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A 73-yr-old patient with idiopathic hypoparathyroidism was admitted to our hospital in May 1981. The immunoreactive PTH (iPTH) level determined by RIA using antiserum specific for the C-terminal region of PTH-(65-69) was in the upper normal range (0.6 ng/mL) and over the next 7 yr increased gradually to 6 ng/mL. Since iPTH levels determined using other commercial RIA kits remained constantly decreased or in the undetectable range, we studied the mechanism of false elevation of iPTH in this patient. The patient's serum contained no binding protein to the tracer ([125I]) [Tyr45] human PTH-(46-84)), nor was any heterophilic antibody to the first [guinea pig immunoglobulin G (IgG)] or the second antibody (goat IgG) detected. Consistent with these findings, the dilution curve of the serum was parallel with that of standard bovine PTH-(1-84). Gel filtration analysis revealed that the iPTH-like substance was eluted in the void volume (apparent mol wt, greater than 70,000). Almost all of the iPTH-like substance was adsorbod by a protein-A-Sepharose column. When the IgG fraction purified by protein-A-Sepharose affinity chromatography was applied to an antihuman IgG lambda-Sepharose column, 72% of the iPTH-like substance was detected in the IgG lambda. These results suggest that the falsely elevated iPTH in the patient's serum was due to IgGs (mainly IgG lambda), which were cross-reactive with the antiserum highly specific for the C-terminal region of human PTH-(65-69).

Direct effects of cyproheptadine, reserpine, synthetic ovine corticotropin-releasing factor (CRF), dexamethasone, and lysine-8-vasopressin (LVP) on the secretion of immunoreactive ACTH and beta-endorphin from the adenoma and the nonadenomatous tissue of patients with Cushing's disease were examined using a superfusion system. Cyproheptadine and reserpine (10(-9)-10(-7) M of each) suppressed immunoreactive ACTH and beta-endorphin secretion from both tissues. CRF (10(10)-10(7) M) stimulated the secretion of both peptides from the nonadenomatous tissue, but only a high dose of CRF could stimulate the secretion of these peptides from some adenomas. Such CRF-induced secretion was partially suppressed by dexamethasone. LVP (10(-9)-10(-7) M) stimulated peptide secretion from both types of tissue. These results suggest direct inhibitory effects of cyproheptadine and reserpine on the secretion of these peptides from the pituitary of patients with Cushing's disease, a different stimulatory mechanism of LVP from that of CRF in these tissues, and low sensitivity of the adenoma to CRF.

[125I]Insulin-like growth factor I (IGF-I) specifically bound to erythrocytes; the binding was saturable, and time and temperature dependent. Steady state binding was reached at 16 h at 4 C, and specific binding averaged 14.3 +/- 0.7% (+/- SEM) at a concentration of 3.6 X 10(9) cells/ml in seven normal subjects. [125I]IGF-I binding to the cells was displaced by unlabeled IGF-I in a dose-dependent manner. Scatchard analysis indicated a linear plot, and Ka and number of binding sites/cell were 1.43 +/- 0.07 X 10(9) M-1 and 20.7 +/- 2.2, respectively. Compared to IGF-I, the relative potencies of multiplication-stimulating activity and insulin for displacing [125I]IGF-I binding were 20% and 1%, respectively. [125I]IGF-I binding to erythrocytes from patients with acromegaly was lower than binding to cells from pituitary dwarfs. An inverse correlation between plasma IGF-I level and the number of IGF-I-binding sites per cell was found (r = -0.75; P less than 0.005). These results demonstrate that [125I]IGF-I binding to erythrocytes can be used for clinical measurement of the IGF-I receptor.

Various aspects of thyroid hormone economy were examined in 15 patients with molar pregnancy and in 5 patients with choriocarcinoma. None of the patients with molar pregnancy was clinically thyrotoxic, though serum thyroxine (T4) was increased in 13 and free T4 concentrations were above normal in four of ten in whom measurements were made. In 2 patients with elevated serum T4 levels and in one patient with normal serum T4 levels, the daily rate of T4 disposal was increase, and most of 131I derived from 131I-T4 was excreted into urine in two patients in whom estimation of urinary excretion was made. Serum total triiodothyronine (T3) concentrations closely paralleled those of serum T4, but T3/T4 ratios were lower than those previously found in patients with toxic diffuse goiter of Graves' disease. Unresponsiveness to exogenous thyrotropin-releasing hormone (TRH) was observed in 5 patients with molar pregnancy whose serum total T4 and T3 levels were increased. Human chorionic gonadotropin (hCG) concentrations in serum ranged from 0.5 to 2830 IU/ml and were less than 200 IU/ml in 36% of the patients, possibly because molar pregnancy was diagnosed by ultrasonography, rather than high titers of urinary or serum hCG. Serum thyroid stimulating activity measured by the McKenzie bioassay closely paralleled values for hCG (r:+0.94). All thyroid abnormalities disappeared quickly after removal of the mole. In choriocarcinoma, no abnormality of thyroid function was found. These results suggest that: 1) some patients with molar pregnancy display a marked elevation of serum T4, T3, and free T4 concentrations, probably as a result of the action of a thyroid stimulator which is closely related to serum hCG or may be hCG itself; 2) T4 production rates are increased in these patients, and the pituitary responds to TRH in a manner similar to that found in thyrotoxicosis. Despite this, frank clinical thyrotoxicosis is usually absent, possibly because of relatively low serum T3/T4 ratios, possibly because of the limited duration of thyroid hyperfunction, and possibly because of other factors that for the present remain unknown.

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.

D-Ala, Mephe, Met, enkephalin (Sandoz FK 33-824) is a stable long acting analog of methionine-enkephalin. FK 33-824 (0.5 or 1.0 mg), elicited plasma GH and PRL responses in normal subjects. In 23 patients with pituitary dwarfism, the response of plasma GH was markedly impaired, while PRL responded to a variable degree. In patients with acromegaly, there was little or no increase in GH and PRL after FK 33-824. Plasma GH increased to a variable degree after FK 33-824 in patients with hyperprolactinemia, with little change in plasma PRL. FK 33-824 decreased plasma cortisol in normal subjects and patients with pituitary disease. These results show that patients with acromegaly and hyperprolactinemia due to pituitary adenomas and patients with pituitary dwarfism do not respond well to FK 33-824, presumably because of hypothalamic or pituitary derangement.

We studied gonadotropin hormone alpha-subunit and gonadotropin secretion in four patients with gonadotropin-producing pituitary adenomas. All four patients had elevated plasma alpha-subunit levels, ranging from 2.8-8.5 ng/ml (normal, less than 0.5 ng/ml). alpha-Subunit responses to LHRH were less than those in seven patients with primary gonadal failure. The relative proportions of the gonadotropin and alpha-subunit peaks in one patient were the same before and after LHRH administration, based on gel filtration studies of plasma. The alpha-subunit levels decreased little during testosterone treatment in the two adenoma patients so treated. Immunohistochemical study of the adenomas from two patients demonstrated definite staining with alpha-subunit and gonadotropin antisera. Elevated plasma levels of alpha-subunit and its relative unresponsiveness to LHRH stimulation or testosterone suppression suggest that the alpha-subunit originated in tumor tissue and that its measurement is useful for the diagnosis of a gonadotropin-producing tumor in patients with elevated plasma levels of LH and/or FSH.

A specific RIA for human pancreatic tumor GH-releasing hormone [hpGRH(1-44)NH2] was developed using an antiserum which recognizes the region (Met27-Leu44)NH2 of hpGRH(1-44)NH2. This RIA was used to measure GH-releasing hormone-like immunoreactivity (GRH-LI) in various human tissue extracts. The highest concentration of GRH-LI was detected in extract of pituitary stalk with moderate amounts found in hypothalamus and optic chiasm but none in the cerebrum, cerebellum, medulla oblongata, spinal cord, and anterior pituitary. In peripheral organs appreciable quantities of GRH-LI were found in the pancreas, whereas extracts of thyroid, lung, stomach, duodenum, ileum, colon, adrenal, and kidney contained very low concentrations of GRH-LI. No GRH-LI was detected in liver and spleen extracts. Gel permeation chromatographic analysis of the tissue extract from the hypothalamus revealed only one peak which eluted at the same position as that of 125I-hpGRH(1-44)NH2. Similar analysis of an extract from the optic chiasm showed one peak at the same position as that of 125I-hpGRH(1-44)NH2 and another peak which eluted after hpGRH(1-44)NH2. In contrast, an extract from the pancreas contained only one peak which eluted before 125I-hpGRH(1-44)NH2, indicating a possible precursor form of hpGRH(1-44)NH2. Limited trypsin digestion of the GRH-LI material from the pancreas, followed by gel permeation chromatographic analysis, yielded a major peak eluting at the same position as that of 125I-hpGRH(1-44)NH2. These results suggest that the GRH-LI detected in the hypothalamus most likely corresponds to hpGRH(1-44)NH2 in structure and that the GRH biosynthesized in the hypothalamus is transported to the stalk median eminence and stored there for release into the portal vessels.

Corticotropin-releasing factor (CRF)-like activity in two different kinds of ACTH-producing tumors (human ectopic ACTH-producing colonic cancer and rat MtT/F4 tumor) was determined by an in vitro method using isolated normal rat pituitary cells. The ACTH content of the post mortem colonic cancer was 5.5 ng/g w.wt. The ACTH content of the medium of MtT/F4 tumor cells was 153+/-32 pg/10(5) cells. The ACTH content of MtT/F4 tumor cell suspensions was elevated with increasing doses of hypothalamic median eminence extract (HME). The response of MtT/F4 tumor cells to HME was suppressed by 1 mug/ml of dexamethasone. Extracts of colonic cancer, MtT/F4 tumor and HME produced elevation of the ACTH content of the medium of isolated rat pituitary cells. The CRF-like activities of two kinds of tumor extracts in multiple dilutions ran parallel to that of HME. The CRF-like activities were 0.037 HME equiv/mg w.wt in MtT/F4 tumor and 0.052 HME equiv/mg w.wt. in colonic cancer. These results demonstrated that CRF-like activity existed in these two kinds of ACTH-producing tumors.

One hundred and sixty-one children with idiopathic GH deficiency who received GH treatment were followed until they reached their final height. Final height was found to be influenced by gonadal function. In 108 patients who had spontaneous puberty (91 boys and 17 girls; group A), the mean final height was 151.8 +/- 6.6 (+/- SD) cm in boys and 141.7 +/- 7.4 cm in girls. In 29 patients with combined GH and gonadotropin deficiency (23 boys and 6 girls; group C), whose pubertal development was induced artificially at age 19.5 +/- 2.1 yr in the boys and 18.6 +/- 1.8 yr in the girls, the mean final height was 163.7 +/- 3.9 cm in boys and 151.0 +/- 5.1 cm in girls. The differences in final height between groups A and C were significant in both boys and girls. The shorter final height in group A was caused by the shorter pubertal duration and smaller pubertal height gain than those in normal children. In 24 patients (17 boys and 7 girls; group B) who developed early signs of puberty, gonadal suppression therapy with cyproterone acetate and/or medroxyprogesterone acetate was given. The mean SD score of the final height in these 24 patients was -2.1 +/- 0.6, significantly higher than that in group A. This beneficial effect of gonadal suppression treatment on final height was caused by increases in the duration of puberty and the pubertal height gain.

Synthetic human pancreatic GRF (hpGRF-44) was administered as an iv bolus to 28 normal children with short stature and 27 patients with GH deficiency. After a dose of 1 or 2 micrograms hpGRF-44/kg BW, mean plasma GH levels peaked at 15 and 30 min, respectively, with corresponding values of 30.1 +/- 4.7 and 33.2 +/- 3.7 ( +/- SE) ng/ml in normal but short children. The overall plasma GH response was greater than that of other GH stimulation tests such as insulin-induced hypoglycemia, glucagon-propranolol or L-dopa administration. Plasma LH, FSH, TSH, PRL, and cortisol levels were not altered by hpGRF-44 injection. Sixteen of 27 patients with GH deficiency did not respond to a 2 micrograms/kg BW hpGRF-44. However, plasma GH increases to greater than 5 ng/ml occurred in the remaining 11 patients. Their GH levels reached peaks between 15 and 90 min, with values ranging between 5.8 and 17.8 ng/ml. Two of these responding patients were infused iv with hpGRF-44 at 2.5 micrograms/min for 90 min after receiving an iv bolus injection of 2 micrograms/kg BW. Their plasma GH levels increased and remained near peak values throughout the infusion period. However, no increase in plasma GH levels occurred after a second bolus injection of hpGRF-44 given at the end of the infusion. These results suggest that hpGRF-44 is useful for the diagnosis of GH deficiency in individuals with short stature and that some patients with GH deficiency, diagnosed on the basis of established tests, have GH responses to hpGRF-44.

The plasma GH response to GH-releasing hormone (GHRH), TRH, or GnRH administration was examined in 25 acromegalic patients. Plasma GH levels increased in 21 patients after GHRH, in 19 after TRH, and in 4 after GnRH. The four GHRH nonresponders had had acromegaly longer than had the GHRH responders. No specific combination of GH responsiveness to these 3 releasing hormones was found among the patients. Infusion of 1 mg GHRH for 150 min gradually increased plasma GH levels, with some fluctuations, from the beginning to the end of infusion in normal subjects and in 7 patients who were GHRH responders, but a bolus injection of 100 micrograms GHRH at the end of the infusion did not further elevate plasma GH levels. These results suggest that desensitization to GHRH occurred in the normal subjects and acromegalic patients. However, in 5 acromegalic patients who responded to both GHRH and TRH, a bolus injection of 500 micrograms TRH given at the end of the 150-min infusion of 1 mg GHRH evoked a further plasma GH rise. In 5 normal subjects and 2 patients who were responders to GHRH but not TRH, a bolus injection of 500 micrograms TRH did not cause plasma GH elevation at the end of 150-min infusion of 1 mg GHRH. These results imply that TRH and GnRH stimulate GH secretion from the adenoma cells in vivo through receptors different from those for GHRH. In vitro studies using cultured pituitary adenoma cells from 2 patients revealed that the responses of GH secretion to GHRH were similar to those in vivo. These data, therefore, suggest that the responsiveness of GH secretion to stimuli is determined by the specificity of the receptors on adenoma cells. The action of somatostatin-28 was more potent than that of somatostatin-14 in the suppression of GH secretion from adenoma cells.

IN RECENT years the relationship between hormones and the mechanism of pigmentation has come to the fore. In this report it will be shown that the pituitary gland elaborates a melanocyte-stimulating hormone (MSH) which affects melanin pigmentation in man. The “peculiar change” in skin color described by Addison in patients with adrenocortical insufficiency, the decreased pigmentation of panhypopituitarism, and the melasma of pregnancy seem to depend in large part upon the activity of MSH. Because the developments leading to this conclusion have involved many people and many aspects of research, it is worthwhile to review the historical background of this problem. In 1916 Smith and Allen, two biologists working independently, almost simultaneously reported that removal of the pituitary gland of tadpoles was followed by loss of skin color (1–4). Three years later Atwell showed that when tadpoles were immersed in pituitary extracts their skin became darker (5). Atwell, Smith, Swingle, and later Zondek found ...

Growth hormone content in the pituitary gland was measured by radioimmunoassay in 48 human fetuses at various gestational stages. None of the fetuses of 6 weeks gestation contained detectable amounts of growth hormone. However, growth hormone was measurable in some fetuses starting at the 7th week, and by the 9th week it was detected in all fetuses studied. Thereafter, growth hormone content increased in excess of the body weight gain. Growth hormone concentration in cord blood was also studied in 7 fetuses. It ranged from 18 ng/ml in a 10-week-old to 120 ng/ml in a 4-month-old fetus. It was concluded that human fetuses synthesize and store growth hormone as early as the 7th gestational week.

ALTHOUGH periodic paralysis is a rare disorder, its association with hyperthyroidism has been reported by several investigators (1–15). In reviewing the literature, it was found that only about 30 such cases have been reported from the United States and Europe, whereas more than 70 cases have been reported from Japan. Possibly the association of these two disorders is less rare in Japan. As the Japanese reports were all concerned with relatively small numbers of patients with hyperthyroidism, the incidence of the association of these two disorders in Japan could not be estimated. In order to obtain a fairly good estimate, the incidence of periodic paralysis among 6,333 cases of hyperthyroidism operated upon in three thyroid hospitals in Japan was studied. These hospitals were located in different parts of country—Noguchi Hospital in Beppu, Kyushu (southern part of Japan), Kuma Hospital in Kobe (central part of Japan) and Ito Hospital in Tokyo (eastern part of Japan), so the study provided data on a cross ...

SINCE 1926, sporadic reports have appeared on the presence of the melanocyte-stimulating hormone (MSH) in mammalian urine and blood. Because many of these studies were performed with inadequate techniques, and because present-day methods make possible the quantitative detection of MSH in minute amounts with an in vitro bioassay method, it was decided to clarify this problem by determining the MSH in the urine and blood of patients with various disorders. REVIEW OF THE LITERATURE Urinary MSH. Collin and Drouet (1) observed the color change of intact frogs after the injection of human urine. Darkening was produced with urine from patients with pituitary tumors, hyperthyroidism, migraine, and retinal hemorrhage. Positive results also were obtained with the urine of normal females, which was obtained the day prior to, or on the first day of menstruation. Konsuloff (2) used hypophysectomized frogs and found that urine from 9 pregnant women contained large amounts of MSH. He suggested that the demonstration of ...

EEG, pulse rate, respiration and eye movement were polygraphically recorded throughout the night in 10 normal adult male subjects. Blood was collected every 20 min throughout the night by means of an indwelling venous catheter without disturbing the natural course of sleep. Human growth hormone (HGH) and blood sugar were measured in these plasma samples. Depth of sleep was classified into 5 stages by EEG. A marked elevation of plasma HGH was constantly observed coincident with the onset of sleep. Following the initial large HGH peak, additional peaks of HGH, with a decrease in the size of subsequent peaks, were observed. Shifting the time of the onset of sleep by 3 hr before or after the usual bedtime did not change the elevation of plasma HGH coincident with the onset of sleep. When a state of full wakefulness was maintained at night, plasma HGH did not rise. The secretion of plasma HGH was inhibited during paradoxical sleep. It is concluded that nocturnal sleep is a potent stimulator for the se...

Quantitative studies of iodine metabolism were carried out in iodide-treated hyperthyroid patients in order to observe the alterations of iodine metabolism which occur in response to clinical improvement and to the recurrence of symptoms. Twelve hyperthyroid patients were given 10 mg of iodide as KI t.i.d. and several thyroid function tests were performed at intervals of 2 weeks thereafter. Serum PBI and T3-resin sponge uptake decreased to the normal range within 2 weeks in all patients and these normal values continued until recurrence of thyrotoxicity. One, 2 and 24 hr thyroidal 131I uptakes decreased from 57.4 to 22.6%, from 68.0 to 24.4%, and from 75.1 to 19.9%, respectively, within 2 weeks of the iodide treatment. However, these values were considerably higher than those obtained from similarly treated euthyroid subjects (2.6, 2.5 and 3.4%, respectively). Thyroidal absolute iodine uptake (AIU), calculated from thyroidal clearance of 131I multiplied by serum inorganic 127I, increased about 3-...

To examine the hypothesis that LATS-protector may cause thyroidal hyperfunction in Graves' disease, the effect of LATS-protector on the intracellular colloid droplet formation in human thyroid tissue was studied in vitro. The IgG's from 9 untreated patients with Graves' disease, 4 thyrotoxic patients who were being treated hut were still thyrotoxic, and 4 normal subjects not showing LATS were chosen to study the presence of LATS-protector and its human thyroid stimulating activity. LATS-protector was assayed as described by Adams with slight modifications. LATS-protector was demonstrated in the IgG's of 6 out of 9 untreated patients with Graves' disease. Their IgG significantly inhibited the inactivation of LATS by the thyroid extract, recovering approximately 30% of the LATS-potency. The IgG from the treated, but thyrotoxic patients or from the normal individual did not show such an inhibition. When sliced normal human thyroid tissue was incubated with the IgG from thyrotoxic patients, an obvious elevati...

The response of pituitary adenomas obtained surgically from patients with Cushing's disease of Nelson's syndrome to synthetic ovine corticotropin-releasing factor (CRF), vasopressins, somatostatin-28, dexamethasone, 3-isobutylmethylxanthine or high [K+] was examined in vitro by measuring the amount of pro-opiomelanocortin (POMC)-derived peptides secreted into the culture medium. CRF did not stimulate the secretion of adrenocorticotropin-, beta-endorphin-, or gamma 3-melanotropin-like peptides from the pituitary adenomas at concentrations ranging from 1 x 10(-13) M to 1 x 10(-7) M whereas vasopressins, 3-isobutyrl-methylxanthine and high [K+] increased, while somatostatin-28 and dexamethasone suppressed, the secretion of these POMC-derived peptides. These findings suggest that either the pituitary ACTH-producing tumors have lost their receptors to CRF or their post-receptor mechanism to CRF is not functional.

The concentrations of immunoreactive corticotropin-releasing factor (I-CRF) in human cerebrospinal fluid (CSF) were measured utilizing immunoaffinity chromatography and RIA in patients with no endocrine disease, patients with Cushing's disease, Nelson's syndrome, Sheehan's syndrome, Addison's disease and steroid treated patients. On high performance liquid chromatography, the elution profile and retention time of I-CRF in CSF were not identical with ovine CRF. I-CRF concentrations in CSF from patients with Cushing's disease and Sheehan's syndrome were lower than those from normal subjects, however those from patients with Nelson's syndrome and Addison's disease were within the normal range. I-CRF concentrations in CSF from patients with Cushing's disease returned to normal levels 2-9 months after pituitary adenomectomy. These results suggest that CSF I-CRF concentrations are reduced by increased plasma corticosteroid levels.

The effect of naloxone, a specific antagonist of opioid peptides, on plasma.GH, PRL, and cortisol responses to insulin-induced hypoglycerriia was studied in five healthy male subjects. The iv administration of regular insulin (0.15 U/kg) led to similar degrees of hypoglycemia on control and experimental days. Plasma GH, PRL, and cortisol levels rose significantly in response to insulin-induced hypoglycemia. A 2-h infusion of naloxone (0.8 mg/h) started 30 min before insulin injection did not alter either basal hormone levels or the hormone responses to insulin-induced hypoglycemia. These results suggest that endogenous opioid peptides do not play a major role in GH, PRL, or cortisol secretion induced by insulin hypoglycemia.

Corticotropin-releasing factor (C R F)-like activity, which was first found in the hypothalamus, was detected in the extracts of human placentas obtained at full term from spontaneous deliveries. The molecular size of the placental CRF-like substance is slightly larger than that of adrenocorticotropin. In cultures of rat anterior pituitary cells, the placental CRF-like material shows bioactivity similar to that of the partially purified rat hypothalamic CRF and synthetic ovine C R F on the release of adrenocorticotropin and (β-endorphin. Furthermore, the CRF-like activity from human placenta was attenuated by trypsin digestion. Thus the human placenta may elaborate a substance similar to hypothalamic CRF.