Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen O, Denmark.
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, Copenhagen O, Denmark.
Hum Reprod. 2019 Aug 1;34(8):1514-1522. doi: 10.1093/humrep/dez118.
How is timing of voice break related to other male pubertal milestones as well as to BMI?
We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men.
Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known.
STUDY DESIGN, SIZE, DURATION: The study included a population-based mixed cross-sectional and longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2).
Voice break occurred at mean age 13.6 (95% CI: 13.5-13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0-11.7) nmol/L, 2.4 (2.2-2.5) IU/L and 24 (23-25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43-0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (-0.35 years/approximate SD, P < 0.001).
LIMITATIONS, REASONS FOR CAUTION: Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations.
We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe.
NCT01411527.
变声的时间与其他男性青春期发育里程碑以及 BMI 有何关系？
我们提供了男性青春期发育里程碑的全面时间分析，包括生殖激素动态，证实变声是男性青春期发育的一个晚期里程碑，并报告了男性 BMI 较高与变声年龄较早之间可能存在因果关系。
变声代表青春期发育的一个晚期里程碑，回忆变声年龄经常被流行病学研究用作青春期的衡量标准。相比之下，临床研究主要使用睾丸增大和/或生殖器 Tanner 分期作为青春期开始的标志。然而，以前没有详细评估过青春期发育里程碑的相关性或生殖激素动态。此外，尽管 BMI 和青春期发育时间密切相关，但这些特征之间的因果关系尚不清楚。
研究设计、大小、持续时间：该研究包括一个基于人群的混合横断面和纵向队列（2006-2014 年，哥本哈根青春期研究），共有 730 名健康丹麦男孩。从 23andMe 研究中获得了 55871 名男性研究参与者的数据，包括全基因组单核苷酸多态性数据和变声年龄。
参与者/材料、设置、方法：我们对青春期发育里程碑和生殖激素水平进行了详细评估（研究人群 1）。采用孟德尔随机化（MR）方法确定 BMI 和变声时间之间可能的因果联系（研究人群 2）。
变声发生在平均年龄 13.6（95%CI：13.5-13.8）岁。在变声时，平均（95%CI）睾酮水平、LH 水平和双睾丸体积分别为 10.9（10.0-11.7）nmol/L、2.4（2.2-2.5）IU/L 和 24（23-25）mL。变声与男性青春期发育里程碑的时间具有中度强相关性，包括睾丸增大、性腺启动、阴毛发育、体臭、腋毛生长和睾酮检测值上限以上（r2 范围：0.43-0.61）。所有里程碑的时间都与年龄特异性 BMI 呈负相关（所有 P≤0.001）。MR 分析推断出 BMI 较高与男性变声年龄较早之间可能存在因果关系（大约 0.35 岁/近似标准差，P<0.001）。
局限性、谨慎的原因：基于人群的队列的参与率为 25%。此外，进行纵向随访的男孩大约每 6 个月检查一次，限制了青春期发育里程碑的时间分辨率。在 MR 分析中使用成年 BMI 作为暴露，而不是青春期前 BMI，以及在低睾酮水平下睾酮免疫测定的已知不准确性可能是进一步的限制。
我们提供了关于男性青春期发育里程碑时间关系的有价值的规范数据。此外，BMI 和青春期发育时间之间的因果关系突出了预防儿童肥胖的重要性。
研究资助/利益冲突：这项工作得到了丹麦科学、技术和创新局（09-067 180）、丹麦环境、CeHoS（MST-621-00 065）、哥本哈根大区（R129-A3966）、丹麦高等教育和科学部（DFF-1331-00 113）、丹麦创新基金会（InnovationsFonden，14-2013-4）和国际内分泌干扰物对男性生殖和儿童健康影响研究与培训中心的支持。B.H.、F.R.D.、J.R.B.P. 和 K.K.O. 得到了医学研究委员会（MC_UU_12015/2）的支持。23andMe 研究得到了美国国立卫生研究院国家人类基因组研究所的支持（R44HG006981）。23andMe 研究小组成员是 23andMe，Inc. 的员工，持有该公司的股票或股票期权。
NCT01411527。
