4) 幼少期の高アンドロゲン環境とインスリン抵抗性からみたPCOSの病因および管理に関する検討(シンポジウム3:生殖「多嚢胞性卵巣症候群(PCOS)の病因・病態と管理」,第65回日本産科婦人科学会・学術講演会)

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The aims of this study were to investigate the etiology of polycystic ovary syndrome (PCOS) with regard to hyperandrogenism in the prepubertal stage and insulin resistance, and to establish a management policy for PCOS in women's healthcare by using data from Japanese women. For this purpose we set out the following four themes. Theme 1: The effects of testosterone on ovarian phenotype, cancellous bone, and marrow adipocytes in a prepubertal female rat model of PCOS. Fifty-one Sprague-Dawley rats were divided into four groups based on the day of testosterone propionate (0.1mg/weight(g)) injection: no testosterone treatment (C); injected on the 9th day after birth (9D); injected 4 weeks after birth (4W); and injected 8 weeks after birth (8W). Approximately 16 weeks after birth, all animals were killed. The ovaries of group 9D showed many cystic follicles without corpora lutea. The bone mineral density for the proximal tibia of group 9D was significantly higher compared with the other groups. Based on bone histomorphometry of the proximal tibia, group 9D had a higher bone volume, lower bone formation, lower bone resorption, and lower rate of longitudinal growth compared with the other groups. Based on fat histomorphometry, group 9D had a lower bone fat volume and number of fat cells in bone marrow compared with the other groups. In contrast, groups 4W and 8W showed similar values of bone and fat histomorphometric parameters to group C. We conclude that female rats receiving testosterone within 9 days of birth, i.e. within the androgen-sensitive period, developed polycystic ovaries, high bone volume, low bone turnover, and lower fat content in the bone marrow. Theme 2: Genetic factors for insulin-resistance in adult human PCOS. The beta 3-adrenergic receptor (BAR-3) gene has been implicated in diabetes and obesity. Previously, we have shown that a BAR-3 (Trp64Arg) mutation has pleiotropic effects on a number physiological systems, including body mass index (BMI), blood pressure, and reproductive history, suggesting evolutionary reasons for its maintenance, i.e. thrifty gene, in the population of elderly Australian women. Thus, we investigated polymorphisms of the beta 2 and beta 3 adrenergic receptor (BAR-2 and BAR-3) genes associated with insulin-resistant PCOS pathogenesis. Fifty-nine infertile Japanese women with PCOS and 97 healthy Japanese controls were studied. Blood metabolites and genomic DNA polymorphisms of BAR-2 (Argl6Gly and Gln27Glu) and BAR-3 (Trp64Arg) were analyzed. The frequency of the Glu 27 allele of BAR-2 was significantly higher in PCOS patients compared with controls (0.07 vs. 0.02, odds ratio (OR) 4.63, 95% CI 1.35-15.93), whereas the frequency of the Gly 16 allele was only slightly higher in the PCOS group compared with controls (0.58 vs. 0.47, OR 1.51, 95% CI 0.95-2.40). The frequency of the Arg 64 allele of BAR-3 was not significantly different between the two groups. The polymorphism in codon 27(Gln27Glu) of BAR-2 is linked to the expression of PCOS in Japanese women. Theme 3: Simple and useful index of insulin resistance in Japanese women with clomipheneresistant PCOS. We evaluated, prospectively, the prognostic factors for ovulatory responses following clomiphene citrate (CC) administration in PCOS. Fifty-nine infertile patients diagnosed with PCOS were recruited. Ovulation was induced using 100mg/day CC administered daily from days 5-9 of the cycle. For a 75g oral glucose tolerance test (75g OGTT), blood glucose levels at 60 and 120min, the area under the curve, and blood insulin levels at 120min in the non-responder group (n=25) were significantly higher compared with the responder group (n=34). However, fasting blood glucose measurements and insulin were not significantly different between the groups. In the receiver operating characteristic curves, the most appropriate cutoff point was 120mg/dL for the blood glucose level at 120min, and 9,000 for the blood glucose multiplied by insulin level at 120min. The levels of blood glucose and blood glucose multiplied by insulin at 120min after 75g OGTT may be good biochemical markers of CC resistance in PCOS. Theme 4: The association between PCOS and the risk of lifestyle-related diseases in later life in Japanese women. The Japan Nurses' Health Study (JNHS) is a cohort study of Japanese women's health. Data from the JNHS baseline survey between 2001 and 2007 were used to conduct a cross-sectional analysis. A total of 44,601 women were classified into three categories: ovarian infertility group (n=1,167), other infertility group (n=4,619), and no infertility group (n=38,815). The rate of obese women (BMI≥25) who were < 45 years old in the ovarian infertility group was significantly higher compared with the other two groups (18.0%, 11.8%, 10.1%, respectively). Logistic regression analysis compared with the no infertility group showed the following. 1) For hypertension, the OR of the ovarian infertility group was significantly higher (OR:1.65-1.87) in women who were ≥ 45 years old, but not in women who were < 45 years old. 2) For hypercholesterolemia, the age-adjusted OR of the ovarian infertility group was significantly higher (OR:1.39-1.42), but the multivariable-adjusted (including BMI and abdominal circumference) OR was not significant. 3) For diabetes mellitus (DM), the age-adjusted OR of the ovarian infertility group was significantly higher (2.92) in women who were < 45 years old, but the multivariable-adjusted OR was not significant. We conclude that Japanese women with ovarian infertility (most women were PCOS) are at high risk of hypertension from 45 years of age onwards, and DM before 45 years of age. DM may be prevented by body weight loss in younger age groups. Women with PCOS have problems with reproduction. However, we conclude in this study that the etiology of PCOS may be hyperandrogenism in the prepubertal stage, and insulin resistance due to genetic factors. Moreover, Japanese women with PCOS are at a high risk of lifestyle-related diseases in later life. Consequently, PCOS is a matter of great importance for women's healthcare for healthy aging across the lifespan.
2013-12-01

4) 幼少期の高アンドロゲン環境とインスリン抵抗性からみたPCOSの病因および管理に関する検討(シンポジウム3:生殖「多嚢胞性卵巣症候群(PCOS)の病因・病態と管理」,第65回日本産科婦人科学会・学術講演会)

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