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Original Studies |
Department of Endocrinology and Metabolism (F.S., L.Ch., P.L., C.M., L.M., G.S., G.C., A.P.), and Neonatal Unit (P.G., L.Co., A.B.), University of Pisa, 56124 Pisa, Italy; and Department of Medicine (I.J.C.), University of California, Los Angeles, California 90024
Address all correspondence and requests for reprints to: Dr. Ferruccio Santini, Dipartimento di Endocrinologia e Metabolismo, Università degli Studi di Pisa, Via Paradisa, 2, 56124 Pisa, Italy.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study, serum levels of different iodothyronines were evaluated in human newborns of various gestational stages. Iodothyronines were measured at birth and thereafter at several time points, up to 3 months of postnatal age. The relationship among various iodothyronines and the changes occurring after delivery were evaluated based on the postconceptional age (PA).
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Subjects and Methods |
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The population studied was a hospital-based cohort of neonates born at the Pisa Neonatal Unit, S. Chiara Hospital, Pisa, Italy. We studied 118 full-term newborns born at 36–40 weeks of PA. The mean PA ± SD was 37.7 ± 1 week, with a mean birth weight ± SD of 3.4 ± 0.4 kg. In addition, we studied 156 preterm newborns at 24–35 weeks of PA. The mean PA of this group ± SD was 29.9 ± 2.9 weeks, with a mean birth weight ± SD of 1.6 ± 0.7 kg. PA was calculated based on the first day of the last menstrual period (minus 2 weeks) and from early ultrasonographic examinations. PA was verified by clinical assessment of the infant, at birth, using the method of Dubowitz and Dubowitz (14). All infants were without malformations, infections, or major clinical problems, except respiratory distress syndrome in preterm newborns. The mothers of preterm neonates did not receive steroid treatment before delivery. Informed parental consent was obtained.
Collection of blood samples and laboratory methods
Blood was drawn from the umbilical cords of 69 newborns immediately after ligation. Venous blood was obtained from 205 infants between 6 h and 14 weeks of postnatal life. Infants taking drugs known to affect thyroid hormone secretion or metabolism were excluded.
Serum T3S levels were measured by RIA, as described previously (15). The range of T3S values in normal adults is 13–79 pmol/L. Total T3 (TT3) and total T4 (TT4) were measured using indirect methods (Method Spac Byk-Sangtec Diagnostic, Dietzenbach, Germany). rT3 and T4-binding globulin (TBG) were measured by RIAs (rT3: BIODATA Spa, Guidonia Montecelio, Italy; TBG: Biocode sa, Sclessin, Belgium). Free T3 (FT3) and free T4 (FT4) were determined by a competitive RIA technique (AMERLEX-MAB+ kits. Johnson & Johnson Clinical Diagnostics Ltd, Milan, Italy). Normal adult values in our laboratory are: TT3 = 1,5–3,2 nmol/L; TT4 = 54–154 nmol/L; rT3 = 0.14–0.54 nmol/L; FT3 = 3.8–8.4 pmol/L; and FT4 = 8.4–21.2 pmol/L.
Statistical analysis
Regression analysis was used to evaluate the relationship between different iodothyronines and between iodothyronine concentrations and PA. Student’s t test for unpaired data was used to compare means of serum iodothyronines in different groups.
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Results |
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Mean levels of T3S in umbilical cord serum of 69 newborns of
various PA are shown in Fig. 1
. Results
of serum T3S from 205 infants between 6 h and 14 weeks of
postnatal life are also shown there. High serum levels of T3S begin to
decrease at about 30 weeks of PA. Soon after delivery, there is a sharp
increase in serum T3S, which peaks at day 2 of extrauterine life. The
concentrations then decline quickly, up to day 5, when mean T3S values
are similar to those in umbilical cord at the time of delivery.
Thereafter, serum T3S levels slowly decrease, and in full-term
neonates, they reach the adult range at about 14 weeks of extrauterine
life. The postnatal T3S peak (day 1–4) is higher in preterm newborns,
as compared with full-term newborns (P < 0.001). The
mean serum concentrations of T3S, at various times after birth, were
always higher in preterm (as compared with full-term) newborns of
equivalent postnatal age (Fig. 1). From the 3rd week of postnatal life
onward, the mean serum levels of T3S were significantly lower than
during fetal life, both in preterm (P < 0.001) and
full-term infants (P < 0.001). Figure 2 shows the mean TT3, TT4, and rT3
concentrations during fetal life (as assessed in cord sera at birth)
and during early extrauterine life (as assessed in full-term newborns).
Data in Fig. 2 are in keeping with those previously reported in the
literature, although the increase in serum T3 in the fetus
after 30 weeks of gestation was more marked in earlier studies (16, 17).
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) but not with TT3, TT4,
FT3, FT4, or TBG concentrations (data not shown). In neonates 5 days or
more postnatal age (i.e. after the peaks of T3,
T4 and T3S), serum T3S concentrations are directly
correlated with rT3 concentrations (r = 0.39, P <
0.001, Fig. 3B). At the same postnatal age, an inverse correlation is
observed between T3S and TT3 (r = 0.39, P <
0.001) or FT3 (r = 0.41, P < 0.001) (Fig. 4), whereas no correlation is observed
between T3S and TT4, FT4, or TBG (data not shown).
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To understand the mechanisms that regulate serum iodothyronine
concentrations in utero vs. postnatal life, we
compared the results obtained in cord sera at birth (group A),
reflecting the fetal condition, with those found in newborns of 5 days
or more postnatal age, within the same range of PA (group B). Figure 5 shows the relationship between PA and
serum levels of TT3 in the two groups. Serum concentrations of TT3 are
low in group A, irrespective of PA [r = 0.15, not significant
(N.S.)]. At variance, in group B, there is a significant direct
correlation between serum T3 levels and PA (r = 0.69,
P < 0.001). A similar pattern is observed for FT3 in
group A (r = 0.23, N.S.) and in group B (r = 0.68,
P < 0.001). Serum levels of TT3 and FT3 in postnatal
life (group B) become significantly higher than those in the fetus
(group A), starting at 30 weeks of PA.
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). Serum rT3 in the neonate (
5 days
old, group B) is much lower than in the fetus (group A) and does not
show major changes with PA (Fig. 6B). With increasing PA, a decrease in
serum T3S (Fig. 7) and an increase in
serum TT4 (Fig. 8) levels occur, both in
the fetus and in the neonate.
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. Although there is no difference in T3S
and TT4 serum concentrations, TT3 is greater than 200%, and rT3 is
lower than 55%, in neonates (as compared with fetuses).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our results also show that the progressive decline in serum levels of T3S, during late intrauterine and early extrauterine life, is briefly interrupted by a sharp peak on day 2 after birth. In our view, this transient rise in serum T3S concentration reflects the postnatal peak of T3 (23). T3 is the substrate for sulfotransferase enzymes that produce T3S (24). The concomitant serum rise of T3 and T3S indicates that the postnatal surge of T3 is mainly caused by an enhanced thyroidal secretion, rather than by an increased peripheral conversion of T4 to T3 by type I-MD. This is because an increased activity of peripheral type I-MD, though raising serum T3 levels, would accelerate the metabolic clearance rate of T3S and ultimately decrease serum concentrations of T3S (25, 26). In keeping with this view, once the postnatal peak of T3 and T3S fades, there is an inverse relationship between serum levels of T3S and T3. These data support the concept that the maturation of peripheral type I-MD activity continues after birth and is responsible for the progressive decline in serum T3S levels. Surprisingly, we did not find an inverse relationship between T3S and T3 levels in umbilical cord sera, because the decrease in serum T3S during the last weeks of gestation was not associated with a corresponding rise of T3. To explain why serum T3 does not rise as expected, we analyzed the results obtained 5 or more days after birth in neonates with a PA ranging from 27–46 weeks. We considered results that were obtained at age 5 days or more, to avoid the interference caused by the postnatal peak of iodothyronines. At variance with results in cord sera, during extrauterine life, serum levels of T3 begin to rise, as early as 30 weeks of PA, and reach the adult range approximately 3 months later. This T3 profile fits with the concept that the maturation of peripheral type I-MD starts at 30 weeks of PA (16). In keeping with this estimate, a previous study (27) showed that L-T4 administration to very premature newborns (<30 weeks of gestational age) produces an increase in serum levels of T4 and rT3 but not of T3, indicating that peripheral type I-MD activity is low at this stage of development. L-T4 administration to full-term hypothyroid newborns normalizes serum T3, confirming that, at this stage, the ability of extrathyroidal tissues to produce T3 has been achieved (28).
Thus, if type I-MD matures, starting at 30 weeks of PA, why then,
don’t serum levels of T3 increase as expected during
intrauterine life? A reasonable explanation for these findings takes
into account the role of the placenta. Though the placenta is rich in
the type III-MD enzyme, which deiodinates T4 to rT3, and
T3 to T2, it does not metabolize
sulfated iodothyronines (10, 11, 29, 30). Common belief says that the
main role of placental type III-MD is to limit the transfer of maternal
thyroid hormones to the fetus (31). Our data suggest that placental
type III-MD is important also in regulating the metabolism of
iodothyronines originated in the fetus. The major role of this enzyme
would consist of maintaining serum T3 at a low level during
intrauterine life, by supporting a high metabolic clearance rate of
this hormone. This mechanism has a particular relevance in late
gestation, because it prevents a rise in serum T3 levels,
while allowing a maturation of the peripheral machinery (type I-MD)
responsible for the production of T3. Exclusion of the
placenta from fetal circulation at birth allows a quick rise in serum
T3 levels, because the production rate of T3 is
no longer counterbalanced by the high degradation rate caused by
placental type III-MD. This mechanism would account for the above
reported observation that serum levels of T3 are lower in
fetuses than in neonates of the same PA. Beside
T3-to-T2 conversion, type III-MD also catalyzes
the monodeiodination of T4 to rT3. This can explain the
finding that serum levels of rT3 are higher in fetuses than in neonates
of the same PA. Because T3S is not deiodinated by type III-MD, the
placenta does not influence the serum levels of this metabolite. As a
consequence, serum levels of T3S are superimposable during fetal and
extrauterine life, provided that PA is the same (see Table 1
).
Previous data support our view that placental type III-MD activity plays an important role in regulating serum levels of T3 and rT3 during intrauterine life. In human embryos, rT3 is much higher in celomic fluid than in amniotic fluid or maternal serum (32), suggesting that the placenta is the most active site for the production of rT3. In newborn lambs, the thyroid gland is the major source of circulating T3 during early hours after delivery, in response to the TSH postnatal surge (33). However, the postnatal T3 peak can be delayed well after the TSH peak, by delaying the umbilical cord cutting (34). In our view, this implies that the interruption of T3 degradation by placental type III-MD is important in allowing the postnatal T3 surge. Most neonates developing neonatal hyperthyroidism caused by the transplacental passage of thyroid-stimulating antibody have normal T3 levels at birth and become clinically thyrotoxic during the first week after delivery (35). It is conceivable that placental type III-MD has a protective role towards the development of thyrotoxicosis, by degrading excess T3 in utero.
The transition from the low T3 state of fetal life to the thyroid hormone pattern of infancy is believed to involve two main mechanisms. The acute postnatal release of TSH produces an early peak in serum T3 concentrations, as a result of enhanced thyroidal secretion (23, 36). The subsequent maintenance of serum T3 levels is attributed to an increased T4-to-T3 conversion by peripheral deiodinases (3, 16). Our findings suggest that an additional important mechanism consists of the abrupt reduction of T3 degradation by placenta after umbilical cord cutting.
Other factors may intervene in the regulation of serum iodothyronines in the fetus. Both T3 and rT3 share T4 as their precursor, and their serum levels are influenced by thyroidal T4 secretion, which progressively increases with PA. A high production rate of T3S by sulfotransferases may contribute to the maintenance of high serum T3S (37). Fetal liver type III-MD may play a role in lowering serum T3 (38). Finally, type II-MD activity might be important in regulating serum T3 levels (39).
In conclusion, our main findings are: 1) changes in serum concentrations of iodothyronines, during fetal life and in the postnatal period, confirm that maturation of extrathyroidal type I-iodothyronine MD accelerates, starting at 30 weeks of PA; 2) high levels of type III-MD activity in fetal tissues prevent the rise of serum T3, while maintaining high levels of rT3 during intrauterine life; 3) an important mechanism leading to the transition from fetal to postnatal thyroid hormone balance is a decrease of type III-MD activity; 4) because the placenta contains a high amount of type III-MD, it is conceivable that the placenta contributes to maintenance of low T3 and high rT3 serum concentrations during fetal life and that its removal at birth is responsible for most changes in iodothyronine metabolism occurring afterwards.
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Acknowledgments |
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Footnotes |
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Received June 29, 1998.
Revised September 30, 1998.
Accepted October 21, 1998.
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