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Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.
Hum Reprod. 2019 08 01; 34(8):1514-1522.HR

Abstract

STUDY QUESTION

How is timing of voice break related to other male pubertal milestones as well as to BMI?

SUMMARY ANSWER

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.

WHAT IS KNOWN ALREADY

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).

MAIN RESULTS AND THE ROLE OF CHANCE

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.

WIDER IMPLICATIONS OF THE FINDINGS

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.

TRIAL REGISTRATION NUMBER

NCT01411527.

Authors+Show Affiliations

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.MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus Box, Cambridge, UK.MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus Box, Cambridge, UK.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.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.MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus Box, Cambridge, UK.Department of Paediatrics, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31348498

Citation

Busch, A S., et al. "Voice Break in Boys-temporal Relations With Other Pubertal Milestones and Likely Causal Effects of BMI." Human Reproduction (Oxford, England), vol. 34, no. 8, 2019, pp. 1514-1522.
Busch AS, Hollis B, Day FR, et al. Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI. Hum Reprod. 2019;34(8):1514-1522.
Busch, A. S., Hollis, B., Day, F. R., Sørensen, K., Aksglaede, L., Perry, J. R. B., Ong, K. K., Juul, A., & Hagen, C. P. (2019). Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI. Human Reproduction (Oxford, England), 34(8), 1514-1522. https://doi.org/10.1093/humrep/dez118
Busch AS, et al. Voice Break in Boys-temporal Relations With Other Pubertal Milestones and Likely Causal Effects of BMI. Hum Reprod. 2019 08 1;34(8):1514-1522. PubMed PMID: 31348498.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI. AU - Busch,A S, AU - Hollis,B, AU - Day,F R, AU - Sørensen,K, AU - Aksglaede,L, AU - Perry,J R B, AU - Ong,K K, AU - Juul,A, AU - Hagen,C P, PY - 2019/03/28/received PY - 2019/05/20/revised PY - 2019/06/10/accepted PY - 2019/7/28/pubmed PY - 2020/8/18/medline PY - 2019/7/27/entrez KW - BMI KW - Mendelian randomization KW - causal KW - male KW - puberty KW - voice break SP - 1514 EP - 1522 JF - Human reproduction (Oxford, England) JO - Hum Reprod VL - 34 IS - 8 N2 - STUDY QUESTION: How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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). MAIN RESULTS AND THE ROLE OF CHANCE: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. TRIAL REGISTRATION NUMBER: NCT01411527. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/31348498/Voice_break_in_boys_temporal_relations_with_other_pubertal_milestones_and_likely_causal_effects_of_BMI_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dez118 DB - PRIME DP - Unbound Medicine ER -