Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
Hum Reprod. 2023 Jun 1;38(6):1168-1182. doi: 10.1093/humrep/dead053.
What is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)?
Excess body fat, even during childhood/adolescence, and metabolic parameters, suggestive of hyperinsulinaemia/insulin resistance, significantly impact the risk of PCOS in a linear fashion.
Observational and Mendelian randomization (MR) data have demonstrated an association between adulthood overweight/obesity and development of PCOS. However, the contribution of body composition in childhood/adolescence to incident PCOS is unclear, as is the influence of childhood overweight/obesity.
STUDY DESIGN, SIZE, DURATION: We conducted a systematic review and meta-analysis and integrated our results with a previously published systematic review. Two blinded investigators screened abstracts published between November 2010 and May 2021. Furthermore, we incorporated summary statistics from genome-wide association study (GWAS) data in subjects of European ancestry. Adult overweight was defined as BMI ≥ 25 kg/m2 and obesity as BMI ≥ 30 kg/m2; in Asian subjects, overweight was defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We utilized meta-analysis and MR together to allow synthesis of genetic and observational data. For the systematic review, the search revealed 71 studies, of which 63 were included in meta-analysis by calculating odds ratios (ORs) using the random-effects model. Furthermore, we conducted a two-sample MR study of GWAS data to determine the impact of childhood and adult body size (defined categorically by BMI and childhood body size proportions), abnormal body composition and metabolic parameters (higher fasting serum insulin or lower sex hormone-binding globulin (SHBG) concentration) on the odds of incident PCOS via the inverse-variance weighted method.
Significant associations were shown between body composition and PCOS incidence. From the systematic review/meta-analysis, women with overweight (OR 3.80, 2.87-5.03), obesity (OR 4.99, 3.74-6.67), and central obesity (OR 2.93, 2.08-4.12) had increased odds of PCOS. For adolescents with overweight and/or obesity, the PCOS odds were greater than for adults. From MR, for every standard deviation increase in BMI (4.8 kg/m2), the odds of PCOS increased by 2.76 (2.27-3.35). Childhood body size had an independent effect on PCOS odds after adjusting for adult body size (OR: 2.56, 1.57-4.20). Genetically determined body fat percentage (OR 3.05, 2.24-4.15), whole body fat mass (OR 2.53, 2.04-3.14), fasting serum insulin (OR 6.98, 2.02-24.13), and SHBG concentration (OR 0.74, 0.64-0.87) were all significantly associated with PCOS in a linear relation.
LIMITATIONS, REASONS FOR CAUTION: The meta-analysis included studies which were cross-sectional and retrospective, limiting our ability to determine causality. MR was limited by interrogating subjects only of European ancestry and including cases classified by either self-diagnosis or diagnostic criteria.
Our study demonstrates for the first time a critical role of the impact of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Our results, driven by genetically determined childhood/adolescent body composition, higher BMI, hyperinsulinaemia, and lower SHBG, clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype. Overall, effective weight maintenance, even from the early years, is likely to reduce the risk of this reproductive endocrine disorder.
STUDY FUNDING/COMPETING INTEREST(S): S.S.Z. was funded by a National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship. U.A. is chair of the NIHR Steering Committee Trial-CASSANDRA-DN. No other authors declare any sources of funding or relevant conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relations that could be construed as a potential conflict of interest.
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儿童期、青春期和成年期的身体成分以及代谢参数对多囊卵巢综合征（PCOS）发病的影响如何？
过多的体脂，甚至在儿童期/青春期，以及代谢参数，提示存在高胰岛素血症/胰岛素抵抗，会以线性方式显著影响 PCOS 的发病风险。
观察性研究和孟德尔随机化（MR）数据表明，成年期超重/肥胖与 PCOS 的发生有关。然而，儿童期/青春期身体成分对 PCOS 发病的影响尚不清楚，儿童期超重/肥胖的影响也是如此。
研究设计、规模、持续时间：我们进行了系统评价和荟萃分析，并将我们的结果与之前发表的系统评价相结合。两名盲法调查员筛选了 2010 年 11 月至 2021 年 5 月期间发表的摘要。此外，我们还将欧洲血统人群的全基因组关联研究（GWAS）数据的汇总统计数据纳入其中。成人超重定义为 BMI≥25kg/m2，肥胖定义为 BMI≥30kg/m2；在亚洲人群中，超重定义为 BMI≥23kg/m2，肥胖定义为 BMI≥25kg/m2。
参与者/材料、设置、方法：我们使用荟萃分析和 MR 一起进行，以允许遗传和观察性数据的综合。对于系统评价，搜索结果显示有 71 项研究，其中 63 项通过使用随机效应模型计算优势比（OR）纳入荟萃分析。此外，我们还进行了两样本 MR 研究，以确定通过逆方差加权法，儿童和成人身体大小（通过 BMI 和儿童身体成分比例分类定义）、异常身体成分和代谢参数（较高的空腹血清胰岛素或较低的性激素结合球蛋白（SHBG）浓度）对 PCOS 发病几率的影响。
身体成分与 PCOS 发病之间存在显著关联。从系统评价/荟萃分析中可以看出，超重（OR 3.80，2.87-5.03）、肥胖（OR 4.99，3.74-6.67）和中心性肥胖（OR 2.93，2.08-4.12）的女性发生 PCOS 的几率更高。对于超重和/或肥胖的青少年，PCOS 的发病几率大于成年人。从 MR 来看，BMI 每增加一个标准差（4.8kg/m2），PCOS 的发病几率就会增加 2.76（2.27-3.35）。在调整成人身体大小后，儿童时期的身体大小对 PCOS 发病几率有独立影响（OR：2.56，1.57-4.20）。身体脂肪百分比（OR 3.05，2.24-4.15）、全身脂肪量（OR 2.53，2.04-3.14）、空腹血清胰岛素（OR 6.98，2.02-24.13）和 SHBG 浓度（OR 0.74，0.64-0.87）均与 PCOS 呈线性关系。
局限性、谨慎的原因：荟萃分析包括横断面和回顾性研究，限制了我们确定因果关系的能力。MR 受到仅研究欧洲血统人群和包括自我诊断或诊断标准分类的病例的限制。
我们的研究首次证明了儿童期/青春期过多的体脂对成年 PCOS 病理生理学的关键作用。我们的结果主要由遗传决定的儿童期/青春期身体成分、更高的 BMI、高胰岛素血症和较低的 SHBG 驱动，明显支持肥胖导致代谢性而非生殖性 PCOS 表型。总的来说，即使是从早期开始，有效维持体重也可能降低这种生殖内分泌疾病的风险。
研究资金/利益冲突：S.S.Z. 得到了英国国家卫生与保健研究所（NIHR）学术临床讲师的资助。U.A. 是 NIHR 指导委员会临床试验-CASSANDRA-DN 的主席。其他作者没有宣布任何资金来源或相关利益冲突。作者声明研究是在没有任何可能被解释为潜在利益冲突的商业或财务关系的情况下进行的。
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