Hipotiroidismo subclínico en mujeres en edad reproductiva y embarazadas / Subclinical hypothyroidism in women of reproductive age and in pregnancy

El hipotiroidismo subclínico suele ser identificado como un cuadro que disminuye la capacidad reproductiva de las mujeresy está asociado a un riesgo aumentado de complicaciones perinatales. A partir de un caso clínico real, revisamos laevidencia disponible y encontramos que existen pruebas que contradicen este conocimiento tradicional sobre el pronósticoy la necesidad de tratamiento de este cuadro. (AU)

Subclinical hypothyroidism is usually identified as a condition that decreases the reproductive capacity of women and isassociated with a higher risk of perinatal complications. From a real clinical case, we review the available evidence andfound that there is evidence that contradicts this traditional knowledge about the prognosis and the need for treatment ofthis condition. (AU)

Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study.

Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspring. Pregnant rats were exposed to PTU (0 or 3 ppm) through the drinking water from gestational day 6 until postnatal day (PN) 14. On PN2 a subset of pups was cross-fostered to a dam of the opposite treatment, to create 4 conditions: pups exposed to PTU prenatally, postnatally, during both periods, or not at all (control). Both PTU and TH concentrations were characterized in the mother and offspring over time, to capture the dynamics of a developmental xenobiotic exposure. Brains of offspring were examined for heterotopia presence and severity, and adult littermates were assessed for memory impairments. Heterotopia were observed under conditions of prenatal exposure, and its severity increased in animals in the most prolonged exposure group. This malformation was also permanent, but not sex biased. In contrast, behavioral impairments were limited to males, and only in animals exposed to PTU during both the gestational and postnatal periods. This suggests a distinct TH-dependent etiology for both phenotypes, and illustrates how timing of hypothyroxinemia can induce abnormal brain structure and function.

Gestational dexamethasone alters fetal neuroendocrine axis.

This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-ß, tumor necrosis factor-alpha; TNF-α, and interferon-γ; IFN-γ) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction.

Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R study.

CONTEXT: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function. DESIGN, SETTING, AND PARTICIPANTS: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates. RESULTS: sFlt1 levels were positively associated with TSH (ß 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (ß -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (ß 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01). CONCLUSION: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.

Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland.

The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.

Impact of foetal-onset hypothyroidism on the epididymis of mature rats.

It is well established that congenital hypothyroidism leads to male infertility. However, there is a dearth of information on foetal-onset hypothyroidism-induced changes in the epididymis. With regard to transient hypothyroidism, the existing literature deals mainly with the testis. However, it is not known whether there is any corresponding alteration in epididymal morphology and physiology under such a condition. The present study is therefore aimed at understanding the impact of persistent and transient hypothyroidism on the concentration of epididymal sex steroids, as they play a vital role in maintaining the normal structure and function of the epididymis. Normal rats of 90 days of age served as controls (Group I). Hypothyroidism was induced by using pregnant/lactating mothers and post-weaning rats to 0.05% (w/v) methimazole (MMI) in the drinking water. Group II were subjected to persistent hypothyroidism from day 9 of post-coitum (pc) to 90 days. Group III rats were subjected to transient hypothyroidism from day 9 day pc to day 1 post-partum (pp), 21 pp or 35 pp (IIIa, b and c, respectively) and group IV rats were given simultaneous T3 supplementation (3 microg/100 g body wt./day i.m.) with MMI from day 9 pc to day 1 pp; 21 pp and 35 pp (Group IVa, b and c). Animals from all groups were killed on day 90 pp. Serum thyroid stimulating hormone (TSH) and thyroid hormones confirmed euthyroidism in group I, IIIa, b and c and IVa, b and c rats and hypothyroidism in group II rats. Caput and cauda epididymal concentration of testosterone, dihydrotestosterone (DHT), estradiol (E2) and androgen binding protein (ABP) markedly decreased in group II rats. While the concentration of testosterone, E2 and ABP increased in group III rats, that of DHT remained unaltered. However, group IV rats maintained normal concentration of the sex steroid and ABP. The activity of 5-alpha-reductase in the epididymis of all the groups followed the same trend as that of the concentration of epididymal DHT. From the present data it is evident that persistent hypothyroidism diminishes the bioavailability of androgens and oestrogens, while transient hypothyroidism enhances the same, indicating the importance of euthyroidism during foetal and neonatal period towards the maintenance of optimal hormonal status in the epididymis required for its maturation.

Hipotiroidismo congenito y neonatal-nuevos conceptos y analisis de dos casos / Congenital and neonatal hypothyroidism and new concepts, analysis of two cases

Las hormonas tiroideas son imprescindibles para el desarrollo y maduracion cerebral normales. El hipotiroidismo congenito es una de las causas mas frecuentes y evitable de retardo mental. Los sintomas clinicos son inespecificos y progresan con la evolucion del hipotiroidismo congenito porque antes del primer mes de vida, etapa en la que se debe iniciarse el tratamiento solamente un 5 por ciento de los niños afectados serian diagnosticados clinicamente, la incidencia mundial es de 1 en 3000 niños. Por estas razones se hace necesario realizar de forma rutinaria el programa de deteccion precoz de HCN, atraves del metodo de Screening neonatal para evitar tales casos

Regulation by thyroid hormones of terminal differentiation in the skeletal dorsal muscle. I. Neonate mouse.

Changes both in the ATPase myofibrillar profile and in the electrophoretic pattern of myosin isoforms were examined in the mouse dorsal skeletal muscle (longissimus) during postnatal development. In the newborn, only type II C and a few type I fibers were present; differentiation into type II A and II B fibers took place during the 3 weeks following birth. During the same period, a transition from three neonatal isomyosins to four adult isoforms was observed. The two phenomena were related to a marked increase in the serum thyroid hormones levels. Hypothyroidism and hyperthyroidism experiments were performed. Hypothyroidism produced by propylthiouracil treatment of pregnant females and thiourea injections of the litters was shown to induce a complete inhibition of postnatal muscular differentiation. Hyperthyroidism produced by triiodothyronine treatment of the neonate mice significantly accelerated the myosin transition and the switch in the myofibrillar pattern. Our results suggest a primordial role for thyroid hormones in directly regulating the appearance of myosin and fiber adult types and in modulating directly or indirectly the disappearance of the neonatal types.