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Objective: To undertake a comprehensive evaluation of apolipoprotein risk markers for cardiovascular disease (CVD) according to gender, age and menopausal status., Design: Cross-sectional analysis of independent associations of gender, age and menopause with serum apolipoproteins., Participants: Apparently healthy Caucasian premenopausal (n = 109) and postmenopausal (n = 252) women not taking oral contraceptives or hormone replacement, and Caucasian men (n = 307)., Measurements: Serum apolipoprotein (apo) B, A-I and A-II concentrations were measured, plus serum total cholesterol, low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), triglycerides, cholesterol in HDL subfractions and the apoB/apoA-I, LDL-C/apoB, HDL-C/apoA-I and HDL-C/apoA-II ratios. Analyses were undertaken with and without standardization for confounding characteristics and in 5-year age ranges., Results: Overall, apoB concentrations were highest in men but in women rose with age and menopause to converge, in the age range of 50-55 years, with concentrations in men. The LDL-C/apoB ratio was generally higher in women than in men. ApoA-I concentrations were highest in postmenopausal women and lowest in men (standardized median (IQR) 144 (130, 158) vs 119 (108, 132) g/l, respectively, P < 0·001). ApoA-II concentrations were also highest in postmenopausal women but were lowest in premenopausal women (40·3 (37·5, 44·5) vs 32·9 (30·5, 35·7) g/l, respectively, P < 0·001). Nevertheless, postmenopausal women had HDL-C/apoA-I and HDL-C/apoA-II ratios approaching the lowest ratios, which were seen in men., Conclusions: Consistent with adverse effects on CVD risk, male gender, ageing in women and menopause were associated with increased apoB concentrations, and menopause and male gender were associated with a decreased cholesterol content of HDL particles., (© 2016 John Wiley & Sons Ltd.)

Aim: The increasing prevalence of fatty liver disease requires routine assessment methods. Proton magnetic resonance spectroscopy ((1)H MRS) is increasingly used for steatosis measurement, but due to cost, is unlikely to become a widely-used screening tool. Ultrasound is cheaper and more widely available, although subject to observer variability. Our aim was to determine the sensitivity and specificity of ultrasound against (1)H MRS, using MRS as a gold standard, for the detection and quantification of hepatic fat content., Methods: Fifty adults participated (43 men, seven women) in this study. Hepatic steatosis was assessed by ultrasound and (1)H MRS. Images were graded by two independent radiologists to classify severity and distribution of liver fat., Results: Ultrasound detected liver fat infiltration in 82% of cases measurable by (1)H MRS, while liver fat was detectable in 44% of cases graded absent by ultrasound. Ultrasound grading was subjective, with the radiologists in agreement in 53% of cases (kappa = 0.39, P = 0.002). Considerable overlap in intrahepatocellular lipid content was observed between different grades: absent (0.0-1.58%), mild (2.2-16.2%), moderate (4.9-26.7%) and severe (8.1-76.8%) steatosis. Ultrasound could not detect liver fat levels below 2% as measured by (1)H MRS Conclusion: Ultrasound is less sensitive than (1)H MRS in detecting very low levels of liver fat content, but is sensitive to fatty infiltration greater than 2%. There is a tendency of higher ultrasound grades to correlate with higher degrees of fatty infiltration, although some overlap exists. Our findings are still consistent with ultrasound being useful as a low cost screening tool.

Background and Objective: Women with previous gestational diabetes (pGDM) are at risk of developing Type 2 diabetes. Glucagon-like peptide-1 (GLP-1) potentiates the insulin response to oral glucose, and its secretion is diminished in Type 2 diabetes. The aim of the study was to see if decreased GLP-1 secretion might be an early abnormality in the progression to Type 2 diabetes and would therefore be diminished in women with pGDM., Patients and Methods: Eleven women with pGDM and previously documented normal glucose tolerance and 11 control women underwent a 75 g oral glucose tolerance test (OGTT). Circulating plasma glucose, insulin, nonesterified fatty acids (NEFA) and GLP-1 concentrations were sampled., Results: One of the women with pGDM had impaired glucose tolerance and was excluded from the study. All other women had normal glucose tolerance. The women with pGDM had higher fasting glucose concentrations than controls (5.1; 4.9-5.3 vs. 4.8; 4.4-5.1 mmol/l, median; interquartile range, P = 0.04) and greater circulating glucose area under the curve (AUC) following the oral glucose load (930; 818-1015 vs. 668; 584-737 min x mmol/l, P = 0.0007). Fasting insulin concentrations and total insulin AUC were similar. The initial (0-30 min) insulin response was decreased in the pGDM women (AUC 3981; 2783-4795 vs. 6167; 5009-8145 min x pmol/l, P = 0.05). The initial (0-30 min) GLP-1 response was reduced in the pGDM women (AUC 816; 663-984 vs. 1163; 872-2024 min x pmol/l, P = 0.02)., Conclusion: A reduced initial GLP-1 response to oral glucose may therefore be an early abnormality in the progression to Type 2 diabetes.

Objective: Women with previous gestational diabetes (GDM) are at increased risk of subsequent type 2 diabetes. To characterize early metabolic abnormalities associated with this increased risk, we studied normoglycaemic women with a history of GDM., Patients and Measurements: We performed an insulin-modified, frequently sampled intravenous glucose tolerance test (FSIVGTT) in 34 normoglycaemic European women with previous GDM and 44 European control women, deriving measures of insulin sensitivity, glucose effectiveness, glucose disappearance rate and acute insulin response to glucose., Results: Post-GDM women were more obese than controls [body mass index (BMI), geometric mean (95% confidence interval); 25.3 kg/m2 (23.8-27.1 kg/m2) vs. 23.1 kg/m2 (21.9-24.3 kg/m2), P = 0.03]. Evidence of insulin resistance was provided by their lower insulin sensitivity as measured by FSIVGTT [0.6 x 10-4/min/pmol/l (0.3-1.2 x 10-4/min/pmol/l) vs. 1.5 x 10-4/min/pmol/l (1.2-1.8 x 10-4/min/pmol/l), P = 0.01] and by homeostatic model assessment [72% (49-107%) vs. 153% (113-206%), P = 0.004]; and by their higher fasting triglycerides [1.0 mmol/l (0.7-1.5 mmol/l) vs. 0.7 mmol/l (0.6-0.8 mmol/l), P = 0.001]. Though there was no difference between groups in fasting NEFA levels, acute NEFA suppression was diminished in the post-GDM group (P = 0.01). Concomitant beta-cell dysfunction in the post-GDM women was revealed by their lower disposition index [0.05/min (0.02-0.10/min) vs. 0.11/min (0.09-0.14/min), P = 0.02] compared to controls. The differences in insulin sensitivity, but not those of beta-cell function, were partly, though not completely, attributable to differences in regional and total adiposity., Conclusions: European normoglycaemic women with previous GDM display both glucoregulatory and antilipolytic insulin resistance, reduced beta-cell function and dyslipidaemia. These metabolic abnormalities are likely to contribute to their increased risk of future type 2 diabetes.

Objective: Increased levels of the soluble adhesion molecule sE-selectin have been reported in normoglycaemic women with previous gestational diabetes but not in other groups at increased risk of future type 2 diabetes. To explore the basis for these discrepant findings, we studied the relationship between sE-selectin and glucose regulation in a large group of women with previous gestational diabetes., Design: Comparison of sE-selectin levels between a study cohort ascertained on the basis of recent gestational diabetes and suitable control subjects., Patients: One hundred and forty women with recent gestational diabetes (104 European, 20 South Asian and 16 Afro-Caribbean) and 125 normoglycaemic control women (90 European, 19 South Asian and 16 Afro-Caribbean)., Measurements: sE-selectin, fasting lipids, insulin and current glucose regulation status., Results: There was no overall difference in sE-selectin levels between women with a history of gestational diabetes and control women among the 3 ethnic groups. European post-GDM women with abnormal glucose regulation postpartum (n = 30) had higher sE-selectin than control women (67 (54-91) ng/ml vs. 57 (43-75) ng/ml, P = 0.049). There was no difference in sE-selectin between normoglycaemic European women with a history of gestational diabetes (n = 74) and control women, even though the former displayed metabolic abnormalities predictive of diabetes. In those European post-GDM women with normal glucose regulation postpartum, sE-selectin levels were negatively correlated with time since delivery (r = -0.25, P = 0.04), suggesting that the previously described elevation of sE-selectin following GDM pregnancies slowly resolves postpartum. There was no correlation between sE-selectin levels and features of insulin resistance., Conclusions: In contrast to previous findings, this larger study does not support a role for sE-selectin as a marker, independent of prevailing glucose levels, of early metabolic abnormalities or future diabetes risk in women with previous gestational diabetes.

Objective: Stereotactic conformal radiotherapy (SCRT) is a high precision technique of fractionated radiotherapy which ensures accurate delivery of radiation with reduction in the volume of normal tissue irradiated as compared to conventional external beam radiotherapy. We describe the technique and preliminary experience of SCRT in patients with residual and recurrent pituitary adenomas., Patients and Methods: Between February 1995 and March 1999, 22 patients (mean age: 45.3, range: 20-67 years) with residual or recurrent pituitary adenomas (13 nonfunctioning, nine secretory) were treated with SCRT. All were immobilized in a relocatable Gill-Thomas-Cosman (GTC) frame and tumour was localized on a postcontrast planning computerized tomography (CT) and MRI scan. The gross tumour volume (GTV) and the critical structures were outlined on contiguous 2-3 mm separated slices. A margin of 5 mm (12 patients) to 10 mm (10 patients) was grown around GTV in three-dimensions (3-D) to generate the planning target volume (PTV). The treatment was delivered by three (five patients) and four (17 patients) maximally separated conformal fixed fields with each field conformed to the shape of the tumour using customized lead alloy blocks (19 patients) or multileaf collimator (three patients). The patients were treated on a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions (18 patients) and 50 Gy in 30 fractions (four patients)., Results: The technique of SCRT has become a part of the routine work of the radiotherapy department. The treatment was well tolerated with minimal acute toxicity. One patient developed transient quadrantanopia 2 weeks after treatment with full recovery after a short course of corticosteroids. One patient had a transient visual deterioration 7 months after treatment due to cystic degeneration of the tumour which fully recovered following surgical decompression. Nine of the 15 patients presenting with visual impairment had improvement after treatment and the visual status remained stable in all others. One patient with acromegaly and one with a prolactinoma achieved normalization of elevated hormonal abnormality four and 10 months after SCRT, respectively. The remaining seven patients with a secretory adenoma had declining hormone levels at last follow-up. Newly initiated hormone replacement therapy was required in five patients. At a median follow-up of 9 months (range 1-44 months), the 1 and 2 year actuarial progression free and overall survival were 100%., Conclusion: Stereotactic conformal radiotherapy is a high precision technique suitable for the treatment of pituitary adenomas requiring radiotherapy. Preliminary results suggest effective tumour control and low toxicity within the range expected for conventional external beam radiotherapy. While the technique is of potential benefit in reducing the volume of normal brain irradiated, the advantages in terms of sustained tumour control and reduced toxicity over conventional radiotherapy need to be demonstrated in long-term prospective studies.

Objective: Hypopituitary adults on conventional replacement have low concentrations of metabolic fuels throughout the night, possibly related to GH deficiency or to decreased cortisol levels overnight. We investigated whether GH replacement corrects the overnight fuel deficiency., Design: We measured circulating levels of metabolic fuels: glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) and insulin concentrations over 24 h (from 0730 h to 0700 h) in hypopituitary adults before and after GH treatment in a randomized double-blind placebo-controlled trial of 3 months' duration., Patients: Thirteen hypopituitary patients, 8 women and 5 men, were studied., Results: Six patients (4 women and 2 men) received GH and 7 patients (4 women and 3 men) were allocated to receive placebo. There was no difference in fasting (0730 h), area under the curve (AUC) between 2400 h and 0700 h (overnight) and AUC over 24 h for plasma glucose, 3-OHB, glycerol and insulin concentrations as a result of GH treatment. Fasting and overnight AUC for NEFA were significantly higher on GH treatment ((mean +/- SEM) 243 +/- 29 vs. 446 +/- 90 micromol/l, P = 0.03, 1522 +/- 208 vs. 2167 +/- 123 micromol/l H, P = 0.046, respectively), but AUC over 24 h was not affected significantly. No significant changes in any fuel were seen in the placebo group. The changes in fasting, overnight and 24 h AUC for glucose, 3-OHB, glycerol and insulin levels with GH and with placebo for 3 months were similar. The changes in fasting and overnight AUC for NEFA before and after 3 months were significantly different in the group treated with GH vs. the group treated with placebo (median (lower-upper quartile) 104 (90-276) vs. -89 (-98 to 26) micromol/l, P = 0.002; 633 (263-967) vs. -895 (-1379 to -494) micromol/l h, P = 0.002, respectively), but the changes in 24-h AUC for NEFA were not significant between the two groups., Conclusions: GH replacement in hypopituitary adults increases fasting and overnight (between 2400 h and 0700 h) non-esterified fatty acid concentrations, consistent with the known lipolytic effect of GH. GH did not influence the concentrations of other metabolic fuels or insulin.

Objective: Leptin acts as a satiety factor in regulating food intake and body homeostasis, but its regulation is not well defined. Specific leptin receptors have been found in the brain and it has been hypothesized that leptin production by adipose tissue is under neuroendocrine control. A circadian rhythm has been demonstrated with highest leptin levels between midnight and early morning hours. The possibility that hypopituitarism (or pituitary surgery +/- radiotherapy) abolishes this leptin rhythm was investigated by measuring serum leptin levels during a 24-h period in patients with impaired pituitary function., Patients and Design: Circulating leptin levels were measured hourly over 24-h in 14 hypopituitary patients (8 women and 6 men) using a sensitive and specific radioimmunoassay. Hypopituitarism was the consequence of pituitary tumors treated surgically and/or with radiotherapy. All patients were GH deficient and were receiving conventional replacement with cortisol (n = 13), thyroxine (n = 12) and desmopressin (n = 4) but not with GH., Results: A significant diurnal variation in circulating leptin concentrations was observed in 13 of the 14 patients. The mean (+/- SEM) leptin levels for 8 women were 51.9 (+/- 10.7) ng/ml and for 6 men 11.0 (+/- 2.0) micrograms/l. The overall lowest leptin levels (29.3 +/- 7.9 ng/ml) were observed at 0830 h after overnight fasting, rising gradually to maximum levels (43.0 +/- 9.8 ng/ml) at 0200 h declining thereafter towards fasting values. The mean (+/- SEM) magnitude of circadian variation in absolute leptin levels from the calculated mean level for each patient was 5.6 (+/- 1.2) ng/ml (8.4 +/- 1.4 for women and 1.9 +/- 0.3 for men). The mean (+/- SEM) of the ratio of the amplitude versus mean leptin levels over 24 h for each individual patient was 0.18 (+/- 0.02) (0.19 +/- 0.03 for women and 0.18 +/- 0.02 for men)., Conclusions: A circadian rhythm for leptin is generally present in hypopituitary patients who had undergone pituitary surgery and/or radiotherapy, with the highest serum leptin levels being obtained between midnight and early morning hours. Although some patients had some residual pituitary activity, intact hypothalamic-pituitary function is not essential for leptin's circadian rhythm.

Objective: To study the effects of long-term growth hormone (GH) treatment on lipid metabolism and carbohydrate tolerance in GH-deficient adults., Design: Open trial of GH treatment for 4 years. GH dose was (median, range) 0.025 (0.010-0.050) IU/kg daily., Patients: Thirteen GH-deficient hypopituitary adults (seven men, six women), aged (median, range) 47 (24-65) years were followed for 4 years., Measurements: Fasting lipids, lipoproteins, apolipoproteins, glucose and insulin concentrations were measured at yearly intervals during GH therapy. A 75-g oral glucose tolerance test (OGTT) was also performed yearly, during which circulating glucose and insulin were measured at 30-minute intervals for 3 h., Results: Fasting total and low density lipoprotein (LDL) cholesterol concentrations decreased on GH therapy, but no change was observed in fasting triglyceride or high density lipoprotein (HDL) concentrations. Compared to pretreatment values, total and LDL cholesterol levels were significantly lower at 1 year (mean +/- SEM) (6.39 +/- 0.46 vs. 5.71 +/- 0.38 mmol/l, P < 0.05; 4.46 +/- 0.36 vs. 3.24 +/- 0.20 mmol/l, P < 0.01, respectively) and the reductions were maintained for the 4 years. Apolipoproteins A-1 and B did not differ significantly from the pretreatment levels. Fasting plasma glucose increased significantly at the first year (4.9 +/- 0.1 vs. 5.3 +/- 0.1 mmol/l, P < 0.05) but it returned to the pretreatment value in the following years. Fasting plasma insulin increased significantly at 1 year (4.3 (1.0-13.6) vs. 11.9 (1.2-26.9) mU/l, P < 0.05) and showed a progressive downward trend but remained significantly raised throughout the subsequent years. The 3-h area under the glucose curve (AUC) during the OGTT tended to be increased at the first year (P = 0.07) and it returned to the pretreatment level in the following years. The AUC of plasma insulin was significantly raised at 1 year (P = 0.024) and it returned to the pretreatment level in the following years., Conclusions: Four years of GH therapy in GH-deficient adults resulted in a sustained improvement in total and LDL cholesterol concentrations. Mild fasting hyperinsulinaemia persisted, although an initial deterioration in glucose tolerance, associated with post-glucose hyperinsulinaemia, was not sustained.

Background: Hypopituitarism with growth hormone (GH) deficiency is associated with obesity characterized by central (abdominal) distribution of fat. Recent work has demonstrated that leptin, a product of obese gene, is raised in obesity., Objective: To study circulating leptin levels in GH-deficient hypopituitary adults and to investigate its anthropometric, gender and metabolic relations., Methods: After an overnight fast of 10-12 hours, anthropometric parameters and body composition were measured and blood was collected for the measurement of circulating leptin, glucose, intact insulin, proinsulin, IGF-I, total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol., Subjects: Fifteen (7 men) GH-deficient hypopituitary adults (maximum stimulated serum GH to provocative testing < 6 mU/l) and 21 (10 men) normal control subjects matched for age, gender and body mass index (BMI)., Results: Fasting serum leptin was significantly higher in hypopituitary patients than controls (12.0 +/- 1.8 vs 8.0 +/- 1.5 micrograms/l, P = 0.04). The increase was more marked in obese (BMI > 26.0 kg/m2) patients compared with obese controls (15.3 +/- 2.0 vs 8.8 +/- 2.3 micrograms/l, P = 0.03) than in lean patients and controls. Obese control women and men had higher leptin levels than non-obese (women, 16.6 +/- 2.7 vs 8.6 +/- 0.6 micrograms/l, P = 0.03; men, 4.9 +/- 0.5 vs 2.9 +/- 0.6 micrograms/l, P = 0.035). Similar changes were observed for obese versus non-obese patients, although the changes did not reach statistical significance. Women in each group had significantly higher leptin concentrations than men (patients: 15.5 +/- 2.3 vs 7.3 +/- 1.4 micrograms/l, P = 0.009; controls: 12.6 +/- 2.4 vs 4.3 +/- 0.5 micrograms/l, P = 0.0001). These gender differences remained significant even when expressed in relation to BMI (patients: 0.57 +/- 0.09 vs 0.26 +/- 0.05 ng.m2/ml.kg, P = 0.009; controls: 0.43 +/- 0.05 vs 0.16 +/- 0.02 ng.m2/ml.kg, P = 0.0001). Serum leptin was positively associated with body mass index (P = 0.003), percentage body fat mass (P = 0.0001) and inversely related with age (P = 0.043). It demonstrated no relation with body weight, waist circumference, waist to hip ratio, fasting IGF-I, glucose, insulin, proinsulin, total cholesterol, triglycerides, HDL and LDL cholesterol in patients nor controls; 85% of variance in leptin was explained by a model including body mass index, gender, age and hypopituitarism., Conclusions: Leptin concentrations are raised in GH-deficient hypopituitary adults to a greater extent than would be expected from the degree of obesity.

Background: Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours., Objective: To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) over 24 hours in hypopituitary subjects and controls., Subjects: Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10-30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary., Measurements: Circulating glucose, NEFA, glycerol and 3-OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol., Results: Levels of glucose, NEFA and 3-OHB were lower in patients than controls (mean +/- SEM) (4.3 +/- 0.1 vs 5.3 +/- 0.1 mmol/l, P = 0.0001; 291 +/- 46 vs 448 +/- 48 mumol/l, P = 0.015; 78 +/- 8 vs 136 +/- 24 mumol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3-OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24-hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 +/- 154 vs 1593 +/- 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 +/- 8 vs 161 +/- 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24-hour AUC: 10.6 +/- 5.1 vs 74.6 +/- 19.6 mU/l h, P = 0.008)., Conclusions: Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non-esterified fatty acids and 3-hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non-specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.

Objective: Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history., Design: A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls., Patients and Methods: We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11)., Results: Results are expressed as mean +/- SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 +/- 0.7 vs LP 35.2 +/- 1.2, P < 0.01; OC 34.7 +/- 1.8 vs OP 37.8 +/- 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 +/- 9 vs LP 179 +/- 9, NS; OC 168 +/- 12 vs OP 133 +/- 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL2-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38-0.62), LP 0.31 (0.26-0.44), P < 0.05; OC 0.34 (0.21-0.47), OP 0.21 (0.12-0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL2-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries., Conclusion: Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.

Objective: The aetiology of non-insulin dependent diabetes is unknown, but defective insulin secretion is a feature. The disease also has a strong genetic basis and first-degree relatives of patients have an increased risk of future diabetes. To investigate whether beta-cell dysfunction is an early feature of the disease, we studied insulin secretion in healthy first-degree relatives of patients with non-insulin dependent diabetes., Design: Each subject underwent a 1-hour intravenous glucose tolerance test (0.3 g/kg)., Patients: Seventeen first-degree relatives of patients (10 of European and 7 of Asian (Indian subcontinent) origin) with normal glucose tolerance were compared with 17 matched control subjects with no family history of diabetes., Measurements: Plasma immunoreactive insulin (IRI) was measured by radioimmunoassay, and specific insulin, intact and 32,33 split proinsulin were measured by specific immunoradiometric assays (IRMA) for the 1st phase (0-10 minutes) and 2nd phase (10-60 minutes) responses. Glucose and intermediary metabolites were measured enzymatically., Results: Fasting concentrations of IRI, IRMA insulin, intact and 32,33 split proinsulin were similar in relatives and controls in each group. Fasting glucose levels were similar in European relatives and controls but lower in Asian relatives compared to their controls (mean +/- SE 4.9 +/- 0.2 vs 5.5 +/- 0.2 mmol/l, P < 0.05). Following intravenous glucose, European relatives had similar IRI and glucose levels to their controls. Secretion of 32,33 split proinsulin was increased in European relatives compared to their controls, significantly so for 2nd phase secretion (1st phase median (range): 71 (7-352) vs 55 (17-118) pmol/l min, NS; 2nd phase: 433 (115-1459) vs 234 (55-745) pmol/l min, P < 0.05). Secretion of IRMA insulin and intact proinsulin were similar in European relatives and controls (IRMA insulin: 1st phase 2757 (700-10,969) vs 2830 (632-4682) pmol/l min; 2nd phase 6387 (3006-15,865) vs 5284 (2060-18,605) pmol/l min; intact proinsulin: 1st phase 31 (13-113) vs 32 (16-72) pmol/l min; 2nd phase: 174 (87-737) vs 159 (97-298) pmol/l min). European relatives had a greater percentage of proinsulin-like molecules (intact + 32,33 split proinsulin) to total insulin (sum of IRMA insulin + intact + 32,33 split proinsulin) during the 2nd phase of secretion (9.1 (5.0-11.8) vs 5.9 (4.3-12.6)%, P < 0.05). In contrast, Asian relatives had similar secretion of IRI, IRMA insulin, intact and 32,33 split proinsulin to their controls. Glucose disappearance (KG) was similar in relatives and controls within each ethnic group (Europeans: relatives 725 +/- 101 vs controls 668 +/- 47/min; Asian: relatives 610 +/- 97 vs controls 783 +/- 936/min). Asian relatives had higher fasting circulating glycerol (65 +/- 7 vs 44 +/- 4 mumol/l, P < 0.05), non-esterified fatty acid (569 +/- 59 vs 375 +/- 64 mumol/l, P < 0.05) and 3-hydroxybutyrate levels (147 (44-187) vs 35 (21-57) mumol/l, P < 0.01) than their controls and this persisted following intravenous glucose. This difference was not observed in the European group., Conclusion: First-degree relatives of European patients with NIDDM possess early signs of beta-cell dysfunction, with increased and disproportionate secretion of 32,33 split proinsulin after intravenous glucose, whilst glucose tolerance is still normal.

Objective: Short-term GH replacement in hypopituitary adults increases bone turnover; data on the consequences of longer-term GH treatment are limited. We report on the effects of 12-18 months of GH replacement treatment with biosynthetic human GH on bone metabolism and bone mass in hypopituitary adults., Design: Patients were studied before and after GH treatment for 12 months (n = 11) and 18 months (n = 27) respectively in an open trial. GH dose was 0.04 +/- 0.01 IU/kg daily., Measurements: Plasma calcium, phosphate and intact PTH concentrations, 24-hour urinary calcium excretion, 3 markers of bone formation (total alkaline phosphatase, osteocalcin and procollagen 1 carboxy terminal peptide (P1CP)) and serum concentration of carboxyterminal cross-linked telopeptide of type 1 collagen (ICTP), as a marker of bone resorption, were measured at 6-month intervals. Lumbar spine and total body bone mineral mass was measured by dual-energy X-ray absorptiometry., Results: Small increases were observed in plasma calcium and phosphate concentrations at 12 months of GH therapy but the differences at 18 months were not statistically significant. Serum intact PTH concentration did not change. Plasma total alkaline phosphatase increased significantly on GH from 75 +/- 26 to 92 +/- 30 (P < 0.01) and 85 +/- 31 U/I (NS) at 12 and 18 months respectively. Serum osteocalcin increased from 6.5 +/- 3.7 to 15.7 +/- 6.2 (P < 0.0001) and 16.6 +/- 5.7 micrograms/I (P < 0.001) at 12 and 18 months respectively and P1CP increased significantly from 106.0 +/- 47.3 micrograms/I to 165.5 +/- 95.3 (P < 0.0001) and 177.2 +/- 72.2 micrograms/I (P < 0.01) at 12 and 18 months respectively. Plasma ICTP concentration increased also from 3.4 +/- 1.8 to 7.3 +/- 3.4 (P < 0.0001) and 7.0 +/- 2.7 micrograms/I (P < 0.003) at 12 and 18 months of GH therapy respectively. No significant change was observed in total body or lumbar spine bone mass, over the 18 months of GH treatment, Conclusions: Replacement therapy with GH in hypopituitary adults for 6-18 months produced a sustained increase in bone turnover (both formation and resorption). Bone mass was maintained but did not increase over the study period.

Objectives: The role of growth hormone in maintaining normal body composition and bone strength in adults has attracted much interest recently. We have assessed body composition and bone mass in GH deficient hypopituitary adults on conventional replacement therapy and compared them with matched controls., Design and Subjects: A cross-sectional study of 64 growth hormone deficient hypopituitary adults (29 males and 35 females) on conventional replacement therapy and a large number of healthy control subjects matched for age, sex and body mass index (BMI)., Measurements: Skinfold thicknesses at two sites (triceps and subscapular), waist and hip girth circumferences were assessed by standard methods. Body composition was assessed using total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA). Bone mineral mass was assessed at the lumbar spine and the total body by DEXA. Not every patient and control participated in every measurement., Results: Obesity was common in the hypopituitary patients; BMI (mean +/- SD) was 27.5 +/- 4.6 kg/m2 and body weight was 111.8 +/- 18.5% of the maximal ideal for height (P < 0.001). The sum of subscapular and triceps skinfolds was significantly higher in hypopituitary patients than in controls (men 46 + 15 vs 37 +/- 14 mm, P < 0.05; women 55 +/- 13 vs 47 +/- 17 mm, P < 0.05). Waist to hip circumference ratio was significantly greater in female hypopituitary patients than in matched controls but was not significantly different in men (men 0.94 +/- 0.07 vs 0.91 +/- 0.07, NS; women 0.84 +/- 0.09 vs 0.77 +/- 0.05, P < 0.001). The difference between patients and controls in the sum of skinfolds and the waist to hip ratio were present in non-obese (BMI < 26 kg/m2) subjects (21 patients and 32 controls). TBK corrected for body weight was significantly lower in hypopituitary patients (n = 44) than in controls (n = 31) (men 43.5 +/- 5.6 vs 50.1 +/- 5.9 mmol/kg, P < 0.003; women: 34.0 +/- 3.2 vs 40.6 +/- 5.3 mmol/kg, P < 0.0001). BIA-derived body water content (corrected for body weight) was significantly lower in hypopituitary patients (n = 56) than in controls (n = 57) (0.492 +/- 0.064 vs 0.545 +/- 0.067 l/kg, P < 0.0004). Percentage body fat derived from all the three methods was significantly higher in hypopituitary patients than in normal controls in both sexes (from TBK: men 34.7 +/- 9.4 vs 28.8 +/- 7.0%, P < 0.05; women 37.8 +/- 8.7 vs 30.4 +/- 9.7%, P < 0.01; from BIA: men 29.3 +/- 8.5 vs 23.2 +/- 8.4%, P < 0.01; women 34.6 +/- 8.1 vs 29.3 +/- 9.1% P < 0.01; and from DEXA: men 24.8 +/- 6.8 vs 20.4 +/- 6.1%, P < 0.05; women 38.9 +/- 7.9 vs 32.5 +/- 9.8%, P < 0.01). There was a significant difference between non-obese patients and controls in BIA-derived percentage fat in both sexes and in TBK-derived percentage fat in females only. Bone mineral density (BMD) of the lumbar spine in the L2-L4 region was lower in hypopituitary patients than in controls (men 1.116 +/- 0.129 vs 1.311 +/- 0.131 g/cm2, P < 0.0001; women 1.001 +/- 0.122 vs 1.131 +/- 0.138 g/cm2, P < 0.001). Spine BMD was also reduced in hypopituitary patients compared to the young adult and age and weight matched reference data. Total body BMD was significantly lower in patients than in controls (men 1.186 +/- 0.102 vs 1.250 +/- 0.080 g/cm2, P < 0.05; women 1.080 +/- 0.077 vs 1.149 +/- 0.073 g/cm2, P < 0.005)., Conclusions: Hypopituitary adults on conventional therapy have abnormal body composition with increased fat content, reduced body water content and reduced bone mineral mass.

Objectives: The physiological role of growth hormone in adult life has recently attracted increased interest. We have studied the clinical effects and the effects on body composition of prolonged replacement with biosynthetic human GH in a large number of hypopituitary adults., Design: A randomized double blind placebo controlled trial for 6 months followed by an open trial of GH treatment for 12 months. GH daily dose was 0.04 (0.02-0.05) IU/kg s.c., Patients: Forty GH deficient hypopituitary patients (19 M, 21 F; aged 19-67 years) on conventional replacement therapy were studied., Measurements: Serum insulin like growth factor I (IGF-I), skinfold thickness, total body potassium, total body water (TBW), exercise tolerance and muscle strength, and well-being., Results: During the 6-month double blind phase, two GH treated patients withdrew because of adverse events. Lean body mass (LBM) increased and percentage body fat (%BF) decreased on GH but not on placebo (P) (LBM: (GH: from 48.5 +/- 9.6 to 49.6 +/- 9.5 kg; P: from 50.9 +/- 9.2 to 50.1 +/- 9.0 kg, P < 0.05 GH vs P) and %BF (GH: from 34.7 +/- 11.4 to 34.2 +/- 10.7; P: from 37.4 +/- 7.6 to 38.7 +/- 8.1, P < 0.05 GH vs P)). TBW increased on GH (P < 0.01) but not on P. No change was observed in waist-to-hip ratio or in muscle strength. During longer-term follow-up combining the double blind and open phase components of the study, 34, 27 and 11 patients received GH for 6, 12 and 18 months respectively. Patients dropped out because of adverse events or lack of perceived benefit. Skinfold thicknesses decreased significantly at 6 and 12 months and the waist circumference at 6 months. Waist-to-hip ratio decreased significantly on GH at 12 months. LBM increased on GH treatment from 49.6 +/- 9.1 to 51.6 +/- 9.4 kg (P < 0.0006), 51.9 +/- 8.9 kg (P < 0.07) and 53.1 +/- 10.5 kg (P < 0.0001) at 6, 12 and 18 months respectively. Percentage body fat decreased on GH from 37.2 +/- 10.7 to 34.7 +/- 10.1 (P < 0.005), 35.1 +/- 12.8 (NS) and 34.5 +/- 8.6 (P < 0.04) at 6,12 and 18 months respectively. TBW also increased at 6 and 12 months of GH treatment. Exercise time increased significantly at 6, 12 and 18 months of GH treatment. Muscle strength in selected muscle groups increased significantly at 6, 12 or 18 months of GH treatment. Randomization resulted in the placebo group having a greater GHQ score (higher morbidity) than the GH group before therapy. Over the controlled phase, GHQ scores improved on placebo but not on GH and CPRS score was unchanged in either group. In the open phase, the GHQ score did not change on GH therapy but CPRS score improved at 6 and 12 months., Conclusions: Growth hormone replacement therapy in adults for 6 months increased lean body mass, total body water and exercise tolerance, and decreased body fat. Growth hormone replacement for longer than 6 months maintains the advantageous effects seen in shorter-term studies and may have additional effects on body fat distribution, muscle strength and psychological well-being.

Background and Objectives: Excess impaired glucose tolerance and diabetes mellitus have been reported in hypopituitary adults on conventional replacement therapy including glucocorticoids. We investigated the effect of the glucocorticoid component on glucose tolerance and intermediary metabolites in hypopituitary adults., Design: A 3-hour 75-g oral glucose tolerance test (OGTT) was performed on two study days, at least one week apart. On one study day, the glucocorticoid replacement morning dose was taken 60 minutes before the OGTT, and on the other it was left until after the OGTT. All other pituitary replacement therapies were kept unchanged on the two study days., Patients: Eight hypopituitary adults (3 males and 5 females; aged 46-76 years) on conventional replacement therapy were studied. Their duration of hypopituitarism was mean (range) 15 (5-31) years. Their mean body mass index (BMI) was 28.4 (24.1-35.1) kg/m2. Their total daily cortisol dose was 26 (15-30) mg., Measurements: Plasma glucose, insulin, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate were measured at 30-minute intervals and plasma cortisol levels were measured hourly., Results: Fasting glucose and insulin concentrations were similar on the glucocorticoid day (GD) and the non-glucocorticoid day (NGD) (glucose (mean +/- SD) 4.9 +/- 0.9 vs 4.4 +/- 0.5 mmol/l; insulin (median (range)) 5 (1-17) vs 2 (1-15) mU/l, respectively). Post-glucose glycaemia was higher on the GD than on the NGD with a significantly higher glucose area under the curve (AUC) (45.0 +/- 8.2 vs 38.9 +/- 11.7 mmol/l h, P < 0.05). Post-glucose insulinaemia was also higher on the GD than on the NGD with significantly higher insulin AUC (270 (47-909) vs 207 (46-687) mU/l h, P < 0.02). Impaired glucose tolerance was found in three patients on the GD, one of whom continued to have impaired glucose tolerance on the NGD. The areas under the curves of NEFA, glycerol and 3-hydroxybutyrate were not significantly different on the two days. On the NGD, plasma cortisol levels were undetectable (< 50 nmol/l) in all patients and on the GD the median (range) peak was 500 (330-740) nmol/l dropping to 125 (60-330) nmol/l at 180 minutes. The difference in glucose AUC between the two days correlated with the maximal plasma cortisol levels (Spearman's p = 0.83, P < 0.01)., Conclusions: Glucocorticoid replacement therapy taken pre-prandially in hypopituitary adults induces mild elevations in circulating glucose and insulin levels even with acceptable plasma cortisol concentrations. Optimal regimens for glucocorticoid replacement require more study.

Objective: The assessment of insulin sensitivity requires an accurate and reproducible technique. The short insulin tolerance test is a simple and rapid method for screening large numbers of subjects when the fasting glucose level is normal. Conventionally, an insulin dose of 0.1 units/kg is used, but this may result in symptomatic hypoglycaemia in healthy thin subjects who are insulin sensitive. In order to overcome this problem we have employed a lower dose of insulin and have studied the reproducibility of this modified technique comparing it with the euglycaemic hyperinsulinaemic clamp., Design: Subjects were studied on two separate occasions, once by a short insulin tolerance test and on a second occasion by either a euglycaemic hyperinsulinaemic clamp (insulin infusion of 40 mU/m2/min) or a repeat short insulin tolerance test., Patients: Eleven healthy subjects were studied twice with a short insulin tolerance test. A further 10 healthy subjects received a short insulin tolerance test on one day and a euglycaemic hyperinsulinaemic clamp study on another occasion., Measurements: Insulin sensitivity was measured in the short insulin tolerance test using the slope of arterialized blood glucose concentration from 3 to 15 minutes after an intravenous bolus of short-acting insulin, 0.05 units/kg body weight. In the clamp study, insulin sensitivity was derived from the average amount of glucose infused at steady state (M) and the mean plasma insulin level (I)., Results: In the short insulin tolerance test no subject developed symptomatic or biochemical hypoglycaemia, defined as a blood glucose < 2.2 mmol/l. The (mean +/- SEM) insulin sensitivities for the 11 subjects studied twice were 174 +/- 10 and 179 +/- 11 mumol/l/min with a coefficient of variation of 6.9 +/- 2.6%. There was a close correlation between insulin sensitivity derived from the short insulin tolerance test and that obtained from the euglycaemic clamp studies (so-called M/I ratio) in the same subjects (r = 0.81; P < 0.005)., Conclusion: The short insulin tolerance test employing 0.05 units/kg insulin is a safe, valid and reproducible method for the assessment of insulin sensitivity.

Objective: The importance of growth hormone (GH) for normal skeletal growth in childhood and adolescence is well established but much less is known about its action on the adult skeleton. We therefore wished to investigate the effects of replacement treatment with biosynthetic human GH in hypopituitary adults on aspects of calcium homeostasis, bone metabolism and bone mineral mass., Patients: Forty hypopituitary adults (21 females and 19 males; aged 19-67 years)., Design: A prospective randomized double-blind placebo-controlled trial lasting for 6 months., Protocol: Following baseline assessments, GH was given in a daily dose of 0.02-0.05 IU/kg body weight subcutaneously (or a placebo (P)) at bedtime. Patients were reviewed at 1, 3 and 6 months., Measurements: Plasma calcium, phosphate and total plasma alkaline phosphatase were measured at 0, 1, 3 and 6 months. Serum insulin like growth factor I (IGF-I), osteocalcin, procollagen 1 carboxyterminal peptide (P1CP) and intact parathyroid hormone (PTH) level, 24-hour urinary calcium and creatinine excretion were all measured at 0 and 6 months. Bone mineral density of total body and lumbar spine was also measured by dual energy X-ray absorptiometry at 0 and 6 months in 12 patients on GH and 14 on placebo., Results: Thirty-eight patients completed the study (18 on GH, 20 on placebo). Serum IGF-I increased significantly on GH treatment (mean +/- SD) (GH: 276 +/- 197 vs P: 88 +/- 50 micrograms/l, P < 0.0001 at 6 months). Plasma calcium increased slightly but significantly in the GH-treated group (2.23 +/- 0.11-2.29 +/- 0.11 mmol/l, P < 0.05). At the end of the study, plasma calcium was however similar on GH and placebo (GH, 2.29 +/- 0.11; P, 2.26 +/- 0.09 mmol/l). Plasma phosphate increased on GH (GH: 1.02 +/- 0.23-1.32 +/- 0.19; P: 0.99 +/- 0.16-0.96 +/- 0.12 mmol/l over the 6 months of treatment, P < 0.001). There was no significant change in the urinary calcium excretion on GH therapy. Plasma total alkaline phosphatase, osteocalcin and P1CP were significantly higher on GH than P at 6 months (alkaline phosphatase: GH: 104 +/- 32 vs P: 69 +/- 32 U/l, P < 0.01, osteocalcin: GH: 17.2 +/- 8.0 vs P: 5.3 +/- 3.2 micrograms/l, P < 0.001 and P1CP: GH: 207 +/- 152 vs P: 93 +/- 31 micrograms/l, P < 0.01). There was no difference in the intact parathyroid hormone level (GH: 31 +/- 14 vs P: 31 +/- 15 ng/l, NS). No significant change was observed in bone mass after 6 months of GH treatment, either in total body bone mineral content or in the lumbar spine., Conclusion: In this large study, GH replacement in hypopituitary adults for 6 months increased bone turnover but did not affect bone mineral content. Longer-term studies are required to assess further any effect on bone mass.

Objective: Non-insulin-dependent diabetes is a heterogeneous disorder, the basis of which may differ in different ethnic groups. In order to investigate early metabolic abnormalities occurring during the development of the condition we assessed insulin secretion and insulin action in subjects predisposed to the later development of non-insulin-dependent diabetes from two different ethnic groups., Design: Subjects were studied on two separate occasions by an oral glucose tolerance test and a short insulin tolerance test., Patients: Twenty-four glucose-tolerant first-degree relatives of patients with non-insulin-dependent diabetes (12 of European and 12 of Asian origin) were compared with 24 ethnically matched control subjects with no family history of diabetes., Measurements: Insulin, proinsulin, glucose and intermediary metabolites were measured during a 75-g oral glucose tolerance test. Insulin sensitivity was assessed using a 15-minute insulin tolerance test (0.05 units/kg)., Results: Asian relatives compared to Asian controls had significantly higher fasting levels of immunoreactive insulin (83 +/- 17 vs 40 +/- 6 pmol/l, P < 0.05), which were not due to increased proinsulin. Blood glycerol concentrations were elevated (83 +/- 9 vs 51 +/- 4 mumol/l, P < 0.005), but fasting glucose and non-esterified fatty acid (NEFA) concentrations were similar. Relatives of European origin did not differ from their European controls in any of these measurements. The glucose response to oral glucose was similar in relatives and controls, irrespective of ethnic group. The insulin responses were non-significantly greater in relatives from both ethnic groups. Proinsulin levels were not significantly different. Asian relatives had higher circulating glycerol and NEFA levels after oral glucose than Asian controls, but these differences were not observed in the European group. Insulin sensitivity was reduced in the Asian relatives compared to their controls (183 +/- 7 vs 139 +/- 12 mumol/l/min, P < 0.01) but there was no difference in insulin sensitivity between the European relatives and European controls (167 +/- 11 vs 160 +/- 11 mumol/l/min)., Conclusions: First-degree relatives of non-insulin-dependent diabetic patients of Asian, but not of European, origin are insulin insensitive in terms of both glucose metabolism and lipolysis, and have true hyperinsulinaemia. This suggests that insulin insensitivity may be an early abnormality in the development of non-insulin-dependent diabetes in the Asian population.

Objective: Insulin insensitivity is a recognized feature of polycystic ovary syndrome (PCOS) but previous studies have suggested that circulating insulin concentrations are normal in hyperandrogenaemic women with regular cycles. The aim of this study was to examine the relationship between insulin sensitivity and menstrual pattern in women with PCO., Design: A cross-sectional study of insulin sensitivity in a cohort of PCO subjects with oligomenorrhoea compared to women with PCO and regular menstrual cycles and a group of normal control subjects., Subjects: Seventy-two women with polycystic ovaries on ultrasonography were studied. PCO subjects had clinical and/or biochemical evidence of hyperandrogenism; 53 had oligo/amenorrhoea (olig) and 19 had regular menses (reg). Results were compared with 31 control subjects. The groups were matched for age, weight and ethnic origin., Methods: Glucose and insulin responses to 75 g oral glucose were measured. Insulin sensitivity was assessed by the decline in plasma glucose following intravenous insulin (0.05 U/kg)., Results: Glucose area (mean +/- SEM) after oral glucose was increased slightly in both PCO groups compared with controls (olig 37.6 +/- 1.4, reg 36.0 +/- 1.8, control 33.7 +/- 0.9 mmol/l h, both P < 0.01). Insulin area median (interquartile range) in response to glucose was significantly greater in the oligomenorrhoeic group (346 (239-734) mU/l h), compared with both PCO with regular cycles (246 (148-355), P < 0.01) and controls (221 (147-277), P < 0.01). Insulin sensitivity was reduced (P < 0.01) in the oligomenorrhoeic group (147 +/- 9.2 mumol/l min) compared to controls (185 +/- 7.4) but was normal in PCO with regular cycles (182 +/- 12.5). Insulin sensitivity did not correlate significantly with plasma testosterone or with SHBG levels, but plasma insulin concentrations correlated negatively with SHBG levels (fasting insulin vs SHBG, r = -0.47, P < 0.01; insulin area vs SHBG, r = -0.41, P < 0.01)., Conclusions: Insulin insensitivity in polycystic ovary syndrome occurs when there is oligo/amenorrhoea but not when the menstrual cycle is regular. This is consistent with PCO and insulin insensitivity being separate abnormalities which when combined are associated with anovulation.

Objective: In order to investigate the possible causes and effects of obesity in polycystic ovary syndrome resting energy expenditure, postprandial thermogenesis and insulin resistance were measured in 14 polycystic ovary syndrome subjects and in 14 controls., Design: A cross-sectional study of a selected group of patients was performed., Patients: Seven of the PCOS subjects were obese and seven lean. Controls were individually matched for age, race, weight, body mass index (BMI) lean body mass and percentage fat. The obese, but not lean, polycystic ovary syndrome subjects had a greater waist:hip ratio than controls (median (range) obese PCOS 0.865 (0.823-0.960) vs obese control 0.804 (0.823-0.940), P less than 0.025)., Measurements: Metabolic rate was measured by continuous indirect calorimetry and insulin sensitivity was assessed by a short insulin tolerance test., Results: The resting energy expenditure (REE) was similar in PCOS subjects and controls (median (range), 6796 (5489-7774) vs 6833 (4893-8492) kJ/day). REE correlated with LBM in the PCOS group (r = 0.83, P less than 0.00) and the control group (r = 0.82, P less than 0.001). Postprandial thermogenesis was reduced in polycystic ovary syndrome (obese: median 45.4 (range 33.6-100.0) vs 86.5 (67.2-109.2) kJ (P less than 0.05); lean: 79.4 (73.5-108.4) vs 89.9 (76.0-109.2) kJ (P less than 0.05). Fasting insulin (9.7 +/- 3.6 vs 4.4 +/- 0.8 mU/l, P less than 0.05) and postprandial incremental insulin rise (163 +/- 31 vs 116 +/- 15 mU/l, P less than 0.025) were higher in polycystic ovary syndrome. Insulin sensitivity was reduced in polycystic ovary syndrome (obese: median 136 (range 92-169) vs 173 (109-225) mumol/l/min (P less than 0.05); lean: 161 (138-225) vs 194 (161-253) mumol/l/min (P less than 0.05)). The reduction in insulin sensitivity correlated with the reduced postprandial thermogenesis in the polycystic ovary syndrome group (r = 0.75, P less than 0.01)., Conclusion: These results confirm previous reports of hyperinsulinaemia and insulin resistance in polycystic ovary syndrome. Furthermore, polycystic ovary syndrome subjects have a reduced postprandial thermogenesis which is related statistically to the reduced insulin sensitivity. The decreased postprandial thermogenesis may predispose women with polycystic ovary syndrome to weight gain.

Objective: The aim of this study was to compare intermediary metabolism in glucose tolerant women with previous gestational diabetes and control women without a history of gestational diabetes., Subjects: Fifteen women with previous gestational diabetes and 15 controls individually matched for race, age and body mass index were included. Only subjects with normal glucose tolerance were included in this study., Methods: Plasma glycerol, 3-OH butyrate, non-esterified fatty acids (NEFA), glucose and insulin were measured fasting and following a 75 g oral glucose load., Results: The women with previous gestational diabetes and their matched controls were of similar racial origin, age and body mass index. There was no difference between those with previous gestational diabetes and controls in fasting glycerol, 3-OH butyrate, NEFA, glucose or insulin concentrations. Following the oral glucose load, glycerol, 3-OH butyrate and NEFA concentrations fell in both groups. However, compared with controls at 120 minutes, those with previous gestational diabetes had significantly higher concentrations of glycerol (median 57, range 24-216 vs 27, range 8-89 mumols/l, P less than 0.005) and 3-OH butyrate (9, range 1-18 vs 5, range 2-11 mumols/l, P less than 0.01). NEFA concentrations were similar in the two groups. Despite similar glucose concentrations during the oral glucose tolerance test the insulin response during the first 60 minutes following oral glucose was significantly reduced in the subjects with previous gestational diabetes when compared with controls (insulin area, 0-60 minutes; 2172, range 788-4767 vs 2830, range 996-4784 pmol min/l, P less than 0.05)., Conclusions: Women with a previous history of gestational diabetes, despite having normal glucose tolerance, have defective insulin release with resultant abnormalities of intermediary metabolism.

Dopamine plays an important role in the hypothalamic-pituitary axis where its major effects are to inhibit pituitary hormone secretion and cell division. Chronic dopamine deficiency has been postulated as a cause of pituitary tumour formation and several lines of evidence exist to suggest that a functional deficiency may develop as a result of defective dopamine receptor action. The available data suggest that a number of sites in the dopamine-D2 receptor-second messenger pathways may be implicated. These abnormalities are reflected in the variety of responses to dopamine and its agonists which have been observed in pituitary tumours both in the clinical situation and in cultured cells in vitro. Whilst it seems likely that the primary defect in pituitary tumour formation lies within the pituitary itself, the role of hypothalamic factors in facilitating tumour growth remains to be explored. Further studies of the dopamine receptor and its function will be of value not only in pathophysiological studies of human pituitary adenomas, but also in the development of new pharmacological agents to treat patients with these tumours.

Objectives: To investigate whether growth hormone (GH) absorption is site dependent., Design and Measurements: Human growth hormone (hGH, Norditropin) 4 IU, was injected subcutaneously on two separate occasions: into the thigh on one occasion and into the abdomen on a second occasion. Blood was sampled for GH, insulin, glucose, non-esterified fatty acids and glycerol at baseline and hourly for 12 hours. Serum insulin-like growth factor I was measured at baseline, and after 12 and 24 hours., Subjects: Eleven healthy young adults (8 M, 3 F)., Results: Following the injection serum GH had risen by 1 hour and peaked by 3-6 hours. The peak GH and growth hormone area under the curve were significantly higher after injection in the abdomen compared with the thigh (GH peak (mean +/- SEM) 103 +/- 20 vs 41 +/- 8 mU/l, P = 0.002 and GH area 528 +/- 86 vs 239 +/- 34 mU/l h, P = 0.003 respectively). Serum insulin-like growth factor I at 12 and at 24 hours showed a significant rise from the baseline level, but no significant difference was observed between the two injection sites. No significant difference in plasma insulin, glucose, non-esterified fatty acids or glycerol was observed between the two methods of injection., Conclusion: Subcutaneously injected GH is better absorbed from the abdominal site than from the thigh.

Objective: Polycystic ovary syndrome (PCOS) is said to be associated with hyperinsulinaemia. Insulin stimulates androgen production by ovarian tissue in vitro and previous studies have identified a positive correlation of insulin with androstenedione. The aim of the present study was to discover whether insulin levels correlate with clinical presentation and with markers of androgen transport and metabolism in women with PCOS., Design: Within-group analysis of clinical and biochemical characteristics of a consecutive series of women with PCOS, focusing on correlations of plasma insulin with clinical presentation and androgens. Insulin levels were also compared with a control group of normal women., Patients: Forty-seven women who presented with hirsutism, cycle abnormalities or both, with ultrasound proven PCOS, were recruited. Mean age was 26.6 +/- 0.7 years (mean +/- SEM), BMI 27.3 +/- 1.2 kg/m2., Measurements: Plasma insulin levels were measured at 30-minute intervals for 3 hours following a 75 g glucose load. Blood was also taken for measurement of testosterone (T), androstenedione (A), free testosterone (fT), sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I). Androsterone glucoronide (AG), a marker of peripheral androgen metabolism, was also measured., Results: Neither basal insulin nor the sum of insulin measurements during the glucose tolerance test (sumINS) in women with PCOS were significantly different from a control group with normal ovaries. Within the PCOS group, basal insulin was greater in women with irregular cycles or amenorrhoea than in those with regular ovulatory menses (8.0 +/- 1.1 vs 3.1 +/- 1.5 mU/l, P less than 0.01) despite similarly raised androgen levels. Both basal insulin and sumINS correlated with BMI in women with PCO (r = 0.37, P less than 0.05 and r = 0.64, P less than 0.01 respectively) but not in controls. There was no significant correlation between insulin or IGF-I levels and T, A or AG despite a positive correlation of AG (but no other androgen) with BMI. SHBG showed an inverse correlation and fT correlated positively with sumINS (r = -0.51, P less than 0.01; r = 0.39, P less than 0.05). Regression analysis of each of the androgens on the other variables demonstrated no significant relationship between insulin and androgens., Conclusions: These data suggest that, in vivo, the major effect of insulin on androgen secretion is mediated by changes in SHBG rather than by direct stimulation of ovarian androgen production. Higher insulin concentrations in anovulatory compared with ovulatory women with hyperandrogenaemia may indicate that insulin resistance in the ovary contributes to the mechanism of anovulation in PCOS.

Fasting plasma proinsulin, insulin and glucose concentrations were measured in ten women with mild gestational diabetes and ten controls matched for race, age (32 +/- 6 vs 31 +/- 6 years), body mass index (28 +/- 8 vs 27 +/- 6) and gestational week (24 +/- 4 vs 25 +/- 4 weeks). There was no significant difference in fasting plasma glucose between these gestational diabetics and their controls (median 4.7, range 3.7-6.0 mmol/l vs 4.5, range 3.4-5.3 mmol/l). The fasting proinsulin levels were significantly higher in the gestational diabetics compared with the controls (median 12.2, range less than 4-14.8 pmol/l vs 5.8, range less than 4-12.8 pmol/l, P less than or equal to 0.02, Wilcoxon Summed Rank Test), while the calculated intact insulin levels (immunoreactive insulin minus proinsulin) were significantly lower (median 14.5, range 6.3-81.8 pmol/l vs 51.6, range 11.7-312 pmol/l, P less than or equal to 0.01). The ratio of proinsulin to calculated intact insulin was significantly higher in the gestational diabetics than the controls (median 0.66, range 0.16-2.04 vs 0.12, range 0.03-0.62), P less than or equal to 0.01). These results demonstrate that gestational diabetics, with normal fasting plasma glucose values, have abnormalities in pancreatic beta-cell secretion, which are likely to be important both in the aetiology of gestational diabetes and non-insulin dependent diabetes.

Twelve-hour hormonal and metabolic profiles were performed in a 68-year-old woman with a benign adrenal phaeochromocytoma (a) prior to adrenergic blockade, (b) after the establishment of pharmacological alpha-blockade with phenoxybenzamine, (c) after combined alpha and beta-blockade with phenoxybenzamine and propranolol, and (d) after successful surgery and withdrawal of medication. Pretreatment, (a) vs (d), significant elevations (12-h mean +/- SD) were observed in the concentrations of noradrenaline (44.9 +/- 14.4 vs 2.3 +/- 0.7 nmol/l, P less than 0.01), glucose (6.9 +/- 1.9 vs 5.0 +/- 1.0 mmol/l, P less than 0.05), glycerol (0.22 +/- 0.02 vs 0.07 +/- 0.01 mmol/l, P less than 0.01), non-esterified fatty acids (0.71 +/- 0.28 vs 0.34 +/- 0.08 mmol/l, P less than 0.01), and total ketone bodies (0.08 +/- 0.03 vs 0.03 +/- 0.02 mmol/l, P less than 0.01). Alpha-blockade, (b) vs (a), was associated with an increase in noradrenaline levels (P less than 0.01) but not with any significant alterations in intermediary metabolite concentrations. Following the establishment of combined alpha and beta-blockade, (c) vs (b), plasma noradrenaline returned to its pretreatment level while the concentrations of glycerol, fatty acids and ketone bodies were normalized. A completely physiological 12-h blood glucose profile, however, was observed only post-operatively. No significant differences were observed in mean plasma insulin levels between the four studies. These results indicate impaired regulation of multiple aspects of carbohydrate, lipid and ketone body metabolism in our patient.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously reported that glucose production assessed using radioisotopic methods is 50% increased in hyperthyroidism but 30% decreased in hypothyroidism. These studies, however, do not distinguish between glycogenolysis and gluconeogenesis. In fasting man more than 80% of circulating glycerol is cleared by the liver and enters the gluconeogenic pathway. We have therefore measured glycerol clearance following bolus intravenous glycerol administration as an indirect assessment of gluconeogenic capacity. Hyperthyroid and hypothyroid subjects were compared with separate matched controls after an overnight fast. In hyperthyroid subjects blood glucose and blood glycerol were increased but lactate, pyruvate, and alanine concentrations were normal. Glycerol clearance was increased in hyperthyroidism and followed a double exponential decay with a shortened second component half-time. Endogenous glycerol production was increased three-fold. In hypothyroidism fasting circulating levels of glucose, lactate, pyruvate, alanine, and glycerol were normal but glycerol clearance was diminished. Both first and second component half-times were prolonged in hypothyroidism and endogenous glycerol production was decreased by 50%. Thus in hyperthyroidism glycerol clearance is greatly enhanced whilst in hypothyroidism glycerol clearance is diminished. The magnitude of the changes suggests that alterations in gluconeogenesis are probably the major factors concerned in the reported increase and decrease in glucose production in hyperthyroidism and hypothyroidism respectively.

The effects of dopamine blockade on the endocrine and metabolic response to starvation have been investigated by administration of metoclopramide, 30 mg daily, or placebo to five normal subjects fasted for sixty hours on two occasions. Blood glucose and alanine concentrations fell with starvation and metoclopramide had no further effect. Concentrations of the other gluconeogenic precursors, lactate and pyruvate, were also unaffected by metoclopramide. The rise in circulating ketone body concentrations with fasting was impaired by metoclopramide, significantly from 44 h onwards (blood total ketone body concentration at 60 h, 3.42 +/- 0.94 mmol/l with placebo; 2.08 +/- 0.67 mmol/l with metoclopramide, P less than 0.05). Blood glycerol and plasma non-esterified fatty acids (NEFA) levels rose with starvation, and metoclopramide had no further effect. Serum insulin concentrations remained low with fasting, while circulating glucagon and growth hormone levels rose. Similar changes were noted with both metoclopramide and placebo. Serum prolactin concentrations during starvation were elevated two to four fold by metoclopramide. The inhibitory effect of dopamine blockade on ketosis thus occurred despite hyperprolactinaemia, and did not result from measurable alterations in insulin, glucagon or growth hormone secretion. The data suggest a stimulatory role for endogenous dopamine on starvation ketonaemia in man.

The role of dopamine in starvation ketonaemia was investigated in male Wistar rats by administration of a specific dopamine receptor antagonist, metoclopramide (4 mg . kg-1 . 24h-1), or placebo, intragastrically during a 48-h fast. Starvation alone caused a fall in blood glucose and gluconeogenic precursor concentrations, which was unaffected by metoclopramide administration. Circulating 3-hydroxybutyrate and acetoacetate levels rose with fasting alone but metoclopramide impaired this ketonaemic response. After 48-h starvation, total ketone body concentrations (mean +/- SEM) were 2.28 +/- 0.19 mmol/l with metoclopramide therapy, 3.49 +/- 0.21 mmol/l with placebo, P less than 0.001. Plasma non-esterified fatty acid levels were similar in metoclopramide- and placebo-treated animals, as were circulating concentrations of insulin, glucagon and growth hormone. Metoclopramide thus decreased the ketonaemic response to starvation without an apparent change in lipolysis or circulating hormone levels, suggesting a direct role for dopamine in production of starvation ketonaemia.

The interaction between the stimulatory effects of hpGRF 1-44 and the inhibitory effects of somatostatin on GH release have been investigated in six normal male subjects receiving continuous 4 h infusions of these peptides alone and in combination. hpGRF 1-44 0.3 microgram/kg/h alone produced a peak GH response of 27.0 +/- 7.6 mU/l (mean +/- SEM). Somatostatin 1.0 microgram/kg/h markedly inhibited the GH response to hpGRF 1-44 with mean levels less than 4.0 mU/l during the infusion, though a rebound rise in GH levels to 26.1 +/- 9.0 mU/l was observed at the end of the infusion period. Somatostatin 0.2 microgram/kg/h inhibited the GH response to hpGRF 1-44 to a lesser degree (peak GH during the infusion 11.7 +/- 2.5 mU/l) and the rebound rise in GH levels (maximum 13.2 +/- 4.3 mU/l) was less than that observed with high dose somatostatin. During somatostatin 1.0 microgram/kg/h alone GH levels were suppressed less than 1.0 mU/l followed by a rebound at the end of the infusion in only two subjects. These data demonstrate a dose-dependent inhibition of hpGRF 1-44 by somatostatin in vivo in man.

Long-acting somatostatin analogues may be of benefit in certain hypersecretory endocrine and gastrointestinal disorders. The 24 h hormonal and metabolic profiles of six normal male subjects receiving a twice daily subcutaneous injection of one such analogue SMS 201-995, 50 micrograms, has been compared to that obtained following placebo injection. Spontaneous daytime peaks of GH secretion were delayed until 1400 h following SMS 201-995 but nocturnal and total 24 h GH secretion were unaffected. The nocturnal rise in thyrotrophin was abolished by SMS 201-995 but thyroid function was unaffected. Insulin levels were suppressed following SMS 201-995 and the response to meals was inhibited. Glucose intolerance followed main meals. Glucagon levels were suppressed for up to 6 h. Circulating alanine levels were raised between 1200 h and 0600 h and there were intermittent elevations in lactate, pyruvate, glycerol and 3-hydroxybutyrate. Amino acid levels, including branched chain amino acids, were also increased. All six subjects suffered gastrointestinal side-effects. SMS 201-995, 50 micrograms, given twice daily shortly before meals does not suppress 24 h GH secretion, but demonstrates significant effects on metabolism and causes side effects in normal subjects.

The serum TSH and prolactin responses to dopamine receptor blockade (domperidone 10 mg i.v.) were measured in eight acromegalic subjects and seven normal controls. The serum TSH response was exaggerated in acromegalics when compared to controls (sum of the increments 12.2 +/- 2.8 mU/l and 4.0 +/- 1.2 mU/l respectively P less than 0.05), whereas the serum prolactin response was blunted (sum of the increments 5029 +/- 1377 mU/l and 14 673 +/- 2889 mU/l respectively P less than 0.01). Dopamine receptor blockade did not significantly alter basal growth hormone levels in either group. To ascertain whether this response was merely a reflection of high circulating growth hormone levels six normal controls were pretreated for 24 h with either intramuscular growth hormone (three injections of 4 IU) or an equivalent volume of saline before the administration of domperidone (10 mg i.v.). The serum TSH and prolactin responses were not affected by prior growth hormone treatment. The opposite TSH and prolactin responses to dopamine blockade do not allow any firm conclusions to be made about the level of hypothalamic dopamine activity in acromegaly.

The long-term sequelae of external pituitary irradiation alone or in combination with surgery and/or bromocriptine therapy have been studied in 14 patients with large prolactinomas over an observation period of 6-22 years (mean 13 years). Galactorrhoea was abolished in four of the five females with this symptom, but menstrual disturbance persisted in five of six patients. Sexual function was normal without sex hormone replacement in only one of the eight males after treatment. Neurological deficits were abolished or improved by treatment in all 9 patients with this presentation. Serum prolactin levels declined after treatment (P less than 0.001) and fell to within the normal range off bromocriptine therapy in six of the 14 patients at a mean of 9 years (range 5-17 years) after radiotherapy. All patients had anterior pituitary deficiency of some degree at reassessment, and 13 required replacement treatment. Serial skull radiographs revealed remineralization of the fossa floor in five patients and a decrease in fossa size in three. All five patients who did not also have surgery had evidence of tumour shrinkage without bromocriptine treatment (on CT scan or metrizamide cisternography). Fourth generation CT scans on completion of the study revealed a decrease in tumour mass in all patients, with varying degrees of empty sella in 13 and a cystic intrasellar tumour in the remaining one. Residual tumour was demonstrated in 10 patients, three of whom had normal serum prolactin levels, while one patient without visible tumour had persistent hyperprolactinaemia. Radiotherapy, alone or in combination with surgery and bromocriptine, effectively decreases prolactin secretion and tumour size in patients with large prolactinomas at the expense of other anterior pituitary function. Circulating prolactin levels are a poor marker of residual tumour volume.

The GH response to a prolonged continuous infusion of human pancreatic growth hormone releasing factor (hpGRF 1-44), 0.3 microgram/kg/h was evaluated in seven patients with severe idiopathic GH deficiency, one patient with partial deficiency and in seven normal controls. Normal controls had a multiphasic response with a first peak between 15 and 90 min of 13.6 to 88.5, mean 45.6 mU/l and a second peak between 105 and 195 min of 8.8 to 73.1, mean 33.8 mU/l. However, the magnitude and pattern of response were highly variable. Six of the seven patients with severe GH deficiency had a response with a maximum level between 30 and 90 min of 3.3 to 7.5, mean 4.8 mU/l. Mean levels remained greater than 2.0 mU/l throughout the infusion but further peaks were absent or minimal. The patient with partial GH deficiency responded in a normal manner. hpGRF 1-44 by continuous infusion thus induced GH release in seven of eight patients with idiopathic GH deficiency though the response was impaired and the pattern of secretion abnormal in severely deficient patients.

The 24-h hormonal and metabolic profiles obtained in five non-insulin-dependent diabetics receiving twice daily s.c. injections of the long-acting somatostatin analogue SMS 201-995 (50 micrograms) have been compared with those obtained following placebo injection. Injections were given 30 min before breakfast and the evening meal. GH secretion was not suppressed by the analogue administered in this manner. Despite suppression of serum insulin levels following breakfast and the evening meal, blood glucose levels were similar during the two study periods with no evidence of worsening in diabetic control. Prolonged suppression of plasma glucagon levels was observed and the nocturnal elevation in serum TSH levels was abolished. Free T4 levels fell significantly following the analogue but total T3 levels were unaffected. Blood alanine levels were elevated throughout the study period following SMS 201-995 but changes in lactate, pyruvate, glycerol and 3-hydroxybutyrate were minor. All five subjects suffered gastrointestinal side-effects. SMS 201-995 (50 micrograms) given twice daily before meals does not cause a deterioration in metabolic control, does not suppress 24-h GH secretion and causes significant side-effects in patients with non-insulin-dependent diabetes mellitus.

To investigate the influence of thyroid hormones on intermediary metabolism in man, hormone and metabolite profiles were obtained over a 12-h period of normal meals and activity in eight hypothyroid subjects before and during thyroxine replacement therapy, and in sixteen matched controls. The fasting blood glucose concentration and the mean 12-h blood glucose concentration were normal in hypothyroid subjects but the blood glucose response to breakfast was exaggerated. Fasting blood lactate and pyruvate levels were normal but post-prandial hyperlactataemia and hyperpyruvicaemia were found and mean 12 h values for lactate (hypothyroid 1.80 +/- 0.06 v. control 0.77 +/- 0.03 mmol/l, P less than 0.01) and pyruvate (0.10 +/- 0.01 v. 0.08 +/- 0.003 mmol/l, P less than 0.01) were elevated. Blood alanine concentrations were elevated only in the evening. Although plasma non-esterified fatty acid levels were normal, fasting blood glycerol levels were decreased (0.06 +/- 0.01 v 0.08 +/- 0.01 mmol/l, P less than 0.001) and this decrease persisted throughout the 12-h period. Blood total ketone body concentrations did not differ from controls, but, as for plasma NEFA and blood glycerol, the normal preprandial rise in concentration was absent. Serum insulin, glucagon and growth hormone concentrations did not differ from control values at any time. Six months of thyroxine (T4) treatment produced a rise in blood glycerol concentration (mean 12 h value during T4 therapy, 0.06 +/- 0.01; before T4 therapy, 0.04 +/- 0.005 mmol/l; P less than 0.01) but not to control values (0.08 +/- 0.01 mmol/l). Concentrations of glucose and other gluconeogenic precursors were unaltered by therapy but the insulin response to meals and the mean 12 h serum insulin concentration were increased.

The metabolic sequelae of hyperprolactinaemia were studied over a 12 h period of normal meals and activity in nine young females hyperprolactinaemic subjects and fourteen matched controls. In the patients, fasting blood glucose and serum insulin concentrations were normal, as was the blood glucose response to meals; the insulin rise with meals was, however, exaggerated and hyperinsulinaemia persisted throughout the day (mean +/- SEM 12 h serum insulin, 26 +/- 8 vs. 16 +/- 9 mu/l, P < 0.01). Blood lactate, pyruvate and alanine response to meals was also increased. Blood glycerol (mean 12 h blood glycerol 0.06 +/- 0.01 vs. 0.09 +/- 0.01 mmol/l, P < 0.01) and blood 3-hydroxybutyrate (mean 12 h blood 3-hydroxybutyrate 0.03 +/- 0.01 vs. 0.05 +/- 0.01 mmol/l, P < 0.05) concentrations were lower in hyperprolactinaemic subjects. There was a strong negative correlation between mean insulin and mean 3-hydroxybutyrate levels in the afternoon period (rs = -0.92, P < 0.01). Excess circulating prolactin in young female is associated with normoglycaemic hyperinsulinaemia. The changes in blood metabolite levels observed are probably secondary to the increased insulin concentrations.

The interaction between the inhibitory effect on growth hormone secretion of a 75 g oral glucose load and the stimulatory effect of human pancreatic growth hormone releasing factor 1-44 (hpGRF 1-44, 10 micrograms i.v.) has been studied in six normal subjects. hpGRF 1-44 alone induced a rise in growth hormone concentrations (maximum mean +/- SEM, 16.5 +/- 1.7 mU/l 15 min after injection) while growth hormone levels were suppressed by oral glucose alone (less than 1.5 mU/l from 45 to 135 min after glucose ingestion). When hpGRF 1-44 was injected 60 min after oral glucose, the growth hormone response was attenuated (maximum, 6.7 +/- 1.4 mU/l at 15 min, P less than 0.05). Increments of blood glucose within the physiological range diminish the growth hormone response to hpGRF 1-44 in normal man.

Prolactin secretion and biological activity have been investigated in 20 females with persistent idiopathic galactorrhoea who had normal resting serum prolactin levels at presentation. Results were compared with those in 34 normal controls. Hyperprolactinaemia, which was persistent in one and intermittent in the other, developed in two patients over an observation period of 1.5 to 8.5 years. Resting prolactin levels stayed normal in the remaining eighteen who were further investigated. Menstruation was disordered in only six of the 18, while ovulation occurred (serum progesterone greater than 20 nmol/l) in all seven patients who were studied over a 5 week period. Serum prolactin concentrations over 24 h were similar in patients and controls (24 h mean +/- SEM prolactin, 288 +/- 36 mU/l, patients, n = 7; 291 +/- 21 mU/l, controls, n = 9) as were prolactin levels estimated twice weekly for 5 weeks. Prolactin responses to thyrotrophin-releasing hormone, 200 micrograms (at 20 min, 2417 +/- 658 mU/l, patients, n = 7; 2113 +/- 424 mU/l, controls, n = 8), the dopamine antagonist, domperidone, 10 mg (at 30 min, 5949 +/- 536 mU/l, patients, n = 7; 5858 +/- 460 mU/l, controls, n = 8) and insulin-induced hypoglycaemia (at 60 min, 1441 +/- 551 mU/l, patients, n = 7; 1298 +/- 183 mU/l, controls, n = 7) were similar in patients and controls. Two different radioimmunoassays using two different antisera gave similar estimates of serum prolactin levels and prolactin bioactivity in serum was normal in an in-vitro bioassay based on the ability of prolactin to stimulate proliferation of Nb2 node rat lymphoma cells (basal bioassayable prolactin, patients 355 +/- 43 mU/l, n = 10; controls 348 +/- 64 mU/l, n = 7). Metabolic abnormalities similar to those previously noted in hyperprolactinaemia were observed in the patients' 24 h profiles. These included mild hyperglycaemia (24 h mean +/- SEM glucose, 5.47 +/- 0.08 mmol/l, patients; 5.05 +/- 0.14 mmol/l, controls; P less than 0.05) and elevations in circulating lactate, pyruvate and alanine. Blood glycerol was decreased (24 h mean +/- SEM, 0.044 +/- 0.004 versus 0.058 +/- 0.004 mmol/l, P less than 0.05). In the majority of patients with idiopathic galactorrhoea, prolactin concentrations, regulation of secretion and bioactivity in vitro are normal. The galactorrhoea and metabolic abnormalities suggest increased tissue sensitivity to the lactogenic and metabolic actions of prolactin, while ovarian cyclical function is relatively spared.

The growth hormone (GH) response of seven obese subjects to a 4 h continuous infusion of human pancreatic GH-releasing factor, 0.3 micrograms/kg/h, has been compared with that obtained in seven sex and age matched controls. The pattern of response was normal in the obese but peak GH levels (mean +/- SEM: 13.8 +/- 1.9 compared to 30.9 +/- 4.7 mU/l, P less than 0.01) and integrated GH levels (mean +/- SEM: 27.1 +/- 3.6 compared to 62.0 +/- 9.7 mU/l/h, P less than 0.01) were reduced in obese subjects. There was a negative correlation between the integrated GH response and the percentage ideal body weight (r = -0.80, P less than 0.05), but no significant correlation with somatomedin-C levels (r = +0.72; P = 0.07). Obese subjects have an impaired GH response to infusion of GH-releasing factor which is not related to negative feedback by somatomedins.

Sensitivity to porcine insulin has been compared in overnight fasted hyperthyroid and control subjects using a euglycaemic clamp technique. Basal values for blood glucose, lactate, pyruvate, alanine, serum insulin and C-peptide were similar in the two groups, whilst blood glycerol (hyperthyroid 0.11 +/- 0.02 (mean +/- S.E.) vs. control 0.06 +/- 0.01 mmol/l, P less than 0.01) and blood 3-hydroxybutyrate (0.28 [0.03-0.79, range ]vs 0.09 [0.01-0.29 ]mmol/l, P less than 0.05) were increased in hyperthyroidism. During the 2 hour insulin infusion (0.05 U/kg/h), serum insulin plateaued at the same level (44 +/- 4 vs 44 +/- 1 mU/l) and insulin metabolic clearance rates were similar (1.21 +/- 0.10 vs 1.25 +/- 0.03 l/min). Serum C-peptide levels also decreased by similar amounts (40 +/- 8 vs 47 +/- 6%). The amount of glucose infused to maintain euglycaemia was identical during the second hour of insulin infusion (290 +/- 50 vs 330 +/- 30 mg/kg) as were the increments in lactate and pyruvate concentrations. Blood glycerol values decreased in both groups although values in hyperthyroid patients remained significantly higher than in controls. 3-Hydroxybutyrate concentrations fell to similar values in the two groups. These findings suggest that insulin-stimulated glucose metabolism and inhibition of ketogenesis are normal in hyperthyroidism.