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Department of Internal Medicine III, Erasmus University Medical School (K.R., E.K., J.P.S., H.v.T., W.W.d.H., E.P.K., T.J.V.), Rotterdam, The Netherlands; Department of Obstetrics and Gynaecology, University of Dundee, Ninewells Hospital and Medical School (K.R., R.H.), Dundee, United Kingdom; Department of Pathology, Erasmus University Medical School (J.C.d.H.), Rotterdam, The Netherlands; and Department of Nuclear Medicine, University Hospital Dijkzigt (E.P.K.), Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Theo J. Visser, Department of Internal Medicine III, Erasmus University Medical School, P.O. Box 1738, Room Bd. 234, 3000 DR Rotterdam, The Netherlands. E-mail: visser{at}inw3.azr.nl
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of the deiodinases in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in experimental animals (9, 10, 11), but little is known about the ontogeny of these enzymes in human development. In animals and humans, fetal serum T3 is low and increases only at the end of gestation and in the neonatal period (11, 12, 13). Conversely, fetal serum rT3 is high and decreases in the late fetal and early neonatal period (11, 12, 13). High levels of iodothyronine sulfates, such as T4S, T3S, rT3S and 3,3'-T2S, have been documented in human and sheep fetal serum (11, 12, 14, 15, 16, 17, 18). Because hepatic D1 is important for production of serum T3 and for clearance of serum rT3 and iodothyronine sulfates (1, 2, 3, 4, 5), and because hepatic D1 activity is only expressed towards the end of fetal development, at least in rats and sheep (9, 11), it is generally believed that the low fetal serum T3 and high fetal serum rT3 and sulfates reflect a low hepatic D1 activity. However, high D3 activity has been detected in human, rat, and guinea pig placenta (19, 20, 21, 22, 23, 24); fetal rat brain (25, 26) and intestine (27); and embryonic chicken liver (28, 29). Therefore, the low T3 and high rT3 levels in human fetal serum may also be caused by rapid degradation of serum T3 and production of serum rT3 in placenta (23, 24) and possibly other tissues, such as liver. The purpose of the present study was to obtain a better understanding of the ontogeny of D1 and D3 activities in human liver. The results indicate a more important role for hepatic D3 activity in the regulation of thyroid hormone bioactivity during human fetal development than previously assumed.
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Materials and Methods |
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Nonradioactive iodothyronines were obtained from Henning Berlin
(Berlin, Germany); [3,5-125I]T3 (
35
Ci/mmol) was obtained from Dr. R. Thoma of Formula (Berlin, Germany)
courtesy of Dr. G. Decker of Henning Berlin.
[3',5'-125I]T4,
[3'-125I]T3, and
[3',5'-125I]rT3 (2000 Ci/mmol) were
obtained from Amersham (Little Chalfont, UK) or prepared in our
laboratory by radioiodination of T3, 3,5-T2,
and 3,3'-T2, respectively, as described previously (30).
[125I]T3 could be used without further
purification, but [125I]T4 and
[125I]rT3 were purified on Sephadex LH-20
before each experiment (30).
N-bromoacetyl-[3'-125I]T3
(BrAc[3'-125I]T3) and
BrAc[3',5'-125I]T4 were prepared as described
previously (31). Dithiothreitol (DTT) and PTU were obtained from Sigma
(St. Louis, MO); electrophoresis grade SDS-PAGE reagents, protein
markers, and protein assay reagent from Bio-Rad (Richmond, IL);
Sephadex LH-20 from Pharmacia (Uppsala, Sweden); and Coomassie
brilliant blue R-250 from Merck (Darmstadt, Germany).
Tissues
Liver tissue was obtained from 10 fetuses (F1–F10) of 15–20
weeks gestation as well as from 8 apparently healthy tissue transplant
donors (A1–A8): 4 males (29–46 yr of age) and 4 females (34–52 yr of
age). Microsomes were prepared by differential centrifugation as
previously described (32), suspended in 100 mM phosphate
(pH 7.2), and 2 mM EDTA (P100E2), containing 1
mM DTT, at a protein concentration of 10 mg/ml. Liver
tissue was also obtained at autopsy from 2 fetuses of 20 weeks
gestation, 5 preterm infants of 27–32 weeks gestation, and 13 term
infants who survived up to 39 weeks postnatally. Postmortem time varied
from 1–48 h. These tissues were homogenized in 10 vol P100E2,
containing 10 mM DTT, yielding protein concentrations of
10 mg/mL. Aliquots of microsomes and homogenates were snap-frozen on
dry ice and stored at -80 C until further analysis. Protein
concentration was determined using Bio-Rad protein assay reagent and
BSA as the standard. Approval for this study was obtained from the
Tayside Committee on Medical Research Ethics.
Deiodinase assays
Deiodinase activities were determined by analysis of the release
of radioiodide by ORD of outer ring-labeled T4 or
rT3 or by IRD of inner ring-labeled T3 during
incubation for 30–60 min at 37 C with liver homogenates or microsomes
and DTT in 0.2 mL P100E2 (32). D1 activity was assayed using 1
µM (105 cpm)
[3',5'-125I]rT3 and 10 mM DTT, D2
activity using 1 nM (105 cpm)
[3',5'-125I]T4 and 25 mM DTT in
the presence of 1 mM PTU (to block D1 activity) and 1
µM T3 (to block D3 activity), and D3 activity
using 10 nM (105 cpm)
[3,5-125I]T3 and 50 mM DTT.
Reactions were stopped at 0 C by addition of 0.1 mL 5% (wt/vol) BSA in
water followed by addition of 0.5 mL 10% (wt/vol) trichloroacetic acid
in water. Precipitated 125I-labeled iodothyronines were
removed by centrifugation, and the 125I-
released was further purified from the supernatant on Sephadex LH-20
microcolumns (bed volume 0.25 mL), equilibrated and eluted with 0.1
M HCl (32).
The assays were validated by high performance liquid chromatography (HPLC) analysis of the deiodination products of T4, T3, and rT3. For this, microsomes were incubated with a) 1 µM [3',5'-125I]rT3 and 10 mM DTT, b) 1 nM [3',5'-125I]T4 and 25 mM DTT in the absence or presence of 1 mM PTU and/or 1 µM T3, or c) 10 nM [3,5-125I]T3 and 50 mM DTT in 0.2 mL P100E2. The reactions were stopped by addition of 0.2 mL ice-cold methanol. After centrifugation, 0.2 mL of the supernatant was mixed with 0.3 mL 0.02 M ammonium acetate (pH 4), and 0.1 mL of the mixture was applied to a 250 x 4.6 mm Symmetry C18 column (Waters, Etten-Leur, The Netherlands) connected to an Alliance HPLC system (Waters) and eluted isocratically with a mixture of acetonitrile and 0.02 M ammonium acetate (33:67, vol/vol) at a flow of 1.2 mL/min. Fractions of 0.3 min were collected and counted for radioactivity.
Affinity labeling
BrAc[125I]T3 or BrAc[125I]T4 (0.1 µCi) was reacted for 20 min at 37 C with 0.1 mg microsomal protein in 0.1 mL P100E2 containing 1 mM DTT (30). The reaction was stopped by addition of 50 µL SDS-sample buffer containing 30% ß-mercaptoethanol and treatment for 5 min at 100 C. Proteins were separated overnight by SDS-PAGE in a 16-cm 10% polyacrylamide gel. Gels were stained with Coomassie brilliant blue R-250 at 60 C, dried at 80 C under vacuum, and autoradiographed at -70 C using Fuji RX film (Fuji Medical Systems, Houten, The Netherlands). Apparent molecular mass (Mr) was determined by interpolation with protein markers.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the D1
activities of these liver homogenates as a function of
gestational/postnatal age. Considering the varying conditions of the
tissues, the appreciable scatter of the data was not surprising.
However, it is clear that hepatic D1 activity demonstrated little or no
dependence on age in the range studied, with activities at 20 weeks
gestation being very similar to those observed after 20 weeks
postnatally. D1 activity was not correlated with postmortem time (not
shown). Figure 1B shows the hepatic D3 activities in these same tissue
homogenates as a function of age. In spite of the considerable scatter,
there was clearly a decrease in hepatic D3 activity with age. In
general, high D3 activities were observed during fetal development,
which virtually disappeared after birth in term infants. Hepatic D3
activity was unexpectedly low for age in 1 infant born at 27 weeks
gestation who died from intrauterine infection. Interestingly, D3
activity was unexpectedly high for age in a term infant with GM1
gangliosidosis who died at 35 weeks of age from pneumonia. Hepatic D3
activity was not correlated with postmortem time (data not shown). D2
activities in these liver homogenates were negligible (data not
shown).
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shows the microsomal D1 and D3
activities in five representative fetal liver samples obtained at
15–20 weeks gestation as well as in five representative adult liver
samples. Again, there was considerable scatter in both D1 and D3
activities in the fetal samples. There was no significant relationship
of either D1 or D3 activity with fetal age (data not shown). However,
D1 and D3 activities were significantly correlated (r = 0.85; data
not shown), suggesting that the variation in both deiodinase activities
was related to the quality of the tissues. Hepatic D1 activity in the
adult tissue transplant donors showed a relatively narrow range of
variation. D1 activity in fetal liver amounted up to 24% of that in
adult liver. In seven of the eight adult liver samples D3 activity was
very low (Fig. 2 and data not shown). However, significant hepatic D3
activity was detected in the remaining adult tissue sample (A1), which
amounted to 56% of the mean fetal hepatic D3 activity. D2 activity was
negligible in both fetal and adult liver (data not shown).
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). Some labeled 3'-T1 was
also produced presumably by IRD of 3,3'-T2 by D3. Addition
of PTU did not affect the IRD of T4 but partially inhibited
the further ORD of rT3 (Fig. 3B). In the presence of 1
µM unlabeled T3, conversion of
[125I]T4 to
[125I]rT3 was completely inhibited, and a
very small amount of [125I]T3 was found to
accumulate, apparently caused by inhibition of its degradation by
D3 (Fig. 3C). Addition of both PTU and unlabeled T3
resulted in the complete inhibition of T4 metabolism (Fig. 3D).
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shows the double-reciprocal
plots of the deiodination rates of rT3 and T3
by fetal and adult liver microsomes as a function of substrate
concentration. Although the maximum velocity (Vmax)
value for rT3 deiodination estimated from these plots was
higher in adult than in fetal liver, the apparent Km value
for rT3 amounted to 0.5 µM with both
representative tissue samples (Fig. 4A). The deiodination of
rT3 was completely inhibited by 1 mM PTU in
both fetal and adult liver (not shown). The deiodination of
T3 by a representative fetal liver sample and by adult
liver sample A1 was characterized by very similar Km values,
i.e. 1.4 and 2.5 nM, respectively (Fig. 4B). In
both cases, deiodination of T3 was not affected by the
addition of 1 mM PTU (not shown).
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shows the results of the
affinity labeling of fetal and adult human liver microsomal proteins by
BrAc[125I]T4 or
BrAc[125I]T3. As demonstrated previously
(30), the radioactive band of 27 kDa represents the affinity
labeling of D1. These findings, therefore, suggest similar levels of D1
protein in fetal and adult human liver. No evidence was obtained
for affinity labeling of D3 with either
BrAc[125I]T3 or
BrAc[125I]T4, which is in agreement with our
previous failure to identify D3 in rat placenta and embryonic chicken
liver using these affinity labels (33).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T4 production by the human fetal thyroid gland has been demonstrated after 10–12 weeks of gestation (11, 12, 13). Before this period all T4 in the fetal circulation is derived from maternal supply across the placenta. However, maternal supply probably remains an important source of fetal thyroid hormone after development of the fetal thyroid gland, as evidenced by substantial T4 levels in newborns with thyroid agenesis or a complete hormone synthesis defect (34). In view of the available T4 levels, serum T3 is low and serum rT3 is high in the human fetus, in particular during the first two trimesters (11, 12, 13, 35). This can be explained by the well-documented high D3 activity in the placenta, which presumably converts a large proportion of T4 to rT3 and of T3 to 3,3'-T2 during placental transfer (19, 20, 21, 22, 23, 24). In addition, findings of high D3 activities in fetal rat brain (25, 26, 27) and intestine (27) and in embryonic chicken liver (28, 29) have suggested that significant D3 activity may also be expressed in fetal human tissues. Furthermore, in analogy with the ontogeny of D1 expression in rat liver (9, 27), it has been generally assumed that hepatic T3 production and rT3 clearance remain low until D1 starts to be expressed towards the end of human fetal development. This is supported by the high levels of T4S, T3S, rT3S, and 3,3'-T2S in human fetal serum (14, 15, 16, 17, 18), because these conjugates are cleared importantly by hepatic D1 (5).
Because very little is known about the potential role of hepatic D1 and D3 in the regulation of thyroid hormone bioactivity during human fetal development, we carried out the present study. Although the autopsy samples were obtained from sick infants, and the condition of the tissues, when they were collected, was in some cases suboptimal, the results clearly indicate that D1 activity already is expressed in the second trimester at levels similar to those observed in infants who survived up to 39 weeks postnatally. Another remarkable finding was the high D3 activity in liver homogenates from preterm infants, which was not detectable in livers from term born infants with one exception (see below). These findings were confirmed by comparing microsomal deiodinase activities in fetal livers of 15–20 weeks gestation with those determined in liver samples from apparently healthy adult tissue, showing that D1 activity in fetal liver amounted to at least 20% of that in adult liver. Furthermore, in contrast to the high D3 activities in fetal liver, D3 activity was absent in adult liver with one exception (see below). These findings strongly suggest that the low serum T3 and high serum rT3 levels in the human fetus are not so much caused by low hepatic D1 activity but rather to high D3 activity in the liver in addition to the placenta and possibly other tissues. The relative importance of the D3 activity in the fetal liver vs. that in the placenta is difficult to assess. The specific activity of the enzyme is similar in these tissues, but because of the difference in tissue weight, the total amount of enzyme is larger in placenta than in fetal liver.
The expression of hepatic D1 and D3 activities during human fetal development is remarkably different from that in rats (9, 27) but resembles the ontogeny of these enzymes in the chicken liver (28, 29, 36). In the chicken, hepatic D1 activity and mRNA level gradually increase until the end (day 20) of embryonic development (E20) (29, 36). In contrast, hepatic D3 activity and mRNA level strongly increase until E17, which is followed by a steep decline after E18 to almost undetectable levels at internal pipping on E20 (29, 36). This fall in hepatic D3 activity is associated with a dramatic increase in serum T3 levels, suggesting that serum T3 in the chicken embryo is determined to an important extent through regulation of its degradation by hepatic D3 activity (29, 36). It has been demonstrated that GH plays an essential role in the down-regulation of D3 expression in chicken liver at the end of embryonic development (37). Interestingly, Darras et al. (38) have also shown an acute and profound decrease in hepatic D3 activity after administration of dexamethasone to E18 chicken embryos. This was accompanied by a marked increase in serum T3 and a marked decrease in serum rT3 (38). It is tempting to speculate that part of the beneficial effect of the antenatal administration of glucocorticosteroids to mothers in case of an imminent premature delivery on the postnatal development of the infant (39) is caused by this down-regulation of hepatic D3 activity and consequent increase in serum T3 levels.
It is generally believed that the high D3 activity in placenta, fetal liver, and possibly other fetal tissues protects the fetus during critical stages of development against active thyroid hormone (11, 12, 13, 23). D3 is an important enzyme for the irreversible degradation of thyroid hormone, because the products generated from T4 and T3 by this enzyme, i.e. rT3 and 3,3'-T2, have very little affinity for the nuclear T3 receptor (TR) nor can they be converted to TR-binding ligands (40). T3 stimulates the differentiation of cells, and premature exposure of growing tissues to active hormone may thus result in congenital abnormalities. Sulfation is another pathway by which thyroid hormone is inactivated, because T3S has lost its affinity for TR (41). Furthermore, in adult subjects, sulfation represents the first step in a pathway leading to the irreversible degradation of thyroid hormone, because IRD of T4S and T3S by D1 is greatly accelerated compared with the deiodination of the nonsulfated iodothyronines (5). The importance of D1 for the clearance of serum T4S, T3S, rT3S, and 3,3'-T2S is indicated by the marked increases in the serum levels of these conjugates after inhibition of D1 by PTU and, in particular, iopanoic acid (14, 42, 43, 44). The high levels of the iodothyronine sulfates in human fetal serum have also been explained by the reduced clearance of these conjugates presumably caused by low hepatic D1 expression, although evidence has also been reported that production of the sulfates is increased in fetal sheep (11, 45). It has been speculated that T3S represents a reservoir of inactive hormone from which active T3 may be released by sulfatases expressed in different tissues (5, 46). Our results show that hepatic D1 activity may be somewhat lower in the human fetus than in the adult but not to the extent that would explain the strongly increased T4S, T3S, rT3S, and 3,3'-T2S levels in fetal serum. This suggests that additional mechanisms contribute to the elevation of serum iodothyronine sulfate levels in human fetal serum, such as decreased expression of plasma membrane transporters involved in tissue uptake of these conjugates (3).
Another surprising finding of our study is the occasional expression of hepatic D3 in livers from older subjects. If this represents a defect in the mechanism that normally shuts off D3 gene expression in the liver after birth or, more likely, reexpression of the gene under pathological conditions, remains to be explored. In this respect, it should be mentioned that high D3 activity has been detected in a monkey hepatocarcinoma cell line (47). It is also tempting to speculate that, like other fetoproteins, hepatic D3 expression may be stimulated by cytokines (48). If this is the case, changes in peripheral thyroid hormone metabolism in the low T3 syndrome associated with nonthyroidal illness (49) may include up-regulation of hepatic D3 activity.
D2 activity was undectable in both fetal and adult human liver samples. We cannot exclude, however, that D2 activity may be expressed in human fetal liver but is lost caused by postmortem inactivation (50).
In conclusion, we have shown that expression of both D1 and D3 in human fetal liver is higher than previously assumed. This suggests that the low T3 and high rT3 levels in human fetal serum is not so much caused by low hepatic D1 expression but rather to high D3 activity in fetal human liver in addition to placenta and perhaps other fetal tissues. The exact role of D3 expression in the tissue-specific and stage-dependent regulation of thyroid hormone bioactivity during human fetal development remains to be fully investigated.
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Footnotes |
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Received January 23, 1998.
Revised April 27, 1998.
Accepted May 4, 1998.
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M. H. A. Kester, R. Martinez de Mena, M. Jesus Obregon, D. Marinkovic, A. Howatson, T. J. Visser, R. Hume, and G. Morreale de Escobar Iodothyronine Levels in the Human Developing Brain: Major Regulatory Roles of Iodothyronine Deiodinases in Different Areas J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3117 - 3128. [Abstract] [Full Text] [PDF]
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N. Murphy, R. Hume, H. van Toor, T. G. Matthews, S. A. Ogston, S.-Y. Wu, T. J. Visser, and F. L. R. Williams The Hypothalamic-Pituitary-Thyroid Axis in Preterm Infants; Changes in the First 24 Hours of Postnatal Life J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2824 - 2831. [Abstract] [Full Text] [PDF]
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 D. Konrad, G. Ellis, and K. Perlman Spontaneous Regression of Severe Acquired Infantile Hypothyroidism Associated With Multiple Liver Hemangiomas Pediatrics, December 1, 2003; 112(6): 1424 - 1426. [Abstract] [Full Text] [PDF]
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 M. H. A. Kester, E. Kaptein, T. J. Roest, C. H. van Dijk, D. Tibboel, W. Meinl, H. Glatt, M. W. H. Coughtrie, and T. J. Visser Characterization of rat iodothyronine sulfotransferases Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E592 - E598. [Abstract] [Full Text] [PDF]
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R. P. Peeters, P. J. Wouters, E. Kaptein, H. van Toor, T. J. Visser, and G. Van den Berghe Reduced Activation and Increased Inactivation of Thyroid Hormone in Tissues of Critically Ill Patients J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3202 - 3211. [Abstract] [Full Text] [PDF]
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F. Santini, P. Vitti, L. Chiovato, G. Ceccarini, M. Macchia, L. Montanelli, G. Gatti, V. Rosellini, C. Mammoli, E. Martino, et al. Role for Inner Ring Deiodination Preventing Transcutaneous Passage of Thyroxine J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2825 - 2830. [Abstract] [Full Text] [PDF]
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G. G. J. M. Kuiper, W. Klootwijk, and T. J. Visser Substitution of Cysteine for Selenocysteine in the Catalytic Center of Type III Iodothyronine Deiodinase Reduces Catalytic Efficiency and Alters Substrate Preference Endocrinology, June 1, 2003; 144(6): 2505 - 2513. [Abstract] [Full Text] [PDF]
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S. Friedrichsen, S. Christ, H. Heuer, M. K. H. Schafer, A. Mansouri, K. Bauer, and T. J. Visser Regulation of Iodothyronine Deiodinases in the Pax8-/- Mouse Model of Congenital Hypothyroidism Endocrinology, March 1, 2003; 144(3): 777 - 784. [Abstract] [Full Text] [PDF]
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S. A. Huang, D. M. Dorfman, D. R. Genest, D. Salvatore, and P. R. Larsen Type 3 Iodothyronine Deiodinase Is Highly Expressed in the Human Uteroplacental Unit and in Fetal Epithelium J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1384 - 1388. [Abstract] [Full Text] [PDF]
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H. C. van Beeren, W. M. C. Jong, E. Kaptein, T. J. Visser, O. Bakker, and W. M. Wiersinga Dronerarone Acts as a Selective Inhibitor of 3,5,3'-Triiodothyronine Binding to Thyroid Hormone Receptor-{alpha}1: In Vitro and in Vivo Evidence Endocrinology, February 1, 2003; 144(2): 552 - 558. [Abstract] [Full Text] [PDF]
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P. Cettour-Rose, A. G. Burger, C. A. Meier, T. J. Visser, and F. Rohner-Jeanrenaud Central stimulatory effect of leptin on T3 production is mediated by brown adipose tissue type II deiodinase Am J Physiol Endocrinol Metab, November 1, 2002; 283(5): E980 - E987. [Abstract] [Full Text] [PDF]
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 C. A. Shepherdley, C. B. Daniels, S. Orgeig, S. J. Richardson, B. K. Evans, and V. M. Darras Glucocorticoids, thyroid hormones, and iodothyronine deiodinases in embryonic saltwater crocodiles Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2002; 283(5): R1155 - R1163. [Abstract] [Full Text] [PDF]
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 A L Ogilvy-Stuart Neonatal thyroid disorders Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2002; 87(3): F165 - 171. [Abstract] [Full Text] [PDF]
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S. A. Huang, S. A. Fish, D. M. Dorfman, D. Salvatore, H. P. W. Kozakewich, S. J. Mandel, and P. R. Larsen A 21-Year-Old Woman with Consumptive Hypothyroidism due to a Vascular Tumor Expressing Type 3 Iodothyronine Deiodinase J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4457 - 4461. [Abstract] [Full Text] [PDF]
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R. M. Calvo, E. Jauniaux, B. Gulbis, M. Asuncion, C. Gervy, B. Contempre, and G. Morreale de Escobar Fetal Tissues Are Exposed to Biologically Relevant Free Thyroxine Concentrations during Early Phases of Development J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1768 - 1777. [Abstract] [Full Text] [PDF]
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A. C. Bianco, D. Salvatore, B. Gereben, M. J. Berry, and P. R. Larsen Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases Endocr. Rev., February 1, 2002; 23(1): 38 - 89. [Abstract] [Full Text] [PDF]
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J.-P. Chanoine, J. Nève, S. Wu, J. Vanderpas, and P. Bourdoux Selenium Decreases Thyroglobulin Concentrations But Does Not Affect the Increased Thyroxine-to-Triiodothyronine Ratio in Children with Congenital Hypothyroidism J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1160 - 1163. [Abstract] [Full Text]
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G. Morreale de Escobar, M. Jesús Obregón, and F. Escobar del Rey Is Neuropsychological Development Related to Maternal Hypothyroidism or to Maternal Hypothyroxinemia? J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 3975 - 3987. [Abstract] [Full Text]
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 A. G. van Wassenaer and J. H. Kok Thyroid Function and Thyroid Hormone Requirements of Very Preterm Infants NeoReviews, June 1, 2000; 1(6): e116 - 121. [Full Text]
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J. P. Sanders, S. Van der Geyten, E. Kaptein, V. M. Darras, E. R. Kühn, J. L. Leonard, and T. J. Visser Cloning and Characterization of Type III Iodothyronine Deiodinase from the Fish Oreochromis niloticus Endocrinology, August 1, 1999; 140(8): 3666 - 3673. [Abstract] [Full Text]
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Outliers with strongly deviating D3 activities.
