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Endocrine Reviews Nov 2021Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to... (Review)
Review
Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to adrenocorticotropin (ACTH) that are best indexed by dehydroepiandrosterone sulfate (DHEAS) rise. These changes are related to the development of the zona reticularis (ZR) and its unique gene/enzyme expression pattern of low 3ß-hydroxysteroid dehydrogenase type 2 with high cytochrome b5A, sulfotransferase 2A1, and 17ß-hydroxysteroid dehydrogenase type 5. Recently 11-ketotestosterone was identified as an important bioactive adrenarchal androgen. Birth weight, body growth, obesity, and prolactin are related to ZR development. Adrenarchal androgens normally contribute to the onset of sexual pubic hair (pubarche) and sebaceous and apocrine gland development. Premature adrenarche causes ≥90% of premature pubarche (PP). Its cause is unknown. Affected children have a significantly increased growth rate with proportionate bone age advancement that typically does not compromise growth potential. Serum DHEAS and testosterone levels increase to levels normal for early female puberty. It is associated with mildly increased risks for obesity, insulin resistance, and possibly mood disorder and polycystic ovary syndrome. Between 5% and 10% of PP is due to virilizing disorders, which are usually characterized by more rapid advancement of pubarche and compromise of adult height potential than premature adrenarche. Most cases are due to nonclassic congenital adrenal hyperplasia. Algorithms are presented for the differential diagnosis of PP. This review highlights recent advances in molecular genetic and developmental biologic understanding of ZR development and insights into adrenarche emanating from mass spectrometric steroid assays.
Topics: Adrenal Hyperplasia, Congenital; Adrenarche; Androgens; Child; Child, Preschool; Female; Humans; Polycystic Ovary Syndrome; Puberty, Precocious
PubMed: 33788946
DOI: 10.1210/endrev/bnab009 -
The Lancet. Diabetes & Endocrinology Apr 2021Prader-Willi syndrome is a rare genetic neurodevelopmental disorder resulting from the loss of expression of maternally imprinted genes located in the paternal... (Review)
Review
Prader-Willi syndrome is a rare genetic neurodevelopmental disorder resulting from the loss of expression of maternally imprinted genes located in the paternal chromosomal region, 15q11-13. Impaired hypothalamic development and function is the cause of most of the phenotypes comprising the developmental trajectory of Prader-Willi syndrome: from anorexia at birth to excessive weight gain preceding hyperphagia, and early severe obesity with hormonal deficiencies, behavioural problems, and dysautonomia. Growth hormone deficiency, hypogonadism, hypothyroidism, premature adrenarche, corticotropin deficiency, precocious puberty, and glucose metabolism disorders are the main endocrine dysfunctions observed. Additionally, as a result of hypothalamic dysfunction, oxytocin and ghrelin systems are impaired in most patients. Standard pituitary and gonadal hormone replacement therapies are required. In this Review, we discuss Prader-Willi syndrome as a model of hypothalamic dysfunction, and provide a comprehensive description of the accumulated knowledge on genetics, pathophysiology, and treatment approaches of this rare disorder.
Topics: Animals; Endocrine System Diseases; Humans; Hypothalamus; Prader-Willi Syndrome; Proteins
PubMed: 33647242
DOI: 10.1016/S2213-8587(21)00002-4 -
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 -
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 -
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 -
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 -
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 -
Hormone Research in Paediatrics 2020
Topics: Adrenarche; Breast; Female; Humans; Male; Puberty, Precocious; Unnecessary Procedures; Watchful Waiting
PubMed: 33352558
DOI: 10.1159/000512764 -
Hormone Research in Paediatrics 2022Descriptions of probable PCOS can be found in ancient Roman writings and in Renaissance art. Attention to domesticated animal reproduction led ancient observers to... (Review)
Review
Descriptions of probable PCOS can be found in ancient Roman writings and in Renaissance art. Attention to domesticated animal reproduction led ancient observers to understand the role of the testes in male phenotypes, proven experimentally by testicular transplantation (in chickens) in 1849. Testosterone was isolated and its structure determined in the 1930s, but the multiple pathways of androgen synthesis have only been delineated recently. Adrenarche as an event separate from puberty was described in 1937, but the mechanism(s) triggering its onset remains unclear, although most work points to intraadrenal events. The identification of 11-ketotestosterone as the principal adrenal androgen is very recent (2018). Definitions of PCOS have evolved with the elucidation of its complex biology. PCOS is now recognized as a complex disorder characterized by irregular menses and hyperandrogenism often associated with infertility; its prevalence may be as high as 20% of reproductive age women. Work in the 1980s associated premature exaggerated adrenarche with PCOS, linking the adrenal to an "ovarian" syndrome. Obesity has long been noted in many patients with PCOS, and associated insulin resistance was noted in the 1980s, possibly associated with fetal developmental events such as low birth weight, but the mechanistic link between carbohydrate metabolism and hyperandrogenism remains unclear, despite intensive investigation. Genome-wide association studies have identified apparently associated genes, but mechanistic links are apparent for only some of these. Adrenarche, PCOS, and adrenal and ovarian hyperandrogenism remain very active areas of clinical and basic research.
Topics: Animals; Female; Male; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Adrenarche; Androgens; Genome-Wide Association Study; Chickens; Sexual Maturation
PubMed: 36446329
DOI: 10.1159/000526722