Measurement of glycated hemoglobin and glycated albumin in umbilical cord: evaluation of the glycemic control indicators in neonates.

OBJECTIVE: As neonatal blood contains a high proportion of fetal hemoglobin (HbF), it is difficult to use high-performance liquid chromatography (HPLC) method, latex-immunoturbidimetry (LA) method and enzymatic methods, which determine hemoglobin A(1C) (HbA(1C)) in order to provide the glycemic control indicators of neonates. In this study, we evaluated glycated hemoglobin (GHb) and glycated albumin (GA) as appropriate indicators of the glycemic control in the neonatal period. STUDY DESIGN: Umbilical cord blood samples collected during delivery were subjected to measurements of GHb (HPLC methods using two different instruments, LA method, enzymatic method and affinity method) and serum GA. RESULT: HbA(1C) levels determined by the HPLC method, the LA method and the enzymatic method were as low as <3.0% in all the cases. Although GHb determined by the affinity method was 3.6 ± 0.2%, this method may not measure accurately the values of glycated HbF plus glycated HbA. Serum GA was 9.4 ± 1.1%. CONCLUSION: We speculate that serum GA, but not GHb, could be used as glycemic control indicators in neonates.

Reduced carotid atherosclerosis in asthmatic patients treated with inhaled corticosteroids.

Although inflammation is an important component of atherosclerosis, it is unknown whether inhaled corticosteroids (ICS) as anti-inflammatory drugs prevent atherosclerosis. In the present study, carotid atherosclerosis was evaluated by ultrasonography in 150 asthmatic patients who had been regularly treated with ICS, and in 150 matched nonasthmatic controls, with an assessment of atherosclerotic risk factors. Carotid intima-media thickness was significantly lower in the asthmatic patients than in the controls. The prevalence of carotid plaque tended to be lower in the asthmatic patients than in the controls. Defined carotid atherosclerosis was diagnosed in 51 of the asthmatic patients, who were older, with a higher prevalence of males, a higher prevalence of dyslipidaemia and a lower mean daily dose of ICS than the 99 patients without carotid atherosclerosis. Stepwise multiple logistic regression analysis identified age, male sex and dyslipidaemia as positive risk factors for carotid atherosclerosis. The mean daily dose of ICS was a negative risk factor. Carotid atherosclerosis is reduced in asthmatic patients treated with ICS compared with matched controls. This study suggests that ICS may have protective effects against atherosclerosis.

Close relationship between serum concentrations of 1,5-anhydroglucitol and uric acid in non-diabetic male subjects implies common renal transport system.

BACKGROUND: 1,5-Anhydroglucitol is found in food. We determined factors other than glucosuria that affect serum 1,5-anhydroglucitol (1,5-AG) concentration. METHODS: The relationships between serum 1,5-AG concentration and metabolic parameters were investigated in 158 males with normal glucose tolerance verified by an oral glucose tolerance test. RESULTS: Serum uric acid was positively correlated to 2-h plasma glucose and serum 1,5-AG concentrations. Serum 1,5-AG levels were not different between hyperuricemic and normouricemic subjects, though those with normouricemia had lower 2-h plasma glucose concentrations than subjects with hyperuricemia. The association between 1,5-AG and uric acid in serum was still evident after adjustment with 2-h plasma glucose concentration. Multivariate regression analyses demonstrated that serum uric acid was an independent variable related to serum 1,5-AG and vice versa. CONCLUSIONS: 1,5-AG and uric acid may share in part a common renal tubular transport system, independent of glucose excretion.

Effects of thyroid hormone on serum glycated albumin levels: study on non-diabetic subjects.

Glycated albumin (GA) is used alongside glycated hemoglobin (HbA(1C)) as an indicator of glycemic control. Although serum GA levels are affected mainly by plasma glucose, they are also influenced by serum albumin metabolism. Thyroid hormone is known to promote albumin catabolism, and it is thus thought to affect serum GA levels. In the present study, the effects of thyroid hormone on serum GA measurements were investigated in patients with thyroid dysfunction. Six patients with untreated hypothyroidism and 17 patients with untreated thyrotoxicosis were investigated. Patients who had anemia or diabetes were excluded. A total of 25 non-diabetic, euthyroid individuals were enrolled as controls. HbA(1C), serum GA, thyroid-stimulating hormone (TSH), free triiodothyronine (T(3)), and free thyroxine (T(4)) levels were measured in all these subjects, and their relationships were examined. Although no intergroup differences were observed for HbA(1C), serum GA was significantly higher among patients with hypothyroidism than controls, and significantly lower among patients with thyrotoxicosis. Serum GA had a significant positive correlation with serum TSH and significant inverse correlations with free T(3) and free T(4). Thyroid hormone levels are inversely associated with serum GA levels. Cautions are necessary when evaluating serum GA levels in patients with thyroid dysfunction.

Factors contributing to increased serum urate in postmenopausal Japanese females.

OBJECTIVE: The level of serum urate is generally elevated in postmenopausal individuals. In addition to estrogen, other menopause-related factors may also affect uric acid metabolism in postmenopausal females. Accordingly, we investigated factors related to increased serum urate levels in addition to lack of estrogen. SUBJECTS AND METHODS: We studied 448 females who participated in an annual health check-up. None were being treated for gout, hyperuricemia, or diabetes mellitus, and no subjects had a history of hysterectomy and had never used estrogens or progestins. Body mass index (BMI), homeostasis model of insulin resistance (HOMA-R), and ethanol ingestion were investigated in all subjects, while information regarding menopause status was also obtained. RESULTS: Serum urate levels rose from the age of 46 to 60 years in the subjects. Multivariate regression analysis showed that BMI, HOMA-R, ethanol ingestion and menopause were independently associated with serum urate level. In addition, BMI and HOMA-R were higher in postmenopausal, as compared to premenopausal, subjects. CONCLUSION: Our results suggest that menopause-related insulin resistance, obesity and ethanol ingestion as well as menopause may contribute to an increase in level of serum urate in postmenopausal Japanese women.

Association of erythrocyte indices with glycated haemoglobin in pre-menopausal women.

AIMS: Although HbA(1c) is known to be affected by the lifespan of erythrocytes, any association of erythrocyte indices with HbA(1c) in subjects without anaemia is poorly understood. Pre-menopausal women may be relatively iron deficient because of menstruation. In this study, we examined the relationship between HbA(1c) and erythrocyte indices in pre- and post-menopausal women. METHODS: We determined HbA(1c), red blood cell (RBC) count, haematocrit, haemoglobin, mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) in 423 women with normal glucose tolerance who had undergone health checks. In addition, age at menopause was recorded in post-menopausal subjects. RESULTS: RBC counts of the 180 pre-menopausal women were positively associated with HbA(1c), whereas haemoglobin, MCV and MCH showed a negative association. In contrast, no significant association of any indices with HbA(1c) was detected in the 243 post-menopausal women. Stepwise multivariate regression analysis in the pre-menopausal women identified fasting plasma glucose and age as positively associated and MCH as negatively associated with HbA(1c), regardless of whether or not these pre-menopausal women were anaemic. CONCLUSIONS: Erythrocyte indices are associated with HbA(1c), independently of plasma glucose levels, in pre-menopausal women even when they are not anaemic. This should be appreciated when interpreting HbA(1c) in pre-menopausal patients with diabetes.

Insulin sensitivity independently influences brachial-ankle pulse-wave velocity in non-diabetic subjects.

AIMS: Measurement of pulse-wave velocity (PWV) is a non-invasive technique for assessing arterial stiffness. Although insulin resistance is associated with intimal-medial thickness of the carotid artery evaluated by B-mode ultrasonography, it is not known whether it is related to PWV. The aim of this study was to determine the relationship between homeostasis model assessment insulin sensitivity index (HOMA-%S) and PWV in non-diabetic subjects. We also examined the effects of oral glucose tolerance test (OGTT) 2-h glucose and plasma high-sensitivity C-reactive protein (CRP) on PWV, as these two parameters are associated with atherosclerosis. METHODS: A 75-g oral glucose tolerance test was performed in 1934 Japanese subjects who were undergoing health examinations. Of these subjects, we recruited 1541 non-diabetic subjects without chronic or acute inflammation, malignant diseases, autoimmune disorders, elevated serum creatinine levels, and abnormal hepatic function tests. Subjects who had an abnormal ankle/brachial blood pressure index of less than 0.9 were also excluded. Brachial-ankle PWV and plasma high-sensitivity CRP were measured on 1541 subjects who satisfied the admission criteria. RESULTS: PWV was 12.55+/-1.61 (mean+/-sd) m/s and plasma CRP concentration was 0.4 mg/l (median, range, 0.1-5.8 mg/l) in the study subjects. By multivariate regression analysis, HOMA-%S was found to be an independent negative risk factor for PWV, while systolic blood pressure, age and triglycerides were positively associated with PWV. OGTT 2-h glucose was weakly and independently related to PWV in male subjects. Plasma CRP was not independently associated with PWV. CONCLUSIONS: Insulin resistance is independently associated with PWV in non-diabetic subjects.

Strong association of C-reactive protein with body mass index and 2-h post-challenge glucose in non-diabetic, non-smoker subjects without hypertension.

AIMS: Increases in C-reactive protein (CRP) levels have been shown to be associated with cardiovascular diseases as well as asymptomatic atherosclerosis and to be closely related to traditional cardiovascular risk factors. The aim of this study was to determine the clinical and biochemical characteristics associated with CRP in non-diabetic, non-smoker subjects without hypertension. METHODS: A 75-g oral glucose tolerance test was performed on 305 Japanese subjects aged 40-70 years who were undergoing health examinations. We recruited non-diabetic, non-smoker subjects without hypertension. Subjects with known cardiovascular diseases, chronic or acute inflammation, malignant diseases, or autoimmune disorders were excluded. Plasma high-sensitivity CRP was measured in 125 subjects who satisfied the admission criteria. RESULTS: Plasma CRP levels were significantly higher in the 28 subjects with impaired glucose tolerance (IGT) than that in the 97 subjects with normal glucose tolerance (NGT) (median 0.53, range 0.18-1.10 mg/l vs. median 0.32, range 0.17-0.49 mg/l; P = 0.032). There was a positive correlation of CRP with body mass index (BMI), triglycerides, uric acid, fasting glucose, oral glucose tolerance test (OGTT) 1-h glucose, OGTT 2-h glucose, and a negative correlation with HDL cholesterol. Multivariate regression analysis identified BMI (F = 8.57, P = 0.004) and OGTT 2-h glucose (F = 5.96, P = 0.016) as independent predictors for CRP. CONCLUSIONS: BMI and OGTT 2-h glucose are the most important predictors for plasma CRP in non-diabetic, non-smoker subjects without hypertension.

Risk factors for asymptomatic atherosclerosis in Japanese type 2 diabetic patients without diabetic microvascular complications.

Atherosclerotic vascular diseases are frequently associated with diabetes mellitus. There has been increasing evidence showing that the atherosclerotic diseases in diabetic patients are distinct from diabetic microvascular complications as to their pathophysiology and epidemiology. However, we have no information on the prevalence of asymptomatic atherosclerosis in diabetic patients before the onset of microvascular diseases. In the present investigation, we aimed to evaluate risk factors for the atherosclerosis in type 2 diabetic patients without the microvascular diseases. For this purpose, we evaluated atherosclerotic change of carotid arteries in 125 Japanese type 2 diabetic patients who had neither atherosclerotic vascular diseases nor diabetic microvascular complications. When atherosclerotic change was defined as the mean intima-media thickness (IMT) of >/= 1.1 mm and/or the presence of plaque lesion, 50% of patients had atherosclerosis of the carotid arteries. Risk factors for the carotid atherosclerosis were age, low-density lipoprotein (LDL)-cholesterol, hypertension, and diabetes treatment. Age and LDL-cholesterol were associated with mean IMT. Age, diabetes treatment, LDL-cholesterol, and hypertension were positively associated with plaque lesion, while high-density lipoprotein (HDL)-cholesterol was negatively associated with it. Fasting plasma glucose, glycosylated hemoglobin (HbA(1c)), and known diabetes duration remained unassociated with any parameters of asymptomatic atherosclerosis of the carotid arteries. These results indicate that glycemic control is unrelated with asymptomatic atherosclerosis in type 2 diabetic patients without diabetic microvascular complications. Conventional risk factors and diabetes treatment are independently associated with atherosclerosis of the carotid arteries in these patients.

Effects of the prostaglandin I2 analogue, beraprost sodium, on vascular cell adhesion molecule-1 expression in human vascular endothelial cells and circulating vascular cell adhesion molecule-1 level in patients with type 2 diabetes mellitus.

Beraprost sodium is an orally active prostaglandin (PG)I(2) analogue, which has antiplatelet and vasodilating properties. In this study, we investigated the effects of beraprost on the expression of vascular cell adhesion molecule-1 (VCAM-1), one of the key molecules involved in atherosclerosis, in cultured vascular endothelial cells. In addition, we examined the effects of beraprost on circulating VCAM-1 level and atherosclerosis progression in patients with type 2 diabetes mellitus. Beraprost significantly decreased tumor necrosis factor-alpha (TNF-alpha)-induced VCAM-1 expression in human vascular endothelial cells. Beraprost also repressed human monocytoid U937 cell adhesion to the vascular endothelial cells. Twenty-five patients with type 2 diabetes mellitus who had atherosclerotic change of carotid arteries were enrolled for an open prospective study: 11 patients received beraprost for 3 years, while the other 14 did not. The 3-year changes of circulating VCAM-1 level, as well as those of carotid arterial intima-media thickness (IMT) were significantly lower in the patients receiving the beraprost treatment than that in the patients without the treatment. Thus, beraprost had an ability to repress the expression of VCAM-1 in human vascular endothelial cells. In addition, beraprost lowered circulating VCAM-1 level and prevented the increase of carotid IMT in patients with type 2 diabetes mellitus. Considering that circulating VCAM-1 and IMT are predictive of future vascular events, beraprost may have a beneficial effect on progression of atherosclerosis in diabetic patients.

Role of advanced glycation end products in adynamic bone disease in patients with diabetic nephropathy.

Adynamic bone disease and elevated serum levels of advanced glycation end products (AGEs) often are found in patients with renal failure caused by diabetic nephropathy. To clarify the role of AGEs in adynamic bone disease, we investigated the effect of these substances on cultured human osteoblasts and parathyroid cells. After 72 hours of incubation with AGEs-bovine serum albumin (BSA) (1,000 microgram/mL), there was significant inhibition of the synthesis of type I collagen and osteocalcin in response to stimulation with 10(-10) to 10(-8) M of 1,25-dihydroxycholecalciferol. In a human osteoblastic cell line (MG 63), AGEs-BSA did not affect human osteocalcin promoter activity. In human parathyroid cells, a receptor for AGEs was detected by reverse-transcriptase polymerase chain reaction. Incubation with AGEs-BSA for 48 hours significantly inhibited parathyroid hormone secretion in response to a low calcium concentration of 0.81 mM (P < 0.01). In HEK-293 cells, expressing calcium-sensing receptors, the same AGE concentration caused a significant potentiation of the extracellular Ca(2+) induced-intracellular calcium concentration after 24 and 48 hours of incubation (P < 0.05 and P < 0.01). These data suggest that AGEs are involved in the pathogenesis of adynamic bone disease by inhibiting osteoblastic activity and by inhibiting parathyroid hormone secretion in response to hypocalcemia.

Characteristics of type 2 diabetic patients responding to voglibose administration as an adjunct to sulfonylurea.

In this study, we characterized type 2 diabetic patients responding well to the alpha-glucosidase inhibitor voglibose administration as an adjunct to sulfonylurea treatment. Thirty-three type 2 diabetic patients were enrolled in an open prospective study. All the patients had been treated for at least 1 year with a sulfonylurea drug, in whom HbA1c level had been stable for at least 12 weeks. The patients were given voglibose at a dose of 0.2 mg t.i.d. for 12 weeks. Voglibose administration significantly decreased the mean HbA1c level in all the patients at 4, 8, and 12 weeks. Twelve (36%) of the study patients were responders, when the responders were defined as patients whose HbA1c level at 12 weeks fell by at least 1.0% from baseline, or those whose HbA1c level at 12 weeks was < or =7.0%, falling by at least 0.5% from baseline. The baseline fasting plasma glucose (FPG) was significantly lower, and the baseline homeostasis model assessment (HOMA) beta-cell function (HOMA-%beta) was significantly higher in the responders than in the non-responders. There were more patients who had FPG <170 mg/dl and/or HOMA-%beta > or =30% in the responders than in the non-responders (P<0.005). None of the patients with both FPG > or =170 mg/dl and HOMA-%beta >30% responded to the adjunct treatment. These results indicate that baseline FPG and HOMA-%beta are useful clinical markers to predict the effectiveness of the adjunct therapy of voglibose in sulfonylurea-treated type 2 diabetic patients.

Antiplatelet agent cilostazol potentiates adipocyte differentiation of 3T3-L1 cells.

Cilostazol is an antiplatelet drug, which has beneficial effects in treatment of intermittent claudication and decreases serum triacyiglycerol level in these patients. In this study, we examined adipogenic potency of cilostazol using 3T3-L1 preadipocyte cell line because cilostazol is one of the tissue specific phosphodiesterase (PDE) inhibitors. Addition of cilostazol into the differentiation medium including insulin and dexamethasone, induced the adipocyte differentiation without isobutyl methylxanthine (IBMX). Compared with the cells incubated with vehicle, the cells treated with cilostazol contain much more lipid droplets in the cells 6 days after induction of differentiation. Adipocyte specific gene like stearoyl-CoA desaturase was strongly induced after addition of cilostazol. C/EBPbeta, which is induced by IBMX was also induced by cilostazol. These findings suggest a possibility that adipogenic effect of cilostazol is one of the mechanisms, by which this agent decreases blood triacylglycerol level in the intermittent claudication patients.

Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence.

Cilostazol is a specific inhibitor of cAMP phosphodiesterase, which is used for treatment of ischemic symptoms of peripheral vascular disease. Although cilostazol has antiplatelet and vasodilator properties, its effect on the expression of adhesion molecules in vascular endothelium is not known. In the present investigation, we examined the effect of cilostazol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured vascular endothelial cells. Cilostazol strongly inhibited tumor necrosis factor (TNF)-alpha-induced expression of VCAM-1 protein and its mRNA. In addition, cilostazol reduced TNF-alpha-induced U937 cell adhesion to the vascular endothelial cells. In transient transfection studies, cilostazol inhibited TNF-alpha-induced transcriptional activation of VCAM-1 promoter. Electrophoretic mobility shift assays revealed that cilostazol repressed TNF-alpha-induced increase in binding of the transcription nuclear factor-kappaB (NF-kappaB) to its recognition site of VCAM-1 promoter. Cilostazol, however, failed to prevent nuclear translocation of the NF-kappaB p65 protein. These data indicate that cilostazol repressed VCAM-1 gene transcription in cultured vascular endothelial cells, via inhibiting NF-kappaB binding to its recognition sequence. Since the expression of the adhesion molecule is one of the earliest events occurred in atherogenic process, cilostazol might have the potential to prevent atherosclerosis at least via inhibition of the expression of the adhesion molecule.

PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells.

The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPARalpha activator fenofibrate and the GR activator dexamethasone on TNFalpha-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNFalpha-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNFalpha-stimulated vascular cell adhesion molecule-1 expression in these cells. Transient transfection of bovine aortic endothelial cells with an IL-6 promoter construct or a vascular cell adhesion molecule-1 promoter construct revealed that fenofibrate inhibited TNFalpha-induced IL-6 promoter as well as vascular cell adhesion molecule-1 promoter activities, whereas dexamethasone inhibited only the former. EMSA demonstrated that both fenofibrate and dexamethasone reduced nuclear factor-kappaB binding to its recognition site on the IL-6 promoter, but only fenofibrate reduced such binding to the vascular cell adhesion molecule-1 promoter. Thus, down-regulation of nuclear factor-kappaB activity by PPARalpha occurs in both the IL-6 and vascular cell adhesion molecule-1 genes, whereas that by GR occurs only in the IL-6 gene in vascular endothelial cells. These results strongly suggest the existence of a target gene-specific mechanism for the nuclear receptor-mediated down-regulation of nuclear factor-kappaB activity.

TNF-alpha inhibits 3T3-L1 adipocyte differentiation without downregulating the expression of C/EBPbeta and delta.

Tumor necrosis factor-alpha (TNF-alpha) has been reported to inhibit adipocyte differentiation in which multiple transcription factors including CCAAT enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptor (PPAR) gamma play an important role. Induction of C/EBPalpha and PPARgamma, which regulate the expression of many adipocyte-related genes, is dependent on the expression of C/EBPbeta and C/EBPdelta at the early phase of adipocyte differentiation. To elucidate the mechanism by which TNF-alpha inhibits adipocyte differentiation, we examined the effect of TNF-alpha on the expression of these transcription factors in mouse 3T3-L1 preadipocytes. TNF-alpha did not abrogate the induction of C/EBPbeta and C/EBPdelta in response to differentiation stimuli. In fully differentiated adipocytes, TNF-alpha rapidly induced C/EBPbeta and C/EBPdelta, whereas it downregulated the expression of C/EBPalpha and PPARgamma. Our results suggest that TNF-alpha inhibits adipocyte differentiation independently of the downregulation of C/EBPbeta and C/EBPdelta.

Characterization of premature atherosclerosis of carotid arteries in acromegalic patients.

OBJECTIVE: Acromegalic patients have increased mortality from vascular diseases. Although atherosclerotic risk factors such as hypertension, diabetes mellitus and dyslipoproteinaemia are highly associated with acromegaly, the prevalence of premature atherosclerosis in acromegalic patients and its relationship to these risk factors have not been reported. DESIGN: We measured mean intima-media thickness (IMT) of the carotid arteries in 21 acromegalic patients without symptomatic atherosclerotic vascular disease, by ultrasound high-resolution B-mode imaging. In analysis 1, it was compared with the predicted mean IMT based on data from existing risk factors (age, male sex, dyslipoproteinaemia, hypertension, diabetes mellitus, smoking status) in 282 non-acromegalic subjects. In analysis 2, the mean IMT in the 21 acromegalic patients was compared with that in 42 non-acromegalic subjects matched for age, sex and the other atherosclerotic risk factors. We also analysed clinical characteristics between the acromegalic patients with and without the atherosclerosis. RESULTS: Mean IMT in 21 acromegalic patients was 0.92 +/- 0.21 (mean +/- SD) mm. It was significantly (P < 0.05) lower than the mean IMT (1.03 +/- 0.12 mm) predicted from their existing risk factors (analysis 1). It was also less than that in 42 non-acromegalic subjects matched for atherosclerotic risk factors (1.07 +/- 0.37 mm; P < 0.05) (analysis 2). Among the acromegalic patients, 10 patients (48%) had increased mean IMT (> or = 1.1 mm) and/or plaque lesions whereas the other 11 had no such atherosclerotic changes. In the patients without the atherosclerotic changes, plasma insulin-like growth factor-I (IGF-I) concentration was significantly (P < 0.01) higher, and the prevalence of hypertension was significantly (P < 0.05) lower than in those with the atherosclerotic changes. CONCLUSIONS: The extent of carotid atherosclerosis in the acromegalic patients was not higher than that in non-acromegalic subjects, considering their atherosclerotic risk factors. Increased concentration of IGF-I might be involved in the lack of susceptibility to atherosclerosis in some acromegalic patients.

Inhaled corticosteroids reduce bone mineral density in early postmenopausal but not premenopausal asthmatic women.

Inhaled corticosteroids are widely used in the treatment of bronchial asthma, but it is still uncertain whether long-term use of the inhaled corticosteroids affects bone metabolism in asthmatic patients. In this study, we examined the effect of inhaled beclomethasone dipropionate (BDP) on bone mineral density (BMD) and biochemical markers of bone metabolism in pre- and early postmenopausal asthmatic women. Thirty-six (17 premenopausal and 19 early postmenopausal) asthmatic women and 45 healthy control (24 premenopausal and 21 early postmenopausal) women were investigated. All the asthmatic patients were treated with BDP (542 +/- 298 microg/day; 100-1200 microg/day) without any systemic administration of corticosteroids for at least 1 year. In premenopausal women, BMD as well as the biochemical markers of bone metabolism did not differ between control subjects and BDP-treated asthmatic patients. By contrast, in early postmenopausal women, BMD was significantly lower in BDP-treated asthmatic patients than in control subjects. In these early postmenopausal women, serum intact osteocalcin concentration was lower in the BDP-treated asthmatic patients than in the control subjects whereas urinary free pyridinoline (F-PYD) and free deoxypyridinoline (F-DPD) concentrations did not differ between the groups. Thus, early postmenopausal, but not premenopausal, asthmatic patients who were treated with inhaled BDP had reduced BMD, which was associated with a decreased level of the bone formation marker. Ovarian hormones may be protective against the adverse effect of inhaled BDP on bone metabolism in the premenopausal patients.

Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells.

-It has been shown that ovarian steroid hormones can reduce the incidence of cardiovascular disease in postmenopausal women. As hormone replacement therapy for postmenopausal women, progestins are added to estrogens to eliminate the increased risk of endometrial cancer. However, the effects of progestins on the atherogenic process have not been well understood. In the present study, we examined the effects of progestins on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Immunocytochemical analysis revealed the presence of progesterone receptors in HUVECs. Progesterone clearly inhibited tumor necrosis factor-alpha-activated expression of VCAM-1 protein and its mRNA in HUVECs. Synthetic progesterone receptor agonist R5020 also inhibited the tumor necrosis factor-alpha-activated VCAM-1 expression, whereas medroxyprogesterone acetate (MPA) failed to do so. Electrophoretic mobility shift assays demonstrated that progesterone, but not MPA, inhibited DNA binding of the transcription nuclear factor-kappaB, which is critical for the inducible expression of VCAM-1. Because the expression of VCAM-1 is one of the earliest events that occurs in the atherogenic process, this adhesion molecule might be a target molecule for progesterone on vascular walls. The contrasting effects of progesterone and MPA seem clinically important, inasmuch as MPA is a widely used progestin in the regimen of hormone replacement therapy.