Biomedical subjects

L H Rees

Publications and source records attributed to L H Rees.

At least 37 records · Page 2Linked to original sources

PubMed1990

Defective glucocorticoid regulation of proopiomelanocortin gene expression and peptide secretion in a small cell lung cancer cell line.

A human small cell lung cancer cell line (COR L103) that actively expresses the proopiomelanocortin (POMC) gene has been used as a model of extrapituitary ACTH-secreting tumors to investigate the phenomenon of resistence of ACTH production to glucocorticoids. After both short term (24 h) and long term (10 days) exposure to hydrocortisone at concentrations of 500 and 1000 nM, the accumulation of intracellular POMC mRNA, ACTH, and ACTH precursor peptides in the culture medium was not suppressed. These finding contrast with those in the pituitary corticotroph cell line AtT20, in which POMC mRNA, ACTH, and ACTH precursors were suppressed under the same conditions. Two other genes that are regulated by glucocorticoids in other cell types, the tyrosine amino transferase gene and the glucocorticoid receptor gene, were expressed in COR L103 cells. However, neither gene appeared to be regulated by hydrocortisone in this small cell lung cancer cell line. Further studies demonstrated that glucocorticoid receptor binding could be detected in the nucleus and cytoplasm, with a Kd of 5 X 10(-9) M. It is concluded that nonsuppression of POMC by glucocorticoids is probably part of a more global defect of glucocorticoid signaling in these cells, but that this defect lies distal to steroid binding in the nucleus.

Adrenocorticotropic Hormone↗

PubMed1990

In vitro and in vivo analysis of the processing and fate of the peptide products of the short proopiomelanocortin mRNA.

Many peripheral tissues express the proopiomelanocortin (POMC) gene as an 800-base mRNA that lacks the 5' end of the 1200-base pituitary transcript. The missing region encodes the peptide signal sequence, and thus, it is unlikely that any translation product would be secreted. We have found that a RNA transcript equivalent to this short message, generated by transcription in vitro from a T7 polymerase promoter, is translatable in a rabbit reticulocyte lysate, generating peptides of 27.5, 22.5, and 15.5 kD. None of these peptides appears to be processed or protected from proteinase-K digestion by a microsomal membrane fraction. In vivo studies were undertaken by transfecting into GH3 cells one of two expression vectors containing sequences that would produce either a full-length mRNA or a short (800-base) mRNA. The neomycin resistance gene was cotransfected with these plasmids, and 30 permanent cell lines were produced after selection in G418. Cell lines containing the full-length RNA secreted large quantities of ACTH and beta-endorphin immunoreactivity, whereas those expressing the short transcript secreted neither of these peptides. However extractable peptide was present in this latter type of cell line, thereby suggesting that the 800-base mRNA was translated, and that no peptide reached the secretory vesicle. These findings raise important questions about the role of peripheral POMC gene expression.

Adrenocorticotropic Hormone↗

PubMed1990

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↗

PubMed1990

Rat melanin concentrating hormone does not modify the release of CRH-41 from rat hypothalamus or ACTH from the anterior pituitary in vitro.

It has been suggested that melanin concentrating hormone (MCH) possesses potent corticotrophin (ACTH) inhibitory activity, on the basis of the inhibitory effects displayed by salmon MCH on ACTH release from either trout or rat isolated pituitary fragments. Recently, rat MCH has been characterised, and this prompted us to investigate the putative inhibitory activity of synthetic rat MCH on basal and stimulated ACTH secretion from freshly-dispersed rat pituitary cells or incubated rat pituitary fragments, as well on KCl (28 mmol/l) or noradrenaline-evoked release of corticotrophin releasing hormone-41 (CRH-41) from rat hypothalamic explants in vitro. There were no effects of rat MCH on either CRH-41 or ACTH release in vitro.

Adrenocorticotropic Hormone↗

PubMed1989

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↗

PubMed1989

Relationship between gastric acid and elevated plasma somatostatinlike immunoreactivity after a mixed meal.

The aim of this study was to examine whether hydrochloric acid plays a role mediating the post-prandial increase in plasma somatostatinlike immunoreactivity in normal subjects. Intravenous infusion of cimetidine was found to reduce by 45% the postprandial increment in plasma somatostatin-like immunoreactivity. This effect was reversed by concomitant intragastric administration of 0.1 N hydrochloric acid, which in previous studies in fasted subjects had not affected plasma somatostatinlike immunoreactivity. The effects of cimetidine on postprandial plasma gastrin were the inverse of those observed on postprandial somatostatin. There was a greatly enhanced increment in postprandial plasma gastrin during cimetidine infusion, which was reduced significantly toward control levels by concomitant intragastric infusion of hydrochloric acid. To exclude direct inhibition by cimetidine of nutrient-stimulated plasma somatostatinlike immunoreactivity we studied the effect of cimetidine on plasma somatostatinlike immunoreactivity stimulated by an intraduodenal infusion of fat. Cimetidine did not alter the incremental response of somatostatinlike immunoreactivity to intraduodenal fat infusion. These data show that cimetidine does not invariably reduce nutrient-stimulated plasma somatostatinlike immunoreactivity and are consistent with the hypothesis that the action of cimetidine in reducing the plasma somatostatin response to ingestion of a meal is a consequence of reduction of postprandial acid secretion. These data suggest that the postprandial elevation in plasma somatostatin observed in humans is mediated in part through postprandial secretion of gastric acid, which in turn acts to elevate plasma somatostatin.

Adult↗

PubMed1989

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↗

PubMed1989

Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy.

Blood samples were obtained, at the time of organ donation, from 31 consecutive brain-stem-dead (BSD) donors referred to one transplant coordinator during a 9-month period. Twenty-four cases (77%) had clinical diabetes insipidus (DI), which was poorly controlled with marked dehydration in a majority of cases (serum osmolality range 268-357; median 302 mOSM/kg). Serum triiodothyronine (T3) was subnormal in 25 (81%); all had normal or high serum reverse T3; and the serum free thyroxine (T4) index was subnormal in 9 (29%), and TSH was subnormal in 7 (23%). In no case were T4 and TSH both subnormal and results were typical of the sick euthyroid syndrome rather than TSH deficiency. Of 21 cases not receiving corticosteroids, 5 (24%) had a serum cortisol above 550 nmol/L (20 micrograms/dl), excluding ACTH deficiency, and only 1 had undetectable cortisol levels. Those with severe hypotension did not have significantly lower serum cortisol (mean 354 vs. 416; P greater than 0.5). Levels of prolactin, growth hormone, gonadotrophins, and gonadal steroids were variable, but only a minority were frankly deficient in these hormones. BSD donors frequently have DI, which is often managed poorly by nonspecialists and requires appropriate replacement therapy. In contrast most patients are not totally deficient in anterior pituitary hormones. Routine hormonal therapy with cortisol and T3 cannot, therefore, be justified on endocrinological grounds. Widespread introduction of such treatment should only follow controlled trials that clearly demonstrate clinically significant improvement in the transplanted organ function, without detriment to the donor.

Adolescent↗

PubMed1989

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↗

PubMed1989

Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-I. A synchronized approach to pubertal development?

In a cross-sectional study of 69 normal adolescents we have found sex hormone-binding globulin (SHBG) levels to fall in both males and females throughout the pubertal period. Multiple regression analysis revealed a close negative correlation with insulin in both sexes. Weaker correlations were also found between SHBG and circulating androgen concentrations, in both males and females. Similar results were also obtained for a second circulating binding protein of primarily hepatic origin. This low molecular weight insulin-like growth factor (IGF) binding protein I (IBP-I) is one of two distinct classes of IGF binding proteins which bind IGF-I and IGF-II. IGF-I in turn mediates, at least in part, the actions of growth hormone. IBP-I also fell throughout puberty, correlating with the increasing insulin levels. In addition IBP-I correlated with androgen levels in both sexes. These similarities between SHBG and IBP-I, together with a strong correlation across puberty between the levels of the two binding proteins themselves (r = 0.737, P less than 0.001), suggest common mechanisms of control over the circulating levels of these two binding proteins. The association with insulin raises the possibility of a synchronized modulation of the actions of sex steroids and IGFs by nutritional intake. Thus pubertal growth and sexual development may occur over the same time with both modulated according to nutritional intake, linked through pancreatic insulin release, to hepatic production of SHBG and IBP-I.

Adolescent↗

PubMed1989

Megavoltage pituitary irradiation in the management of Cushing's disease and Nelson's syndrome: long-term follow-up.

We report the long-term follow-up of the clinical and biochemical effects of megavoltage pituitary irradiation (radiotherapy; RT), administered as primary or secondary therapy, for pituitary Cushing's disease and Nelson's syndrome in 52 patients. Irradiation was administered, from a 4-15 MeV linear accelerator, via a three-field technique (two lateral, one frontal), to a total dose of 4500 cGy (rad) in 25 fractions over 35 days. Twenty-one patients received RT as primary ablative therapy for Cushing's disease and were under follow-up 5.8 to 15.5 years later (median 9.5 years). All were initially treated with metyrapone to induce normal mean plasma cortisol levels, and all achieved clinical remission on this therapy. At latest follow-up, 12 (57%) are off all therapy, in clinical remission, with a normal mean cortisol through the day; however, only two show completely normal plasma cortisol responses to dynamic testing; four remain on medical therapy with metyrapone or op'DDD and all have required a steady dose reduction accompanied by falling plasma ACTH levels; five have required alternative therapy with bilateral adrenalectomy and/or transsphenoidal hypophysectomy. Fifteen patients received RT for Nelson's syndrome, developing after bilateral adrenalectomy, and have been followed up for 1.5 to 17.3 years (median 9.6 years). Fourteen patients showed progressive depigmentation, shrinkage of the pituitary adenoma and fall in plasma ACTH levels to 1-72% (median 16%) of the pre-RT basal value. In the remaining patient an initial fall in plasma ACTH was followed by tumour enlargement at 6 years, leading to death at 11 years after RT. Of the remaining patients, results are assessed in nine who received RT after unsuccessful transsphenoidal surgery, three after transfrontal surgery for aggressive macroadenomas, and four prophylactically after bilateral adrenalectomy. Radiotherapy remains a valuable second-line therapy for Cushing's disease and its complications.

Adolescent↗

PubMed1989

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↗

PubMed1989

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↗

PubMed1989

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↗

PubMed1989

Expression of pro-opiomelanocortin gene and quantification of adrenocorticotropic hormone-like immunoreactivity in human normal peripheral mononuclear cells and lymphoid and myeloid malignancies.

Using Northern blotting with a human genomic DNA probe for the pro-opiomelanocortin (POMC) gene, we have shown specific mRNA in normal human peripheral mononuclear cells (PBMC); the presence of specific mRNA was also observed in a T lymphocyte cell line derived from a patient with lymphoma. We then demonstrated that PBMC translate the message into protein. Thus, using a radioimmunoassay with an antibody for ACTH, a median of 29 pg of ACTH-like immunoreactivity (ACTH-LIR) was found in 10(7) PBMC. ACTH-LIR was also detected in seven different cell lines derived from patients with lymphoid and myeloid malignancies, two of them JM and U937 showing the highest values 135 and 108 pg/10(7) cells, respectively. The chromatographic characterization of this ACTH-LIR showed, at least, three molecular forms of immunoreactive ACTH with molecular weights of the order of 31,000 POMC, 22,000 ACTH, and 4,500 ACTH, in addition to high-molecular-weight material (greater than 43,000). We conclude that PBMC produce ACTH-LIR which may act as a paracrine immunomodulator in a similar way to lymphokines and/or may signal the adrenal gland to secrete glucocorticoids.

Adrenocorticotropic Hormone↗

PubMed1989

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↗

PubMed1989

Long-term effects of radiotherapy for acromegaly on circulating prolactin.

In 61 acromegalic patients, serum PRL was assessed (off medical treatment) before and 2 to 12 (mean 6.4) years after external beam radiotherapy. Before radiotherapy elevated PRL levels were present in 22 of 35 males (63%) and 12 of 26 females (46%) and were above 1000 mU/l in 11 males and 5 females. When studied for up to 5 years after radiotherapy, 22 of 23 (96%) patients who had not had surgery and who had normal PRL pre-radiotherapy showed an increased PRL level and this was also seen in 17 of 27 (63%) who had been hyperprolactinaemic initially. In contrast, 10 of 27 patients (37%) who had elevated pre-radiotherapy levels (all greater than 1000 mU/l) had a reduction in PRL values after radiotherapy. In all 11 patients who underwent surgery before radiotherapy, an increase in PRL was seen after radiotherapy. In the 21 patients followed for 10-12 years, the peak PRL value occurred 1-6 years after radiotherapy. After this, a progressive reduction of PRL to normal was seen. Normal levels were reached 4 to 10 years after radiotherapy. No correlation was found between pretreatment PRL values and final GH values in the whole group, nor between changes in PRL and the development of impaired ACTH or TSH secretion. Thus, different patterns of PRL behaviour suggest that radiotherapy treatment may either produce hyperprolactinemia from mild hypothalamic damage or ablate PRL secreting cells if they were present in the tumour before treatment. These changes do not predict final GH results or the development of hypopituitarism after radiotherapy.

Acromegaly↗

PubMed1989

Pro-opiomelanocortin mRNA size heterogeneity in ACTH-dependent Cushing's syndrome.

As an approach to understanding the abnormalities of pro-opiomelanocortin (POMC) gene regulation in human ACTH-secreting tumours, we have analysed the POMC mRNA content of nine such tumours using the Northern blot technique. Most of the tumours and normal human pituitary contained easily detectable quantities of POMC mRNA. The length of this message in most tumours was similar to, or slightly larger than, that in the normal pituitary (1150-1200 bases). Ribonuclease H studies suggested that the origin of any size heterogeneity was a longer poly(A) tail in the tumour RNA. Some tumours, however, expressed a short POMC mRNA (800 bases) which may lack the first two exons of the POMC gene as has been described. A third POMC mRNA size variant (1500 bases) was also seen in low levels in two cases, and as the principal mRNA species in one case. Primer extension and S1 nuclease protection studies suggested that most transcripts in the tumours analysed originated from the conventional promoter, and thus the use of an alternative promoter is not an adequate explanation for the expression of this gene in ectopic ACTH-secreting tumours.

ACTH Syndrome, Ectopic↗