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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 -
Frontiers in Pediatrics 2019Puberty is a sensitive period of life characterized by the appearance of secondary sex characteristics which leads to a complete sexual maturation. It physiologically... (Review)
Review
Puberty is a sensitive period of life characterized by the appearance of secondary sex characteristics which leads to a complete sexual maturation. It physiologically starts between the age of 8 and 13 years in girls and 9 and 14 years in boys. In the last two decades, several studies have showed that start of puberty has moved up to younger ages by 12-18 months, and some of the hypotheses trying to explain this change include the role of nutritional status and obesity and the influence of extrinsic factors such as exposure to endocrine-disrupting chemicals (EDCs), as well. The hypothalamic-hypophysis-gonadal axis develops during embryogenesis, and except for a period of activation immediately after birth, remains suppressed until the onset of pubertal development. At the beginning of puberty, the pulse generator is reactivated, probably due to progressive stimulatory influences on GnRH neurons from glial signals and neurotrasmitters. Kisspeptin and its receptor play a fundamental role in this phase. Premature Pubarche/Adrenarche, Premature Thelarche, and Premature Menarche are incomplete forms of precocious pubertal development that have their origin in endocrine mechanisms that only recently have started to be understood. It is important to distinguish these forms from the complete ones in order to reassure patients and parents about the non-evolution of pubertal progression and avoid non-useful treatments with analogous LHRH.
PubMed: 31139600
DOI: 10.3389/fped.2019.00147 -
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 -
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 -
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 -
Hormone Research in Paediatrics 2018We propose that the normal adrenarche-related rise in dehydroepiandrosterone (DHEA) secretion is ultimately caused by the rise in cortisol production occurring during... (Review)
Review
We propose that the normal adrenarche-related rise in dehydroepiandrosterone (DHEA) secretion is ultimately caused by the rise in cortisol production occurring during childhood and adolescent growth, by the following mechanisms. (1) The onset of childhood growth leads to a slight fall in serum cortisol concentration due to growth-induced dilution and a decrease in the negative feedback of cortisol upon ACTH secretion. (2) In response, ACTH rises and stimulates increased cortisol synthesis and secretion in the growing body to restore the serum cortisol concentration to normal. (3) The cortisol concentration produced within and taken up by adrenocortical steroidogenic cells may rise during this time. (4) Cortisol competitively inhibits 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2)-mediated conversion of 17αOH-pregnenolone to cortisol, causing a further fall in serum cortisol, a further decrease in the negative feedback of cortisol upon ACTH, a further rise in ACTH, and further stimulation of adrenal steroidogenesis. (5) The cortisol-mediated inhibition of 3βHSD2 also blocks the conversion of DHEA to androstenedione, causing a rise in adrenal DHEA and DHEA sulfate relative to androstenedione secretion. Thus, the combination of normal body growth plus inhibition of 3βHSD2 by intra-adrenal cortisol may cause normal adrenarche. Childhood obesity may hasten this process by causing a pathologic increase in body size that triggers these same processes at an earlier age, resulting in the premature onset of adrenarche.
Topics: 3-Hydroxysteroid Dehydrogenases; Adolescent; Adrenal Cortex; Adrenarche; Adrenocorticotropic Hormone; Animals; Child; Child, Preschool; Female; Humans; Hydrocortisone; Male; Models, Biological; Obesity
PubMed: 29847819
DOI: 10.1159/000488777 -
Anales de Pediatria Oct 2018Premature pubarche (PP) is generally thought to be a benign condition, but it can also be the first sign of underlying disease. (Observational Study)
Observational Study
INTRODUCTION
Premature pubarche (PP) is generally thought to be a benign condition, but it can also be the first sign of underlying disease.
OBJECTIVE
To analyse the aetiology and the evolution of the anthropometric, analytical and metabolic risk parameters of a group of patients with PP.
MATERIAL AND METHODS
A descriptive and analytical retrospective study of 92 patients affected by PP. Anthropometry, analyses, bone age and indicators of lipid metabolism were all evaluated.
RESULTS
The sample included 92 patients with PP (67 female and 25 male), with a mean age of 7.1±0.6 for girls and 8.3±0.7 for boys. Small for gestational age was recorded in 7.7%. There was an accelerated bone age (1.20±0.1 years). A total of 21 patients were classified as idiopathic (23%), 60 as idiopathic premature adrenarche (65%), and 11 with non-classic congenital adrenal hyperplasia (12%). Puberty was reached early (11+0.9 years old in boys and 9.9±0.8 in girls), as was menstruation age (11.8+1.1 years old), P<.001. The stature finally reached was close to their genetic stature. There is a positive correlation between body mass index, blood glucose and LDL cholesterol, as well as a tendency towards hyperinsulinaemia.
CONCLUSIONS
The present study shows that PP is a benign condition in the majority of cases, but non-classic congenital adrenal hyperplasia (12%) is not uncommon. Menstruation and puberty started early and bone age was accelerated. Growth was normal, and more or less in line with genetic size. PP associated with obesity is linked with analytical variations of metabolic risks.
Topics: Child; Disease Progression; Female; Humans; Male; Puberty, Precocious; Retrospective Studies
PubMed: 29705181
DOI: 10.1016/j.anpedi.2017.11.012