0.64, p=0.023); FT4 i testosterona (r=0.78, p=0.021); testosterona i pulsa (r=0.86, p=0.012), testosterona i HOMA (r=0.93, p=0.002).

U podgrupi bolesnika sa klini kim hipotiroidizmom dobijena je zna ajna pozitiv-na korelacija izme u ITM i dijastolnog KP (r=0.42, p=0.020), ITM i glikemije (r=0.40, p=0.032), ITM i triglicerida (r=0.58, p=0.002), ITM i insulina (r=0.69, p<0.0001), ITM i HOMA (r=0.78, p<0.0001); glikemije i triglicerida (r=0.57, p=0.001); triglicerida i HOMA (r=0.53, p=0.006); kortizola i ukupnog holesterola (r=0.51, p=0.004). Zna-ajna negativna korelacija je dobijena izme u ukupnog holesterola i pulsa (r=-0.36,

p=0.049); HDL holesterola i glikemije (r=-0.57, p=0.001); triglicerida i estradiola (r=-0.911, p=0.009); FT4 i TSH (r=-0.82, p<0.0001) i FT4 i anti TPO At (r=-0.42, p=0.027); TSH i pulsa (r=-0.39, p=0.041).

Diskusija

Nekoliko studija sprovedenih u Evropskim zemljama sa dovoljnim unosom joda je pokazalo postojanje i do 7 puta eš eg hipotiroidizma kod žena (14–17). Kada se posmatra incidenca hipotiroidizma izme u regiona iste zemlje, pokazano je da se ona može znatno razlikovati usled razli itosti u unosu joda (3). S obzirom na to da su naši pacijenti bili u komparabilnom opsegu godina sa navedenim studijama,


možemo zaklju iti da je i kod nas postojala sli na zastupljenost hipotiroidizma po polu. Pored toga što je naša grupa bolesnika bila mala, ograni enja studije se odnose na nepostojanje podataka o jodnom unosu.

Retke promene na koži kod naših ispitanika mogu se objasniti blagom disfunkci-jom tiroideje u slu aju supklini ke forme bolesti, odnosno ve le enim hipotiroidnim stanjem kod klini ke forme bolesti ili nedavno u injenim hirurškim odstranjenjem štitaste žlezde, a gde se znaci na koži još nisu razvili.

Kod žena u reproduktivnom periodu hipotiroidizam dovodi do promena u dužini menstrualnog ciklusa i koli ini menstrualnog krvarenja. Promena u koli ini men-strualnog krvarenja je verovatno uzrokovana estrogenskim probojnim krvarenjem, koje je sekundarno u odnosu na anovulaciju. Neregularnosti menstrualnog ciklusa u hipotiroidizmu mogu doprineti defekti u hemostazi, kao što je snižen nivo faktora VII, VIII, IX i XI (18). Za razliku od ranijih studija koje su ukazivale da se poreme aj menstrualnog ciklusa ispoljava u 56–80% žena (19, 20), istraživanja gr kih autora su ukazala da kod 23.4% hipotiroidnih žena postoji iregularnost menstrualnog ciklusa, od kojih 42.5% imaju oligomenoreju kao i da su poreme aji menstrualnog ciklusa kod hipotiroidnih bolesnica bili 3 puta eš i u odnosu na opštu populaciju (21). U objašnjenju ovako velikih razlika u obzir su uzeti genetski i drugi faktori izme u ispitivanih populacija ili kasnija dijagnoza hipotiroidizma (18). U naših ispitanica sa supklini kom i klini kom formom bolesti, oligomenoreja je bila re e zastupljena (13.3% i 5.7%).

Hipertenzija je zna ajno eš a u hipotiroidnih bolesnika u odnosu na eutiroidne osobe (14.8 vs. 5.5%) (22). Pokazano je da kod žena sa supklini kom formom bolesti postoje više vrednosti i sistolnog i dijastolnog krvnog pritiska u odnosu na eutiro-idne kontrolne žene (23). Potencijalni mehanizmi, koji bi mogli objasniti nastanak hipertenzije u hipotiroidizmu uklju uju pove anje periferne vaskularne rezistencije i vaskularne krutosti (24), odsustvo vazodilatatornog efekta T3 na glatke miši e krvnog suda (25) ili postojanje višeg nivoa cirkulišu eg noradrenalina i smanjenog broja beta-adrenergi kih receptora (22). De cit tiroidnih hormona može biti udružen sa sniženjem stope glomerulske ltracije i protoka krvi kroz bubrege (26). Kona no, pokazano je da hipotiroidne osobe imaju esto pove anu telesnu masu ili su gojazne, što dovodi do povišenog krvnog pritiska i pove anog kardiovaskularnog rizika (27). Vrednosti sistolnog i dijastolnog arterijskog krvnog pritiska u naših bolesnika su se kretale u rasponu normalnih vrednosti i nisu se razlikovale izme u posmatranih podgrupa bolesnika. Me utim, ovakav na in procene krvnog pritiska ne predstavlja prose no dnevno kretanje pritiska i njegove mogu e promene u hipotiroidizmu, zbog ega bi postojala potreba za detaljnijom analizom diurnalnog kretanja krvnog pritiska

u bolesnika sa hipotiroidizmom. Prose ne vrednosti TSH bile su više kod naših bolesnika sa klini kom hipo-

tireozom u odnosu na bolesnike sa supklini kom formom (19.5 ± 5.7 vs. 5.9 ± 0.3 mIU/l) ali bez postizanja statisti ke zna ajnosti. Dobijene više vrednosti TSH kod


bolesnika sa klini kom hipotireozom odražavaju visoke vrednosti kod novootkri-venih, a nesupstituisanih bolesnika, ili nezadovoljavaju u supstituciju bolesnika sa ve ustanovljenim hipotiroidizmom. Kod 70–80% zdravih osoba nivo TSH se nalazi izme u 0.3 i 2 mIU/l, a u 97% slu ajeva on iznosi manje od 5.0 mU/l. Ako se iz opšte populacije stanovništva izuzmu osobe s pove anim nivoima antitiroidnih antitela, ispostavlja se da u 95% osoba nivo TSH nije ve i od 2.5 do 3.0 mIU/l (28). Bez razlike koji gornji limit normale odaberemo, može se re i da je potrebno pažljivije pra enje osoba sa nivoom TSH od 3 do 5 mIU/l, posebno ukoliko postoje i pozitivna antitiroidna antitela. Kod osoba starijih od 70 godina, vrednosti TSH do 6.0 ili ak 7.0 mIU/l, u odsustvu antitiroidnih antitela, ne bi trebalo da budu kriterijum za dijagnozu hipotiroidizma (29). Kod naših bolesnika sa supklini kim hipotiroidizmom, TSH se kretao izme u 5 i 6 mIU/l, što predstavlja grani ne biohemijske kriterijume za ocenu postojanja disfunkcije tiroideje.

Doza primenjivanog L-tiroksina zna ajno se razlikovala izme u naših bolesnika sa supklini kom i klini kom hipotireozom (21.4 ± 3.5 vs. 81.2 ± 4.6 mg/dan). Prose -no primenjivana doza L-tiroksina kod naših bolesnika sa klini kim hipotiroidizmom iznosila je 1.6 mg/kg telesne težine i odgovarala je preporu enim dozama za starost bolesnika (28). Kod supklini ke forme bolesti se u svakom slu aju preporu uje uvo-enje levotiroksina u malim dozama, po evši sa 25 mg dnevno uz kontrolu TSH posle

8 nedelja i zatim prilago avanjem doze. Neki autori smatraju da se, zbog o ekivane progresije tiroidne slabosti, ve na po etku može primeniti puna terapija nadoknade od 50 do 75 mg dnevno. Kod mla ih osoba se zadovoljavaju im smatra postizanje ciljnog TSH u opsegu od 0.3 do 3.0 mIU/l. Nakon postizanja ovih ciljnih vrednosti TSH, naredne kontrole se odre uju za 6 i 12 meseci (30).

Vrednosti bazalne glikemije za celu grupu, i kada su pacijenti analizirani prema podgrupama, kretale su se u opsegu normalnih vrednosti i nije bilo razlike izme u grupa. Me utim, u injena kategorizacija vrednosti glikemije je ukazala da kod na-ših bolesnika postoji zna ajno prisustvo glukoznih poreme aja. Tiroidna bolest je esto pridružena tipu 1 i tipu 2 dijabetesa sa prevalencom od 10 do 15%. Pokazano

je da snižene vrednosti tiroidnih hormona poboljšavaju insulinom posredovanu raspoloživost glukoze (31). Tako e, pokazano je da bolesnici sa supklini kim hipotiroidizmom i tipom 2 dijabetesa nisu imali eš e ispoljenu dislipidemiju ili koronarnu sr anu bolest (32), kao i da nemaju pove an kardiovaskularni mortalitet u odnosu na bolesnike sa tipom 2 dijabetesa bez supklini kog hipotiroidizma (33). Nedavno je ukazano da supklini ki hipotiroidizam može delovati na smanjenje nekardiovaskularnog mortaliteta u tipu 2 dijabetesa (33). Poreme aj glikoregulacije kod naših bolesnika može se objasniti pove anim indeksom telesne mase i posle-di nom insulinskom rezistencijom.

Hipotireoza spada me u naj eš e uzro nike nastanka sekundarne dislipidemije, koja se karakteriše pove anim nivoom holesterola, LDL holesterola, apolipoproteina B, lipoproteina (a) ili triglicerida. Tromsø studija je pokazala udruženost nivoa TSH,


ukupnog holesterola i LDL holesterola, kao i sniženje lipida na primenu levotiroksina u hipotiroidnih bolesnika (34). ini se da je efekat supstitucije tiroksinom zna ajan samo u osoba koje imaju koncentraciju TSH preko 10 mIU/l (35). Roterdamska stu-dija je ukazala da supklini ka forma bolesti predstavlja indikator rizika za nastanak ateroskleroze i infarkta miokarda kod starijih žena (36). Supklini ka hipotireoza je udružena sa kongestivnim popuštanjem srca (37), ali nije pokazana uzro na povezanost sa nastankom cerebrovaskularnog insulta kod ovih bolesnika (38). U naših bolesnika vrednosti ukupnog holesterola i LDL holesterola bile su više u podgrupi sa hipotiroi-dizmom, dok se vrednosti HDL holesterola i triglicerida nisu razlikovale izme u pod-grupa bolesnika. Analiza odnosa pojedinih lipida ili lipidnih frakcija i drugih klini kih pokazatelja potvrdila je postojanje poznatog uticaja starosti na nastanak dislipidemije, kao i povezanost telesnog sastava, glikoregulacije i dislipidemije (39, 40).

Vrednosti jonizovanog kalcijuma i paratiroidnog hormona u našoj studiji su bile u opsegu normalnih vrednosti kod obe podgrupe bolesnika. Dobijeni rezultati su u saglasnosti sa nalazima drugih autora koji govore da se markeri formiranja i resorpcije kosti kod hipotiroidnih bolesnika, ak i tokom supstitucije tiroksinom, ne razlikuju od eutiroidnih kontrola (41).

Poznato je da tiroidni hormoni u estvuju u regulaciji hipotalamo-hipo zno-adrenalne osovine. Kao što je ranije pomenuto, u hipotiroidizmu postoji ošte en odgovor kortizola tokom ITT-a (10). Tako e, postoji snižen odgovor kortikosterona na oslobo eni ACTH tokom stimulacije kortikotropin-osloba aju im hormonom u hipotiroidnih pacova (42). Me utim, kod bolesnika sa primarnim hipotiroidizmom nije pokazana izmenjena funkcija adrenalne osovine (43). U naših ispitanika nije bilo razlika u vrednostima jutarnjeg kortizola i ACTH izme u dve analizirane grupe, ime se svakako ne može isklju iti postojanje drugih funkcionalnih poreme aja.

Pokazano je da dugotrajni hipotiroidizam može biti udružen sa ovulatornom disfunkcijom (11) i u 1 do 3% slu ajeva sa galaktorejom (44). Navedeno se objašnjava pove anom produkcijom TRH (45), smanjenim hipotalamusnim prometom dopamina (46) ili mogu im poreme ajem pulsatilnosti TSH, koji bi mogao uticati na GnRH pulsni generator i ovulatornu funkciju. Me utim, studija Bals-Pratsch i saradnika je pokazala da supklini ki hipotiroidizam ne remeti funkciju hipotalamusnog GnRH pulsnog generatora i ne menja normalan izgled LH pulseva u ranoj folikularnoj fazi. Zbog toga se smatra da žene sa supklini kim hipotiroidizmom i neke žene sa klini kim hipotiroidizmom mogu imati ovulatorne cikluse i normalnu funkciju žutog tela (47). Kod muškaraca, hipotiroidizam može da uzrokuje erektilnu disfunkciju i gubitak libida (12), kao i sniženje cirkulišu eg testosterona (48). Nedavno je pokazano da kod hipotiroidnih muškaraca sniženje serumskog testosterona može biti uzrokovano manjim preuzimanjem LDL holesterola od strane Leydigovih elija, posledi nim sniženjem sinteze progesterona i testosterona, višom stopom

konverzije testosterona u estradiol, sniženjem serumskog T3 i hiperprolaktinemi-jom (49). Kod naših hipotiroidnih pacijenata nisu dobijene razlike izme u FSH,


LH, estradiola i testosterona. Me utim, povezanost estradiola i triglicerida kod žena sa klini kom formom bolesti potvr uje postojanje proaterogenog stanja kod poreme ene tiroidne funkcije (50).

Izjava

Ovaj rad je podržalo Ministarstvo obrazovanja i nauke Republike Srbije, projekat broj 41009.

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Jelica Bjeki -Macut*,1Božo Trbojevi **

FREQUENCY OF OTHER ENDOCRINE DISORDERS IN HYPOTHYROIDISM

Abstract: Hypothyroidism is a condition of reduced production, distri-bution, or absence of action of thyroid hormones. Clinical diagnosis of hypothyroidism is not easily established due to the nonspeci c clinical manifestations. Determination of serum TSH is the rst-line test for the diagnosis of hypothyroidism. The aim of the study was to determine the presence of other endocrine disorders in patients with subclinical (TSH levels between 5 and 10 mIU/l), or clinical (TSH above 10 mIU/l) hy-pothyrodism. We analyzed 50 patients (35 with clinical hypothyroidism and 15 with subclinical form). In all patients anthropometric data (age, sex, weight, height, body mass index, blood pressure and heart rate), and clinical signs of hypothyroidism (skin changes, menstrual disorders) were determined. Blood was drawn in fasting state for measurement of FT4, sTSH, glucose, lipids, ionized calcium, PTH, cortisol, ACTH, prolactin, gonadotropins, estradiol in women of reproductive age, and testosterone in men. Skin lesions were rarely present. Oligomenorrhea was more frequent in subclinical hypothyroidism, and menopause in clinical hypothyroidism. Blood pressure was normal in all subjects. Pa-tients with clinical hypothyroidism compared to those with subclinical form had higher TSH values (19.5 ± 5.7 vs. 5.9 ± 0.3 mIU/l), and higher doses of L-thyroxine (81.2 ± 4.6 vs. 21.4 ± 3.5 g/day). Disturbance of glycemic control was present in 18% of patients. Total cholesterol and LDL were insigni cantly higher in patients with hypothyroidism than in subclinical form of the disease. FT4, calcium, PTH, cortisol, ACTH, gonadotropins, estradiol and testosterone did not differ between groups. The proatherogenic relation of estradiol with triglycerides was established in women with clinical form of hypothyroidism.

Key words: hypothyroidism, subclinical hypothyroidism, TSH, FT4, endocrine disorders

* CHC „Bežanijska kosa“, **Clinic for Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

43FREQUENCY OF OTHER ENDOCRINE DISORDERS IN HYPOTHYROIDISM

Introduction

Hypothyroidism is a condition caused by reduced production, distribution or absence of abnormal thyroid hormone action (1). Hypothyroidism can occur from the intrauterine period until old age, as a mild or subclinical and clinically manifest hypothyroidism (1, 2). Recent Scandinavian studies have shown that the incidence of manifest hypothyroidism ranges from 32 to 156/100.000 patient-years depending on country and age of the subjects (3). In contrast to clinically manifest hypothyroidism, prevalence of the subclinical hypothyroidism is 4 to 8.5% with an increase to 20% in women older than 60 years (4). Study by Diez and Iglesias analyzed the course of subclinical hypothyroidism and showed that 26.8% of patients developed manifest hypothyroidism, while 37.4% of patients normalized TSH (5).

Chronic autoimmune thyroiditis or Hashimoto’s thyroiditis is nowadays con-sidered the most common cause of acquired hypothyroidism. The disease is seven times more common in women than in men, and the incidence increases with age. The disease has a hereditary character whose nature is still not resolved (6).

While in clinical hypothyroidism signs and symptoms of the disease are associated with increased TSH and decreased thyroxine (T4) and triiodothyronine (T3), subclinical hypothyroidism is characterized by an increased concentration of TSH with normal total or free T4 and T3. Therefore, determination of TSH is fundamental for the diagnosis of subclinical hypothyroidism. Population studies have shown that normal reference range for TSH is from 0.4 to 4 mU/l (7). Some authors consider that the upper limit of the TSH concentration should not exceed 2.5 mU/l (8).

Disorders of lipid metabolism represent an important consequence of hypot-hyroidism. It is shown that substitution with levothyroxine in subclinical hypothyro-idism decreases total cholesterol and LDL cholesterol, and without affecting HDL cholesterol and triglycerides. TSH concentrations above 10 mU/l are considered to be associated with adverse effects on lipid metabolism which is not clearly shown for TSH concentrations between 4 and 10 mU/l (4, 9). Electrolyte disorders in hypot-hyroidism are common but usually mild. The most common electrolyte disorder in hypothyroidism is decrease in sodium due to the lack of thyroid hormones on renal function and pituitary, and consequent change in excretion of water (2). It is known that in patients with hypothyroidism cortisol response to hypoglycemia during insulin tolerance test is damaged (10). In women, hypothyroidism can be associated with ovulatory dysfunction (11), while in men can cause erectile dysfunction and loss of libido (12).

Considering the above facts on the importance of thyroid hormones in the me-tabolic pathways and role in the functioning of the endocrine axis, the objective of this study was to determine the presence of other endocrine disorders in patients with subclinical or clinical form of hypothyroidism.


Material and methods

Clinical characteristics of the group

We included 50 patients that were referred for the endocrine outpatient exa-mination at the Clinical Hospital Centre “Bežanijska kosa.” Patients were under observation for having subclinical or clinical hypothyroidism, or for the regular monitoring and adjustment of therapy of the preexisting subclinical or clinical hypothyroidism.

Subclinical hypothyroidism was de ned by the presence of clinical signs and symptoms, and TSH levels between 5 and 10 mIU/l. Clinical hypothyroidism was de ned by using TSH level of more than 10 mIU/l.

In all subjects we determined gender, age, body weight, body height, calculated body mass index (BMI), determined systolic and diastolic blood pressure (systolic BP and diastolic BP) at the cubital fossa while seated, and determined the pulse. We assessed if the subject had changes in the skin (dryness, change in elasticity), and in women, if there is a change in menstrual regularity (oligomenorrhea or amenorrhea) or menopause.

Determination of the biochemical and hormonal parameters

In all patients fasting blood samples were drawn for the determination of biochemical and hormonal parameters. Glucose (mmol/l) were determined by en-zymatic UV test (hexokinase method), manufacturer Beckman, USA. Cholesterol (mmol/l), HDL cholesterol (mmol/l) and triglycerides (mmol/l) were determined by enzymatic color test, manufacturer Beckman, USA. LDL cholesterol (mmol/l) was calculated using Friedwald formula. Ionized calcium (mmol/l) was determined using the ion selective electrode, AVL 9180 Electrolyte Analyzer Roche-Diamond Diagnostics, Germany. FT4 (pmol/l), anti-microsomal antibodies (anti-TPO At, IU/l), anti-tireoglobulin antibodies (anti Tg At, IU/l), PTH (pg/ml) and testosterone (ng/ml) were determined using Roche electro-chemiluminiscence method, Germany. TSH (mIU/l), cortisol (nmol/l), ACTH (pg/ml), FSH (mIU/l), LH (mIU/l), prolactin (mIU/l), C-peptide (ng/ml), insulin ( IU/l) and estradiol (pg/ml) were determined using electro-chemiluminiscence method, DPC-Siemens, Germany. Antiovarian antibodies (IU/ml) were determined using ELISA method, Bioserv Diagnostics, Germany.

In the assessment of glycemic status, we performed categorization of fasting blood glucose on values between 6.0 and 6.9 mmol/l, and more than 7.0 mmol/l. The assessment of insulin sensitivity was performed using homeostatic model assessment or HOMA index that was calculated from the values of insulin and glucose (13).


Statistical analyzes

All calculations were performed using a standard software package SPSS (v.10.0.1) on a personal computer. In the text and tables continuous variables are pre-sented as mean ± standard error (standard error, SE). In the statistical analysis of data, we used t-test, ANOVA and Spearman’s correlation coef cient for the quanti cation of the correlations between variables. Statistically signi cant was considered P<0.05.





(n=35)


hypothyreosis)

Age (years) 53.4 ± 2.2 48.2 ± 5.0 55.7 ± 2.2 0.114

Weight (kg) 79.2 ± 2.6 79.3 ± 6.3 79.2 ± 2.7 0.982

BMI (kg/m2) 28.8 ± 0.8 28.0 ± 1.9 29.2 ± 0.9 0.569

Systolic BP(mmHg) 127.2 ± 2.4 125.0 ± 5.8 128.0 ± 2.5 0.581

Diastolic BP(mmHg) 80.9 ± 1.1 79.6 ± 2.3 81.4 ± 1.3 0.482

Puls (heart beats per min) 68.6 ± 1.7 71.1 ± 3.6 67.6 ± 1.9 0.363

Dose L-thyroxin ( g/day) 70.8 ± 5.3 21.4 ± 3.5 81.2 ± 4.6 <0.0001


Whole group Subclinical hypothyreosis (n=15)


(n=35)


hypothyreosis)

Glucose 5.7 ± 0.2 5.6 ± 0.3 5.8 ± 0.3 0.716Cholesterol 6.1 ± 0.2 5.4 ± 0.3 6.5 ± 0.3 0.077HDL cholesterol 1.3 ± 0.05 1.3 ± 0.08 1.3 ± 0.07 0.720LDL cholesterol 4.0 ± 0.2 3.5 ± 0.3 4.3 ± 0.3 0.107Triglycerides 1.6 ± 0.1 1.5 ± 0.2 1.6 ± 0.1 0.718Ionized calcium 1.18 ± 0.007 1.16 ± 0.01 1.19 ± 0.007 0.103FT4 13.7 ± 0.7 14.2 ± 0.6 13.4 ± 1.0 0.640sTSH 15.2 ± 4.0 5.9 ± 0.3 19.5 ± 5.7 0.118Anti TPO At 522.4 ± 123.4 346.8 ± 88.3 596.9 ± 171.0 0.360Anti Tg At 1067.9 ± 345.8 702.4 ± 362.8 1250.7 ± 486.8 0.462Cortisol 462.5 ± 20.7 481.8 ± 47.2 454.5 ± 22.3 0.556ACTH 28.0 ± 2.2 35.0 ± 6.0 25.4 ± 1.9 0.057


Whole group Subclinical hypothyreosis (n=15)


(n=35)


hypothyreosis)

FSH 6.7 ± 1.1 6.7 ± 2.0 6.7 ± 1.3 0.993LH 6.4 ± 1.4 7.9 ± 2.8 4.9 ± 0.9 0.332PTH 48.1 ± 2.5 41.7 ± 3.6 51.2 ± 3.1 0.073Prolactin 273.2 ± 15.5 310.5 ± 33.2 255.2 ± 15.9 0.096Insulin 9.2 ± 1.1 12.7 ± 3.2 7.7 ± 0.7 0.044C-peptid 0.9 ± 0.08 0.9 ± 0.09 1.0 ± 0.1 0.766HOMA 2.6 ± 0.3 3.3 ± 0.9 2.2 ± 0.3 0.203Estradiol 18.4 ± 3.3 13.4 ± 11.5 20.9 ± 0.3 0.351Testosterone 5.7 ± 1.0 5.5 ± 2.5 5.9 ± 0.3 0.873Antiovarian At 0.8 ± 0.1 0.6 ± 0.2 0.8 ± 0.1 0.368

Results

Clinical characteristics of the patients

From 50 subjects included in the study, 6 (12%) were males and 44 (88%) females. Fifteen (30%) subjects had subclinical hypothyroidism while 35 (70%) had clinical hypothyroidism. From patients with hypothyroidism, 7 (20%) were clinically newly diagnosed and 12 (34.2%) developed hypothyroidism after total thyroidectomy.

From total number of analyzed patients, 10 subjects (20%) had typical hypot-hyroid skin changes. From total number of women, regular menstrual cycle was found in 7 (14%), irregularity of menstrual cycle was found in 5 (10%) while 32 women (64%) were in menopause. When analyzed as subgroups of hypothyroi-dism, skin changes were found in one patient (6.7%) with subclinical hypothyro-idism, and in 9 patients (25.7%) with clinical hypothyroidism. In subgroup with subclinical hypothyroidism, 2 women (13.3%) had irregular menstrual cycles (oligomenorrhea) and 6 (40%) were in menopause while in the subgroup with clinical hypothyroidism 2 women (5.7%) had oligomenorrhea, and 26 women (74.3%) were in menopause.

Anthropometric characteristics of the whole group of patients and subgroups are shown in Table 1. Presented dose of L-thyroxine in Table is in patients with subclinical hypothyroidism related to the dose at introduction of therapy, while in patients with clinical form of disease represents current dose. In patients with subclinical disease initial therapeutic approach considered only follow-up or use of small doses of L-thyroxine (12.5-25 g). The decision on the therapeutic approach was brought individually. In clinical form of the disease applied therapeutic dose of L-thyroxine ranged from 25 to 150 g.


Metabolic characteristics of the patients

Biochemical and hormonal characteristics of the whole group of patients and in relation to the type of hypothyroidism are presented in Table 2. Data for FSH, LH and estradiol are related to women in reproductive period.

According to the categorization of serum glucose level in the whole group, 5 patients (10%) had serum glucose level between 6.0 and 6.9 mmol/l while 4 (8%) had serum glucose level over 7.0 mmol/l, and that could represent glucose intolerance or diabetes. One patient had fasting glucose of 11.7 mmol/l.

Correlations in subgroups of the patients

In subgroup of patients with subclinical hypothyroidism, signi cant positive correlation was found between patient age and total cholesterol (r = 0.58, p = 0029) and ACTH (r = 0.58, p = 0.048), BMI and HOMA (r = 0.64, p = 0.023); diastolic BP and PTH (r = 0.64, p = 0.032), glucose and ACTH (r = 0.64, p = 0.023), FT4 and testosterone (r = 0.78, p = 0.021), testosterone and heart rate (r = 0.86, p = 0012), testosterone and HOMA (r = 0.93, p = 0.002).

In subgroup of patients with clinical hypothyroidism, signi cant positive corre-lation was found between BMI and diastolic BP (r = 0.42, p = 0.020), BMI and blood glucose (r = 0.40, p = 0.032), BMI and triglycerides (r = 0.58, p = 0.002), glucose and triglycerides (r = 0.57, p = 0.001), triglycerides and HOMA (r = 0.53, p = 0.006), cortisol and total cholesterol (r = 0.51, p = 0.004). Signi cant negative correlation was found between total cholesterol and heart rate (r =- 0.36, p = 0.049), HDL cholesterol and blood glucose (r =- 0.57, p = 0.001), triglycerides and estradiol (r =- 0,911, p = 0.009); FT4 and TSH (r =- 0.82, p <0.0001) and FT4 and anti TPO At (r =- 0.42, p = 0.027), TSH and heart rate (r =- 0.39, p = 0.041).

Discussion

Several studies conducted in European countries with suf cient iodine intake had shown up to 7 fold higher incidence of hypothyroidism in women (14-17). When looking at the incidence of hypothyroidism among regions of the same country, it was shown that incidence could signi cantly vary due to differences in iodine intake (3). As our patients were age-compared to the subjects in the above mentioned studies, we concluded that our group had similar representation of hypothyroidism by sex. The limitations of our study were in small group of examined patients and the lack of data on iodine intake.


Rare skin changes in our patients may be explained by mild thyroid dysfunction in subclinical disease, or by treated hypothyroidism in clinical disease, or recent surgical removal of the thyroid gland when the skin signs have not developed yet.

In women of reproductive period hypothyroidism causes changes in menstrual cycle length and amount of menstrual bleeding. Change in the amount of menstrual bleeding is probably caused by estrogen breakthrough bleeding that is secondary to anovulation. In hypothyroidism, defects in hemostasis due to reduced concen-trations of factors VII, VIII, IX and XI could contribute to the irregularities of the menstrual cycle (18). In contrary to the previous studies that indicated disruption of the menstrual cycle in 56-80% of the hypothyroid women (19, 20), Greek studies indicated irregularities of menstrual cycles in 23.4% of hypothyroid women. From those women, 42.5% had oligomenorrhea. Authors suggested that in hypothyroid women disturbances of the menstrual cycle were three times more frequent than in the general population (21). Genetic and other factors were taken into considera-tion for the explanation of such large differences among populations or prolonged period for the diagnosis of hypothyroidism (18). In our patients with subclinical and clinical forms of disease, oligomenorrhea was less frequently presented (13.3% and 5.7%).

Hypertension is more frequent in patients with hypothyroidism in comparison to healthy population (14.8 vs. 5.5%) (22). Higher values of systolic and diastolic blood pressure were found in women with subclinical form of disease in compa-rison to control euthyroid women (23). Potential mechanisms that might explain the occurrence of hypertension in hypothyroidism include increased peripheral vascular resistance and vascular stiffness (24), the absence of T3 vasodilatative effect on smooth muscles of blood vessels (25) or the existence of higher levels of circulating norepinephrine and reduced the number of beta-adrenergic receptor (22). Thyroid hormone de cit may be associated with a decrease in glomerular l-tration rate and blood ow through the kidneys (26). Finally, it was demonstrated that hypothyroid subjects often have an increased weight or were obese that lead to high blood pressure and increased cardiovascular risk (27). Values of systolic and diastolic blood pressure in our patients were within normal values and did not differ between subgroups of patients. However, this method of assessment of blood pressure did not represent an average daily values and possible changes in hypothyroidism. Therefore, more detailed analysis of the trends of diurnal blood pressure is needed in patients with hypothyroidism.

Average values of TSH were higher in our patients with clinical hypothyroidism compared to the patients with subclinical form of disease (19.5 ± 5.7 vs. 5.9 ± 0.3 mIU/l) but without reaching statistical signi cance. Higher TSH values obtained in patients with clinical hypothyroidism re ect the high value in the newly discovered, non-treated patients, or in patients with an unsatis ed supplementation of hypothyroid state. In 70-80% of healthy subjects, TSH level lies between 0.3 and 2 mIU/l, and


in 97% of cases it is less than 5.0 mU/l. If we exclude from the general population subjects with elevated antithyroid antibodies, it 95% cases TSH level is not greater than 2.5-3.0 mIU/l (28). Regardless of the upper normal limit is selected, it is nece-ssary to monitor closely individuals with TSH levels of 3 to 5 mIU/l, and especially if they have positive anti-thyroid antibodies. In individuals older than 70 years, TSH values up to 6.0 or even 7.0 mIU/l in the absence of antibodies anti-thyroid antibodies, should not be criteria for the diagnosis of hypothyroidism (29). In our patients with subclinical hypothyroidism, TSH was between 5 and 6 mIU/l that represent the limit of biochemical criteria for the presence of thyroid dysfunction.

The dose of the applied L-thyroxine differed signi cantly between our patients with subclinical and clinical hypothyroidism (21.4 ± 3.5 vs. 81.2 ± 4.6 g/day). The average applied dose of L-thyroxine in patients with clinical hypothyroidism was 1.6 g/kg body weight and corresponded to the age-recommended doses (28). In subclinical form of disease, a small starting dose of 25 g/day of levothyroxine is recommended, with control of TSH after 8 weeks and adjusting the dose. Some authors believe that due to the expected progression of thyroid weakness, a full daily dose of 50-75 g can be applied from the beginning. In younger subjects on therapy, obtained TSH range from 0.3-3.0 mIU/l is considered satisfactory. After achieving these targeted TSH values, the following controls are set for 6 and 12 months (30).

Basal blood glucose values for the whole group and when analyzed by subgro-ups of patients, were within normal values and without differences between groups. However, when classi cation of glucose was performed, a signi cant presence of glucose disorders was found in our patients. Thyroid disease is often associated with type 1 and type 2 diabetes with a prevalence of 10 to 15%. It was shown that lower values of thyroid hormones enhance insulin-mediated glucose availability (31). Also, it was shown that patients with subclinical hypothyroidism and type 2 diabetes had more frequently manifested dyslipidemia or coronary heart disease (32) and increased cardiovascular mortality compared to patients with type 2 diabetes without subcli-nical hypothyroidism (33). Recently it was shown that subclinical hypothyroidism may reduce the non-cardiovascular mortality in type 2 diabetes (33). Disruption of glycemic control in our patients may be explained by an increased body mass index and consequent insulin resistance.

Hypothyroidism is among the most common causes of the secondary dyslipi-demia that is characterized by elevated cholesterol, LDL cholesterol, apolipoprotein B, lipoprotein (a) or triglycerides. Tromsø study had shown the association of TSH levels, total cholesterol and LDL cholesterol, as well as decrease of those lipids after introduction of levothyroxine in hypothyroid patients (34). It appears that the effect of thyroxine substitution is signi cant only in patients with TSH over 10 mIU/l (35). Rotterdam study showed that subclinical form of disease represents a risk for atherosc-lerosis and myocardial infarction in elderly women (36). Subclinical hypothyroidism


is associated with congestive heart failure (37) but was not related to the development of stroke in these patients (38). Our patients had higher total cholesterol and LDL cholesterol only in hypothyroid subgroup, while HDL cholesterol and triglycerides did not differ between subgroups of patients. Relationship of lipid fractions with other clinical indicators con rmed the existence of well-known effect of age on the occurrence of dyslipidemia and a relation of body composition, glycemic control and dyslipidemia (39, 40).

The values of ionized calcium and parathyroid hormone in our study were within the normal range in both subgroups of patients. These results are consi-stent with data of other authors that markers of bone formation and resorption in hypothyroid patients and during thyroxine therapy did not differ from euthyroid controls (41).

It is known that thyroid hormones participate in regulation of the hypothala-mic-pituitary-adrenal axis. As previously mentioned, cortisol response during ITT in hypothyroidism is damaged (10). There is also a reduced corticosterone response to ACTH after stimulation with corticotrophin-releasing hormone in hypothyroid rats (42). However, in patients with primary hypothyroidism an altered adrenal function was not shown (43). In our patients there was no difference in the values of morning cortisol and ACTH between the two groups which certainly can not exclude the existence of other functional disorders.

It was shown that long-term hypothyroidism may be associated with ovula-tory dysfunction (11), and in 1-3% of cases associated with galactorrhoea (44). This is explained by increased production of TRH (45), reduced hypothalamic dopamine turnover (46) or possible change in TSH pulsatility that could affect GnRH pulse generator and ovulation. However, the study by Bals-Pratsch and colleagues showed that subclinical hypothyroidism does not disturb the function of the hypothalamic GnRH pulse generator, and does not change the normal appearance of LH pulses in the early follicular phase. Therefore, it is considered that women with subclinical hypothyroidism and some women with clinical hypothyroidism can have ovulatory cycles and normal function of the corpus luteum (47). In men, hypothyroidism can cause erectile dysfunction and loss of libido (12) as well as the reduction of circulating testosterone (48). Recently it was shown that in hypothyroid men decrease of serum testosterone may be caused by lower LDL cholesterol overtake by Leydig cells, subsequent decre-ase in the synthesis of progesterone and testosterone, higher conversion rate of testosterone to estradiol, decrease in serum T3 and by hyperprolactinemia (49). We did not show differences between FSH, LH, estradiol and testosterone in our hypothyroid patients. However, we found association of estradiol and triglycerides in women with clinical form of the disease, and that confirmed the existence of proatherogenic state in disturbed thyroid function (50).


Acknowledgement

This work was supported by the Ministry of Education and Science, Serbia, grant No 41009.

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