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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., 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.

Background: The transient postnatal activation of the hypothalamic-pituitary-gonadal hormone axis is termed minipuberty and considered an important developmental period, which is highly sensitive to endocrine disruption. Here, we explore exposure-outcome associations during minipuberty between concentrations of potentially endocrine disrupting chemicals (EDCs) in urine of infant boys and their serum reproductive hormone concentrations. Methods: In total, 36 boys participating in the COPENHAGEN Minipuberty Study had data available for both urine biomarkers of target endocrine disrupting chemicals and reproductive hormones in serum from samples collected on the same day. Serum concentrations of reproductive hormones were measured by immunoassays or by LC-MS/MS. Urinary concentrations of metabolites of 39 non-persisting chemicals, including phthalates and phenolic compounds, were measured by LC-MS/MS. Nineteen chemicals had concentrations above the limit of detection in ≥50% of children and were included in data analysis. Associations of urinary phthalate metabolite and phenol concentrations (in tertiles) with hormone outcomes (age- and sex-specific SD-scores) were analysed by linear regression. Primarily, we focused on the EU regulated phthalates; butylbenzyl phthalate (BBzP), di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and di-(2-ethylhexyl) phthalate (DEHP) as well as bisphenol A (BPA). Urinary metabolites of DiBP, DnBP and DEHP were summed and expressed as ∑DiBPm, ∑DnBPm and ∑DEHPm. Results: Compared to boys in the lowest ∑DnBPm tertile, urinary concentration of ∑DnBPm was associated with concurrent higher luteinizing hormone (LH) and anti-Müllerian hormone (AMH) SD-scores as well as lower testosterone/LH ratio in boys in the middle ∑DnBPm tertile (estimates (CI 95%) 0.79 (0.04; 1.54), 0.91 (0.13; 1.68), and −0.88 (−1.58;-0.19), respectively). Further, higher insulin-like peptide 3 (INSL3) SD-scores and lower DHEAS SD-score in boys in the highest

Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenalglands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids,adult patients with CAH often experience impaired gonadal function. In pubertal boys andin men with CAH, circulating testosterone is produced by the adrenal glands as well as thetesticular, steroidogenic cells. In this European two-center study, we evaluated the functionof Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylasedeficiency. Despite conventional hormone replacement therapy, our results indicated asignificant reduction in serum concentrations of both Leydig cell-derived hormones (i.e.insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibinB and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3were particularly reduced in those with testicular adrenal rest tumors. To our knowledge,this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitorLeydig cell function in patients with CAH., Congenital adrenal hyperplasia (CAH) is a recessive condition t hat affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cel l-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candi date biomarker to monitor Leydig cell function in patients with CAH.

Introduction: Breast tissue in infancy is a rather undescribed phenomenon. We aimed to describe the prevalence and progression of palpable breast tissue in healthy boys and girls aged 0-1 years and to evaluate clinical markers, individual serum hormone concentrations as well as combined hormone profiles as determinants of the persistence of breast tissue. Methods: In total, 233 term infants (119 boys, 114 girls) were included and followed from birth until 1 year of age in The COPENHAGEN Minipuberty Study (ClinicalTrials.gov #NTC02784184). Infants were followed up to six times with a clinical examination and serum sampling. Principal component analyses (PCAs) produced combined hormone profiles. Results: A total of 98% of all infants aged 0-1 year exhibited breast tissue at some point. 50% still had breast tissue present at 0.5-0.6 years in girls and 0.3-0.4 years in boys (‘persistent’). At one year, more girls than boys had breast tissue present (p=0.010). Most clinical and hormonal markers did not differ in infants with/without persistent breast tissue. However, in those with persistent breast tissue, estradiol (first visit, girls, p=0.034), androstenedione, corticosterone, cortisol (first visit, boys, all p<0.050), length (first visit, boys, p=0.030), and testicular volume (0.3-0.4 years, p=0.040) were higher, while IGF-I (0.3-0.4, boys, p=0.033) was lower. In boys, a combined, PCA-derived hormone profile (first visit) was able to predict the persistence of breast tissue (area under the curve=83%) better than any single marker. Discussion: Palpable breast tissue in infancy is common in both sexes although it persists in significantly more girls than boys at one year of age. Data supports both the early origin of breast tissue (in utero- and early postnatal) as well as a role of endogenous hormone production in later development and maintenance.

BACKGROUND: Humans are widely exposed to chemicals with known or suspected endocrine disrupting effects. Among those are several benzophenones, bisphenols and other phenols commonly used in consumer products. OBJECTIVES: To provide human biomonitoring data from young families including infants and their parents as well as longitudinal data of infants exclusively breastfed versus on mixed diet. METHOD: Twenty-two benzophenones, bisphenols and other phenols, were measured in urine sample sets collected from more than 100 infants and their parents (the TRIO study) and in paired samples from 61 infants when exclusively breastfed and after introduction of mixed diet (the FOOD study). RESULTS: Twelve out of 22 substances were detectable in more than half of the urine samples from infants, mothers or fathers. Large variation in excreted levels of almost all the substances were observed. The TRIO study showed that infants had comparable or even significantly higher daily urinary excretion (DUE) of benzophenone, 4-hydroxy-benzophenone, bisphenol A, bisphenol S, triclosan and 2-phenylphenol than their parents. In the FOOD study, exclusively breastfed infants had higher or similar DUE of triclosan and benzophenones compared to when they received mixed diet. Urinary levels of triclosan and the benzophenones, BP-1 and BP-3 were significantly correlated between all trio members, indicating exposure from the same sources at home. For triclosan, BP-1 and BP-3, the within family variation was lower than between families in the TRIO study. Many substances were positively correlated both within infants and parents, indicating that some families were exposed to several of these substances concurrently. CONCLUSION: Participants in this study excreted relatively low chemical levels, however, simultaneous exposure to several chemicals with endocrine disrupting abilities is of concern due to the dose-additive effects of these substances in combination with other chemicals.

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.

Context The male hypothalamic-pituitary-gonadal (HPG) axis is transiently active during the first months of life with surging serum concentrations of reproductive hormones. This period, termed minipuberty, appears to be essential for priming testicular function. Despite the central role for male reproductive function, longitudinal data on HPG axis activation in infancy is sparse. Objective To explore the dynamics of HPG hormone activity in healthy male infants, to assess the association of HPG axis activity and testicular volume, and to establish reference curves for serum levels of reproductive hormones. Design Prospective, longitudinal birth cohort (the COPENHAGEN Minipuberty Study, 2016-2018, 1-year follow-up). Setting Population-based. Patients or Other Participants Healthy, male, term, singleton newborns were followed from birth on with repeated clinical examinations including blood sampling during a 1-year follow-up. A total of 128 boys contributed to this study, while 119 participated in the postnatal follow-up. Main Outcome Measures Serum reproductive hormone concentrations and testicular volume. Results Reproductive hormone concentrations showed marked dynamics during the first 6 months of age. Gonadotropins, total testosterone, and insulin-like factor 3 peaked at around 1 month of age. Inhibin B, anti-Mullerian hormone, and testicular volume peaked at around 4 to 5 months. Correlations largely recapitulated typical HPG axis pathways but also differed significantly from adult men. Conclusions We demonstrate a temporal dissociation of Leydig and Sertoli cell activity during male minipuberty and provide reference curves for reproductive hormones.

Objective: Several phthalates have been restricted/banned due to their adverse endocrine disrupting properties. The use of other phthalates and substitutes has increased. Here we examine the current exposure to phthalates in family trios comprised of infants and their parents and in infants exclusive breastfed and following introduction to a mixed diet. Methods: Metabolites of 15 phthalates and two substitutes, di(2-ethylhexyl)-teraphthalate (DEHTP) and diisononyl-cyclohexane-1,2-dicarboxylate (DINCH), were measured in urine samples collected from >100 infants and their parents and in paired urine samples collected from 67 infants, while they were exclusively breastfed and when they got mixed diet. Results: Among infants and their parents, metabolites of nine out of 15 phthalates and both substitutes were detected in >74% of all samples. Estimated daily intake (DI) calculated as µg/kg/day, showed similar exposure levels among infants and their parents for several of the substances, and infants were more exposed to DEHTP than their mothers. Significantly higher estimated DIs were observed for some low-molecular phthalates in infants exclusively breastfed. In contrast, comparable estimated DIs were observed for many other phthalates and DEHTP regardless of feeding status. For most of the substances, the within-family variation, was lower than the between-family variation. Likewise, the within-infant variation on exclusively breast vs. mixed diet was lower than the between-infant variation. Independent of food status, some infants were concurrently exposed to almost all the measured phthalates and substitutes in higher amounts than others. Conclusion: Surprisingly, irrespective of diet status infants were exposed to several phthalates and substitutes some of which have been regulated for years. Exposure patterns and levels were similar in infants and their parents. Importantly, risk assessment based on new refined reference doses (RfD-AA) exceeded the safety l

Objective: Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism. Methods: Retrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS/MS methodology, and gonadal INSL3 immunohistochemical expression. Results: Serum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed. Conclusions: In this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3.

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.

Purpose: Principal component analysis (PCA) is a mathematical model which simplifies data into new, combined variables. Optimal treatment of pediatric congenital adrenal hyperplasia (CAH) remains a challenge and requires evaluation of all biochemical and clinical markers. The aim of this study was to introduce PCA methodology as a tool to optimize management in a cohort of pediatric and adolescent patients with CAH by including adrenal steroid measurements and clinical parameters. Methods: This retrospective, longitudinal cohort of 33 children and adolescents with CAH due to 21-hydroxylase deficiency included 406 follow-up observations. PCAs were applied to serum hormone concentrations and compared to treatment efficacy evaluated by clinical parameters. Results: We provide and describe the first PCA models with hormone parameters denoted in sex- and age-adjusted standard deviation (SD) scores to comprehensibly describe the combined ‘endocrine profiles’ of patients with classical and non-classical CAH, respectively. Endocrine profile scores were predictive markers of treatment efficacy for classical (AUC=92%; accuracy 95%; p=1.8e-06) and non-classical CAH (AUC=80%; accuracy 91%; p=0.004). A combined PCA demonstrated clustering of patients with classical and non-classical CAH by serum 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone-sulphate (DHEAS) concentrations. Conclusion: As an example of the possibilities of PCA, endocrine profiles were successfully able to distinguish between patients with CAH according to treatment efficacy and to elucidate biochemical differences between classical and non-classical CAH.

Background The hypothalamic-pituitary-gonadal (HPG) axis governs sexual maturation and reproductive function in humans. In early postnatal life, it is transiently active during which circulating sex steroids reach adult levels. While this so-called minipuberty represents a universal phenomenon in infants of both sexes, its role for early maturation and growth remains incompletely understood. Objectives To provide normative data on auxology as well as serum and urinary hormone levels in healthy, full-term infants throughout the first year of life and to investigate associations of postnatal HPG axis dynamics as well as hormonal, genetic and environmental exposures with early genital development and growth. Population Healthy, Danish, full-term, singleton newborns including their parents. Design Single-centre, prospective, observational longitudinal pregnancy and birth cohort. Methods Newborns were followed with six repeated clinical examinations during a one-year follow-up period. An umbilical cord blood sample was drawn at birth. At each visit, infants underwent a clinical examination focusing on auxology and genital development. Further, blood (serum, plasma, DNA) and urine samples were collected at each visit. Mothers and fathers underwent a clinical examination and provided blood samples prior to and after birth. A subset of parents provided urine samples and breast milk samples. Pregnancy and obstetrical outcomes, and detailed parental questionnaires were compiled. Preliminary results Between August 2016 and August 2018, 2481 women with singleton pregnancies were invited to participate of which 298, including their partners, were enrolled (12.0%). A total of 268 healthy, full-term newborns born appropriate for gestational age (AGA) were included at birth, 233 newborns participated in the postnatal follow-up period and 186 completed the one-year follow-up period (9.4% and 7.5%, respectively).

Objectives: To determine trends in clinical practice for individuals with D SD requiring gonadectomy. Design: Retrospective cohort study. Methods: Information regarding age at gonadectomy according to diagnosis ; reported sex; time of presentation to specialist centre; and location of centre from cases reported t o the International DSD Registry and who were over 16 years old in January 2019. Results: Data regarding gonadectomy were available in 668 (88%) individu als from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cas es (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (7 6%). The most common indication was mitigation of tumour risk in 172 (64%). Variatio ns in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergo ne gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high -income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), r espectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions: The likelihood of gonadectomy depends on the underlying diagnos is, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all f orms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

BACKGROUND: Serum concentrations of the peptide hormone insulin-like factor 3 (INSL3) is a candidate marker for improved distinction between constitutional delay of growth and puberty (CDGP) and permanent hypogonadotropic hypogonadism (HH) in boys.AIM: To assess the possible diagnostic role of LC-MS/MS-based INSL3 measurements as a marker of imminent puberty by comparison with testosterone (T) and luteinizing hormone (LH) levels in serum longitudinally collected from 18 healthy boys throughout puberty.RESULTS: The first increase in serum LH was detected on average 4 months earlier, as compared with the first observed increases in INSL3 and T. When comparing the 2 testicular hormones only, we found that in 22% (4 of 18) of the boys the first increase in serum INSL3 was observed prior to the first observed increase in T, whereas in 44% (8 of 18) the first increase in T was observed before the first observed increase in INSL3. In the remaining 6 boys, the 2 testicular hormones showed the first increase at the same examination.CONCLUSION: In some boys with delayed puberty, the first indication of testicular maturation may be detectable by observing serum INSL3. Further studies of LC-MS/MS determination of serum INSL3 in patients with CDGP and HH are warranted.

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia.OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs).DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018.PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia.RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia.CONCLUSIONS: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research.

Objective: Non-palpable testes remain a diagnostic challenge, often involving exploratory laparoscopy. We evaluated the diagnostic value of a wide range of reproductive hormones in order to distinguish between bilateral cryptorchidism and bilateral anorchia. Design: In this retrospective study, we identified and included 36 boys with non-palpable testes (20 with cryptorchidism, 3 with congenital hypogonadotropic hypogonadism (CHH), and 13 with anorchia) at first examination during childhood. Methods: Information on karyotype, phenotype, surgical results from laparoscopy, and biochemistry was retrieved from patient files. We compared serum concentrations of AMH, inhibin B, FSH, LH, testosterone, estradiol, and hCG stimulation testing in cryptorchid and anorchid boys to serum concentrations in a large, age-matched control group. Receiver-operating characteristic curves were used to determine the cut-off values of each reproductive hormone as a predictor of the presence of functional testicular tissue. Results: Concentrations of AMH in 0-1 year olds: ≥155 pmol/L and >1-15 year olds: ≥19 pmol/L, inhibin B (≥22 pg/mL and ≥4 pg/mL), FSH (≤28.9 IU/L and ≤20.3 IU/L) and hCG-induced testosterone (>1-15 year olds: ≥2 nmol/L) were significantly sensitive and specific markers in predicting the presence of functional testicular tissue in boys with non-palpable testes. In infancy, anorchid infants had significantly elevated gonadotropin levels, while CHH had low levels. Conclusion: Our findings suggest that laparoscopy may not be necessary in all boys with non-palpable testes if reproductive hormones unequivocally confirm the presence of functional testicular tissue. However, proving the absence may still be a diagnostic challenge.

Context: The use of anogenital distance (AGD) in clinical and epidemiological settings is increasing; however, sex-specific reference data on AGD and data on longitudinal changes in AGD in children is scarce.Objective: To create age-, sex-, and method-related reference ranges of AGD in healthy boys and girls aged 0-24 months, to assess the age-related changes in AGD and to evaluate the 2 predominantly used methods of AGD measurement.Design: The International AGD consortium comprising 4 centers compiled data from 1 cross-sectional and 3 longitudinal cohort studies (clinicaltrials.gov [NCT02497209]).Setting: All data were collected from population-based studies, recruiting from 4 maternity or obstetric centers (United States, Cambridge [United Kingdom], Odense, and Copenhagen [Denmark]).Subjects: This study included a total of 3705 healthy, mainly Caucasian children aged 0-24 months on whom 7295 measurements were recorded.Main Outcome Measures: AGD(AS) (ano-scrotal), AGD(AF) (ano-fourchette), AGD(AP) (ano-penile), AGD(AC) (ano-clitoral), AGD body size indices (weight, body mass index [BMI], body surface area, and length), and intra- and interobserver biases.Results: We created age-specific reference ranges by centers. We found that AGD increased from birth to 6 months of age and thereafter reached a plateau. Changes in AGD/BMI during the first year of life were minor (0-6% and 0-11% in boys and girls, respectively).Conclusions: Reference ranges for AGD can be used in future epidemiological research and may be utilized clinically to evaluate prenatal androgen action in differences-in-sex-development patients. The increase in AGD during the first year of life was age-related, while AGD/BMI was fairly stable. The TIDES and Cambridge methods were equally reproducible.

CONTEXT: Larger studies on outcomes in males with 45,X/46,XY mosaicism are rare.OBJECTIVE: To compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life.DESIGN: A retrospective, multicenter study.SETTING: Sixteen tertiary centers.PATIENTS OR OTHER PARTICIPANTS: Sixty-three males older than 13 years with 45,X/46,XY mosaicism.MAIN OUTCOME MEASURES: Health outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia.RESULTS: Thirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm.CONCLUSION: Patients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.

Standardized description of external genitalia is needed in the assessment of children with atypical genitalia., info:eu-repo/semantics/published

Context The early activation of the hypothalamic-pituitary-gonadal axis during infancy can be used in the evaluation of infants suspected of disorders of sex development (DSD). However, few data exist on sex-specific reference ranges for these hormones during early life. Objective To evaluate sex differences in reproductive hormone concentrations in serum from healthy infants to define sex-specific cutoff values and to apply these in infants with DSD. Design A cross-sectional study. Setting A tertiary center for pediatric endocrinology at the University Hospital of Copenhagen. Patients or Other Participants Healthy infants (1840) and patients with DSD (27), aged 2 to 5 months. Main Outcome Measures Serum concentrations of LH, FSH, testosterone (T), estradiol, sex hormone–binding globulin (SHBG), inhibin B, anti-Müllerian hormone (AMH), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and LH/FSH ratio. Results LH and FSH concentrations showed overlap between sexes, with LH being highest in boys and FSH being highest in girls. The LH/FSH ratio separated infant boys from girls with minimal overlap at a cutoff value of 0.32. Inhibin B and AMH concentrations were markedly higher in boys compared with girls, with minimal or no overlap. In infants with Klinefelter syndrome, 45,X/46,XY mosaicism and male phenotype, and Turner syndrome, the LH/FSH ratio matched the gender of rearing. However, infants with complete androgen insensitivity syndrome had LH/FSH ratios within the male range. Conclusions Reference ranges for reproductive hormones and LH/FSH ratio during mini-puberty were established in this study. The classifiers that best separated sex in mini-puberty were AMH, LH/FSH ratio, and T. Use of the LH/FSH ratio may add valuable information in the workup of infants suspected of DSD.