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The Journal of Clinical Endocrinology... Dec 2020Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche... (Observational Study)
Observational Study
CONTEXT
Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche is unknown and the role of novel biosynthetic pathways remains unclear.
OBJECTIVE
To compare the urinary steroid metabolome and enzyme activities of girls with PA to age-matched control girls and to published steroid values of girls with normal adrenarche and of women with PCOS and their newborn daughters.
DESIGN
Prospective observational study from 2009 to 2014.
SETTING
Academic pediatric endocrinology referral center.
PARTICIPANTS
Twenty-three girls with PA and 22 healthy, age-matched girls.
MAIN OUTCOME MEASURES
Steroid metabolites in 24-hour urine samples, including 4 progesterones, 5 corticosterones, aldosterone, 13 androgens, 2 estrogens, 14 glucocorticoids, and enzyme activities represented by metabolite ratios.
RESULTS
Girls with PA had a higher body mass index (mean standard deviation scores 0.9 vs -0.3, P = 0.013). Androgen excretion was higher in PA girls than in control girls (median 3257 nmol/24 hours vs 1627 nmol/24 hours, P < 0.001), in particular metabolites from alternate androgen pathways. The amount of progesterone, corticosterone, aldosterone, estrogen, and cortisol metabolites were similar between groups. Activities of 17β-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3β-hydroxysteroid-dehydrogenase, 21-hydroxylase, and 5α-reductase activity were not different between groups, in contrast to published results on girls with normal adrenarche or PCOS females.
CONCLUSIONS
Metabolites and enzymes involved in alternate androgen pathways appear to be markers of PA. Prospective studies should assess whether steroid production in PA also differs from adrenarche at normal timing and persists into adulthood.
Topics: 17-Hydroxysteroid Dehydrogenases; Adrenarche; Androgens; Case-Control Studies; Child; Child, Preschool; Corticosterone; Estrogens; Female; Humans; Hydrocortisone; Metabolome; Puberty, Precocious; Steroid 17-alpha-Hydroxylase; Switzerland; Up-Regulation
PubMed: 32865200
DOI: 10.1210/clinem/dgaa598 -
Hormone Research in Paediatrics 2015Adrenarche refers to a maturational increase in the secretion of adrenal androgen precursors, mainly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In premature... (Review)
Review
Adrenarche refers to a maturational increase in the secretion of adrenal androgen precursors, mainly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In premature adrenarche (PA), clinical signs of androgen action appear before the age of 8/9 years in girls/boys, concurrently with the circulating DHEA(S) concentrations above the usually low prepubertal level. The most pronounced sign of PA is the appearance of pubic/axillary hair, but also other signs of androgen effect (adult type body odor, acne/comedones, greasy hair, accelerated statural growth) are important to recognize. PA children are often overweight and taller than their peers, and the higher prevalence of PA in girls than in boys is probably explained by higher female adiposity and peripheral DHEA(S) conversion to active androgens. PA diagnosis requires exclusion of other causes of androgen excess: congenital adrenal hyperplasia, androgen-producing tumors, precocious puberty, and exogenous source of androgens. PA has been linked with unfavorable metabolic features including hyperinsulinism, dyslipidemia, and later-appearing ovarian hyperandrogenism. Although this common condition is usually benign, PA children with additional risk factors including obesity should be followed up, with the focus on weight and lifestyle. Long-term follow-up studies are warranted to clarify if the metabolic changes detected in PA children persist until adulthood.
Topics: Adrenal Glands; Adrenarche; Female; Humans; Hyperandrogenism; Male
PubMed: 25676474
DOI: 10.1159/000369458 -
Metabolomics : Official Journal of the... Oct 2022Premature adrenarche (PA) for long time was considered a benign condition but later has been connected to various diseases in childhood and adulthood which remains...
INTRODUCTION
Premature adrenarche (PA) for long time was considered a benign condition but later has been connected to various diseases in childhood and adulthood which remains controversial.
OBJECTIVE
To investigate the effect of premature adrenarche on the metabolic phenotype, and correlate the clinical and biochemical data with the metabolic profile of children with PA.
METHODS
Nuclear magnetic resonance (NMR)-based untargeted and targeted metabolomic approach in combination with multivariate and univariate statistical analysis applied to study the metabolic profiles of children with PA. Plasma, serum, and urine samples were collected from fifty-two children with Idiopathic PA and forty-eight age-matched controls from the division of Pediatric Endocrinology of the University Hospital of Patras were enrolled.
RESULTS
Metabolomic results showed that plasma and serum glucose, myo-inositol, amino acids, a population of unsaturated lipids, and esterified cholesterol were higher and significantly different in PA children. In the metabolic profiles of children with PA and age-matched control group a gradual increase of glucose and myo-inositol levels was observed in serum and plasma, which was positively correlated their body mass index standard deviation score (BMI SDS) values respectively. Urine H NMR metabolic fingerprint of PA children showed positive correlation and a clustering-dependent relationship with their BMI and bone age (BA) respectively.
CONCLUSION
This study provides evidence that PA driven metabolic changes begin during the childhood and PA may has an inductive role in a BMI-driven increase of specific metabolites. Finally, urine may be considered as the best biofluid for identification of the PA metabolism as it reflects more clearly the PA metabolic fingerprint.
Topics: Adrenarche; Amino Acids; Cholesterol; Glucose; Inositol; Lipids; Magnetic Resonance Spectroscopy; Metabolomics
PubMed: 36239863
DOI: 10.1007/s11306-022-01941-4 -
Journal of Clinical Research in... Mar 2015Idiopathic premature adrenarche (PA) refers to presence of androgenic signs before the age of eight years in girls in the absence of thelarche. In children with PA,... (Comparative Study)
Comparative Study
OBJECTIVE
Idiopathic premature adrenarche (PA) refers to presence of androgenic signs before the age of eight years in girls in the absence of thelarche. In children with PA, increased adrenal androgens lead to changes in body composition and transient growth acceleration. Although the association between PA and some components of the metabolic syndrome is well known, body composition has not been extensively studied in these patients.
METHODS
We examined 47 girls with PA with a median age of 7.39 years and 57 healthy controls with a median age of 7.11 years. For PA group, the inclusion criteria were appearance of pubic/axillary hair before 8 years of age, absence of findings of central puberty and absence of use of any medication. Patients with steroidogenic enzyme defects and virilizing tumors were excluded. Height, body weight, waist and hip circumference were measured. The bioelectrical impedance method was used for body composition analysis.
RESULTS
In the PA group, both body weight standard deviation score (SDS) and height SDS were significantly higher than in the controls (p<0.001 for both). While total body fat percentage values were significantly higher in the PA group than in the controls (median 22.8% vs. 19.95%, p=0.049), fat-free mass (FFM) and total muscle mass percentages were significantly lower than in the controls (median 76.8% vs. 79.9%, p=0.024 and 72.6% vs. 75.7%, p=0.018, respectively).
CONCLUSION
Our findings revealed that girls with PA have higher body weight and height for age values. They also show significant changes in body composition such as an increase in total body fat percentage with a concomitant decrease in the percentages of FFM, muscle mass and total body water.
Topics: Adipose Tissue; Adrenarche; Age of Onset; Anthropometry; Body Composition; Body Height; Body Weight; Case-Control Studies; Child; Female; Follow-Up Studies; Humans; Male; Prognosis; Puberty, Precocious
PubMed: 25800475
DOI: 10.4274/jcrpe.1525 -
Pediatric Endocrinology, Diabetes, and... 2017Polycystic ovary syndrome (PCOS) is a complex disease. Depending on the used criteria the prevalence of PCOS ranges from 6 to 20%. It is necessary to exclude diseases... (Review)
Review
Polycystic ovary syndrome (PCOS) is a complex disease. Depending on the used criteria the prevalence of PCOS ranges from 6 to 20%. It is necessary to exclude diseases leading to androgen excess. The participation of genetic and environmental factors is considered in the etiology of PCOS development. The highest rate of incidence of PCOS is assessed in girls who were born SGA and developed premature adrenarche later in life.The free androgen index (FAI) is concerned as the most sensitive marker of hyperandrogenaemia in PCOS although insulin resistance, anti-Müllerian hormone (AMH),and deficiency of vitamin D may intensify metabolic disturbances. The ultrasound criteria used in adolescent patients prefer the estimation of the ovarian volume or the ratio of ovarian stroma to total ovary, rather than the number of ovarian follicles. PCOS is connected with different metabolic disorders. Post-binding defect in signal transduction is responsible for insulin resistance. This defect results from an impaired activity of the kinase receptor. Moreover, the adipose tissue of PCOS women differs substantially from the tissue of the others according to morphology and function. The adipocytes produce lower amounts of adiponectin, which is an insulin-sensitizing agent. Dyspidemia with high triglycerides and low high density lipoprotein cholesterol concentrations is frequently noticed. Cardio-metabolic risk factors, insulin resistance, and endothelial dysfunction accompany PCOS from the very beginning. Oxidative stress plays a role as a link among systemic inflammation and dysfunction of endothelial cells and abnormal thecal cell action. The treatment efforts in PCOS depend on the patient's main problems. Modification of diet and lifestyle is the most important recommended advice to each woman independent of age and weight.
Topics: Adipose Tissue; Adult; Female; Humans; Insulin Resistance; Metabolic Diseases; Polycystic Ovary Syndrome
PubMed: 29574473
DOI: 10.18544/PEDM-23.04.0094 -
Journal of Pediatric Endocrinology &... Feb 2023Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported...
OBJECTIVES
Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported hypothalamic-pituitary-adrenal axis dysfunction. While idiopathic premature adrenarche is associated with accelerated pre-pubertal growth and advanced bone age, the consequences of elevated adrenal androgens on growth and bone maturation in PWS remain unknown. This study therefore sought to describe age-related changes in dehydroepiandrosterone sulfate (DHEAS) and their effects on growth and bone maturation in PWS.
METHODS
This retrospective observational study included 62 children with PWS. Simple and multiple regression models were constructed to relate age and BMI-SDS with DHEAS levels. Height velocity was compared to age and sex-based norms with t-tests and two-way ANOVA. Patterns in bone age Z-score were examined with two-way ANOVA, and the contributions of age, BMI-SDS, and DHEAS to bone age Z-score were analyzed with multiple regression.
RESULTS
DHEAS levels rose earlier and were less strongly correlated with age in males and females with PWS (R=0.12 and 0.30) compared to healthy controls (R=0.89 and 0.88) in a pattern unrelated to BMI-SDS (adjusted R=0.076, p=0.10 for age, and 0.29 for BMI-SDS). Mid-childhood height velocity was increased in males and preserved in females with PWS before declining at the age of expected puberty (p<0.0001). Peri-adrenarchal bone age was advanced in a manner associated with DHEAS but not BMI-SDS (p<0.0001; adjusted R=0.48, p=0.0014 for DHEAS, and 0.78 for BMI-SDS).
CONCLUSIONS
An obesity-independent increase in adrenal androgens is associated with accelerated mid-childhood growth and bone maturation in PWS.
Topics: Child; Female; Humans; Male; Adrenarche; Androgens; Hypothalamo-Hypophyseal System; Obesity; Pituitary-Adrenal System; Prader-Willi Syndrome; Puberty, Precocious
PubMed: 36458449
DOI: 10.1515/jpem-2022-0468 -
Hormone Research 2008Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the... (Review)
Review
Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the adrenal cortex. Cells could then migrate to differentiate the zona glomerulosa (ZG) and zona fasciculata (ZF) during fetal life, and the ZR during postnatal life. After adrenarche, there are detectable increases in circulating DHEA and DHEA-S. Adrenarche could result from an increase in 17,20-lyase activity of P450c17 secondary to high levels of cytochrome b(5) expression, and from a decrease in 3betaHSD2 expression along with an increase in the expression of SULT2A1 in the ZR. The GH-IGF system and insulin, among other factors, might also modulate adrenal androgen production. Furthermore, high concentrations of estradiol enhance basal and ACTH-stimulated DHEA-S production, while aromatase expression was observed in the human adrenal medulla but not in the ZR, suggesting that estrogens produced in the adrenal medulla might be involved in the regulation of androgen production in the ZR. Premature adrenarche might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as well as with insulin resistance in both sexes. However, many questions remain, transforming adrenal androgens into markers of diseases important for human health.
Topics: Adrenal Cortex; Adrenal Medulla; Adrenarche; Adult; Androgens; Cell Differentiation; Child; Child, Preschool; Dehydroepiandrosterone; Estrogens; Female; Human Growth Hormone; Humans; Male; Puberty, Precocious; Somatomedins; Steroid 17-alpha-Hydroxylase; Zona Reticularis
PubMed: 18824863
DOI: 10.1159/000157871 -
Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.Epigenetics Dec 2023Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its...
Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 μg/dL] and High DHEAS (HD) [≥42 μg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.
Topics: Female; Humans; Child; Adrenarche; Androgens; Pilot Projects; DNA Methylation; Dehydroepiandrosterone Sulfate; Obesity
PubMed: 37053179
DOI: 10.1080/15592294.2023.2200366 -
Clinics (Sao Paulo, Brazil) 2019Follow-up studies of girls with premature adrenarche have reported the development of polycystic ovary syndrome, insulin resistance, and dyslipidemia and a propensity to...
OBJECTIVE
Follow-up studies of girls with premature adrenarche have reported the development of polycystic ovary syndrome, insulin resistance, and dyslipidemia and a propensity to cardiovascular disease. The aim of this study was to analyze the presence of these conditions in patients previously treated at the Universidade Federal do Triângulo Mineiro.
METHODS
A total of 130 medical records reported premature adrenarche. One hundred and twenty-two patients were invited to participate, of whom 54 accepted; 34 patients were selected, as they had reached their final height. Anthropometric, blood glucose, insulin, and lipid and hormonal profile (LH, FSH, estradiol, 17α-OH-progesterone, androstenedione, dehydroepiandrosterone sulfate, testosterone) data were obtained, the HOMA-IR index was calculated, and pelvic ultrasonography was performed. To characterize polycystic ovary syndrome and metabolic syndrome, the Rotterdam and International Diabetes Federation criteria, respectively, were used. Data were analyzed according to measures of dispersion, frequency and correlations of interest.
RESULTS
The age of the participants ranged from 15.2 to 28.2 years/months; 23.5% of the patients were overweight, 11.8% were obese, 29.4% had a large waist circumference, and 8.8% were hypertensive. None of the patients had altered glucose levels, and insulin levels and HOMA-IR were elevated in 29.4% and 38.2% of the participants, respectively; 14.7% of the patients exhibited acanthosis nigricans. The lipid profiles of the participants were variable, and one patient (2.9%) had metabolic syndrome. Polycystic ovary syndrome was found in 41.2% of patients.
CONCLUSION
The percentage of patients with polycystic ovary syndrome who also had overweight, obesity and insulin resistance corroborates the literature data about the need for follow-up aiming at interventions, especially for conditions associated with cardiometabolic risk.
Topics: Adolescent; Adrenarche; Adult; Body Mass Index; Cardiovascular Diseases; Cholesterol; Dyslipidemias; Female; Hormones; Humans; Insulin Resistance; Metabolic Syndrome; Overweight; Polycystic Ovary Syndrome; Puberty, Precocious; Reference Values; Retrospective Studies; Risk Factors; Triglycerides; Young Adult
PubMed: 31241662
DOI: 10.6061/clinics/2019/e836