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Objective: Being born small for gestational age (SGA) is frequently associated with unexplained disorders of sex development (nonspecific DSD) in boys. Little is known about their future growth, puberty and testicular function. Our objective is to determine the long-term endocrine outcome of boys born SGA who have a nonspecific DSD., Design: Boys with a nonspecific DSD born SGA and appropriate for GA (AGA) were retrieved through the International Disorders of Sex Development registry and retrospective data collected, based on a spreadsheet containing 102 items., Patients and Measurements: In total, 179 boys were included, of which 115 were born SGA and 64 were born AGA. Their growth and pubertal development were compared. Serum LH, FSH, testosterone, AMH and inhibin B levels in infancy and puberty were analysed to assess testicular function., Results: At 2 years of age, 30% of SGA boys had incomplete or absent catch-up growth. Boys born SGA also had higher LH during minipuberty and lower testosterone in stimulation tests (p = 0.037 and 0.040, respectively), as compared to boys born AGA. No differences were observed in timing or course of puberty or end-pubertal hormone levels., Conclusions: Almost one out of three SGA boys with a nonspecific DSD experiences insufficient catch-up growth. In addition, our data suggest dysfunction of infantile Leydig cells or altered regulation of the hypothalamic-pituitary-gonadal axis in SGA boys during childhood. Sex steroid production during puberty seems unaffected., (© 2021 John Wiley & Sons Ltd.)

Objective: Gynaecomastia is frequent in pubertal boys and is regarded as a self-limiting abnormality. However, longitudinal studies proving this hypothesis are scarce., Design: Longitudinal follow-up study (median 2.4, range 1.0-4.8 years)., Methods: The regression of breast diameter was analysed in 31 pubertal boys aged 11.7-16.1 (median 13.2) years with gynaecomastia. Furthermore, weight changes (as BMI-SDS) and pubertal stage, oestradiol [E2], oestriol, oestrone, androstenedione, testosterone [T], dihydrotestosterone, gonadotropins, IGF-1, and IGFBP-3 serum concentrations determined at first clinical presentation were related to breast diameter regression determined by palpation and disappearance of breast glandular tissue in ultrasound in follow-up to identify possible predictors of breast regression., Results: During the observation period, the breast diameter decreased (in median -1 (interquartile range [IQR] -5 to +1) cm). At follow-up, 6% of boys had no breast enlargement any more, and 65% developed lipomastia. Gynaecomastia was still present in 29%. None of the analysed hormones was related significantly to breast diameter regression or disappearance of breast glandular tissue. In multiple linear regression analyses adjusted for observational period, as well as age and BMI-SDS at first presentation, changes in BMI-SDS (β-coefficient 6.0 ± 2.3, p = .015) but not the E2/T ratio or any other hormone determined at baseline was related to changes in breast diameter., Conclusions: Breast diameter regression seems not to be predictable by a hormone profile in pubertal boys with gynaecomastia. In pubertal boys presenting with gynaecomastia, conversion to lipomastia of smaller volume is common. The reduction of weight status was the best predictor of breast diameter regression., (© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: To delineate the role of gonadotropins in male androgen biosynthesis pathways., Design: Case-control study., Patients and Measurements: Twenty five males with congenital hypogonadotropic hypogonadism (CHH) underwent hCG/rFSH and testosterone treatment sequentially. Serum steroid hormone profiles (testosterone precursors and metabolites) on both replacement regimens were analysed, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared to those of healthy controls, matched by age, BMI and serum testosterone., Results: On testosterone replacement, serum concentrations of the classic Δ4 pathway hormones progesterone and 17-hydroxy-progesterone (17-OHP), and the marker steroid of an alternative pathway of testosterone synthesis (androstenediol) were decreased, compared to controls. Androstanediol, a marker of the backdoor pathway of dihydrotestosterone (DHT) synthesis, was increased. 17-OH-pregnenolone, androstenedione and DHEAS (Δ5 pathway), three 11-oxygenated C19 androgens (11-keto-A4, 11-keto-T and 11-keto-DHT) and the testosterone (T) metabolites DHT and 17ß-oestradiol (E2) were similar to controls. On gonadotropin replacement, 17-OHP, 17-OH-pregnenolone, DHEAS and androstenedione, as well as DHT, androstenediol, and all 11-oxygenated C19 androgens were normal. Progesterone (Δ4 pathway) was slightly decreased, and androstanediol (backdoor DHT pathway) and E2 (T metabolite) were increased., Conclusions: In males with CHH, serum steroid hormone profiles resemble those of healthy men, if hCG/rFSH is used for substitution. Gonadotropins contribute to steroid hormone production along the classic Δ4 pathway and co-activate an alternative pathway of testosterone biosynthesis via androstenediol. Backdoor DHT biosynthesis, Δ5 17-OH-pregnenolone, DHEA(S) and androstenedione synthesis and 11-oxygenated C19 androgen production are activated independently of gonadotropins. The androgen replacement modality used for treatment of hypogonadal males with absent or reduced endogenous LH/FSH secretion may impact on long-term health and quality of life., (© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: The Anti-Muellerian Hormone (AMH) has been reported as surrogate marker of antral follicles, which are the origins of hyperandrogenism in polycystic ovarian syndrome (PCOS). Therefore, AMH may be useful for the diagnosis of PCOS. The objective was to study the longitudinal changes in AMH concentrations in girls with and without PCOS., Design: This is a longitudinal study of obese girls participating in a 1-year lifestyle intervention., Patients: Forty obese girls aged 13-16 years (50% with PCOS) were included in the study. Girls with and without PCOS were matched to age, BMI and change in weight status., Measurements: AMH, gonadotropins, androstenedione, testosterone, oestradiol and sex hormone-binding globulin (SHBG) were determined., Results: Obese girls with PCOS demonstrated significantly (P<.001) higher AMH concentrations (5.8±3.1 ng/mL) compared to obese girls without PCOS (2.4±1.4 ng/mL). None of the girls without PCOS had AMH concentrations ≥6 ng/mL and none of the PCOS girls showed AMH concentrations ≤3 ng/mL. Weight loss in girls with PCOS was associated with a significant drop in AMH concentrations (-1.4±1.8 ng/mL, P=.045). AMH was significantly related to testosterone (cross-sectional: b-coefficient 3.7±1.7, P=.001, longitudinal: b-coefficient 0.54±0.47, P=.026) and luteinizing hormone (LH) (cross-sectional: b-coefficient 0.05±0.04, P=.039, longitudinal: b-coefficient 0.005±0.004, P=.039), but not to any other analysed parameter in multiple linear regression analyses adjusted to multiple confounders., Conclusions: AMH was increased in adolescent girls with PCOS and normalized with weight loss. AMH was cross-sectionally and longitudinally related to hyperandrogenism., (© 2017 John Wiley & Sons Ltd.)

Objective: Copeptin has been reported to be associated with stress, obesity and the metabolic syndrome (MetS) in adults. However, data in childhood are scarce. Therefore, we studied the relationships between copeptin, cortisol, puberty and parameters of the MetS in children., Design: Cross-sectional study., Patients: A total of 51 obese children (10·8 ± 3·2 years, 39% male, 45% prepubertal, body mass index standard deviation score (BMI-SDS) 2·77 ± 0·56) and 24 lean children of similar age, gender and pubertal stage., Measurements: Copeptin, serum cortisol, 24-h urinary free cortisol, BMI-SDS and, as parameters of the MetS, insulin resistance index (HOMA), HbA1c, uric acids, blood pressure and lipids., Results: Copeptin levels were significantly (P = 0·047) higher in obese children (5·8 ± 2·8pmol/l) compared to lean children (4·6 ± 2·2pmol/l). BMI-SDS (β-coefficient 0·38 ± 0·35, P =0·033), but not any parameter of the MetS, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender and pubertal stage. A 24-h urinary free cortisol (β-coefficient 0·13 ± 0·06, P < 0·001), but not serum cortisol, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender, pubertal stage and BMI-SDS. Pubertal boys (6·6 ± 2·8pmol/l) demonstrated significantly (P = 0·042) higher copeptin levels compared to pubertal girls (4·8 ± 2·6pmol/l), while copeptin concentrations did not differ between prepubertal girls and boys., Conclusions: Copeptin levels are related to 24-h urinary free cortisol in obese children. Pubertal boys, but not prepubertal boys, demonstrated higher copeptin levels than girls, suggesting that sex hormones are involved in the regulation of copeptin levels. Further studies are necessary to understand the relationship between obesity, cortisol, gender, pubertal stage and copeptin levels., (© 2016 John Wiley & Sons Ltd.)

Objective: Pseudohypoaldosteronism type I (PHA1) is a rare inborn disease causing severe salt loss. Mutations in the three coding genes of the epithelial sodium channel (ENaC) are responsible for the systemic autosomal recessive form. So far, no phenotype has been reported in heterozygous carriers., Patients: A consanguineous family from Somalia giving birth to a neonate suffering from PHA1 was studied including clinical and hormonal characteristics of the family, mutational analysis of the SCNN1A, SCNN1B, SCNN1G and CFTR genes and in vitro analysis of the functional consequences of a mutant ENaC channel., Results: CFTR mutations have been excluded. SCNN1A gene analysis revealed a novel homozygous c.1684T > C mutation resulting in a S562P substitution in the alphaENaC protein of the patient. Functional analysis showed a significantly reduced S562P channel function compared to ENaC wild type. Protein synthesis and channel subunit assembly were not altered by the S562P mutation. Co-expression of mutant and wild-type channels revealed a dominant negative effect. In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes., Conclusion: Hence, the novel mutation S562P is causing systemic PHA1 in the homozygous state. A thorough clinical investigation of the heterozygote SCNN1A mutation carriers revealed increased sweat sodium and chloride levels consistent with a dominant effect of the mutant S562P allele. Whether this subclinical phenotype is of any consequence for the otherwise asymptomatic heterozygous carriers has to be elucidated.