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For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09×10−3 and 4.37×10−3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10−5 and 1.02×10−4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.

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Previous reports have shown that exercise improves serum leptin and adiponectin abnormalities in overweight and obese individuals; however, results to date are controversial. Here we performed a systematic review and meta-analysis of the available randomized controlled trials (RCTs) of the possible beneficial action of exercise on serum leptin and adiponectin levels in overweight and obese individuals. We searched PubMed, EMbase, The Cochrane Library, and the Clinicaltrial.gov databases for relevant studies published between January 1980 and September 2015. Two independent reviewers extracted relevant data and assessed study quality and risk of bias. Data were pooled using a random-effects model for leptin and a fixed-effects model for adiponectin. Effect of size was expressed as mean difference (MD) with 95% confidence interval (CI). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I ). Twenty-eight RCTs (40 studies) were identified, of which 24 were on the effects of exercise on leptin (n=1 358) and 31 referred to changes in adiponectin (n=1 774). Our analysis revealed that exercise significantly reduced serum leptin (MD=-2.24 ng/ml; 95% CI, -3.26, -1.23; p<0.001) and increased adiponectin (MD=0.44 μg/ml; 95% CI, 0.13, 0.75; p=0.005) levels compared to no exercise as well as control (who were also overweight or obese). Exercise, particularly aerobic exercise, had a significant effect on serum leptin and a possible influence on adiponectin levels, suggesting its therapeutic implications.