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Objectives: 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare type of congenital adrenal hyperplasia caused by recessive loss-of-function mutations in HSD3B2 gene. Case presentation: We report an 8.5-year-old, 46XY, Roma boy with advanced adrenarche signs born to consanguineous parents. He was born at term with ambiguous genitalia. At 15 days of age, he underwent replacement therapy with hydrocortisone and fludrocortisone due to a salt wasting (SW) crisis and adrenal insufficiency. At 3.5 years, he was admitted again with SW crisis attributed to the low – unadjusted to body surface area – hydrocortisone dose and presented with bilateral gynecomastia and adrenarche. At 8.5 years, his bone age was four years more advanced than his chronological age and he was prepubertal, with very high testosterone levels. Gas chromatography-mass spectrometry (GC-MS) urinary steroid metabolome analysis revealed the typical steroid metabolic fingerprint of 3β-HSD deficiency. Sequencing of the HSD3B2 gene identified in homozygosity the novel p.Lys36Ter nonsense mutation. Furthermore, this patient was found to be heterozygous for p.Val281Leu in the CYP21A2 gene. Both parents were identified as carriers of the p.Lys36Ter in HSD3B2. Conclusions: A novel nonsense p.Lys36Ter mutation in HSD3B2 was identified in a male patient with hypospadias. 3β-HSD deficiency due to mutations in the HSD3B2 gene is extremely rare and the finding of a patient with this rare type of disorders of sex development (DSD) is one of the very few reported to date. The complexity of such diseases requires a multidisciplinary team approach regarding the diagnosis and follow-up. [ABSTRACT FROM AUTHOR]

A lower 24-h urine pH (24h-pH), i.e., a higher renal excretion of free protons, at a given acid load to the body, denotes a reduction in the kidney's capacity for net acid excretion (NAE). There is increasing evidence, not only for patients with type 2 diabetes but also for healthy individuals, that higher body fatness or waist circumference (WC) has a negative impact on renal function to excrete acids (NAE). We hypothesized that adiposity-related inflammation molecules might mediate this relation between adiposity and renal acid excretion function. Twelve biomarkers of inflammation were measured in fasting blood samples from 162 adult participants (18-25 yr old) of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study who had undergone anthropometric measurements and collected 24-h urine samples. Both Baron and Kenny's (B&K's) steps to test mediation and causal mediation analysis were conducted to examine the potential mediatory roles of biomarkers of inflammation in the WC-24-h pH relationship after strictly controlling for laboratory-measured NAE. In B&K's mediation analysis, leptin, soluble intercellular adhesion molecule 1 (sICAM-1), and adiponectin significantly associated with the outcome 24-h pH and attenuated the WC-pH relation. In agreement herewith, causal mediation analysis estimated the "natural indirect effects" of WC on 24-h pH via leptin (P = 0.01) and adiponectin (P = 0.03) to be significant, with a trend for sICAM-1 (P < 0.09). The calculated proportions mediated by leptin, adiponectin, and sICAM-1 were 64%, 23%, and 12%, respectively. Both mediation analyses identified an inflammatory cytokine (leptin) and an anti-inflammatory cytokine (adiponectin) along with sICAM-1 as being potentially involved in mediating adiposity-related influences on renal acid excretion capacity. [ABSTRACT FROM AUTHOR]

The composition of follicular fluid (FF) has an impact on the developmental capacity of the oocyte and the resulting embryo. FF is composed of blood plasma constituents which cross the blood follicular barrier and the secretory components of granulosa and theca cells. Moreover, it has been shown recently that follicular cells have the ability to synthesize bile acids (BAs). BAs are present in several fluids of mammals especially in bile, blood and urine. FF is an essential impacting factor on the oocyte quality and therefore resulting embryos. To achieve a better understanding of this subject, the presence and concentration of BAs were measured in fluid collected from bovine follicles, categorized according to their size, throughout two entire oestrus cycles and compared to those in blood and urine. The body fluids were collected during the same examination procedure and in total samples from four heifers were obtained. A broad spectrum of 11 BA derivatives was measured applying liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The simultaneous and direct quantification of BAs in different body fluids of cattle are reported. Within the follicular fluid, blood and urine, cholic acid and glycocholic acid are the dominant BA subspecies irrespective of the oestrus cycle stage. Moreover, BA concentrations in blood compared to those in the FF were similar. For the first time these results clearly highlight the presence of different BA subspecies in FF, blood and urine during the oestrus cycle in cattle. [ABSTRACT FROM AUTHOR]

Objective: On the basis of urinary steroidal gas chromatography-mass spectrometry (GC-MS), we previously defined a novel concept of a disease-specific "steroid metabolomic signature" and reclassified childhood obesity into five groups with distinctive signatures. The objective of the current study was to delineate the steroidal signature of insulin resistance (IR) in obese children.Research Design and Methods: Urinary samples of 87 children (44 girls) aged 8.5-17.9 years with obesity (BMI >97th percentile) were quantified for 31 steroid metabolites by GC-MS. Defined as HOMA-IR >95th percentile and fasting glucose-to-insulin ratio >0.3, IR was diagnosed in 20 (of 87 [23%]) of the examined patients. The steroidal fingerprints of subjects with IR were compared with those of obese children without IR (non-IR). The steroidal signature of IR was created from the product of IR - non-IR for each of the 31 steroids.Results: IR and non-IR groups of children had comparable mean age (13.7 ± 1.9 and 14.6 ± 2.4 years, respectively) and z score BMI (2.7 ± 0.5 and 2.7 ± 0.5, respectively). The steroidal signature of IR was characterized by high adrenal androgens, glucocorticoids, and mineralocorticoid metabolites; higher 5α-reductase (An/Et) (P = 0.007) and 21-hydroxylase [(THE + THF + αTHF)/PT] activity (P = 0.006); and lower 11βHSD1 [(THF + αTHF)/THE] activity (P = 0.012).Conclusions: The steroidal metabolomic signature of IR in obese children is characterized by enhanced secretion of steroids from all three adrenal pathways. As only the fasciculata and reticularis are stimulated by ACTH, these findings suggest that IR directly affects the adrenals. We suggest a vicious cycle model, whereby glucocorticoids induce IR, which could further stimulate steroidogenesis, even directly. We do not know whether obese children with IR and the new signature may benefit from amelioration of their hyperadrenalism. [ABSTRACT FROM AUTHOR]

Background/Aims: Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) classically associated with hypogonadotropic hypogonadism. Unexpectedly, precocious puberty (PP) has been reported in some cases, its mechanism remaining unclear. Methods: We longitudinally studied a boy with AHC due to DAX1 gene mutation who developed peripheral PP at age 4.5 years. Initially he presented pubic hair, penile enlargement, advanced bone age and elevated testosterone levels. PP progressed with acne, body odour and ejaculations. In addition, we summarized reported findings of patients with DAX1 mutations and PP in the literature in a structured manner providing a basis to discuss possible pathomechanisms of PP in DAX1 patients. Results: In our patient, hydrocortisone treatment was increased to 20 mg/m2/day as suggested in similar published cases. However, despite the suppression of adrenocorticotropic hormone (ACTH), this remained without clinical effect or change in laboratory results. The progression of symptoms of pubertal development was well suppressed under cyproterone acetate treatment. Twenty-four-hour steroid urine excretion rate measurements excluded an effect of adrenal androgens and showed a prepubertal rise of excreted testosterone. Testes size remained small. GnRH testing showed peripheral PP. Conclusion: We hypothesize that an intrinsic, gonadotropin- and ACTH-independent activation of steroidogenesis in the DAX1 deficient testes leads to PP in AHC patients with DAX1 mutations. [ABSTRACT FROM AUTHOR]

Purpose: Flavonoid consumption during adolescence could contribute to preventing adult onset of type 2 diabetes mellitus. We investigated the prospective association between habitual intake of flavonoids from fruit and vegetables (FlavFV) during adolescence and risk markers of type 2 diabetes in early adulthood. Methods: This analysis included participants of the DONALD Study, who had provided a fasting blood sample in adulthood (18–39 years), data on FlavFV-intake during adolescence (females: 9–15 years, males: 10–16 years) and relevant covariates. Habitual FlavFV-intake was either estimated using repeated 3-day weighed dietary records (n = 268), or the validated biomarker hippuric acid (uHA)-excretion in repeated 24-h urine samples (n = 241). Multivariable linear regressions were performed to analyse the prospective associations of FlavFV or uHA with homeostasis model assessment insulin sensitivity (HOMA2-%S), hepatic steatosis index (HSI), fatty liver index (FLI) and a pro-inflammatory score. Results: Higher FlavFV-intake was independently related to higher HOMA2-%S among females (Ptrend = 0.03), but not among males. Both FlavFV-intake and uHA-excretion were inversely associated with HSI (Ptrend < 0.0001 and Ptrend = 0.02, respectively) and the pro-inflammatory score (Ptrend = 0.02 and Ptrend = 0.008, respectively), but not with FLI. Conclusions: Our data indicate that flavonoid consumption from fruit and vegetables during adolescence is associated with a favourable risk factor profile for type 2 diabetes in early adulthood. [ABSTRACT FROM AUTHOR]