Extensive mutagenesis studies of the long extracellular domain of the TSH receptor (TSHR) revealed important residues (Cys-301, Tyr-385 and Cys-390) for binding of TSH in its C-terminal region. These two cysteines were postulated to form a disulfide bond catalyzed by TSH.
On the other hand, binding sites of a thyroid stimulating antibody were located in the N-terminal region of the extracellular domain.
The long extracellular domain of the TSHR has 5 or 6 possible asparagine-linked glycosylation sites. However, only two sites are essential for the expression of a functional receptor among them. Although point mutation at residue 113 of the human TSHR lost TSH binding, the equivalent mutation of the rat TSHR did not, implying a difference in the significance of sugar chains among species.
G protein interaction sites have recently been defined by mutagenesis studies. However, the details of how TSH binding to the long extracellular domain causes conformational change in the transmembrane domain remains to be elucidated.

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Serum LH increased rapidly in both sexes after gonadectomy, showing a peak at the 8th week. Afterwards, LH decreased gradually until the 75th week. In general, LH values in males were lower than those in females. FSH, as well as LH, increased rapidly after gonadectomy. In male serum FSH reached a peak at the 8th week and then decreased showing two peaks at the 34th and 92nd weeks. Serum FSH level decreased remarkably after the 96th week in males. In females FSH increased gradually with a subsequent rapid increase from the 28th week and reached a peak at the 42nd week. Afterwards, this FSH level was maintained to the 128th week. Serum progesterone (P₄) decreased after gonadectomy in females, whereas it increased to 4 fold in males. In males this high level was maintained to the 66th week. Serum estradiol (E₂) decreased in both sexes until the 3rd week after gonadectomy. However, in males the serum E₂ level increased at the 4th and 5th weeks and reached the level of the 1st week after gonadectomy. Afterwards, the E₂ level decreased to 10pg/ml at the 40th week which was maintained to the 128th week. In females, E₂ increased from the 5th to 22nd week and decreased again from the 33rd week, and then the E₂ level decreased rapidly to about 10pg/ml which was maintained to the 128th week.
The present experiment indicated two results in male rats. 1. Serum FSH decreased remarkably after the 96th week of gonadectomy. 2. Serum P₄ increased in spite of gonadectomy.

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A 67-year-old man with SIADH complicated by slowly progressing autonomic failure was described. The patient noticed constipation at the age of 57. In the following years, he suffered from urinary incontinence, depletion of sweating, impotence, sleeplessness with snore, and dizziness while walking. Physical examination revealed a masked oily face with slight cerebellar disturbance.
Abnormality of autonomic function tests was recognized and he was diagnosed as Shy-Drager syndrome with gradually progressing, diffuse autonomic failure accompanied by slight cerebellar ataxia and Parkinsonism. Both serum sodium level and plasma osmotic pressure were reduced, whereas daily sodium excretion was more than 100mEq and urinary osmolality was about 500mOsm/kgH₂O. His renal function was intact, and the adreno-cortical and thyroid hormone levels were normal, then criteria of SIADH was fulfilled. SIADH was thought to have occurred on the basis of Shy-Drager syndrome.
Water load test showed failure of adequate water diuresis, but intravenous phenytoin administration following the water load test ameliorated the diuresis to normal. The relationship between plasma osmolality and the ADH response indicates that ADH was adequately secreted in response to the increase in plasma osmolality but not suppressed in response to the decrease in plasma osmolality below 280mOsm/kgH₂O. These results suggest that ADH synthesis in the hypothalamus and its secretion from the pituitary gland were both intact.
The response of ADH secretion to the orthostatic hypotension induced by head-up tilt was quite blunted, being compatible with Shy-Drager Syndrome. Sleep disturbance was studied by polysomnography and laryngoscopy, and was revealed to be based upon severe sleep apnea due to incomplete paralysis of the bilateral vocal cords. Sleep apnea due to vocal cord paralysis is sometimes found to be complicated in patients with multiple system atrophy (MSA) including Shy-Drager syndrome, and is known as Gerhardt syndrome.
This is the first report on a case of Shy-Drager syndrome complicated with SIADH and bilateral vocal cord paralysis. In this case, SIADH is caused by impaired afferent pathways from baroreceptors to the hypothalamus, which transfer inhibitory stimuli on ADH secretion. It is suggested that Shy-Drager syndrome should be considered one of the causes of SIADH.

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The effects of nutrition on serum insulin-like growth factor-1 (IGF-1) concentrations during pregnancy of rats were investigated by using rat cultured hepatocytes in vitro, and by the assessment of nitrogen balance in vivo. IGF-1 concentration was measured by radioimmunoassay, and nitrogen balance was calculated by Pregl-Dumas method. The results were as follows:
(1) Cultured rat hepatocytes produced IGF-1 in medium and it was significantly stimulated by the addition of various concentrations of glucose (1.1-4.4mM) and/or several amino acid concentrations in a doserelated manner.
(2) Serum IGF-1 concentrations, which indicated 368.6±143.8ng/ml in a non-pregnant fed state, markedly decreased in a fasted state, reaching the levels of 143.8±30.4ng/ml after 72 hours fasting. Nitrogen balance in these fasted rats also decreased according to the fasted period.
(3) In early pregnancy (Day 0-12), serum IGF-1 concentrations were indistinguishable from those of non-pregnant fed rats. It gradually declined after the 13th day of pregnancy and reached the minimum levels of 77.0±12.1ng/ml on the 21st day. On the other hand, mean nitrogen balance which was calculated from the difference of nitrogen retention in the maternal body and that in the fetal body, also decreased after 13 days of pregnancy and reached the levels of 14.9g/day on the 21st day of pregnancy.
These results suggested that IGF-1 concentrations in rat serum and conditioned medium might be regulated by nutritional factors, i. e., glucose and/or several amino acids. The curious profiles of IGF-1 concentrations observed in pregnant rats might be due in part to the effects of nutritional changes between the maternal and fetal body, especially, the changes of protein metabolism represented by the nitrogen balance.

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To investigate the influences of intrauterine stress on the aromatase activity (AA) in the perinatal rat's brain, mothers underwent 3 grades of stress: saline injection stress (S), light-heat-mild restraint stress (M), and forced immobilization stress (F). The aromatase activities in the offsprings' hypothalamus and amygdala were determined on day 19 of gestation and on the 1st day after birth. In addition, serum levels of testosterone (T) and androstenedione (A) were measured.
In males, perinatal levels of T and A decreased with every grade of prenatal stress. In females, T levels were not affected by prenatal stress. Fetal hypothalamic AA on the 19th day of gestation decreased significantly only in male fetuses of group M and F. Neonatal hypothalamic AA on day 1 after birth decreased only in males of all stress groups. Meanwhile, fetal and neonatal AA in the amygdala did not show any changes in either sex. These results indicate that intrauterine stress depletes both serum androgens and hypothalamic AA in the critical period for sexual differentiation of the brain, which mainly regulates the hypothalamic sex differentiation.

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