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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 -
Frontiers in Endocrinology 2020An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are...
An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP. A novel heterozygous nonsense mutation in the gene and a known heterozygous missense variant in the gene were found. The heterozygous nonsense mutation in the gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids.
Topics: Adolescent; Case-Control Studies; Codon, Nonsense; Dehydroepiandrosterone Sulfate; Female; Humans; Multidrug Resistance-Associated Protein 2; Pediatric Obesity; Prognosis; Steryl-Sulfatase; Young Adult
PubMed: 32435230
DOI: 10.3389/fendo.2020.00240 -
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 -
International Journal of Pediatric... 2020Premature adrenarche has been described as clinical and biochemical hyperandrogenism before the age of 8 years in girls and 9 years in boys and absence of signs of...
BACKGROUND
Premature adrenarche has been described as clinical and biochemical hyperandrogenism before the age of 8 years in girls and 9 years in boys and absence of signs of true puberty. Adrenal pathology such as adrenal tumors or non-classical congenital adrenal hyperplasia (NCCAH) and exogenous androgen exposure need to be excluded prior to diagnosing (idiopathic) premature adrenarche. Premature adrenarche is more common among black girls compared to white girls and other racial groups. Adrenal pathology such as NCCAH is less common as a cause for premature adrenarche compared with idiopathic premature adrenarche. The evaluation guidelines for premature adrenarche however are not individualized based on racial/ethnic differences. Few studies have been done to evaluate a largely black population with premature adrenarche to assess the incidence of adrenal pathology.
METHODS
This cross-sectional retrospective study evaluated characteristics of prepubertal patients seen in an endocrine clinic for premature adrenarche.
RESULTS
Two hundred and seventy three subjects had signs of early adrenarche. Three subjects were found to have CAH (2 with NCCAH and 1 with late diagnosis classical CAH). None were black. Exogenous androgen exposure was etiology in 4 additional subjects. These 7 patients were excluded from further analysis. The remaining subjects had idiopathic PA ( = 266); 76.7% were females. The mean age at initial visit was 6.42 +/- 1.97 years (with no racial difference) although black subjects were reported symptom onset at a significantly younger age compared to non-Hispanic white patients.
CONCLUSIONS
Our study showed organic pathology was very uncommon in a predominantly black population with premature adrenarche. Patient factors that influence the probability of an underlying organic pathology including race/ ethnicity should be considered to individualize evaluation.
PubMed: 32165891
DOI: 10.1186/s13633-020-0075-8 -
Journal of Pediatric Genetics Mar 2020Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency...
Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the and genes. Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome where heterozygous mutations of gene have been associated with a mild clinical presentation (CDLS type 4; MIM: 614701). We report a female patient with a 2.3-Mb interstitial deletion at 8q23.3-q24.1 encompassing and genes but not . Clinical findings in this patient are correlated with a mixed phenotype of LGS and CdLS type 4.
PubMed: 31976145
DOI: 10.1055/s-0039-1694779 -
AACE Clinical Case Reports 2019Prader-Willi syndrome (PWS) is a rare genetic neuroendocrine disorder characterized by hypotonia, obesity, short stature, and mental retardation. Incomplete or delayed...
OBJECTIVE
Prader-Willi syndrome (PWS) is a rare genetic neuroendocrine disorder characterized by hypotonia, obesity, short stature, and mental retardation. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty is rarely seen.
METHODS
This study reports the clinical, biochemical, and histologic findings in 2 boys with PWS who developed central precocious puberty.
RESULTS
Both boys were started on growth hormone therapy during the first years of life according to the PWS indication. They had both bilateral cryptorchidism at birth and had orchidopexy in early childhood. Retrospective histologic analysis of testicular biopsies demonstrated largely normal tissue architecture and germ cell maturation, but severely decreased number of prespermatogonia in one of the patients. Both boys had premature adrenarche around the age of 6. Precocious puberty was diagnosed in both boys with enlargement of testicular volume (>3 mL), signs of virilization and a pubertal response to a gonadotropin-releasing hormone (GnRH) test and they were both treated with GnRH analog.
CONCLUSION
The cases described here displayed typical characteristics for PWS, a considerable heterogeneity of the hypothalamic-pituitary function, as well as testicular histology. Central precocious puberty is extremely rare in PWS boys, but growth hormone treatment may play a role in the pubertal timing.
PubMed: 31967069
DOI: 10.4158/ACCR-2019-0245 -
BMC Pediatrics Nov 2019Obesity is associated with many chronic diseases including cortisol rhythm disorder and low testosterone. Furthermore, studies on obese children are quite limited and no...
BACKGROUND
Obesity is associated with many chronic diseases including cortisol rhythm disorder and low testosterone. Furthermore, studies on obese children are quite limited and no concordance results have been obtained, especially for boys in puberty. Moreover, the sample sizes of previous studies were small, and were not representative.
METHODS
We conducted a cross-sectional survey including 1148 boys aged 6-14 years, they were divided into overweight/obesity (OW/OB) group and normal weight (NW) group. Puberty status was assessed according to Tanner scale and testicular volume. Serum levels of pregnenolone, 17-OH progesterone, corticosterone, dehydroepiandrosterone (DHEA), and androstenedione were detected by LC-MS. Serum free testosterone and sex hormone-binding globulin (SHBG) levels were measured by chemiluminescence immunoassay.
RESULTS
The 17-OH progesterone, DHEA, androstenedione and free testosterone levels of OW/OB boys at prepubertal stage or at the age 6 = < 10 years group were higher than those of the NW boys (all the P values were < 0.01). Furthermore, androstenedione and free testosterone levels were lower in OW/OB boys at late puberty, and the trend continued at the post pubertal stage for FT (P < 0.01-0.05). DHEA, androstenedione, and FT levels persisted to be higher at the 10~ < 12 years in OW/OB boys but not for 17-OH progesterone. FT level was lower in the OW/OB group at the 12~ < 15 years group. The SHBG levels in the OW/OB boys were lower than those in the NW ones at the 6~12 years group, and prepubertal to early pubertal stage.
CONCLUSIONS
Premature adrenarche is more likely in OW/OB boys. More attention should be given to the lower androgen levels of OW/OB boys at late pubertal and post pubertal stages.
Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Cortex Hormones; Age Factors; Androstenedione; Child; Corticosterone; Cross-Sectional Studies; Dehydroepiandrosterone; Humans; Male; Organ Size; Overweight; Pediatric Obesity; Pregnenolone; Puberty; Puberty, Precocious; Sex Hormone-Binding Globulin; Testis; Testosterone
PubMed: 31690265
DOI: 10.1186/s12887-019-1755-5 -
Clinical Pediatric Endocrinology : Case... 2019Children born small for gestational age (SGA) face an increased risk of health problems in later life, particularly persistent short stature, neurocognitive dysfunction,... (Review)
Review
Children born small for gestational age (SGA) face an increased risk of health problems in later life, particularly persistent short stature, neurocognitive dysfunction, impaired renal and pulmonary function, decreased bone density, sensorineural hearing loss, premature adrenarche, and metabolic syndrome. Insulin resistance appears to be a key component underlying these metabolic complications. Long-term, continuous, GH treatments in short children born SGA lead to a normalization of height through childhood to adulthood. Recombinant human GH has been proven to be relatively safe. We recommend early surveillance in a growth clinic for children born SGA without catch-up growth. Obesity, insulin resistance, and the risk of metabolic syndrome increase with catch-up growth, but short stature and cognitive dysfunction increase without catch-up growth in children born SGA. A solution to this catch-up dilemma is breast feeding for a minimum of 6 to 12 mo. Because the overall prevalence of metabolic risk factors is very low, routine evaluation of metabolic parameters is not recommended for all children born SGA, but it may be useful to consider metabolic evaluations in overweight or obese children born SGA. Since children born SGA have many risk factors, long-term management from neonate to adulthood is very important.
PubMed: 31666762
DOI: 10.1297/cpe.28.97 -
Journal of the Endocrine Society Oct 2019Premature adrenarche (PA) is associated with childhood overweight and hyperinsulinemia; the long-term cardiometabolic outcome is unknown.
CONTEXT
Premature adrenarche (PA) is associated with childhood overweight and hyperinsulinemia; the long-term cardiometabolic outcome is unknown.
OBJECTIVE
To study cardiometabolic profile in adult women with previous PA.
DESIGN AND PARTICIPANTS
Thirty women with PA and 41 control subjects were followed from prepuberty to young adulthood.
MAIN OUTCOME MEASURES
Prevalence of the metabolic syndrome (MetS) and clinical and biochemical cardiovascular risk factors.
RESULTS
There were no differences in the prevalence of MetS or in any parameters indicating dyslipidemia, hypertension, hepatosteatosis, atherosclerosis, or low-grade inflammation between the study groups. However, prevalence of insulin resistance (IR; = 0.014) and acanthosis nigricans ( = 0.010) was higher in the PA group. Neither fasting glucose nor insulin concentrations differed between the study groups, but HbA1c [adjusted for body mass index (BMI) = 0.011] and Homeostatic Model Assessment of Insulin Resistance ( = 0.044; BMI-adjusted = nonsignificant) were higher in the PA group. Although BMI and fat percentage were comparable between the study groups, the PA group had higher central fat mass than the control group. In the whole study population, MetS and IR were associated with greater adult fat mass, but no prepubertal factors predicting later IR were found.
CONCLUSION
PA does not seem to be associated with MetS, dyslipidemia, hypertension, atherosclerosis, or low-grade inflammation in young adult women. However, some women with PA may be at an increased risk of unfavorable glucose metabolism, which is associated with increased central adiposity at adult age rather than determined by prepubertal factors.
PubMed: 31528825
DOI: 10.1210/js.2019-00193 -
Journal of Clinical Research in... Jun 2020Loss-of-function mutations of are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69...
Loss-of-function mutations of are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69 years for evaluation of obesity. Previous thyroid function evaluation suggested CeH [FT4 0.6 ng/mL, thyroid-stimulating hormone (TSH) 2.2 mIU/L] but his physician took no action. At presentation he was clinically and biochemically euthyroid, prepubertal and obese. Serum prolactin (PRL) was undetectable. Biochemistry was normal except for mild hypercholesterolemia, total cholesterol 198 mg/dL. Subsequently FT4 and TSH levels fluctuated between 0.72-0.95 ng/dL (normal 0.8-2.0) and 1.94-5.77 mIU/L (normal 0.3-5.0), respectively. Sequencing of gene revealed a novel genetic change c.3805C>T in exon 19; substitution of amino acid Arginine at position 1269 with a premature «stop» codon resulting in an altered protein product. The patient additionally presented delayed adrenarche, low height velocity that resolved spontaneously and normal pubertal onset associated with increased FSH levels. At 14 years-of-age, while the patient was at Tanner stage 4, PRL levels became detectable, rising gradually to 2.3 ng/mL at last examination. Thyroxine replacement therapy resulted in decrease in total cholesterol 103 mg/dL. A high index of suspicion for the disorder is needed since several measurements of thyroid function may be required for CeH to be disclosed. The patient’s normal FT4 levels and normal intelligence would have resulted in a missed diagnosis if the serum PRL levels had not been measured. This case highlights the importance of measuring PRL in a boy with low normal FT4 and normal TSH levels.
Topics: Adolescent; Humans; Hypothyroidism; Immunoglobulins; Male; Membrane Proteins; Prolactin
PubMed: 31448769
DOI: 10.4274/jcrpe.galenos.2019.2019.0085