Radiotherapy in the treatment of pituitary tumors.
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Humans↗
Biomedical subjects
A Grossman
Publications and source records attributed to A Grossman.
Analysis of urinary and plasma catecholamines using a single LC-EC system.
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Adrenal Gland Neoplasms↗
Subcutaneous growth hormone-releasing hormone augments pulsatile nocturnal GH release in GH-insufficient children, but may also raise basal GH secretion.
Growth hormone-releasing hormone (GHRH) when given s.c. to GH-insufficient children either as pulses, or once or twice daily, promotes linear growth. These treatment regimens, however, are not ideal as they require frequent drug administration and a significant proportion of patients do not show improved growth. We have now investigated the GH response to a nocturnal s.c. infusion of GHRH (1-29)NH2, at two dosages, 5 and 10 micrograms/kg/h, in a group of five GH-insufficient children. The s.c. infusion of GHRH between 2100 h and 0600 h augmented nocturnal pulsatile GH release in all five children. There was a dose-dependent response for the GH area under the curve (AUC), and mean total GH concentration. The AUC for GH was significantly greater after the 10 than 5 micrograms/kg/h GHRH which in turn was greater than that after placebo; mean (SD) AUC: 14816 (3978), 8125 (1931), 3032 (1582) mU min/l respectively (P less than 0.01 and P less than 0.05). There was no significant change in the number of GH pulses during the 9-h infusions when the subjects were infused with GHRH 10 or 5 micrograms/kg/h compared to placebo, and they occurred at similar times although the number of pulses tended to be greater after GHRH; the mean (SD) numbers of GH pulses were 5.0 (0.7), 3.8 (0.8), 3.2 (0.8), respectively. There was however a significant rise in the mean baseline GH concentration in all patients during the infusion of GHRH 10 micrograms/kg/h compared to placebo, but not with 5 micrograms/kg/h. Thus, GHRH(1-29)NH2 given s.c. augmented nocturnal pulsatile GH release in GH-insufficient children but it also increased baseline GH secretion. These results suggest that a sustained release preparation of GHRH could be a potential treatment for GH-insufficient children, and that a dose of 5 micrograms/kg/h would promote pulsatile GH release, but that at higher dosage it may also raise basal GH secretion.
Child↗
Opiate receptor subtype regulation of CRF-41 release from rat hypothalamus in vitro.
We have previously shown that the release of corticotrophin-releasing factor 41 (CRF-41) induced by a variety of neurotransmitters and depolarizing agents from the rat hypothalamus in vitro is inhibited by morphine. In order to further characterize the opiate receptors mediating this inhibitory action, we have now investigated the effects of a variety of opioid compounds with relatively high selectivity for mu-, kappa- and delta-opiate receptors on K(+)-stimulated CRF-41 release. The selective mu-opioid receptor agonist 202-250 inhibited K(+)-evoked CRF-41 release in a dose-dependent manner with a maximum inhibition of approximately 60% at 10(-5) M (p less than 0.01), as did the kappa-selective agonists PD-117,302 and U-50,488, with a similar plateau in response of approximately 40% inhibition at 10(-6) M (p less than 0.05). The effects of these agonists were specifically reversed by the mu- and kappa-receptor antagonists naloxone and MR2266, respectively, while the specific delta-receptor antagonist ICI 154,129 was ineffective. Both naloxone and MR2266 slightly but significantly increased the basal release of CRF-41. The delta-agonist D-Pen2,5-enkephalin was without significant effect in the same dose range. These data suggest that both mu- and kappa-receptors, but not delta-receptors, mediate the inhibitory effect of opiates on stimulated CRF-41 release from the rat hypothalamus.
Animals↗
Atrial natriuretic peptides inhibit the release of corticotrophin-releasing factor-41 from the rat hypothalamus in vitro.
Atrial natriuretic peptide, ANP(99-126), is derived from cardiac atrial tissue and has potent effects on salt and water homeostasis, including the inhibition of aldosterone and vasopressin release. Recent studies have also suggested that it may suppress the pituitary-adrenal axis. In addition, N-truncated forms of ANP, such as ANP(103-126), have been identified within the central nervous system, with a prominent hypothalamic localization in the paraventricular nucleus. We have therefore investigated whether ANP(99-126) and ANP(103-126) are able to modulate the release of the principal ACTH-releasing factor, corticotrophin-releasing factor-41 (CRF-41), from the rat hypothalamus in vitro. The static incubation system has been previously described in detail. Male Wistar rats were decapitated between 09.00 and 09.30 h, their hypothalami rapidly removed, and four half-hypothalami incubated for 20-min intervals following a period of stabilization. The effect of the ANP peptides on the basal (B) and KCl (28 mmol/l)-stimulated (S) release of immunoreactive CRF-41 was studied by means of successive incubations in the absence (B1, S1) and presence (B2, S2) of the peptides. The ratios B2:B1 and S2:S1 were compared with parallel control incubations by ANOVA. Neither form of ANP had any effect on the basal release of CRF-41. ANP(99-126) caused a dose-dependent inhibition of CRF-41 release in the concentration range 1-100 nmol (P less than 0.01). ANP(103-126) also suppressed the release of CRF-41 in the concentration range 100 pmol/l-100 nmol/l (P less than 0.01), with a minimum S2:S1 ratio at 10 nmol/l, and a decrease in effect at 100 nmol/l. Finally, the stimulation of CRF-41 release induced by noradrenaline (10 nmol/l and 1 mumol/l) was non-competitively antagonized by 100 nmol ANP(99-126)/l and 10 nmol ANP(103-126)/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Multiple restriction enzyme digests are required to rule out polymorphism in the molecular diagnosis of chronic myeloid leukemia.
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Blotting, Southern↗
Neuropeptide-Y stimulates CRF-41 release from rat hypothalami in vitro.
There is increasing evidence that neuropeptide-Y (NPY) exerts a stimulatory effect on the hypothalamo-pituitary-adrenal axis. Although it has been suggested that this stimulatory effect may be mediated via an action on hypothalamic CRF-41 release, direct measurements have not previously been made. In this study, the direct effect of NPY on hypothalamic CRF-41 secretion has been investigated in vitro using acute hypothalamic explants and previously described incubation techniques. NPY in the concentration range 10(-8)-10(-5) M produced a dose-dependent stimulation of CRF-41 release which was maximum at a concentration of 10(-6) M. The possibility that this stimulatory effect might reflect an interaction with noradrenergic inputs to CRF-41 neurons was excluded by incubating the hypothalami in the presence of NPY in combination with either the beta-adrenoceptor antagonist, propranolol (10(-5) M), or the alpha 1-adrenoceptor antagonist, prazosin (10(-5) M); neither inhibited NPY-stimulated CRF-41 release, suggesting that this effect is unrelated to noradrenergic pathways and is exerted through distinct receptor mechanisms. Furthermore, norepinephrine-stimulated (10(-8)-10(-6) M) CRF-41 release was not potentiated in the presence of NPY (10(-6) M). In summary, these data provide evidence for a direct stimulatory effect of NPY on CRF-41 secretion from the rat hypothalamus in vitro. This effect is independent of catecholaminergic interactions, suggesting that it is mediated either directly on CRF-41 neurons or through non-catecholaminergic neuronal systems.
Animals↗
Location of breakpoints within the major breakpoint cluster region (bcr) in 33 patients with bcr rearrangement-positive chronic myeloid leukemia (CML) with complex or absent Philadelphia chromosomes.
We report the sublocalization of the breakpoint in chromosome 22 in 33 patients with chronic myeloid leukemia (CML) who also had unusual marrow cytogenetics. In 23 patients, the leukemic clones were characterized by Philadelphia (Ph1) chromosomes that arose through complex translocations that involved three or more chromosomes. In the remaining ten patients, there were no detectable Ph1 chromosomes despite molecular evidence for the presence of rearrangements in the major breakpoint cluster region (bcr) of chromosome 22 in all cases. There was no significant difference between the two groups with respect to location of the breakpoints within the bcr. When these two groups of patients were combined, there was a significant excess of breakpoints in one segment of the bcr when compared to the distribution of breakpoints seen in 119 patients with simple 9;22 translocations. The difference in breakpoint distributions did not appear to be entirely attributable to differences between groups in disease duration at the time of study. These data support the notion that the unusual genetic recombinations that give rise to BCR/ABL fusion genes in CML involve specific DNA sequences of BCR (and possibly ABL) and additional, recombinogenic sequences, at least some of which are present in loci known to be nonrandomly involved in complex Ph1 translocations.
Adult↗
Comparison of phenotyping and genotyping of lymphoid neoplasms.
Comparison of phenotyping (PT) and genotyping (GT) of lymphoid neoplasms was performed on 51 specimens including lymph nodes, bone marrows, and body fluids. PT was performed with a flow cytometer using a large monoclonal antibody panel. GT included the testing for gene rearrangements of heavy chain, kappa and lambda light chains, and T-cell receptor beta-chain genes with DNA probes. The results obtained from these two techniques were generally compatible in terms of clonality and cell lineage. Only one case of B-cell lymphoma was not diagnosed by PT but showed gene rearrangement. For T-cell lymphoma, GT offers a more definitive diagnosis than does PT. Biclonality was demonstrated in one case of hairy cell leukemia by GT only. The rearranged band also offers a definitive clonal identification based on electrophoretic mobility. GT can detect a monoclonal population as small as 5% and can be performed on old or fresh specimens. PT requires 20% abnormal cells and a fresh specimen. It is concluded that GT is superior to PT for lymphoid tumor diagnosis, but it should be reserved as a supplementary test at this stage because of its technical complexity.
Antibodies, Monoclonal↗
Species comparison of steroid UDP-glucuronyl transferase: correlation to TCDD sensitivity.
Estradiol glucuronidation via steroid UDP-glucuronyl transferase (sUDPGT) was examined in 2,3,7,8-te trachlorodibenzo-p-dioxin (TCDD) sensitive and resistant species and strains. Steroid UDPGT was not induced by treatment with TCDD or estradiol. The most sensitive species to TCDD lethality, the guinea pig, had relatively high steroid UDPGT activity, while the hamster, the most resistant species, and rats had low levels of activity; no differences in sUDPGT activities were observed between mouse or rat strains differing in susceptibility to TCDD intoxication. These results suggest a role for differences in steroid physiology in the determination of species susceptibility to TCDD, but also demonstrate that other factors are involved.
Animals↗
Long-term treatment with a new repeatable injectable form of bromocriptine, Parlodel LAR, in patients with tumorous hyperprolactinemia.
A new long-acting repeatable injectable form of bromocriptine, (Parlodel LAR, Sandoz, Basle, Switzerland) has recently been developed. We studied the clinical, hormonal and radiological changes in six female patients with microprolactinomas and eight (3 female and 5 male) with macroprolactinomas receiving monthly injections of Parlodel LAR 50 to 100 mg for 6 months. Five patients with microadenomas and 4 with macroadenomas had normal prolactin (PRL) levels with Parlodel LAR 50 mg after one (5 patients), two (2 patients), or five (2 patients) injections; two patients with macroadenomas had normal or near normal PRL levels only after 4 monthly injections of 100 mg. Clinical improvement paralleled the changes in serum PRL. A complete normalization of a visual field defect occurred in one patient after 5 months of therapy. Marked shrinkage of the adenoma was shown by magnetic resonance and/or computed tomographical imaging in three patients with macroadenomas after 1 week. Side-effects were mild and usually transient. Parlodel LAR represents a novel treatment of hyperprolactinemic states which is both effective and well tolerated, and appears to be a useful alternative to oral therapy for long-term treatment.
Adenoma↗
Differential effect of high-dose naloxone on the plasma adrenaline response to the cold-pressor test.
1. Although the opiate antagonist naloxone has been shown to affect sympathoadrenomedullary function in some studies, this has not been a uniform finding in all investigations, using different doses of naloxone. We have therefore investigated the actions of saline placebo and increasing bolus doses of intravenous naloxone (25, 100 and 250 micrograms/kg) on the plasma noradrenaline, adrenaline, adrenocorticotrophin (ACTH) and cortisol responses to a cold-pressor test in six males and two females in a double-blind randomized study. 2. Basal levels of adrenaline did not differ on any of the study occasions: the cold-pressor stimulus produced a significant rise in mean plasma adrenaline to a peak of 0.16 nmol/l, with a peak incremental rise of 0.08 nmol/l. In the presence of the two higher doses of naloxone, the incremental rise in the mean adrenaline level was significantly enhanced, reaching 0.30 nmol/l at 100 micrograms of naloxone/kg and 0.29 nmol/l at 250 micrograms of naloxone/kg, with no significant enhancement observed at the lowest dose of naloxone. The rise in plasma noradrenaline, systolic and diastolic blood pressure and pulse rate during the cold-pressor test was not consistently altered by any dose of naloxone, but there was a significant trend for the degree of discomfort to increase with the dose of naloxone. 3. Neither plasma ACTH nor serum cortisol rose in response to the cold-pressor stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
The pituitary-adrenal response to CRF-41 is unaltered by intravenous somatostatin in normal subjects.
We have previously reported that the hypothalamo-pituitary-adrenal response to insulin-induced hypoglycaemia is normal while the cortisol release to pituitary stimulation by corticotrophin releasing factor (CRF-41) is reduced in obesity. Impaired growth hormone (GH) secretion is also found in obesity which may result from altered central levels of somatostatin (SMS). We have investigated, by giving a simultaneous infusion of SMS to six volunteer normal weight men during a CRF test, whether it is possible for SMS to modify pituitary-adrenal function. Each subject received intravenous CRF-41 (0.5 micrograms/kg) on two occasions during an infusion of isotonic saline or SMS (4 micrograms/min) in a randomized double-blind study. Plasma GH, cortisol, ACTH and SMS were measured. Three subjects demonstrated GH peaks during saline infusion but no peaks were seen in any subject during SMS infusion. No significant difference was found between peak cortisol responses during saline or SMS infusion (SMS cortisol 443 +/- 61 nmol/l, saline cortisol 485 +/- 52 nmol/l); neither was there any difference in the ACTH responses. We conclude that SMS does not alter the pituitary response to CRF in normal weight men and is thus less likely to be responsible for the altered pituitary-adrenal function seen in obesity. Further studies of alternative mechanisms are required to explain the cause of this abnormality.
Adrenocorticotropic Hormone↗
Prolactinomas presenting as primary amenorrhoea and delayed or arrested puberty: response to medical therapy.
Fourteen patients presented with arrested pubertal development associated with prolactin-secreting pituitary tumours; serum prolactin ranged from 4000-104,300 mU/l in the ten females and 920-68,000 in four males. Skull X-ray showed a markedly expanded pituitary fossa in eight patients. CT scan and/or air encephalography showed macroadenomas in nine, of whom seven had large suprasellar extensions to their tumours, yet only five had complained of headache and only two had visual field defects. All were treated with bromocriptine (7.5-60 mg/day) which lowered prolactin substantially in all and into the normal range in 11 (range less than 60-3090, median 105 mU/l). Puberty thereafter progressed spontaneously in 13, but in one patient, whose prolactin did not suppress completely, menarche could be induced only with clomiphene. Anterior pituitary function improved on bromocriptine. In seven patients with macroadenomas, tumour shrinkage into the pituitary fossa was complete and in two others incomplete shrinkage was followed by transsphenoidal hypophysectomy. Seven patients received pituitary irradiation, six after bromocriptine-induced shrinkage and one after transsphenoidal surgery. At follow-up 6 months to 10 years (median 5 years) after presentation, ten remain on bromocriptine with a suppressed serum prolactin, one has a normal prolactin after surgery, and three are off bromocriptine with residual hyperprolactinaemia (418-4680 mU/l). To date, four females have become pregnant and one male has fathered two children. Prolactinomas are an important, albeit rare, cause of arrested puberty and should therefore be sought. Most patients respond well to bromocriptine, with or without pituitary irradiation.
Adolescent↗
The effect of ovine corticotrophin-releasing factor on the hormonal response to insulin-induced hypoglycaemia.
In order to investigate the role of hypothalamic corticotrophin-releasing factor (CRF41) in the mediation of the pituitary ACTH response to hypoglycaemia, eight normal adult males were studied on four occasions. Commencing at 0830 h after an overnight fast, each received, in double-blind, random order, intravenous boluses of: A, normal saline control; B, soluble insulin 0.15U/kg; C, ovine CRF41 (oCRF41) 100 micrograms; D, soluble insulin 0.15U/kg followed immediately by oCRF41 100 micrograms. Adequate hypoglycaemia (blood glucose less than 2.2 mmol/l) was achieved in each subject when insulin was given alone or with oCRF41, and there was no difference in the glucose nadir between the 2 days. Peak plasma ACTH was significantly higher after insulin plus oCRF41 than after insulin alone (P less than 0.05) or oCRF41 alone (P less than 0.01) and this enhancement of ACTH release was most marked in the first phase of the response at 30 min (P less than 0.001, b vs d). There was no difference in the peak serum cortisol response whether oCRF41 and insulin were given alone or together and although the area under the cortisol curve was greater after insulin plus oCRF41, this difference was explicable simply on the basis of the earlier onset of the cortisol response to oCRF41. There were no differences in the serum GH responses to hypoglycaemia on the 2 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
Massive prolactinoma with galactorrhoea in a prepubertal boy.
An 8 year old prepubertal boy presented with raised intracranial pressure, left proptosis and was noted to have galactorrhoea. Cranial computerized tomography revealed a large pituitary tumour infiltrating the cavernous sinus and left orbit. The serum prolactin was 180,600 mU/l (normal value less than 360 mU/l). Prolactinomas are rare in children and galactorrhoea has not previously been reported in a prepubertal child. The management of massive prolactinomas is difficult, but the child presented has made an impressive response to a combination of treatment with surgery, dopamine agonist therapy and radiotherapy.
Child↗
Interleukin-1 directly stimulates the release of corticotrophin releasing factor from rat hypothalamus.
While interleukin-1 (IL-1), a monocyte-derived polypeptide, clearly stimulates the hypothalamo-pituitary-adrenal (HPA) axis, its precise site of action is controversial. In these studies, the possibility of a hypothalamic and/or a pituitary site of action was investigated in vitro, using incubated rat hypothalami and perifused dispersed pituitary cells. Both forms of IL-1, IL-1 alpha and IL-1 beta, produced a dose-dependent stimulation of CRF-41 release from incubated rat hypothalami in the dose range of 1-100 U/ml (p less than 0.01). However, concentrations of both interleukins of 1-1,000 U/ml given as 10-min infusions had no effect on ACTH release from dispersed pituitary cells. Moreover, IL-1 beta, used in the concentration range of 1-100 U/ml, was unable to potentiate CRF-41-induced ACTH release. These data therefore provide evidence that at least the acute stimulatory effects of IL-1 on the HPA axis are predominantly mediated via a direct stimulation of hypothalamic CRF-41, suggesting that the hypothalamus may provide an interface between the neuroendocrine and immune axes.
Animals↗
Morphine directly modulates the release of stimulated corticotrophin-releasing factor-41 from rat hypothalamus in vitro.
The actions of opioids and opiates on the hypothalamo-pituitary-adrenal axis are currently controversial. In the rat, morphine is reported to both stimulate and inhibit ACTH and corticosterone secretion, but the precise sites and mechanisms of these effects have remained unclear. To analyze further the hypothalamic actions of morphine, we have investigated its effect on hypothalamic fragments in vitro and measured the major CRF, CRF-41, by a specific RIA. The acute effects of morphine on both basal and stimulated ACTH release from dispersed pituitary cells were also investigated. Morphine (10(-8)-10(-6) M) did not significantly alter the basal secretion of CRF-41. However, similar concentrations of morphine inhibited CRF-41 release stimulated by norepinephrine in a dose-dependent manner. Similarly, morphine (10(-6) M) inhibited acetylcholine (10(-9) M)- and serotonin (10(-7) M)-stimulated CRF-41 release. The stimulatory effect on CRF-41 release induced by veratridine (10(-6) M) was inhibited by approximately 50% in the presence of morphine. KCl (28 nM)-mediated CRF-41 release was also significantly inhibited by morphine. Naloxone (10(-7)-10(-5) M) had no significant effect on either basal or norepinephrine-induced CRF-41 release, but reversed the inhibitory effect of morphine on norepinephrine-induced CRF-41 secretion in a dose-dependent manner. Morphine (10(-6)-10(-5) M) had no effect on either basal or CRF-41-stimulated ACTH release from dispersed pituitary cells. These data suggest that the predominant effect of morphine on hypothalamic CRF-41 release in vitro is suppression of the release induced by a variety of putative neurotransmitters and depolarizing agents. This inhibitory effect is reversed by naloxone, suggesting that it is mediated by opiate receptors, presumably situated directly on CRF-41 neurons.
Adrenocorticotropic Hormone↗