help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2320
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/5/2696    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eugène, D.
Right arrow Articles by Van Vliet, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eugène, D.
Right arrow Articles by Van Vliet, G.
Related Collections
Right arrow Pediatric Endocrinology
Right arrow Thyroid
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2696-2700
Copyright © 2005 by The Endocrine Society

Sexual Dimorphism of Thyroid Function in Newborns with Congenital Hypothyroidism

Dardye Eugène, Anissa Djemli and Guy Van Vliet

Endocrinology Service (D.E., G.V.V.) and Department of Clinical Biochemistry (A.D.), Sainte-Justine Hospital and Research Center, and Departments of Pediatrics (D.E., G.V.V.) and Biochemistry (A.D.), University of Montréal, Québec H3T 1C5, Canada

Address all correspondence and requests for reprints to: Guy Van Vliet, M.D., Room 1719, Sainte-Justine Hospital, 3175 Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada. E-mail: guy.van-vliet{at}recherche-ste-justine.qc.ca.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Several characteristics of congenital hypothyroidism (CH) from thyroid dysgenesis (ectopy and athyreosis) are sexually dimorphic: girls are more often affected, and boys are twice more likely than girls to have absent knee epiphysis at diagnosis, an indicator of severity of CH. Whether the biochemical severity of CH is sexually dimorphic is unknown. We therefore reviewed the charts of all newborns referred to our clinic from 1990 to 2004 because of a TSH greater than 15 mU/liter on newborn screening. In ectopy (24 boys, 78 girls) at screening, median TSH was lower in boys than girls (75 vs. 135 mU/liter, P = 0.017), whereas total T4 was higher (123 vs. 68 mmol/liter, P = 0.003); the same differences were present at diagnosis: TSH was 90 and 284 mU/liter (P = 0.001) and free T4 10 and 7 pmol/liter (P = 0.049) in boys and girls, respectively. The log-linear relationships between TSH and T4 at screening and diagnosis were similar in both sexes. In athyreosis (10 boys, 14 girls) at screening and diagnosis, TSH was higher in boys [308 vs. 207 (P = 0.053) and 712 vs. 555 mU/liter (P = 0.0057)]. In infants with an orthotopic gland (dyshormonogenesis, nine boys, 13 girls), there was no sex difference in biochemical severity of CH. In conclusion, sexual dimorphism in biochemical severity of CH from thyroid dysgenesis is apparent but differs according to etiology. These novel findings suggest that sexual dimorphism should be considered as a modulator of the mechanisms underlying the fate and function of ectopic thyroid cells.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PERMANENT PRIMARY CONGENITAL hypothyroidism (CH) is the most common endocrine disorder in neonates, with an overall prevalence of one in 3000–4000 births, and is the leading cause of preventable mental retardation. Abnormalities in the differentiation or survival of thyroid follicular cells (athyreosis, about 15% of CH cases), in their migration (ectopy, about 70% of CH cases), or in the growth of a normally located gland (orthotopic hypoplasia, fewer than 1% of CH cases) are the most frequent causes of CH and are grouped under the term thyroid dysgenesis. CH from thyroid dysgenesis (CHTD) is generally sporadic, and its molecular mechanisms have been elucidated in only a handful of cases. By contrast, children with CH associated with an enlarged orthotopic gland have a functional disorder that is inherited in an autosomal recessive fashion (thyroid dyshormonogenesis, about 15% of CH cases) (1).

Several characteristics of CHTD are sexually dimorphic. CHTD is more frequent in girls; this female predominance is generally more marked for ectopy than for athyreosis, with three affected girls for every affected boy (2, 3). Conversely, males with CHTD are twice more likely than girls to have absent knee epiphyses at diagnosis (4), a criterion commonly used to define the severity of CH (5). This sexual dimorphism seems to be restricted to the time of appearance of the knee epiphyses because the tendency to prolonged gestation and high birth weight for gestational age is similar in both sexes (4). Likewise, there does not seem to be a sexually dimorphic impact of CH on intellectual development (6). The present study was undertaken to evaluate whether the more severe impact of CH on bone maturation in boys with CHTD could be due to more severe biochemical hypothyroidism.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

The screening procedure for CH in Québec has been previously described (7, 8) and is illustrated in Fig. 1Go. If the TSH level, measured on a dried blood spot collected on filter paper after 24 h of life, is more than 30 mU/liter, the newborn is immediately referred for evaluation and treatment. If the TSH concentration is 15–29 mU/liter, total T4 (TT4) is measured on the same filter paper, and the newborn is referred if the TT4 value is below the range for age; if TT4 is normal, a second filter paper is requested. If the results on this second filter paper specimen are still ambiguous, a third specimen is requested.



View larger version (26K):
[in this window]
[in a new window]
  		FIG. 1. Algorithm for neonatal CH screening in Québec.

 
We reviewed all charts of infants referred to the pediatric endocrinology clinic of the Sainte-Justine Hospital between 1990 and 2004 because of a TSH 15 mU/liter or more on a newborn screening specimen taken between 24 and 96 h of life. Exclusion criteria were: 1) newborns with transient hypothyroidism (n = 13); 2) newborns whose birth weight was less than 2500 g (n = 9, of which seven were born before 37 wk, including two of the twins mentioned below) because they often have a low TT4 on the screening sample (9); 3) twins (n = 5) because they are generally discordant for CHTD and fetal blood mixing lowers the screening TSH of the affected twin (8); and 4) two patients with apparent athyreosis, one boy who is a compound heterozygote for mutations inactivating the TSH receptor (10) and one girl who has a 22q11 deletion. Thus, 148 newborns were included in the present study: 102 with ectopy (24 boys/78 girls), 24 with athyreosis (10 boys/14 girls), and 22 with an orthotopic gland (nine boys/13 girls). Data collected included: gestational age, birth weight, age at diagnosis, biochemical data including whole blood TSH and TT4 (nanomoles per liter) at screening and plasma TSH, free T4 (FT4, picomoles per liter), total T3 (TT3, nanomoles per liter), and FT4 to T3 ratio at diagnosis.

To establish the etiology of CH, a 99mTc scintigraphy was performed at diagnosis. In all but two of the newborns with an orthotopic gland, the gland was enlarged on scintigraphy. The permanence of hypothyroidism in patients with orthotopic glands or with absent uptake was established on the basis of one of the following criteria: 1) an increase in the plasma level of TSH during T4 treatment; 2) an increase in plasma TSH after withdrawal of T4 for 4 wk at 3 yr of age; and 3) permanent hypothyroidism from dyshormonogenesis in an older sibling. Newborns with an area of the knee epiphyses less than 0.05 cm2 (5) were considered to have absent epiphyses.

Hormone assays

On the neonatal blood spots, TSH and TT4 were measured using time-resolved fluorometric immunoassays (PerkinElmer, Woodbridge, Ontario, Canada) at the Provincial Screening Laboratory (Centre Hospitalier de l’Université Laval). On the plasma obtained at diagnosis, TSH, FT4, and TT3 were measured at the Sainte-Justine Hospital by RIA (Intermedico, Markham, Ontario, Canada) until 1996 and by time-resolved fluorometric immunoassay (Wallac Oy, Turku, Finland) thereafter. Samples with undetectably low FT4 were assigned to the lower limit of detection of the assay.

Statistical analysis

Results are expressed as median and range. Within etiological groups, comparison of males and females was performed by the Mann-Whitney U test for TSH and TT4 at screening and for TSH, FT4, TT3, and FT4 to TT3 ratio at diagnosis. Among the three etiological groups, the Kruskall-Wallis test was used for comparison. Linear regression after logarithmic transformation of TSH values was used to correlate TSH and TT4 at screening and TSH and FT4 at diagnosis. The proportion of males and females without knee epiphyses was compared by {chi}2 analysis. The level of significance was set at 0.05 (two tailed).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The median age at screening for all groups was 3 d. The median age at diagnosis is shown in Table 1Go: it was 14 d for the whole group and 13 d if only those diagnosed after the first blood spot result were considered. The diagnosis was made after a second or third blood spot result was obtained in 15 newborns: 12 with ectopy (five boys, seven girls) and three with orthotopic gland. All newborns with athyreosis had a TSH greater than 30 mU/liter on the first blood spot. As already reported (2), the female predominance was more pronounced for ectopy than for athyreosis.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Number of CH newborns diagnosed after a first or a second/third screening sample and age at diagnosis

 
Table 2Go shows the clinical characteristics of the patients according to etiology of CH and sex. There were no significant differences between sexes for age at diagnosis, which was also similar in the three etiological groups. In two newborns with an orthotopic gland, CH was diagnosed before the screening results were available: in one at d 4 on the basis of goiter and respiratory distress and in another at d 8 because of a history of dyshormonogenesis in a sibling. For the whole CH group, the median birth weight was 3500 g, and birth weight was less than 2500 g in 5% and above 4500 g in 1.7%. The corresponding figures for the general population of Québec are 3336 g, 5.3, and 1.2%, respectively (11). Nine CH newborns (5%) were delivered after a gestation of 42 wk or more; in the general population of Québec, this percentage has decreased from 2.9% in 1989–1990 to 0.7% in 1998 (12). As in the general population, boys with ectopy or athyreosis were about 150 g heavier than girls. Gestational age and birth weight did not differ significantly by sex or etiology.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Clinical characteristics [median (range)] of CH newborns according to etiology and sex

 
Table 3Go shows the biochemical data at screening and diagnosis of CH for ectopy, athyreosis, and orthotopic gland, respectively. The control values in euthyroid newborns at the ages corresponding to screening and diagnosis have been previously published by our laboratories (13, 14). In ectopy at screening, TSH was significantly lower in boys than girls (P = 0.017) and TT4 significantly higher (P = 0.003); at diagnosis, the same difference was observed in the severity of CH between boys and girls (P = 0.001 for TSH and 0.049 for FT4); however, TT3 levels at diagnosis were similar in boys and girls. Thus, the significantly higher FT4 to TT3 ratio of boys is due to their higher FT4. Log TSH was negatively correlated with TT4 at screening and FT4 at diagnosis, and these correlations were similar in boys and girls (at screening: r = –0.78, P = 0.0001 for boys; r = –0.57, P = 0.001 for girls; at diagnosis: r = –0.75, P = 0.0001 for boys, r = –0.67, P = 0.001 for girls) (Fig. 2Go). By contrast, in athyreoses at screening, median TSH was marginally higher in boys than girls (308 vs. 207 mU/liter, P = 0.053), whereas median TT4 was similar (39 vs. 31 nmol/liter); at diagnosis, median TSH was higher in boys than girls (712 vs. 555 mU/liter, P = 0.0057). FT4 and TT3 were equally low in both sexes and, accordingly, the FT4 to TT3 ratio was similar. All biochemical data from boys and girls with orthotopic glands were similar.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Biochemical data of CH newborns according to etiology and sex

 


View larger version (28K):
[in this window]
[in a new window]
  		FIG. 2. Correlation between TSH and TT4 at screening (top) and between TSH and FT4 at diagnosis (bottom) in the group with ectopy according to gender. Boys are represented by open circles (left panels) and girls by filled circles (right panels).

 
At diagnosis of CH, 70% of boys (vs. 50% of girls) with athyreosis had no visible knee epiphysis. By contrast, only 13% of boys with ectopy had absent knee epiphyses vs. 19% of girls.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our novel findings expand the concept of sexual dimorphism in newborns with CHTD to the biochemical severity of hypothyroidism. Boys with CH from ectopy are biochemically less severely affected than girls at screening and at diagnosis of CH, whereas athyreotic boys are more severely affected. Interestingly, the growth characteristics of the CHTD newborns did not show a sexual dimorphism: specifically, boys with ectopy or athyreosis were on average about 150 g heavier than girls, the same androgen-dependent difference that is seen in the general population (15). As in the French database, newborns with CHTD were more often born post term than normal newborns and more had a high birth weight, but there was no excess of low-birth-weight newborns (4).

To our knowledge, no sex differences in biochemical function in newborns with CHTD have been reported. In normal newborns, thyroid size as assessed by ultrasound (16, 17), TT4 in cord blood (18), and thyroid function parameters from d 1 to 25 (14) do not differ significantly between genders. The difference in biochemical severity of CH between boys and girls is in opposite directions in ectopy and athyreosis and is not observed in dyshormonogenesis, suggesting that the sex difference is not one of hypothyroidism per se. Plasma TT3 was similar in boys and girls with ectopy despite lower FT4 in girls, suggesting adequate up-regulation of type 2 deiodinase activity in girls. In the ectopy group, the similar negative correlations between TT4 and TSH at screening and between FT4 and TSH at diagnosis in boys and girls suggest that there is no sex difference in the sensitivity of the negative feedback control mechanisms.

Our data suggest that the quantity and the functional capacity of the ectopic tissue should be compared between genders. From the standpoint of the developmental biology of the thyroid, our results provide evidence that, even though ectopy and athyreosis may result from a common molecular event during early embryonic life, sex differences during the fetal period modulate thyroid gland development. Thus, sexual dimorphism should be considered in the study of molecular mechanisms of thyroid dysgenesis: for instance, 50% of Ttf-2–/– mice at embryonic d 11.5–15.5 have an ectopic gland, whereas the thyroid bud has disappeared entirely in the other 50%, but gender as the potential modifier of the effect of Ttf-2 ablation was not examined (19). A recent study has shown differences in sensitivity of primary neurons to cytotoxicity and apoptosis depending on the gender of the donor animal (20), but similar studies on thyrocytes have not been reported. However, apoptosis is involved in thyroid gland development: in Ttf-1–/– mice, the median thyroid bud develops to disappear only later through apoptosis; whether this process occurs differently in male and female animals was not reported (21).

There is also little information about sexual dimorphism in thyroid hormone action during development. Carrascosa et al. (22) reported that cultured human fetal epiphyseal chondrocytes express functional T3 receptors, but the gender of the fetuses studied was not given. In mice, the only situation in which the end-organ consequences of a genetic ablation affecting thyroid hormone metabolism are influenced by gender is the Dio2–/– model: plasma T3 is normal in both sexes, but mild transient growth retardation is seen in the males only (23).

In the present series, the differences in proportions of boys and girls with absent knee epiphyses did not reach statistical significance, probably because of the small sample size. However, more girls with ectopy and more boys with athyreosis had a severely affected bone maturation, consistent with the observed difference in biochemical severity of CH between boys and girls in each diagnostic category. In contrast, the 2-fold higher probability of boys having absent knee epiphyses found in the much larger French database (containing 1827 patients) was highly significant but apparently not due to the athyreosis group only (4). This discrepancy may reflect the different screening and evaluation strategies used, the different populations studied, and the different proportions of ectopy and athyreosis in the French and Québec databases. The cohort described in the present paper is predominantly French-Canadian: whether our observations are generalizable to other groups remains to be determined.

In conclusion, sexual dimorphism in biochemical function of CH from thyroid dysgenesis is apparent but differs according to etiology: girls with ectopy are more severely affected, whereas boys with athyreosis are more severely affected. Studies on the mechanisms of thyroid dysgenesis and on the consequences of CH should consider sexual dimorphism as a possible modulating factor.


   Acknowledgments
 
The Quebec Screening Laboratory continues to provide excellent service under the supervision of Drs. Claude Laberge and Yves Giguère; the collaboration of Nicole Bélanger, André Grenier, and Jean Ruel is gratefully acknowledged. At the Sainte-Justine Hospital, we thank Dr. Edgard Delvin for his support and Mr. Lubomir Alexandrov for statistical advice.


   Footnotes
 
D.E. was supported by a postdoctoral fellowship in pediatric thyroid diseases funded by Mr. John H. MacBain through the Sainte-Justine Hospital Foundation.

First Published Online February 22, 2005

Abbreviations: CH, Congenital hypothyroidism; CHTD, CH from thyroid dysgenesis; FT4, free T4; TT3, total T3; TT4, total T4.

Received November 29, 2004.

Accepted February 14, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Van Vliet G 2005 Hypothyroidism in infants and children. In: Braverman LE, Utiger RD, eds. The thyroid: a fundamental and clinical text. 9th ed. New York: Lippincott, Williams & Wilkins;1029–1047
  2. Devos H, Rodd C, Gagne N, Laframboise R, Van Vliet G 1999 A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab 84:2502–2506[Abstract/Free Full Text]
  3. Hanukoglu A, Perlman K, Shamis I, Brnjac L, Rovet J, Daneman D 2001 Relationship of etiology to treatment in congenital hypothyroidism. J Clin Endocrinol Metab 86:186–191[Abstract/Free Full Text]
  4. Van Vliet G, Larroque B, Bubuteishvili L, Supernant K, Leger J 2003 Sex-specific impact of congenital hypothyroidism due to thyroid dysgenesis on skeletal maturation in term newborns. J Clin Endocrinol Metab 88:2009–2013[Abstract/Free Full Text]
  5. Glorieux J, Desjardins M, Letarte J, Morissette J, Dussault JH 1988 Useful parameters to predict the eventual mental outcome of hypothyroid children. Pediatr Res 24:6–8[Medline]
  6. Leger J, Larroque B, Norton J 2001 Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study. Acta Paediatr 90:1249–1256[CrossRef][Medline]
  7. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, Van Vliet G 1996 Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J Clin Endocrinol Metab 81:222–227[Abstract]
  8. Perry R, Heinrichs C, Bourdoux P, Khoury K, Szots F, Dussault JH, Vassart G, Van Vliet G 2002 Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab 87:4072–4077[Abstract/Free Full Text]
  9. Vincent MA, Rodd C, Dussault JH, Van Vliet G 2002 Very low birth weight newborns do not need repeat screening for congenital hypothyroidism. J Pediatr 140:311–314[CrossRef][Medline]
  10. Gagne N, Parma J, Deal C, Vassart G, Van Vliet G 1998 Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities? J Clin Endocrinol Metab 83:1771–1775[Abstract/Free Full Text]
  11. Luo ZC, Wilkins R, Platt RW, Kramer MS 2004 Risks of adverse pregnancy outcomes among Inuit and North American Indian women in Québec, 1985–97. Paediatr Perinat Epidemiol 18:40–50[CrossRef][Medline]
  12. Collège des Médecins du Québec 1998 Comité d’enquête sur la mortalité et la morbidité périnatales. Report
  13. Van Vliet G, Czernichow P 2004 Screening for neonatal endocrinopathies: rationale, methods and results. Semin Neonatol 9:75–85[CrossRef][Medline]
  14. Djemli A, Van Vliet G, Belgoudi J, Lambert M, Delvin EE 2004 Reference intervals for free thyroxine, total triiodothyronine, thyrotropin and thyroglobulin for Québec newborns, children and teenagers. Clin Biochem 37:328–330[Medline]
  15. de Zegher F, Francois I, Boehmer AL, Saggese G, Muller J, Hiort O, Sultan C, Clayton P, Brauner R, Cacciari E, Ibanez L, Van Vliet G, Tiulpakov A, Saka N, Ritzen M, Sippell WG 1998 Androgens and fetal growth. Horm Res 50:243–244[CrossRef][Medline]
  16. Chanoine JP, Toppet V, Lagasse R, Spehl M, Delange F 1991 Determination of thyroid volume by ultrasound from the neonatal period to late adolescence. Eur J Pediatr 150:395–399[CrossRef][Medline]
  17. Perry RJ, Hollman AS, Wood AM, Donaldson MD 2002 Ultrasound of the thyroid gland in the newborn: normative data. Arch Dis Child Fetal Neonatal Ed 87:F209–F211
  18. Bernard B, Oddie TH, Fisher DA 1977 Correlation between gestational age, weight, or ponderosity and serum thyroxine concentration at birth. J Pediatr 91:199–203[Medline]
  19. De Felice M, Ovitt C, Biffali E, Rodriguez-Mallon A, Arra C, Anastassiadis K, Macchia PE, Mattei MG, Mariano A, Scholer H, Macchia V, Di Lauro R 1998 A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet 19:395–398[CrossRef][Medline]
  20. Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, Graham SH, Clark RS 2004 Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem 279:38563–38570[Abstract/Free Full Text]
  21. Kimura S, Ward JM, Minoo P 1999 Thyroid-specific enhancer-binding protein/thyroid transcription factor 1 is not required for the initial specification of the thyroid and lung primordia. Biochimie (Paris) 81:321–327
  22. Carrascosa A, Ferrandez MA, Audi L, Ballabriga A 1992 Effects of triiodothyronine (T3) and identification of specific nuclear T3-binding sites in cultured human fetal epiphyseal chondrocytes. J Clin Endocrinol Metab 75:140–144[Abstract]
  23. Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St. Germain DL, Galton VA 2001 Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 15:2137–2148[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
J. Deladoey, N. Belanger, and G. Van Vliet
Random Variability in Congenital Hypothyroidism from Thyroid Dysgenesis over 16 Years in Quebec
J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3158 - 3161.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
S M Ng, S C Wong, D M Isherwood, and M Didi
Biochemical severity of thyroid ectopia in congenital hypothyroidism demonstrates sexual dimorphism
Eur. J. Endocrinol., January 1, 2007; 156(1): 49 - 53.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/5/2696    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eugène, D.
Right arrow Articles by Van Vliet, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eugène, D.
Right arrow Articles by Van Vliet, G.
Related Collections
Right arrow Pediatric Endocrinology
Right arrow Thyroid

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals