Proopiomelanocortin gene (POMC) is recognised as playing an important role in the regulation of the hypothalamo-pituitary-adrenal axis, adrenal development and obesity. POMC is activated in ACTH-dependent Cushing's syndrome. The syndrome may occur when the highly tIssue-specific 5' promoter of human POMC is activated in pituitary and non-pituitary sites. Whilst the factors involved in transcription in the corticotrophs of the anterior pituitary gland are becoming well delineated, the mechanism of activation in non-pituitary sites is not fully understood. This promoter is embedded within a defined CpG island, and, in contrast to somatically expressed CpG island promoters reported to date, is methylated in normal non-expressing tIssues, but is specifically unmethylated in expressing tIssues, tumours and the POMC-expressing DMS-79 small-cell lung cancer cell line. Methylation in vitro is sufficient for silencing of expression. In particular, methylation near the response element for the tIssue-specific POMC activator PTX1, diminishes POMC expression. Sites outside the PTX1 response element may be important for binding, and this may have implications for pituitary development. DMS-79 cells lack POMC-demethylating activity, implying that the methylation and expression patterns are likely to be set early or prior to neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy. It is conceivable that in POMC neurons of the hypothalamus the POMC promoter is subject to a variable density of methylation with clear implications for the signalling of satiety and obesity.
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W. H. PRICE and H. J. VAN DER MOLEN
No difference could be demonstrated between the plasma testosterone levels in 17 males with the 47,XYY karyotype and appropriately selected controls.
Significantly higher levels of testosterone were recorded in both 47,XYY and 46,XY males at the maximum security hospital than in males with both karyotypes in other hospitals and in the general population.
L Lanyon, V Armstrong, D Ong, G Zaman, and J Price
The ability of bones to withstand functional loading without damage depends upon their cell populations establishing and subsequently maintaining a mass and architecture that are appropriately robust for the purpose. In women, the rapid loss of bone associated with the menopause represents a steplike decline in the effectiveness of this process with consequent increase in bone fragility. In men, loss of bone tissue and reduction in bone strength are more gradual and the increased incidence of fragility fractures occurs later. In both sexes, bone mass is associated with levels of bioavailable estrogen. This poses the major question as to how the presence or concentration of the reproductive hormone estrogen influences the relationship between bone mass and bone loading. In this paper, we briefly review evidence of the mechanism(s) by which the mechanical strains engendered by loading influence bone cells to establish and maintain structurally competent bone architecture. We highlight the finding that at least one strain-related cascade responsible for adaptive control of bone architecture is mediated through estrogen receptor (ER) alpha, the number and activity of which are regulated by estrogen. We hypothesize that a major contributor to the rapid loss of bone mass that occurs in females, and the slower age-related fall in males and females, is reduced effectiveness of ER-mediated processing of strain-related information by resident bone cells.
B. Fournier, J. M. Ferralli, P. A. Price, and J. M. Schlaeppi
The effects of insulin-like growth factor-I (IGF-I) and IGF-II on the human osteoblast cell-line OHS-4 were investigated. Both IGF-I and IGF-II stimulated cell proliferation at nanomolar concentrations and alkaline phosphatase activity was decreased in a dose-dependent manner with either IGF-I or IGF-II. The production of the bone-specific protein osteocalcin was not influenced by either IGF-I or IGF-II. However, they acted synergistically with 1,25-dihydroxyvitamin D3 at concentrations ranging from 10 to 100 nmol/l. Neither IGF-I nor IGF-II had an effect on either the basal or the parathyroid hormone-stimulated level of adenylate cyclase activity, and likewise they had no effect on phosphodiesterase activity. Binding and cross-linking experiments confirmed the presence of both type-I and type-II IGF receptors on the OHS-4 cells. The present study shows that IGF-I and IGF-II have similar effects on the parameters studied in these osteoblastic cells. They influenced both proliferation and differentiation markers.
Journal of Endocrinology (1993) 136, 173–180
J. P. Hinson, G. P. Vinson, B. J. Whitehouse, and G. Price
The extent to which results obtained using in-vitro techniques can be taken to reflect in-vivo physiological responses in the study of adrenocortical function has not been subjected to systematic study. Some evidence suggests that in-vitro preparative methods may affect the secreted steroid profile. For this reason it seemed desirable to study adrenal function using an isolated perfused whole gland technique, and this study reports results obtained with known aldosterone stimulants.
Angiotensin II, ACTH and potassium ions all stimulated aldosterone secretion in a dose-dependent manner. The stimulation thresholds of these substances were compatible with their normal circulating concentrations. For angiotensin II stimulation this preparation was two orders of magnitude more sensitive than any in-vitro preparation. Most importantly, the specific glomerulosa effectors, angiotensin II and potassium, selectively stimulated aldosterone output, and had no consistent effect on corticosterone secretion at any dose used. On the other hand, ACTH stimulated both corticosterone and aldosterone output at all effective concentrations.
The actions of α-MSH were also studied using this preparation. Low doses of α-MSH selectively stimulated aldosterone secretion, while higher doses were needed to stimulate corticosterone. The onset of response to all stimulants was invariably seen within the first 10 min after administration of stimulants. Maximal aldosterone output was achieved within the first 10 min whereas corticosterone secretion usually peaked 10–20 min later. The amount of aldosterone produced by this preparation was much higher than the amount produced by dispersed cell preparations, and closely approximated to the levels of aldosterone obtained in adrenal vein blood.
The data indicate that the isolated circulation perfused gland system is a sensitive preparation which approximates to the physiological condition. In particular, aldosterone is the prominent glomerulosa product, and corticosterone is, in this system, a more specific marker for inner zone function.
J. Endocr. (1985) 104, 387–395
J. P. Hinson, G. P. Vinson, B. J. Whitehouse, and G. M. Price
Using the in-situ, isolated, perfused rat adrenal system, the actions of adrenal stimulants on steroidogenesis and perfusion medium flow rates (under constant perfusion pump conditions) have been studied. In a series of 100 experiments, initial rates of corticosterone output and flow rates were found to be positively correlated, although there was no such relationship between initial rates of aldosterone output and flow rates. Furthermore, in stable perfusion conditions, bolus injections of ACTH increased both flow rate and steroid output in a dose-related manner. In individual experiments there was a clear correlation between corticosterone and flow, but the association between aldosterone secretion rate and flow was less evident. It is possible that this discrepancy arises because of temporal differences in the responses of these two steroids. Flow was also stimulated by dibutyryl cyclic AMP (dbcAMP), with correlations with steroid output similar to ACTH, but the specific zona glomerulosa stimulants angiotensin II amide and potassium ions had, if anything, inhibitory effects on flow, but only at high concentrations.
The data suggest that ACTH and dbcAMP evoke specific responses in the adrenal vasculature, resulting in relatively decreased intraglandular vascular resistance. They furthermore suggest that the secretory functions of the inner adrenocortical zones are subject to the additional control of vascular elements in the intact gland.
J. Endocr. (1986) 109, 279–285
I. D. Porter, B. J. Whitehouse, G. M. Price, J. P. Hinson, and G. P. Vinson
The rat adrenal cortex contains quantities of dopamine that are compatible with its function as a neurotransmitter, suggesting that locally released dopamine may act as a neuroregulator within the gland. This possibility has been tested by comparing the effects of dopamine on aldosterone secretion in the perfused adrenal with the effects of stimuli designed to provoke the release of intraglandular dopamine.
Infusion of dopamine (0·1–100 μmol/l for 10-min periods) into the isolated perfused rat adrenal gland resulted in a transient, dose-related reduction of aldosterone secretion to a minimum of approximately 50% of the basal value at 1 μmol dopamine/l (ratio of experimental to control measurements, R = 0·53 ± 0·06 (s.e.m.); n = 5). In contrast, dopamine (1–100 μmol/l) had no effect on aldosterone production by dispersed zona glomerulosa cell preparations incubated in vitro.
The effects of changes in K+ concentration (3·9–52 mmol/l) on aldosterone secretion in the perfused gland and dispersed cell preparations were also compared. A similar bell-shaped dose–response relationship was seen in both preparations between 6 and 32 mmol K+/l, with a maximum at 8·4 mmol K+/l and a return to control values with 16, 24 or 32 mmol K+/l. However, infusion of media with very high K+ concentrations (42 or 52 mmol K+/l) reduced the secretion of aldosterone by the perfused gland to approximately 50% of the basal value (R = 0·51 ± 0·05, n = 9; R = 0·49± 0·08, n = 9; respectively) but produced no change in aldosterone production by zona glomerulosa cells. Electrical field stimulation (pulse width 1 ms, 1 Hz at 60 V for 5 min) of the perfused gland also resulted in a reduction in aldosterone secretion (R = 0·66 ± 0·66, n = 6). In the presence of 1 μmol haloperidol/l, a dopamine antagonist, no effect on aldosterone secretion was seen under control conditions, but the responses to 1 μmol dopamine/l, 52 mmol K+/l and field stimulation were eliminated.
The results are consistent with the view that aldosterone secretion by the perfused adrenal gland is subject to an inhibitory dopaminergic control, which may originate from catecholaminergic neurones within the gland itself.
Journal of Endocrinology (1992) 133, 275–282
A. M. Cotterill, J. M. P. Holly, S. C. Davies, V. J. Coulson, P. A. Price, and J. A. H. Wass
Non-islet-cell tumours which induce hypoglycaemia are rare. Insulin-like growth factor-II (IGF-II) produced by some tumours is thought to be responsible for the hypoglycaemia and other systemic effects, despite normal or even low serum IGF-II levels. We studied a 44-year-old woman presenting with symptomatic hypoglycaemia associated with a large intraabdominal haemangiopericytoma. The serum IGF-II level was 455 μg/l when measured after acid-ethanol extraction (normal range (NR) 450–750 μg/l) and 1063 μg/l after acid chromatography (normal human serum pool 1068 μg/l). Levels of fasting plasma insulin, C-peptide, glucose and serum IGF-I levels were low before the operation (< 2 mU/l (NR <2-14), 0·23 nmol/l (NR 0-4-1-2), 3-1 mmol/l, (NR 3-7-5-9) and 002 U/ml respectively). After tumour removal, the symptoms resolved rapidly and the patient made a full recovery. Secretion of both insulin and growth hormone was suppressed before the operation in response to a 75 g glucose meal and to an infusion of 100 μg GH-releasing hormone (GHRH) respectively in comparison with studies after the operation. Serum IGF-II levels 6 weeks and 12 weeks after the operation fell to 385 μg/1 (777 μg/1; acid chromatography) and 280 μg/1 (647 μg/1; acid chromatography) and serum IGF-I levels increased to 0-35 U/ml and 0-26 U/ml. Serum before the operation and tumour extract contained chiefly a large molecular weight precursor IGF-II (molecular weight 15 000–20 000) which disappeared from the serum after the operation. The IGF-binding proteins (IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-4) were examined. The preoperation fasting serum IGFBP-1 level was lower than expected (31 μg/l (NR 20–70 μg/l)) and similar to levels at 6 weeks after the operation (33 μg/l). This was surprising given the differences in plasma insulin levels before and after the operation (< 2 mU/l versus 13 mU/l). Using Western ligand blotting techniques, serum IGFBP-3 levels were found to be low and IGFBP-2 appeared to be the dominant IGFBP before the operation. Serum IGFBP-3 levels after the operation fell further. This further decrease appeared, in part, to be due to the presence of a cation-dependent IGFBP-3-specific protease which has previously only been described in late pregnancy.
We conclude that in this subject, despite normal serum IGF-II levels, the hypoglycaemia and systemic effects on insulin and GH secretion were due to increased bioavailability of a circulating tumour-produced precursor form of IGF-II. This increased bioavailability appears to be due to alterations in the circulating levels and perhaps affinities of the IGFBPs.
Journal of Endocrinology (1991) 131, 303–311
D. R. E. Abayasekara, H. Vazir, B. J. Whitehouse, G. M. Price, J. P. Hinson, and G. P. Vinson
In rats, chronic treatment with high doses of ACTH (10–40 μg/100 g body weight per day) leads to a marked reduction in aldosterone synthesis by adrenal capsules. The possibility that this inhibition is secondary to a decrease in plasma potassium levels or in renin angiotensin system (RAS) activity has been explored.
The effects of chronic ACTH treatment were compared in (I) animals in which the endogenous RAS activity was stimulated by restricting dietary sodium intake, (II) animals in which plasma angiotensin II was increased by infusion from implanted osmotic minipumps and (III) animals which received supplementary potassium and in which hypokalaemia was prevented. In all cases, rates of aldosterone biosynthesis in vitro by adrenal capsules were decreased in ACTH-treated animals to an extent similar to those in untreated controls. In addition, ACTH treatment of hypophysectomized rats resulted in a similar inhibition of aldosterone biosynthesis to that found in sham-operated controls. It may be concluded that the ACTH-induced reduction of aldosterone biosynthesis is independent of the secretion of other pituitary hormones, and cannot be simply ascribed to either a reduction in RAS activity or in plasma potassium levels. The results are consistent with the view that the effects of chronic ACTH treatment are mediated by a direct action on the zona glomerulosa cell, which leads to its transformation into a zona fasciculata-like form.
Journal of Endocrinology (1989) 122, 625–632
A.C. Hale, J. Price, J.F. Ackland, I. Doniach, S. Ratter, G.M. Besser, and L.H. Rees
The remission of Cushing's syndrome following surgical removal of a tumour containing bombesin-like immunoreactivity (BLI), but insignificant levels of ACTH, is described. However, an acid extract of the tumour tissue caused the release of ACTH from isolated rat anterior pituitary cells in vitro. These observations led to an investigation of the effects of synthetic C-terminal gastrin-releasing peptide (GRP(14-27)) on ACTH release from isolated rat anterior pituitary cells. GRP(14-27) (10-1000 ng/ml) directly stimulated the release of ACTH in vitro, whereas lower doses (10-1000 pg/ml), ineffective themselves in eliciting ACTH release, potentiated the CRF-mediated in-vitro release of ACTH.