Search

Context Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age. Objective We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI). Methods Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established “LMS” growth chart algorithm in R. Results Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (β = 0.5, P Conclusion Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients.

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-Müllerian 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.

Objectives To determine trends in clinical practice for individuals with DSD 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 to the International DSD Registry and who were over 16 years old in January 2019. Results Data regarding gonadectomy were available in 668 (88%) individuals 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 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone 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), respectively (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 diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC–MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS). This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC–MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated. In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01). The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

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 ∑DnBPm tertile (0.91 (0.12; 1.70) and −0.85 (−1.51;-0.18), respectively) were observed. In addition, boys in the middle and highest ∑DEHPm tertile had higher LH (1.07 (0.35; 1.79) and 0.71 (−0.01; 1.43), respectively) and in the highest ∑DEHPm tertile also higher AMH (0.85 (0.10; 1.61)) concentration SD-scores, respectively. Boys in the highest BPA tertile had significantly higher AMH and lower DHEAS concentration compared to boys in the lowest BPA tertile (1.28 (0.54; 2.02) and −0.73 (−1.45; −0.01)), respectively. Discussion: Our findings indicate that exposure to chemicals with known or suspected endocrine disrupting potential, especially the EU-regulated DnBP, DEHP and BPA, may modify male reproductive hormone concentrations in infant boys suggesting that minipuberty is a critical window sensitive to endocrine disruption.

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 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.

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). Conclusion The COPENHAGEN Minipuberty Study provides detailed, longitudinal data on early genital development and growth including hormonal and genetic profiles and environmental exposure in healthy infants including additional data in their parents.

Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC-MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS).This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC-MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated.In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01).The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

STUDY QUESTION What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? SUMMARY ANSWER The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients. WHAT IS KNOWN ALREADY The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood. STUDY DESIGN, SIZE, DURATION This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0–80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the healthy males (n = 3144) and females (n = 3273) aged 0–80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9). MAIN RESULTS AND THE ROLE OF CHANCE An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios. LIMITATIONS, REASONS FOR CAUTION The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible. WIDER IMPLICATIONS OF THE FINDINGS In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs. STUDY FUNDING/COMPETING INTEREST(S) M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation. TRIAL REGISTRATION NUMBER NA DATE OF FIRST PATIENT’S ENROLMENT June 1990 (the launch of the department from which this project stems).

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 AGDAS (ano-scrotal), AGDAF (ano-fourchette), AGDAP (ano-penile), AGDAC (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.

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.

Introduction: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease predominantly caused by 21-hydroxylase deficiency. Clinical management in children includes glucocorticoid and often mineralocorticoid treatment alongside monitoring outcomes such as an­thro­po­metry, pubertal status, blood pressure, and biochemistry. Objective: The objective of this pilot study was to present the use of 17-hydroxyprogesterone (17-OHP) and androgen metabolites expressed as standard deviation (SD) scores rather than actual concentrations as a tool in the management of children with CAH as well as in research settings. Methods: The study was a retrospective, longitudinal study that took place in a single, tertiary center and included 38 children and adolescents aged 3–18 years with CAH due to 21-hydroxylase deficiency. Biochemical measurements of 17-OHP, androstenedione, dehydroepiandrosterone-sulphate (DHEAS), and testosterone using liquid chromatography-tandem mass spectrometry were expressed as SD scores, and outcomes such as genotype, height, bone maturation, blood pressure, and treatment doses were extracted from patient files. Results: The majority (86%) of CAH patients had 17-OHP measurements above +2 SD during standard hydrocortisone therapy, receiving an average daily hydrocortisone dose of 12.6 mg/m2. Androstenedione concentrations were mostly within ±2 SD, whereas DHEAS values were below –2 SD in 47% of patients. Conclusions: Applying sex- and age-related SD scores to 17-OHP and androgen metabolite concentrations allows for monitoring of hydrocortisone treatment independent of age, sex, assay, and center. We propose that 17-OHP and androgen metabolites expressed as SD scores be implemented as a unifying tool that simplifies research and, in the future, also optimal management of treatment.

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-Mullerian 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. (J Clin Endocrinol Metab 103: 3028-3037, 2018)

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 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.

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.