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STUDY QUESTION: What is the impact of variants in the genes INSL3 (Insulin Like 3) and RXFP2 (Relaxin Family Peptide Receptor 2), respectively, on cryptorchidism and male infertility? SUMMARY ANSWER: Bi-allelic loss-of-function (LoF) variants in INSL3 and RXFP2 result in bilateral cryptorchidism and male infertility, whereas heterozygous variant carriers are phenotypically unaffected. WHAT IS KNOWN ALREADY: The small heterodimeric peptide INSL3 and its G protein-coupled receptor RXFP2 play a major role in the first step of the biphasic descent of the testes, and variants in the INSL3 and RXFP2 genes have long been implicated in inherited cryptorchidism. However, only one single homozygous missense variant in RXFP2 has clearly been linked to familial bilateral cryptorchidism, so the effects of bi-allelic variants in INSL3 and heterozygous variants in both genes on cryptorchidism and male infertility remain unclear. STUDY DESIGN, SIZE, DURATION: Exome data of 2412 men from the MERGE (Male Reproductive Genomics) study cohort including 1902 infertile men with crypto-/azoospermia, of whom 450 men had a history of cryptorchidism, were screened for high-impact variants in INSL3 and RXFP2. PARTICIPANTS/MATERIALS, SETTING, METHODS: For patients with rare, high-impact variants in INSL3 and RXFP2, detailed clinical data were collected and the testicular phenotype was determined. Genotyping of family members was performed to analyse the co-segregation of candidate variants with the condition. Immunohistochemical staining for INSL3 in patient testicular tissue and measuring serum INSL3 concentration was performed to analyse the functional impact of a homozygous loss-of-function variant in INSL3. For a homozygous missense variant in RXFP2, its impact on the protein's cell surface expression and ability to respond to INSL3 in CRE reporter gene assay was determined. MAIN RESULTS AND THE ROLE OF CHANCE: This study presents homozygous high-impact variants in INSL3 and RXFP2 and clearly correlates these to bilateral cryptorchidism. Functional impact of the identified INSL3 variant was demonstrated by absence of INSL3-specific staining in patients' testicular Leydig cells as well as undetectable blood serum levels. The identified missense variant in RXFP2 was demonstrated to lead to reduced RXFP2 surface expression and INSL3 mediated receptor activation. LIMITATIONS, REASONS FOR CAUTION: Further investigations are needed to explore a potential direct impact of bi-allelic INSL3 and RXFP2 variants on spermatogenesis. With our data, we cannot determine whether the infertility observed in our patients is a direct consequence of the disruption of a possible function of these genes on spermatogenesis or whether it occurs secondarily due to cryptorchidism. WIDER IMPLICATIONS OF THE FINDINGS: In contrast to previous assumptions, this study supports an autosomal recessive inheritance of INSL3- and RXFP2-related bilateral cryptorchidism while heterozygous LoF variants in either gene can at most be regarded as a risk factor for developing cryptorchidism. Our findings have diagnostic value for patients with familial/bilateral cryptorchidism and additionally shed light on the importance of INSL3 and RXFP2 in testicular descent and fertility. STUDY FUNDING/COMPETING INTEREST(S): This study was carried out within the frame of the German Research Foundation (DFG) funded by Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG, CRU326). Research at the Florey was supported by an NHMRC grant (2001027) and the Victorian Government Operational Infrastructure Support Program. A.S.B. is funded by the DFG ('Emmy Noether Programme' project number 464240267). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
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Criptorquidismo , Infertilidad Masculina , Humanos , Masculino , Criptorquidismo/genética , Criptorquidismo/diagnóstico , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Insulina/metabolismo , Células Intersticiales del Testículo/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Testículo/metabolismoRESUMEN
In brief: Minipuberty is a transient activity period of the hypothalamic-pituitary-gonadal axis in the postnatal and infant period including surging serum concentrations of reproductive hormones. Increasing evidence points to an important role of this period for maturation of the testes and thereby for male reproductive function. Abstract: Minipuberty is a transient activity period of the hypothalamic-pituitary-gonadal (HPG) axis in the postnatal and infant period in humans and non-human primates. Hallmarks of this period are surging serum concentrations of reproductive hormones. While in females, the role of minipuberty seems to be dispensable for future fertility, in males, it is significantly associated with reproductive function in later life. In males, this activity period promotes further masculinization, including testicular and penile growth, as well as completion of testicular descent if not already achieved at birth. At the testicular level, both, somatic and germ cells undergo proliferation and partial maturation during this period. Minipuberty is thought to prime male gonadal tissue for subsequent growth and maturation. Notably, perturbed or absent minipuberty is associated with reduced male reproductive function in adulthood. While the sustained HPG axis activity during adulthood is known to control reproductive function, minipuberty appears to be a prerequisite for obtaining full male reproductive function in later life, thereby determining future fertility potential, i.e. the ability to father a child. This review maps the role of male minipuberty for reproductive function and presents suitable animal models to study minipuberty. Also, it describes the development and maturation of testicular cell types, discusses short- and long-term effects of minipuberty and highlights future research perspectives.
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Primates , Semillas , Animales , Recién Nacido , Femenino , Lactante , Humanos , Masculino , Gónadas , Testículo , FertilidadRESUMEN
BACKGROUND: Pubertal timing is closely linked to growth regulated by the growth hormone/insulin-like factor (GH/IGF) axis that includes IGF-regulating factors such as pregnancy-associated plasma protein-A/A2 (PAPP-A/PAPP-A2) and stanniocalcin 2 (STC2). We investigated the association between height, IGF-I concentration, and PAPPA, PAPPA2, and STC2 genotypes on the timing of female pubertal milestones. METHODS: Height, IGF-I, and genotypes were analyzed in 1382 Danish girls from the general population, 67 patients with tall stature (height ≥2 SD), and 124 patients with short stature (height ≤-2 SD). The main outcomes were breast stage and menarche. RESULTS: Thelarche occurred significantly earlier in patients with tall stature (mean age 9.37 years [95% confidence interval (CI) 8.87-9.87]) and later in patients with short stature (11.07 years [95% CI 10.7-11.43]) compared with girls within the normal range (9.96 years [95% CI 9.85-10.07]) (p = 0.02 and p < 0.01, respectively). Girls with higher IGF-I levels experienced thelarche and menarche earlier compared with the rest of the cohort (p < 0.01). Genotypes were not associated with age at thelarche nor menarche, but the PAPPA2 minor allele carriers were shorter compared with major allele carriers, p = 0.03. CONCLUSIONS: Height and IGF-I, but not PAPP-A, PAPP-A2, and STC2 genotypes, were negatively associated with age at thelarche and menarche. IMPACT: Girls with tall and short stature enter puberty earlier and later compared with girls with normal height. Girls with higher insulin-growth factor-I in childhood enter puberty earlier. Pubertal timing is influenced by longitudinal growth and IGF-I levels earlier in childhood. Childhood growth and the levels of IGF-I in childhood may be biomarkers of pubertal timing.
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Estatura , Factor I del Crecimiento Similar a la Insulina/metabolismo , Pubertad , Niño , Preescolar , Estudios de Cohortes , Dinamarca , Femenino , Genotipo , Glicoproteínas/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Menarquia , Polimorfismo de Nucleótido Simple , Proteína Plasmática A Asociada al Embarazo/genéticaRESUMEN
STUDY QUESTION: Do variants of the genes encoding follicle stimulating hormone (FSH) beta subunit (B) and FSH receptor (R) impact circulating reproductive hormone levels and ovarian follicle maturation in healthy peripubertal girls? SUMMARY ANSWER: FSHB and FSHR genetic variants exert, alone or their combination, distinct effects on reproductive hormone levels as well as ovarian follicle maturation in healthy peripubertal girls. WHAT IS KNOWN ALREADY: FSHB and FSHR genetic variants impact reproductive hormone levels as well as associated pathologies in women. While FSHR c. 2039A>G is known to alter gonadotrophin levels in women, FSHR c.-29G>A has not yet been shown to exert effect and there are conflicting results concerning FSHB c.-211G>T. STUDY DESIGN, SIZE, DURATION: This population-based study included 633 girls recruited as part of two cohorts, the COPENHAGEN Puberty Study (2006-2014, a cross-sectional and ongoing longitudinal study) and the Copenhagen Mother-Child Cohort (1997-2002, including transabdominal ultrasound (TAUS) of the ovaries in a subset of 91 peripubertal girls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical examinations, including pubertal breast stage (Tanner's classification B1-B5) were performed. Circulating levels of FSH, luteinizing hormone (LH), estradiol, anti-Mullerian hormone (AMH) and inhibin-B were assessed by immunoassays. In a subset of the girls (n = 91), ovarian volume and the number/size of antral follicles were assessed by TAUS. Genotypes were determined by competitive PCR. MAIN RESULTS AND THE ROLE OF CHANCE: FSHR c.2039A>G minor alleles were positively associated with serum FSH (ß = 0.08, P = 0.004), LH (ß = 0.06, P = 0.012) and estradiol (ß = 0.06, P = 0.017) (adjusted for Tanner stages). In a combined model, FSHR c.-29G>A and FSHR c.2039A>G alleles were positively associated with FSH levels in early-pubertal girls (B2 + B3, n = 327, r = 0.1, P = 0.02) and in young adolescents (B4 + B5, n = 149, r = 0.2, P = 0.01). Serum AMH and inhibin B levels were not significantly influenced by the single nucleotide polymorphisms (SNPs). Single SNPs were not associated with follicles counts, however, a cumulative minor allele count (FSHB c.-211 G>T and FSHR c.-29G>A) was negatively associated with the number of large follicles (≥5 mm) (n = 91, P = 0.04) (adjusted for Tanner stages). LIMITATIONS, REASONS FOR CAUTION: Since we studied girls and young adolescents during pubertal transition, our study may not be fully comparable with previous studies on FSHB and FSHR variants in adult women. The group of young adolescents (Tanner B4 + B5) reflects the endocrine situation in adult women best, however, the group is not large enough to contribute substantially to the conflicting results concerning the influence of FSHB c.-211G>T in adult women. Furthermore, we have no information about the exact day of the menstrual cycle in the subgroup of girls with menarche. WIDER IMPLICATIONS OF THE FINDINGS: The sex-specific interaction of FSHB and FSHR genetic variants and physiological as well as pathological conditions is being increasingly elucidated. The variant triplet set might serve as diagnostic and pharmacogenetic marker. For the first time, we show an additional effect of FSHR c.-29G>A on serum FSH levels in healthy girls. Moreover, morphological data suggest impaired FSH-induced maturation of ovarian follicles in minor allele carriers of FSHB c.-211G>T and FSHR c.-29G>A. This may explain previous findings of delayed pubertal onset in these girls. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Danish Agency for Science, Technology and Innovation (09-067180), Danish Ministry of the Environment, CeHoS (MST-621-00065), Capital Region of Denmark (December 2011), Ministry of Higher Education and Science (DFF-1331-00113) and EDMaRC (Danish Ministry of Health). A.S.B. was funded from December 2015 by ReproUnion (EU Interreg Öresund-Kattegat-Skagerrak). The authors declare no conflict of interest.
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Hormona Folículo Estimulante de Subunidad beta/genética , Folículo Ovárico/patología , Polimorfismo Genético , Pubertad Tardía/genética , Receptores de HFE/genética , Adolescente , Adulto , Alelos , Niño , Estudios de Cohortes , Estudios Transversales , Dinamarca , Estradiol/sangre , Femenino , Hormona Folículo Estimulante Humana/sangre , Hormona Folículo Estimulante de Subunidad beta/sangre , Hormona Folículo Estimulante de Subunidad beta/metabolismo , Estudios de Asociación Genética , Humanos , Inhibinas/sangre , Estudios Longitudinales , Hormona Luteinizante/sangre , Polimorfismo de Nucleótido Simple , Pubertad Tardía/sangre , Pubertad Tardía/metabolismo , Pubertad Tardía/patología , Receptores de HFE/sangre , Receptores de HFE/metabolismo , Adulto JovenRESUMEN
Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.
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Frecuencia de los Genes , Menarquia , Pubertad , Humanos , Femenino , Menarquia/genética , Pubertad/genética , Animales , Herencia Multifactorial/genética , Ratones , Estudio de Asociación del Genoma Completo , Adolescente , Pubertad Precoz/genética , Polimorfismo de Nucleótido Simple , Receptores Acoplados a Proteínas G/genética , Pubertad Tardía/genética , NiñoRESUMEN
Background: Anti-Müllerian hormone (AMH) is produced by granulosa cells in small growing ovarian follicles. In adult women, serum concentrations of AMH reflect the ovarian reserve of resting primordial follicles, and low AMH is associated with risk of early menopause. In contrast, patients with polycystic ovary syndrome (PCOS) have elevated AMH. The primary aim of this study was to evaluate the individual tracking of serum AMH concentrations, as well as whether AMH in early childhood reflects ovarian activity in adolescence. Methods: In this large longitudinal study of healthy girls were examined from infancy to adolescence (1997-2019) including physical examination, assessment of serum concentrations of reproductive hormones (in infancy, median age 0.3 yrs; mid-childhood, 7.2 yrs; puberty, 11.3 yrs; and adolescence, 15.9 yrs), transabdominal ultrasound (TAUS, puberty and adolescence) and magnetic resonance imaging (MRI, puberty) of the ovaries. Findings: Each girl maintained her relative AMH concentration (expressed as standard deviation (SD) scores) over time; mean variation of individual age adjusted AMH concentrations was 0.56 ± 0.31 SD.Serum concentrations of AMH in adolescence correlated with AMH in infancy and childhood; infancy: r = 0.347; mid-childhood: r = 0.637; puberty: r = 0.675, all p < 0.001.AMH correlated negatively with FSH concentrations in all age groups (infancy: r = -0.645, p < 0.001; mid-childhood: r = -0.222, p < 0.001; puberty: r = -0.354, p < 0.001; adolescence: n = 275, r = -0.175, p = 0.004).Serum AMH concentrations in mid-childhood correlated with the number of follicles in puberty (TAUS and MRI) as well as in adolescence (TAUS); e.g. total number of follicles: TAUS puberty (r = 0.607), MRI puberty (r = 0.379), TAUS adolescence (r = 0.414), all p < 0.001.AMH concentration in infancy as well as in mid-childhood predicted low AMH (<10 pmol/L) in adolescence; AMH infancy <7.5 pmol/L as predictor of low AMH in adolescence: sensitivity 0.71, specificity 0.70, AUC 0.759; AMH mid-childhood < 8.4 pmol/L as predictor of low AMH in adolescence: sensitivity 0.88, specificity 0.87, AUC 0.949.Girls with high serum AMH concentration in mid-childhood (AMH >30.0 pmol/L vs. other girls) had higher adolescent LH (median 4.53 vs. 3.29 U/L p = 0.041), LH/FSH ratio (1.00 vs 0.67, p = 0.019), testosterone (1.05 vs 0.81 nmol/L, p = 0.005), total number of follicles (23 vs. 19, p = 0.004), and higher prevalence of irregular cycles (10/15 = 67% vs. 28/113 = 25%, p = 0.002). Interpretation: The present findings suggest remarkably stable ovarian activity from small growing follicles in healthy girls, supporting AMH in early life as a useful clinical tool to predict future ovarian activity. Funding: The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065), the EU (QLK4-CT1999-01422; QLK4-2001-00269), the Novo Nordisk Foundation and The Danish Ministry of Science Technology and Innovation (2107-05-0006). A.S.B. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 464240267. KM receives honoraria from Novo Nordisk A/S for teaching at the Danish annual postgraduate course of pituitary diseases.
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The ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) has previously been described as an excellent marker of sex in healthy infants. However, LH/FSH remains not fully described in patients with differences of sex development (DSD). The aim was therefore to describe LH/FSH in infants with DSD. This was a retrospective study of DSD patients, all aged 0-1.2 years. In total, 87 infants with DSD and at least one serum sample per infant were included. Longitudinal samples from single patients were included whenever possible. Serum LH/FSH ratios in these patients were plotted against recently published age-related and sex-dimorphic cutoffs. Overall, LH/FSH sometimes corresponded to assigned sex without any obvious pattern in terms of diagnoses. LH/FSH corresponded to the biological sex in all patients with Turner or Klinefelter syndrome. In patients with 46,XX or 46,XY DSD (except congenital adrenal hyperplasia (CAH)), the ratios did not correspond to the assigned sex in all cases and were interchangeably within the male and female range. In patients with CAH, the ratio corresponded to biological sex (based on sex chromosomes) in some cases but also ranged across the cutoffs. In the 15 patients with 45,X/46,XY mosaicism, the LH/FSH ratios corresponded to the assigned sex in all cases (12 were raised as males, 3 as females) and at all time points in cases with multiple sampling. While this study describes LH/FSH in infants with DSD, the exact clinical role of the ratio in the management of these patients remains to be further elucidated.
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Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.
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CONTEXT: Minipuberty, a period of a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in both sexes, enables evaluation of gonadal function in infants suspected of hypogonadism. However, female minipuberty remains poorly elucidated. OBJECTIVE: We aimed to establish continuous reference ranges for the most commonly used reproductive hormones and to evaluate the dynamics of the HPG axis in females aged 0 to 1 year. DESIGN: The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), a longitudinal, prospective cohort study. SETTING: Healthy infants from Copenhagen. PATIENTS OR OTHER PARTICIPANTS: A total of 98 healthy, term female infants followed with 6 examinations including venipuncture during the first year of life. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum concentrations of LH, FSH, inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), and SHBG were quantified using highly sensitive methods in 266 serum samples. RESULTS: Reference ranges were established for LH, FSH, inhibin B, AMH, E1, E2, and SHBG. Two peaks were observed in normalized mean curves for all hormones. The first peaks were timed around postnatal days 15 to 27 followed by a general nadir for all hormones around days 58 to 92. The second peaks occurred around days 107 to 125 for inhibin B, AMH, E1, E2, and SHBG and days 164 to 165 for LH and FSH. CONCLUSIONS: We present age-related, continuous reference ranges of the most commonly used reproductive hormones and present novel data revealing a biphasic and prolonged female minipuberty. CLINICALTRIALS.GOV ID: NCT02784184.
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Hipogonadismo , Inhibinas , Hormona Antimülleriana , Estradiol , Femenino , Hormona Folículo Estimulante , Humanos , Lactante , Masculino , Estudios ProspectivosRESUMEN
Objective: Little is known about the ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants. Design: A prospective, longitudinal cohort study of healthy infants aged 0-1.2 years. Methods: In total, 236 healthy infants (122 boys and 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), with 567 serum and 603 urine samples, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants. Results: In both serum and urine, LH/FSH was highest in males with minimal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0 to 1.2 years with median sensitivities and specificities ranging from 93 to 100% with correspondingly narrow 95% CIs. Conclusions: Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the ratio remain to be elucidated.
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Hormona Folículo Estimulante , Hormona Luteinizante , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Estudios Prospectivos , Desarrollo SexualRESUMEN
CONTEXT: IGF-I is important for postnatal growth and may be of diagnostic value in infants suspected of pituitary disease; however, little is known about the impact of IGF-I and its determinants on infant growth. Importantly, detailed reference ranges for IGF-I and IGF binding protein-3 (IGFBP-3) concentrations during infancy are lacking. OBJECTIVE: To evaluate the rapid changes in weight and length as well as their determinants in healthy infants, and to establish age- and sex-specific reference curves for IGF-I and IGFBP-3 in children aged 0 to 1 years. DESIGN: Prospective longitudinal study. SETTING: Cohort study. PARTICIPANTS: A total of 233 healthy children (114 girls) with repeated blood samples during the first year of life. MAIN OUTCOME MEASURE(S): Serum concentrations of IGF-I and IGFBP-3, length velocity, weight velocity, and PAPPA2 (rs1325598) genotype. RESULTS: Individual trajectories of length and weight velocities were sex specific. We provide detailed reference curves based on longitudinal data for IGF-I and IGFBP-3 during infancy. In both girls and boys, IGF-I decreased during infancy, whereas IGFBP-3 remained stable. IGF-I and IGFBP-3, but not PAPPA2 genotype, were positively associated with weight gain, but not with longitudinal growth. When stratified by sex, the association between weight gain and IGF-I only remained significant in girls. CONCLUSIONS: Interestingly, we found a significant association between IGF-I and infant weight gain in girls, but not with longitudinal growth in the first year of life. Our findings highlight the role of IGF-I as an important anabolic hormone that is not limited to linear growth.
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Desarrollo Infantil , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Proteína Plasmática A Asociada al Embarazo/genética , Estatura , Peso Corporal , Femenino , Técnicas de Genotipaje , Voluntarios Sanos , Humanos , Lactante , Recién Nacido , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Valores de Referencia , Factores Sexuales , Aumento de PesoRESUMEN
CONTEXT: A close link between body mass index (BMI) and female pubertal onset is well established. However, observations in boys remain inconclusive. OBJECTIVE: We aim to determine whether BMI as well as total and central adiposity in prepubertal Chilean boys is associated with pubertal timing. METHODS: We performed a longitudinal study in which 494 boys from the Growth and Obesity Chilean Cohort Study were followed starting from birth and throughout puberty, including 5 prepubertal visits. The main outcome measures included anthropometric data and semi-annual clinical pubertal staging. The association between BMI, obesity (BMI standard deviation score [SDS] ≥ 2) and central adiposity (waist circumference ≥ 90th centile) with precocious puberty and age at gonadarche was analyzed using survival- and logistic regression models. RESULTS: BMI, prevalence of total obesity, and central obesity increased throughout childhood. Among the study population, 45 boys entered puberty before the age of 9 years (9.1%). Obesity at 4 to 7 years and childhood mean BMI SDS were significantly associated with precocious gonadarche. Mean age at testicular enlargement (≥4 mL), was 11.0 years (95% CI, 10.9-11.1) and was inversely associated with BMI SDS, waist circumference, and percentage fat mass in almost all prepubertal visits. Age at testicular enlargement in normal weight, overweight, and obese boys was 11.2 (11.0-11.3), 10.9 (10.6-11.1) and 10.7 (10.4-11.1) years, respectively. CONCLUSION: Our observation supports the association of BMI SDS and obesity with pubertal timing and precocious gonadarche in boys, respectively. Early intervention controlling the obesity epidemic could be useful in decreasing detrimental impact on later health.
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Obesidad Abdominal/epidemiología , Obesidad Infantil/epidemiología , Pubertad Precoz/epidemiología , Pubertad/fisiología , Adiposidad/fisiología , Factores de Edad , Edad de Inicio , Niño , Preescolar , Chile/epidemiología , Estudios de Cohortes , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Obesidad Abdominal/complicaciones , Obesidad Infantil/complicaciones , Pubertad Precoz/etiología , Factores de RiesgoRESUMEN
Hamer et al argue that the variable "ever versus never had a same-sex partner" does not capture the complexity of human sexuality. We agree and said so in our paper. But Hamer et al neglect to mention that we also reported follow-up analyses showing substantial overlap of the genetic influences on our main variable and on more nuanced measures of sexual behavior, attraction, and identity.
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Estudio de Asociación del Genoma Completo , Conducta Sexual , Humanos , Solución de ProblemasRESUMEN
OBJECTIVE: Pubertal timing is highly heritable. Observational studies were inconclusive concerning a potential sex-specific difference in the parental contribution, while genome-wide association studies highlighted a heterogeneity in the genetic architecture of pubertal timing between sexes. Our objectives were to evaluate the association of timing of pubertal milestones in offspring with parental pubertal timing and to identify the genetic basis of the heterogeneity. DESIGN: (1.) Population-based mixed cross-sectional/longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) comprising 1381 healthy Danish children including their parents. (2.) UK Biobank-based summary statistics of genetic data on timing of menarche (n = 188 644), voice-break (n = 154 459) and facial hair (n = 161 470). METHODS: (1.) Participants underwent clinical examination(s) including blood sampling. Parental pubertal timing was obtained by questionnaire. Timing of milestones were analyzed using SAS-lifereg. (2.) Genetic correlations between pubertal outcomes were estimated using LD Score regression. Genetic heterogeneity was analyzed using METAL. RESULTS: We observed significant associations of relative parental pubertal timing with timing of pubertal milestones in offspring of concordant sex, that is, fathers/sons (e.g. testicular enlargement: P = 0.004, ß = 0.34 years per relative category) and mothers/daughters (e.g. thelarche: P < 0.001, ß = 0.45 years per relative category). Fewer milestones were associated with relative parental pubertal timing in offspring of discordant sex compared to concordant sex. Large-scale genetic data highlight both moderate to strong genetic correlations between timing of menarche, voice-break and facial hair. Out of 434 lead single-nucleotide polymorphisms significantly associated with at least one outcome, 39 exhibited a significant genetic heterogeneity between sexes (P < 1.15 × 10-4). CONCLUSION: Our results highlight a distinct genetic heterogeneity of pubertal timing between sexes.
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Pubertad/genética , Pubertad/fisiología , Caracteres Sexuales , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Menarquia/genética , Menarquia/fisiología , PadresRESUMEN
CONTEXT: Pubertal timing in boys is associated with body mass index (BMI). Studies consistently report an inverse correlation of BMI and pubertal timing within the normal BMI range. However, observations in obese boys are conflicting with different studies reporting either early or delayed pubertal onset in obese boys. OBJECTIVE: We aimed to assess the association of male pubertal timing with age-specific BMI (zBMI) in obese boys. DESIGN, SETTING, AND PARTICIPANTS: A total of 218 obese boys (zBMI > +2SD, with a median age at baseline of 10.8 years (range 4.2-17.0), were recruited as part of a prospective outpatient childhood obesity intervention program at Nordsjællands Hospital, Hillerød, Denmark, between 2009 and 2017. Serving as controls, we included 660 healthy boys participating in the population-based COPENHAGEN Puberty Study (-2SD < zBMI ≤ +2SD, 2006-2014). Subanalyses were performed on overweight controls (+1SD < zBMI ≤ +2SD). The clinical assessment of pubertal development by Tanner staging, including testis volume using a Prader's orchidometer, was performed by trained physicians. The timing of pubertal milestones was estimated by probit analyses. MAIN OUTCOME MEASURES: Timing of testicular volume ≥ 4 mL, genital stage ≥ 2, and pubarche. RESULTS: The mean (95% confidence interval [CI]) age of onset of pubertal event in obese boys was as follows: testicular volume ≥ 4 mL, 11.3 years (11.0-11.6); genital stage ≥ 2, 11.6 yrs (11.3-11.9); and pubarche, 11.9 years (11.5-12.3). Testicular volume ≥ 4 mL occurred significantly earlier in obese boys compared to controls (-2SD < zBMI ≤ +2SD) (P = 0.01). We did not observe significant differences for either the timing of pubarche nor the genital stage ≥ 2 (P = 0.06 and P = 0.94, respectively). CONCLUSIONS: We demonstrate that testicular enlargement in obese boys occurs significantly earlier compared to a population-based normal-weight reference cohort.
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Índice de Masa Corporal , Sobrepeso/fisiopatología , Obesidad Infantil/fisiopatología , Pubertad Precoz/epidemiología , Adolescente , Niño , Preescolar , Dinamarca/epidemiología , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Pronóstico , Estudios ProspectivosRESUMEN
CONTEXT: Gynecomastia, the proliferation of mammary glandular tissue in the male, is a frequent but little-studied condition. Available prevalence data are based on selected patient populations or autopsy cases with their inherent bias. OBJECTIVE: The objective of this work is to evaluate the age-related incidence and secular trends in gynecomastia in the general population. DESIGN: An observational, 20-year national registry study was conducted. SETTING: This population-based study used nationwide registry data. PARTICIPANTS: Participants included all Danish males (age 0-80 years) with a first-time diagnosis of gynecomastia. MAIN OUTCOME MEASURES: All Danish males (age 0-80 years) were followed up for incident diagnosis of gynecomastia in the Danish National Patient Registry from 1998 to 2017 using the International Codes of Diseases, 10th revision, and the Danish Health Care Classification System. Age-specific incidence rates were estimated. The hypothesis tested in this study was formulated prior to data collection. RESULTS: Overall, a total 17â 601 males (age 0-80 years) were registered with an incident diagnosis of gynecomastia within the 20-year study period, corresponding to 880 new cases per year and an average 20-year incidence of 3.4 per 10â 000 men (age 0-80 years). The average annual incidence was 6.5/10â 000 in postpubertal males age 16 to 20 years and 4.6/10â 000 in males age 61 to 80 years, with a respective 5- and 11-fold overall increase in these 2 age groups over the 20-year period. CONCLUSIONS: The incidence of gynecomastia has dramatically increased over the last 20 years, implying that the endogenous or exogenous sex-steroid environment has changed, which is associated with other adverse health consequences in men such as an increased risk of prostate cancer, metabolic syndrome, type 2 diabetes, or cardiovascular disorders.
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Ginecomastia/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Adulto JovenRESUMEN
Importance: There has been a worldwide secular trend toward earlier onset of puberty in the general population. However, it remains uncertain if these changes are paralleled with increased incidence of central precocious puberty (CPP) and normal variant puberty (ie, premature thelarche [PT] and premature adrenarche [PA]) because epidemiological evidence on the time trends in the incidence of these puberty disorders is scarce. Objective: To provide valid epidemiological data on the 20-year secular trend in the incidence rates of CPP and normal variant puberty. Design, Setting, and Participants: This population-based, 20-year cohort study used national registry data for all youth in Denmark registered with an incident diagnosis of CPP, PT, or PA in the Danish National Patient Registry from 1998 to 2017 (N = 8596) using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). We applied the maximum diagnostic age limit for precocious puberty (ie, onset of puberty before age 8 years for girls and age 9 years for boys) with and without a 12-month lag to address time from first contact to final registration in the Danish National Patient Registry. Data analysis was conducted in 2019. Exposures: Diagnosis of CPP, PT, or PA. Main Outcomes and Measures: The age-specific and sex-specific incidence rates of first-time diagnosis of CPP, PT, and PA were estimated using data from the Danish National Patient Registry from 1998 to 2017, and information about the total number of children at risk within the same age groups and sex from Statistics Denmark. Incidences were stratified according to immigration group (Danish origin, first-generation immigrant, second-generation immigrant). Results: Overall a total 8596 children (7770 [90.4%] girls; median [interquartile] age at diagnosis for boys, 8.0 [7.1-9.0] years; for girls, 8.0 [7.6-8.5] years) were registered with an incident diagnosis of CPP, PT, or PA, of whom 7391 (86.0%) had Danish origin (6671 [90.3%] girls), corresponding to 370 new cases in children with Danish origin per year. The 20-year mean annual incidence rates of CPP, PT, PA, and all 3 conditions per 10â¯000 girls with Danish origin were 9.2 (95% CI, 8.0 to 10.3), 1.1 (95% CI, 0.7 to 1.5), 1.3 (95% CI, 0.9 to 1.7), and 11.5 (95% CI, 10.3 to 12.8), respectively. For boys with Danish origin, the 20-year mean annual incidence rates per 10â¯000 boys were lower: 0.9 (95% CI, 0.6 to 1.2), 0.2 (95% CI, 0.1 to 0.4), and 1.1 (95% CI, 0.7 to 1.4) for CPP, PA, and the sum, respectively. There was a 6-fold increase in incidence for girls with Danish origin (from 2.6 per 10â¯000 to 14.6 per 10â¯000) and a 15-fold increase for boys with Danish origin (from 0.1 per 10â¯000 to 2.1 per 10â¯000). The 20-year mean incidence of CPP and PA among girls in the first-generation and second-generation immigrant groups were greater than that of girls with Danish origin. The incidence rate for CPP per 10â¯000 girls in the first-generation and second-generation groups were 13.7 (95% CI, 9.3 to 18.2) and 14.2 (95% CI, 4.6 to 23.9), respectively; the incidence rate for PA per 10â¯000 girls in the first-generation and second-generation groups were 2.0 (95% CI, 0.3 to 3.6) and 1.5 (95% CI, -1.6 to 4.7), respectively. No differences associated with immigration status were observed among boys. Conclusions and Relevance: Our findings suggest that the annual incidence of CPP and normal variant puberty has substantially increased in Denmark during the last 20 years. These findings have implications for short-term and long-term health and potentially for the international classification of the reference age of puberty.
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Pubertad Precoz/epidemiología , Pubertad , Adolescente , Factores de Edad , Niño , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Incidencia , MasculinoRESUMEN
CONTEXT: Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. OBJECTIVE: To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. EXPERIMENTAL DESIGN: Longitudinal study. SUBJECTS AND METHODS: 401 boys from the Growth and Obesity Chilean Cohort Study (nâ =â 1194; 49.2% boys). MAIN OUTCOME MEASURES: Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. RESULTS: The PRS was associated with AAG (ß=0.01, Pâ =â 0.04) and AAP (ß=0.185, Pâ =â 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (Pâ =â 0.013 and Pâ =â 0.007). CONCLUSIONS: Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.
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Biomarcadores , Herencia Multifactorial/genética , Pubertad/genética , Voz/genética , Adolescente , Factores de Edad , Biomarcadores/análisis , Niño , Preescolar , Chile , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Estudios Longitudinales , Masculino , Pubertad/fisiología , Proyectos de Investigación , Factores Sexuales , Voz/fisiologíaRESUMEN
Importance: The initial clinical sign of pubertal onset in girls is breast gland development (thelarche). Although numerous studies have used recalled age at menarche (first menstruation) to assess secular trends of pubertal timing, no systematic review has been conducted of secular trends of thelarche. Objectives: To systematically evaluate published data on pubertal timing based on age at thelarche and evaluate the change in pubertal onset in healthy girls around the world. Data Sources: A systematic literature search was performed in PubMed and Embase of all original peer-reviewed articles published in English before June 20, 2019. Study Selection: Included studies used clinical assessment of breast development in healthy girls and used adequate statistical methods, including the reporting of SEs or CIs. The quality of the articles was evaluated by assessing study design, potential sources of bias, main characteristics of the study population, and methods of statistical analysis. Data Extraction and Synthesis: In accordance with PRISMA guidelines, all articles were assessed for eligibility independently by 2 authors. Weighted regression analysis was performed using a random-effects model. Main Outcomes and Measures: Studies examining age at thelarche (development of Tanner breast stage 2) in healthy girls. Results: The literature search resulted in a total of 3602 studies, of which 30 studies fulfilled the eligibility criteria. There was a secular trend in ages at thelarche according to race/ethnicity and geography. Overall, the age at thelarche decreased 0.24 years (95% CI, -0.44 to -0.04) (almost 3 months) per decade from 1977 to 2013 (P = .02). Conclusions and Relevance: The age at thelarche has decreased a mean of almost 3 months per decade from 1977 to 2013. A younger age at pubertal onset may change current diagnostic decision-making. The medical community needs current and relevant data to redefine "precocious puberty," because the traditional definition may be outdated, at least in some regions of the world.
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Mama/crecimiento & desarrollo , Pubertad/fisiología , Adolescente , Factores de Edad , Niño , Femenino , HumanosRESUMEN
The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.