Biomedical subjects
Publications and source records attributed to H E Carlson.
The effect of a single 50 mg dose of warfarin sodium on thyroxine monodeiodination was examined in eight healthy human subjects. There was no evidence that warfarin inhibits 5'-monodeiodination, although such inhibition exists in rats.
Contrary to a previous report, pretreatment of normal men with carbidopa plus L-dopa (Sinemet 25/250) markedly inhibited the PRL response to TRH, a stimulus that acts directly on the pituitary. Thus, the results of carbidopa/L-dopa testing cannot be used to determine whether agents that stimulate PRL secretion act on the pituitary or at a higher central nervous system level.
Single or graded doses of glucagon (Eli Lilly) were given to patients with pseudohypoparathyroidism (PsHP) type I to examine the possible presence of hormone resistance. The doses of glucagon ranged from 0.25-15 micrograms/kg. The following individuals were studied: 13 normal subjects, 5 patients with low erythrocyte N-protein activity (PsHP type Ia), and 7 patients with normal erythrocyte N-protein activity (PsHP type Ib). Two additional patients with treated primary hypothyroidism who were relatives of a patient with PsHP type Ib were also studied. The patients with PsHP type Ia had blunted plasma cAMP responses to all glucagon doses. In contrast, the patients with PsHP type Ib had normal cAMP responses to glucagon infusion. However, the 2 relatives of the patient with PsHP type Ib had clearly decreased cAMP responses to glucagon infusion; both had normal renal responses to PTH and were clinically and biochemically euthyroid at the time of study. Glucose responses to glucagon were normal in both PsHP groups; the glucose response per unit cAMP response was slightly, but not significantly, enhanced in PsHP type Ia patients. Glucagon resistance appears to be a common finding in patients with PsHP type Ia, but not in those with PsHP type Ib. However, the observation of reduced glucagon responsivity in association with familial hypothyroidism in a kindred with PsHP type Ib suggests the possibility that this disorder may also cause disturbances in several hormone systems.
Hormonal, neurologic, and vascular factors affecting potency were evaluated in 10 men with scleroderma and in 10 age-matched men with rheumatoid arthritis. Impotence was reported by 6 of the patients with scleroderma and none with rheumatoid arthritis. Studies of serum testosterone, free testosterone index, follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, thyroxine, and thyrotropin did not show a hormonal basis for impotence in any patient. Neurologic causes were not found on physical examination. Penile blood pressures were markedly abnormal in 4 impotent patients, intermediate in 2 impotent and 3 potent patients, and normal in 11 potent patients. A history of claudication and diminished ankle blood pressures indicated large vessel disease in 2 impotent patients; the remaining 4 impotent men had normal ankle pressures, suggesting that their poor penile blood pressures and impotence were due to small vessel disease, perhaps the small artery lesions of scleroderma.
Cowden disease (CD) is a familial syndrome characterized by tumors of the skin, oral mucosa, breast, thyroid, and intestinal epithelium. Since the syndrome is inherited as an autosomal dominant, we examined a battery of gene markers in a family with CD to detect linkage between the CD gene and known marker genes. There was no positive evidence for linkage of a CD locus with any of the markers; other investigators can add to our data to confirm and extend these findings. Additionally, we measured epidermal growth factor (EGF) in body fluids from CD patients and controls to determine if elevated EGF levels might be responsible for the widespread epithelial proliferation in CD. EGF levels in saliva, serum, plasma, and urine were similar in CD patients and control subjects. Although alterations in growth factors or their receptors may play a role in CD, excess circulating EGF is not responsible for the manifestations of the syndrome.
We evaluated the effects of chronic massive elevations of serum GH and PRL on calcium metabolism in rats bearing the MStT/W15 and 7315a transplantable pituitary tumors. MStT/W15 tumor rats manifest elevated serum GH and PRL levels, hypercalcemia, hypercalciuria, and elevated serum levels of PTH and 1,25-dihydroxyvitamin D. The hypercalcemia was not reversed by dexamethasone or propranolol treatment, but was ameliorated by starvation. Parathyroidectomy produced hypocalcemia in the MStT/W15 tumor rats, confirming the parathyroid dependence of the hypercalcemia. The 7315a tumor produced a milder degree of hypercalcemia, along with elevated serum levels of PRL, ACTH, and corticosterone; serum GH was normal. In high concentrations, PRL and/or GH may stimulate the secretion of PTH as well as enhance dietary calcium absorption, in part through the mediation of 1,25-dihydroxyvitamin D.
Salsolinol is a tetrahydroisoquinoline compound with opiate agonist and dopamine antagonist properties. The role of salsolinol, a minor constituent of beer, in beer-induced PRL secretion was investigated in humans and rats. Beer-stimulated PRL release was greater in women than in men; the PRL-stimulating effect of beer was not blocked by naloxone pretreatment. Administration of a solution of salsolinol or cocoa (another salsolinol-containing beverage) did not stimulate PRL secretion in normal women. In rats, administration of large doses of salsolinol ip or iv was required to raise serum PRL levels, and high concentrations of salsolinol were needed to antagonize the PRL-suppressive effects of dopamine in vitro. We conclude that salsolinol is not responsible for PRL secretion induced by beer ingestion.
The lipolytic response to isoproterenol infusion was examined in seven normal subjects and six patients with pseudohypoparathyroidism type I [two had deficiency of the hormone receptor-cyclase coupling protein (N-protein) and four did not]. Despite blunted plasma cAMP responses to isoproterenol in both subgroups of pseudohypoparathyroidism patients, the serum FFA responses were normal. We conclude that changes in plasma cAMP do not reflect the adequacy of the lipolytic response to isoproterenol.
Two male patients with scleroderma and hypogonadism are described. One patient had Klinefelter's syndrome. The second had normal testosterone but elevated gonadotrophins. Possible relationships between scleroderma and hypogonadism are discussed.
The neuroleptic malignant syndrome (NMS) developed in a 32-year-old man following fluphenazine enanthate administration. Hypercalcemia was initially present, perhaps reflecting release of calcium from skeletal muscle stores. The elevated serum calcium levels support the existence of a peripheral muscle abnormality in the pathogenesis of the NMS and provides another point of similarity between NMS and malignant hyperthermia.
Nickel (Ni++) is a potent inhibitor of prolactin (PRL) secretion from isolated rat pituitary quarters in vitro, suppressing both basal PRL release and the stimulation of PRL secretion due to theophylline and dibutyryl cyclic AMP. Stimulation of growth hormone (GH) secretion by synthetic GHRH is also blunted by Ni++, although basal GH release and stimulated GH release due to theophylline or dibutyryl cyclic AMP are not suppressed. Ni++ antagonizes the stimulation of both PRL and GH secretion by barium (Ba++) ion, suggesting that the inhibitory effects of Ni++ on hormone release are due to an antagonism of calcium uptake or redistribution.
The stimulating effect of naloxone on plasma beta-endorphin immunoreactivity (beta EI) was examined in dogs. Intravenous naloxone at 5, 1, or 0.1 mg/kg caused a significant increase in beta EI while doses of 0.01 or 0.001 mg/kg had no effect. The peak plasma beta EI levels occurred at 25 mins after naloxone. The neurotransmitter and antagonists metergoline, atropine, diphenhydramine and phentolamine all failed to significantly alter basal beta EI secretion; further, they all failed to prevent the increase in beta EI resulting from naloxone administration. Dexamethasone prevented the naloxone-induced rise in beta EI. Our results suggest naloxone's effect on beta EI is not mediated through several neurotransmitter systems known to affect ACTH secretion. Additionally, beta EI secreted in response to naloxone appears to originate mainly from the anterior lobe of the pituitary.
Because hypothalamic and extrahypothalamic levels of thyrotropin-releasing hormone immunoreactivity (TRH-IR) undergo profound changes during the prenatal and early postnatal period in rats, similar effects with advanced aging were anticipated. For this reason we measured hypothalamic and reproductive tissue levels of TRH-IR, hypothalamic levels of somatostatin (SRIF), and beta-endorphin (EP), serum levels of prolactin (Prl), growth hormone (GH), thyrotropin (TSH), and thyroxine (T4) in young, sexually mature and 24-28 month-old male Long-Evans and Sprague-Dawley rats. Hypothalamic and prostatic levels of TRH-IR were consistently reduced as were the levels of T4 in old rats compared to young controls. Aging did not change the ratio of TRH to the major TRH-like peptide in prostates, as determined by high pressure liquid chromatography (HPLC) or the levels of hypothalamic SRIF and EP. All of the hypothalamic TRH-IR in both old and young male rats consisted of TRH by HPLC. Falling hypothalamic TRH levels and TRH secretory capacity may play a role in the blunted TSH response to cold stress in old rats.
Diazepam has been reported to influence pituitary hormone secretion, with several studies claiming that diazepam provokes growth hormone release. Normal volunteers were therefore examined for anterior pituitary responsiveness to 10 mg diazepam i.v. and p.o. The drug had no significant effect on the secretion of prolactin or thyrotropin when compared to control saline injections in all subjects. Growth hormone response was variable; serum growth hormone increased significantly in only 4 of 10 patients after i.v. diazepam and in only 1 of 7 subjects tested with oral diazepam. Serum cortisol rose in only 1 subject, precluding a stress-related explanation for the increase in growth hormone. We conclude that diazepam inconsistently stimulates growth hormone secretion and should not be relied upon as a test of growth hormone reserve.
Clinical and hormonal responses to bromocriptine therapy were assessed in 10 patients with acromegaly. Although substantial falls (greater than or equal to 50%) in serum GH occurred in only 4 of the patients, subjective clinical improvement and improved glucose tolerance were seen in 9, including 2 subjects in whom serum GH rose in response to bromocriptine. Serum somatomedin levels, measured by both radioimmunoassay and radioreceptor assay, fell in only 2 subjects (both of whom had falls in GH) and did not correlate with clinical status. These results suggest that some of the reported beneficial effects of bromocriptine in acromegaly may be independent of GH secretion or somatomedin generation.
Eighteen postmenopausal women with severe hot flashes had continuous recordings of finger temperature and skin resistance as objective indexes of flushing episodes, and serial measurements of anterior pituitary hormones as indirect indexes of hypothalamic neurotransmitter activity. Significant increases of growth hormone, adrenocorticotropic hormone (ACTH), and luteinizing hormone (LH) occurred with maximal concentrations at 30, five, and 15 minutes, respectively, after the onset of the skin temperature rises. No significant fluctuations of prolactin (PRL), thyroid-stimulating hormone (TSH), or follicle-stimulating hormone (FSH) were observed. The mean serum cortisol concentration increased 15 minutes after the hot flash, presumably consequent to the preceding elevation of ACTH. Pituitary ACTH release may be secondary to hypothalamic cooling, whereas increased growth hormone and LH output and the thermoregulatory adjustments comprising the flushing episodes are all consistent with cyclic episodes of increased hypothalamic norepinephrine activity.
A 47-year-old woman with acromegaly and hyperthyroidism was found to have an inappropriately normal serum thyrotropin level (1.5 to 2.5 microU/ml) that responded poorly to thyrotropin-releasing hormone but showed partial responsiveness to changes in circulating thyroid hormones. Serum alpha-subunit levels were high-normal and showed a normal response to thyrotropin-releasing hormone. Growth hormone and thyrotropin hypersecretion persisted despite radiotherapy and bromocriptine treatment. Selective trans-sphenoidal removal of a pituitary adenoma led to normalization of both growth hormone and thyrotropin levels. Both thyrotropes and somatotropes were demonstrated in the adenoma by the immunoperoxidase technique and electron microscopy.
Plasma cAMP, serum glucose, and cardiovascular responses to isoproterenol infusion were examined in seven normal subjects and seven patients with pseudohypoparathyroidism (PHP), type I (three with deficiency of the hormone receptor-cyclase coupling protein (N-protein) and four who were N-protein replete). Although plasma cAMP responses were blunted in both subgroups of PHP patients, the cardiovascular and glucose responses to isoproterenol were normal. We conclude that the blunted plasma cAMP response to isoproterenol in PHP does not depend on deficient N-protein coupling of adenylate cyclase to the beta-adrenergic receptor and that the cardiovascular and glucose responses to isoproterenol are not reflected in changes in plasma cAMP.