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Clinical Endocrinology Jun 2024Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS.
OBJECTIVES
Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS.
DESIGN, PATIENTS AND MEASUREMENTS
A chart review of children with PWS treated at our institution between 1990 and 2021 was performed. PP was defined as Tanner stage 2 (TS2) pubic hair in girls <8 and boys <9 years old. Demographic, anthropometric, and laboratory data were collected to assess predisposing factors and consequences of PP in comparison to patients with PWS who had normal pubarche (NP).
RESULTS
Analysis included 43 children with PWS, 23 (53.5%) with PP and 20 (46.5%) with NP. Median age at pubarche was 7.0 years in PP group and 10.0 years in NP group. Age at pubarche was not correlated with age of recombinant human growth hormone (rhGH) initiation, body mass index (BMI) z-score, or homeostasis model assessment of insulin resistance (HOMA-IR) at pubarche. BMI z-score at pubarche was modestly correlated with degree of pubarchal BA advancement (p = 0.033). Those with PP were more likely to have a lower high-density lipoprotein (HDL) (1.05 mmol/L vs. 1.41 mmol/L in the NP group, p = 0.041). The difference between target and final height did not differ between groups (p = 0.507).
CONCLUSION
PP is common in PWS but does not compromise final height in comparison to the NP group. Obesity and insulin resistance were not associated with PP in children with PWS, contrary to what has been seen in obese children without PWS.
PubMed: 38935853
DOI: 10.1111/cen.15108 -
Molecular and Cellular Endocrinology Jun 2024Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been...
CONTEXT
Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear.
OBJECTIVE
To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche.
DESIGN
A longitudinal study of children aged 6-8 years at baseline, followed up at ages 8-10 and 14-16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8-10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.
MAIN OUTCOME MEASURES
Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways.
RESULTS
The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6-8 and 8-10 years. Pregnenolone concentrations at adrenarchal age (8-10 years) and cortisol concentrations at adolescence (14-16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best.
CONCLUSIONS
The classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.
PubMed: 38838762
DOI: 10.1016/j.mce.2024.112293 -
Endocrinology and Metabolism Clinics of... Jun 2024Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order... (Review)
Review
Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order laboratory testing and a bone age to try to rule out other diagnoses including nonclassic congenital adrenal hyperplasia and gonadal or adrenal tumors. I review the natural history of PP and studies which suggest that without clinical features such as rapid growth and progression or genital enlargement, it is unlikely that a treatable condition will be found. Therefore it is recommended that patients with PP not undergo testing unless there are red flags at the time of the initial visit.
Topics: Humans; Puberty, Precocious; Child; Female; Child, Preschool
PubMed: 38677863
DOI: 10.1016/j.ecl.2024.02.001 -
Hormone Research in Paediatrics Mar 2024Children with premature adrenarche (PA) have increased adrenal androgen concentrations and earlier pubertal development than their peers. Early sexual maturation and...
INTRODUCTION
Children with premature adrenarche (PA) have increased adrenal androgen concentrations and earlier pubertal development than their peers. Early sexual maturation and exposure to androgens have both been associated with an increased risk for neuropsychological adversities in adulthood. Such adversities would presumably influence the experienced health-related quality of life (HRQoL) of those affected.
METHODS
A longitudinal case-control cohort study, in which 30 PA girls and 40 age-matched controls were followed from childhood to young adult age. The main outcome measure was the total 15D HRQoL score. In addition, we assessed specific dimensions of the questionnaire, the subjects' relationship statuses and living arrangements.
RESULTS
There were no differences between the groups in the overall 15D scores (PA, 0.956 (0.052); control, 0.947 (0.055); p 0.482), or on any dimension of this instrument.
CONCLUSION
The study suggests that a history of PA does not lead to impaired HRQoL in adult age.
PubMed: 38471476
DOI: 10.1159/000538283 -
Endocrine Reviews Mar 2024From 1965-2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary...
From 1965-2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology; insulin resistance, hyperinsulinism, type 2 diabetes mellitus; folliculogenesis; androgen secretion; obesity; phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicates that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and pro-inflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in one-quarter of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.
PubMed: 38457123
DOI: 10.1210/endrev/bnae007 -
Journal of Pediatric Endocrinology &... Apr 2024This study aimed to analyze the cardiac effects of hyperandrogenism in premature adrenarche (PA) and evaluate the risk of arrhythmia development.
OBJECTIVES
This study aimed to analyze the cardiac effects of hyperandrogenism in premature adrenarche (PA) and evaluate the risk of arrhythmia development.
METHODS
Fifty patients with PA and 50 healthy children from a pediatric endocrinology outpatient clinic were included in the study. The patients underwent echocardiography and electrocardiographic evaluations. Conventional echocardiography, tissue Doppler echocardiography, repolarization time, and repolarization dispersion time were evaluated.
RESULTS
The median age in the PA and control groups was 7.91 years (5.83-9.25), 8.08 years (5.75-9.33), respectively. Thirty percent of patients in the PA group were male. While mitral early diastolic velocity deceleration time (DT), isovolumetric relaxation time (IRT), and E/e' ratio were significantly higher in the PA group than in the control group, mitral lateral annulus tissue Doppler early diastolic velocity was significantly lower (p=0.0001, 0.0001, 0.003, 0.0001). While P wave dispersion (PWD), Tpe, and QT-dispersion (QT-d) values were significantly higher in the PA group than in the control group, the P minimum value was significantly lower in the PA group (p=0.0001, 0.02, 0.004, and 0.0001, respectively).
CONCLUSIONS
Early subclinical diastolic dysfunction was observed in the PA group. There was an increased risk of atrial arrhythmia with PWD and an increased risk of ventricular arrhythmia with increased Tpe and QT-d. There was a correlation between testosterone levels and diastolic function parameters. The increased risk of atrial arrhythmia is closely related to diastolic function.
Topics: Child; Humans; Male; Female; Adrenarche; Echocardiography, Doppler; Echocardiography; Diastole; Arrhythmias, Cardiac; Ventricular Dysfunction, Left
PubMed: 38386924
DOI: 10.1515/jpem-2023-0460 -
Pediatrics in Review Feb 2024We describe congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common primary adrenal insufficiency in children and adolescents. In... (Review)
Review
We describe congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common primary adrenal insufficiency in children and adolescents. In this comprehensive review of CAH, we describe presentations at different life stages depending on disease severity. CAH is characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands. Diagnosis of CAH is most common during infancy with elevated 17-hydroxyprogesterone levels on the newborn screen in the United States. However, CAH can also present in childhood, with late-onset symptoms such as premature adrenarche, growth acceleration, hirsutism, and irregular menses. The growing child with CAH is treated with hydrocortisone for glucocorticoid replacement, along with increased stress doses for acute illness, trauma, and procedures. Mineralocorticoid and salt replacement may also be necessary. Although 21-hydroxylase deficiency is the most common type of CAH, there are other rare types, such as 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase deficiency. In addition, classic CAH is associated with long-term comorbidities, including cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects. Overall, early identification and treatment of CAH is important for the pediatric patient.
Topics: Infant, Newborn; Adolescent; Child; Humans; Adrenal Hyperplasia, Congenital; Glucocorticoids; Hydrocortisone; Puberty, Precocious
PubMed: 38296783
DOI: 10.1542/pir.2022-005617 -
The Journal of Clinical Endocrinology... May 2024Adrenarche marks the timepoint of human adrenal development when the cortex starts secreting androgens in increasing amounts, in healthy children at age 8-9 years, with... (Review)
Review
CONTEXT
Adrenarche marks the timepoint of human adrenal development when the cortex starts secreting androgens in increasing amounts, in healthy children at age 8-9 years, with premature adrenarche (PA) earlier. Because the molecular regulation and significance of adrenarche are unknown, this prepubertal event is characterized descriptively, and PA is a diagnosis by exclusion with unclear long-term consequences.
EVIDENCE ACQUISITION
We searched the literature of the past 5 years, including original articles, reviews, and meta-analyses from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms adrenarche, pubarche, DHEAS, steroidogenesis, adrenal, and zona reticularis.
EVIDENCE SYNTHESIS
Numerous studies addressed different topics of adrenarche and PA. Although basic studies on human adrenal development, zonation, and zona reticularis function enhanced our knowledge, the exact mechanism leading to adrenarche remains unsolved. Many regulators seem involved. A promising marker of adrenarche (11-ketotestosterone) was found in the 11-oxy androgen pathway. By current definition, the prevalence of PA can be as high as 9% to 23% in girls and 2% to 10% in boys, but only a subset of these children might face related adverse health outcomes.
CONCLUSION
New criteria for defining adrenarche and PA are needed to identify children at risk for later disease and to spare children with a normal variation. Further research is therefore required to understand adrenarche. Prospective, long-term studies should characterize prenatal or early postnatal developmental pathways that modulate trajectories of birth size, early postnatal growth, childhood overweight/obesity, adrenarche and puberty onset, and lead to abnormal sexual maturation, fertility, and other adverse outcomes.
Topics: Humans; Adrenarche; Child; Puberty, Precocious; Female; Male; Zona Reticularis
PubMed: 38181424
DOI: 10.1210/clinem/dgae008 -
Acta Bio-medica : Atenei Parmensis Dec 2023Children born small for gestational age (SGA), defined by a birth weight and/or length standard deviation score (SDS) of < -2 based on an appropriate reference...
Children born small for gestational age (SGA), defined by a birth weight and/or length standard deviation score (SDS) of < -2 based on an appropriate reference population, represent a diverse group due to multiple underlying causes of reduced growth. This classification results in a heterogeneous patient cohort. SGA children are prone to endocrinological and metabolic issues not only in childhood but also extending into adolescence and adulthood. This population faces elevated health risks, including persistent short stature, premature adrenarche, pubertal development alterations, neurocognitive problems, and metabolic syndrome. Insulin resistance emerges as a pivotal factor c nht6j7ikontributing to these metabolic complications, prominently featuring obesity, insulin resistance, hypertension, and an increased risk of type 2 diabetes mellitus in adulthood. These medium- to long-term complications significantly impact their quality of life. Growth hormone (GH) therapy for short children born SGA facilitates height normalization throughout childhood, adolescence, and into adulthood. Catch-up growth, however, correlates with heightened risks of obesity, insulin resistance, and metabolic syndrome. Conversely, those without catch-up growth tend to exhibit pronounced short stature and cognitive dysfunction. Given these determinants, comprehensive management and clinical monitoring of SGA children should commence in the neonatal period and extend into adulthood. Recognizing and addressing these challenges early in life can mitigate the long-term impact on health and well-being, emphasizing the importance of a lifelong approach to their care.
Topics: Infant, Newborn; Child; Humans; Adolescent; Adult; Insulin Resistance; Diabetes Mellitus, Type 2; Metabolic Syndrome; Gestational Age; Quality of Life; Infant, Small for Gestational Age; Obesity
PubMed: 38054664
DOI: 10.23750/abm.v94i6.15428