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Clinical Pediatric Endocrinology : Case... 2020
PubMed: 32694892
DOI: 10.1297/cpe.29.131 -
Current Opinion in Pediatrics Aug 2020Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when... (Review)
Review
PURPOSE OF REVIEW
Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair.
RECENT FINDINGS
The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta.
SUMMARY
The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.
Topics: Adrenal Glands; Adrenarche; Androgens; Child; Child Development; Dehydroepiandrosterone Sulfate; Female; Humans; Pregnancy; Puberty; Puberty, Precocious; Steroids; Zona Reticularis
PubMed: 32692055
DOI: 10.1097/MOP.0000000000000928 -
Journal of Chromatography. B,... Sep 2020The C11-oxy androgens have been implicated in the progression of many diseases and endocrine-linked disorders, such as polycystic ovarian syndrome (PCOS), congenital...
The C11-oxy androgens have been implicated in the progression of many diseases and endocrine-linked disorders, such as polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia, specifically 21-hydroxylase deficiency (21OHD), castration resistant prostate cancer (CRPC), as well as premature adrenarche. While the C11-oxy C steroids have been firmly established in the steroid arena, the C11-oxy C steroids are now also of significance. The current study reports on a high-throughput ultra-performance convergence chromatography tandem mass spectrometry (UPC-MS/MS) method for the separation and quantification of 52 steroids in peripheral serum, which include the C11-oxy C and C11-oxy C steroids. Fifteen deuterium-labelled steroids were included for absolute quantification, which incorporates steroid extraction efficiency, together with one steroid and four non-steroidal compounds serving as quality controls (QC). The 15 min run-time per sample (16 min injection-to-injection time with an 8-step gradient) quantifies 68 analytes in a 2 µL injection volume. A single chromatographic step simultaneously identifies steroids in the mineralocorticoid, glucocorticoid and androgen pathways in adrenal steroidogenesis, together with steroid metabolites produced in the periphery, presenting an analytical method for the application of screening in vivo clinical samples. This study highlights cross-talk between the C11-oxy steroids, and describes the optimisation of multiple reaction monitoring required to measure steroids accurately. The limit of detection for the steroid metabolites ranged from 0.002 to 20 ng/mL and the limit of quantification from 0.02 to 100 ng/mL. The calibration range for the steroids ranged from 0.002 to 1000 ng/mL and for the QC compounds from 0.075 to 750 ng/mL. The method is fully validated in terms of accuracy (%RSD, <13%), precision (including inter-day variability across a three-day period) (%RSD, <16%), recovery (average 102.42%), matrix effect (ranging from -15.25 to 14.25%) and process efficiency (average 101.79%). The dilution protocol for the steroids, internal standards and QC compounds were validated, while the ion ratios of the steroid metabolites (%RSD, <16%) and QC compounds were monitored and the accuracy bias values (%RSD, <9%) were within acceptable limits. The method was subsequently used to quantify steroid levels in a cohort of healthy women. C11-oxy steroid metabolites produced as intermediates in steroidogenic pathways, together with end-products included in the method can potentially characterise the 11β-hydroxyandrostenedione-, C- and C11-oxy backdoor pathways in vivo. The identification of these C11-oxy C and C11-oxy C intermediates would allow insight into active pathways, while steroid metabolism could be traced in patients and reference ranges established in both normal and abnormal conditions. Furthermore, conditions currently undefined in terms of the C11-oxy steroids would benefit from the analysis provided by this method, while the C11-oxy steroids could be further explored in PCOS, 21OHD, CRPC and adrenarche.
Topics: Adult; Chromatography, High Pressure Liquid; Female; Humans; Limit of Detection; Linear Models; Reproducibility of Results; Steroids; Tandem Mass Spectrometry; Young Adult
PubMed: 32593151
DOI: 10.1016/j.jchromb.2020.122243 -
Frontiers in Endocrinology 2020An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are...
An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP. A novel heterozygous nonsense mutation in the gene and a known heterozygous missense variant in the gene were found. The heterozygous nonsense mutation in the gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids.
Topics: Adolescent; Case-Control Studies; Codon, Nonsense; Dehydroepiandrosterone Sulfate; Female; Humans; Multidrug Resistance-Associated Protein 2; Pediatric Obesity; Prognosis; Steryl-Sulfatase; Young Adult
PubMed: 32435230
DOI: 10.3389/fendo.2020.00240 -
Primary Care Jun 2020Evaluation of the child with abnormal pubertal development can be challenging for the primary care provider. Understanding the factors associated with timing of pubertal... (Review)
Review
Evaluation of the child with abnormal pubertal development can be challenging for the primary care provider. Understanding the factors associated with timing of pubertal onset and the normal sequence of pubertal changes is useful in evaluation of children with puberty disorders. A thorough workup includes assessment of growth rate, Tanner staging, and rate of pubertal progression, in addition to an extensive history and physical examination to identify signs and symptoms of disorders associated with abnormal pubertal timing. Initial diagnostic studies will most often include a bone age, levels of gonadotropins, and levels of estradiol (for girls) or testosterone (for boys).
Topics: Child; Female; Gonadal Disorders; Gonadal Steroid Hormones; Humans; Hypogonadism; Male; Primary Health Care; Puberty, Delayed; Puberty, Precocious
PubMed: 32423709
DOI: 10.1016/j.pop.2020.02.001 -
Nature Reviews. Endocrinology May 2020The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the... (Review)
Review
The adrenal gland is a source of sex steroid precursors, and its activity is particularly relevant during fetal development and adrenarche. Following puberty, the synthesis of androgens by the adrenal gland has been considered of little physiologic importance. Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the major adrenal androgen precursors, but they are biologically inactive. The second most abundant unconjugated androgen produced by the human adrenals is 11β-hydroxyandrostenedione (11OHA4). 11-Ketotestosterone, a downstream metabolite of 11OHA4 (which is mostly produced in peripheral tissues), and its 5α-reduced product, 11-ketodihydrotestosterone, are bioactive androgens, with potencies equivalent to those of testosterone and dihydrotestosterone. These adrenal-derived androgens all share an oxygen atom on carbon 11, so we have collectively termed them 11-oxyandrogens. Over the past decade, these androgens have emerged as major components of several disorders of androgen excess, such as congenital adrenal hyperplasia, premature adrenarche and polycystic ovary syndrome, as well as in androgen-dependent tumours, such as castration-resistant prostate cancer. Moreover, in contrast to the more extensively studied, traditional androgens, circulating concentrations of 11-oxyandrogens do not demonstrate an age-dependent decline. This Review focuses on the rapidly expanding knowledge regarding the implications of 11-oxyandrogens in human physiology and disease.
Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Androgens; Endocrine System Diseases; Female; Humans; Male; Oxygen; Polycystic Ovary Syndrome; Prostatic Neoplasms; Puberty, Precocious
PubMed: 32203405
DOI: 10.1038/s41574-020-0336-x -
International Journal of Pediatric... 2020Premature adrenarche has been described as clinical and biochemical hyperandrogenism before the age of 8 years in girls and 9 years in boys and absence of signs of...
BACKGROUND
Premature adrenarche has been described as clinical and biochemical hyperandrogenism before the age of 8 years in girls and 9 years in boys and absence of signs of true puberty. Adrenal pathology such as adrenal tumors or non-classical congenital adrenal hyperplasia (NCCAH) and exogenous androgen exposure need to be excluded prior to diagnosing (idiopathic) premature adrenarche. Premature adrenarche is more common among black girls compared to white girls and other racial groups. Adrenal pathology such as NCCAH is less common as a cause for premature adrenarche compared with idiopathic premature adrenarche. The evaluation guidelines for premature adrenarche however are not individualized based on racial/ethnic differences. Few studies have been done to evaluate a largely black population with premature adrenarche to assess the incidence of adrenal pathology.
METHODS
This cross-sectional retrospective study evaluated characteristics of prepubertal patients seen in an endocrine clinic for premature adrenarche.
RESULTS
Two hundred and seventy three subjects had signs of early adrenarche. Three subjects were found to have CAH (2 with NCCAH and 1 with late diagnosis classical CAH). None were black. Exogenous androgen exposure was etiology in 4 additional subjects. These 7 patients were excluded from further analysis. The remaining subjects had idiopathic PA ( = 266); 76.7% were females. The mean age at initial visit was 6.42 +/- 1.97 years (with no racial difference) although black subjects were reported symptom onset at a significantly younger age compared to non-Hispanic white patients.
CONCLUSIONS
Our study showed organic pathology was very uncommon in a predominantly black population with premature adrenarche. Patient factors that influence the probability of an underlying organic pathology including race/ ethnicity should be considered to individualize evaluation.
PubMed: 32165891
DOI: 10.1186/s13633-020-0075-8 -
Hormone and Metabolic Research =... Mar 2020If circulating adrenal androgens levels rise before the age of 8 years in girls, this phenomenon is termed premature adrenarche (PA), while the concomitant appearance of... (Comparative Study)
Comparative Study
If circulating adrenal androgens levels rise before the age of 8 years in girls, this phenomenon is termed premature adrenarche (PA), while the concomitant appearance of pubic hair is called premature pubarche (PP). Girls with PA-PP display an unfavorable hormonal profile compared to their normal peers and have an increased risk of developing polycystic ovary syndrome (PCOS) features peripubertally. However, the sequelae of premature adrenarche remains unclear. We assessed metabolic, hormonal, psychologic profiles, and ovarian morphology in 21 women of mean age (±SD) 21.3±3.3 years, BMI: 23.6±4.4 kg/m with PA-PP, 45 women with PCOS and 26 controls, matched for age and BMI. PA-PP women displayed a favorable lipid profile compared to PCOS and controls. Insulin resistance index (HOMA-IR), however, were similar in PA-PP and PCOS women (2.09±1.42, 2.08±0.83) and higher than controls (1.13±0.49, p <0.05). Circulating androstenedione levels did not differ between PA-PP and PCOS women (0.11±0.05 vs. 0.12±0.03), but was higher than that of controls (0.02±0.0 nmol/l, p <0,05). Ovarian volume was increased in PA-PP and PCOS (11.14±3.3 vs. 10.99±4.61) compared to controls (6.74±1.83 cm). PA-PP women had a higher score of state/trait anxiety and depressive and eating disorder symptoms than controls, with a pattern that matched that of PCOS women. Only 14% of the PA-PP group fulfilled the Rotterdam PCOS criteria. Some women with a history of PA-PP displayed hormonal and psychologic profile similar to PCOS, and accordingly a regular monitoring of these girls during adulthood is advised.
Topics: Adolescent; Adrenarche; Androgens; Body Mass Index; Cross-Sectional Studies; Female; Hormones; Humans; Ovary; Polycystic Ovary Syndrome; Puberty, Precocious; Ultrasonography; Young Adult
PubMed: 32074632
DOI: 10.1055/a-1109-2630 -
Journal of Pediatric Genetics Mar 2020Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency...
Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the and genes. Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome where heterozygous mutations of gene have been associated with a mild clinical presentation (CDLS type 4; MIM: 614701). We report a female patient with a 2.3-Mb interstitial deletion at 8q23.3-q24.1 encompassing and genes but not . Clinical findings in this patient are correlated with a mixed phenotype of LGS and CdLS type 4.
PubMed: 31976145
DOI: 10.1055/s-0039-1694779 -
The Journal of Adolescent Health :... May 2020This project investigated internal consistency and test-retest reliability of the frequently used Pubertal Development Scale (PDS) and compared parent and child reports...
PURPOSE
This project investigated internal consistency and test-retest reliability of the frequently used Pubertal Development Scale (PDS) and compared parent and child reports with clinician-rated Tanner staging.
METHODS
Using a repository of data collected from 1995 to 2016, 252 participants (aged 7.8-17.7 years) provided self- and parent-reported PDS and received Tanner staging by a certified health care professional within 30 days. Internal consistency and test-retest reliability statistics were evaluated for 56 children across two assessments occurring within 6 months. Comparisons with Tanner staging involved examining concurrent validity and calibration analysis using data from 233 child and 252 parental ratings.
RESULTS
Self- and parent-reported PDS demonstrated good internal consistency, with Cronbach's alpha .91-.96; high test-retest reliability was confirmed with intraclass correlation coefficient .81-.92. The association of Tanner stage with self- and parent-reported PDS was moderate to high; Kendall's Tau ranged from .67 to .76, and intraclass correlation coefficient ranged from .73 to 83. The absolute agreement of Tanner stage with self- and parent-reported PDS was low; Cohen's Kappa ranged from .20 to .37. However, combining pubertal scores into three stages of development (pre/early-, mid-, and late/post-pubertal) improved interrater agreement across measures (κ = .65, 95% confidence interval = .57-.73).
CONCLUSIONS
The present study shows that the PDS is reliable and generally tracks with Tanner staging (for both self and parent report). Low absolute agreement indicates that PDS categories do not map directly to specific Tanner stages, partly because a premature adrenarche is often misinterpreted by parents and pediatricians alike. However, three broad categories showed better agreement and are generally adequate for most applications in child and adolescent research.
Topics: Adolescent; Child; Family; Humans; Puberty; Reproducibility of Results; Surveys and Questionnaires
PubMed: 31974011
DOI: 10.1016/j.jadohealth.2019.11.308