To clarify whether serum free fatty acid (FFA) is an inhibitor of extrathyroidal conversion (IEC) of thyroxine (T₄) to thyronine (T₃), we measured the concentration of FFA, IEC activity and thyroid hormones in normal subjects, acute ketotic children and children with low T₃ syndrome due to nonthyroidal illness (NTI). Iodothyronine (I) 5'-deiodinase activity was assayed with reverse triiodothyronine (rT₃) as substrate and liberated ¹²⁵I-was measured. The IEC was determined by the inhibition of I 5'-deiodination by ether extract of sera or standard oleate solution. IEC values were represented as mM oleate. The serum concentration of FFA was 0.470±0.117 (SD) mM in 11 normal subjects, and it was significantly higher (1.242±0.248mM; P<0.01) in 10 acute ketotic children and in 7 samples from 6NTI children (0.904±0.530mM; P<0.05). In contrast, there was no difference in IEC among three groups (normal subject, 0.451±0.069mM; acute ketosis, 0.437±0.040mM; NTI, 0.465±0.224mM). No correlations were found between IEC activity and the serum FFA concentration or thyroid hormones in 28 samples from three groups. The sequential changes in serum thyroid hormones, FFA and IEC in 3 of 6 NTI children revealed no consistent relationship. Furthermore, one NTI child had significantly high IEC (>1.000mM) but its serum FFA (1.182mM) was below the mean value for the acute ketotic group. These results indicate that 1) many NTI patients may bear no relation to IEC and 2) IEC may not be caused by serum FFA only but includes several factors.

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A familial case of generalized resistance to thyroid hormone (GRTH) is described. A 17-year-old man (case 1), who had been treated with methimazole under the diagnosis of Graves' disease and his 11-year old sister (case 2) visited our clinic for the evaluation of their thyroid function. They lacked the signs and symptoms of thyrotoxicosis in spite of extremely high serum thyroid hormone levels. Their plasma TSH levels were not suppressed, but in fact markedly increased after TRH loading. Their peripheral indices of thyroid hormone were within normal limits and were not influenced by exogenous T₃ administration. Even 150μg T₃ administration for 7 days did not fully suppress the TRH-stimulated TSH level in case 2. The two patients thus were diagnosed to have GRTH. Sera from their father and another sister showed identical abnormalities.

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To examine whether or not dehydroepiandrosterone sulfate (DHAS) is a substrate for steroidogenesis in the corpus luteum, we studied 17 women in the luteal phase, the follicular phase, and after castration. Following suppression of adrenal function with dexamethasone, DHAS was administered intravenously and the serum levels of DHAS, dehydroepiandrosterone (DHA), androstenedione (ADS), testosterone (T), 17β-estradiol (E₂) and progesterone (P) were measured serially for 24h. Anobvious increase in the serum levels of all steroids except for E₂ and P was observed in each subject for at least 8h after DHAS administration. To evaluate the effect of DHAS on the serum levels of the steroid hormones, the integrated response area (IRA) was calculated for each hormone in all the subjects. The IRA values for ADS, T and E₂ (at 2 and 4h) in the luteal phase group were significantly higher than in the other DHAS treated groups, and the IRA values for DHA and P tended to be higher than in the other groups. These results suggest that the corpus luteum utilizes serum DHAS as a substrate for steroidogenesis.

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Increasing evidence of the interaction of glucocorticoids and ovarian steroids prompted the current study. Effects of exogenously administered corticosterone acetate (3.5mg/100g b.w/day for one week) were examined on splenic nucleic acids, protein, lactate, and on lactate dehydrogenase (LDH) specific activity and its isozymes in ovariectomized and ovary-intact Wistar rats (65-75 days old). Ovariectomy resulted in no significant change in the parameters studied except DNA which increased significantly. The administration of corticosterone to these rats did not produce any remarkable change in the ovariectomy caused increase in splenic DNA content. Nevertheless, it decreased the ratio of heart type subunits (H)/muscle type subunits (M)[H/M] of LDH isozymes. In the case of ovary-intact rats, corticosterone produced an increase in the concentration of splenic lactate but a decrease in the H/M ratio. Exogenously administered corticosterone exerts selective synergistic interaction with ovarian hormones on splenic lactate. The specific activity of LDH and the concentrations of RNA and protein remained unchanged during the interaction between ovarian hormones and corticosterone.

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To characterize parathyroid hormone-related protein (PTHrP) in the human placenta, we measured PTHrP-like immunoreactivity (PRP-LI) in the term placenta and studied the elution profiles of placental tissue extracts on Sephadex G-75 chromatography with a specific RIA. We also examined the gene expression of PTHrP mRNA by Northern blot analysis and the localization of PRP-LI in the placenta by immunohistochemistry. The amount of PRP-LI in placental extracts (n=7) was 20.9±2.2pg/g wet tissue (mean±SE). Dilution curves of placental tissue ran parallel to those of synthetic PTHrP (1-34) standards. Sephadex G-75 gel chromatography demonstrated two major PRP-LI peaks; the first peak was eluted around the molecular size between 10 kilodaltons (Kda) and 20 Kda and the other around 5 Kda. Northern blot analysis of PTHrP mRNA extracted from placental tissues showed a major hybridization signal around 18S. PTHrP immunohistochemistry showed PRP-LI staining in the cytoplasm of syncytiotrophoblasts and stroma cells (Hofbauer cells) in the term placenta. These results suggest that syncytiotrophoblasts and stroma cells in the term placenta synthesize PTHrP in two major molecular forms, 10 Kda-20 Kda and around 5 Kda.

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Adrenal computed tomographic (CT) scanning was conducted in twelve patients with Addison's disease during the clinical course. In tuberculous Addison's disease (n=8), three of four patients examined during the first two years after disease onset had bilaterally enlarged adrenals, while one of four had a unilaterally enlarged one. At least one adrenal gland was enlarged after onset in all six patients examined during the first four years. Thereafter, the adrenal glands may atrophy bilaterally, in contrast to adrenal glands in idiopathic Addison's disease, which atropy bilaterally from disease onset (n=2). Adrenal calcification was a less sensitive clue in tracing pathogenesis, i.e., adrenal calcification was observed in five of eight patients with tuberculous Addison's disease, but not in idiopathic patients. Thus, adrenal CT scanning could show the etiology of Addison's disease (infection or autoimmunity) and the phase of Addison's disease secondary to tuberculosis, which may be clinically important for initiating antituberculous treatment.

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Transient extreme insulin resistance was encountered during an episode of diabetic ketoacidosis (DKA) in an insulin-treated diabetic patient. On admission, the plasma glucose level was 1241 mg dl^-1 and arterial blood pH 6.895 with HCO₃^- 4.7mEql^-1. An intravenous bolus injection of 20 units, followed by continuous infusion of 20 units h^-1 of short-acting regular human insulin, was instituted. Ischemic myocardial changes were noted on the initial electrocardiogram, therefore fluid replacement was limited to 1, 000ml of 0.9% saline solution in the first hour. As the plasma glucose level declined by only 203 mg dl^-1 (41 mg dl^-1 h^-1) in the first 5h, the insulin dose was doubled every 2h. At hour 4, the patient developed circulatory shock which required vasopressor support and respiratory assistance. A plasma glucose level of 300 mg dl^-1 was not achieved until the total dosage of insulin amounted to 91, 580 units at hour 25. Insulin resistance was not observed from that point on. The patient had neither insulin antibodies nor anti-insulin receptor antibodies in serologic testing. Theinsulin binding characteristics of the patient's erythrocytes were similar to those from healthy controls both with and without experimental acidosis and with a high level of β-hydroxybutyrate. Among multiple potential factors, the severe shock associated with DKA has been considered as a primary cause of the transient severe insulin resistance in this case.

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Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein. Several inherited TBG variants resulting in partial or complete TBG deficiencies have been shown to be caused by either one or two nucleotide substitutions, or one nucleotide deletion in the coding regions of the TBG gene. In this report, a Japanese female patient (proband) with hyperthyroid state, whose lower TBG levels did not return to normal under the euthyroid state after treatment was examined. Genomic DNA samples from the proband with thyroxine-binding globulin deficiency (termed TBG-Kumamoto) and her family were subjected to the polymerase chain reaction, and the generated DNA fragments were sequenced. A single nucleotide substitution in the codon for the amino acid 363 of native TBG molecule (CCT to CTT) was found, resulting in the replacement of proline by leucine. It was revealed that the proband was a heterozygote and her father was a hemizygote. The mutation was confirmed by the allele-specific amplification of genomic DNAs from the proband and her father using oligonucleotide primers of normal or mutant residues at the 3' position in the polymerase chain reaction. These results indicate that the abnormality of TBG-Kumamoto is the consequence of this mutation. Genetically, this point mutation observed in TBG-Kumamoto might be classified as a new type of TBG deficiency.

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To analyze the utility of insulin-like growth factor binding protein-3 (IGFBP-3) radioimmunoassay for diagnosis of growth hormone deficiency (GHD) we measured IGFBP-3 in sera from normal children, short children and patients with GHD. The sensitivity (true positive ratio) of IGFBP-3 for complete GHD (cGHD) was 93%, while the specificity (true negative ratio) for normal short children (NS) was 88%. In contrast, the sensitivity of IGFBP-3 for partial GHD (pGHD) was only 43%. The poor discrimination between patients with pGHD and NS may be the result of their relatively similar GH level, as compared to cGHD, or due to the limitations of GH stimulation tests. The specificity of IGFBP-3 for NS was excellent in children of all ages: less than 10 years old (87%) and older than 10 (88%). However, sensitivity for GHD was good for children less than 10 years old (84%) but poor for children older than 10 (64%). IGFBP-3 may be less sensitive for diagnosing GHD in older children because IGFBP-3 levels may also increase during puberty due to mechanisms independent of the GH-IGF-I axis.

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We report the case of a 70-year-old man who developed hypothyroidism associated with TSH receptor antibodies and severe ophthalmopathy during lithium therapy. He had received lithium therapy for more than 20 years for manic depression, when ophthalmopathy (class VI of the American Thyroid Association classification) and mild hypothyroidism developed. Orbital magnetic resonance imaging indicated marked enlargement of the superior, medial and inferior rectus muscles in the left eye. He had anti-eye muscle antibodies in his serum, detected by Western blotting and quantified by chromatoscanning, as well as anti-TSH receptor antibodies. He was treated with supplementation of levothyroxine and four cycles of methylprednisolone pulse therapy. After the pulse therapy, both anti-eye muscle antibodies and anti-TSH receptor antibodies decreased and disappeared in parallel with the improvement in eye symptoms and signs. These observations suggest the importance of anti-eye muscle antibodies as clinical markers in the development of thyroid-associated ophthalmopathy.

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To analyze whether prolactin (PRL) in human follicular fluid (FF) is synthesized locally or derived from the circulation, PRL concentrations of plasma and FF were determined in the patients after ovarian stimulations. The amounts of PRL messenger ribonucleic acid (mRNA) in the follicular tissues during different menstrual phases were also determined. The FF PRL concentration was correlated positively with plasma PRL and highest estradiol levels during the stimulatory cycle. No PRL mRNA sequence was detected in the RNAs extracted from follicles at any stage in the menstrual cycle, although β-actin mRNA was detected in all samples. In a comparison with pituitary RNA, the PRL mRNA concentration in ovarian follicular tissues seemed to be 10, 000 times less than that in the pituitary. These results suggest that FF PRL may not be synthesized locally, but derived from the pituitary via the circulation through passive diffusion, and thus regulated by estrogen.

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Immunocytochemical double-staining analysis revealed that in the rat anterior pituitary 86% of cells containing the βll-subspecies of protein kinase C also contained follicle stimulating hormone (FSH), and that 22% of these FSH cells expressed the βII-subspecies. These findings suggest a close relationship between the βll-subspecies of protein kinase C and FSH regulation.

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The in vivo effects of gestrinone (R2323) and medroxyprogesterone acetate (MPA) on the estrogen production by rat ovaries were investigated. Hypophysectomized immature female rats treated with 2.5 or 5 IU of pregnant mare serum gonadotropin (PMS) were daily given vehicle only, gestrinone (0.5mg/kg body weight) or MPA (10mg/kg body weight), and the activities of 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, 17, 20-lyase, 17β-hydroxysteroid dehydrogenase and aromatase in ovaries of these rats were measured. Gestrinone suppressed the 3β-hydroxysteroid dehydrogenase activity and increased activities of 17α-hydroxylase, 17, 20-lyase and aromatase in ovaries stimulated by 5 IU of PMS, while MPA suppressed activities of 17α-hydroxylase and aromatase in these ovaries. On the other hand, the aromatase activity in ovaries stimulated by 2.5 IU of PMS was suppressed by gestrinone and increased by MPA, and neither gestrinone nor MPA affected the production of aromatizable androgens from progesterone by these ovaries. Thus, gestrinone and MPA administrated in vivo showed divergent influences on steroidogenic enzyme activities in ovaries, but they did not affect the serum concentration of estradiol-17β. The present results suggest that neither gestrinone nor MPA reduced estrogen production by the rat ovary under the gonadotropin stimulation although they influenced some process of its steroidogenesis.

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