Bradykinin-forming components in Kuwaiti patients with type 2 diabetes.

Diabetes is the most common risk factor in inducing hypertension, nephropathy and retinopathy. The bradykinin (BK)-forming system has been proposed to protect cardiovascular and renal functions. We therefore evaluated urinary active and proactive kallikrein, total kininogen, plasma tissue kallikrein, plasma creatinine, plasma glucose and plasma HbA1c in newly diagnosed untreated type 2 diabetic patients and healthy subjects. In diabetic patients, urinary and plasma tissue kallikrein concentrations were significantly increased. In addition, plasma prekallikrein levels were also significantly higher. However, urinary kininogen values were significantly reduced in diabetic patients when compared with healthy subjects. This is the first investigation among Kuwaiti Arab patients with type 2 diabetes showing abnormal activities in the BK-forming system. High levels of plasma prekallikrein may be a risk factor for developing high blood pressure as well as nephropathy. The urinary and plasma tissue kallikrein concentrations were higher in diabetic patients, which could indicate the hyperactivities of these components, and may result in increased levels of plasma glucose to induce diabetes. Furthermore, the urinary kininogen levels were reduced in diabetic patients. These alterations might reflect the utilization of urinary kininogen to form BK, a potent inflammatory agent. However, this hypothesis needs further investigation.

Normal measurement of orbital structures: implications for the assessment of Graves' ophthalmopathy.

Compute tomography anatomy of the orbits is well described, but only a few reports are available on normal measurements of the extraocular muscles (EOM) and globe position (GP). We obtained CT images from patients who were referred to our department for CT of the paranasal sinuses using a standard protocol for evaluation of normal orbital measurements. Our study suggests that optimum results are attained with the use of a coronal scan at a window level and width setting that results in an optimum image at the maximum muscle width for assessment of EOM and an axial scan at the mid-GP for GP and interzygomatic line. Based on our normal values, a right-to-left ratio of more than 1.4 for EOM diameter or 1.2 for GP is indicative of asymmetry. An absolute diameter of EOM > 8 mm and GP < 2 mm are abnormal.

Optimal use and interpretation of the aldosterone renin ratio to detect aldosterone excess in hypertension.

With the introduction of the aldosterone/renin ratio as a screening test, the detection rate of primary aldosteronism has increased considerably. Nevertheless, no consensus has so far been reached regarding the cutoff points, operating characteristics or indeed even the reference values for reporting the aldosterone/renin ratio using plasma active renin (ng/l or mU/l) measured by immunoradiometric assay. We review the characteristics of this ratio in normal individuals, essential hypertension and primary hyperaldosteronism in an attempt to reach an agreement regarding its optimum use and interpretation - both using the renin activity or concentration. It seems that the optimal cutoff for patients with primary aldosteronism is above 30 ng/dl per mug/l/h or 800 pmol/l per mug/l/h or 130 pmol/ng or 80 pmol/mU. We explore enhancing measures such as captopril loading or use with a plasma aldosterone cutoff as well as pitfalls with the test such as confounding medications or the need for confirmatory testing. For the latter, demonstration of autonomous aldosterone production via salt loading is widely used, but may not be most advantageous and may even be contraindicated in patients with severe hypertension. The renin stimulation test may be an alternative being safe, well tolerated, and cost effective.

Ovarian steroids modulate neuroendocrine dysfunction in polycystic ovary syndrome.

OBJECTIVE: Neuroendocrine dysfunction in polycystic ovary syndrome (PCOS) was addressed by studying the steroid hormone changes in women with PCOS with either high or normal LH levels leading to inferences regarding the primacy of elevated LH in the pathophysiology of PCOS. METHODS: A cross-sectional study was designed in an academic clinical facility involving 234 women with PCOS. Patients were divided into two groups based on an LH/FSH ratio < or >1 and hormonal and metabolic studies were performed in both groups. Factors were determined by binomial logistic regression that predicted group membership of these women. RESULTS: Higher follicular phase estradiol (E2) and androstenedione (A4) levels as well as greater insulin sensitivity were the only factors that predicted the presence of neuroendocrine dysfunction with elevated A4 being necessary for neuroendocrine dysfunction. CONCLUSIONS: It was concluded that uncoupling of hypothalamic E2 inhibition by elevated ovarian A4 associated with E2 related sensitization of pituitary LH leads to neuroendocrine dysfunction in PCOS.

The effects of growth hormone replacement therapy on overnight metabolic fuels in hypopituitary patients.

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.

Leptin levels in Arabs with primary hyperthyroidism.

BACKGROUND: The aim of this report was to study leptin status in hyperthyroid men and women (prior to and after medical treatment) and in matched controls in Arabs. SUBJECTS AND METHODS: Twenty-nine hyperthyroid patients (19 women and 10 men) and 32 controls (20 women and 12 men) matched for age, ethnic status and body mass index (BMI) were studied. The patients were studied at the time of diagnosis and six months after antithyroid treatment with carbimazole-titrating dose, which rendered them euthyroid. On each study occasion, the subjects fasting blood was collected for the measurement of leptin, glucose, insulin and C-peptide. RESULTS: Fasting leptin level was significantly lower in women with hyperthyroidism at baseline (mean+/-SEM, 15.8+/-2.9 microg/L, P=0.01), and after six months of antithyroid treatment (13.4+/-1.7 microg/L, P=0.004) than in control women (25.6+/-2.7 microg/L), but the difference was not significant in the men. Women in each group had significantly higher leptin concentrations than men (patients: 15.8+/-2.9 vs. 4.9+/-0.9 microg/L, P=0.009; controls: 25.67+/-2.7 vs. 7.9+/-1.4 microg/L, P=0.0005). The differences in women leptin remained significant even when expressed in relation to BMI. Baseline fasting glucose (P=0.01), insulin (P=0.007), and C-peptide (P=0.02) were significantly higher in the patients than controls. After six months of antithyroid therapy, fasting glucose, insulin and C-peptide levels were similar in the patients and controls. Within the patients, baseline leptin concentrations correlated positively with BMI (rho=0.65, P=0.02) and negatively with free T3 (rho=0.62, P=0.03). It neither demonstrated an association with baseline nor with six-month values of fasting glucose, insulin and C-peptide. CONCLUSION: Leptin concentration is decreased in Arab women with hyperthyroidism. Six months of antithyroid therapy is not associated with alterations in leptin levels.

Long-term effects of growth hormone therapy on intermediary metabolism and insulin sensitivity in hypopituitary adults.

Experience with growth hormone (GH) therapy in adult hypopituitarism has been gained for more than 10 years. Most of the data on GH therapy derive from studies with a duration of 2 years or less, but longer term information is required if patients are to be treated with GH replacement therapy for many years. We have studied patients after 4 years of treatment. At the end of this time, body mass index was unchanged but short-term benefits in body composition (decreased percentage body fat and increased fat-free mass) which had been evident at 2 years were still apparent. Fasting plasma glucose and the plasma glucose area under the curve during an oral glucose tolerance test were similar before and after 4 years of therapy, although fasting insulin levels were increased in comparison with baseline. Total cholesterol and low density lipoprotein cholesterol concentrations were lower at 4 years than at the outset but high density lipoprotein cholesterol and triglyceride levels were unchanged. The available evidence therefore suggests that concerns regarding glucose intolerance in patients receiving long-term GH therapy have not been substantiated. The beneficial effects on body composition, and on total and low density lipoprotein cholesterol levels, persisted over the 4 years of study.

The circadian rhythm of leptin is preserved in growth hormone deficient hypopituitary adults.

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.

Effects of four years' treatment with biosynthetic human growth hormone (GH) on glucose homeostasis, insulin secretion and lipid metabolism in GH-deficient adults.

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.

Fasting and postprandial lipid abnormalities in hypopituitary women receiving conventional replacement therapy.

Hypopituitary patients, particularly women, have excess mortality, mostly due to vascular disease. We have studied circulating lipid and lipoprotein concentrations, fasting and over 24 h, in hypopituitary women and men and in matched controls. Firstly, 67 hypopituitary patients (36 women) and 87 normal controls (54 women) were studied after an overnight fast. Secondly, 12 patients (6 women) and 14 matched controls (7 women) were studied over 24 h of normal meals and activity. The patients were all GH deficient and were replaced with cortisol, T4, and sex hormones where appropriate, but not with GH. In the first study, circulating triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol were measured after an overnight fast. In the second study, fasting levels of apolipoprotein B, apolipoprotein A1, and lipoprotein(a) were also measured, and then circulating triglyceride and total cholesterol concentrations were measured over 24 h. Fasting concentrations of triglyceride (mean +/- SEM, 1.73 +/- 0.22 vs. 1.11 +/- 0.09 mmol/L; P = 0.0025), total cholesterol (6.45 +/- 0.25 vs. 5.59 +/- 0.21 mmol/L; P = 0.002), LDL cholesterol (4.58 +/- 0.24 vs. 3.80 +/- 0.19 mmol/L; P = 0.007), and apolipoprotein B (135 +/- 10 vs. 111 +/- 9 mg/dL; P = 0.048) were elevated in hypopituitary compared to control women. The lipid alterations were observed in older and younger women and occurred independently of sex hormone or glucocorticoid replacement. Fasting values were not significantly different in hypopituitary and control men. Patients and controls (women and men) had similar fasting HDL cholesterol, apolipoprotein A1, and lipoprotein(a) concentrations. Although the differences that existed in fasting lipid values were most marked in women, the men were also abnormal in this respect, in that a higher proportion of hypopituitary than control men had total and LDL cholesterol above recommended values (> or = 6.2 and > or = 4.1 mmol/L, respectively). In the postprandial period (0730-2030 h), the areas under the curve (AUC) for circulating triglyceride and total cholesterol were significantly higher in hypopituitary than control women (P = 0.0089 and P = 0.0016, respectively). The AUC for triglyceride and total cholesterol over 24 h were also significantly increased (P = 0.009 and P = 0.0004, respectively). No significant differences were observed for postprandial and 24-h AUC for triglyceride and total cholesterol concentrations in men. We conclude that hypopituitarism with conventional replacement therapy is associated with unfavorable fasting and postprandial lipid and lipoprotein concentrations, particularly in women. The changes may contribute to the observed increased vascular morbidity and mortality.

Elevated leptin concentrations in growth hormone-deficient hypopituitary adults.

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.

Effects of four years' treatment with biosynthetic human growth hormone (GH) on body composition in GH-deficient hypopituitary adults.

Short-term trials of growth hormone (GH) substitution in hypopituitary adults have shown beneficial effects on body composition. To evaluate the long-term effects on body composition, we followed thirteen GH-deficient adults (GH < 6 mU/l following standard provocative tests) for 4 years of GH replacement. At yearly intervals, serum insulin-like growth factor I (IGF-I), body weight, body mass index (BMI), waist, waist-to-hip circumference ratio (WHR) and resting systolic (SBP) and diastolic blood pressure (DBP) were determined, and body composition was assessed using three independent methods: total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). Compared to baseline, IGF-I levels increased significantly at 1 (p = 0.0001), 2 (p = 0.0004), 3 (p = 0.006) and 4 years (p = 0.002). Body weight and BMI changed minimally at 1, 2 and 3 years and increased significantly only at the fourth year (p = 0.012 and p = 0.0009, respectively) of GH therapy. Waist and WHR decreased significantly at 1, 2 and 4 years (waist: p = 0.0009, p = 0.0004, p = 0.049; WHR: p = 0.0025, p = 0.012, p = 0.047, respectively). Neither resting SBP nor DBP changed significantly. Fat-free mass (FFM) derived from TBK and BIA increased significantly at 1 (p = 0.004; p = 0.004), 2 (p = 0.003; p = 0.05), 3 (p = 0.005; p = 0.04) and 4 years (p = 0.02; p = 0.002). Using DXA, the increase in FFM was significant at 1 (p = 0.007) and 2 years (p = 0.008) but not at 3 and 4 years. Percentage body fat measured by TBK, BIA and DXA decreased significantly at 1 (p = 0.008; p = 0.003; p = 0.03), 2 (p = 0.018; p = 0.06; p = 0.049) and 4 years (p = 0.03; p = 0.002; p = 0.04). A rise in total body water, calculated from BIA, was observed at 1 year (p = 0.004) and was maintained throughout the treatment period. These data demonstrate that 4 years of GH treatment in hypopituitary adults is associated with sustained improvement in body composition.

Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism.

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.

Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults.

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.