Tetsuro Yahata

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.

Gene expression profile for predicting survival in advanced-stage serous ovarian cancer across two independent datasets.

Background Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. Methodology/Principal Findings Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66–5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20–1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008). Conclusions/Significance The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

Serum leptin-adiponectin ratio and endometrial cancer risk in postmenopausal female subjects

OBJECTIVE Obesity is a well-known risk factor for the development of endometrial cancer. Elevated endogenous estrogen and insulin resistance are recognized to be major factors that link obesity and cancer development. However, there is increasing evidence that the adipokines adiponectin and leptin, which are directly produced in adipose tissue, impact several obesity-related cancers. The purpose of the current study was to investigate the relationships of the concentration of leptin, adiponectin, and the leptin-to-adiponectin ratio (L/A ratio) with the endometrial cancer risk in postmenopausal female subjects. METHODS A case-control study was performed in 146 postmenopausal female subjects with endometrial cancer and 150 control subjects with no history of cancer. The serum levels of the adipokines leptin and adiponectin were measured, and the associations of these adipokines and the L/A ratios with the endometrial cancer risk were analyzed. RESULTS The leptin levels and the L/A ratios were significantly higher in the incident cases of endometrial cancer (8.2 ± 0.5, 2.05 ± 1.08 ng/ml) than in the controls subjects (4.5 ± 0.5, 0.98 ± 0.18, P<0.0001), whereas the adiponectin levels were significantly lower in the incident cases (6.2 ± 0.4 μg/ml) than in the control subjects (9.0 ± 0.4 μg/ml, P<0.0001). For the incident cases, the serum levels of the adipokines were significantly correlated with the patient body mass index (BMI) (P<0.001 for leptin, P<0.05 for adiponectin), and the leptin levels and the L/A ratios were significantly correlated with the homeostasis model assessment ratio (HOMA-R) and the fasting insulin levels (P<.001). Higher L/A ratios were found to be significantly associated with an increased risk of endometrial cancer [OR (95% CI) for the top vs. the bottom tertile of the L/A ratio was 6.0 (3.2-11.9), P-value<0.0001]. Moreover, the ORs of the L/A ratios were higher than those of leptin or adiponectin alone. The association of the L/A ratios with endometrial cancer risk remained after adjusting for the obesity indices, hypertension, and presence of diabetes mellitus. CONCLUSION The present results suggested that the L/A ratio was independently associated with an increased risk for endometrial cancer development. Additional research will elucidate the molecular mechanisms by which these adipokines are associated with the development of endometrial cancer.

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.

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.

Germline Copy Number Variations in BRCA1- Associated Ovarian Cancer Patients

We investigated characteristics of germline copy number variations (CNV) in BRCA1‐associated ovarian cancer patients by comparing them to CNVs present in sporadic ovarian cancer patients. Germline CNVs in 51 BRCA1‐associated, 33 sporadic ovarian cancer patients, and 47 healthy women were analyzed by both signal intensity and genotyping data using the Affymetrix Genome‐Wide Human SNP Array 6.0. The total number of CNVs per genome was greater in the sporadic group (median 26, range 12–34) than in the BRCA1 group (median 21, range 11–35; post hoc P < 0.05) or normal group (median 20, range 7–32; post hoc P < 0.05). While the number of amplifications per genome was higher in the sporadic group (median 13, range 7–26) than in the BRCA1 group (median 8, range 3–23; post hoc P < 0.001), the number of deletions per genome was higher in the BRCA1 group (median 12, range 6–24) than in the sporadic group (median 9, range 3–17; post hoc P < 0.01). In addition, 31 previously unknown CNV regions were present specifically in the BRCA1 group. When we performed pathway analysis on the 241 overlapping genes mapped to these novel CNV regions, the ‘purine metabolism’ and ‘14‐3‐3‐mediated signaling’ pathways were over‐represented (Fishers exact test, P < 0.01). Our study shows that there are qualitative differences in genomic CNV profiles between BRCA1‐associated and sporadic ovarian cancer patients. Further studies are necessary to clarify the significance of the genomic CNV profile unique to BRCA1‐associated ovarian cancer patients.

Association of vitamin D and estrogen receptor gene polymorphism with the effects of longterm hormone replacement therapy on bone mineral density

We longitudinally studied whether vitamin D receptor (VDR) and estrogen receptor (ER) gene polymorphisms in Japanese women influenced the effect of longterm hormone replacement therapy (HRT) on bone mineral density (BMD) in the lumbar spine. The 81 subjects were aged 40 to 64 years (mean ± SEM, 49.5 ± 0.6 years), and had received sequential or continuous HRT regimens, including 0.625 mg of conjugated equine estrogen and 2.5 to 5 mg of medroxy-progesterone acetate, for at least 3 years. Genomic DNA was extracted from blood cells, and analyzed for restriction fragment length polymorphism, using the restriction endonucleases Taq I, Apa I, and Fok I for VDR, and Pvu II and Xba I for ER. At 1 year, subjects with a Taq I genotype of TT (i.e., site absent) showed a significantly greater increase in BMD with treatment (ΔBMD) than subjects with the Tt genotype (2.6 ± 0.5% vs −0.8 ± 1.4%; P = 0.016). A small difference between genotypes remained at 2 years (3.8 ± 0.6% vs 0.8 ± 1.6%; P = 0.069), but no significant difference between genotypes was seen at 3 years. In multiple regression analyses, ΔBMD at 1 year was significantly affected by VDR-Taq I, Apa I, and ER-Pvu II genotypes and by age at treatment initiation, although at 3 years or more, ΔBMD was significantly affected only by age. These results indicate that Taq I VDR gene polymorphism predicted the effect on lumbar BMD for the first year of HRT in Japanese women, and that the differences in BMD versus the polymorphism disappeared if the treatment was continued for over 2 years.

Decrease in the proportion of granulated CD56 + T-cells in patients with a history of recurrent abortion

We investigated levels of CD56+ T-cells (CD3+ CD56+ cells) in peripheral circulation, which express one of the natural killer (NK) cell markers, by flow cytometry and with monoclonal antibodies in patients with a history of recurrent abortion. We compared these values with those obtained in normal women who were not pregnant as well as in normal pregnant subjects. The percentage of CD56+ T-cells in the peripheral blood of patients with a history of recurrent abortion was less than that in the non-pregnant or pregnant women. These results suggest that CD56+ T-cells with extrathymic properties may be associated with the maintenance of normal pregnancy in humans.

Resolution of uterine arteriovenous malformation and successful pregnancy after treatment with a gonadotropin-releasing hormone agonist.

BACKGROUND: Uterine arteriovenous malformations are a rare and potentially life-threatening condition. Medical therapy has not been popular because of the propensity for excessive bleeding in the patient. As a result, the effect of gonadotropin-releasing hormone (Gn-RH) agonists on uterine arteriovenous malformations has not been established. CASE: A 30-year-old patient presented with persistent vaginal bleeding. Based on the color Doppler ultrasound and magnetic resonance imaging findings, a uterine arteriovenous malformation was diagnosed. Because initial treatment with methylergonovine maleate was unsuccessful, the patient was treated with Gn-RH agonists. The lesion completely disappeared after 6 months of Gn-RH agonist treatment. Five months after the completion of Gn-RH agonist therapy, the patient conceived spontaneously and successfully completed a normal pregnancy. The patient has remained free from recurrence of the lesion. CONCLUSION: Gonadotropin-releasing hormone agonist therapy has the potential to be a conservative treatment modality for uterine arteriovenous malformations in hemodynamically stable patients.

Analysis of the complications after radical hysterectomy for stage IB, IIA and IIB uterine cervical cancer patients.

Aim:  This study was undertaken to assess whether radical hysterectomy and pelvic lymphadenectomy could be carried out within acceptable complications in uterine cervical cancer patients.