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K Noonan

Publications and source records attributed to K Noonan.

At least 19 recordsLinked to original sources
PubMed2002

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?

BACKGROUND: Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are risk factors for several disorders with inflammatory components, including coronary heart disease (CHD) and diabetes, though the mechanisms involved are unclear. AIM: To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase (MMP) system in a population with a high prevalence of vitamin D deficiency, a situation affecting susceptibility to CHD and diabetes. DESIGN: Prospective cross-sectional, interventional and embedded studies. METHODS: Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults, free of known diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1, folate and homocysteine were measured. Vitamin-D-deficient subjects were re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up. Independent determinants of circulating concentrations of MMP9, TIMP-1 and CRP were assessed by multiple regression analysis. RESULTS: Vitamin D status was the sole determinant of circulating MMP9 (inversely) and an independent determinant of CRP (inversely). Determinants of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype (TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%) concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.

Adult↗
PubMed2001

The release of leptin and its effect on hormone release from human pituitary adenomas.

BACKGROUND: Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary. AIM: The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT-PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin. RESULTS: Leptin receptor long isoform expression was detected in 2/4 GH-secreting adenomas, 12/17 non-functioning adenomas, 5/9 ACTH-secreting adenomas, 1/2 prolactinomas, 2/2 FSH-secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH-secreting adenomas, 9/14 non-functioning adenomas, 2/3 ACTH-secreting adenomas, 1/3 prolactinomas and 1/3 FSH-secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non-tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and alpha-subunit secretion from a non-functioning adenoma and TSH secretion from a somatotroph adenoma. CONCLUSION: We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.

Adenoma↗
PubMed2001

Decontamination issues for chemical and biological warfare agents: how clean is clean enough?

The objective of this assessment is to determine what level of cleanup will be required to meet regulatory and stakeholder needs in the case of a chemical and/or biological incident at a civilian facility. A literature review for selected, potential chemical and biological warfare agents shows that dose information is often lacking or controversial. Environmental regulatory limits or other industrial health guidelines that could be used to help establish cleanup concentration levels for such agents are generally unavailable or not applicable for a public setting. Although dose information, cleanup criteria, and decontamination protocols all present challenges to effective planning, several decontamination approaches are available. Such approaches should be combined with risk-informed decision making to establish reasonable cleanup goals for protecting health, property, and resources. Key issues during a risk assessment are to determine exactly what constitutes a safety hazard and whether decontamination is necessary or not for a particular scenario. An important conclusion is that cleanup criteria are site dependent and stakeholder specific. The results of a modeling exercise for two outdoor scenarios are presented to reinforce this conclusion. Public perception of risk to health, public acceptance of recommendations based on scientific criteria, political support, time constraints, and economic concerns must all be addressed in the context of a specific scenario to yield effective and acceptable decontamination.

Biological Warfare↗
PubMed1999

An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes.

AIMS/HYPOTHESIS: Linkage between markers close to the uncoupling protein 2 and 3 genes (11q13) and resting metabolic rate and a pre-diabetic phenotype have been found. The syntenic region in mouse has been found to be linked to quantitative traits associated with obesity and diabetes. UCP2 and UCP3 could therefore have an important role in body weight regulation and susceptibility to diabetes. We investigated a recently identified variant of the UCP2 gene in exon 8 as a marker for glucose and weight homeostasis. METHODS: Length variation of the UCP2 exon 8 variant was studied by the polymerase chain reaction and agarose gel electrophoresis. Sequence variants of the UCP3 gene were sought by semi-automated DNA sequencing. RESULTS: In 453 South Indian subjects, we found an association in women between the UCP2 exon variant and body mass index (p = 0.018). These findings were replicated in a separate group of South Indian subjects (n = 143, p < 0.001) irrespective of sex. Although no association was found between the UCP2 exon 8 variant and overt obesity in British subjects, the UCP2 genotype of obese women (n = 83) correlated with fasting serum leptin concentration (p = 0.006) in the presence of extreme obesity. These observations could not be explained by tight linkage disequilibrium with a coding region variant in the region of the UCP3 gene of biological significance. Lastly, no association was found between UCP2 and Type II (non-insulin-dependent) diabetes using either a family based design (85 families) or case control study (normal glucose tolerance n = 335, impaired glucose tolerance n = 42, Type II diabetes n = 76). CONCLUSION/INTERPRETATION: We have described a UCP2 gene exon 8 variant that may affect susceptibility to weight gain by influencing regulation of leptin.

Adult↗
PubMed1998

The effect of growth hormone replacement therapy on cortisol-cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11 beta-hydroxysteroid dehydrogenase activity.

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults has been associated with a decreased urinary ratio of 11-hydroxy/11-oxo-cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1 and 2), the enzymes responsible for cortisol-cortisone interconversion, or alternatively it might reflect decreased cortisol availability. To elucidate this, we examined the effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement. DESIGN: Patients received increasing twice daily doses of hydrocortisone (HC) (10/10, 20/10, 40/20 mg) each week, before and during 2 months of GH replacement (0.25 U/kg/week). PATIENTS: Seven hypopituitary adults (three men and four women, age range 47-64 years) with combined GH and ACTH deficiency. Three additional patients with GH deficiency, but intact ACTH reserve, were also studied. MEASUREMENTS: Urine steroid metabolite profiles were measured in 24-hour urine collections by gas chromatography after each week of treatment. Urinary free cortisol and free cortisone were measured by radioimmunoassay as a measure of renal 11 beta-HSD-2 activity. RESULTS: Total urinary CoM increased with rising doses of HC, but at each particular HC dose, were unchanged after GH (before versus after GH, median (range): 9.67 (7.86-12.59) versus 9.93 (8.31-14.08); 15.87 (12.37-31.39) versus 17.07 (12.64-23.81); 26.68 (19.07-42.14) versus 26.77 (8.01-37.62) mg/24 hours). The urine ratio 11-hydroxy/11-oxo-CoM decreased significantly with GH treatment, at each HC dose schedule (1.22 (1.02-1.96) versus 0.92 (0.83-1.63) P = 0.018; 1.53 (1.30-2.23) versus 1.23 (0.93-1.46) P = 0.018; 1.87 (1.45-2.70) versus 1.56 (1.22-1.79) P = 0.018). The urinary ratio tetrahydrocortisols/tetrahydrocortisone, an alternative index of 11 beta-HSD activity, also fell with GH therapy at each HC dose (P = 0.049; P = 0.018; P = 0.043). In contrast, the urinary 20-hydroxy/20-oxo-CoM ratio exhibited a small increase with GH, suggesting that the changes observed above were not simply due to changes in redox status. The patients with GH deficiency, but intact ACTH reserve, demonstrated changes in urine steroid profiles similar to the group receiving hydrocortisone replacement. Urinary free cortisone and urinary free cortisol/free cortisone ratios did not change with GH therapy, but the serum cortisol/ cortisone ratio fell significantly with GH therapy at each hydrocortisone dose. CONCLUSIONS: GH therapy decreases the urinary ratios 11-hydroxy/11-oxo-cortisol metabolites and tetrahydrocortisols/tetrahydrocortisone, but not urinary free cortisone or the urinary free cortisol/free cortisone ratio. This effect is not secondary to reduced cortisol availability. These findings provide further evidence for direct or indirect modulation of cortisol metabolism by growth hormone and suggest that this occurs at hepatic or an alternative site of 11 beta-hydroxysteroid dehydrogenase-1 activity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

"Bone bruises" of the knee: a review.

Magnetic resonance (MR) imaging is often used to assess the location and degree of ligamentous or cartilage damage in the knee following acute traumatic injury. Occasionally, these studies will also document abnormal signal within the adjacent subchondral bone. These "bone bruises" are considered incidental findings by some, while others suggest possible clinical significance. The purpose of this paper is to review the literature and consolidate current thinking on the radiographic characteristics, classification, histopathology and natural history of bone bruises.

Adult↗
PubMed1997

Assessment of the performance of a capture immunoassay for the bone isoform of alkaline phosphatase in serum.

We report the analytical validation of an immunocapture assay for the bone isoform of alkaline phosphatase in serum. A between batch imprecision of less than 10% was found, being about 8% at the upper limit of the reference range, and with a detection limit of 0.8 IU/l at 37 degrees C. The crossreactivity of the method with the liver isoform was found to be in the range of 3-13% depending on the method employed. Unexpectedly the correlation of results with a non-immunological method for the quantitation of bone ALP showed significant differences between samples from children and patients with Paget's disease, with an apparent lower level of capture in the case of children. These data suggest that there may be differences in the epitope recognised by the antibody, which may be due to the presence of different forms of bone enzyme in these two populations. The significance of these observations is not clear at this stage.

Alkaline Phosphatase↗
PubMed1997

Examining technical aspects of the monoclonal antibody immobilisation of granulocyte antigen assay.

BACKGROUND AND OBJECTIVES: This study was an attempt to improve detection and characterization of alloantibodies to neutrophil antigens, using the monoclonal antibody immobilisation of granulocyte antigens (MAIGA) assay. MATERIALS AND METHODS: We explored the effect of different detergent concentrations, detergent class, stabilising additives, combinations of detergents, and use of a broad range of monoclonal antibodies on the results of the MAIGA assay. RESULTS: Non-ionic detergents, Triton X and Nonidet, were confirmed as the most suitable for solubilisation of the recognised, neutrophil-associated alloantigens. Anionic and zwitterionic detergents did not assist the demonstration and characterisation of new neutrophil alloantigens in the MAIGA assay. Some reproducible positive MAIGA assay results were obtained for antisera 01, 08, anti-RED, anti-NB2, and anti-NB1, using particular monoclonal antibodies. CONCLUSIONS: Although we are reluctant to suggest association of the targeted antigens with the particular glycoproteins identified by the capture monoclonal antibodies, NB1 glycoprotein may be closely associated, before or after antibody binding, with CD46, CD11b, CD50, and/or CD66b.

Antibodies, Monoclonal↗
PubMed1997

Reduced calcium dialysate in CAPD patients: efficacy and limitations.

BACKGROUND: The increasing use of 'reduced calcium' dialysate in CAPD patients treated with calcium-based phosphate binders has raised concerns that this could lead to negative calcium balance, worsening hyperparathyroidism, and osteopenia. METHODS: The present study was conducted to examine the possibilities (a) that 1.25 mM calcium dialysate leads to negative calcium balance and worsening hyperparathyroidism, and (b) that conversely 1.25 mM calcium dialysate is still too high for some patients. We studied 22 patients who, after a 2-month run in using 1.75 mM calcium dialysate and aluminium hydroxide binders, entered a 3-month phase of 1.25 mM calcium dialysate with continuation of aluminium hydroxide as the sole phosphate binder. The patients then entered a final 9-month phase in which dialysate calcium remained at 1.25 mM and calcium carbonate was substituted for aluminium hydroxide and progressively titrated to achieve optimum phosphate control. RESULTS: During the initial 3-month period, parathyroid hormone increased from 259, range 11-1149 to 405, range 16-1318 pg/ml (P = 0.0001) and ionized calcium decreased from 1.17 +/- 0.06 to 1.11 +/- 0.08 mM (P = 0.0004). The subsequent 9-month phase was associated with return of parathyroid hormone to baseline levels. Further dialysate calcium reduction to 0.6 mM was implemented in the four patients who became hypercalcaemic. CONCLUSION: This study has clearly shown that reduction of dialysate calcium to 1.25 mM can be harmful to CAPD patients if oral calcium availability is inadequate. It has also shown that dialysate calcium at 1.25 mM is a compromise, with increased risk of hyperparathyroidism if calcium intake is too low and, conversely, risk of hypercalcaemia and unacceptable increases of the Ca x Pi product in a minority of patients. At these extremes there is a need for a high-calcium dialysate (1.75 mM) and a very low-calcium dialysate (0.6 mM or less), to optimize management.

Adult↗
PubMed1997

A longitudinal study of markers of bone turnover in Graves' disease and their value in predicting bone mineral density.

Whether biochemical markers can predict improvement in reduced bone mineral density (BMD) associated with thyrotoxicosis in unclear. We investigated the relationship between serum osteocalcin (OC), bone-specific alkaline phosphatase (b-ALP), serum deoxypyridinoline (Sdpd) and pyridinoline (Spyr), 24-hour urinary deoxypyridinoline (Udpd), and BMD in 17 thyrotoxic patients during 1 yr of treatment. Coinciding with euthyroidism at 4-8 weeks, there was a peak in b-ALP and OC and a prompt fall into the normal range in Udpd and Sdpd, but not Spyr, levels. Mean b-ALP continued to be raised at week 52 when it was inversely correlated with BMD. Mean BMD rose approximately 6%, P < 0.01, over 1 yr. Coupling indices were calculated as a measure of bone balance and, at diagnosis, was [minus4.26 in favor of bone resorption and rose with treatment in favor of bone formation: weeks 2: -0.23; 4: +4.01; 8: +4.37; 12: +4.44; 24: +2.32; and 52: +1.56. Bone turnover is balanced within 2 weeks of starting treatment for thyrotoxicosis. Udpd accurately indicates thyrotoxic bone resorption. Serum b-ALP indicates continuing bone formation and, at 1 yr, may provide a marker for low BMD. OC, Sdpd, and Spyr are less sensitive in documenting bone remodeling during treatment of thyrotoxicosis.

Adult↗
PubMed1996

Dependence of retinopathy (and other complications) on glycaemic control and on weight over 5/10 years from diagnosis of type II diabetes.

Glycosylated haemoglobins and weights were recorded for 200 consecutive diabetic clinic attenders seen yearly for 5 years, 76 of whom were also seen up to 10 years from diagnosis of type 2 diabetes, representing 1380 patient years. Weight fluctuation (> 3 kg) was associated with increased final prevalence of hypertension, macroalbuminaemia and a raised creatinine (P < 0.002) but this relationship was abolished by correction for higher initial weight. Average glycaemia over 5/10 years [itself related to initial weight in women on tablets (N = 53) but not others, and to waist but not waist/hip ratio], correlated with prevalence and severity of retinopathy (N = 200; r = 0.38, P < 0.0006) seen also in the subgroup of patients on tablets (N = 145, P < 0.006). At HbA1 levels > 10.5% an increased prevalence of retinopathy was seen in those on insulin (N = 37, P < 0.001) and an increased prevalence of peripheral vascular disease was seen in men but not women (x2 = 2.87, P < 0.01) as well as in the prevalence of neuropathy. These findings suggest that good glycaemic control is of value in type 2 diabetes and less easily achieved in obesity.

Aged↗
PubMed1996

Effect of different storage temperatures, sample collection procedures and immunoassay methods on osteocalcin measurement.

The apparent instability of measured osteocalcin has been reported as method-dependent and related to preanalytical variables such as storage temperature, and the use of anticoagulants and protease inhibitors. The aim of this study was to determine a sample collection procedure which minimised osteocalcin degradation. Blood samples from five normal individuals were collected with or without anticoagulants and protease inhibitors (heparin, EDTA, or heparin and aprotinin) and stored at 4 degrees C, -20 degrees C or -70 degrees C for up to 7 days, 28 days and 90 days respectively. Osteocalcin was measured by both a monoclonal EIA specific for intact osteocalcin and a bovine polyclonal RIA. Osteocalcin concentrations in serum and EDTA-treated samples significantly decreased by 40% (P < 0.001) with the ELISA and 72% (P < 0.001) with the RIA after 7 days storage at 4 degrees C. Similar falls were documented in these samples when stored at -20 degrees C and -70 degrees C and measured by the ELISA. Minimal changes in osteocalcin immunoreactivity were observed in either assay when heparin-treated plasma with or without aprotinin was stored at -20 degrees C or -70 degrees C for up to 90 days. The apparent instability of measured osteocalcin can be minimised using these conditions.

Adult↗
PubMed1995

Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in east London Asians.

Vitamin D deficiency reduces insulin secretion and still occurs in East London Asians in whom the prevalence of diabetes mellitus is at least four times that of Caucasians. Vitamin D status was assessed in 44 of 65 non-diabetic subjects 'at risk' of diabetes (spot blood glucose level >6.0 mmol/l <2 h post cibum, or>4.6 mmol/l >2 h post cibum on two separate occasions) and in 15 of 60 age and sex-matched 'low-risk' control subjects who attended for oral glucose tolerance test (OGTT) after screening of 877 omnivorous subjects not known to have diabetes. It was found that 95% of at-risk and 80% of low-risk subjects were vitamin D deficient (serum 25-hydroxy-vitamin D <11 ng/ml). Diabetes was present in 16, impaired glucose tolerance in 12 and normoglycaemia in 19 at-risk subjects, imparied glucose tolerance in 2, and normoglycaemia in 13 low-risk subjects. Correlation of 30-min OGTT blood glucose, specific insulin and C-peptide levels with 25-hydroxy-vitamin D concentrations in 44 at-risk subjects were -0.31 (p=0.04), 0.59 (p=0.0001) and 0.44 (p=0.006). In 15 'not-at-risk' subjects 30-min OGTT specific insulin and C-peptide levels correlated with 25-hydroxy-vitamin D, r=0.39 (p=0.04) and 0.16 (p=0.43), respectively. Serum alkaline phosphatase concentration was higher in at-risk than not-at-risk subjects (59.6 vs 46.5 IU/l, p=0.012); corrected calcium concentrations were comparable (2.38 vs 2.39 mmol/l, p=0.7). Following treatment with 100,000 IU vitamin D by i.m. injection, specific insulin, C-peptide [30 min on OGTT] and 25-hydroxy-vitamin D concentrations had risen 8-12 weeks later [mean +/- DS] from 57 +/- 62 to 96.2 +/- 82.4 mU/l [p=0.0017], 1.0 +/- 0.4 to 1.7 +/- 0.8 pmol/ml [p=0.001] and 3.6 +/- 1.8 to 13.5 +/- 7.4 ng/ml [p=0.0001], (but not to low-risk group values of 179 +/- mU/l, 2.7 +/- 1.14 pmol/ml and 8.16 +/- 6.4 ng/ml), respectively. Both total serum alkaline phosphatase and corrected calcium concentrations rose following vitamin D treatment in the at-risk subjects by 11.1 +/- 8.22 (from 44 to 55 IU/l) and 0.15 +/- 0.18, (2.43 to 2.57 mmol/l), respectively (p=0.004). Abnormal glucose tolerance was unchanged by vitamin D treatment. The value of early and sustained repletion with vitamin D in diabetes prophylaxis should be examined in communities where vitamin D depletion is common.

Asian People↗
PubMed1995

Mass versus activity: validation of an immunometric assay for bone alkaline phosphatase in serum.

A detailed investigation of the performance of an immunometric assay for the quantitation of bone alkaline phosphatase (ALP) in serum showed that precision of this assay was similar to that of lectin precipitation and electrophoretic methods. Relationships for mass and activity measurements of the bone isoform using samples from children and patients with Paget's disease were similar for lectin and electrophoretic methods. Purified liver enzyme showed 100% cross reactivity in the immunometric assay. However, comparison of the slopes between bone ALP mass and total ALP activity using only samples with predominantly liver or bone isoforms showed that the cross reactivity of the liver isoform in serum was 18.3%. Experiments in which increasing amounts of a sample containing 90% of liver isoform adding to a serum sample from a patient with Paget's disease showed a cross reactivity of 16.5%. The reference range for bone ALP mass was 7-28 micrograms/L for men (n = 77) and 5-20 micrograms/L for women (n = 110) in the age group 20-50 years. In women over 50 years bone ALP was 28% higher. Increased bone ALP mass was also demonstrated in patients with Paget's disease (n = 59), liver disease (n = 95), chronic renal failure (n = 41) and hyperthyroidism (n = 17).

Adolescent↗
PubMed1995

The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults.

GH deficiency is associated with increased cardiovascular morbidity, which may be determined by alterations in vascular risk factors. We report the effect of partially treated hypopituitarism and subsequent GH replacement (mean dose, 0.2 IU/kg.week) on putative cardiovascular risk factors in 22 nondiabetic hypopituitary subjects in a 6-month, double blind, controlled study (active/placebo ratio, 11:11). All patients were subsequently treated with GH for a further 6 months. Total fat, percent body fat, and central fat were measured by dual energy x-ray absorptiometry. The hypopituitary patients had increased percent fat (P = 0.03) and central fat (P < 0.01) compared with body mass index-matched controls. Before GH treatment, fasting (total) and specific insulin positively correlated with body mass index (P = 0.02 and P < 0.001, respectively), waist/hip ratio (P = 0.05 and P = 0.01), and central fat (P = 0.03 and P = 0.003). Specific insulin and insulin sensitivity (IS), calculated by homeostatic model of assessment, were related to total fat (P < 0.001 and P = 0.02). GH treatment for 6 months led to a reduction in total fat (P < 0.02), percent fat (P = 0.002), central fat (P = 0.012), waist/hip ratio (P < 0.05), total cholesterol (P = 0.03), and apolipoprotein-B (P = 00001), as well as a decrease in the IS from 36.9% (range, 12-100%) to 25% (range, 2.5-55%; P = 0.0002). This was paralleled by a rise in fasting (total) and specific insulin (P = 0.016 and P = 0.002). The degree of correlation among indices of IS, body composition, and fat distribution increased after GH treatment. Fasting plasma glucose rose significantly, but was within the reference range. During 12 months of GH therapy, a significant increase in serum lipoprotein-(a) was observed (P < 0.05). Although GH has beneficial effects on central adiposity and lipid fractions, it is also associated with a decrease in IS; these effects may vary between individuals.

Adipose Tissue↗
PubMed1994

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults.

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.

Adult↗
PubMed1993

Parathyroid sensing of the direction of change of calcium in uremia.

It could be advantageous for the parathyroids to be able to sense not only the absolute concentration of extracellular Ca2+, but also the rate and direction of change of Ca2+, thereby allowing the parathyroids to respond earlier to threats to Ca2+ homeostasis. By using high and low Ca2+ dialysis in a single session, we examined the parathyroid response to direction of change of Ca2+ during acute Ca2+ perturbation in nine hemodialysis patients. Separate PTH/ionized calcium (PTH/iCa) response curves were generated for rising Ca2+ and falling Ca2+. Significant directional hysteresis (higher PTH level during falling than during rising Ca2+) was found. During hypercalcemia, PTH levels were between 2.2 and 1.6 times higher at iCa concentrations of between 0 and +0.1 mM above the baseline iCa, when Ca2+ was falling than when it was rising. During the phase of induced hypocalcemia, parathyroid fatigue was seen in six of the nine patients. Fatigue patients tended to have higher basal PTH (1-84) levels than those not showing fatigue. The existence of fatigue provides an explanation for directional hysteresis during hypocalcemia, and therefore parathyroid sensing of the direction of change of Ca2+ could not be assessed during hypocalcemia. These studies demonstrate a capacity of the parathyroids to sense the direction of movement of Ca2+ during hypercalcemia.

Adult↗