-
Annals of Pediatric Endocrinology &... Dec 2018Premature adrenarche (PA) often leads to polycystic ovary syndrome (PCOS). Higher anti-mullerian hormone (AMH) levels are reported in PCOS. We studied the androgen...
PURPOSE
Premature adrenarche (PA) often leads to polycystic ovary syndrome (PCOS). Higher anti-mullerian hormone (AMH) levels are reported in PCOS. We studied the androgen profile and AMH profiles in Hispanic girls with PA (aged 5-8 years) and age and body mass index (BMI) matched controls.
METHODS
Retrospective review of electronic medical records of girls who met the inclusion criteria for premature adrenarche were done.
RESULTS
PA girls (n=76) were matched to control girls (n=12) for age (mean±standard deviation) (6.7±1 years vs. 6.2±1.3 years) and BMI (20±10 kg/m2 vs. 17.8±2.7 kg/m2). Dehydroepiandrostenedione sulfate (63.3±51.3 μg/dL vs. 29.8±17.3 μg/dL, P<0.001) and testosterone levels (11.4±4.8 ng/dL vs. 8.2±2.9 ng/dL, P=0.001) were significantly higher in the PA group than controls. AMH values (<14 years: reference range, 0.49-3.15 ng/mL) were 3.2±2.2 ng/mL vs. 4.6± 3.2 ng/mL respectively in the PA and control groups and were not different (P=0.4). AMH did not show a correlation with bone age (P=0.1), and testosterone (P=0.9) in the PA group. 17-hydroxyprogesterone levels (17-OHP ng/dL) were 39.5±30.5 ng/dL vs. 36.8±19.8 ng/dL in PA versus control girls. The concentration of 17-OHP was not statistically different between the control and PA groups.
CONCLUSION
Higher AMH was not observed in PA girls and no correlation with BA and androgen levels was observed.
PubMed: 30599482
DOI: 10.6065/apem.2018.23.4.210 -
European Journal of Endocrinology Mar 2019Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce,...
Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.
Topics: Adolescent; Androgens; Androstenedione; Child; Child, Preschool; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Endocrine System Diseases; Female; Humans; Male; Puberty; Puberty, Precocious; Retrospective Studies; Risk Factors; Severity of Illness Index; Sexual Maturation; Testosterone
PubMed: 30566905
DOI: 10.1530/EJE-18-0854 -
Frontiers in Endocrinology 2018Molecular defects of consistently decrease 21-hydroxylase activity and result in a variable expression of disease severity in patients with congenital adrenal...
Molecular defects of consistently decrease 21-hydroxylase activity and result in a variable expression of disease severity in patients with congenital adrenal hyperplasia (CAH). The genotype and biochemical findings were examined in an attempt to reveal any association to the degree of virilization in classic CAH patients. The study included 18 CAH patients with complete characterization of mutations and were sorted based on the severity of the inherited mutations and the expected percentage of 21-hydroxylase enzyme activity. Eleven out of the 18 patients manifested the SW form with the remaining seven exhibiting the SV form. The most frequent genetic defect in the classic salt-wasting (SW) and simple virilising (SV) forms was the IVS2-13A/C>G (36.1%) mutation, followed by delEX1-3 (19.4%) and p.Ile172Asn (19.4%). Four patients, who shared a combination of two mutations belonging to the most severe type, manifested only the SW form. Four out of five patients who shared homozygosity in the IVS2-13A/C>G mutation, demonstrated the SW form and only one demonstrated the SV form. All four patients who shared the p.Ile172Asn mutation, either in the homozygous or compound heterozygous state, manifested the SV form. Interestingly, a female neonate with SW, bearing the IVS2-13A/C>G/Large del, exhibited complete male virilisation (Prader 5). The remaining four affected female new-borns also exhibited the SW form, with two of them virilised as Prader 3 and the other two as Prader 4. Virilisation with clitoromegaly was also observed in one female, who presented premature adrenarche and carried the least severe p.Pro30Leu mutation. The frequency of the underlying mutations in our patients, with the classic form of CAH, varies but were quite similar to the ones reported in the Mediterranean region. Therefore, the identification of severe defects in Cypriot patients and their comparison with the incidence and severity in different populations, will create a valuable diagnostic tool for genetic counseling in the classic form of CAH.
PubMed: 30559721
DOI: 10.3389/fendo.2018.00733 -
The Journal of Pediatrics Feb 2019To assess whether the serum levels of anti-Müllerian hormone (AMH) are increased in girls with premature adrenarche because they are at a higher risk of developing...
OBJECTIVES
To assess whether the serum levels of anti-Müllerian hormone (AMH) are increased in girls with premature adrenarche because they are at a higher risk of developing polycystic ovary syndrome (PCOS) later in life.
STUDY DESIGN
We measured serum levels of AMH, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone binding globulin, androstenedione, and 17-hyroxyprogesterone in 89 girls with premature adrenarche aged 6.98 ± 1.60 years, and in 55 prepubertal normal girls aged 6.78 ± 1.60 years.
RESULTS
AMH was significantly higher in girls with premature adrenarche (2.95 ± 1.20 ng/mL) compared with normal prepubertal girls (2.00 ± 0.95 ng/mL; P < .001), whereas their body mass index SD score was similar (P > .05). DHEAS, testosterone, and androstenedione were increased in premature adrenarche, whereas sex hormone binding globulin was decreased in girls with premature adrenarche. Among the 89 girls with premature adrenarche, 33 were daughters of mothers with a positive history of PCOS, whereas the mothers of the remaining 56 girls with premature adrenarche had a negative history of PCOS. The girls with a mother with a positive history of PCOS had significantly higher AMH serum levels compared with girls with a mother with a negative history of PCOS (3.37 ± 1.72 ng/mL vs 2.70 ± 1.25 ng/mL; P < .05) with no differences in testosterone, DHEAS, androstenedione, and sex hormone binding globulin. The serum concentration of AMH was only positively related to androstenedione (r = 0.538; P < .0001).
CONCLUSIONS
Girls with premature adrenarche, especially those from mothers with a history of PCOS, could have a higher risk of developing PCOS later in life because they have increased serum AMH.
Topics: Adrenarche; Anti-Mullerian Hormone; Biomarkers; Body Mass Index; Child; Female; Genetic Predisposition to Disease; Humans; Mothers; Nuclear Family; Polycystic Ovary Syndrome; Puberty; Radioimmunoassay
PubMed: 30529136
DOI: 10.1016/j.jpeds.2018.09.064 -
Journal of Ovarian Research Sep 201811β-hydroxylase deficiency (11OHD) is extremely rare, and reports of non-classical 11OHD are even rarer. Non-classical 11OHD usually presents as premature adrenarche,... (Review)
Review
BACKGROUND
11β-hydroxylase deficiency (11OHD) is extremely rare, and reports of non-classical 11OHD are even rarer. Non-classical 11OHD usually presents as premature adrenarche, hyperandrogenism, menstrual disorders, and hypertension. Because the symptoms of non-classical 11OHD are mild, delayed diagnosis or misdiagnosis as polycystic ovary syndrome or primary hypertension is common.
CASE PRESENTATION
This paper introduces a case of a young female patient presenting hypertension and menstrual disorders. Laboratory examination revealed increased androgen levels, mild adrenal hyperplasia, mild left ventricular hypertrophy, and mild sclerosis of the lower limb arteries. 11OHD was confirmed by genetic testing, and the patient was found to carry compound heterozygous mutations in CYP11B1 (c.583 T > C and c.1358G > A). The mutation Y195H is located in exon 3 and has not been reported previously. In silico studies indicated that this mutation may cause reduced enzymatic activity. After treatment with hydrocortisone and spironolactone, blood pressure was brought under good control, and menstruation returned to normal. We also conducted a retrospective review of previously reported cases in the literature (over 170 cases since 1991).
CONCLUSIONS
Early diagnosis of non-classical 11OHD is difficult because its symptoms are mild. The possibility of this disease should be considered in patients with early-onset hypertension, menstrual disorders, and hyperandrogenism to provide early treatment and prevent organ damage due to hypertension and hyperandrogenism. CYP11B1 mutations are known to be race-specific and are concentrated in exons 3 and 8, of which mutations in the former are mostly associated with non-classical 11OHD, whereas mutations in the latter are mostly found in classical 11OHD, characterized by severe loss of enzymatic activity.
Topics: Adrenal Hyperplasia, Congenital; Adult; Female; Humans; Mutation; Steroid 11-beta-Hydroxylase; Young Adult
PubMed: 30223866
DOI: 10.1186/s13048-018-0450-8 -
The Journal of Clinical Endocrinology... Dec 2018Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of... (Observational Study)
Observational Study
CONTEXT
Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT).
OBJECTIVE
The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA.
PARTICIPANTS AND METHODS
With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years).
RESULTS
In reference population girls, dehydroepiandrosterone, DHEA-S, androstenediol-3-sulfate, T, and 11KT all increased at the onset of adrenarche (6 to 8 years) and beyond (9 to 10 years) (P < 0.05 vs younger subjects 4 to 5 years). T, 11OHT, and 11KT were further elevated in PremA vs age-matched girls (P < 0.001). Circulating concentrations of 11KT during adrenarche and PremA exceeded those of T and 11OHT (11KT > T ≥ 11OHT). Androgen receptor activity and nuclear translocation studies demonstrated that 11KT is a potent androgen similar to T.
CONCLUSIONS
Our findings suggest that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Its androgenic capacity suggests that it may be responsible for the phenotypic changes seen in these phenomena.
Topics: Adrenarche; Androgens; Child; Child, Preschool; Cohort Studies; Dehydroepiandrosterone Sulfate; Female; Humans; Mass Spectrometry; Puberty, Precocious; Testosterone; Zona Reticularis
PubMed: 30137510
DOI: 10.1210/jc.2018-00736 -
Pediatrics International : Official... Oct 2018Vitamin D, an important factor in calcium-phosphate homeostasis, has recently been suggested to play an important role in the pathogenesis of numerous chronic conditions...
BACKGROUND
Vitamin D, an important factor in calcium-phosphate homeostasis, has recently been suggested to play an important role in the pathogenesis of numerous chronic conditions such as hyperandrogenism. The aim of this study was to investigate the relationship between vitamin D status and premature adrenarche (PA).
METHODS
A total of 71 girls with PA and 52 healthy girls, as the control group, were recruited. Axillary and/or pubic hair development before the age of 8 years was defined as PA. Bone age and anthropometric measures including height, weight, and body mass index (BMI) were obtained. 25-Hydroxyvitamin D (25(OH)D), fasting plasma glucose and insulin were measured. Vitamin D insufficiency was defined as <20 ng/mL.
RESULTS
The PA patients had older bone age, higher BMI standard deviation score, homeostasis model of assessment-insulin resistance (HOMA-IR), and androgen but lower 25(OH)D than the control group. HOMA-IR and dehydroepiandrosterone sulfate were also higher in PA patients with vitamin D insufficiency compared with those with normal vitamin D. There was a negative correlation between 25(OH)D and HOMA-IR.
CONCLUSION
Low vitamin D is associated with PA; and insulin resistance may be a factor in this association.
Topics: Adrenarche; Case-Control Studies; Child; Cross-Sectional Studies; Female; Humans; Hyperandrogenism; Insulin Resistance; Logistic Models; Puberty, Precocious; Risk Factors; Vitamin D Deficiency
PubMed: 30129969
DOI: 10.1111/ped.13682 -
European Journal of Pediatrics Nov 2018The aim of this study was to analyze the relationship between premature adrenarche (PA) and metabolic syndrome (MeS) parameters at presentation and during puberty. This...
The aim of this study was to analyze the relationship between premature adrenarche (PA) and metabolic syndrome (MeS) parameters at presentation and during puberty. This study comprised 47 girls with PA. Age- and puberty-matched 22 healthy girls without PA were the control group. Patients were evaluated at admission (first evaluation) and later in puberty (second evaluation). Anthropometric measurements, lipid levels, and hormonal parameters were studied and oral glucose tolerance test was performed. Indices for insulin resistance (IR) were calculated. The study group was divided in subgroups according to body mass index (BMI) and compared with the control group. The age of the PA group at first evaluation was 8.0 ± 1.1 years; mean height SDS and BMI SDS were 0.4 ± 1.2 and 0.6 ± 0.9, respectively. Age of PA group at the second evaluation was 12.9 ± 2.4 years. Frequency of obesity and overweight was 14.9 and 23.4%. Dyslipidemia ratio was 28.3%. PA group had significantly higher BMI than controls. Mean insulin concentration was higher and mean glucose and FGIR were lower in PA group and also dyslipidemia ratio was 5.3 times higher in PA than controls (p = 0.040). In PA group, overweight/obese subjects had still higher BMI at second evaluation and also higher fasting glucose, insulin, HOMA-IR. However, PA children with exaggerated DHEAS concentrations compared to those without had similar BMI SDS, insulin sensitivity, and secretion indices and lipid profile at second evaluation. BMI SDS at first evaluation was positively correlated with HOMA-IR at puberty; however, there is no correlation between DHEAS at first evaluation and HOMA-IR at puberty.Conclusion: BMI at adrenarche is more important than prepubertal adrogen concentrations such as DHEAS, while predicting the IR in puberty. Long-term follow-up of children supports the observation that PA per se may be related to IR; however, the risk increases with obesity. What is Known: • Premature adrenarche (PA) is receiving more attention as evidence emerges for a relation between early androgen excess and metabolic syndrome. • The onset of the adrenal androgen production before 8 years in girls defined as PA. Pubarche, axillary hair, apocrine body odor, acne are typical phenotypic features of PA. What is New: • Body mass index at adrenarche is an important risk factor for development of insulin resistance in pubertal ages. • Degree of dehydroepiandrosterone sulfate elevation was not shown as a risk factor for insulin resistance.
Topics: Adolescent; Adrenarche; Androgens; Anthropometry; Body Mass Index; Child; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Metabolic Syndrome; Puberty; Puberty, Precocious; Risk Factors
PubMed: 30056577
DOI: 10.1007/s00431-018-3211-1 -
Frontiers in Endocrinology 2018It has been speculated that premature adrenarche (PA) could lead to unfavorable outcome, including shorter adult stature, but longitudinal follow-up data are...
It has been speculated that premature adrenarche (PA) could lead to unfavorable outcome, including shorter adult stature, but longitudinal follow-up data are insufficient. This prospective case-control study included 30 PA and 42 control females who were born mostly full-term and appropriate for gestational age. They were examined first at the median age of 7.6 years and now at 18.1 years. Main outcome measures were height, body mass index (BMI), age at menarche, and serum dehydroepiandrosterone sulfate (DHEAS) and insulin-like growth factor 1 (IGF-1) concentrations. The PA and control females had comparable mean (standard deviation) adult height [167.2 (6.8) vs. 164.5 (5.1) cm, = 0.059] and median (25th-75th percentiles) BMI [22.8 (21.1-28.9) vs. 21.6 (19.8-24.3) kg/m, = 0.068, respectively]. Adult heights were comparable with the mid-parental heights in both study groups. The PA females were taller than the controls until the age of 12 years and they lacked a distinct pubertal growth spurt. Serum DHEAS and IGF-1 concentrations did not differ between the PA and control groups at the age of 18 years. Median (range) age at menarche was significantly lower in the PA than control females [11.5 (9.5-15.0) vs. 13.0 (10.0-15.0), = 0.001]. Although PA girls have advanced growth and earlier pubertal development together with a tendency to be more overweight, their height, BMI, and serum DHEAS and IGF-1 concentrations are comparable to those of their peers at the age of 18 years. Our findings indicate a benign outcome of PA in appropriate for gestational age -born females concerning adult height and adrenal androgen secretion.
PubMed: 30042733
DOI: 10.3389/fendo.2018.00375 -
Stress (Amsterdam, Netherlands) Nov 2018Concerns over anxiety and depressive symptoms in children with premature adrenarche (PA) have been recently raised. However, to date, most relevant studies are on a...
Increased symptoms of anxiety and depression in prepubertal girls, but not boys, with premature adrenarche: associations with serum DHEAS and daily salivary cortisol concentrations.
Concerns over anxiety and depressive symptoms in children with premature adrenarche (PA) have been recently raised. However, to date, most relevant studies are on a small number of girls. In this cross-sectional study, 82 pre-pubertal children (66 girls and 16 boys) diagnosed with PA, were compared to 63 control children regarding their psychological characteristics and hypothalamic-pituitary-adrenal (HPA) axis function, as assessed by salivary cortisol measurement. Symptoms of anxiety and depression were assessed by child self-report (Spence Children's Anxiety Scale (SCAS) and Depression self-rating scale for Children (DSRS)) and parent-report (Child Behaviour Checklist (CBCL)) tests validated for the Greek population. Salivary cortisol levels were determined directly after awakening (approximately 7am) and evening (8pm) of the same day. Morning serum DHEAS levels were assessed in PA children. Girls with PA scored significantly higher on anxiety (p = .016) and depression (p =.039) scales than controls. No group differences were noted for parent reports and children's salivary cortisol concentrations. Boys with PA did not demonstrate significant differences in any of the aforementioned parameters. Our findings suggest that girls with PA may be at higher risk for reporting symptoms of anxiety and depression than their non-PA peers. HPA axis dysregulation in this population was not documented.
Topics: Adrenarche; Anxiety; Child; Child, Preschool; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Depression; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Pituitary-Adrenal System; Puberty, Precocious; Saliva; Sex Factors
PubMed: 29916751
DOI: 10.1080/10253890.2018.1484446