Takumi Kurabayashi

Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome

OBJECTIVE To investigate the effect of troglitazone, a new antidiabetic agent that improves insulin resistance, on endocrine, metabolic, and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome (PCOS). DESIGN Prospective clinical study. SETTING Infertility outpatient clinic, Niigata University Hospital, Niigata, Japan. PATIENT(S) Thirteen women with PCOS and insulin resistance. INTERVENTION(S) Troglitazone (400 mg/d) was administered for 12 weeks. MAIN OUTCOME MEASURE(S) Insulin and other hormone (gonadotropins, androgens) levels; various parameters relating to glucose and lipid metabolism before, during, and after troglitazone administration; and ovulation rate. RESULT(S) The mean (+/-SD) fasting insulin concentration was significantly reduced, from 18.3+/-8.9 to 10.5+/-7.1 microU/mL. The LH level was reduced from 9.7+/-3.4 to 4.8+/-3.9 mIU/mL and the testosterone level was reduced from 0.9+/-0.5 to 0.5+/-0.3 ng/mL in accordance. Atherosclerotic lipid levels also were normalized. Before troglitazone administration, the ovulation rate during clomiphene citrate therapy was 34.9% per cycle (15/43). This increased significantly to 72.7% (8/11) during troglitazone coadministration. Further, an ovulation rate of 42.3% (11/26) was achieved with troglitazone alone. CONCLUSION(S) In women with PCOS and insulin resistance, the reduction of hyperinsulinemia that is produced by troglitazone improves the hyperandrogenism that characterizes PCOS, restoring ovulation.

Association of vitamin D and estrogen receptor gene polymorphism with the effect of hormone replacement therapy on bone mineral density in Japanese women.

OBJECTIVE We studied whether vitamin D receptor and estrogen receptor gene polymorphism is associated with the effect of hormone replacement therapy on lumbar-spinal bone mineral density in Japanese women. STUDY DESIGN The subjects were 82 Japanese women aged 40 to 64 years (49.7 +/- 0.6 years, mean +/- SEM) who had taken hormone replacement therapy for >1 year. Genomic deoxyribonucleic acid was extracted from blood and analyzed for restriction fragment length polymorphism with the restriction endonucleases Taq I, Apa I, and Fok I for vitamin D receptor and Pvu II and Xba I for estrogen receptor. RESULTS The subjects with genotype TT had a significantly higher percentage change in bone mineral density per year than those with the Tt genotype (2.8% +/- 0.6% vs -0.8% +/- 1.4%, P =.019). The serum level of pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen decreased by 13% during 1 year of hormone replacement therapy in subjects with the TT genotype (P =. 001) but did not change in women with the Tt genotype. In multiple regression analysis including age, height (centimeters), weight (kilograms), and polymorphisms of the vitamin D receptor and estrogen receptor genes, only age and Taq I polymorphism of the vitamin D receptor gene were associated independently with change in bone mineral density (P =.001 and.004, respectively). CONCLUSION Taq I polymorphism of the vitamin D receptor gene is associated with the effect of hormone replacement therapy on lumbar-spinal bone mineral density and bone resorption markers in Japanese women. Analysis of the vitamin D receptor alleles may prove useful for selection of the optimum therapy for osteoporosis management.

Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization

OBJECTIVE To evaluate the effect of prednisolone plus low-dose aspirin (PSL/LDA) in women with autoimmune conditions who were enrolled in an IVF-ET program. DESIGN A retrospective clinical study. SETTING In vitro fertilization unit, Niigata University Hospital, Niigata, Japan. PATIENT(S) Three hundred seven women who underwent IVF-ET between January 1996 and December 1997. INTERVENTION(S) Prednisolone (10 mg/d) and aspirin (81 mg/d) were administered to the women with autoantibodies who chose to participate. MAIN OUTCOME MEASURE(S) Pregnancy and implantation rates with IVF-ET. RESULT(S) Women undergoing IVF who had positive antinuclear antibodies, with or without antiphospholipid antibodies, had significantly lower pregnancy and implantation rates than did women without autoantibodies (14.8% versus 21.7% and 6.8% versus 10.4%, respectively). The administration of PSL/LDA to women with antinuclear antibodies significantly improved the outcome of IVF-ET (40.6% pregnancy rate and 20.3% implantation rate). CONCLUSION(S) A high proportion of women who are undergoing IVF-ET have autoantibodies, which are associated with poor IVF outcomes. The administration of PSL/LDA to these women may improve their implantation rate.

Bone structural and metabolic changes at the end of pregnancy and lactation in rats.

OBJECTIVE The objective of this study was to elucidate the net change of bone structure and metabolism in the lumbar trabecular bone of rats at the end of the pregnancy and lactation. STUDY DESIGN Female virgin Sprague-Dawley rats aged 200 days were mated, and bone mineral density by dual-energy x-ray absorptiometry, bone histomorphometry, and serum bone metabolic markers were measured at the end of pregnancy (day 22 of pregnancy), after delivery (day 5 post partum), and at the end of lactation (day 21 post partum). RESULTS At the end of pregnancy bone mineral density, bone volume, trabecular thickness, and serum calcium decreased; serum parathyroid hormone increased; and the histomorphometric parameters indicated that bone resorption were higher than those variables in nonpregnant rats, but bone formation was suppressed, as demonstrated by the low histomorphometric parameters and by the low serum alkaline phosphatase levels. After delivery the bone mineral density of nonlactating rats recovered rapidly, as in nonpregnant rats, but nonlactating rats showed more bone formation by histomorphometry than nonpregnant rats did. At the end of lactation, bone mineral density and serum calcium levels decreased considerably, and lactating rats showed substantial bone formation, bone resorption, and high serum alkaline phosphatase levels. The correlation between the number of pups (x) of the lactating and nonlactating groups and the bone mineral density (y, in grams per square centimeter) showed simple linear regression (y = -0.0067 . x +0.2517, r = 0.949, p < 0.0001). CONCLUSIONS These results indicate that significant decreases occur in the trabecular bone of rats at the end of pregnancy and lactation and that lactational intensity is related to bone mineral density.

Effects of uncoupling protein 1 and ß3-adrenergic receptor gene polymorphisms on body size and serum lipid concentrations in Japanese women

OBJECTIVES To investigate whether the -3826 A-G point mutation of the uncoupling protein 1 (UCP1) gene and the Trp64Arg mutation of the beta3-adrenergic receptor (beta3-AR) gene are associated with increased susceptibility to weight gain and hyperlipidemia in postmenopausal women. METHODS We genotyped 312 Japanese women for UCP1 and beta3-AR gene polymorphisms, and investigated their effects on anthropometrical parameters, serum lipid concentrations, and their changes after 4 years. RESULTS Although body mass index (BMI), serum triglyceride, total cholesterol, and low-density lipoprotein levels were significantly higher and high-density lipoprotein levels significantly lower in postmenopausal (n=182) than in premenopausal (n=99) women, there was no significant difference in these parameters between carriers and non-carriers of the G allele in the postmenopausal women. In the premenopausal women, BMI and the 4-year change in body weight (BW) of carriers of the G allele were significantly higher than those of non-carriers of the G allele (P=0.022 and 0.048, respectively). In the postmenopausal women, the 4-year change in the level of serum triglyceride of carriers of the G allele was significantly higher (P=0.049), and the change of high-density lipoprotein was significantly lower (P=0.020) than those of non-carriers of the G allele. The beta3-AR polymorphism showed no apparent affect on these parameters. CONCLUSIONS The -3826 A-G polymorphism of the UCP1 gene is associated with an increase in BW of premenopausal women and with the 4-year changes in serum triglyceride and high-density lipoprotein levels in postmenopausal women.

Lumbar bone mineral density changes during pregnancy and lactation

Objective: To elucidate the change of bone metabolism in the lumbar trabecular and its relationship with serum hormonal changes in pregnancy and lactation. Study design: In a cross‐sectional study, we measured the bone mineral density (BMD) of 2–4 lumbar vertebrae of 571 puerperae at days 3–5 postpartum and 341 healthy, non‐pregnant women (control subjects) of approximately the same age by dual energy X‐ray absorptiometry. In a longitudinal study, we also measured the BMD of 111 puerperae at 3 and 6 months after delivery. Results: The mean BMD at days 3–5 postpartum was significantly lower than that of the control (1.013 ± 0.005 vs. 1.032 ± 0.006 g/cm2, P = 0.019). The lactating group showed BMD decrement to 95.1 ± 0.5% (n = 69) and 94.1 ± 0.7% (n = 61) at 3 and 6 months postpartum, respectively, compared with days 3–5 postpartum, and the amenorrhea group showed the same tendency. The non‐lactating group and resumption of menses group did not show a BMD decrement postpartum. In the lactating group, serum estradiol was significantly lower than in the non‐lactating group at 3 months postpartum, serum prolactin and bone alkaline phosphatase levels were higher than in the non‐lactating group at 3 and 6 months postpartum. Conclusions: Pregnancy may cause a decrease of lumbar BMD, and the lactation and amenorrhea also cause a decrease of BMD. In addition to lactation status, the ovarian dysfunction is one of the factors in bone loss during lactation.

Eicosapentaenoic acid effect on hyperlipidemia in menopausal Japanese women

Objective To assess the efficacy and safety of eicosapentaenoic acid for the treatment of hyperlipidemia in symptomatic menopausal Japanese women. Methods We performed a prospective observational 48-week study in hyperlipidemic menopausal women. We randomly assigned 141 women, whose levels of serum total cholesterol were 220 to 280 mg/dL or whose serum triglycerides were 150 to 400 mg/dL at baseline to groups treated with estriol (E3) 2 mg daily (control group, n = 72) or ethyl icosapentate 1800 mg daily and E3 2 mg (eicosapentaenoic acid group, n = 69). Results Serum levels of total cholesterol decreased significantly from 249.4 to 238.6 mg/dL (−4.3%, P = .003) in the control group and from 252.3 to 234.0 mg/dL (−7.3%, P = .001) in the study group at week 48 in the women whose total cholesterol was not less than 220 mg/dL at baseline. Serum levels of triglycerides decreased significantly from 194.5 to 141.5 mg/dL (−27.2%, P = .001) in the study group but increased slightly from 192.9 to 207.4 mg/dL (+7.5%) in the control group at week 48 in the women whose level of triglycerides was not less than 150 mg/dL. There were significant differences between these two groups at weeks 12, 24, and 48. Serum levels of total cholesterol and triglycerides were significantly decreased at week 48 in the study group regardless of whether the women were obese. There were no severe adverse effects. Conclusion Combination therapy with eicosapentaenoic acid and E3 was effective and safe for menopausal women with hypertriglyceridemia.

Effect of Estriol on Bone Loss in Postmenopausal Japanese Women: A Multicenter Prospective Open Study

Objectives: To assess the effects of oral estriol on the bone mineral density (BMD) and bone metabolism in postmenopausal women.

Management of patients with pregnancy-associated gastric cancer in Japan : a mini-review

Gastric cancer associated with pregnancy is quite rare, and is most often diagnosed at an advanced stage. Furthermore, physicians are confronted with two conflicting issues in this condition: the need for early treatment of the maternal gastric cancer and the continuation of the pregnancy. To clarify the characteristics of pregnancy-associated gastric cancer and to obtain useful information that would help us choose the best treatment strategy for pregnancy-associated gastric cancer, we reviewed the existing literature, using the key words “pregnancy” and “gastric cancer”. We were able to accumulate 136 cases, including 100 cases reported previously in Japan, and 1 case that we report here. We analyzed a total of 137 cases in the present study. With respect to the stage of gastric cancer, 92.5% of the patients studied had advanced gastric cancer, and only 45.3% of the patients underwent gastrectomy, including incomplete resection. Accordingly, the prognosis was very poor; the 1- and 2-year survival rates were 18.0% and 15.1%, respectively. However, the number of patients found to have early gastric cancer by endoscopic examination has been increasing recently. An endoscopic examination should be conducted immediately in pregnant patients presenting with persistent gastrointestinal symptoms for the differential diagnosis of hyperemesis gravidarum. When an endoscopic examination reveals that pregnant patients have gastric cancer, a therapeutic plan should be promptly formulated, in accordance with the number of weeks of gestation, by a medical team consisting of specialists in perinatal obstetrics and gastric cancer specialists.

Effect of vitamin D receptor and estrogen receptor gene polymorphism on the relationship between dietary calcium and bone mineral density in Japanese women.

In a longitudinal analysis of the results of bone mineral density (BMD) screenings conducted in local communities, we examined the effect of lifestyle improvements on BMD and investigated the influence of allelic variations of the vitamin D receptor (VDR) and estrogen receptor (ER) genes. The subjects were 484 women (age, 24–80 years) who underwent BMD screenings at least twice between 1994 and 2002. We conducted BMD measurements of the lumbar spine by dual-energy X-ray absorptiometry and performed a simple questionnaire survey of lifestyle factors. Women receiving pharmacotherapy, or those with bone fractures, were excluded, leaving 338 women eligible for the study. They were retrospectively divided into three groups: (i) premenopause, women who were at least 5 years preceding menopause; (ii) perimenopause, women who were within 5 years before or after menopause; and (iii) postmenopause, women who were at least 5 years past menopause. There was no correlation at all between improvements of lifestyle factors (i.e., calcium intake from dairy products and time spent walking) and fluctuations in lumbar-spine BMD after 1, 3, or 5 years in the pre-, peri-, and postmenopausal groups. For women in the postmenopausal group, the PP genotype for the ER gene correlated with a significantly higher initial BMD than those with the Pp and pp genotypes (P = 0.04). After 3 years, presence of the TT genotype of Taq I of VDR gene polymorphism exhibited positive correlations (r = 0.29, P = 0.03) with the improvements in calcium intake and in lumbar spine BMD for the perimenopausal group, whereas the Tt genotype showed negative correlations (r = −0.48, P = 0.04). After 1, 3, and 5 years, presence of the Tt genotype showed a tendency toward a negative correlation with the increases in calcium intake and in lumbar spine BMD for the pre- and perimenopausal groups, although almost of these were not significantly different. In this study, we could not prove a positive correlation between the improvement of lifestyle and the fluctuation of BMD within a 5-year timeframe, although the polymorphisms within the VDR gene may have some influence.