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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. [ABSTRACT FROM AUTHOR]

Abstract Background Gender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females. Results A discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures. Conclusion A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.

Abstract Background To better understand the molecular programs of normal and abnormal genital development, clear-cut definition of androgen-dependent gene expression patterns, without the influence of genotype (46, XX vs. 46, XY), is warranted. Previously, we have identified global gene expression profiles in genital-derived fibroblasts that differ between 46, XY males and 46, XY females with complete androgen insensitivity syndrome (CAIS) due to inactivating mutations of the androgen receptor (AR). While these differences could be due to cell autonomous changes in gene expression induced by androgen programming, recent work suggests they could also be influenced by the location from which the fibroblasts were harvested (topology). To minimize the influence of topology, we compared gene expression patterns of fibroblasts derived from identical urogenital anlagen: the scrotum in normally virilized 46, XY males and the labia majora from completely feminized 46, XY individuals with CAIS. Results 612 transcripts representing 440 unique genes differed significantly in expression levels between scrotum and CAIS labia majora, suggesting the effects of androgen programming. While some genes coincided with those we had identified previously (TBX3, IGFBP5, EGFR, CSPG2), a significant number did not, implying that topology had influenced gene expression in our previous experiments. Supervised clustering of gene expression data derived from a large set of fibroblast cultures from individuals with partial AIS revealed that the new, topology controlled data set better classified the specimens. Conclusion Inactivating mutations of the AR, in themselves, appear to induce lasting changes in gene expression in cultured fibroblasts, independent of topology and genotype. Genes identified are likely to be relevant candidates to decipher androgen-dependent normal and abnormal genital development.

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. [ABSTRACT FROM AUTHOR]

Introduction Regarding pediatric diabetes, hospital admission for acute complications of type 1 diabetes (T1D) has often been investigated, but little is known about other causes of hospitalization. This study aimed to explore the total burden of hospitalization in individuals with diabetes<20 years of age in Germany. Methods Using the German Diagnosis-Related Groups data for 2015, we examined the frequencies of hospitalization with diabetes (20 251 inpatient cases), stratified by diabetes type [T1D, type 2 diabetes (T2D), other specified diabetes types (T3D), and unclear diabetes], and without diabetes (1 269 631 inpatient cases). Using estimates of the population at risk with T1D, T2D, and without diabetes, we evaluated hospitalization rates (per patient-year) by Poisson regression. For T1D, T2D, and T3D, we investigated the most frequent diagnoses and the median length of stay. Most analyses were stratified by sex, age-group and east/west residence. Results Children and adolescents with diabetes had a 6 to 9 times higher hospitalization risk than peers without diabetes (hospitalization rate 0.09). The hospitalization rate was higher for T2D compared with T1D (0.84 vs. 0.53, P<0.001). In T2D, two-third of inpatient cases were not directly related to diabetes, and stay was shorter compared with T1D and T3D (3 vs. 4 and 5 days, respectively). In T1D, hospitalization was more frequent among girls than boys (0.58 vs. 0.49, P<0.001), and mostly due to "diabetes without complications" (65.7%). Hospitalization tended to be more frequent and longer in the youngest patients, and in those with east residence. Conclusion Hospitalization rate in pediatric diabetes in Germany remained high, especially for T2D patients, girls with T1D, and young children. [ABSTRACT FROM AUTHOR]