Hideki Mizunuma

Early menarche, nulliparity and the risk for premature and early natural menopause

Abstract STUDY QUESTION Are parity and the timing of menarche associated with premature and early natural menopause? SUMMARY ANSWER Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40–44 years), a risk that is amplified for nulliparous women. WHAT IS KNOWN ALREADY Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power. STUDY DESIGN, SIZE, DURATION This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). PARTICIPANTS/MATERIALS, SETTING, METHODS Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40–44 years), 45–49 years, 50–51 years, 52–53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation. MAIN RESULTS AND THE ROLE OF CHANCE The median age at FMP was 50 years (interquartile range 48–53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12–13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53–2.12) and early menopause (1.31, 1.19–1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84–2.77) and early menopause (1.32, 1.09–1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04–7.87) and 2-fold increased risk of early menopause (2.16, 1.48–3.15) compared with women who had menarche at ≥12 years and two or more children. LIMITATIONS, REASONS FOR CAUTION Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias. WIDER IMPLICATIONS OF THE FINDINGS Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause. STUDY FUNDING/COMPETING INTEREST(S) InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.

Gene therapy for ovarian cancer using carbonyl reductase 1 DNA with a polyamidoamine dendrimer in mouse models

Ovarian cancer (OC) in which carbonyl reductase 1 (CBR1) is highly expressed has good prognosis. The aims of this study were to determine the optimal conditions for delivering CBR1 DNA to OC cells via a polyamidoamine (PAMAM) dendrimer and to examine the therapeutic effectiveness of using a CBR1/PAMAM dendrimer to treat OC. The ratio for mixture of the PAMAM dendrimer and CBR1 plasmid DNA was defined as the ratio of the number of moles of phosphate groups in plasmid DNA to the number of moles of amino groups in PAMAM, which was expressed as N/P ratio. Mice were intraperitoneally injected with OC cells (HRA) to create peritoneal carcinomatosis. CBR1 DNA/PAMAM dendrimer complexes were administered on alternate days after injection of HRA cells. Cells transfected with CBR1 DNA at N/P ratio of 20:1 for 48u2009h produced the highest level of CBR1 expression. All the mice in control group died prior to day 25. However, all the mice administered the CBR1 DNA/PAMAM dendrimer survived (P<0.001). Use of a PAMAM dendrimer allowed CBR1 DNA to be delivered to cancer cells. The results suggested that CBR1 DNA/PAMAM dendrimer complexes may represent a potent gene therapy for the treatment of advanced OC.

Expression of Natural Cytotoxicity Receptors on and Intracellular Cytokine Production by NK Cells in Women with Gestational Diabetes Mellitus.

To determine the role of peripheral blood NK (pNK) cells in putative etiology of gestational diabetes, the expression of surface markers on pNK cells and the percentage of cytokine‐producing pNK cells in women at 12 weeks of pregnancy with gestational diabetes mellitus (GDM) were studied.

The InterLACE study: Design, data harmonization and characteristics across 20 studies on women's health.

OBJECTIVESnThe International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of womens reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE.nnnSTUDY DESIGNnInterLACE is an individual-level pooled study of 20 observational studies (12 of which are longitudinal) from ten countries. Variables were harmonized across studies to create a new and systematic synthesis of life-course data.nnnMAIN OUTCOME MEASURESnHarmonized data were derived in three domains: 1) socio-demographic and lifestyle factors, 2) female reproductive characteristics, and 3) chronic disease outcomes (cardiovascular disease (CVD) and diabetes).nnnRESULTSnInterLACE pooled data from 229,054 mid-aged women. Overall, 76% of the women were Caucasian and 22% Japanese; other ethnicities (of 300 or more participants) included Hispanic/Latin American (0.2%), Chinese (0.2%), Middle Eastern (0.3%), African/black (0.5%), and Other (1.0%). The median age at baseline was 47 years (Inter-quartile range (IQR): 41-53), and that at the last follow-up was 56 years (IQR: 48-64). Regarding reproductive characteristics, half of the women (49.8%) had their first menstruation (menarche) at 12-13 years of age. The distribution of menopausal status and the prevalence of chronic disease varied considerably among studies. At baseline, most women (57%) were pre- or peri-menopausal, 20% reported a natural menopause (range 0.8-55.6%) and the remainder had surgery or were taking hormones. By the end of follow-up, the prevalence rates of CVD and diabetes were 7.2% (range 0.9-24.6%) and 5.1% (range 1.3-13.2%), respectively.nnnCONCLUSIONSnThe scale and heterogeneity of InterLACE data provide an opportunity to strengthen evidence concerning the relationships between reproductive health through life and subsequent risks of chronic disease, including cross-cultural comparisons.

A Strategy Using Photodynamic Therapy and Clofibric Acid to Treat Peritoneal Dissemination of Ovarian Cancer.

BACKGROUNDnThe current study examined the effectiveness of concurrent therapy using photodynamic therapy (PDT) and clofibric acid (CA) to treat peritoneal carcinomatosis resulting from ovarian cancer.nnnMATERIALS AND METHODSnNude rats were used to create a model of peritoneal carcinomatosis resulting from ovarian cancer and the effectiveness of PDT with 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA-PDT) was determined. The survival time of rats receiving that therapy was compared to the survival time of a control group. Rats with peritoneal carcinomatosis resulting from ovarian cancer were divided into 3 groups: a group that received debulking surgery (DS) alone, a group that received DS+methyl-ALA-PDT, and a group that received DS+methyl-ALA-PDT+CA. The survival time of the 3 groups was compared. Protoporphyrin, a metabolite of methyl-ALA, produces a photochemical action when activated by light. The level of protoporphyrin (the concentration) that reached organs in the abdomen was measured with HPLC.nnnRESULTSnRats receiving methyl- ALA-PDT had a significantly longer survival time compared to the controls. Rats with peritoneal carcinomatosis that received DS+methyl-ALA-PDT+CA had a significantly longer survival time compared to the rats that received DS alone. Some of the rats that received concurrent therapy survived for a prolonged period. Protoporphyrin was highly concentrated in peritoneal metastases, but only small amounts reached major organs in the abdomen. PDT was not found to result in necrosis in the intestines.nnnCONCLUSIONSnThe results indicated that concurrent therapy consisting of PDT with methyl-ALA and CA is effective at treating peritoneal carcinomatosis resulting from ovarian cancer without damaging organs.

Impact of birth weight on adult-onset diabetes mellitus in relation to current body mass index: The Japan Nurses' Health Study

Background Although birth weight is considered as a fetal determinant of the development of adult-onset diabetes mellitus (DM), its public health importance relative to adult body mass index (BMI) remains unclear. We aimed to examine the association between adult-onset DM and birth weight in relation to adult BMI. Methods We conducted a self-administered questionnaire as a baseline survey of the Japanese Nurses Health Study cohort between 2001 and 2007. Exclusion criteria were applied to the volunteer sample of 49,927 female nurses (age <30 years or unknown, current pregnancy, development of DM before the age of 30 years, unknown core variables), and data from 26,949 female nurses aged 30 years or older were used. The association between history of DM diagnosis and birth weight was analyzed using logistic regression. Results A linear inverse association was observed between birth weight and DM, after adjustment for age, BMI, and parental history of DM. The odds ratio for developing DM per 100 g increase in birth weight was 0.93 (95% confidence interval [CI], 0.90–0.96). The association was unchanged when birth weight was converted to percentile for gestational age. In the BMI-stratified analysis, the odds ratio for DM in the <2500 g birth weight group reached 4.75 (95% CI, 1.22–18.44, compared to the reference 3000–3499 g group) among women with normal low BMI (18.5–20.9). Conclusions Birth weight and its percentile for gestational age were associated with adult-onset DM. Attention should be paid to the risk of DM among women born with low weight, even when their current BMI is normal.

Ovarian infertility is associated with cardiovascular disease risk factors in later life: A Japanese cross-sectional study.

OBJECTIVESnThis study aimed to clarify the association between ovarian infertility and cardiovascular disease risk factors in later life in Japanese women.nnnSTUDY DESIGNnThe Japan Nurses Health Study (JNHS) is a cohort study of Japanese womens health. Data from the JNHS baseline survey (n = 49,927) between 2001 and 2007 were used in a cross-sectional, retrospective analysis. A total of 44,601 women were classified into three categories: ovarian infertility group (n=1167), other infertility group (n = 4619), and no infertility group (n = 38,815). Logistic regression analysis compared with the no infertility group was performed.nnnMAIN OUTCOME MEASURESnAge-adjusted odds ratios (ORs) and multivariable-adjusted ORs for hypertension, hypercholesterolemia, and diabetes mellitus (DM).nnnRESULTSnThe prevalence of obese women (BMI ≥ 25) who were < 45 years old in the ovarian infertility group was significantly higher compared with that in the other groups. Women in the ovarian infertility group were at risk for hypertension at ≥ 45 years old (age-adjusted OR: 1.65%, confidence interval [CI]: 1.23-2.21); for hypercholesterolemia at < 45 and ≥ 45 years old (age-adjusted OR: 1.42, 95% CI: 1.06-1.88 at < 45 years; age-adjusted OR: 1.39, 95% CI: 1.06-1.81 at ≥ 45 years); and for DM at < 45 years old (age-adjusted OR: 2.92, 95% CI: 1.57-5.46).nnnCONCLUSIONSnJapanese women with ovarian infertility (most women have polycystic ovary syndrome) are at high risk of hypertension from 45 years of age, hypercholesterolemia at all ages, and diabetes mellitus (DM) before 45 years old.

Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences

Protoporphyrin IX (PpIX) levels are crucial to the antitumor action of photodynamic therapy (PDT). In the present study, the underling molecular mechanisms for the variation in PpIX levels in ovarian cancer cells were investigated. Five ovarian cancer cell lines were subcutaneously grafted onto the backs of nude mice. Once tumors had developed, 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA) was administered intraperitoneally and the tumor was irradiated twice/week. PpIX levels in the tumor were assayed using high-performance liquid chromatography. Enzymes involved in heme synthesis and degradation were screened using a microarray technique. Expression of the glutathione transferase Omega-1 (GSTO1) gene involved in the conversion of PpIX into heme in cells was quantified using the reverse transcription-quantitative polymerase chain reaction. In HTOA, HRA and DISS cells, PDT resulted in significant tumor shrinkage in comparison with the controls. In MCAS and TOV21G cells, no significant alterations in tumor growth were identified compared with the untreated cells. PpIX levels increased significantly in HTOA, DISS and HRA cells compared with in MCAS and TOV21G cells. A comparison of genetic profiles using PDT-sensitive DISS cells and PDT-resistant MCAS cells indicated that MCAS cells exhibited significantly increased levels of δ-aminolevulinate synthase (a rate-limiting enzyme in heme synthesis), heme oxygenase 2 (an enzyme that degrades heme into biliverdin), and biliverdin reductase B (an enzyme that reduces biliverdin into bilirubin) in comparison with DISS cells. The level of GSTO1 expression in HTOA, HRA and DISS cells was ~2.5-fold that in MCAS and TOV21G cells. Sensitivity to PDT is related to PpIX levels in cells. The results of the present study suggested that PpIX tends not to accumulate in PDT-resistant cells despite active heme synthesis and degradation, and that high levels of GSTO1 expression are associated with increased sensitivity to PDT.

Expression of retinoid‐related orphan receptor (ROR)γt on NK22 cells in the peripheral blood and uterine endometrium of women with unexplained recurrent pregnancy loss and unexplained infertility

Recently, NK22 cells, a subset of interleukin (IL)‐22‐producing natural killer (NK) cells, were identified. We have previously reported the higher percentage of NK22 cells in women suffering recurrent pregnancy loss (RPL). Moreover, we have also reported lower expression of NKp46, a kind of natural cytotoxicity receptor (NCR), on NK cells and the changes of NK cell producing cytokines in women who experience RPL. NK22 cells express NCRs, such as NKp44 or NKp46. Retinoid‐related orphan receptor γt (RORγt) is known as a regulator of NK22 cells; however, in NK22 cells of peripheral blood (PB) and the uterine endometrium (UE), the relationship between NCRs and RORγt is unclear. We investigate RORγt expression NK22 cells in the PB and UE of women with unexplained infertility (uI) or unexplained RPL (uRPL).

Monthly oral ibandronate 100 mg is as effective as monthly intravenous ibandronate 1 mg in patients with various pathologies in the MOVEST study

The non-inferiority of oral ibandronate 100xa0mg to intravenous (i.v.) ibandronate 1xa0mg in increasing lumbar spine (LS) bone mineral density (BMD) after 12xa0months of treatment was demonstrated in the randomized, phase III MOVEST study. We conducted subgroup analyses in the per-protocol set of the study (nxa0=xa0183 oral ibandronate; nxa0=xa0189 i.v. ibandronate). In patients with LS BMD T score ≥ –3.0 or < –3.0 at screening, LS BMD gains from baseline were 4.42 and 5.79%, respectively, with oral ibandronate, and 4.60 and 5.83%, respectively, with i.v. ibandronate. LS BMD gains in patients with or without prevalent vertebral fractures were 5.21 and 5.23%, respectively, with oral ibandronate, and 5.01 and 5.49%, respectively, with i.v. ibandronate. In patients aged <75 or ≥75xa0years, LS BMD gains were 5.46 and 4.51%, respectively, with oral ibandronate, and 5.25 and 5.77%, respectively, with i.v. ibandronate. LS BMD gains in patients with baseline 25-hydroxyvitamin D levels ≥20 or <20xa0ng/mL were 5.35 and 4.76%, respectively, with oral ibandronate, and 5.05 and 6.57%, respectively, with i.v. ibandronate. Similar results were obtained in patients with or without prior bisphosphonate (BP) treatment, and in those receiving osteoporosis drug treatment other than BPs. In conclusion, oral ibandronate 100xa0mg demonstrated comparable BMD gains with monthly i.v. ibandronate, and thus shows high utility in the lifestyle and disease conditions associated with osteoporosis in Japanese patients.