Gene amplification as a common cause of inherited thyroxine-binding globulin excess: analysis of one familial and two sporadic cases. (73/3269)

T4-binding globulin (TBG) is the major thyroid hormone transport protein in humans. Inherited abnormalities in the level of serum TBG have been classified as partial deficiency, complete deficiency and excess. A single nucleotide deletion or substitution in the TBG gene, located on Xq22, has been detected in partial and complete deficiencies. As for inherited TBG excess, the gene amplification has been recognized in two Japanese families recently. In this study, an additional three Japanese families, one familial (F-I) and two sporadic TBG excess (F-II, F-III), were analyzed. Serum TBG levels in hemizygous males were 73, 47 and 42 microg/ml, three- to two-fold the normal value. The molecule had normal properties in terms of heat stability and isoelectric focussing pattern. The gene dosage of TBG was evaluated by coamplification with autosomal betaGlobin or X-chromosomal Duchenne Muscular Dystrophy (DMD) and subsequent quantitation by HPLC. The TBG/betaGlobin ratios of the affected male and female of F-I were 3.09- and 3.86-times, respectively, compared to that of the normal males. The TBG/DMD ratios were 2.93- and 2.09-times, respectively. These results are compatible with three copies of the TBG gene on the affected X-chromosome. Similarly, a twofold increase in gene dosage was demonstrated in the affected males of sporadic cases. Their mothers with normal TBG values had the same TBG gene dosage as normal females, suggesting that de novo gene duplication arose in gametes probably during meiosis. Amplification of the TBG gene was not recognized in these three families by in situ hybridization of prometaphase chromosomes. Though the mechanism remains unproved, gene amplification of TBG was considered to be a common cause for inherited TBG excess.  (+info)

Maternal hypothyroxinemia influences glucose transporter expression in fetal brain and placenta. (74/3269)

The influence of maternal hypothyroxinemia on the expression of the glucose transporters, GLUT1 and GLUT3, in rat fetal brain and placenta was investigated. Fetal growth was retarded in hypothyroxinemic pregnancies, but only before the onset of fetal thyroid hormone synthesis. Placental weights were normal, but placental total protein concentration was reduced at 19 days gestation (dg). Immunoblotting revealed a decreased abundance of GLUT1 in placental microsomes at 16 dg, whereas GLUT3 was increased. Fetal serum glucose levels were reduced at 16 dg. In fetal brain, the concentration of microsomal protein was deficient at 16 dg and the abundance of parenchymal forms of GLUT1 was further depressed, whereas GLUT3 was unaffected. Northern hybridization analysis demonstrated normal GLUT1 mRNA levels in placenta and fetal brain. In conclusion, maternal hypothyroxinemia results in fetal growth retardation and impaired brain development before the onset of fetal thyroid function. Glucose uptake in fetal brain parenchyma may be compromised directly, due to deficient GLUT1 expression in this tissue, and indirectly, as a result of reduced placental GLUT1 expression. Though corrected by the onset of fetal thyroid hormone synthesis, these deficits are present during the critical period of neuroblast proliferation and may contribute to long term changes in brain development and function seen in this model and in the progeny of hypothyroxinemic women.  (+info)

Pregnancy, parturition, and lactation in hypophyseal stalk-transected beef heifers. (75/3269)

Progesterone secretion is crucial for maintaining pregnancy to parturition in mammalian species, and in cattle the corpus luteum is the primary source of this hormone. This study determined the roles of prolactin (PRL), growth hormone (GH) and luteinizing hormone (LH) in the luteotropic process in beef heifers hypophyseal stalk-transected (HST, n=7) or sham operated (sham operated controls, SOC, n=9) during midgestation. The main finding was that endogenous PRL and GH maintained progesterone secretion in HST heifers in a similar manner to that in SOC throughout pregnancy. Serum PRL averaged 37 vs 187 and GH 2 vs 4 ng/ml in HST heifers compared with SOC, whereas LH abruptly decreased to undetectable levels after HST compared with a modest 0.4 ng/ml in SOC heifers. The second finding was that parturition and lactation occurred in HST heifers with calf delivery induced to occur at the same time as SOC. Milk production in HST animals was severely limited, and postpartum estrus obliterated compared with SOC. The suckling stimulus sustained milk ejection in HST heifers in spite of diminished PRL, GH, thyroid stimulating hormone, thyroxine and tri-iodothyronine secretion. The results suggest that PRL, GH and possibly placental lactogen are luteotropic during pregnancy in cattle.  (+info)

The effect of L-DOPA administration on thyrotropin (TSH) and thyrotropin releasing hormone (TRH) levels in serum in primary or pituitary hypothyroidism. (76/3269)

The effect of acute administration of L-DOPA on TSH and TRH levels in serum was studied in primary or pituitary hypothyroidism. TRH levels in serum fell and then returned to initial levels after L-DOPA administration in primary or pituitary hypothyroidism. TSH levels in serum fell and then returned to initial levels after L-DOPA administration in primary hypothyroidism. T4 and T3 levels in serum did not change after L-DOPA administration in primary or pituitary hypothyroidism. These data suggested that L-DOPA might act directly to hypothalamus.  (+info)

Maternal compound W serial measurements for the management of fetal hypothyroidsm. (77/3269)

OBJECTIVE: The diagnosis of fetal hypothyroidism is based at present on measurements of TSH and free thyroxine (FT4) in fetal blood samples obtained by cordocentesis. The measurement of maternal serum and urinary concentrations of compound W, immunologically similar to but chromatographically distinct from diiodothyronine sulfate (T2S), has been advocated as a new possible marker for fetal hypothyroidism. DESIGN: In this paper, we measured serum compound W levels in 84 pregnant women, 20 with and 64 without thyroid disorders before and during specific treatment. Compound W was also assessed in fetal blood obtained by cordocentesis from 49 normal fetuses and 4 fetuses with suspected hypothyroidism due to transplacental passage of propylthiouracil (PTU). Compound W levels were measured by T2S RIA in maternal and fetal serum. To assess the possible usefulness of 3, 5,3'-triiodothyroacetic acid (TRIAC) for therapy of fetal hypothyroidism we evaluated the transplacental passage of TRIAC by administering the drug to four pregnant women before therapeutic abortion. RESULTS: In normal pregnancies, both maternal and fetal compound W levels increased progressively during gestation with a significant direct correlation (P<0.001, in both mothers and fetuses). Moreover, a significant positive correlation was observed between fetal compound W and fetal FT4 values (P<0.005), whereas no correlation was observed between maternal serum compound W and maternal FT4 in either euthyroid or hyperthyroid women, suggesting the fetal origin of compound W. The hypothyroid fetuses of PTU-treated mothers showed low compound W levels, and maternal compound W values were in the low normal range and did not show the typical increase during progression of gestation. A significant increase of maternal compound W was observed when the PTU dose was reduced. TRIAC was documented to cross the placental barrier and the treatment of a hyperthyroid pregnant woman on PTU caused the high fetal TSH levels and goiter to normalize. CONCLUSIONS: Serial measurements of 3,3'-T2S crossreactive materials (compound W and 3, 3'-diiodothyroacetic acid sulfate) in maternal blood and the administration of TRIAC to the mother may represent a useful and safe alternative to invasive techniques for the diagnosis and therapy of fetal hypothyroidism.  (+info)

Hormonal changes during the first year of oestrogen treatment in constitutionally tall girls. (78/3269)

OBJECTIVE: Oestrogens are used to inhibit growth in girls with constitutionally tall stature. We studied the changes in different hormones that accompany such therapy. SUBJECTS AND METHODS: In this longitudinal study we examined the levels of total insulin-like growth factor-I (IGF-I), free thyroxine (FT(4)), thyrotrophin (TSH), testosterone, dehydroepiandrosterone sulphate (DHEA-S), cortisol and prolactin in two groups of girls receiving ethinyloestradiol at a dose of either 0.1mg daily (group A, n=22) or 0.2mg daily (group B, n=36). Hormonal measurements were performed at start of therapy and after 3, 6 and 12 months. RESULTS: In both groups the levels of IGF-I, testosterone and DHEA-S were reduced while the concentrations of cortisol and prolactin were increased. The pituitary-thyroid axis was not significantly affected by this therapy. The girls receiving 0.2mg ethinyloestradiol daily had lower IGF-I levels after 12 months of therapy and had higher serum prolactin concentrations than the girls treated with 0.1mg daily. The reduction in predicted height and the advancement in bone age were similar in both groups. CONCLUSIONS: Therapy with pharmacological doses of ethinyloestradiol changes the levels of several hormones including IGF-I, testosterone, DHEA-S, prolactin and cortisol but the role of the respective changes in the inhibition of growth is not clear. The suppression of DHEA-S levels by 40% suggests that the ovaries contribute significantly to the production of this hormone in pubertal girls.  (+info)

Differential expression of gender-dependent hepatic isoforms of cytochrome P-450 by pulse signals in the circulating masculine episodic growth hormone profile of the rat. (79/3269)

The masculine profile of growth hormone (GH) secretion characterized by episodic bursts ( approximately 200-300 ng/ml plasma) every 3.5 to 4 h, separated by interpulse periods devoid of detectable hormone, was restored at various peak heights to hypophysectomized, thyroxine-supplemented male rats to determine the minimum signaling amplitudes of the hormone pulse required to maintain male-like expression levels of gender-dependent hepatic cytochrome P-450s (CYP P-450s). Restoration of the pulse to as little as 2.5% of normal elevated CYP2C11 (the predominant isoform in male liver) protein and dependent catalytic activities to approximately 50% of normal, whereas transcript concentrations increased to 150% of physiologic. Renaturalizing the masculine plasma GH profile to 5% of normal was sufficient to increase CYP2C11 protein and catalytic activity to intact levels while further elevating mRNA to approximately 200% of normal (subsequently declining to intact concentrations with physiologic pulses). In dramatic contrast, CYP2C7 (mRNA and protein) declined to barely detectable levels following hypophysectomy and remained completely unresponsive to GH until replaced with the physiologic masculine profile. The repressive effects of the episodic GH profile on CYP2A2 and CYP3A2 expression similarly required replacement of near physiologic pulse amplitudes. Exhibiting an intermediate response to the masculine profile, restoration of 25% of the normal pulse amplitude was sufficient to significantly elevate CYP2A1 and CYP2C6 expression levels in hypophysectomized rats. These findings illustrate the importance of the pulse amplitudes (in addition to the interpulse periods) in the circulating masculine GH profile as differential signals regulating the expression and/or repression of each sex-dependent hepatic P-450 isoform in the rat.  (+info)

Maternal thyroid function in multifetal pregnancies before and after fetal reduction. (80/3269)

The aim of the study was to investigate maternal thyroid function in pregnancy by monitoring the circulating concentrations of thyroid stimulating hormone (TSH), free thyroxine (fT(4)) and human chorionic gonadotrophin (hCG) in multifetal pregnancies before and after embryo reduction. We studied two groups of women: group 1 comprised singleton (n=12) and twin (n=12) pregnancies achieved after superovulation and in vitro fertilisation and embryo transfer (IVF-ET), and group 2 were multifetal pregnancies (n=39) undergoing selective fetal reduction to twin pregnancies. Blood samples were obtained initially at 10-12 weeks gestation (before fetal reduction) and then 4 and 8 weeks afterwards. Before fetal reduction, the circulating concentrations of fT(4) in multifetal pregnancies were significantly greater than those in singleton or twin pregnancies (singleton, mean 16.49 pmol/l (interquartile range 14.09-18.13 pmol/l); twins, 15.84 (15.36-16.95 pmol/l); multifetal, 21.08 (16. 64-26.29 pmol/l); P<0.005 for singleton and twins), and in a multiple regression analysis, fT(4) was significantly related to the number of fetuses (F=23.739, P=0.0001), but not to hCG. After fetal reduction to twins, the circulating concentrations of fT(4) in multifetal pregnancies decreased progressively towards those in control twin pregnancies, but remained significantly greater at both 4 (P=0.003) and 8 weeks (P=0.050). This pattern of change in the concentrations of fT(4) is similar to, but lags behind, that of hCG, which attains twin levels 4 weeks after fetal reduction. This may represent a delayed thyroid response to the decreasing concentrations of hCG, but the alternative is that the maternal thyroid function is controlled by a fetal factor in addition to hCG.  (+info)