The Unique Role of 11-Oxygenated C19 Steroids in Both Premature Adrenarche and Premature Pubarche

Abstract

<b><i>Introduction:</i></b> Recent studies have shown 11-oxygenated androgens (11oAs) are the dominant androgens in premature adrenarche (PA). Our objective was to compare 11oAs and conventional androgens in a well-defined cohort of children with PA or premature pubarche (PP) and correlate these androgens with metabolic markers. <b><i>Methods:</i></b> A prospective cross-sectional study was conducted at a university hospital. Fasting early morning serum steroids (including 11oAs) and metabolic biomarkers were compared and their correlations determined in children ages 3–8 years (F) or 3–9 years (M) with PA or PP (5 M and 15 F) and healthy controls (3 M and 8 F). <b><i>Results:</i></b> There were no differences between PA, PP, and controls or between PA and PP subgroups for sex, BMI z-score, or criteria for childhood metabolic syndrome. Dehydroepiandrosterone sulfate (DHEAS) was elevated only in the PA subgroup, as defined. 11oAs were elevated versus controls in PA and PP although no differences in 11oAs were noted between PA and PP. Within the case cohort, there was high correlation of T and A4 with 11-ketotestosterone and 11β-hydroxyandrostenedione. While lipids did not differ, median insulin and HOMA-IR were higher but not statistically different in PA and PP. <b><i>Conclusions:</i></b> PA and PP differ only by DHEAS and not by 11oAs or insulin sensitivity, consistent with 11oAs – rather than DHEAS – mediating the phenotypic changes of pubarche. Case correlations suggest association of 11oAs with T and A4. These data are the first to report the early morning steroid profiles including 11oAs in a well-defined group of PA, PP, and healthy children.

Salivary microbiome differences in prepubertal children with and without adrenal androgen excess

“…Exclusion criteria were a history of chronic illness or other known endocrinopathies, evidence of adrenal enzyme defect, elevated inflammatory marker (C-reactive protein), history of hormone exposure, chronic glucocorticoid use, psychostimulant use, use of antibiotics in the prior 3 months, or use of probiotics in the last 1 month. The case group was previously subdivided into PA and PP subgroups based on elevation of adrenal androgen serum DHEAS in a prior study 4 ; however, as described in our publication, there did not appear to be any significant anthropometric or biochemical differences in this population (notably in 11oAs). Therefore, the PA and PP subgroups were treated as one case cohort (referred to in this study as the AAE group) for analysis of salivary microbiome measures.…”

“…Laboratory data usually reflect increased levels of DHEA, DHEAS, and androstenedione; recent studies have correlated 11-oxygenated 19-carbon steroids (11-oxygenated androgens [11oAs]) with the clinical signs of pubarche independent of adrenarche. 2 - 4 PA has been associated with obesity, metabolic syndrome, and polycystic ovary syndrome (PCOS), and may represent an early hyperandrogenic state in girls who later present with PCOS, with hyperinsulinism playing a key role. 5 - 9 …”

Case report: 11-ketotestosterone may potentiate advanced bone age as seen in some cases of Wiedemann-Steiner Syndrome

“…At the age of 3 years and 5 months, a serum 11-ketotestosterone (11KT) level was measured by commercial laboratory (Esoterix, Inc., Calabasas Hills, CA, USA) using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS). 11KT was 26.3 ng/dL, which is elevated when compared to published data on a reference population of girls aged 4-5 years (range 7.3-10.9 ng/dL) and girls with premature adrenarche age 4-7 years (range 12.3-22.9 ng/dL) ( 17 ). The repeat 11KT at follow-up (chronological age 4 year 6 months) was still elevated at 33.8 ng/dL.…”

“…Systematic longitudinal studies in children with WSS are warranted to address the apparent link between premature adrenarche, advanced bone age, and the pathophysiologic role of elevated 11KT, and to ensure reproducibility. We also acknowledge that the reference ranges for 11-oxygenated androgens in pediatric populations have been limited to two publications based on small sample sizes ( 17 , 18 ), and further studies are needed to validate age and sex-specific reference intervals. We do not have a DHEAS measurement in Case 1, however the DHEA concentration of Case 1 was normal.…”

11-Oxygenated androgens are not secreted by the human ovary: in-vivo data from four different cases of hyperandrogenism

“…As the biosynthesis of 11-oxygenated androgens depends on cytochrome P450 family 11 subfamily B member 1 (CYP11B1), an adrenal-specific enzyme, they should also be adrenal-specific [13]. It has been shown that 11-oxygenated androgens are elevated in adrenal-related androgen excess as congenital adrenal hyperplasia (CAH) or premature adrenarche and Cushing's disease [14,17,18]. In addition, they may also be elevated in some [19,20], but not all patients [21] with PCOS.…”