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Biomedical subjects

M O Thorner

Publications and source records attributed to M O Thorner.

At least 199 records · Page 11Linked to original sources
PubMed1984

Intensified rates of venous sampling unmask the presence of spontaneous, high-frequency pulsations of luteinizing hormone in man.

To test the validity of venous sampling rates that are generally used to characterize pulsatile LH release in man (e.g. sampling every 15-20 min), we characterized apparent LH pulse frequency in blood withdrawn variously at 20- or 4-min intervals in 19 men, at 2-min intervals in 14 men, and at 1-min intervals in 6 men. In an effort to minimize detection bias, significant LH pulses were evaluated objectively using a computerized pulse-detection algorithm, which tended to maximize recognition of true-positive LH pulses, and minimize false-positive and false-negative pulses. Under these conditions, intensified rates of venous sampling at 4-, 2-, and 1-min intervals exposed approximately 3.6, 4.9, and 13.7-fold more LH pulses, respectively, than could be discerned at a 20-min sampling frequency. In addition, more rapid rates of venous sampling disclosed a previously unobserved pattern of LH pulses, in which higher frequency, lower amplitude LH pulsations were interposed among low frequency, high amplitude LH peaks. Quantitatively, LH pulses unmasked by intensified rates of venous sampling exhibited significantly lower pulse amplitudes, expressed either as a fractional (%) or absolute (mIU/ml) increment, than pulses identified at 20-min intervals. In conclusion, we demonstrated that intensified rates of venous sampling unmask a significant number of otherwise unrecognized LH pulses in the circulation of normal men. Moreover, because generally employed sampling rates overlooked these more rapid physiological fluctuations in LH concentrations, patterns of both high and low frequency LH pulsations must now be characterized in various states of health and disease using more rapid sampling paradigms.

Adult↗
PubMed1984

Circulating growth hormone forms after stimulation of pituitary secretion with growth hormone-releasing factor in man.

Human GH (hGH) in the circulation of acromegalic patients and pharmacologically stimulated normal subjects consists of several monomeric and oligomeric molecular forms. However, little is known about the nature of plasma hGH under physiological conditions. We examined the molecular composition of plasma hGH secreted in response to synthetic human pancreatic tumor GRF-(1-40) (hpGRF-40), a peptide closely resembling or identical to hypothalamic GRF. The peptide (10 micrograms/kg) was injected iv into six normal men, and blood was obtained 30 min later. Plasma hGH was characterized by gel filtration and by polyacrylamide gel electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and isoelectric focusing after extraction from plasma by immunoadsorbent chromatography. At least 53% of hGH eluted as little (monomeric) hGH, 27% as big (dimeric) hGH, and 20% or less as big-big (oligomeric and spurious) hGH during gel filtration. Among the monomeric forms, the 22,000-dalton form was predominant (83%), with smaller quantities of the 20,000-dalton variant (11%), and one or more unidentified acidic forms (N alpha-acetylated, deamidated, or cleaved hGH) (6%) also present. The molecular composition of plasma hGH secreted in response to hpGRF-40 is similar to that released after pharmacological stimuli or that circulating in acromegaly.

Adult↗
PubMed1984

Growth hormone release in response to human pancreatic tumor growth hormone-releasing hormone-40 in children with short stature.

Forty children with short stature were evaluated for GH reserve after pharmacological tests and after a single iv injection of human pancreatic tumor GH-releasing hormone [hpGRH-40). These children were grouped into four diagnostic categories: 1) idiopathic GH deficiency (n = 10); 2) organic hypopituitarism (n = 7); 3) intrauterine growth retardation (n = 5); and 4) constitutional delay of growth and/or familial short stature (n = 18), by standard clinical criteria and physiological and pharmacological tests of GH reserve. Venous blood was sampled for GH concentrations on 2 consecutive days: on day 1, after the iv administration of L-arginine (0.5 g/kg for 30 min) and oral administration of L-dopa (9 mg/kg), and on day 2, after the administration of hpGRH-40, 3.3 micrograms/kg, as an iv bolus. No GH-deficient patient in categories 1 or 2 increased his/her circulating GH concentration to more than 7 ng/ml after the arginine-L-dopa test; however, six children had marked GH responses after hpGRH-40 administration. As a group the lowest peak responses (mean +/- SE) to GRH were found in the organic hypopituitary (3.4 +/- 1.1 ng/ml) and in the idiopathic GH deficiency (8.2 +/- 2.4 ng/ml) categories. All children in the intrauterine growth retardation and constitutional delay of growth (controls for the GH-deficient children) responded briskly to hpGRH-40, although there was wide variation of the peak GH levels (5-51 ng/ml). Circulating concentrations of somatomedin-C did not differ in subjects in any category 24 h after hpGRH-40 injection when compared to basal values. These data indicate that hpGRH-40 can be employed to evaluate GH reseve in short children and may be useful in the diagnosis of hypothalamic-pituitary disorders.

Adolescent↗
PubMed1984

Effects of human pancreatic growth hormone-releasing factor-40 on serum growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and somatomedin-C concentrations in normal women throughout the menstrual cycle.

Human pancreatic tumor GH-releasing factor-40 (hpGRF-40) selectively stimulates GH secretion in normal men and in some adults with GH deficiency. To study its effects in women, we administered hpGRF-40 (3.33 micrograms/kg) or an equivalent volume of vehicle as an iv bolus at 0900 h to 10 normal women during the early follicular, late follicular, and midluteal phases of the menstrual cycle. Serum concentrations of GH, PRL, LH, and FSH were measured at intervals between 0800-1100 h. Serum somatomedin-C concentrations were measured before and 24 h after the administration of vehicle of hpGRF-40. Within 1-3 min after the injection of hpGRF-40 all women described warmth localized to the head and neck and exhibited facial flushing. No changes in pulse rate or blood pressure were noted. When expressed as change from baseline and compared to control values, peak levels of serum GH (nanograms per ml; mean +/- SEM) were higher after hpGRF-40 treatment during the early follicular (5.4 +/- 3.2 vs. 34.9 +/- 8.3; control vs. test day; P = 0.011), late follicular (5.6 +/- 1.5 vs. 25.2 +/- 6.8; P = 0.014), and luteal (0.8 +/- 1.0 vs. 32.7 +/- 12.8; P = 0.033) phases of the menstrual cycle. Similarly, integrated serum GH levels (nanograms per ml/h) were higher after hpGRF-40 administration during the early follicular (0.72 vs. 16.1; P = 0.011), late follicular (0.83 vs. 9.9; P = 0.037), and luteal (-1.54 vs. 17.0; P = 0.036) phases of the cycle. When the increases in serum GH after hpGRF-40 treatment were compared among the phases of the menstrual cycle, however, no differences were found. Serum somatomedin-C values 24 h after hpGRF-40 treatment were higher than those 24 h after vehicle at all stages of the menstrual cycle. hpGRF-40 did not stimulate the release of PRL, LH, or FSH. We conclude that hpGRF-40 stimulates the release of GH, but that in response to the dose used, hpGRF-40-stimulated GH release does not vary during the menstrual cycle.

Adult↗
PubMed1984

Extrahypothalamic growth-hormone-releasing factor (GRF) secretion is a rare cause of acromegaly: plasma GRF levels in 177 acromegalic patients.

To assess the frequency with which acromegaly is caused by ectopic secretion of GRF, we collected plasma samples from 177 unselected acromegalic patients. The samples together with those of three acromegalic patients with previously diagnosed tumors secreting GRF and of normal subjects were assayed in 3 independent GRF RIAs. Plasma immunoreactive GRF (IR-GRF) levels in normal subjects were either undetectable or detectable at levels up to 62.5 pg/ml. In none of the 177 specimens from acromegalic patients were IR-GRF values detectable in all assays, and in the most sensitive assay, the levels were similar to those in normal subjects, with the highest level measuring 82 pg/ml. In contrast, plasma IR-GRF found in the 3 patients with tumors that secreted GRF ranged from 2.0-24.4 ng/ml. These data suggest that extrahypothalamic GRF secretion is a rare cause of acromegaly. However, it is important that this rare cause of acromegaly be diagnosed before the patient has unnecessary surgery and/or irradiation directed at the pituitary. We recommend that plasma IR-GRF be measured in each new acromegalic patient.

Acromegaly↗
PubMed1984

Pituitary response to growth hormone-releasing factor in diabetes. Failure of glucose-mediated suppression.

To evaluate the mechanism underlying raised growth hormone levels in diabetes, we compared the response to growth hormone-releasing factor (GRF) in type I diabetic and healthy control subjects. In 12 poorly controlled diabetic subjects (fasting plasma glucose 276 +/- 27 mg/dl) basal serum growth hormone levels were elevated by 200-300% (P less than 0.02), yet the incremental increase in growth hormone after GRF injection was no greater than in control subjects. Furthermore, five additional diabetic subjects with normal growth hormone levels after long-term insulin pump treatment also showed an identical response to GRF. Thus, raised basal growth hormone levels in diabetes and the fall that follows intensive insulin treatment may reflect changes in hypothalamic regulation of, rather than in pituitary responsiveness to, GRF. However, when five normal subjects were restudied during glucose infusion, even quite modest hyperglycemia (plasma glucose approximately 150 mg/dl) caused marked suppression of the response to GRF (P less than 0.005). Thus, the "normal" response to GRF in poorly controlled diabetes is actually inappropriate. Failure of the pituitary to suppress in response to hyperglycemia in diabetes implies a second abnormality that may further aggravate disordered growth hormone secretion.

Adolescent↗
PubMed1984

Clinical and pathological effects of bromocriptine on prolactin-secreting and other pituitary tumors.

Bromocriptine inhibits prolactin secretion and causes size reduction of prolactin-secreting adenomas. The effect of the drug upon pituitary tumors other than prolactinomas is uncertain. The authors report a prospective series of 12 patients with pituitary macroadenomas in whom bromocriptine was administered for 6 weeks prior to transsphenoidal surgery. Five of the patients had computerized tomographic documentation of significant reductions in tumor size (Group A) and six had no change (Group B) during 3 and 6 weeks of bromocriptine administration. One patient who demonstrated size reduction in his tumor was not assigned to either group as he was treated with high-dose dexamethasone concurrently with the bromocriptine. Pathological examination (light and electron microscopy and immunocytochemistry) indicated that all Group A patients harbored tumors with prolactin granules whereas all Group B tumors lacked such granules. Adenoma cells in the responsive tumors were involuted with reduced cytoplasmic, nuclear, and nucleolar areas. Neither widespread cell necrosis, infarction, nor vascular injury was observed. Two of the five Group A patients discontinued bromocriptine prior to completion of the 6-week protocol and had a rapid return of their tumors to pre-treatment size. Although bromocriptine has been reported to cause shrinkage of nonfunctional tumors, there was no radiological evidence of size reduction or pathological changes in the nonfunctional tumors of this series. Interestingly, serum levels of prolactin were modestly elevated (84 and 113 ng/ml) in two of the six Group B patients, an elevation due to stalk compression rather than secretion by adenoma cells. This finding underscores the fact that failure of bromocriptine to reduce pituitary tumor size in the presence of hyperprolactinemia may occur because the tumor is other than a prolactinoma. This is the first moderate-sized group of patients in whom pathological changes in responsive prolactinomas during bromocriptine therapy have been demonstrated. As bromocriptine is not tumoricidal, and thus not curative, there is insufficient evidence to recommend this drug as primary therapy for either prolactin-secreting or nonfunctional macroadenomas, but the drug may have potential as a preoperative adjunct to effect shrinkage of prolactinomas and theoretically, at least, make excision easier and possibly more complete.

Adenoma↗
PubMed1984

Bromocriptine inhibits growth hormone release from rat pituitary cells in primary culture.

The action of the potent dopamine receptor agonist bromocriptine was studied in primary cultures of rat anterior pituitary cells. Bromocriptine inhibited both prolactin and growth hormone release in a concentration-dependent manner. This effect was blocked by the dopamine receptor antagonist spiperone when the agonist and antagonist were added coincidently. In contrast, spiperone was unable to affect the actions of bromocriptine if added 1 min after bromocriptine application or later. These results suggest that dopamine receptors exist not only on mammotrophs, but also on somatotrophs in vitro.

Animals↗
PubMed1984

Drugs five years later. Bromocriptine.

Bromocriptine, a specific dopamine receptor agonist, has been used for the treatment of various hyperprolactinemic conditions and as adjunctive therapy for acromegaly (with or without concomitant hyperprolactinemia) and Parkinson's disease. Bromocriptine is extremely effective in suppressing prolactin secretion regardless of the cause, in restoring gonadal function and fertility, and in decreasing the size of prolactin-secreting pituitary tumors. Most patients with acromegaly have clinical improvement with this drug. When bromocriptine is added to a regimen of levodopa or carbidopa, patients with Parkinson's disease frequently have additional clinical improvement and, in most patients, the levodopa or carbidopa dose can be reduced. Withdrawal of bromocriptine therapy is associated in most patients with reversal of its beneficial effects--return of hyperprolactinemia, return of excess growth hormone secretion, and exacerbation of Parkinson's disease.

Acromegaly↗
PubMed1983

Effects of human pancreatic tumour growth hormone releasing factor on growth hormone and somatomedin C levels in patients with idiopathic growth hormone deficiency.

Human pancreatic tumour growth hormone releasing factor (hpGRF-40) 10 micrograms/kg was administered intravenously to 6 normal young men and 12 adult patients who had presented in childhood with growth hormone (GH) deficiency (7 patients had isolated GH deficiency, 4 had multiple anterior pituitary hormone deficiencies, and 1 had Hand-Schüller-Christian [HSC] disease). hpGRF-40 administration increased serum GH concentrations in all normal subjects and in 3 of 7 patients with isolated GH deficiency and in the 1 with HSC disease; however, the mean serum GH concentration in the patients who responded was less than that of the normal subjects. Somatomedin C concentrations were increased 24 h after a single dose of hpGRF-40 in 8 of 10 patients with GH deficiency. All subjects experienced flushing in response to hpGRF-40. A patient with isolated GH deficiency received 0.33 micrograms/kg hpGRF-40 every 3 h for 5 days. Despite the modest increase in GH in response to a subsequent dose of 10 micrograms/kg hpGRF-40, serum somatomedin C levels increased within 12 h from 0.06 to 0.1 U/ml and peaked at 0.36 U/ml at 72 h; in addition the patient with HSC disease, treated with hpGRF-40 daily for 5 days, demonstrated an increase in somatomedin C from 0.4 to 0.58 U/ml. The increase after hpGRF-40 in serum GH levels in this patient and the similar or greater responses in 3 of 7 patients suggest that at least some of these patients may have hypothalamic GH-releasing-hormone deficiency. hpGRF-40 may be useful in distinguishing pituitary disease from hypothalamic disease. After hpGRF-40 administration serum somatomedin C levels may increase without a change in serum immunoreactive GH concentrations. Further studies are needed to determine whether hpGRF-40 is useful in promoting linear growth in children with GH deficiency.

Adult↗
PubMed1983

Human pancreatic growth-hormone-releasing factor selectively stimulates growth-hormone secretion in man.

A growth-hormone-releasing factor has been characterised and sequenced from a pancreatic tumour removed from a patient with acromegaly. It is a 40-residue linear peptide. Synthetic human pancreatic growth-hormone-releasing factor (hpGRF-40), 1 microgram/kg bodyweight, was administered as an intravenous bolus to six healthy men. hpGRF-40 selectively stimulated growth-hormone secretion. Serum growth-hormone concentrations were increased within 5 min, reaching a peak between 30 and 60 min (20 . 4 +/- 6 . 5 ng/ml compared with 2 . 1 +/- 0 . 1 ng/ml after placebo). Serum levels of prolactin, thyrotropin, luteinising hormone, and corticotropin (measured indirectly through plasma cortisol) were not increased after administration of hpGRF-40. Similarly, the concentrations of blood glucose, plasma insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, and somatostatin were unaffected by hpGRF-40. There were no changes in blood pressure, pulse rate, or body temperature, and no side-effects were noted. The characteristics of this peptide fulfil many of the criteria required of the hypophysiotropic growth-hormone-releasing hormone. hpGRF holds promise for a new approach to the diagnosis and treatment of various disorders of growth-hormone secretion.

Acromegaly↗
PubMed1983

Continuous perifusion of dispersed anterior pituitary cells: technical aspects.

Continuous perifusion of dispersed anterior pituitary cells is a powerful dynamic in vitro technique that complements the static incubation technique of primary culture. The major advantages of perifusion include the ability to challenge cells with test substance in a pulsatile manner and to monitor the immediate response. Furthermore, the accumulation of hormonal product and proteolytic enzymes, with their potential effects on cell function, is essentially eliminated as a concern. Finally, although methods using static techniques are available, experiments using continuously perifused dispersed cells can be initiated soon after removal of the gland from the donor animal. We and others have found this system to be useful in the study of hormone secretion by the anterior pituitary. We expect that the system will lend itself equally well to investigations of other cellular processes involving the export of organic and inorganic substances.

Animals↗
PubMed1983

Biological activity of a growth hormone-releasing factor secreted by a human tumor.

A substance released by a pancreatic islet cell tumor induced signs and symptoms of acromegaly in a young woman. The culture medium in which the tumor was placed after resection was added to rat anterior pituitary cells and incubated in vitro. Both newly synthesized and total rat growth hormone (GH) release as well as cellular cyclic AMP accumulation were stimulated in a dose-dependent manner by the tumor medium. Coincubation with somatostatin blocked these effects. The increase of cyclic AMP preceded the enhanced GH release, indicating that cyclic AMP may be a second messenger for the tumor factor(s). Neither prolactin nor luteinizing hormone secretion was affected by the tumor medium. When measured by a perfused cell column apparatus, there was a rapid and dramatic release of GH by the dispersed rat pituitary cells during a 2.5-, 10-, and 40-min pulse of tumor medium; both the onset and termination of the GH response reached maximal or control values, respectively, within 5 min. Pretreatment of the tumor medium with pepsin markedly attenuated the tumor medium activity, indicating the peptide nature of the factor(s). Finally, ultrastructural analysis indicated that the somatotrophs were degranulated by the tumor medium, whereas there was no similar effect apparent on the mammotrophs. Whether this tumor polypeptide is identical to native hypothalamic GH-releasing hormone remains to be proved.

Adult↗
PubMed1983

Human pancreatic GRF stimulates phosphatidylinositol labeling in cultured anterior pituitary cells.

The effects of natural and synthetic human pancreatic growth hormone-releasing factor (hpGRF) on 32P incorporation into phospholipids were studied in cultured rat anterior pituitary cells. Natural hpGRF (1:30 dilution) significantly (P less than 0.01) stimulated phosphatidylinositol labeling at all times studied (15, 30, and 60 min). Synthetic hpGRF-(1-40)OH also significantly (P less than 0.05; P less than 0.01) increased 32P incorporation into phosphatidylinositol in a dose-related (1-30 nM) and time-dependent (5, 10, and 30 min) manner. In contrast, phosphatidylcholine and phosphatidylethanolamine labeling was not affected at any time studied. Somatostatin (30 nM) did not affect basal or hpGRF-stimulated phosphatidylinositol labeling but inhibited the hpGRF stimulation of cyclic AMP accumulation and growth hormone release. These results suggest that the phosphatidylinositol cycle may be involved in the mechanism of action of hpGRF in the anterior pituitary gland.

Animals↗
PubMed1983

Luteinizing hormone secretion is enhanced by pertussis toxin, cholera toxin, and forskolin. Evidence for the involvement of the cyclic AMP-generating system.

Pertussis toxin, cholera toxin and forskolin, all of which can increase adenylate cyclase activity, stimulated luteinizing hormone LH release from cultured rat anterior pituitary cells. Although cellular cyclic AMP and growth hormone were increased rapidly by cholera toxin and forskolin, enhanced LH release occurred significantly later with no change in total radioimmunoassayable LH (i.e., released plus stored). These data suggest that changes in cyclic AMP levels may regulate the tonic availability of releasable LH in the gonadotroph.

Animals↗
PubMed1983

Zinc may have a physiological role in regulating pituitary prolactin secretion.

We studied the in vitro influence of physiologically relevant zinc concentrations on the pituitary synthesis and secretion of prolactin (Prl). Zinc in concentrations between 1 and 10 microM reduced Prl secretion and, to a milder extent, synthesis, but not basal or stimulated growth hormone (GH) or LH release. At a supraphysiological concentration of 100 microM, zinc markedly decreased Prl synthesis and secretion, but increased LH secretion. The ability of a physiological zinc concentration to influence Prl secretion suggests that this trace element may have a role in the in vivo regulation of Prl release.

Animals↗