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.

While misuse of testosterone esters is widespread in elite and recreational sports, direct detection of intact testosterone esters in doping control samples is hampered by the rapid hydrolysis by esterases present in the blood. With dried blood spot (DBS) as sample matrix, continued degradation of the esters is avoided due to inactivation of the hydrolase enzymes in dried blood. Here we have developed the method further for detection of testosterone esters in DBS with focus on robustness and applicability in doping control. To demonstrate the method's feasibility, DBS samples from men receiving two intramuscular injections of Sustanon ® 250 (n = 9) or placebo (n = 10), were collected, transported and stored prior to analysis, to mimic a doping control scenario. The presented nanoLC-HRMS/MS method appeared reliable and suitable for direct detection of four testosterone esters (testosterone decanoate, isocaproate, phenylpropionate and propionate) after extraction from DBS.Sustanon ® was detected in all subjects for at least five days, with detection window up to 14 days for three of the esters. Evaluation of analyte stability showed that while storage at room temperature is tolerated well for a few days, testosterone esters are highly stable (> 18 months) in DBS when stored in frozen conditions. Collectively, these findings demonstrate the applicability of DBS sampling in doping control for detection of steroid esters. The fast collection and reduced shipment costs of DBS compared to urine and standard blood samples, respectively, will allow more frequent and/or large-scale testing to increase detection and deterrence.

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 1) to explore the dynamics of HPG hormone activity in healthy male infants, 2) to assess the association of HPG axis activity and testicular volume and 3) to establish reference curves for serum levels of reproductive hormones. Design Prospective, longitudinal birth cohort (The COPENHAGEN Minipuberty Study, 2016-2018, one 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 one-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 six months of age. Gonadotropins, total testosterone and insulin-like factor 3 peaked at around one month of age. Inhibin B, anti-Müllerian hormone and testicular volume peaked at around 4-5 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.

Testosterone treatment stimulates the production of red blood cells and alters iron homeostasis. Thus, we investigated whether the ‘haematological module’ of the athlete biological passport (ABP) used by the World Anti‐Doping Agency can be used to indicate misuse of testosterone. Nineteen eugonadal men received intramuscular injections of either 250 mg Sustanon®, a blend of four testosterone esters, or placebo on days 0 and 21 in a randomized, placebo‐controlleddouble‐blind design. Urine samples and blood samples were collected twice pre‐treatment, at least 5 days apart, and on days 1, 3, 5, 10 and 14 post‐injections to assess steroidal and haematological biomarkers of the ABP. The steroidal profile was flagged suspicious in all Sustanon®‐treated subjects, whereas the haematological profile was flagged suspicious in six out of nine subjects. When both sensitivity and specificity were considered, reticulocyte percentage (RET%) appeared as the best marker of the haematological module for implying testosterone ester misuse. Atypical blood passport samples were used to select time points for further isotope‐ratio mass spectrometry (IRMS) analysis of testosterone and its metabolites in simultaneously collected urine. In addition to the testosterone (T) to epitestosterone (E) ratio, the RET% and OFF‐Score could help identify suspicious samples for more targeted IRMS testing. The results demonstrate that unexpected fluctuations in RET% can indicate testosterone doping if samples are collected 3–10 days after injection. From an anti‐doping perspective, the haematological and steroidal modules of the ABP should complement each other when planning targeted follow‐up testing and substantiating likely misuse of testosterone.

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This study was the first to demonstrate SHOX duplications in three girls with tall stature and normal karyotypes.

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 0-1 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 six examinations including venipuncture during the first year of life. Intervention(s) None. Main Outcome Measure(s) Serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), and sex hormone-binding globulin (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 15-27 followed by a general nadir for all hormones around days 58-92. The second peaks occurred around days 107-125 for inhibin B, AMH, E1, E2, and SHBG and day 164-165 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.

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