Polymorphisms in period genes and bone response to hormone therapy in postmenopausal Korean women.

OBJECTIVE: In this study, we aimed to explore the association between polymorphisms in the period (PER) gene and bone response to hormone therapy (HT) in postmenopausal Korean women. METHODS: The PER1 c.2284C > G, c.2247C > T, PER2 c.3731G > A, PER3 c.2592G > A, c.3083T > C polymorphisms, and PER3 54bp variable number of tandem repeats (VNTR) were analyzed in 509 postmenopausal Korean women who received HT. Bone mineral density (BMD) at the lumbar spine and femoral neck before and after 1 year of HT and serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-κB ligand (sRANKL) and bone turnover markers were measured after 6 months of HT. RESULTS: The PER1 c.2884 C > G polymorphism and PER3 54bp VNTR were associated with annual percent changes in BMD of the femoral neck after 1 year of HT (p < 0.05). Changes in BMD at the femoral neck in the non-CC genotype of the PER1 c.2884C > G polymorphism and in the 4-repeat homozygote of PER3 54bp VNTR were significantly lower than those in CC genotype and non-4-repeat homozygote, respectively. The PER1 c.2884C > G polymorphism was associated with the non-response (>3% BMD loss/year after HT) of HT. The non-CC genotype of the PER1 c.2884C > G polymorphism showed a 1.92-times higher risk of non-response at the lumbar spine and/or femoral neck (p = 0.01) compared with the CC genotype. No significant changes in bone markers after 6 months of HT were noted according to the PER1 c.2884C > G polymorphism. CONCLUSIONS: The PER1 c.2884C > G polymorphism may be associated with risk of non-response to HT in postmenopausal Korean women.

Association between polymorphisms in period genes and bone density in postmenopausal Korean women.

OBJECTIVE: In the present study, we aimed to investigate the association between genetic polymorphisms in period (PER) genes and bone mineral density (BMD) in postmenopausal Korean women. METHODS: The PER1 c.2247C> T and c.2884C> G polymorphisms; the PER2 c.661G> A and c.3731G> A polymorphisms; the PER3 c.2592G> A, c.3029C> T, c.3035C> T, and c.3083T> C polymorphisms, and the 54 bp variable number tandem repeats polymorphism were analyzed in 551 postmenopausal Korean women. Serum leptin, soluble leptin receptor, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, and bone markers including bone alkaline phosphatase and carboxy-terminal telopeptide of type I collagen were measured, and the lumbar spine and femoral neck BMDs were also determined. RESULTS: The PER2 c.661G> A, PER3 c.3029C> T and c.3035C> T polymorphisms were not observed. The PER2 and PER3 polymorphisms evaluated were not related to BMD, whereas associations of the c.2247C> T and c.2884C> G polymorphisms in PER1 with the lumbar spine BMD were observed both singly and in combination. The CC haplotype homozygotes showed significantly lower lumbar spine BMD than participants with other genotypes. Additionally, 2.01-fold higher odds for osteoporosis of the lumbar spine were found in the CC haplotype homozygotes compared to women not carrying the haplotype CC allele. No significant differences in bone markers were detected according to the PER1 haplotype genotype. CONCLUSIONS: Our results suggest that both the PER1 c.2247C> T and c.2884C> G polymorphisms may be genetic factors affecting the lumbar spine BMD in postmenopausal Korean women.

Atherogenic changes in low-density lipoprotein particle profiles were not observed in non-obese women with polycystic ovary syndrome.

STUDY QUESTION: Is a preponderance of small dense low-density lipoprotein-cholesterol (LDL-C) observed in non-obese women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Non-obese Korean women with PCOS have no quantitative or qualitative changes in LDL-C profiles. WHAT IS KNOWN ALREADY: Small dense LDL particles (sd-LDL) are more atherogenic than large buoyant ones and are strongly associated with coronary artery disease independent of other risk factors. Many investigators have found an increased proportion of atherogenic sd-LDL or a decreased mean LDL particle size in women with PCOS, but all of these studies have been based primarily on obese or overweight women with PCOS. STUDY DESIGN, SIZE, DURATION: This was a case-control study evaluating complete lipid and lipoprotein profiles in 64 PCOS patients and 64 age- and BMI-matched controls. All women with PCOS in our study population were not obese. To determine the differences in the LDL particle profiles between PCOS phenotypes, the patients with PCOS were divided into two subgroups according to the presence of clinical or biochemical hyperandrogenism. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using the Rotterdam criteria, we recruited 64 women (18-40 years) with PCOS who were attending a tertiary university hospital. A total of 64 premenopausal control women were matched with patients based on exact age and BMI (± 1.0 kg/m(2)). All the participants fell within the non-obese range of the BMI (<25 kg/m(2)) according to the definition of obesity for Asians. The LDL subfraction was analyzed by 3% polyacrylamide gel tube electrophoresis. Seven LDL subclasses were quantified and LDL subclasses 3-7 were small LDL subfractions. LDL subfraction scores were calculated based on the following weighted scoring system developed by the manufacturer: scores of <5.5 were categorized as phenotype A (large, buoyant LDLs), and those >5.5 were categorized as non-A phenotype (sd-LDLs). The system also determined the mean LDL particle size diameter. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in the absolute level of LDL-C, mean LDL diameter or percentage of atherogenic sd-LDLs between PCOS patients and controls or between hyperandrogenic and non-hyperandrogenic PCOS subgroups. Also, none of the subjects showed a non-A LDL phenotype. The most notable finding of our study was the difference in the lipoprotein (a) levels and prevalence of its elevation in PCOS patients versus controls (P = 0.002 and P = 0.004, respectively), and between PCOS subgroups (P = 0.030 and P = 0.047, respectively). LIMITATIONS, REASONS FOR CAUTION: Inclusion of only non-obese subjects, small sample size and lack of information on other potential confounding factors, such as differences in diet and/or exercise patterns. WIDER IMPLICATIONS OF THE FINDINGS: Although our findings suggest that non-obese women with PCOS have no significant quantitative or qualitative changes in LDL-C profile, data on obese Korean women with PCOS could offer complementary findings about the possible relationship between the magnitude of obesity and LDL phenotype. Further investigations are needed to determine whether a change in lipoprotein (a) in non-obese women with PCOS is also found in other ethnic groups. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest exists. This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A100624). TRIAL REGISTRATION NUMBER: N/A.

Association between hormone therapy and nerve conduction study parameters in postmenopausal women.

OBJECTIVE: We aimed to analyze the association between hormone therapy (HT) and nerve conduction parameters. METHODS: This retrospective study consisted of 46 postmenopausal women not receiving HT, and 18 postmenopausal women who received HT. Eligible patients were identified from the hospital's database and the nerve conduction study was performed on the upper or lower limb without pain or other symptoms. RESULTS: No significant difference was demonstrated in the unadjusted nerve conduction parameters according to HT. After adjusting for age and body mass index, the latency of the posterior tibial motor nerve in postmenopausal women receiving HT was significantly shorter than that in women not receiving HT. Moreover, the velocity of the median motor nerve tended to be faster in postmenopausal women receiving HT than those not receiving HT, although the difference was not statistically significant. CONCLUSION: These findings imply that HT may affect the nerve conduction parameters in postmenopausal women.

The effects of hormone therapy on metabolic risk factors in postmenopausal Korean women.

OBJECTIVE: We sought to assess the prevalence of metabolic syndrome (MetS) among Korean postmenopausal women and to investigate the effect of hormone therapy status and reproductive characteristics on body composition and MetS risk factors. STUDY DESIGN: We performed a cross-sectional study involving a cohort of 2005 postmenopausal Korean women. We defined MetS using the modified National Cholesterol Education Program (NCEP) criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute guidelines. The criteria for abdominal obesity were adopted from the cut-offs suggested by the Korean Society for the Study of Obesity. Participants with three or more of the following conditions were classified as having MetS: waist circumference ≥ 85 cm; blood pressure ≥ 130/85 mmHg; fasting plasma triglycerides ≥ 150 mg/dl; high density lipoprotein cholesterol < 50 mg/dl; glucose ≥ 100 mg/dl and/or receiving treatment for their condition. RESULTS: The prevalence of MetS was 22.1% in the study population and increased with age. After adjusting for age and related reproductive characteristics, it was found that ever-use of hormone therapy (prior or current) was associated with decreased risk of postmenopausal MetS. Among individual risk factors for MetS, current hormone therapy seemed to be associated with decreased prevalence of abdominal obesity and better glucose metabolism and prior use of hormone therapy were associated with lower risk of abdominal obesity and high blood pressure. CONCLUSION: Postmenopausal hormone therapy is associated with decreased risk of MetS in postmenopausal Korean women.

Isoflurane decreases death of human embryonic stem cell-derived, transcriptional marker Nkx2.5(+) cardiac progenitor cells.

BACKGROUND: Cardiac progenitor cells (CPCs) derived from human embryonic stem cells (hESCs) can multiply and generate cardiomyocytes, offering their tremendous potential for cardiac regenerative therapy. However, poor survival under stressful conditions is a major hurdle in the regeneration. We investigated whether isoflurane-induced preconditioning can increase hESC-derived CPC survival under oxidative stress. METHODS: Undifferentiated hESCs were cultured in suspension with 20% FBS (fetal bovine serum) and 20 ng/ml of BMP-4 (bone morphogenetic protein-4) to form embryoid bodies and grown onto Matrigel-coated plates for 2-3 weeks. To characterise the differentiated CPCs, immunostaining for Nkx2.5 (nonspecific transcriptional marker) and Isl-1 was performed. hESC-derived CPCs were exposed to oxidative stress induced by H(2) O(2) and FeSO(4) . For anaesthetic preconditioning, CPCs were exposed to isoflurane (0.25, 0.5, 1.0 mM). CPC survival was determined by trypan blue exclusion. A mitoK(ATP) channels inhibitor, 5-hydroxydecanoic acid (200 µM) and an opener, diazoxide (100 µM), were used to investigate the involvement of mitoK(ATP) channels. RESULTS: hESC-derived CPCs stained with Nkx2.5 were 95 ± 3% of total cell number. Isoflurane (0.5 and 1.0 mM)-preconditioned CPCs showed a significantly lower death rate compared with control (0.5 mM: 30.6 ± 10.7% and 1.0 mM: 28.5 ± 6.2% vs. control: 43.2 ± 9.9%). Inhibition of mitoK(ATP) channels with 5-HD completely abolished the protective effects of isoflurane. Diazoxide significantly decreased CPC death (29.5 ± 12.4%). However, when diazoxide was applied to CPC preconditioned with isoflurane, CPC death did not decrease further (28.7 ± 10.9%). CONCLUSION: Isoflurane increased hESC-derived Nkx2.5(+) CPC survival under oxidative stress, and mitoK(ATP) channels may be involved in the protective effect.

Polycystic ovary syndrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with polycystic ovary syndrome (PCOS). However, most studies investigated the prevalence of NAFLD in obese PCOS patients. AIM: To compare the prevalence of non-obese NAFLD in women with or without PCOS, and to assess an independent association between PCOS and NAFLD in a non-obese Asian cohort. METHODS: This was a case-control study using a prospective PCOS cohort. After subjects with other potential causes of chronic liver disease were excluded, 275 non-obese women with PCOS and 892 non-obese controls were enrolled. NAFLD was determined by hepatic ultrasonography. Main outcomes were the prevalence of NAFLD on hepatic ultrasonography between non-obese women with or without PCOS, and an independent association between non-obese NAFLD and PCOS. RESULTS: Non-obese women with PCOS had a significantly higher prevalence of NAFLD than those without PCOS (5.5% vs. 2.8%, P = 0.027). PCOS was associated with non-obese NAFLD (odds ratio: 2.62, 95% confidence intervals: 1.25-5.48) after adjustment for age and body mass index (BMI). In women with PCOS, the level of androgenicity represented by free testosterone or free androgen index was associated with NAFLD after adjustment for age, BMI, lipid profile, insulin resistance or glycaemic status. CONCLUSIONS: Non-obese NAFLD is more prevalent in women with polycystic ovary syndrome than in those without. In non-obese patients with polycystic ovary syndrome, hyperandrogenemia may be an independent risk factor for non-obese NAFLD.

Effects of Anesthetic Agent Propofol on Postoperative Sex Hormone Levels.

Introduction: Several studies have found anesthetic agents including propofol in ovarian follicular fluid. However, little is known about the effect of anesthetic agents on ovarian function. We aimed to investigate whether there were differences in the postoperative levels of sex hormones when propofol was used as the anesthetic agent. Methods: A retrospective review was done of 80 patients who underwent ovarian surgery, with 72 infertile women serving as controls. Patients were included in the study if their serum estradiol (E2) and follicle stimulating hormone (FSH) levels were measured during their first postoperative menstrual cycle. Results: Patients were grouped according to the use or non-use of propofol as follows: propofol group (n = 39) and non-propofol group (n = 41). The control group did not undergo surgery. Postoperative E2 levels did not differ between the three groups, but FSH levels were significantly higher in the patients who had undergone surgery compared to controls (p < 0.05). Post-hoc analysis of E2 and FSH levels in the propofol and non-propofol groups did not show any significant differences. Conclusions: The use of propofol did not result in any differences compared to other anesthetic agents in terms of postoperative sex hormone levels after gynecologic surgery. The type of anesthetic agent does not seem to affect the postoperative levels of female sex hormones.

MicroRNA Profile of Granulosa Cells after Ovarian Stimulation Differs According to Maturity of Retrieved Oocytes.

Background: Recent animal studies demonstrated that regulating the microRNA (miRNA) in granulosa cells (GCs) modulates the meiotic competence of oocytes. However, the difference in expression profiles of miRNAs in human GCs according to the maturity of the oocyte still remains to be elucidated. Objective: This observational study investigated whether the miRNA profile of human GCs differs according to the maturity of the retrieved oocyte after controlled ovarian stimulation for in vitro fertilization (IVF). Methods: Ten women who underwent ovarian stimulation cycles with GnRH agonist long protocols were recruited. The follicular fluid (FF) from dominant follicles was individually aspirated at oocyte retrieval. Oocytes were divided into two groups according to oocyte maturity ("mature group" vs. "immature group"). GCs were collected from the FF and miRNA was analyzed using real-time PCR. Results: Mean number of MII oocytes in the mature group was 1.6 ± 0.9 with none in the immature group (p = 0.008). Mean number of MI oocytes was 5.6 ± 2.1 in the mature group and 1.0 ± 0.0 in the immature group (p = 0.008). The total number of retrieved oocytes was 8.8 ± 1.9 in the mature group and 2.0 ± 1.2 in the immature group (p = 0.008). The GCs of the mature group showed a significantly lower expression of hsa-let-7b compared to the GCs of the immature group (p < 0.001). Conclusion: Taken together, the miRNA expression profiles of human GCs obtained from dominant follicles are associated with maturity of the adjacent oocyte and may be useful as a prognosticator of IVF outcome.

The structure of the ferric siderophore binding protein FhuD complexed with gallichrome.

Siderophore binding proteins play a key role in the uptake of iron in many gram-positive and gram-negative bacteria. FhuD is a soluble periplasmic binding protein that transports ferrichrome and other hydroxamate siderophores. The crystal structure of FhuD from Escherichia coli in complex with the ferrichrome homolog gallichrome has been determined at 1.9 ¿ resolution, the first structure of a periplasmic binding protein involved in the uptake of siderophores. Gallichrome is held in a shallow pocket lined with aromatic groups; Arg and Tyr side chains interact directly with the hydroxamate moieties of the siderophore. FhuD possesses a novel fold, suggesting that its mechanisms of ligand binding and release are different from other structurally characterized periplasmic ligand binding proteins.

Association of the vitamin D receptor start codon polymorphism (FokI) with bone mineral density in postmenopausal Korean women.

We undertook this study in order to examine the association between bone mineral density (BMD) and a polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene. This polymorphism was detected by restriction fragment length polymorphism analysis, using polymerase chain reaction (PCR) and the restriction endonuclease FokI. The f allele indicates the presence of the FokI site, and the F allele its absence. The FokI genotype was determined in 174 postmenopausal Korean women, aged 43-71 years. The distribution of FokI genotypes in Koreans was found not to differ significantly from those found in Caucasians and Japanese, although it does differ significantly from that found in the black American population. We observed a significant association between the FokI polymorphism and lumbar BMD; P = 0.048, analysis of covariance [ANCOVA], but no association with femoral neck BMD (P = 0.505, ANCOVA). Those with the ff genotype had a 13.3% lower BMD in the lumbar spine than the FF subjects. In addition, a significantly higher prevalence of the ff genotype was observed in osteoporotic compared with osteopenic or normal women (P = 0.036, chi2 test). These data suggest that the ff genotype of the VDR gene correlates with decreased BMD in the lumbar spine in postmenopausal Korean women.