Yoshiyuki Miyashita

Estrogen Deficiency is a Potential Cause for Osteopenia in Adult Male Patients with Noonan's Syndrome

Abstract. Osteopenia is frequently observed in patients with Turners syndrome. By contrast, there is no report concerning bone metabolism in patients with Noonans syndrome which comprises Turners phenotypic characteristics without any sex chromosome abnormalities. In the present investigation, we determined bone mineral density (BMD) as well as serum and urine indices of bone turnover in two male patients with Noonans syndrome. Both patients showed remarkably decreased BMD, measured at two sites on the lumbar spine (L2-L4) and the distal end of the radius using dual energy X-ray absorptiometry (DXA). Urinary pyridinoline (PYD) and deoxypyridinoline (DPD) concentrations were significantly elevated in both patients, and serum osteocalcin and carboxyterminal propeptide of type I procollagen (PICP) concentrations were elevated in one patient. Surprisingly, both patients had a low level of serum 17β-estradiol compared with control males, whereas they had normal levels of serum testosterone and dihydrotestosterone. Conjugated estrogens (Premarin 0.625 mg/day) were continued to be administered to these patients, followed up for 12 months. Urinary PYD and DPD concentrations gradually decreased, followed by an increase in their BMD. This is the first report that male patients with Noonans syndrome showed osteopenia associated with increased bone resorption. Our data indicate that hypoestrogenism plays a potentially significant role in the abnormal bone metabolism in these patients.

Comparison of effects of a potassium channel, opener BRL34915, a specific potassium ionophore valinomycin and calcium channel blockers on endothelin-induced vascular contraction

The effects of a potassium (K+) channel opener BRL34915 and a specific K+ ionophore valinomycin on vasoconstriction induced by endothelin (ET) were compared with those of calcium (Ca2+) channel blockers, nicardipine and verapamil, using helical strips from rat thoracic aorta. ET induced potent and persistent contraction in control solution and similar but smaller contraction in Ca2+-free solution. BRL34915 and valinomycin inhibited the ET-induced contraction dose-dependently in control solution, but not in Ca2+-free solution. The ET-induced contraction was also inhibited by nicardipine and verapamil, though less strongly. On the other hand, high K+ (35 mM)-induced vasoconstriction was strongly inhibited by nicardipine and verapamil, but not by BRL34915 or valinomycin. These results support the idea that the extracellular Ca2+-dependent component of the ET-induced contraction may be mediated by Ca2+ influx by a route other than voltage-dependent Ca2+-channels.

Effect of ipriflavone on bone mineral density and calcium-related factors in elderly females

SummaryThe effects of ipriflavone (7-isopropoxy-3-phenyl-4H-1-benzopyran-4-one) on bone mineral density (BMD) of the 3rd lumbar vertebra and on calcium (Ca)-related factors, including serum calcitonin (CT) levels before and after rapid calcium infusion (4 mg/kg for 5 minutes), were studied in 11 elderly female subjects (80 ± 2 years of age, mean ± SE). Ipriflavone (IP) administration (600 mg/day, 7 months) resulted in inhibition of BMD loss in 7 patients (responders, mean change of BMD value 2.2 ± 2.3%), whereas 4 patients showed a loss of BMD (nonresponders, mean change of BMD value -13.1 ± 2.6%) compared with pretreatment values. The responder group showed a significant increase in mean pretreatment serum CT levels (from 20 ± 2 pg/ml to 42 ± 7 pg/ml,P < 0.05) after treatment with IP, and a significant decrease in the mean basal serum level of corrected Ca (from 9.6 ± 0.2 mg/dl to 8.7 ± 0.1 mg/dl,P < 0.01) after treatment with IP; nonresponders did not show these changes. For responders, both the percentage of change and the maximal value of serum CT in response to Ca infusion were maintained at rather high levels, both before and after IP treatment; nonresponders showed almost no response to a stimulation test for CT. These findings suggest that IP inhibits bone loss in elderly female subjects possibly through the mechanism of increasing CT secretion.

Participation of Decreased Serum CholesteryI Ester Transfer Activity, Independent of Increased Serum Lipoprotein(a), in Angina Pectoris in Normolipemic Elderly Subjects

The cholesteryl ester transfer activity (CETA) is a measurement of the transfer of cholesteryl ester from HDL to VLDL, LDL or peripheral cells. Its role in the development of early coronary heart disease is not clear. In the present study, serum levels of CETA, lipoprotein(a) [Lp(a)] and other lipid-related factors were compared in 10 normal young subjects, 28 healthy elderly subjects and 14 normolipemic elderly patients with angina pectoris. Compared to the young normals and healthy elderly subjects, the elderly patients with angina pectoris showed significantly decreased mean serum CETA levels, and significantly increased mean serum levels of Lp(a) and apoprotein B. These results may indicate that decreased serum values of CETA participate in the development of angina pectoris in normolipemic elderly patients.

Participation of both intracellular free Ca2+ and protein kinase C in tonic vasoconstriction induced by prostaglandin F2α

The roles of intracellular free Ca2+ and protein kinase C in the tonic contraction induced by prostaglandin were studied. Prostaglandin F2 alpha induced tonic contraction of rat thoracic aorta in both control and Ca2(+)-free solution. Close correlations were observed between the contractile response of aortic strips and the changes in intracellular free Ca2+ concentration in vascular smooth muscle cells assessed with the fluorescent Ca2+ indicator fura 2, both in control and Ca2(+)-free solutions. Prostaglandin F2 alpha also enhanced the production of inositol 1,4,5-trisphosphate in vascular smooth muscle cells before the rise of the intracellular free Ca2+ concentration. Moreover, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, inhibited the tonic contractions induced by PGF2 alpha and 12-O-tetradecanoyl phorbol-13-acetate, a direct activator of protein kinase C, at similar concentrations. These results suggest that both intracellular free Ca2+ and protein kinase C participate in prostaglandin F2 alpha-induced tonic contraction.

Relation between low serum cholesteryl-ester transfer activity and abdominal aortic calcification in normolipidemic elderly subjects.

We studied the relation between cholesteryl-ester transfer activity (CETA) and abdominal aortic calcification in elderly subjects. Compared with 10 young healthy subjects (mean +/- S.D. age, 27 +/-2 years) and to 26 elderly subjects without abdominal aortic calcification (79 +/- 7 years), 16 elderly patients with abdominal aortic calcification (82 +/- 6 years) had significantly lower levels of serum CETA. However, there were no differences in the levels of serum lipids and apolipoproteins, including total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol and apolipoproteins A-I, A-II, B, C-II and E, between the two elderly groups. When the two groups of elderly subjects were considered together, the level of serum CETA did not correlate significantly with any lipids and apolipoproteins. These results provide evidence that CETA may prevent the development of aortic calcification in normolipidemic elderly people.

Comparison of the production of cyclic AMP in response to parathyroid hormone in fibroblasts from aged subjects and young subjects: lack of an age-dependent decrease.

An age-dependent effect on the ability to produce cyclic AMP in response to parathyroid hormone (PTH) stimulation was examined using culture skin fibroblasts from both young and elderly female subjects. The mean values of both absolute and comparative production of intracellular cyclic AMP due to various concentrations of PTH administration did not differ between the two age groups, although the mean serum PTH level was significantly higher in the elderly subjects. These results indicate that the decreased response of the target organ to PTH in aged subjects can be explained mainly by the decreased number of intact cells rather than a decreased response of individual cells to PTH.