Ichiro Kodama

Relationship between dental panoramic radiographic findings and biochemical markers of bone turnover

We investigated whether mandibular cortical measures on dental panoramic radiographs are associated with biochemical markers of bone turnover in 82 postmenopausal women. Mandibular cortical shape was significantly associated with biochemical markers and spinal BMD. Our results suggest that dentists may be able to identify postmenopausal women with low BMD by using dental panoramic radiographs.

Estrogen regulates the production of VEGF for osteoclast formation and activity in op/op mice.

op/op mice have a severe deficiency of osteoclasts because of lacking functional M‐CSF that is an essential factor of osteoclast differentiation and function. We now report that OVX induces osteoclast formation and cures osteopetrosis by increasing the VEGF that regulates osteoclast formation in these mice.

Relationship between the angiotensin-converting enzyme genotype and the forearm vasodilator response to estrogen replacement therapy in postmenopausal women

OBJECTIVES We sought to evaluate the relationship between the angiotensin-converting enzyme (ACE) genotype and the change in forearm vasoreactivity in response to a three-month course of oral estrogen in postmenopausal women. BACKGROUND The ACE genotype is a known predictor of the response to an ACE inhibitor drug; however, it is not clear whether it can modify the effect of estrogen replacement therapy (ERT) on endothelial function in postmenopausal women. METHODS Fifty-five postmenopausal women received 0.625 mg of conjugated equine estrogen daily for three months. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. RESULTS Twenty-one, 25 and 9 patients had the insertion/deletion (ID), II and DD genotypes, respectively. Plasma ACE activity was significantly higher at baseline in patients with either the DD or ID genotype than in those with the II genotype (p < 0.05). A significant decrease in plasma ACE activity with ERT was seen in the ID and II genotypes (p < 0.05), but not in the DD genotype. There were no significant differences in the FBF responses to reactive hyperemia at baseline between the three groups. Estrogen replacement therapy did not alter the FBF response to reactive hyperemia in the DD genotype (4.0 +/- 1.3%), although ERT significantly increased the FBF response in the ID and II genotypes (32.6 +/- 7.5% and 30.6 +/- 6.5%, respectively; p < 0.05). Forearm blood flow after administration of sublingual nitroglycerin did not change over three months in any of the three groups. CONCLUSIONS These findings suggest that the effect of ERT in postmenopausal women on forearm endothelial function may be determined in part by the genotype of the ACE gene.

Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity

The precise mechanism of the vasoprotective effect of estrogen replacement therapy in postmenopausal women is not fully understood. The present study sought to determine the role of nitric oxide (NO) and angiotensin-converting enzyme (ACE) in the vasodilator response of the forearm vessels induced by estrogen administration to postmenopausal women. Subjects were divided into two groups. One group received conjugated equine estrogen (0.625 mg daily) orally for 3 months (n=26), while the other received no treatment (control group, n=10). Forearm blood flow was measured by strain-gauge plethysmography. The concentrations of nitrite/nitrate (metabolites of NO), ACE activity, and lipid parameters were measured. Basal forearm blood flow, body weight, blood pressure, and heart rate were similar at baseline in both groups. After 3 months of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase over baseline values: from 23.6+/-2.0 to 36.5+/-3.1 ml/min per 100 ml tissue (P<0.01), and from 24.8+/-2.3 to 38.6+/-3.6 micromol/l (P<0.01), respectively. Plasma levels of ACE activity were significantly reduced from baseline after 3 months of estrogen treatment (from 12.2+/-0.6 to 10.9+/-0.6 IU/l, P<0.01). No changes were seen in controls. The change in forearm blood flow after sublingual nitroglycerin was similar at baseline versus after 3 months of estrogen administration. The increase in the serum level of nitrite/nitrate after 3 months of estrogen therapy showed a significant inverse correlation (r=0.52, P<0.01) with the reduction in the plasma level of ACE activity. There was no significant correlation between the increase in serum nitrite/nitrate and any change in serum lipids, blood pressure, or other parameters. The administration of oral estrogen to postmenopausal women for 3 months increased the NO-mediated forearm endothelium-dependent vasodilatation. This was likely due, at least in part, to ACE inhibition. The latter may be one mechanism by which ERT provides its well-known cardiovascular benefit.

Phenotype of apolipoprotein E influences the lipid metabolic response of postmenopausal women to hormone replacement therapy

OBJECTIVES We investigated whether the phenotype of apolipoprotein E (apo E) would influence the response of postmenopausal Japanese women to hormone replacement therapy (HRT). METHODS We measured the plasma levels of lipoprotein and apolipoprotein in 242 postmenopausal women at baseline and again after 12 months of HRT. Patients were divided into three groups according to apo E phenotype: E2+ (E2/2 and E2/3, n=21), E3/3 (n=176), E4+ (E3/4 and E4/4, n=45). RESULTS We found that the E4+ group had the highest levels of total and low density lipoprotein (LDL) cholesterol and apolipoprotein B, being significantly higher than in the E2+ group at baseline. The plasma levels of total and LDL cholesterol showed a significant decrease only in the E2+ and E3/3 groups after 12 months of HRT (E2+ group, total cholesterol -8.9% and LDL cholesterol -21.5%; E3/3 group, total cholesterol -2.9% and LDL cholesterol -9.5%). No significant difference in the reduction of total and LDL cholesterol was found in the E4+ group. Other lipid parameters did not differ in the three groups. CONCLUSIONS These data show that the apo E phenotype influenced the response of lipid metabolism in postmenopausal women to HRT, especially in the reduction of LDL cholesterol. Therefore, apo E phenotyping may be important in predicting the cholesterol-lowering effect of HRT.

The effect of hormone replacement therapy on metabolism of lipoprotein remnants in postmenopausal women

OBJECTIVE The measurement of remnant-like particles reflects chylomicron and very low density lipoprotein remnants which are most likely atherogenic particles. We investigated the effects of menopausal status and postmenopausal hormone replacement on metabolism of remnant lipoprotein-cholesterol. METHODS We measured remnant lipoprotein-cholesterol by an immunoseparation assay in 20 premenopausal, 40 postmenopausal, and 30 bilaterally oophorectomized women. Of 70 postmenopausal subjects, 21 surgically menopausal women (with total hysterectomy) were started on hormone replacement with conjugated equine estrogen, 0.625 mg/day, and 36 naturally postmenopausal women were begun on a combination of conjugated equine estrogen 0.625 mg/day, plus medroxyprogesterone acetate, 2.5 mg/day. Plasma levels of remnant lipoprotein-cholesterol and other common lipids were measured after 6 and 12 months of treatment. RESULTS Plasma remnant lipoprotein-cholesterol levels in postmenopausal and surgically menopausal women were significantly higher than in premenopausal women (P < 0.005). Plasma total and low-density lipoprotein cholesterol levels decreased and high-density lipoprotein cholesterol increased significantly (P < 0.01) in both treatment groups, respectively. Plasma triglyceride levels were not changed by treatment; however, remnant lipoprotein-cholesterol levels decreased in both treatment groups (estrogen group; P = 0.07, estrogen-progestin group; P < 0.05). No side effects of therapy were consistently reported. CONCLUSIONS We confirmed that remnant lipoprotein-cholesterol increases after menopause. Hormone replacement therapy improves disordered lipoprotein metabolism and exerts a favorable effect on lipoprotein remnant metabolism in postmenopausal women.

Comparison of forearm endothelial function between premenopausal and postmenopausal women with or without hypercholesterolemia.

We sought to determine whether menopausal status or postmenopausal hypercholesterolemia affects forearm resistance artery endothelial function. We studied the forearm resistance artery endothelial function in 75 Japanese women: 25 premenopausal volunteers, 25 postmenopausal women with normal serum low-density lipoprotein (LDL) cholesterol concentrations, and 25 hypercholesterolemic postmenopausal women. Excluded from the study were patients with hypertriglyceridemia, hypertension, or diabetes, cigarette smokers. The forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin (NTG) administration was measured by strain-gauge plethysmography. The serum concentrations of lipoprotein (a) [Lp(a)] were significantly higher in the hypercholesterolemic postmenopausal group than in the other two groups (P<0.01). These lipid parameters were similar between the premenopausal and postmenopausal women with normal cholesterol. The FBF responses to reactive hyperemia were significantly lower in the postmenopausal hypercholesterolemic women than in the other two groups (P<0.01). The reactive hyperemia also was impaired in the postmenopausal group with normal cholesterol as compared with the premenopausal group (P<0.01). Increases in FBF after NTG were similar between the three groups. By stepwise multivariate analysis, menopausal status and serum LDL cholesterol was the significant predictor of forearm endothelial function. These findings suggest that reactive hyperemia is impaired in forearm resistance arteries after menopause, especially in postmenopausal women with hypercholesterolemia.

Oral estrogen replacement therapy increases forearm reactive hyperemia accompanied by increases in serum levels of nitric oxide in postmenopausal women

The present study sought to determine the correlation between the vasodilator response of forearm resistance vessels and the circulating levels of nitric oxide (NO) after the administration of oral estrogen for 12 weeks to postmenopausal women. We classified postmenopausal women into two groups: those treated with conjugated equine estrogen (0.625 mg daily) orally for 12 weeks (n = 24) or those who received no treatment (control group ,n = 8). Forearm blood flow was measured using strain-gauge plethysmography during hyperemia to evaluate endotheliumdependent vasodilation ,and after sublingual nitroglycerin administration to evaluate endothelium-independent vasodilation. Serum levels of nitrite/nitrate (metabolites of NO) and lipid parameters were measured. Basal forearm blood flow ,body weight and heart rate were similar in each group. After 12 weeks of estrogen administration ,the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase from 26.9 ± 1.9 to 37.9 ± 3.5 ml/min per 100 ml tissue (p < 0.01) ,and from 25.2 ± 2.2 to 37.5 ± 3.7 μmol/l (p < 0.05) ,respectively. No increases were seen in controls. The changes in forearm blood flow after sublingual nitroglycerin were similar before and after 12 weeks of estrogen administration. The increase in maximal forearm blood flow with reactive hyperemia was significantly correlated with the increase in nitrite/nitrate in the group administered estrogen (r = 0.48 ,p < 0.05). There was no significant correlation between maximal forearm blood flow with reactive hyperemia ,nor any change in serum lipids ,blood pressure or other parameters. In conclusion ,the 12-week administration of oral estrogen increased forearm reactive hyperemia in postmenopausal women ,probably via an increase in the production of NO.

Apolipoprotein E phenotype associations with plasma lipoproteins and bone mass in postmenopausal women

OBJECTIVE The aim of the study was to investigate the effects of apolipoprotein E (apo E) phenotype on plasma lipids and bone mass in postmenopausal Japanese women. METHODS In 320 subjects aged 40-65 years (mean +/- SE, 54.0 +/- 0.6), apo E phenotype was determined by isometric electrophoresis. Phenotypic frequencies were 0.3% for E2/2 (n = 1), 8.1% for E3/2 (n = 26), 70.3% for E3/3 (n = 225), 0.6% for E4/2 (n = 2), 19.4% for E4/3 (n = 62) and 1.3% for E4/4 (n = 4). Apo E2/2 and apo E3/2 were classified as E2+ (n = 27); apo E3 homozygotes were placed in another group (E3/3; n = 225), as were apo E4/3 together with apo E4/4 subjects (group E4+; n = 66). Bone density and bone quality were assessed with a newly developed ultrasonic bone densitometer, and plasma lipids were also measured. RESULTS Age, body mass index and years since menopause did not differ significantly between the three groups. The E4+ group had the highest levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B, significantly higher than in the E2+ group. Plasma lipoprotein(a) concentrations were significantly higher in the E4+ group than in the other two groups. Ultrasonic parameters of bone density and quality tended to be lower in the E4+ group than in the E2+ group. CONCLUSIONS The apo E4 allele was associated with high plasma cholesterol levels and an unfavorable change of bone structure in postmenopausal women.

Combination therapy of low-dose medroxyprogesterone acetate and oral estrogen does not affect endothelial function in the forearms of postmenopausal women.

ObjectiveWe investigated whether low-dose medroxyprogesterone acetate (MPA) combined with oral estrogen had adverse effects on endothelial function compared with oral estrogen alone in postmenopausal women with mild hypercholesterolemia. DesignSubjects were divided into two groups. One group received conjugated equine estrogen (CEE, 0.625 mg daily) orally for the first 3 months, followed by estrogen combined with MPA (2.5 mg daily) orally for an additional 3 months (n = 26). The other group received no treatment (control group, n = 12). Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin administration was measured by strain-gauge plethysmography. Nitrite/nitrate, angiotensin-converting enzyme, and lipid concentrations were measured in the serum. ResultsBoth CEE and CEE combined with MPA significantly increased the FBF during reactive hyperemia. This increase was similar in both active treatment phases. No changes were seen in controls. FBF after sublingual nitroglycerin did not change over 6 months in either group. Significant and similar increases in serum concentration of nitrite/nitrate and plasma renin activity as well as decreases in angiotensin-converting enzyme activity were found in both treatment phases. No such changes occurred in the control group. There was no significant increase in high-density lipoprotein cholesterol or decrease in low-density lipoprotein cholesterol between the treatment phases. Likewise, no such changes were observed in the control group. ConclusionsOur 6-month study suggests that the addition of low-dose MPA with CEE had no adverse effects on forearm resistance artery endothelial function compared with CEE alone.