scholarly journals Normal and Premature Adrenarche

2021 ◽  
Author(s):  
Robert L Rosenfield
Keyword(s):  
Polycystic Ovary ◽  
Molecular Genetic ◽  
Bone Age ◽  
Dehydroepiandrosterone Sulfate ◽  
Hydroxysteroid Dehydrogenase ◽  
Pubic Hair ◽  
Growth Potential ◽  
Adrenal Androgen ◽  
Premature Adrenarche ◽  
Premature Pubarche

Abstract Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to 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. 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. Five-10% of premature pubarche 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 premature pubarche.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.

Premature Adrenarche and its Association with Cardiovascular Risk in Females

2020 ◽  
Vol 26 (43) ◽  
pp. 5609-5616
Author(s):  
Sarantis Livadas ◽  
Christina Bothou ◽  
Djuro Macut
Keyword(s):  
Polycystic Ovary ◽  
Dehydroepiandrosterone Sulfate ◽  
Adrenal Androgen ◽  
Premature Adrenarche ◽  
Adrenal Hyperandrogenism ◽  
Long Term Follow Up ◽  
History Of ◽  
Hormonal Milieu ◽  
The Impact

Early activation of the adrenal zona reticularis, leading to adrenal androgen secretion, mainly dehydroepiandrosterone sulfate (DHEAS), is called premature adrenarche (PA). The fact that adrenal hyperandrogenism in females has been linked to a cluster of cardiovascular (CV) risk factors, even in prepubertal children, warrants investigation. Controversial results have been obtained in this field, probably due to genetic, constitutional, and environmental factors or differences in the characteristics of participants. In an attempt to understand, in depth, the impact of PA as a potential activator of CV risk, we critically present available data stratified according to pubertal status. It seems that prepubertally, CV risk is increased in these girls, but is somewhat attenuated during their second decade of life. Furthermore, different entities associated with PA, such as polycystic ovary syndrome, non-classical congenital adrenal hyperplasia, heterozygosity of CYP21A2 mutations, and the impact of DHEAS on CV risk, are reviewed. At present, firm and definitive conclusions cannot be drawn. However, it may be speculated that girls with a history of PA display a hyperandrogenic hormonal milieu that may lead to increased CV risk. Accordingly, appropriate long-term follow-up and early intervention employing a patient-oriented approach are recommended.

scholarly journals Approach to the Girl with Early Onset of Pubic Hair

2011 ◽  
Vol 96 (6) ◽  
pp. 1610-1622 ◽  
Author(s):  
Sharon E. Oberfield ◽  
Aviva B. Sopher ◽  
Adrienne T. Gerken
Keyword(s):  
Normal Development ◽  
Preventive Measures ◽  
Polycystic Ovary ◽  
Pubic Hair ◽  
Children At Risk ◽  
Ovary Syndrome ◽  
Zona Reticularis ◽  
Premature Adrenarche ◽  
Axillary Hair ◽  
Premature Pubarche

Premature pubarche, or the development of pubic hair before the age of 8 in girls or 9 in boys, is most commonly caused by premature adrenarche. Adrenarche is the maturation of the adrenal zona reticularis in both boys and girls, resulting in the development of pubic hair, axillary hair, and adult apocrine body odor. Although originally thought to be a benign variant of normal development, premature adrenarche has been associated with insulin resistance and the later development of metabolic syndrome and polycystic ovary syndrome. Although further studies are needed to confirm these relationships, the case presented herein argues for periodic assessment of children at risk. Indeed, recognition of these associations may allow for early preventive measures.

scholarly journals OR27-06 11-Oxygenated C19 Steroids Are Alternative Markers of Androgen Excess in Children with Premature Adrenarche and Premature Pubarche

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Brittany K Wise-Oringer ◽  
Anne Claire Burghard ◽  
Patrick O’Day ◽  
Abeer Hassoun ◽  
Aviva B Sopher ◽  
...  
Keyword(s):  
Laboratory Data ◽  
Bone Age ◽  
Early Morning ◽  
Pubic Hair ◽  
Androgen Excess ◽  
Cross Sectional ◽  
Metabolic Markers ◽  
Clinical Criteria ◽  
Premature Adrenarche ◽  
Premature Pubarche

Abstract Premature adrenarche (PA), the early onset of pubic hair and/or axillary hair/odor in children, is associated with elevated adrenal androgens and precursors in the absence of gonadotropin-dependent puberty. Laboratory data in PA classically demonstrate increased DHEAS, T, and A4 levels that correlate with pubic hair development. In premature pubarche (PP), the clinical presentation occurs in the absence of elevated DHEAS, T, and A4. PA is associated with insulin resistance and progression to metabolic syndrome (MetS) and PCOS; it is unclear which of these children are at risk for metabolic abnormalities. Adrenally-derived 11-oxygenated C19 steroids (11oAs) have comparable androgenic potency to T and DHT and are elevated in disorders of androgen excess. We sought to characterize the 11oA profiles of children with PA/PP and controls and to correlate them with traditional androgens and metabolic markers, including criteria for childhood MetS. A prospective cross-sectional study was performed of subjects with PA or PP (5 M, 14 F) and controls (2 M, 6 F) ages 3 – 8 yrs (F) or 3 – 9 yrs (M). Children with precocious puberty, steroid use, or recent illness were excluded. Fasting early morning serum was collected, a complete physical exam was performed, and BP and waist circumference were measured; a bone age was obtained only in PA/PP subjects. 11oAs (11OHT, 11KT, 11OHA4, 11KA4) were analyzed by LC-MS. Subjects were divided into PA (DHEAS ≥ 50 µg/dL, n=10) or PP (DHEAS < 50 µg/dL, n=9) for sub-analysis. There were no significant differences in sex, race/ethnicity, BMI z-score, preterm gestation, birth weight, family history, or clinical criteria for childhood MetS. T, A4, DHT, DHEAS, and all 11oAs were significantly higher in PA/PP subjects. While lipids did not differ, insulin and HOMA-IR were higher in PA/PP vs. controls {insulin Mdn = 8.2 (IQR 3.5 – 10.0) vs. 2.0 (2.0 – 3.3) µIU/mL, p < 0.03; HOMA-IR Mdn = 1.8 (IQR 0.8 – 2.1) vs. 0.4 (0.4 – 0.8), p < 0.03}. In a sub-analysis of PA vs. PP, there were no differences in baseline characteristics or metabolic markers. DHEAS was elevated in PA vs. PP {Mdn = 95 (IQR 73 – 111) vs. 42 (36 – 46) µg/dL, p < 0.00003}, although no differences were noted in 11oA levels. Correlations of androgens and their precursors suggested best correlation of 11KT and 11OHA4 with T (ρ=0.87; ρ=0.87) and A4 (ρ=0.87; ρ=0.88). There was moderate correlation of 11KT and 11OHT with insulin (ρ=0.47; ρ=0.51) and HOMA-IR (ρ=0.43; ρ=0.47). We conclude that PA and PP differ only by DHEAS (by definition) and not by insulin sensitivity or 11oA, consistent with 11oA – rather than DHEAS – mediating the phenotypic changes of pubarche. These pilot data are the first to report the early morning steroid metabolite levels including 11oAs in a phenotypically and metabolically well-defined group of PA, PP, and age-matched male and female controls. The relationships between PA, PP, risk for MetS, and 11oA warrant further study.

scholarly journals Continuum of phenotypes and sympathoadrenal function in premature adrenarche

2009 ◽  
Vol 160 (4) ◽  
pp. 657-665 ◽  
Author(s):  
Pauliina Utriainen ◽  
Raimo Voutilainen ◽  
Jarmo Jääskeläinen
Keyword(s):  
Clinical Signs ◽  
Dehydroepiandrosterone Sulfate ◽  
Pubic Hair ◽  
Adrenal Androgen ◽  
Pronounced Increase ◽  
Adrenal Steroid ◽  
Premature Adrenarche ◽  
Adrenal Hyperandrogenism ◽  
Early Rise ◽  
Design And Methods

ObjectivesPremature adrenarche (PA), the early rise in adrenal androgen (AA) production, can manifest with different clinical signs of androgen effect. Premature pubarche defined as appearance of pubic hair before the age of 8/9 years in girls/boys, is the most prominent clinical sign of PA and often erroneously described as a synonym of PA. Our aim was to determine the association of circulating AA concentrations with different prepubertal signs of androgen action (SAA). Secondly, we tested whether adrenomedullary function is altered in children with SAA, as it is in congenital adrenal hyperplasia (CAH) also causing adrenal hyperandrogenism.Design and methodsWe examined 73 Finnish prepubertal children with any hyperandrogenic sign(s) having appeared before the age of 8/9 years (girls/boys) (35 with pubic and/or axillary hair=PAH; 38 without=nonPAH), and 98 age- and sex-matched controls. Circulating adrenal steroid and catecholamine concentrations were measured and correlated with clinical parameters.ResultsNone of the children with SAA had CAH or virilizing tumor. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione concentrations overlapped between the SAA and control children, and they were lower in the nonPAH than PAH group (P<0.01). SAA children had similar plasma epinephrine but higher norepinephrine (NE) concentrations than their controls (mean (95% confidence interval) 1.61 (1.44, 1.77) versus 1.39 (1.30, 1.49) nmol/l, P=0.03).ConclusionsPA forms a continuum with more pronounced increase in circulating androgens in children with PAH than in those without. Some children show SAA with fairly low androgen concentrations. The clinical significance of elevated NE concentrations associated with SAA needs to be confirmed in further studies.

scholarly journals Familial Hyperinsulinism due to HNF4A Deficiency and Benign Premature Adrenarche: A Case Report

2021 ◽  
Author(s):  
Edward Compton ◽  
David Geller ◽  
Alaina Vidmar
Keyword(s):  
Fasting Blood Glucose ◽  
Tanner Stage ◽  
Bone Age ◽  
Free Testosterone ◽  
Dehydroepiandrosterone Sulfate ◽  
Pubic Hair ◽  
Hyperinsulinemic Hypoglycemia ◽  
Premature Adrenarche ◽  
Synergistic Mechanism ◽  
Work Up

Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI-HNF4A deficiency and benign premature adrenarche (BPA) is unknown. The Case: We report the case of a 5-year-old girl with FHI-HNF4A, controlled on diazoxide, who presented with BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings of hyperandrogenism. Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic mechanism exists between insulin-induced hyperandrogenism and HNF4A deficiency leading to a transient decrease of SHBG and thus increased free testosterone levels. Further investigation is required to determine the association between HNF4A dysfunction and BPA.

REPLACEMENT ORAL ETHINYLOESTRADIOL THERAPY FOR GONADAL DYSGENESIS: GROWTH AND ADRENAL ANDROGEN STUDIES

1979 ◽  
Vol 91 (3) ◽  
pp. 519-528 ◽  
Author(s):  
Anne W. Lucky ◽  
Samuel P. Marynick ◽  
Robert W. Rebar ◽  
Gordon B. Cutler ◽  
Michael Glen ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Bone Age ◽  
Pubic Hair ◽  
Height Velocity ◽  
First Year ◽  
Adrenal Androgen ◽  
Secondary Sexual Characteristics ◽  
Sexual Characteristics ◽  
Second Year ◽  
Pre Treatment

ABSTRACT We have studied growth and adrenal dehydroepiandrosterone (DHA) responses to iv synthetic adrenocorticotrophic hormone (ACTH, Cortrosyn) in 6 girls with gonadal dysgenesis before and during treatment with lowdose ethinyloestradiol (EOe2). In all patients there was a statisfactory induction of secondary sexual characteristics including increase in breasts and pubic hair and onset of withdrawal bleeding within 6 months of therapy. Height velocity increased from 2.8 ± 0.9 cm/year pre-treatment to 5.3 ± 1.5 cm/year (P < 0.02) in the first year. There was deceleration to 1.9 ± 1.1 cm/year in the second year. There was no disproportionate advancement in bone age and thus, presumably, no loss of ultimate height. We could demonstrate no change in basal or ACTH-stimulated levels of DHA, a specific adrenal androgen, to account for the increased pubic hair and growth in these patients.

scholarly journals Delayed Diagnosis of Congenital Adrenal Hyperplasia with Salt Wasting Due to Type II 3β-Hydroxysteroid Dehydrogenase Deficiency

2005 ◽  
Vol 90 (4) ◽  
pp. 2076-2080 ◽  
Author(s):  
Trine H. Johannsen ◽  
Delphine Mallet ◽  
Harriet Dige-Petersen ◽  
Jørn Müller ◽  
Katharina M. Main ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Delayed Diagnosis ◽  
Bone Age ◽  
Hydroxysteroid Dehydrogenase ◽  
Type Ii ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
21 Hydroxylase Deficiency ◽  
Premature Pubarche

Abstract Classical 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3β-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight growth acceleration, and advanced bone age, whereas sibling 2 had no signs of virilization. At referral, increased 17α-hydroxyprogesterone associated with premature pubarche at first suggested a nonclassical 21-hydroxylase deficiency. Sequencing of the CYP21 gene showed both girls only heterozygotes (V281L mutation). This result, combined with SW in infancy, suggested a 3β-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Δ5-steroids, in particular 17α-hydroxypregnenolone greater than 100 nmol/liter (the clue to the diagnosis) and elevated Δ5-/Δ4-steroid ratios. Sequencing of the type II 3β-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17α-hydroxyprogesterone were found on blood spots from Guthrie’s test. There is no previous report of the combination of SW and premature pubarche due to mutations in the type II 3β-HSD gene. Because neonatal diagnosis could have prevented life-threatening crises in these girls, this report further supports the benefits for neonatal screening for congenital adrenal hyperplasia whatever the etiology.

Low-Dose Testosterone Effect on Somatic Growth

PEDIATRICS ◽  
1986 ◽  
Vol 77 (6) ◽  
pp. 593-857
Author(s):  
Robert L. Rosenfield
Keyword(s):  
Growth Rate ◽  
Turner Syndrome ◽  
Low Dose ◽  
Anabolic Steroids ◽  
Somatic Growth ◽  
Tanner Stage ◽  
Bone Age ◽  
Pubic Hair ◽  
Growth Potential ◽  
Average Dose

Low-dose testosterone has been found to preserve the growth potential of hypogonadal children requiring anabolic or androgenic therapy. Five girls with Turner syndrome were treated when their chronologic ages were 13 to 14 years and their bone ages were 10.6 to 12.75 years; six hypogonadal boys were treated when their chronologic ages were 11 to 15 years and their bone ages were 10.9 to 14.2 years. Depot testosterone was given as an anabolic agent in an average dose of 28 mg/m2/mo for 6 months to the patients with Turner syndrome and was given to initiate puberty in an average dose of 44 mg/m2/mo for 6 months to the hypogonadal boys. Growth rate doubled on these doses of testosterone, and bone age did not advance disproportionately. Consequently, height potential was preserved. Pubic hair advanced one Tanner stage during the 6-month treatment. Clitoral hypertrophy was observed in only one of the five girls with Turner syndrome and regressed when testosterone therapy was discontinued. Four hypogonadal boys were continued on low-dose testosterone until their bone ages passed 14 years of age and their growth rate waned. Then, the testosterone dosage was increased in increments to 100 to 200 mg/m2/mo. This group reached a height of 100.3 ± 0.8% of the height initially predicted. In addition, all attained an adult height at least 15 percentiles greater than that before therapy. These studies indicate that testosterone in very low doses resembles "anabolic steroids" in that growth is stimulated without an inordinate androgenic effect. Furthermore, these studies show that institution of low-dose therapy in the early teenage years stimulates pubertal growth normally without loss of height potential.

scholarly journals Refining Hormonal Diagnosis of Type II 3β-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping

2005 ◽  
Vol 90 (3) ◽  
pp. 1287-1293 ◽  
Author(s):  
Livia M. Mermejo ◽  
Lucila L. K. Elias ◽  
S. Marui ◽  
Ayrton C. Moreira ◽  
Berenice B. Mendonca ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Matched Control ◽  
Autosomal Recessive Disorder ◽  
Hydroxysteroid Dehydrogenase ◽  
Ambiguous Genitalia ◽  
Pubic Hair ◽  
Salt Wasting ◽  
17 Hydroxyprogesterone ◽  
The Relationship ◽  
Premature Pubarche

Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3βHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3βHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3βHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-hydroxypregnenolone (Δ5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3βHSD2 deficiency. Basal and ACTH-stimulated Δ5-17P levels (nanomoles per liter) ranged from 4–41 (−0.2 to 14 sd) and 36–97 (3.5–15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69–153 (25–57 sd) and 201–351 (36–65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Δ5-17P to F ratios ranged from 11–159 (0.5–25 sd) and 42–122 (2.4–11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29–282 sd) and 487-1523 (52–167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3βHSD2 deficiency in children with premature pubarche: ACTH-stimulated Δ5-17P and Δ5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Δ5-17P and Δ5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Δ5-17P levels and Δ5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3βHSD2 deficiency.

Glucocorticoids and adrenal androgens in children with end stage renal disease

1991 ◽  
Vol 124 (3) ◽  
pp. 245-250 ◽  
Author(s):  
Jorge R. Ferraris ◽  
José A. Ramírez ◽  
Victoria Goldberg ◽  
Marco A. Rivarola
Keyword(s):  
Inverse Correlation ◽  
Serum Cortisol ◽  
Bone Age ◽  
Pubic Hair ◽  
High Serum ◽  
Chronic Hemodialysis ◽  
Dehydroepiandrosterone Sulphate ◽  
Acth Stimulation ◽  
Adrenal Androgen ◽  
Pituitary Dysfunction

Abstract. We studied the effects of chronic renal failure on the pituitary-cortisol axis and adrenal androgen function in 26 patients (16 male and 10 female), aged 6.5 to 22.5 years (mean 14.5). Ten patients were prepubertal, 8 pubertal, and 8 post-pubertal. All of them were on chronic hemodialysis. Pubic hair development was delayed in 56% of the patients. Serum cortisol was increased in 15 out of the 26 patients. Serum Δ4-androstenedione was high in 11 out of 15 patients in Tanner's stage I or II and in 1 out of 11 patients in Tanner's stage III, IV or V (p<0.01). Serum cortisol was elevated in 10 out of 12 patients with high serum Δ4-androstenedione and in only 5 out of 14 with normal Δ4-androstenedione (p<0.02). Serum dehydroepiandrosterone sulphate was normal in 22 patients and elevated in 4 males. There was a significant inverse correlation between bone age and serum cortisol (r:-0.59; p<0.005) and a significant positive correlation between bone age and serum dehydroepiandrosterone sulphate (r: 0.45 p<0.01). Serum ACTH was normal. A reduction by 50% in cortisol and 78% in dehydroepiandrosterone sulphate was found after dexamethasone suppression, but Δ4-androstenedione did not suppress after dexamethasone. After ACTH stimulation test cortisol increased by 50% and Δ4-androstenedione by 80%. Conclusions: The increased levels of cortisol and Δ4-androstenedione with partial resistance to dexamethasone suggest that these patients have a hypothalamic-pituitary dysfunction similar to that found in Cushing's disease or in chronic stress. The difference in the responses of Δ4-androstenedione and dehydroepiandrosterone sulphate observed is consistent with the existence of different mechanisms of control for these two steroids.

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