**6. Summary**

138 Thyroid Hormone

**Figure 3.** Different cases of hyperthyroidism.

medication, respectively [150].

effects on maternal and neonatal outcome. The risk for premature fetal loss, preeclampsia, preterm delivery, intrauterine growth retardation and low birth weight is significantly increased [144]. It has to be considered that the transfer of stimulating receptor antibodies (TSAbs) are transferred from the mother to the child, and therefore the fetus is at risk to develop Graves' disease. Close monitoring of the fetus is, therefore, strictly recommended, even in

Taken together, there are two known causes of central hyperthyroidism [1,146]; (1) TSHproducing pituitary tumors (TSHomas) and (2) the syndrome of pituitary resistance to thyroid hormone (PRTH). In general, thyrotoxicosis is the syndrome resulting from an excess of circulating free T4 and/or free T3 [147,148]. Babies likely to become hyperthyroid have the highest TSH receptor antibody titer whereas if TSH receptor antibodies are not detectable, the baby is most unlikely to become hyperthyroid (Figure 3) [1,2,149]. In the latter case, it can be anticipated that the baby will be euthyroid, have transient hypothalamic-pituitary suppression or have a transiently elevated TSH, depending on the relative contribution of maternal hyperthyroidism versus the effects of maternal antithyroid

mothers treated by thyroidectomy before pregnancy but have still elevated TSAbs [142].

about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human [1,2,50,52,127,130,151-154], rat [1,2,41,60,135,154- 156] and chicken [7,157-170]. Note that the chicken is born early compared to the rat and human, as well as the rat is born early compared to the human (Table 6).



Maternal-Fetal Thyroid Interactions 141

E4-E8 - DIII mRNA levels are

days.

secretion.

E10 - The thyroid gland is fully functional.

E13 - Brain DII is elevated at the peak of neuroblast proliferation.

E9-10 - Several elements of the TH

action cascade are present in the brain of embryos long before their own thyroid gland starts hormone

markedly different in the telencephalon and diencephalon but remain stable, while the levels in mesencephalon and rhombencephalon show a sharp decrease and increase, respectively, during these


term. 14 W - Expressions of

term

16 W - DIII is observed in placenta and fetal epithelial

> - DIII and TRs are detected in fetal



concentrations.

cells.

liver.

TBG

16-20 W

mRNAs encoding MCT8, MCT10, OATP1A2 and LAT1 are significantly lower prior to 14 W compared to

14 GD - TRH mRNA is detected in neurons of the

fetal

15 GD - Pituitary TSH mRNA expression begins.

16-19.5 GD

hypothalamus.



observed in liver, heart and lung. - DI and DII are noticed in fetal tissues. - TRH is

produced in low

levels in hypothalamus and increases approximately threefold by GDI9.5.

17 GD - TH synthesis

begins in fetal thyroid


8-10 W

8-11 W

8 W - T4, T3 and rT3 are detected in coelomic/amniotic

fluids.

10 W - TSH is first


detected in the fetal pituitary.


11 W - TBG levels are

gestation.

in fetal

12 W - T4 and T3 are

high.


and brain. - Total serum T4 and T3 are low, free T4 is relatively high. - rT3 is noticed in serum relatively

detected in fetal serum and increased through


hypothalamus.

observed in serum

13 GD - Placental

circulation established. - TRs and TH are observed in fetal

brain.


10 GD - T4, T3 and TRβ

ast unit.

are detected in embryo/trophobl E2-E4 - T3, THTs, Ds and TRs are

E4 - OATP1c1 expression is

E5 - TRα mRNA is widely

hind-brain.

E6 - T4 and T3 are detected in embryonic brain.

E7 - DII activity is observed in

E8 - DII mRNA is noticed in cell clusters throughout the brain, particularly in rhombencephalon. - OATP1c1 levels are declined substantially in all

brain regions.

the brain before the onset of thyroid function and increases significantly.

expressed in whole embryos.

more than 10-fold higher in the telencephalon and diencephalon compared to the mesencephalon and rhombencephalon. - DII mRNA levels are highest in the diencephalon.

distributed in fore-, mid- and


Maternal-Fetal Thyroid Interactions 143


E18 - DI and DIII are expressed in

is found mostly in the molecular layer and the Purkinje cells at that time.

E19 - The increase in brain T3

lobes.

hatching.

detected.

hatching.

detected.

E20 (at the moment of pipping )

the granule cells, whereas DII

production correlates with the appearance of TRβ expression in the cerebellum, telencephalon and optic






10 PND - Brain

10-20 PND

14-50 PND

development equivalent to human birth.


days.

PND 50. - Adult TRH mRNA expression patterns are present at PND

22.


E13/14– E17 (synapt ogenesis )

concentrations of the different iodothyronine sulfates, T4S, T3S, rT3S and T2S, have been documented in human fetal and neonatal plasma as well as in amniotic fluid during the pregnancy.

40 W - Birth state. - Complete maturation of thyroid system. -MCT8 has been localized in the placenta in all three trimesters of pregnancy. - High


20 W - A steady

term.

22-32 W

increase in serum TH levels begins and continues to




E14 - The strong increase in

observed.

intracellular T3 has been

E15 - Plasma T4 levels start rising markedly around this day.

E16 - The decrease in DI activity

activity.

DIII activity.

in gonads is combined with the relatively high DIII


development of the placenta itself through the progress of gestation.



19 GD - Significant fetal TH secretion begins.

in adult.

22 GD - Birth state.

is less developed. - As much as 17.5% of THs found in the newborn are of maternal origin.

18 -22 GD


Maternal-Fetal Thyroid Interactions 145

started to increase gradually during the first week after

C2 - Highest DI-activities and mRNA expressions are detected in the liver, kidney,

and intestine. C1-C7 - The circulating T3/T4 ratio

hatching.

Abbreviations: W is week, GD is gestation day, E is incubation day, PND is postnatal day, C is posthatch day, THs is thyroid hormones, TRH is thyroid releasing hormone, TSH is thyroid stimulating hormone, THTs is thyroid hormone transporters, MCT is monocarboxylate transporter, OATP is organic anion transporter, Ds is deiodinases (DI, II, III), TRs is thyroid hormone receptors (TRα, β), T4 is Thyroxine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine

**Table 6.** Summary about the developmental thyroid hormone mechanisms (deiodinases, transporters,

The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or

Maternal THs are important in promoting normal fetal development especially the placental and CNS development. Clinical epidemiological and basic findings clearly show that maintaining normal TH regulation from the beginning of pregnancy is important to reduce the risk of obstetric complications and to ensure optimal neurodevelopment of the offspring. In normal pregnancy, transplacental TH passage is modulated by plasma membrane THTs,

In pathological/abnormal pregnancies with either maternal or fetal THs disturbances (hypoor hyper-thyroidism), the placenta lacks the full compensatory mechanisms necessary to optimize the maternal–fetal transfer of THs to achieve the normality of TH levels in the

Further studies are still needed to improve our understanding of the mechanisms mediating the transplacental transport of THs in both human and animals, particularly the role of the different THTs, and the mechanisms that ensure that sufficient amounts of THs are protected from D3 inactivation during their transit across the placenta. Such knowledge would facilitate the development of interventions to increase TH passage in pathological situations, in order to ensure normal fetal development. A better understanding of these mechanisms would also permit us to refine the timing and dosage of the increase in

Ds, sulfotransferases, TRs and several different proteins within placental cells.

sulfate, HPT is hypothalamic-pituitary-thyroid axis and TBG is thyroxin binding globulin.

sulfotransferases and receptors) in human, rat and chicken.

**7. Conclusion** 

transformation status.

**8. Future challenges** 

fetus.


Abbreviations: W is week, GD is gestation day, E is incubation day, PND is postnatal day, C is posthatch day, THs is thyroid hormones, TRH is thyroid releasing hormone, TSH is thyroid stimulating hormone, THTs is thyroid hormone transporters, MCT is monocarboxylate transporter, OATP is organic anion transporter, Ds is deiodinases (DI, II, III), TRs is thyroid hormone receptors (TRα, β), T4 is Thyroxine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine sulfate, HPT is hypothalamic-pituitary-thyroid axis and TBG is thyroxin binding globulin.

**Table 6.** Summary about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human, rat and chicken.
