Effect of hyperprolactinemia on pituitary-adrenal function.

Three patients with hyperprolactinemia (2 with pituitary tumors and 1 with a hypothalamic disturbance) underwent evaluation of their hypothalamic-pituitary-adrenal axis using ACTH, metyrapone and in one case repetitive insulin tolerance tests. With the exception of a suggestion of a slight increase in adrenal responsiveness to pharmacological doses of ACTH in one of the patients, there was no alteration in the adrenal responsiveness of the 3 patients evaluated. We conclude that hyperprolactinemia probably does not systematically modify the responsiveness of the hypothalamic-pituitary-adrenal axis.

Pituitary-gonadal function in the carcinoid syndrome: effect of parachlorophynylalanine therapy.

Six patients with the carcinoid syndrome (C.S) had serum luteinizing hormone (LH) concentrations that were greater than age and sex matched control subjects. The serum follicle stimulating hormone (FSH) and testosterone concentrations of the groups did not differ. Four of the 5 C.S. patients tested had an increase in serum testosterone after human chorionic gonadotropin administration and 5 of the 5 subjects tested had an increase in serum LH after clomiphene citrate administration. One of the 4 subjects treated with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA) had a reduction in serum testosterone. He was also receiving methysergide. The other 3 subjects treated with PCPA did not have any persistent alterations in serum testosterone.

Gastrointestinal and metabolic function in patients with the carcinoid syndrome.

We evaluated gastrointestinal absorption in six consecutive patients with metastatic serotonin-secreting carcinoid tumors. One patient had a consistent defect in fat absorption and two other patients malabsorbed fat during spontaneous or dopamine-induced exacerbation of the carcinoid syndrome. The steatorrhea of the patient with the persistent defect in fat absorption was reduced when tumor serotonin production was reduced by the tryptophan hydroxylase inhibitor parachlorophenylalanine. The six patients had normal hemoglobin levels and the serum concentration of the following urinary constituents was normal in most of the patients: albumin, carotene, 25-hydroxycalciferol, parathyroid hormone, calcitonin, calcium, phosphorous, osteogenous alkaline phosphatase, cholesterol, triglycerides, and serum lipoproteins. The excretion of the following urinary constituents was also normal in most of the patients: creatinine clearance, tubular reabsorption of phosphorous, calcium, D-xylose, cyclic 3'5' monophosphate and hydroxyproline. We conclude that patients with the carcinoid syndrome may have steatorrhea, and that their hyperserotoninemia plays a role in this process.

99mTc-pyrophosphate bone scans in patients with metastatic carcinoid tumors.

Three patients with foregut (bronchial), hindgut (rectal) or (ovarian) carcinoid tumors had symptomatic bone metastasis with abnormal 99m Tc pyrophosphate bone scans and bone roentgenograms. Six patients with midgut (small intestine or caecal) carcinoid) carcinoid tumors who had no symptoms of bone metastasis had no evidence of bone metastasis on bone scan or bone roentgenographic examination. This study supports the clinical impression that patients with midget carcinoid tumors have a low incidence of bone metastasis.

Plasma amino acids in patients with the carcinoid syndrome.

Plasma tryptophan (Trp) is reported to be decreased in some patients with the carcinoid syndrome. To determine if the plasma levels of other amino acids are also altered in the carcinoid syndrome, we used a fas-liquid chromatographic method to determine the plasma amino acid concentration of nine patients with the carcinoid syndrome and nine age-matched healthy control subjects. In comparison to the control subjects, the patients with the carcinoid syndrome had decreased plasma concentration of valine (Val), isoleucine (Ile), lysine (Lys), and ornithine (Orn), and an increased plasma concentration of methionine (Met). With the exception of a decrease in urinary excretion of proline (Pro) and hydroxyporline (Hyp), the patients with the carcinoid syndrome had normal quantities of amino acids in their urine. Plasma Met returned to normal when serotonin production by the tumor was reduced 60% by parachlorophenylalanine (PCPA); the other amino acid abnormalities persisted. Further studies are needed to determine the significance of these amino acid abnormalities.

Therapeutic doses of cyproheptadine do not inhibit monoamine oxidase in man.

Cypro, a serotonin and histamine antagonist, has been shown to be a moderately potent reversible inhibitor of tissue monoamine oxidase (MAO) obtained from hamsters and rabbits. In the present study, Cypro inhibits MAO obtained from human platelets with the same potency as harmine (Ki = 5 x 10(-5) M). However, when ten normal volunteers received conventional therapeutic doses of Cypro (16 mg/day) for two days, there was no alteration in their urinary excretion of tryptamine, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxymandelic acid, epinephrine, or norepinephrine. We conclude that, when used in conventional clinical doses, Cypro does not inhibit MAO in man.

Reliability of copper reduction methods for quantitation of glucosuria.

In the present study we evaluated the reliability of the "2-drop" Clinitest method in determining the 24-h glucose spill of a diabetic patient. The urine glucose content over the 33 day study period was measured with a Beckman glucose analyzer that employed a glucose oxidase method. There was no statistical difference between the glucose content determined by the two methods. There was a mean error of +4.4 +/- 3.6% between the values obtained with the "2-drop" method and values obtained with glucose analyzer. The mean coefficient of variation for determining the glucose content of urine with the "2 drop" method was 19%. In a group of 10 normal volunteers we found that there was a falsely elevated glucose value in urines with osmolality of less than 295 mosm/kg when the "5-drop" method was used. The "2-drop" Clinitest and the Beckman analyzer could accurately determine glucose concentration even in these dilute urines. The "2-drop" Clinitest method is a useful and reasonably reliable method for evaluationg 24-h glucosuria.

Inhibitory effect of serotonin antagonists on growth hormone release in acromegalic patients.

We evaluated the effect of the serotonin antagonists cyproheptadine (Cypro) and methysergide (Methy) on growth hormone secretion in six patients with acromegaly. Two days administration of Cypro decreased the plasma GH concentration during oral glucose tolerance tests in four of the six patients evaluated; 2 days administration of Methy reduced the plasma GH levels of only one of the four patients evaluated. The one patient whose plasma GH concentration was lowered by Methy, did not have a decrease in plasma GH concentration after Cypro administration. Acromegalic patients have normal serum serotonin concentration and normal 5-hydroxyindoleacetic acid excretion. If Cypro lowers plasma GH by antagonizing serotonin, our data would suggest that serotoninergic neuronal pathways are important in the regulation of pituitary GH secretion in some patients with acromegaly.

Effect of age on intravenous glucose tolerance and insulin secretion.

Twenty-seven normal volunteers whose ages ranged from 22 to 67 (mean, 37 years) were given intravenous glucose tolerance tests (IVGTT). Age was not correlated with the glucose disposal rate constant (KG), incremental insulin secretion (deltaI), or the "insulinogenic index (deltaI/DELATG). The volunteers were divided into three age groups: 1) mean age 25 years, 2) mean age 42 years, and 3) mean age 62 years. Groups 2 and 3 did not differ from Group 1 with respect to the mean level of fasting plasma glucose, KG, or deltaI/AG. Group 2 (but not Group 3) had a greater mean deltaI than Group 1, and Group 3 (but not Group 2) had a higher mean fasting insulin concentration than Group 1. No significant deterioration was detected in the intravenous glucose tolerance of healthy volunteers up to age 67. This may be attributable to the previously described feed-back system that calibrates the pancreatic beta-cell response according to the insulin sensitivity of the peripheral tissues.

Effect of intravenous glucose and insulin on plasma tryptophan and tyrosine concentrations in normal subjects and patients with carcinoid tumors.

We evaluated the effect of intravenous (i.v.) glucose on the plasma tryptophan (TRP) and tyrosine (TYR) concentration of 12 normal subjects, six patients with carcinoid tumors and the carcinoid syndrome (carcinoid syndrome), and five patients with carcinoid tumors without the carcinoid syndrome (tumor.) Following i.v. glucose administration, the plasma Trp concentration of the normal subjects and the tumor patients incresed, while the plasma Trp concentration of the carcinoid syndrome patients decreased. Following i.v. glucose administration, the plasma Tyr concentration of the normal subjects and the tumor patients decreased, while the plasma Tyr concentration of the carcinoid syndrome patients did not change. The response to i.v. insulin differed in some respects from the response to i.v. glucose: the plasma Trp of normal subjects did not change while the plasma Trp of carcinoid syndrome patients decreased; the plasma Tyr of the normal subjects increased while the plasma Tyr concentration of the carcinoid syndrome patients did not change. The carcinoid syndrome patients had high serum serotonin concentrations and impaired glucose tolerance and insulin secretion as compared to both normal subjects and tumor patients. We conclude that under appropriate experimental conditions, glucose administration can increase the plasma Trp concentration of normal human subjects.

The role of cortisol and growth hormone in the counter-regulation of insulin-induced hypoglycemia.

Four normal volunteers underwent a control insulin tolerance test (ITT) and an insulin tolerance test (ITT) after two days administration of the serotonin antagonist cyproheptadine (Cypro). Cypro administration resulted in an 81 +/- 11.4% (M +/- SEM) reduction in cortisol secretion and a 73 +/- 15.1% reduction in growth hormone (GH) secretion. Despite the reduction in hypoglycemia-induced cortisol and GH secretion, there was a similar decline and recovery of plasma glucose in the control ITT and the ITT after Cypro administration. Although previous studies indicate that normal basal levels of cortisol and growth hormone are needed for normal counter-regulation after insulin-induced hypoglycemia, augmented secretion of these hormones is probably not essential for this response. Hypoglycemia-induced increases in epinephrine and glucagon, secretion may contribute to the restoration of the normal plasma glucose concentration after insulin-induced hypoglycemia.

Glucose intolerance in the carcinoid syndrome.

We assayed glucose tolerance and insulin secretion in ten patients with metastatic carcinoid tumors and the carcinoid syndrome ("active tumors") and in seven patients with metastatic carcinoid tumors without the carcinoid syndrome ("inactive tumors"). The patients with "active tumors" had elevated serum serotonin levels while the patients with "inactive tumors" had normal serum serotonin levels. Of the ten patients with "active tumors," five had diabetic and three had borderline intravenous glucose disposal rate constants (KG = 0.88 +/- 0.07, M. +/- S.E.M.). Their KG was significantly lower (p less than 0.01) than a group of age-matched normals. All of the patients with "inactive tumors" had normal KG values (KG = 1.67 +/- 0.24). Their KG did not differ from that of age-matched normal subjects. Both groups of carcinoid patients had a comparable decrease in their insulinogenic index. Two days' administration of the serotonin antagonist cyproheptadine (Cypro) to eight of the patients with "active tumors" resulted in a significant increase in the "insulinogenic index" (50%) but a nonsignificant increase in the KG (12%). Administration of p-chlorophenylalanine, a compound that blocks serotonin synthesis, resulted in an increase in both the KG (60%) and the "insulinogenic index" (55%). The insulin half-life (t1/2) of patients with "active tumors" (6.1 +/- 0.4 min.) did not differ from the t1/2 of normal subjects (6.6 +/- 0.4 min.), suggesting that the decreased plasma insulin levels following intravenous glucose were due to impaired insulin secretion rather than accelerated insulin destruction. Seven of the patients received treatment with the antitumor agent streptozotocin (Strepto). The patients received cumulative doses of from 70 to 300 mg. of Strepto per kilogram body weight with no impairment in glucose tolerance or insulin secretion. We conclude that there is high incidence of glucose intolerance (80%) and impaired insulin secretion in patients with the carcinoid syndrome and that serotonin plays a role in producing these alterations.

Growth hormone and prolactin secretion in the carcinoid syndrome.

We evaluated plasma growth hormone (GH) and plasma prolactin (PRL) levels in ten patients with metastatic carcinoid tumors and the carcinoid syndrome ("active tumors") and seven patients with metastatic carcinoid tumors without the carcinoid syndrome ("inactive tumors"). The patients with active tumors had elevated serum serotonin levels and increased urinary 5-hydroxyindoleacetic acid (5-HIAA) while these values were normal in patients with inactive tumors. Forty-five per cent of patients with active tumors had elevated fasting plasma GH levels that were either not suppressed or showed a paradoxical increase in response to I.V. glucose. There was a positive correlation between the plasma GH levels and serotonin production by the tumor. Twenty-eight per cent of patients with inactive tumors had elevated fasting plasma GH levels. GH levels were decreased by the administration of serotonin antagonists in some but not all of the patients. Parachlorophenylalanine (PCPA) an inhibitor of serotonin synthesis caused a paradoxical rise in GH levels. GH release in response to insulin hypoglycemia was normal. Plasma prolactin levels were normal in most of the patients with metastatic carcinoid tumors. PCPA administration did not systematically alter plasma prolactin levels. We conclude that elevated plasma GH levels are frequently present in patients with the carcinoid syndrome. Both serotonin produced by the tumors and the tumor itself may be responsible for the elevated GH levels.