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A total of 203 patients with Turner's syndrome were treated with three different kinds of recombinant hGH preparations for one year. One hundred and seven patients were treated with hGH at a weekly dosage of 0.5 IU/kg, 71 with 1.0 IU · kg−1 · week−1, and the remaining 25 patients with combined administration of 0.5 IU · kg−1 · week−1 hGH and a small amount of anabolic steroid. All three treatment groups showed statistically significant growth increases during the treatment. Fifty percent of the patients treated with 0.5 IU · kg−1 · week−1 and 80% of the patients treated with 1.0 IU · kg−1 · week−1 showed growth rates more than 2 cm per year greater than pretreatment values or beyond the second sd of the untreated growth rate. Plasma somatomedin C levels were elevated and no remarkable advances in bone age were observed during the treatment. Antibody against hGH was observed in 71.4% and 10.8% of the methionylhGH and methionine-free-hGH treated patients, respectively. However, the antibodies did not suppress the growth promoting effect of methionyl-hGH. Otherwise, there were no significant changes in physical or laboratory examinations. No glucose intolerance was observed. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.

The presence of IGF-I receptors was demonstrated in normal and neoplastic tissues of human thyroid. Binding of [125I]IGF-I to thyroid membranes was dependent on time and temperature of incubation, and maximal binding was achieved at 4°C and 18 h of incubation. [125I] IGF-I binding was dose-dependently displaced by unlabelled IGF-I; half-maximal inhibition occurred at concentrations of 10–20 μg/l. IGF-II and insulin had relative potencies of 5 and 1% compared with IGF-I. Scatchard analysis of binding data revealed a single class of IGF-I receptors with high affinity (Ka: 1.2–8.6 × 109 1/mol) in normal thyroid tissues. Affinity cross-linking and autoradiography demonstrated the type I IGF receptors. Specific binding of [125I] IGF-I in thyroid cancer tissues (9.69 ± 2.07% per 200 μg protein; mean ± sem, N = 8) was significantly (p

The effect of iodide on growth of rat thyroid cells (FRTL-5) was studied. TSH-stimulated cell growth was inhibited by iodide in a concentration-dependent manner, and an effect of iodide was detected at 10−6 mol/l. KClO4 or 1-methylimidazole-2-thiol blocked the effect of iodide, suggesting that iodide uptake and its organification are required to produce the inhibitory effect of iodide on cell growth. Iodide not only decreased TSH-stimulated cAMP production in FRTL-5 cells but also cell growth induced by cAMP. These observations suggest that iodide inhibits TSH-stimulated growth of the cells by attenuating cAMP production and also by acting on the step(s) distal to cAMP generation. The inhibitory effect of iodide was also seen in growth stimulated by insulin, insulin-like growth factor-I or 12-O-tetradecanoyl phorbol 13-acetate, suggesting multiple sites of action of iodide in the process of growth of FRTL-5 cells.

Twenty patients with Turner's syndrome were treated with methionyl human growth hormone (met-hGH) produced by recombinant DNA technology. Plasma non-esterified fatty acid (NEFA) (mean ± sem) increased significantly from 0.52 ± 0.06 to 1.30 ± 0.09 mEq/l at 4 h after the first administration of 4 IU of met-hGH (P P < 0.001). For long-term treatment, the patients were given 16 IU of met-hGH per week for 6 months. The height increase during treatment was greater in 16 patients, but smaller in 4 than before treatment. The heights increased between 1.4 and 3.7 cm during 6 months of treatment, which corresponds to between 2.8 and 7.4 cm/year. The mean increase of 5.7 ± 0.4 cm/year was greater than the pretreatment value of 3.7 ± 0.2 cm/year (P P < 0.05). Antibody against hGH appeared in 3 patients after 2 months; 10 of the 20 patients had antibody after 6 months of treatment. However, the antibody did not suppress the growth effect of met-hGH. Otherwise there were no significant changes in physical, blood, or urine examinations. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.

The effect of phorbol diester tumour promoters on the release of growth hormone (GH) and prolactin (Prl) was studied in rat pituitary cells cultured in monolayer. 12-O-tetradecanoyl phorbol-13-acetate (TPA), the most potent phorbol ester, stimulated GH accumulation in the cultured medium in a dose-dependent manner. TPA also stimulated Prl accumulation. A time course study indicated that TPA mainly stimulates release of GH. The maximal stimulation of GH release by TPA (100 ng/ml) was 3–4-fold over control. Phorbol-12,13-dibutyrate (PDB), another tumour-promoting phorbol ester, stimulated GH release to an extent similar to that of TPA, while a biologically inactive compound, phorbol-12,13-diacetate (PDA), had no effect. TPA-stimulated GH release was not affected by the presence of indomethacin, an inhibitor of prostaglandin (PG) synthesis, indicating that PG is not involved in the process of TPA-stimulated GH release. Co++, a competitive antagonist of Ca++, at 2.0 mm completely suppressed the GH release induced by TPA, and this inhibition was partially reversed by the addition of 2.0 mm Ca++. Verapamil, a Ca++ channel blocker, reduced TPA-stimulated GH release, and trifluoperazine, an inhibitor of Ca-calmodulin formation, had a similar effect. Somatostatin (SRIF) also inhibited the GH release by TPA. These observations are compatible with the idea that Ca++ may be involved in the process of TPA-stimulated GH release. Since TPA has been reported to activate a Ca++- and phospholipiddependent protein kinase (protein kinase C), it is possible that TPA stimulate GH release by activating the enzyme. Further studies are required to clarify this point.

Nocturnal urinary growth hormone values were measured by a sensitive enzyme immunoassay in normal adults, patients with GH deficiency, patients with Turner's syndrome, normal but short children who had normal plasma GH responses to provocative tests, and patients with acromegaly. The mean nocturnal urinary GH values in patients with acromegaly were significantly greater than those in normal adults (1582.3 ± 579.8 vs 53.5 ± 8.6 pmol/mmol creatinine (± sem); p < 0.05). In the normal but short children and patients with Turner's syndrome, the mean nocturnal urinary GH values were 83.1 ± 5.2 and 79.8 ± 29.5 pmol/mmol creatinine, respectively. In patients with GH deficiency, the nocturnal urinary GH values were undetectable (< 5.3 pmol/mmol creatinine) except in one patient where the value was 6.3 pmol/mmol creatinine. The nocturnal urinary GH values of the patients with GH deficiency were significantly lower than those of the other groups (p < 0.05). In normal but short children, the nocturnal urinary GH values correlated significantly with mean plasma nocturnal GH concentrations (r = 0.76, p < 0.001), and 24-hour urinary GH values (r = 0.84, p < 0.001), respectively. In 4 patients with GH deficiency who had circulating anti-hGH antibody, the urinary GH values were also undectable. These data indicate that nocturnal urinary GH value reflects endogenous GH secretion during collection time, and that measurement of the nocturnal urinary GH values is a useful method for screening of patients with GH deficiency and acromegaly.

LH is composed of isoforms which exhibit microheterogeneity. We recently demonstrated that a particular ovine or porcine LH preparation (G100-fr.3) stimulates kidney growth. This study was conducted to clarify the physiological role of this renotropic activity and other extragonadal effects of the ovine LH preparation in CD-1 mice. Hypophysectomy caused a significantly greater reduction in relative dry kidney weight (i.e. g/100 g body weight) when compared to adrenalectomy, castration, thyroidectomy, and castration plus thyroidectomy. Supplementation with G100-fr.3 in these animals partially restored not only kidney size but also DNA, RNA and protein content. Treatment with standard LH preparations (NIDDKoLH24 and G3-268DA), as well as PRL, GH, FSH and TSH, failed to reverse the renal atrophy induced by hypophysectomy and castration. Administration of testosterone to castrated hypophysectomized mice increased kidney weight and RNA content, but not renal DNA. The relative dry kidney weight increased significantly at the onset of puberty in intact male mice, but not in castrated males or intact female mice. In addition, human CG increased kidney size in hypophysectomized male mice, but not in castrated hypophysectomized animals. These findings indicate that LH isoforms may regulate kidney growth in the male mouse both directly as a renotropin stimulating hyperplasia and indirectly as a gonadotropin via testicular androgen, producing cellular hypertrophy. It was also noted that G100-fr.3 decreased hepatic weight, DNA, RNA and protein, but produced no significant change in the spleen, heart or adrenal glands in castrated-hypophysectomized mice. Such extragonadal effects of G100-fr.3 were also observed in intact female mice. These results suggest that certain LH isoforms may have extragonadal actions involving the kidney and liver.

Changes in serum somatomedin A levels and [125I]somatomedin A binding to membrane fractions from kidney were studied in rats 1–80 days of age. The mean level of serum somatomedin A was 0.80 U/ml at birth and increased with age; at 80 days the mean level was 7.41 ± 0.67 U/ml. There was a close correlation between serum levels of somatomedin A and body weight. Labelled somatomedin A binding to membrane fractions from kidney was highest at birth and decreased with age up to 50 days. In Scatchard analysis of the data the affinity constant did not show a clear change with age, but the binding capacity decreased with age up to 30 days. An inverse correlation was observed between serum somatomedin A levels and labelled somatomedin A binding to membrane fractions from kidney. Compared to changes in circulating somatomedin A, the change in tissue binding was modest. This observation suggests that other circulating growth factors not measured by this radioreceptor assay or altered post-receptor sensitivity to somatomedins may be involved in growth.

Nb2 cell is a rat lymphoma cell line that responds to lactogens such as prolactin and human growth hormone (hGH) with an increased rate of proliferation. We explored the relationship between the biochemical events induced by hGH and its derivatives and their receptor binding activities. hGH stimulated RNA, DNA and protein synthesis of Nb2 cells as a function of time. Stimulation of RNA and protein was maximal at 2–3 h and 12 h, respectively, after the addition of hGH. DNA synthesis, measured by the rate of [3H]thymidine incorporation, reached a maximum after 18-h incubation with hGH. Stimulation of DNA synthesis was elicited by hGH in a dose-dependent manner between 0.45 and 45 pmol/l. The activity of the 20 K hGH variant in stimulating DNA synthesis was approx 30% of that of hGH. In contrast, S1-hGH, which lacks a sequence of ten amino acids (140–149) of hGH, showed a 3.2-fold greater activity than hGH. F1 (aminoterminal sequence 1–134 of hGH) was only 0.06% as active as hGH, and the activity of F2 (C-terminal 42 amino acid residue of hGH) was less than 0.01%. Both fragment 1–15 and 32–46 were without effect. The relative potencies of these hGH derivatives in stimulating DNA synthesis were similar to their relative abilities to inhibit [125I]hGH binding to lactogenic receptors on Nb2 cell. Nb2 cells provide a suitable model to study the relationship between receptor binding and the biochemical events induced by lactogens.

The effect of insulin on the generation of somatomedin by a monolayer culture of rat hepatocytes was investigated. Release of somatomedin into the medium of cultured hepatocytes was observed for at least three days, as determined by a radioreceptor assay for somatomedin A. The addition of 1–100 μg/ml insulin to the medium caused dose-related increases in somatomedin A in the conditioned medium for up to three days. The conditioned medium also stimulated DNA synthesis in human fibroblasts. To investigate hormone degradation by hepatocytes, labelled somatomedin A or insulin was added to the medium and the degradation was examined by trichloroacetic acid (TCA) precipitation, and gel chromatography. Although [125I]somatomedin A was slightly degraded even after 24 h of incubation, [125I]insulin was degraded within 6 h and the TCA precipitation at 24 h was 15% only. This degradation of hormones was inhibited by 1 mm bacitracin. Insulin stimulation of somatomedin production was significantly increased to 131.2% as compared with cultures without bacitracin. The molecular size of the somatomedin released into the medium was greater than that of purified somatomedin, suggesting that this somatomedin is bound to carrier proteins.

A 72-year-old man with Cushing's disease was treated with trilostane, a competitive inhibitor of adrenal 3β-hydroxysteroid dehydrogenase (3β-HSDH). The treatment with trilostane successfully lowered urinary excretion of 17-hydroxycorticosteroids (17-OHCS) and plasma levels of cortisol and elevated the plasma level of dehydroepiandrosterone. Unexpectedly, plasma ACTH fell from 109.7 ± 45.0 to 42.7 ± 27.3 pg/ml (P < 0.01) in parallel with plasma cortisol. The hyperresponsiveness of plasma ACTH observed both in the metyrapone test and the lysine-vasopressin test was also ameliorated by treatment with trilostane. Then low dose of pituitary irradiation with cobalt-60 was added and his urinary excretion of 17-OHCS and plasma levels of cortisol decreased further. After treatment with trilostane was finally stopped, the plasma ACTH increased from 45.9 ± 21.9 to 69.6 ± 25.3 pg/ml (P < 0.05) in parallel with plasma cortisol. Since then he has had no recurrence for 12 months. These observations suggest that trilostane, like other adrenal enzyme-inhibiting drugs, may induce unexpected improvement of the abnormality of the hypothalamic-pituitary axis present in Cushing's disease.

Somatomedin A was determined by radioreceptor assay of serum from rats with various conditions. The mean value of somatomedin A in 28 day old male rats was 6.2 ± 0.44 U/ml. Following hypophysectomy, serum somatomedin A decreased with a half-life of approximately 6 h. After a single ip injection of human growth hormone into hypophysectomized rats, the levels of somatomedin A increased within 4 h and reached the maximal level between 8 and 24 h. There was a dose-dependent increase of somatomedin A at 24 h after injection of hGH when the injected dose was between 3.2 and 80 μg. Serum somatomedin A was significantly decreased after 24 h of fasting to the same levels as after hypophysectomy. However the changes in serum rGH between fasting rats and fed rats did not show any significant differences. After different intakes of diets with different composition for 32 days, the mean levels of serum somatomedin A were 14.5 ± 2.2, 6.22 ± 0.4, 2.5 ± 0.3 and 13.0 ± 1.1 U/ml when control-, high protein-, high carbohydrate-low protein- and high fat diets were given respectively. There was a positive correlation between the per cent increase in weight and the serum level of somatomedin A. These results indicate that not only growth hormone but also adequate food intake is required for the generation of somatomedin.

Serum levels of somatomedin A, as measured by radioreceptor assay, and body weight gain were 86.5 ± 9.2% and 166.9 ± 7.8% (N = 5) of the initial values, respectively, after 18 days administration of 2.5 mg cortisone acetate (CA). These values were significantly lower than those for saline treated rats (P < 0.005). Reduced serum somatomedin A and body growth rate were partially restored after halting the injection of CA. Combined administration of daily doses of 100 μg hGH with CA did not prevent the decrease in somatomedin activity in treated rats. This observation suggests that GH plays a minor (or no) role in the fall of serum somatomedin A in CA-treated rats. From these data we conclude that glucocorticoids reduce serum somatomedin by inhibiting the effect of GH on the generation of somatomedin.

Eighteen patients with pituitary dwarfism were treated for 1 7/12 to 6 years with human growth hormone (hGH) at a dose of 0.19–0.62 unit (U) per kg of body weight per week. The mean increment in height was 2.0 ± 0.4 and 8.8 ± 0.5 cm/year before and the first year after treatment of hGH, respectively. A significant positive correlation was observed between serum levels of somatomedin A and growth rate, especially in children with bone age below 10 and a duration of treatment of less than one year (r = 0.66, P < 0.005). Long-term treatment with hGH was accompanied by a decreasing response. However, the serum levels of somatomedin A did not decrease significantly. Therefore, decreased growth increment in these situations was not due to decreased serum levels of somatomedin A.

Synthetic human pancreatic GRF (hpGRF-44) was administered sc to 8 normal children with short stature and 11 patients with GH deficiency. After a dose of 100–200 μg hpGRF-44, mean plasma GH levels reached a peak at 15 min of 27.2 ± 6.4 (± se) ng/ml in normal children. However the responses were variable and peak plasma GH varied from 10.1 to 56.5 ng/ml. Eight of 11 patients with idiopathic GH deficiency did not respond to sc administration of 100–300 μg hpGRF-44. However, a plasma GH increase of more than 5 ng/ml occurred in 2 patients and to twice the basal level in 1 patient. Their GH values were 14.3, 5.2 and 3.4 ng/ml, respectively. After repetitive administration of hpGRF-44 (200 μg, twice a day) sc for 5 consecutive days, 2 of 8 patients restored their responsiveness, but the remaining patients did not show GH rise in response to both sc and iv bolus administration of hpGRF-44. Repetitive hpGRF-44 administrations for 5 days had no effect on somatomedin-C production.

Pituitary growth hormone (GH) responses during a 10-h iv infusion of saline or human GH-releasing factor (hGRF-44) at 500 ng/kg/h, followed by an iv bolus injection of hGRF-44 at 2 μg/kg body weight, were studied in 10 patients with GH deficiency. During saline infusion in 4 patients, small plasma GH increase were observed in 2 patients. However, during hGRF infusion in 6 patients, up to 4 or 13 pulses of GH secretion were observed. The mean integrated GH pulse area during hGRF infusion was 22.5 ± 5.2 (se) ng/ml × h, which was greater than that obtained during saline infusion. Plasma somatomedin C levels did not increase after hGRF infusion. After saline or hGRF infusion all patients responded to an iv bolus injection of the peptide. These results indicate that hGRF infusion augments GH secretion by increasing the number and amplitude of GH pulses and that the infusion does not cause pituitary somatotrophs to lose their capacity to respond to hGRF subsequently.

Effects of chlorpromazine (CPZ) on plasma GH and prolactin levels were observed in conscious rats provided with chronic indwelling right atrial cannulae. The administration of CPZ (200 μg/100 g b.w. iv) suppressed episodic plasma GH burst and resulted in significant elevations of plasma prolactin levels. These were also observed in rats in which two types of hypothalamic deafferentation, i.e. anterior and complete, had been carried out. The data suggest that CPZ acts within the medial basal hypothalamus and inhibits episodic plasma GH secretion. In addition, it is inferred that catecholamines are involved in the generation of episodic plasma GH burst.

IM-9 cultured human lymphocytes were treated with N-linked glycosylation inhibitors, N-linked oligosaccharide processing inhibitors, or neuraminidase to study the effect of glycosylation modification on human growth hormone binding and molecular weight of surface hGH receptor. One mg/l tunicamycin and 20 mmol/l glucosamine decreased 125I-hGH binding to the cells to 46.3 ± 2.4% (mean ± sem) and 21.9 ± 0.2% of the controls, respectively. The hGH binding was 33.0 ± 18.4% of the control value in the cells treated with monensin. The inhibition of binding was due to a decrease in the hGH receptor number without any affinity changes in these cells. Neither 1 mg/l swainsonine nor 100 mg/l castanospermine had any effect on the hGH binding. On the other hand, 125I-hGH binding to neuraminidase-treated cells was significantly enhanced with accompanying affinity changes. When 125I-hGH was cross-linked to IM-9 cells, there were no differences in the molecular weight of hGH receptor complexes (140K) between untreated cells and cells treated with tunicamycin, glucosamine, monensin, or castanospermine. However, the 128K hGH-receptor complex appeared in swainsonine-treated cells; this complex was sensitive to endoglycosidase H. These data show that the altered carbohydrate moiety changed hGH binding and the size of surface hGH receptor and suggest that glycosylation of receptor is important for the binding of hGH and for its physiological action.

Three patients with idiopathic hyperaldosteronism were continuously treated with trilostane, a competitive inhibitor of adrenal 3β-hydroxysteroid dehydrogenase (3β-HSDH) (3 to 4⅔ years). Trilostane, in conjunction with antihypertensive drugs, effectively decreased plasma aldosterone levels and improved hyperaldosteronism symptoms without undesirable side effects. Trilostane continued to be effective even when treatment was continuous. Rapid ACTH testing (iv bolus of 0.25 mg α1–24 ACTH) was done on the day without trilostane after long-term treatment, and plasma levels of aldosterone and cortisol were compared to those obtained during a pre-treatment period. Results suggest that the inhibitory effect of trilostane on steroid biosynthesis rapidly disappears following discontinuance of trilostane administration even after long-term treatment, and that continuous treatment causes no significant or irreversible change in steroid biosynthesis. These results suggest that trilostane is a safe, feasible therapeutic agent for long-term treatment of idiopathic hyperaldosteronism.

Recombinant human growth hormone is more antigenic than pituitary preparations. Since GH antibodies interfere with radioimmunoassay of GH, we measured plasma free and total GH in patients with pituitary dwarfism with GH antibodies during treatment with a recombinant methionyl GH preparation. Plasma free GH was measured in the supernatant after polyethylene glycol precipitation. Total GH was measured after extracting plasma with acid-ethanol. In normal subjects, both free and total GH levels were similar to those measured in plasma by a direct conventional RIA. Peak free GH levels after administration of 4 IU methionyl GH to 3 normal subjects were 38.0,30.7 and 13.2 μg/l, values similar to those measured in most of the patients with GH antibodies. All values were undetectable in one patient with a very high antibody titre. Total GH levels were similar to free GH levels in normal subjects. In patients with GH antibodies, total GH levels were high compared with their free levels, but similar to those assayed by conventional RIA. The patient with the highest antibody titre had total GH levels which were the lowest of those observed in the patients with GH antibodies in spite of having the highest GH levels measured by conventional RIA. The antibody in this particular case may have a high capacity and a high affinity. A relatively poor growth rate in this patient may be associated with the finding of undetectable free GH levels. Measurement of plasma free and total GH may be of value in examining GH dynamics and their relation to the clinical effectiveness of GH treatment in patients with GH antibodies.

The distribution of immunoreactive ACTH (I-ACTH) and corticotropin-releasing factor (I-CRF) in the human adrenal was determined and these peptides were indentified in adrenocortical adenomas from patients with primary aldosteronism, Cushing's syndrome, and ovarian tumours and compared with the results in phaeochromocytomas. I-ACTH and I-CRF, mainly localized in the adrenal medulla from patients without endocrine disorders, showed a good correlation with the epinephrine concentrations. I-ACTH and I-CRF were present in all the above-mentioned tumours. Gel filtration of I-ACTH and I-CRF from these tumours showed the presence of large molecular weight forms of these peptides as well as authentic peptides. The trypsinization study of I-CRF from phaeochromocytoma suggested that such large molecular weight forms were the precursors of authentic CRF. High performance liquid chromatography showed I-CRF in these tumours to be similar to hypothalamic CRF. Phaeochromocytoma tissue slices incorporated [3H]leucine into ACTH and CRF. These findings raised the possibility that I-ACTH and I-CRF are synthesized and processed in phaeochromocytoma.

The levels of serum somatomedin A were determined in 59 growth retarded Japanese children by a radioreceptor assay. Low levels were found in 10 children with growth hormone (GH) deficiency and 7 children with relative GH deficiency with means of 0.26 ± 0.03 and 0.48 ± 0.04 U/ml, respectively. Serum somatomedin A levels in 42 growth retarded children with normal growth hormone levels were within the range of normal adults, and did not correlate with degree of short stature. Significant increases of somatomedin A after hGH administration were found in children with growth hormone deficiency but not in children with normal growth hormone. These results show that determination of somatomedin A in serum correlates well with the state of growth hormone secretion, and is of great importance in the selection of patients for treatment with human growth hormone.

To elucidate the effect of rT3 on iodothyronine-5′-deiodinating activity (I-5′-DA) in the liver of neonatal mice, rT3 was injected sc on the 5–8th day after birth and I-5′-DA in the liver was determined. A single injection of rT3 (0.01–1 μg/g) inhibited the ontogenetically developing I-5′-DA in a dose- and time-dependent manner. The inhibitory effect was reversible and specific for I-5′-DA. Lineweaver-Burk analysis revealed that the time- and dose-dependent decrease in the enzyme activity was due to a decrease in Vmax with no alteration in Km values (5 × 10−8 mol/l). The maximal inhibitory effect was observed at a dose of 1 μg rT3/g, whereas the inhibitory effect was diminished at greater doses (4–10 μg/g), probably owing to a contamination with T4 of the rT3 preparation administered. Furthermore, consistent with our previous in vitro findings, rT3 inhibited the I-5′-DA induced by T3 in the liver of neonatal mice. These findings suggest that rT3 inhibited I-5′-DA in the liver of neonatal mice by decreasing the amount of enzyme available to the substrate and that rT3 also elicited an antagonistic effect against T3 in the induction of I-5′-DA in vivo.

The effect of growth hormone (hGH) on the hypothalamic-pituitary-thyroid function was studied in patients with pituitary dwarfism. Twenty-six patients were given KABI hGH, 0.5 U/kg/week, for a period of 4—18 months. Three groups of patients were identified according to their T4 levels before and during the treatment. Group 1: T4 levels were initially normal and stayed in the normal range throughout a course of treatment. Group 2: T4 levels were initially normal but dropped to the subnormal range after hGH. Group 3: T4 levels were initially subnormal and decreased further after hGH. Changes in T4 levels after hGH in groups 2 and 3 were accompanied by a decrease in plasma T3RSU without concomitant decrease in plasma T3. Clinically, most of them lacked symptoms and signs of hypothyroidism and exhibited a good growth response to hGH. Plasma TSH response to TRH in these patients revealed a sustained delayed pattern, which was suggestive of hypothalamic hypothyroidism. This pattern of TSH response to TRH became further exaggerated after hGH therapy. In contrast, TSH response to TRH among patients in group 1 was normal and was not influenced by hGH. Administration of 4.0 U of KABI hGH daily for 21 consecutive days to 3 patients resulted in a shortened half-life of T4 and inversely prolonged that of T3. These results suggest that various degrees of TRH deficiency exist among patients with idiopathic pituitary dwarfism. Therapy with hGH discloses a mild TRH deficiency by accelerating the half-life of T4. This also causes a further drop in the T4 levels in those with marked TRH deficiency. The development of clinical hypothyroidism is not so obvious in these patients because of inverse delay in half-life of T3 by hGH.

The placental secretion of Prl, ACTH and immunoreactive (IR)-beta-endorphin were examined in early and later pregnancy with a perfusion method and by determining tissue concentrations of these hormones. Prl was secreted mainly from decidual tissue during 5-6 h long perfusions. Tissue concentrations of Prl were also significantly higher in decidual than in trophoblastic tissue. In contrast, the tissue concentrations of hCG, hPL, ACTH and IR-beta-endorphin were significantly higher in decidual than in trophoblastic tissues. In contrast, the tissue concentrations of hCG, hPL, ACTH and IR-beta-endorphin were significantly higher in trophoblastic than in decidual tissues. Production of hCG and hPL was predominantly demonstrated in trophoblastic tissues by the perfusion method but ACTH and IR-beta-endorphin were too low to be detected by perfusion.

This study was done to confirm that aldosterone-producing adenomas secrete cortisol in vivo. Plasma cortisol and aldosterone concentrations were measured in samples obtained by selective adrenal-vein sampling in 8 patients with primary aldosteronism due to unilateral adenoma. All cases revealed higher adrenal-vein plasma cortisol concentrations on the adenoma side than the opposite, irrespective of adenoma location. These concentrations correlated significantly with plasma aldosterone concentrations (r = 0.972, P < 0.001) in effluents from the adenoma side, but not from the opposite. Plasma concentrations also correlated significantly with estimated adenoma volume (r = 0.918, P < 0.05). These findings strongly suggest that aldosterone-producing adenomas secrete cortisol in vivo. In a second study, we used metyrapone to test 6 patients with adenomas. Their responsiveness to cortisol and corticotrophin was found to be the same as that in normal subjects, suggesting that adenoma-secreted cortisol did not disturb the relationship between corticotrophin and cortisol. We thus concluded that cortisol is secreted concomitantly with aldosterone from aldosterone-producing adenomas under corticotrophin influence.

Serum somatomedin A was significantly reduced after 3 days of fasting in rats with a mean decrease of 23.6 ± 2.4% (N = 18) of initial values. Re-feeding for one day produced a definite increase in somatomedin A, with a rise in body weight. When re-fed isocalorically for 21 days with diets of different quality, a low protein diet led to smaller increases in both seum somatomedin A and body weight in comparison to those of control-, high-protein- and high fat-diets (P < 0.001). There is a positive correlation between the increase in body weight and serum somatomedin A levels (N = 70, r = 0.71, P< 0.001). The effect of growth hormone on somatomedin generation was abolished in hypophysectomized rats fed with low-protein diet. Our study suggests that protein in the diet is important for the generation of somatomedin A, which is necessary for normal growth.

The serum levels of propylthiouracil (PTU) were determined by radioimmunoassay in 10 normal subjects and in 11 patients with Graves' disease after a single 100 or 200 mg oral dose of PTU. The serum half-life of PTU in the normal subjects and in hyperthyroid patients with uneventful clinical course was 75 ± 19 min (mean ± sd, n = 6) and 73 ± 13 min (n = 7), respectively. Maximum serum PTU concentrations were usually attained within 1 h after a single 200 mg oral dose and at 1 h were 5.3 ± 1.4 μg/ml (3.1 ± 0.82 × 10−5 m) in normal subjects (n=6) and 4.8 ± 2.4 μg/ml (2.8 ± 1.4 × 10−5 m) in hyperthyroid patients (n = 7). These betweengroup differences were not significant. Serum PTU concentrations were low in a pregnant hyperthyroid patient with a weak response to PTU treatment. In another patient, who appeared resistant to PTU therapy, the serum PTU level increased as expected at testing, and it was later confirmed that, during treatment, he had not taken the drug as prescribed. In a patient who developed agranulocytosis due to methimazole and subsequently fever due to PTU, the half-life of PTU was prolonged to about 130 min. These findings suggest that monitoring the serum PTU levels in patients with Graves' disease can be of clinical value in patients who do not respond to treatment. Furthermore, it may provide some clues as to the mechanism by which toxic reaction develops.

A 47 year old woman examined for hypertension (200/100 mmHg) was normokalaemic, and had low plasma renin activity (PRA) (0.1 ng/ml · h) and normal aldosterone levels in both plasma (7–13 ng/dl) and urine (4.7–7.4 μg/day). Computed tomography (CT) and scintiscan indicated an adenoma on the right adrenal gland, which was then removed. The histology of the adenoma and analysis of the aldosterone content were compatible with the criteria for an aldosterone-producing adenoma. Three months after surgery, her hypertension had improved, serum potassium levels had increased slightly, and PRA had normalized. This was an unusual form of primary aldosteronism which showed normal levels of aldosterone in both blood and urine.

Computed tomography (CT) of the pituitary before and after bromocriptine treatment were performed in 10 patients with microprolactinoma. Intra-pituitary low densities were demonstrated in 7 out of the 10 patients before bromocriptine. Low densities shrank in size and increased in density after normalization of the plasma prolactin (Prl) level following bromocriptine. At the same time, various degrees of empty sella were demonstrated in these patients and in 2 out of the 3 without noticeable changes before treatment. It was concluded that enhanced CT scans, especially sagittal reconstruction images, were very informative for the diagnosis of microprolactinoma and that bromocriptine reduced the size of the microprolactinoma and often led to empty sella.

Mouse adrenal tissue has been reported to contain high renin activity. However, it is not clear whether the renin is produced inside the tissue or is derived from a blood-borne component. We have investigated a cloned cell line of mouse adrenocortical tumour (Y-1) which has a steroidogenic activity. Sizable quantities of renin were demonstrated, predominantly in the cell lysate. This renin activity was distinguished from cathepsin D in view of its specific affinity to anti-renin antibody, optimal pH was determined, and the substrate specificity was checked with haemoglobin. Immunoreactive angiotensins were also detectable, but were demonstrated both in the cell and in the culture medium. This study provides further evidence for the existence of renin intrinsic to the adrenal gland. This study also suggests an intracellular role for renin and possible secretion of generated angiotensins.