The Journal of Clinical Endocrinology & Metabolism, 2009
The aim was to evaluate changes in chromogranin A (CgA) concentration in hyperthyroidism and to a... more The aim was to evaluate changes in chromogranin A (CgA) concentration in hyperthyroidism and to assess its metabolic correlations. We studied CgA levels in hyperthyroidism. First, 38 hyperthyroid patients matched with 86 normal controls were studied after an overnight fast. Second, 30 if the 38 patients were followed up for 6 months with medical antithyroid drug therapy (carbimazole). In the first study, after 10-12 h overnight fasting, blood was collected for measurement of CgA, glucose, insulin, intact proinsulin, and thyroid function. These variables were remeasured in the second study for the patients after attainment of euthyroidism with the antithyroid drug carbimazole for 6 months. Pretreatment CgA level was significantly higher in patients compared with controls. CgA levels dropped significantly to levels similar to those of controls after antithyroid therapy. Although baseline and follow-up fasting glucose, insulin, and intact proinsulin demonstrated similar pattern of CgA changes before and after medical treatment, CgA did not correlate with any of them. However, CgA levels demonstrated a significant positive correlation with free T(3) and free T(4) only. These studies demonstrate that untreated hyperthyroidism is associated with elevated CgA level that changes in parallel to thyroid status. It is therefore possible to use CgA concentration as a potential marker of disease activity in hyperthyroidism.
International journal of immunopathology and pharmacology
Diabetes is the most common risk factor in inducing hypertension, nephropathy and retinopathy. Th... more 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 plasm...
The aim of this report was to study leptin status in hyperthyroid men and women (prior to and aft... more 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. 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. 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....
Compute tomography anatomy of the orbits is well described, but only a few reports are available ... more 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 rightto-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.
Neuroendocrine dysfunction in polycystic ovary syndrome (PCOS) was addressed by studying the ster... more 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. 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. 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. 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.
Adults with hypopituitarism and growth hormone deficiency (GHD) have been found to have low conce... more Adults with hypopituitarism and growth hormone deficiency (GHD) have been found to have low concentrations of metabolic fuels during the night. The aim of this study was to investigate whether GH replacement therapy could correct overnight fuel deficiency. Thirteen adults with hypopituitarism (eight women, five men) were recruited into a randomized, double-blind, placebo-controlled trial., Six patients were randomized to receive GH (Genotropin ®, Pharmacia & Upjohn, Stockholm, Sweden), 0.125 IU/kg/week (0.04 mg/kg/week) for 4 weeks, then 0.25 IU/kg/week (0.08 mg/kg/week), and seven to receive placebo for 6 months; all patients received GH for the following 6 months (0.125 IU/kg/week for 4 weeks, then 0.25 IU/kg/week). Levels of glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate were measured over 24 hours (from 07.30 hours to 07.00 hours) before and after GH treatment. In six of the patients, no differences in fasting levels of plasma glucose, 3-hydroxybutyrate and glycerol at 07.30 hours, in overnight area under the curve (AUC; between 24.00 hours and 07.00 hours) and in 24-hour AUC were observed before and 3 months after GH treatment. Furthermore, fasting and overnight levels of NEFA were significantly higher after 3 months of GH treatment compared with pretreatment levels (median [75% confidence interval], fasting: 347.3, [288.7-557.1] vs 254.0 pmol/1 [195.8-290.@ P < 0.05; overnight AUC: 2099AUC: .8, [1995AUC: .1-2240.0] vs 1722.9 pmol/1/hour [1265.9-1896.2], P < 0.05, respectively). The 24-hour AUC for NEFA did not differ before and after 3 months of GH treatment. No changes in any parameter were seen in the placebo group. In conclusion, GH replacement therapy does not alter overnight glucose, glycerol and 3-hydroxybutyrate levels. After 3 months of GH therapy, a rise in overnight NEFA levels was observed, which is consistent with the known lipolytic effect of GH.
Many studies have shown that growth hormone deficiency (GHD) is associated with increased levels ... more Many studies have shown that growth hormone deficiency (GHD) is associated with increased levels of total cholesterol and triglycerides. However, the mechanisms that contribute to abnormalities in the lipid profiles of patients with GHD are not fully understood. Increased hepatic secretion of very lowdensity lipoprotein (VLDL) apolipoprotein B100 (apoB100) has been implicated in the hyperlipidaemia of patients with GHD. The aim of this study was to investigate the metabolism of VLDL apoBlO0 both in adults with GHD and in controls, using a stable isotope of leucine. Fourteen patients with GHD (eight women, six men; mean age [-+ SEM], 46.0 _+ 2.5 years; body mass index [BM1], 30.2 _+ 1.6 kg/m 2) and nine control individuals (four women, five men; mean age, 32.7 _+ 2.2 years; BMI, 24.2 _+ 0.9 kg/m 2) were included in the study. All patients were receiving conventional replacement therapy, and achieved a maximal GH response of less than 6 mU/1 in a provocative test. A 6-hour infusion of [~3C]leucine was administered (1 mg/kg/hour) following a priming dose of 1 mg/kg. Enrichment of VLDL apoB 100 with [13C]leucine was determined using chromatography/mass spectrometry. VLDL apoB100 concentrations were measured using enzyme-linked immunosorbent assays. The fractional secretion rate (FSR) was measured as the rate of increase in [13C]leucine enrichment of VLDL apoB100 divided by the enrichment of the precursor pool (R-ketoisocaproic acid, the deamination product of leucine). The absolute secretion rate (ASR) was calculated as the product of the FSR and VLDL pool size. No significant differences were found in the FSR between patients with GHD and controls (0.35 ± 0.04 vs 0.48 _+ 0.06), but the GH-deficient patients had a significantly increased ASR compared with controls (56.2 +_ 5.1 vs 40.1 _+ 3.3 mg/dl/day; P = 0.03). These data suggest that the increased hepatic production of VLDL apoB 1 O0 could be an underlying cause of the hyperlipidaemia seen in patients with GHD. secretion of leptin exhibits a circadian rhythm, with nocturnal secretion being greater than daytime secretion. The aim of this study was to investigate the possibility that hypopituitarism (or' pituitary surgery with or without radiotherapy) alters the leptin rhythm. This was done by measuring serum leptin levels during a 24-hour period in patients with impaired pituitary function. Twenty-four-hour profiles of circulating leptin levels were measured in 14 patients with hypopituitarism (8 women, 6 men) using a sensitive and specific radioimmunassay. Hypopituitarism in these patients resulted from pituitary tumours treated surgically or with radiotherapy. The original diagnosis was chromophobe adenoma for seven patients, macroprolactinoma for three patients, Cushing's syndrome for three patients and craniopharyngioma for one patient. All patients were found to be growth hormone (GH)-deficient following a provocative test (GH concentration < 6 muff). They received conventional replacement therapy with cortisol (n = 13), thyroxine (n = 11), sex hormones (n = 12) and desmopressin (n = 4). None of the patients received GH. Mean age (_+ SEM) was 46.0 _+ 2.5 years, body mass index was 30.2 _+ 1.6 kg/m 2, and duration of hypopituitarism was 10.8 + 2.7 years. A marked diurnal variation in circulating leptin concentrations was observed in the patients. The lowest leptin levels (29.3 _+ 7.9 ng/ml) were observed at 08.30 hours after overnight fasting, rising gradually to maximum levels (43.0 _+ 9.8 ng/ml) at 02.00 hours, and then declining towards fasting levels. The mean amplitude between the highest and lowest leptin levels was 49.8 _+ 6.0%. This study shows that the circadian rhythm of leptin is maintained in patients with hypopituitarism, suggesting that the pituitary gland is not essential in this process. This indicates that regulatory factors other than those derived from the pituitary gland are likely to be involved in preserving the circadian rhythm of leptin.
The standard thyrotropin releasing hormone (TRH) test (200 μg) with synthetic TRH is no longer us... more The standard thyrotropin releasing hormone (TRH) test (200 μg) with synthetic TRH is no longer used commonly for the detection of primary hypothyroidism or hyperthyroidism. The reason has been that this test has been replaced by the development of more sensitive thyroid-stimulating hormone (TSH) assays, and hence suppression or elevation of TSH has been regarded as a sufficient criterion for the diagnosis of thyroid dysfunction in conjunction with measurements of free thyroid hormones. 1
BACKGROUND Hypopituitarism with growth hormone (GH) deficiency is associated with obesity charact... more 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 GHdeficient 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 Ϯ 1 . 8 vs 8 . 0 Ϯ 1 . 5 mg/l, P ¼ 0 . 04). The increase was more marked in obese (BMI > 26 . 0 kg/m 2 ) patients compared with obese controls (15 . 3 Ϯ 2 . 0 vs 8 . 8 Ϯ 2 . 3 mg/l, P ¼ 0 . 03) than in lean patients and controls. Obese control women and men had higher leptin levels than non-obese (women, 16 . 6 Ϯ 2 . 7 vs 8 . 6 Ϯ 0 . 6 mg/l, P ¼ 0 . 03; men, 4 . 9 Ϯ 0 . 5 vs 2 . 9 Ϯ 0 . 6 mg/l, P ¼ 0 . 035). Similar changes were observed for obese versus Rapid communication 153 ᭧ 1997
Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional... more Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. 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. 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. 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. 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). 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.
Excess impaired glucose tolerance and diabetes mellitus have been reported in hypopituitary adult... more 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. 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. 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. 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. 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 &lt; 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 &lt; 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 (&lt; 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&#39;s p = 0.83, P &lt; 0.01). 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 Leptin acts as a satiety factor in regulating food intake and body homeostasis, but its... more 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 Ϯ 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 ¼ 13), thyroxine (n ¼ 12) and desmopressin (n ¼ 4) but not with GH. RESULTS A significant diurnal variation in circulating leptin concentrations was observed in 13 of the 14 patients. The mean (ϮSEM) leptin levels for 8 women were 51·9 (Ϯ10·7) ng/ml and for 6 men 11·0 (Ϯ2·0) mg/l. The overall lowest leptin levels (29·3 Ϯ 7·9 ng/ml) were observed at 0830 h after overnight fasting, rising
OBJECTIVE To study the effects of long-term growth hormone (GH) treatment on lipid metabolism and... more 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 Ϯ SEM) (6·39 Ϯ 0·46 vs. 5·71 Ϯ 0·38 mmol/l, P < 0·05; 4·46 Ϯ 0·36 vs. 3·24 Ϯ 0·20 mmol/l, P < 0·01, respectively) and the reductions were maintained for
Experience with growth hormone (GH) therapy in adult hypopituitarism has been gained for more tha... more 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 uncha...
The Journal of Clinical Endocrinology & Metabolism, 2009
The aim was to evaluate changes in chromogranin A (CgA) concentration in hyperthyroidism and to a... more The aim was to evaluate changes in chromogranin A (CgA) concentration in hyperthyroidism and to assess its metabolic correlations. We studied CgA levels in hyperthyroidism. First, 38 hyperthyroid patients matched with 86 normal controls were studied after an overnight fast. Second, 30 if the 38 patients were followed up for 6 months with medical antithyroid drug therapy (carbimazole). In the first study, after 10-12 h overnight fasting, blood was collected for measurement of CgA, glucose, insulin, intact proinsulin, and thyroid function. These variables were remeasured in the second study for the patients after attainment of euthyroidism with the antithyroid drug carbimazole for 6 months. Pretreatment CgA level was significantly higher in patients compared with controls. CgA levels dropped significantly to levels similar to those of controls after antithyroid therapy. Although baseline and follow-up fasting glucose, insulin, and intact proinsulin demonstrated similar pattern of CgA changes before and after medical treatment, CgA did not correlate with any of them. However, CgA levels demonstrated a significant positive correlation with free T(3) and free T(4) only. These studies demonstrate that untreated hyperthyroidism is associated with elevated CgA level that changes in parallel to thyroid status. It is therefore possible to use CgA concentration as a potential marker of disease activity in hyperthyroidism.
International journal of immunopathology and pharmacology
Diabetes is the most common risk factor in inducing hypertension, nephropathy and retinopathy. Th... more 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 plasm...
The aim of this report was to study leptin status in hyperthyroid men and women (prior to and aft... more 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. 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. 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....
Compute tomography anatomy of the orbits is well described, but only a few reports are available ... more 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 rightto-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.
Neuroendocrine dysfunction in polycystic ovary syndrome (PCOS) was addressed by studying the ster... more 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. 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 &lt; or &gt;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. 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. 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.
Adults with hypopituitarism and growth hormone deficiency (GHD) have been found to have low conce... more Adults with hypopituitarism and growth hormone deficiency (GHD) have been found to have low concentrations of metabolic fuels during the night. The aim of this study was to investigate whether GH replacement therapy could correct overnight fuel deficiency. Thirteen adults with hypopituitarism (eight women, five men) were recruited into a randomized, double-blind, placebo-controlled trial., Six patients were randomized to receive GH (Genotropin ®, Pharmacia & Upjohn, Stockholm, Sweden), 0.125 IU/kg/week (0.04 mg/kg/week) for 4 weeks, then 0.25 IU/kg/week (0.08 mg/kg/week), and seven to receive placebo for 6 months; all patients received GH for the following 6 months (0.125 IU/kg/week for 4 weeks, then 0.25 IU/kg/week). Levels of glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate were measured over 24 hours (from 07.30 hours to 07.00 hours) before and after GH treatment. In six of the patients, no differences in fasting levels of plasma glucose, 3-hydroxybutyrate and glycerol at 07.30 hours, in overnight area under the curve (AUC; between 24.00 hours and 07.00 hours) and in 24-hour AUC were observed before and 3 months after GH treatment. Furthermore, fasting and overnight levels of NEFA were significantly higher after 3 months of GH treatment compared with pretreatment levels (median [75% confidence interval], fasting: 347.3, [288.7-557.1] vs 254.0 pmol/1 [195.8-290.@ P < 0.05; overnight AUC: 2099AUC: .8, [1995AUC: .1-2240.0] vs 1722.9 pmol/1/hour [1265.9-1896.2], P < 0.05, respectively). The 24-hour AUC for NEFA did not differ before and after 3 months of GH treatment. No changes in any parameter were seen in the placebo group. In conclusion, GH replacement therapy does not alter overnight glucose, glycerol and 3-hydroxybutyrate levels. After 3 months of GH therapy, a rise in overnight NEFA levels was observed, which is consistent with the known lipolytic effect of GH.
Many studies have shown that growth hormone deficiency (GHD) is associated with increased levels ... more Many studies have shown that growth hormone deficiency (GHD) is associated with increased levels of total cholesterol and triglycerides. However, the mechanisms that contribute to abnormalities in the lipid profiles of patients with GHD are not fully understood. Increased hepatic secretion of very lowdensity lipoprotein (VLDL) apolipoprotein B100 (apoB100) has been implicated in the hyperlipidaemia of patients with GHD. The aim of this study was to investigate the metabolism of VLDL apoBlO0 both in adults with GHD and in controls, using a stable isotope of leucine. Fourteen patients with GHD (eight women, six men; mean age [-+ SEM], 46.0 _+ 2.5 years; body mass index [BM1], 30.2 _+ 1.6 kg/m 2) and nine control individuals (four women, five men; mean age, 32.7 _+ 2.2 years; BMI, 24.2 _+ 0.9 kg/m 2) were included in the study. All patients were receiving conventional replacement therapy, and achieved a maximal GH response of less than 6 mU/1 in a provocative test. A 6-hour infusion of [~3C]leucine was administered (1 mg/kg/hour) following a priming dose of 1 mg/kg. Enrichment of VLDL apoB 100 with [13C]leucine was determined using chromatography/mass spectrometry. VLDL apoB100 concentrations were measured using enzyme-linked immunosorbent assays. The fractional secretion rate (FSR) was measured as the rate of increase in [13C]leucine enrichment of VLDL apoB100 divided by the enrichment of the precursor pool (R-ketoisocaproic acid, the deamination product of leucine). The absolute secretion rate (ASR) was calculated as the product of the FSR and VLDL pool size. No significant differences were found in the FSR between patients with GHD and controls (0.35 ± 0.04 vs 0.48 _+ 0.06), but the GH-deficient patients had a significantly increased ASR compared with controls (56.2 +_ 5.1 vs 40.1 _+ 3.3 mg/dl/day; P = 0.03). These data suggest that the increased hepatic production of VLDL apoB 1 O0 could be an underlying cause of the hyperlipidaemia seen in patients with GHD. secretion of leptin exhibits a circadian rhythm, with nocturnal secretion being greater than daytime secretion. The aim of this study was to investigate the possibility that hypopituitarism (or' pituitary surgery with or without radiotherapy) alters the leptin rhythm. This was done by measuring serum leptin levels during a 24-hour period in patients with impaired pituitary function. Twenty-four-hour profiles of circulating leptin levels were measured in 14 patients with hypopituitarism (8 women, 6 men) using a sensitive and specific radioimmunassay. Hypopituitarism in these patients resulted from pituitary tumours treated surgically or with radiotherapy. The original diagnosis was chromophobe adenoma for seven patients, macroprolactinoma for three patients, Cushing's syndrome for three patients and craniopharyngioma for one patient. All patients were found to be growth hormone (GH)-deficient following a provocative test (GH concentration < 6 muff). They received conventional replacement therapy with cortisol (n = 13), thyroxine (n = 11), sex hormones (n = 12) and desmopressin (n = 4). None of the patients received GH. Mean age (_+ SEM) was 46.0 _+ 2.5 years, body mass index was 30.2 _+ 1.6 kg/m 2, and duration of hypopituitarism was 10.8 + 2.7 years. A marked diurnal variation in circulating leptin concentrations was observed in the patients. The lowest leptin levels (29.3 _+ 7.9 ng/ml) were observed at 08.30 hours after overnight fasting, rising gradually to maximum levels (43.0 _+ 9.8 ng/ml) at 02.00 hours, and then declining towards fasting levels. The mean amplitude between the highest and lowest leptin levels was 49.8 _+ 6.0%. This study shows that the circadian rhythm of leptin is maintained in patients with hypopituitarism, suggesting that the pituitary gland is not essential in this process. This indicates that regulatory factors other than those derived from the pituitary gland are likely to be involved in preserving the circadian rhythm of leptin.
The standard thyrotropin releasing hormone (TRH) test (200 μg) with synthetic TRH is no longer us... more The standard thyrotropin releasing hormone (TRH) test (200 μg) with synthetic TRH is no longer used commonly for the detection of primary hypothyroidism or hyperthyroidism. The reason has been that this test has been replaced by the development of more sensitive thyroid-stimulating hormone (TSH) assays, and hence suppression or elevation of TSH has been regarded as a sufficient criterion for the diagnosis of thyroid dysfunction in conjunction with measurements of free thyroid hormones. 1
BACKGROUND Hypopituitarism with growth hormone (GH) deficiency is associated with obesity charact... more 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 GHdeficient 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 Ϯ 1 . 8 vs 8 . 0 Ϯ 1 . 5 mg/l, P ¼ 0 . 04). The increase was more marked in obese (BMI > 26 . 0 kg/m 2 ) patients compared with obese controls (15 . 3 Ϯ 2 . 0 vs 8 . 8 Ϯ 2 . 3 mg/l, P ¼ 0 . 03) than in lean patients and controls. Obese control women and men had higher leptin levels than non-obese (women, 16 . 6 Ϯ 2 . 7 vs 8 . 6 Ϯ 0 . 6 mg/l, P ¼ 0 . 03; men, 4 . 9 Ϯ 0 . 5 vs 2 . 9 Ϯ 0 . 6 mg/l, P ¼ 0 . 035). Similar changes were observed for obese versus Rapid communication 153 ᭧ 1997
Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional... more Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. 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. 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. 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. 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). 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.
Excess impaired glucose tolerance and diabetes mellitus have been reported in hypopituitary adult... more 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. 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. 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. 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. 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 &lt; 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 &lt; 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 (&lt; 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&#39;s p = 0.83, P &lt; 0.01). 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 Leptin acts as a satiety factor in regulating food intake and body homeostasis, but its... more 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 Ϯ 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 ¼ 13), thyroxine (n ¼ 12) and desmopressin (n ¼ 4) but not with GH. RESULTS A significant diurnal variation in circulating leptin concentrations was observed in 13 of the 14 patients. The mean (ϮSEM) leptin levels for 8 women were 51·9 (Ϯ10·7) ng/ml and for 6 men 11·0 (Ϯ2·0) mg/l. The overall lowest leptin levels (29·3 Ϯ 7·9 ng/ml) were observed at 0830 h after overnight fasting, rising
OBJECTIVE To study the effects of long-term growth hormone (GH) treatment on lipid metabolism and... more 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 Ϯ SEM) (6·39 Ϯ 0·46 vs. 5·71 Ϯ 0·38 mmol/l, P < 0·05; 4·46 Ϯ 0·36 vs. 3·24 Ϯ 0·20 mmol/l, P < 0·01, respectively) and the reductions were maintained for
Experience with growth hormone (GH) therapy in adult hypopituitarism has been gained for more tha... more 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 uncha...
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Papers by K. Al-shoumer