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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 -
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 -
Journal of Ovarian Research Nov 2023Existing studies have investigated the relationship between the levels of serum inhibin B (INHB), anti-müllerian hormone (AMH) and precocious puberty in girls, but the... (Meta-Analysis)
Meta-Analysis
BACKGROUNDS
Existing studies have investigated the relationship between the levels of serum inhibin B (INHB), anti-müllerian hormone (AMH) and precocious puberty in girls, but the results are inconsistent.
OBJECTIVE
The aim of this meta-analysis was to assess whether the INHB and AMH levels changed in girls with precocious puberty relative to healthy controls.
METHODS
PubMed, Embase, Cochrane Library and Web of Science were searched through June 2022. We included observational clinical studies reporting the serum levels INHB and AMH in girls with precocious puberty. Conference articles and observational study abstracts were included if they contained enough information regarding study design and outcome data. Case series and reports were excluded. An overall standard mean difference (SMD) between precocious puberty and healthy controls was estimated using a DerSimonian-Laird random-effects model.
RESULTS
A total of 11 studies featuring 552 girls with precocious puberty and 405 healthy girls were selected for analysis. The meta-analysis showed that the INHB level of precocious puberty [including central precocious puberty (CPP) and premature the larche (PT)] were significantly increased. While there was no significant association between precocious puberty [including CPP, PT, premature pubarche (PP) and premature adrenarche (PA)] and the level of serum AMH.
CONCLUSION
Scientific evidence suggested that the INHB level, but not the AMH level, altered in girls with precocious puberty compared with healthy controls. Through our results we think that INHB level might be a marker for the auxiliary diagnosis of precocious puberty (especially CPP and PT). Therefore, it is important to evaluate and thoroughly investigate the clinical indicators (e.g., INHB) in order to ensure early diagnosis and medical intervention, and the risk of physical, psychological and social disorders in immature girls with precocious puberty is minimized.
Topics: Female; Humans; Anti-Mullerian Hormone; Follicle Stimulating Hormone; Inhibins; Observational Studies as Topic; Puberty, Precocious
PubMed: 37996919
DOI: 10.1186/s13048-023-01302-2 -
Frontiers in Endocrinology 2023Prader-Willi syndrome (PWS) is a rare genetic disorder resulting from lack of expression of the paternally derived chromosome 15q11-13, associated with several... (Review)
Review
A rare occurrence of non-classic congenital adrenal hyperplasia and type 1 diabetes mellitus in a girl with Prader-Willi Syndrome: Case report and review of the literature.
Prader-Willi syndrome (PWS) is a rare genetic disorder resulting from lack of expression of the paternally derived chromosome 15q11-13, associated with several complications, including pubertal disorders, short stature, hyperphagia, obesity, glucose metabolism abnormalities, scoliosis, obstructive sleep apnea syndrome (OSAS) and behavioral problems. We report the case of a girl affected by PWS who presented at the age of 5.9 with premature pubarche, accelerated linear growth and advanced bone age (BA). She was subsequently diagnosed with non-classic congenital adrenal hyperplasia (CAH) confirmed by genetic analysis. Considering the clinical, biochemical, and genetic findings, hydrocortisone therapy was started to prevent rapid BA acceleration and severe compromission of final height. During infancy, short stature and low levels of insulin-like growth factor-1 (IGF-1) for age and gender led to suspicion of growth hormone deficiency (GHD), confirmed by stimulation testing (arginine and clonidine). rhGH therapy was administered and continued until final height was reached. During endocrinological follow up she developed impaired glucose tolerance with positive markers of β-cell autoimmunity (anti-glutamic acid decarboxylase antibodies, GAD Ab), which evolved over time into type 1 diabetes mellitus and insulin therapy with a basal-bolus scheme and an appropriate diet were needed.
Topics: Female; Humans; Prader-Willi Syndrome; Diabetes Mellitus, Type 1; Adrenal Hyperplasia, Congenital; Human Growth Hormone; Obesity
PubMed: 37124733
DOI: 10.3389/fendo.2023.1148318 -
Journal of the Endocrine Society Mar 2023Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict...
CONTEXT
Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict overall health, but no data exist on the CRF of women with a history of PA.
OBJECTIVE
To study if hyperandrogenism in childhood resulting from PA leads to a measurable difference in CRF between young adult PA and control women.
METHODS
A total of 25 women with PA and 36 age-matched controls were followed from prepubertal age until adulthood. Anthropometric measurements, body composition, biochemical, and lifestyle factors were assessed. The main outcome measure was maximal cycle ergometer test result at the mean age of 18.5 years. We also assessed prepubertal predicting factors for CRF with different linear regression models.
RESULTS
Though prepubertal children with PA were taller and heavier than their non-PA peers, there were no significant differences in height, body mass index, body composition, or physical activity in young adulthood. We observed no significant differences in any of the parameters of the maximal cycle ergometer test, including maximal load ( = .194) or peak oxygen consumption ( = .340). Hemodynamic responses of the groups were similar. None of the examined models or prepubertal factors significantly predicted CRF at adult age.
CONCLUSION
This study suggests that hyperandrogenism in childhood/adolescence resulting from PA does not have a significant impact on adulthood CRF.
PubMed: 37077523
DOI: 10.1210/jendso/bvad041 -
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 -
The Journal of Clinical Endocrinology... Aug 2023Accelerated early growth and early timing of puberty or pubertal variant have been noticed as risk factors for metabolic syndrome, more frequently observed in children... (Review)
Review
Accelerated early growth and early timing of puberty or pubertal variant have been noticed as risk factors for metabolic syndrome, more frequently observed in children born small for gestational age (SGA) or children with premature adrenarche (PA). Children with SGA, especially if they make an accelerated catch-up growth in early life, carry a higher risk for long-term metabolic consequences, such as type 2 diabetes, insulin resistance, and cardiovascular diseases. Furthermore, multiple studies support that these children, either born SGA or with a history of PA, may have earlier pubertal timing, which is also associated with various metabolic risks. This review aims to summarize the recent studies investigating the association between early infantile growth, the timing of puberty, and metabolic risks to expand our knowledge and gain more insight into the underlying pathophysiology.
Topics: Infant, Newborn; Female; Humans; Child; Diabetes Mellitus, Type 2; Puberty; Infant, Small for Gestational Age; Fetal Growth Retardation; Metabolic Syndrome
PubMed: 37029976
DOI: 10.1210/clinem/dgad202 -
Frontiers in Pediatrics 2023The purpose of this study was to investigate the frequency of autoimmune thyroiditis (AT) among euthyroid prepubertal girls presenting with premature adrenarche (PA). We...
OBJECTIVE
The purpose of this study was to investigate the frequency of autoimmune thyroiditis (AT) among euthyroid prepubertal girls presenting with premature adrenarche (PA). We also aimed to identify the clinical, metabolic, and endocrine profile of girls with AT and concurrent PA and compare them to girls with AT without PA, PA alone and healthy controls.
METHODS
Ninety-one prepubertal girls aged 5-10 years, who attended our department for AT, PA and normal variants of growth and puberty were recruited for the study: 73 girls had PA, 6 AT without PA and 12 were referred for investigation of growth. All girls underwent clinical examination, detailed biochemical and hormonal screen. Standard dose Synachten stimulation test (SDSST) and oral glucose tolerance test (OGTT) were performed in all girls with PA. The whole study population was divided in 4 groups: Group PA-/AT+ included 6 girls with AT without PA; Group PA+/AT- PA subjects without AT; Group PA+/AT+ girls with PA and concomitant AT; Group PA-/AT- twelve healthy girls without PA nor AT (controls).
RESULTS
Among 73 girls presenting with PA 19 had AT (26%). BMI, systolic blood pressure (SBP) and the presence of goiter significantly differed between the four groups ( = 0.016, = 0.022 and < 0.001, respectively). When comparing hormonal parameters among the four groups significant differences were found in leptin ( = 0.007), TSH ( = 0.044), anti-TPO ( = 0.002), anti-TG ( = 0.044), IGF-BP1 ( = 0.006), 4- ( = 0.01), DHEA-S (= <0.001), IGF-1 ( = 0.012) and IGF-BP3 ( = 0.049) levels. TSH levels were significantly higher in Group PA+/AT+ compared to PA+/AT- and PA-/AT- ( = 0.043 and = 0.016, respectively). Moreover, girls with AT (Groups PA-/AT+ and PA+/AT+) had higher TSH levels than those in Group PA+/AT- ( = 0.025). Girls in Group PA+/AT + showed higher cortisol response at 60 min post-SDSST than girls in Group PA+/AT- ( = 0.035). During the OGTT, insulin concentrations at 60 min were significantly higher in Group PA+/AT + compared to Group PA+/AT- ( = 0.042).
CONCLUSION
A high frequency of AT among euthyroid prepubertal girls with PA was observed. The combination of PA with AT even in euthyroid state may be associated with a greater degree of insulin resistance, than PA alone.
PubMed: 37009276
DOI: 10.3389/fped.2023.1064177 -
Frontiers in Endocrinology 2023Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy...
Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy unless they develop symptoms of hyperandrogenemia. The current practice is to treat symptomatic children with hydrocortisone aimed at suppressing excess adrenal androgen production irrespective of the child's level of endogenous cortisol production. Once on hydrocortisone therapy, even children with normal cortisol production require stress dosing. Some children with NC-CAH may present with premature adrenarche, growth acceleration, and advanced bone age, but with no signs of genital virilization and normal endogenous cortisol production. In these cases, an alternative therapy to hydrocortisone treatment that does not impact the hypothalamic-pituitary-adrenal axis, but targets increased estrogen production and its effects on bone maturation, could be considered. Aromatase inhibitors (AIs), which block the aromatization of androgen to estrogen, have been used off-label in men with short stature to delay bone maturation and as an adjunct therapy in children with classic CAH. The use of AI as a monotherapy for children with NC-CAH has never been reported. We present three pre-pubertal female children with a diagnosis of NC-CAH treated with anastrozole monotherapy after presenting with advanced bone age, early adrenarche, no signs of genital virilization, and normal peak cortisol in response to ACTH stimulation testing. Bone age z-scores normalized, and all three reached or exceeded their target heights. Monotherapy with anastrozole can be an effective alternative in slowing down bone maturation and improving height outcomes in children with NC-CAH and normal adrenal cortisol production.
Topics: Child; Female; Humans; Adrenal Hyperplasia, Congenital; Anastrozole; Androgens; Estrogens; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Virilism
PubMed: 36936152
DOI: 10.3389/fendo.2023.1101843