3) 中高年女性の健康管理プログラム策定における基礎的・臨床的検討(シンポジウム1:女性ヘルスケア「中高年に対する女性医学の展開」,第64回日本産科婦人科学会・学術講演会)

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Objectives It is supposed that many disorders increased in middle-aged women are resulting from the dysfunction of the organ accompanying aging changes and the chronic decrease or lack of estrogens due to the menopause. These disorders are sometimes detected in especially only a single organ but also overlapped organs by changing component of extracellular matrix as collagens, proteoglycans and hyaluronic acids distributed in the whole body. In any case, dysfunctions of organs have considerable influence on middle-aged women's quality of life (QOL). Then it might be very important that when and how we perform medical intervention for the prevention or treatment of organ dysfunctions or diseases. The aim of this report is to grasp middle-aged women's health condition comprehensively and consider how to predict these organ dysfunctions effectively using epidemiological, clinical and basic data. Materials and Methods The data from the cohort study were mainly used in this report. This cohort study named Iwaki Project is longitudinal observational study of residents in the rural area of Hirosaki city and has been performed annually since 2005. This cohort study is investigating several factors concerning about the health condition of residents gathering the participants at same place once a year. About 1,100 persons participate every year and about 700 persons are women (including about 400 perimenopausal or postmenopausal women), and a repetitive participating rate is high. In this report, we also used other data which were obtained from women in the outpatient clinic of our hospital or co-researchers institution and from rats in basic research. These data were analyzed following researches as below. 1) Frequency of morbidity of the life-style related diseases in the local residents: We analyzed morbidity of these diseases including the osteoporosis horizontally in 240 postmenopausal women at Iwaki project and the relation among each disease was investigated. 2) The new predictive marker of osteoporosis: Clinically we investigated the relation between plasma homocysteine or urine pentosidine and the future fractures of the 251 osteoporotic women at the hospital or the clinic. Basically using osteoporotic animals (OVX rats), we compared the changes of some components, for example, proteoglycan (PG) or its functional sugar chain (glycosaminoglycan, GAG) in the extracellular matrix of the femur bone tissue with control (both groups were consisted of ten Wistar female rats respectively) and otherwise using human urine we also compared urine GAG between healthy and osteoporotic postmenopausal women (ten cases each). 3) The common factor between osteoporosis and dyslipidemia: It is supposed that the common factor in the relationship of bone-fat-vascular disorders may be some cytokines including adipocytokines or some aging markers like a pentosidine. To observe relationship between bone mineral density (BMD) using osteo-sono index and data of lipoprofiles, cytokines and aging markers within an annual interval in 99 postmenopausal women participated in Iwaki project at least twice. 4) The relationship between the past information at her pregnant and the present state about lifestyle related diseases using their maternity record books: We collected the 148 maternity record books from the residents participated in Iwaki Project at 2011 and observed the relationship between the data from each maternity record book at her younger age giving the birth and the present morbidity of life-style related diseases at her middle-aged phase. The data from maternity record books as described below; weight, urine findings, blood pressures in their course at pregnant were analyzed in relation to middle-aged women's health condition of postmenopausal group. 5) More exact prediction of the menopause: We examined the possibility of the anti-mullerian hormone (AMH), which is already has used to assess the ability of ovarial reservation in the field of reproductive medicines, as more predictive factor of the menopause. Pursuing the inhibin B, follicular stimulating hormone (FSH) and 17beta-estradiol (E2) were also measured besides AMH from same cases for several years in the 256 healthy women participated repeatedly in Iwaki Project and the relationships of each data with onset of the menopause or irregular cycle of menstruation were compared respectively. Results 1) In 240 postmenopausal women who have at least one of lifestyle-related diseases such as hypertension, dyslipidemia, diabetes mellitus and osteoporosis at the time participated in this project, there were detected 27% of women who have more than two kinds of these diseases. This trend is also observed in the Japan Nurses' Health Study (JNHS) which is nationwide cohort study of women performed by The Japan Society for Menopause and Women's Health. 2) Observation of 251 osteoporotic women treated with bisphosphonates for several years showed that the high level of plasma homocysteine and urine pentosidine at baseline were related significantly with the new fracture in future. In basic research, it showed that PGs in the femur bone of the OVX rats decreased hugely more than hyaluronic acids or acid soluble collagens in same tissues. And clinically in the human urine, it showed that the GAGs, which are functional domains of PGs, in postmenopausal osteoporotic women increased more than the healthy postmenopausal women. We analyzed urine extracts from both by electrophoresis and detected the different type of GAGs (for example, chondroitin sulfate) in these urines between the osteoporotic and healthy women. There may be the possibility that osteoporotic change is started as the quantity and quality in the bone firstly, but the findings is a preliminary and further studies will be required. 3) In the analysis which pursued 99 postmenopausal women, bone mineral density would significantly decreased in the group with higher total cholesterol (TC) at one year before and also in the group with higher LDL cholesterol as a tendency. At the viewpoint of cytokines, there were detected high level of IL-8, one of inflammatory cytokine, in both groups of high TC and low BMD. 4) From analysis of the data from 148 maternity record books, it indicated that the average of the systolic arterial blood pressure above 120mmHg or diastolic blood pressure 70mmHg during pregnancy significantly increased the odds ratio for the risk of hypertension to 2.69 significantly. 5) In the 256 women observed for several years, it detected that measured values of AMH would be lower level or under sensitivity from 3 years before menstruation turned into irregularity and 4 years before onset of menopause during the observation period. Conclusion It was confirmed that the life-style related diseases in middle-aged women was often overlapped or related to each other. Beyond that, in this report, we detected high values of homocysteine or pentosidine related to new bone fracture and showed the possibility that the PGs in the bone might be a new biomarker for bone fragility. Among life-style related diseases, there was relationships between the abnormal state of lipoprofiles and the subsequent fragility of bone and the common predictive factor may be IL-8. It was also suggested that over some levels of the average blood pressure at pregnant were raised the risk of hypertension at middle-aged women. Then for the healthcare of middle-aged women, it might be important to take those predictive factors described as above into consideration at medical intervention or prevention for these diseases. Moreover, using AMH as a prediction of menopause, middle-aged women may take the opportunity watching their health around perimenopose and beyond. From the viewpoint of preventive medicine, it needs to preparing health care program of middleaged women based on more useful predictive factors. Although several factors we showed in this report including AMH may play a valuable role for prevention of life-style related diseases, further researches and verification will be required.
2012-10-01

3) 中高年女性の健康管理プログラム策定における基礎的・臨床的検討(シンポジウム1:女性ヘルスケア「中高年に対する女性医学の展開」,第64回日本産科婦人科学会・学術講演会)

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