Pituitary relapse of acute promyelocytic leukemia after ATRA.
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Aged↗
Biomedical subjects
Y Halperin
Publications and source records attributed to Y Halperin.
Down-regulation of type II L-thyroxine, 5'-monodeiodinase in cultured GC cells: different pathways of regulation by L-triiodothyronine and 3,3',5'-triiodo-L-thyronine.
The current consensus is that iodothyronines down-regulate type II T4 monodeiodinase (5'-DII) by an extranuclear acceleration of enzyme inactivation. We have investigated 5'-DII regulation in cultured GC cells, in which thyroid hormone responses are mediated by nuclear thyroid receptor (TR). GC cells actively converted T4 to T3, independent of propylthiouracil and with a Km of 1.4 nM, which are characteristics of 5'-DII. When GC cells were incubated with 10 nM T3, the Km was not affected. However, the maximum velocity was significantly down-regulated by 10 nM T3, from 0.15 to 0.018 pmol/mg protein.min. Dose-response studies showed that a 50% reduction in enzyme activity was achieved with either 0.25 nM T3 or 12 nM rT3. Time-course studies showed that a 50% reduction in enzyme activity occurred after 40 min of incubation with 100 nM rT3 and after 160 min of incubation with 10 nM T3. The down-regulation of 5'-DII by physiological concentrations of T3 has the characteristics of an effect that is mediated by nuclear TR. Our studies, therefore, suggest that down-regulation of 5'-DII by these iodothyronines in GC cells may occur by different mechanisms: enzyme inactivation for rT3, in agreement with the current consensus, and decreased enzyme production for T3, probably mediated by TR.
Animals↗
Role of L-thyroxine in nuclear thyroid hormone receptor occupancy and growth hormone production in cultured GC cells.
The contribution of L-thyroxine (T4) to nuclear thyroid receptor occupancy was studied in GC cells incubated with concentrations of 3,5,3'-triiodo-L-thyronine (T3) and T4 that resulted in free iodothyronine levels similar to those in serum of euthyroid rats. T4 accounted for 5.4-10% of the occupied receptors: T3 derived from T4 [T3(T4)] and T3 added to medium accounted for the remainder of receptor occupancy. Incubation with increasing medium free T4 resulted in a progressive increase in the contribution of T4 and T3(T4) to receptor occupancy. In incubations with 3.6-fold increased medium free T4, T4 accounted for 20.4%, and T3(T4) for 40.3% of receptor occupancy. These occupancy data and the experimentally determined Ka of thyroid receptor for T3 and T4 allowed calculation of nuclear free iodothyronine concentrations. Nuclear free T3 was 3-6-fold greater than medium free T3 and nuclear [corrected] free T4 was 12-19-fold greater than medium free T4. When GC cells were incubated with decreased medium free T3 and physiological medium free T4, both nuclear receptor occupancy and growth hormone production decreased as well. However, a twofold increase in medium free T4, in the presence of decreased medium free T3, restored receptor occupancy and growth hormone production to or near control values. These findings establish a role for T4 in addition to T3(T4) in nuclear receptor occupancy and biological activity in rat anterior pituitary tissue both in physiologic conditions and when medium free T4 is raised. The findings may have relevance to the sick euthyroid thyroid syndrome in which free T4 may be increased in some patients who have decreased serum free T3.
Animals↗
Acromegaly due to ectopic growth hormone-releasing hormone secretion by a bronchial carcinoid tumour. Dynamic hormonal responses to various stimuli.
Ectopic GHRH is a relatively uncommon cause of acromegaly, which should be differentiated from pituitary adenoma, in order to avoid damage to the pituitary gland from unnecessary interventions. We report here on a 66-year-old man with acromegaly due to a GHRH-secreting bronchial carcinoid tumour, who recovered completely following removal of the tumour. His hormonal status was studied before and after the operation. Basal GH, GHRH, IGF-I and PRL levels, as well as plasma GH response to glucose load and TRH administration were abnormal before the operation, and became normal thereafter. The somatostatin analogue SMS 201-995 was found to be a potent inhibitor of the ectopic GHRH and the GH secretion (greater than 500 to 42 ng/l and 15.4 micrograms/l to 0.8 microgram/l, respectively). The effect on GHRH proved to be due to direct effect of somatostatin on the tumour cells, as demonstrated in tissue culture studies. A mixed meal was found immediately to suppress GHRH levels without such an effect on GH secretion. We conclude that the neuroendocrine tests usually practised in acromegaly cannot differentiate between ectopic GHRH secretion and pituitary adenoma. High plasma GHRH levels may serve as a diagnostic test for excessive GHRH production, which is almost always ectopic. These high levels are suppressible by somatostatin and a mixed meal.
Acromegaly↗
L-triiodothyronine (T3) regulates cellular growth rate, growth hormone production, and levels of nuclear T3 receptors via distinct dose-response ranges in cultured GC cells.
Cultured rat somatotrophic cells have been useful models for the study of thyroid hormone action. A consensus of previous reports has indicated that approximately 0.2 nM T3 results in 50% occupancy of T3 nuclear receptors as well as half-maximal stimulation of several T3 responses. To characterize the nature of thyroid hormone responses in GC cells, we studied in detail the T3 dose relationships between nuclear receptor occupancy and three thyroid hormone responses (cell growth, GH production, and T3 nuclear receptor regulation). The dose response to T3 for each parameter was unique, and none was identical to the dose response for receptor occupancy. Respective T3 concentrations and percentage of T3 nuclear receptor occupancy resulting in 50% of the maximal response for GC cell growth were 0.05 +/- 0.02 nM and 15 +/- 3% (four experiments), 0.15 +/- 0.04 nM and 27 +/- 3% for GH production (three experiments), and 2.1 nM and 69% for down-regulation of T3 nuclear receptors (two experiments). We conclude that the dose response for occupancy of the T3 nuclear receptor covers a wide range of T3 concentrations. Within the wide dose-response range for nuclear occupancy a spectrum of biological responses are regulated by distinct thyroid hormone dose ranges. These data suggest that the impact of T3 nuclear receptor occupancy on T3 responses might be variable and that the mechanisms involved may be clarified through studies in GC cells.
Animals↗
Medium 3,5,3'-triiodo-L-thyronine (T3) and T3 generated from L-thyroxine are exchangeable in cultured GC cells.
Previous studies in rats have shown that the ratio anterior pituitary nuclear L-triiodothyronine (T3) derived from intracellular deiodination of L-thyroxine [T3(T4)]/plasma T3(T4) is much greater than for exchangeable T3 [T3(T3)]. We have addressed the hypothesis that T3(T4) is either selectively accumulated or selectively retained by nuclei in comparison to exchangeable T3 [T3(T3)] in cultured GC cells. GC cells readily generated T3 from T4. When mean medium T3(T4) was experimentally maintained at a low percentage (less than 16%) of total medium T3, to mimic in vivo conditions, nuclear T3(T4) was 2-fold greater than nuclear T3(T3) and the nuclear: medium ratio for T3(T4) was 11-13-fold greater than for T3(T3). The t1/2 of release of nuclear T3(T4) and T3(T3) were indistinguishable from one another and both sources of T3 distributed similarly between the nuclear and cytosol compartments. Thus, in agreement with previous in vivo studies, T3(T4) is derived from cellular T4 and is a significant source of nuclear T3 in GC cells. No evidence for a separate nonexchangeable T3(T4) pool was found as the almost identical cellular distribution and release rates of T3(T4) and T3(T3) from nuclei suggest that T3(T4) generated in these pituitary tumor cells is fully exchangeable. Our findings suggest that the high concentration of T3(T4) in the nuclear fraction is the result of a high intracellular production rate of T3 from T4 relative to the rate of release of T3 from the cell.
Animals↗
Chronic treatment of a benign insulinoma using the long-acting somatostatin analogue SMS 201-995.
The newly developed long-acting somatostatin analogue SMS 201-995 was used to treat a patient with the presumptive diagnosis of benign insulinoma. Although intermittent injections with 50-100 micrograms s.c. every 8 h failed to produce any clinical improvement, continuous s.c. infusion with 150-300 micrograms/day prevented the hypoglycemic episodes absolutely, both during normal dietary intake and throughout 72 h of fasting. Chronic treatment (to date 30 months) has not been associated with any evidence of tachyphylaxis or rebound hypersecretion of insulin.
Adenoma, Islet Cell↗
Development and characterization of a variant GC cell line with L-triiodothyronine-independent growth and growth hormone production.
To facilitate studies of cell growth regulation by T3, we developed a variant GC cell line (V-GC) characterized by normal growth in T3-depleted (-T3) medium. The doubling time (dt) of V-GC cells was 28.8 h (-T3) and 28.0 h (+0.2 nM T3), respectively, whereas the dt of the parent GC cells, 24.0 h (+0.2 nM T3), increased to more than 100 h (-T3). The dt of V-GC cell was unaffected even by maximal T3 (5 nM). Cell protein (micrograms) per microgram DNA increased in GC cells in a T3 concentration-dependent manner, whereas V-GC cell protein was unaffected by T3. GH production appeared partially independent of T3 in V-GC cells. GH production (nanograms per 10(6)/h) in V-GC cells maintained for 3 months in -T3 medium was 3.3- to 4.6-fold greater than that in GC cells after 4 days in -T3 medium (P less than 0.001). Addition of T3 resulted in similar maximal GH production in both cell lines. The binding capacity and Ka of nuclear T3 receptors were similar in GC and V-GC cultures, and receptor down-regulation in response to added T3 occurred similarly in both cultures. Lastly, studies employing conditioned medium indicated that T3-independent growth of V-GC cells did not result from production of an autocrine growth factor. Our findings raise the possibility that overexpression of a transacting cell-specific gene-regulating protein that variably affects thyroid hormone-dependent genes may account for the phenotype of the V-GC cultures.
Animals↗
Bromocriptine treatment of acromegaly: possible dose dependency of the tumor size-reducing effect.
The effect of long-term, high-dose therapy with bromocriptine (BR) on the clinical and hormonal response, tumor size and neuro-ophthalmological status was studied in seven acromegalic patients. The mean BR dose was 64 mg/day (range 35 to 80) for a mean period of 11 months (range 10 to 12). In six patients there was a clinical improvement already manifest at low BR doses (10 to 20 mg). Serum growth hormone levels fell substantially (greater than 50%) in five patients, and the growth hormone response to thyrotropin-releasing hormone (TRH) and glucose were similar to those previously reported at lower doses of the drug, as were the prolactin and thyroid-stimulating hormone responses to TRH. In three patients, repeat CT scan disclosed a reduction in tumor size. In none of the patients was there evidence of tumor progression, with the possible exception of one patient who developed an impairment of the visual evoked potential response. These results suggest that when compared to previous studies in which lower doses of BR were used, a high BR dose is not superior in terms of clinical response and hormone secretion, but does appear to increase the percentage of patients who respond with a reduction in tumor size.
Acromegaly↗
Medical treatment of primary hyperparathyroidism: effects on parathormone and vitamin D metabolites.
A 63-year-old woman was treated medically for primary hyperparathyroidism because of a recent myocardial infarction. She received propranolol alone or combined with either cimetidine, calcitonin or disodium etidronate (EHDP). The treatment did not affect the elevated serum parathormone or urinary cyclic AMP levels, nor did it correct the elevated serum 1,25(OH)2D and the decreased serum 24,25(OH)2D levels in this patient. Propranolol combined with either cimetidine or with EHDP (600 mg/day) caused a mild decrease in the serum calcium level which, however, remained within the hypercalcemic range. Following surgery all parameters returned to normal. We conclude that the above medical regimens were incapable of correcting the hyperparathyroid condition in this patient.
Calcitonin↗
Acute desensitization of lymphocyte beta-adrenergic-stimulated adenylate cyclase in old age and Alzheimer's disease.
The effect of prior incubation with a single concentration of isoproterenol (10(-4) M) for 2 hours at 37 degrees C on isoproterenol-stimulated cyclic AMP accumulation in intact lymphocytes from young, old and subjects with Alzheimer's disease was studied. In lymphocytes from all three subjects groups prior incubation of cells with isoproterenol resulted in a significant reduction of cyclic AMP accumulation upon subsequent stimulation with isoproterenol.
Adenylyl Cyclases↗
A predictor index for hospitalization for patients with acute asthmatic attack.
Thirty-nine patients, aged 14 to 50 years (mean 33), were treated for an acute asthmatic attack in the hospital emergency room. A scored index was estimated on admission for each patient, based on pulse, respiratory and peak expiratory flow rates (PEFR), amplitude of paradoxical pulse and degree of dyspnea, wheezing and accessory muscle use. All patients were treated according to a standard protocol including oxygen, fluids, salbutamol inhalations and aminophylline infusions, with hydrocortisone infusion in selected patients. The decision to hospitalize of discharge was based on clinical grounds and was taken after 4 to 8 h of treatment without prior knowledge of the patient's index. The mean index of 13 hospitalized patients (Group 1) was 4.5 +/- 1.7 (mean +/- 2 SD), compared with 4.3 +/- 1.3 of 7 patients who were discharged but returned for additional treatment within 10 days (Group 2). Both indices were significantly higher than that of 19 patients who were discharged and remained well (2.5 +/- 1.5) (Group 3). The most important differentiating parameters were the degree of dyspnea, wheezing and PEFR. We conclude that patients with scored indices of greater than 4 should be hospitalized immediately, those with indices less than 4 could probably be discharged with relative safety, and patients with an index of 4 should be considered individually, with dyspnea, wheezing and PEFR being the major criteria for the decision.
Acute Disease↗
Rapid regression of aneurysms in polyarteritis nodosa.
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Adult↗
Prolactin response to metoclopramide and chlorpromazine in primary testicular failure and isolated gonadotrophin deficiency.
The aim of the present study was to measure the PRL response to metoclopramide (MET) and chlorpromazine (CPZ) in seventeen patients with primary testicular failure and eight patients with isolated gonadotrophin deficiency (IGD). The responses were compared with those to TRH. Basal gonadotrophins and peak responses to LHRH were increased in testicular failure and reduced in IGD. Basal PRL levels were normal in both groups of patients. However, when compared with controls, the PRL response to both MET and CPZ as well as to TRH was exaggerated in primary testicular failure, whereas the responses wee decreased in IGD. In both patient groups, as well as in the controls, the PRL response to MET exceeded that to TRH and CPZ. It is suggested that alterations in the steroid milieu are responsible for the exaggerated PRL response to MET, CPZ and TRH in primary testicular failure and the reduced response observed in IGD.
Adolescent↗
Clomiphene attenuates the exaggerated prolactin response to thyrotropin-releasing hormone and metoclopramide occurring in primary testicular failure.
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Adult↗
Surgical management of periadnexal adhesions.
The importance of the lysis of periadnexal adhesions with regard to pregnancy rate was evaluated in 101 infertile patients. All patients had at least one patent tube and normal fimbria. The periadnexal adhesions were classified into four grades according to their nature and extent. A significant inverse relationship was noted between the grade of adhesions and the pregnancy rate. The overall pregnancy rate was 45.5%. The pregnancy rate in grade 1 adhesion group was 64.7%, compared with 25.0% in grade IV (P less than 0.05). Postoperative early hydrotubations with hydrocortisone yielded a significantly higher pregnancy rate (52%), compared with patients not treated (25%, P less than 0.02). In order to improve the results, more effort should be directed to the prevention of adhesion formation.
Abortion, Spontaneous↗