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Endocrinology and Metabolism Clinics of... Jun 2024Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order... (Review)
Review
Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order laboratory testing and a bone age to try to rule out other diagnoses including nonclassic congenital adrenal hyperplasia and gonadal or adrenal tumors. I review the natural history of PP and studies which suggest that without clinical features such as rapid growth and progression or genital enlargement, it is unlikely that a treatable condition will be found. Therefore it is recommended that patients with PP not undergo testing unless there are red flags at the time of the initial visit.
Topics: Humans; Puberty, Precocious; Child; Female; Child, Preschool
PubMed: 38677863
DOI: 10.1016/j.ecl.2024.02.001 -
Endocrinology and Metabolism Clinics of... Mar 2021The pathophysiology of symptomatic polycystic ovary syndrome (PCOS) often unfolds across puberty, but the ontogeny of PCOS is difficult to study because, in general, its... (Review)
Review
The pathophysiology of symptomatic polycystic ovary syndrome (PCOS) often unfolds across puberty, but the ontogeny of PCOS is difficult to study because, in general, its pathophysiology is well entrenched before the diagnosis can be confirmed. However, the study of high-risk groups (daughters of women with PCOS, girls with premature pubarche, and girls with obesity) can offer insight in this regard. Available data support the hypothesis that the pubertal development of PCOS involves various combinations of genetic predisposition, intrauterine programming, hyperinsulinism, and numerous other abnormalities that provoke reproductive symptoms (eg, hyperandrogenism, ovulatory dysfunction) in response to the pubertal increase in gonadotropin secretion.
Topics: Adolescent; Female; Humans; Hyperandrogenism; Obesity; Polycystic Ovary Syndrome; Puberty; Puberty, Precocious
PubMed: 33518184
DOI: 10.1016/j.ecl.2020.10.003 -
Journal of Clinical Research in... Feb 2023Premature adrenarche (PA) has been associated with an increase in adrenal androgens, and the hyperandrogenic hormonal environment is known to lead to increased platelet...
OBJECTIVE
Premature adrenarche (PA) has been associated with an increase in adrenal androgens, and the hyperandrogenic hormonal environment is known to lead to increased platelet (PLT) aggregation. Here, we evaluated the effects of PA on PLT aggregation in PLT-rich plasma samples from female patients.
METHODS
The study included 40 female patients diagnosed with PA between February, 2014 and June, 2018 and 30 healthy female individuals as a control group. Adenosine diphosphate (ADP) and collagen-induced PLT aggregation were studied via the photometric aggregometry method.
RESULTS
There were no significant differences in the PLT count or volume values between those participants with PA and the control group. Additionally, the ADP-induced maximum aggregation time, value, and slope values did not significantly differ between the patient and control groups (p>0.05). However, the collagen-induced maximum aggregation time, value, and slope values were significantly higher in the studygroup (p<0.001).
CONCLUSION
Increased collagen-induced PLT aggregation was detected in female patients with PA. As PA is associated with a higher risk of cardiovascular events later in life, close follow-up of PA in this respect may be beneficial.
Topics: Humans; Female; Platelet Aggregation; Adrenarche; Androgens; Puberty, Precocious; Adenosine Diphosphate; Collagen
PubMed: 36264033
DOI: 10.4274/jcrpe.galenos.2022.2022-6-13 -
Clinical Endocrinology Mar 2022Premature adrenarche (PA) has been suggested as a risk factor for future health problems, such as metabolic syndrome and early menarche. However, not all girls with PA...
OBJECTIVE
Premature adrenarche (PA) has been suggested as a risk factor for future health problems, such as metabolic syndrome and early menarche. However, not all girls with PA have these features and it is not certain who will develop them. We propose that these abnormalities might be identified earlier, even before they are visible.
DESIGN
Case-control study.
SETTING
Tertiary care hospital.
PARTICIPANTS
Forty-eight girls with premature pubarche due to PA and age (mean age 7.6 ± 1.0 years), weight, body mass index (BMI), birth weight and gestational age-matched 49 girls with no palpable breast tissue.
MEASUREMENTS
Early pubertal pelvic and breast ultrasonographic changes and their associations with obesity and metabolic parameters were evaluated. Blood samples were collected, breast and pelvic ultrasound examinations were performed and bone ages were assessed.
RESULTS
Girls with PA were taller and their bone ages were higher (p = .049 and p = .005). Fasting blood glucose, insulin, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol were not different between the groups. Luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol were not different either. Ultrasonography revealed breast gland tissue in 30% of girls with PA and 5% of controls (p = .006). Uterine volume and endometrial thickness were higher in girls with PA (p = .03 and p = .04). Endometrial thickness was positively associated with serum insulin levels in the whole study group and after adjusting for age, diagnosis, BMI, mean ovarian volume and LH, FSH, estradiol levels, this association remained with a borderline p-value (R = 0.486, p = .050).
CONCLUSIONS
We found early changes in uterus and breast glands of girls with PA and endometrial thickness was positively associated with insulin levels.
Topics: Adrenarche; Case-Control Studies; Child; Estradiol; Female; Follicle Stimulating Hormone; Humans; Insulin; Luteinizing Hormone; Puberty, Precocious; Ultrasonography
PubMed: 34918373
DOI: 10.1111/cen.14662 -
Seminars in Reproductive Medicine Mar 2022Hyperandrogenism-clinical features resulting from increased androgen production and/or action-is not uncommon in peripubertal girls. Hyperandrogenism affects 3 to 20% of...
Hyperandrogenism-clinical features resulting from increased androgen production and/or action-is not uncommon in peripubertal girls. Hyperandrogenism affects 3 to 20% of adolescent girls and often is associated with hyperandrogenemia. In prepubertal girls, the most common etiologies of androgen excess are premature adrenarche (60%) and congenital adrenal hyperplasia (CAH; 4%). In pubertal girls, polycystic ovary syndrome (PCOS; 20-40%) and CAH (14%) are the most common diagnoses related to androgen excess. Androgen-secreting ovarian or adrenal tumors are rare (0.2%). Early pubic hair, acne, and/or hirsutism are the most common clinical manifestations, but signs of overt virilization in adolescent girls-rapid progression of pubic hair or hirsutism, clitoromegaly, voice deepening, severe cystic acne, growth acceleration, increased muscle mass, and bone age advancement past height age-should prompt detailed evaluation. This article addresses the clinical manifestations of and management considerations for non-PCOS-related hyperandrogenism in adolescent girls. We propose an algorithm to aid diagnostic evaluation of androgen excess in this specific patient population.
Topics: Acne Vulgaris; Adolescent; Androgens; Female; Hirsutism; Humans; Hyperandrogenism; Polycystic Ovary Syndrome
PubMed: 35052005
DOI: 10.1055/s-0041-1742259 -
The Journal of Clinical Endocrinology... Dec 2020Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche... (Observational Study)
Observational Study
CONTEXT
Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche is unknown and the role of novel biosynthetic pathways remains unclear.
OBJECTIVE
To compare the urinary steroid metabolome and enzyme activities of girls with PA to age-matched control girls and to published steroid values of girls with normal adrenarche and of women with PCOS and their newborn daughters.
DESIGN
Prospective observational study from 2009 to 2014.
SETTING
Academic pediatric endocrinology referral center.
PARTICIPANTS
Twenty-three girls with PA and 22 healthy, age-matched girls.
MAIN OUTCOME MEASURES
Steroid metabolites in 24-hour urine samples, including 4 progesterones, 5 corticosterones, aldosterone, 13 androgens, 2 estrogens, 14 glucocorticoids, and enzyme activities represented by metabolite ratios.
RESULTS
Girls with PA had a higher body mass index (mean standard deviation scores 0.9 vs -0.3, P = 0.013). Androgen excretion was higher in PA girls than in control girls (median 3257 nmol/24 hours vs 1627 nmol/24 hours, P < 0.001), in particular metabolites from alternate androgen pathways. The amount of progesterone, corticosterone, aldosterone, estrogen, and cortisol metabolites were similar between groups. Activities of 17β-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3β-hydroxysteroid-dehydrogenase, 21-hydroxylase, and 5α-reductase activity were not different between groups, in contrast to published results on girls with normal adrenarche or PCOS females.
CONCLUSIONS
Metabolites and enzymes involved in alternate androgen pathways appear to be markers of PA. Prospective studies should assess whether steroid production in PA also differs from adrenarche at normal timing and persists into adulthood.
Topics: 17-Hydroxysteroid Dehydrogenases; Adrenarche; Androgens; Case-Control Studies; Child; Child, Preschool; Corticosterone; Estrogens; Female; Humans; Hydrocortisone; Metabolome; Puberty, Precocious; Steroid 17-alpha-Hydroxylase; Switzerland; Up-Regulation
PubMed: 32865200
DOI: 10.1210/clinem/dgaa598 -
European Journal of Endocrinology Apr 2023For many decades, the prevailing paradigm in endocrinology was that testosterone and 5α-dihydrotestosterone are the only potent androgens in the context of human... (Review)
Review
For many decades, the prevailing paradigm in endocrinology was that testosterone and 5α-dihydrotestosterone are the only potent androgens in the context of human physiology. The more recent identification of adrenal derived 11-oxygenated androgens and particularly 11-ketotestosterone have challenged these established norms, prompting a revaluation of the androgen pool, particularly in women. Since being recognized as bone fide androgens in humans, numerous studies have focused their attention on understanding the role of 11-oxygenated androgens in human health and disease and have implicated them as role players in conditions such as castration resistant prostate cancer, congenital adrenal hyperplasia, polycystic ovary syndrome, Cushing's syndrome, and premature adrenarche. This review therefore provides an overview of our current knowledge on the biosynthesis and activity of 11-oxygenated androgens with a focus on their role in disease states. We also highlight important analytical considerations for measuring this unique class of steroid hormone.
Topics: Male; Humans; Female; Androgens; Testosterone; Polycystic Ovary Syndrome; Adrenal Hyperplasia, Congenital; Steroids; Prostatic Neoplasms
PubMed: 37041725
DOI: 10.1093/ejendo/lvad047 -
Journal of the Endocrine Society Sep 2020We hypothesize that impaired glucocorticoid sensitivity (GC sensitivity) plays a role in the development of premature adrenarche (PA) and polycystic ovarian syndrome...
CONTEXT
We hypothesize that impaired glucocorticoid sensitivity (GC sensitivity) plays a role in the development of premature adrenarche (PA) and polycystic ovarian syndrome (PCOS) by increasing androgen synthesis.
OBJECTIVE
To study glucocorticoid sensitivity in vitro in subjects with PA and PCOS.
PATIENTS AND METHODS
Fourteen subjects (10 girls, 4 boys, 6.9 ± 0.6 years) with PA; 27 subjects with PCOS (17 ± 2.5 years) and 31 healthy controls were enrolled in the study. All subjects and controls underwent GC sensitivity analysis in vitro using a fluorescein labeled-dexamethasone (F-DEX) assay. A GC sensitivity index (GCSI) was calculated as area under the curve of the F-DEX assay results. Subjects were classified as GC resistant if the GCSI ≤ 264 and GC sensitive if the GCSI ≥ 386.
RESULTS
In the PA group, 8 of 14 subjects were resistant with GCSI of 179.7 ± 39.9, 4 were within the normal range with GCSI of 299.6 ± 27.9, and 2 had increased GC sensitivity with GCSI of 423.5 ± 47.9. In the PCOS group, 18 of 27 subjects were GC-resistant with GCSI of 180.9 ± 58.2, 8 were within the normal range with GCSI of 310.7 ± 26.4, and 1 had increased GCSI of 395.4. In the PCOS GC-resistant subgroup, cortisol was higher compared with PCOS with normal GCSI ( < 0.05). In the combined PCOS plus female control group, GCSI correlated negatively with cortisol and testosterone ( < 0.05).
CONCLUSION
GC resistance was found in more than 50% of patients with PCOS and PA. The findings strongly suggest that GC resistance is associated with states of PA and PCOS.
PubMed: 32904537
DOI: 10.1210/jendso/bvaa111 -
Journal of Pediatric Endocrinology &... Feb 2023Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported...
OBJECTIVES
Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported hypothalamic-pituitary-adrenal axis dysfunction. While idiopathic premature adrenarche is associated with accelerated pre-pubertal growth and advanced bone age, the consequences of elevated adrenal androgens on growth and bone maturation in PWS remain unknown. This study therefore sought to describe age-related changes in dehydroepiandrosterone sulfate (DHEAS) and their effects on growth and bone maturation in PWS.
METHODS
This retrospective observational study included 62 children with PWS. Simple and multiple regression models were constructed to relate age and BMI-SDS with DHEAS levels. Height velocity was compared to age and sex-based norms with t-tests and two-way ANOVA. Patterns in bone age Z-score were examined with two-way ANOVA, and the contributions of age, BMI-SDS, and DHEAS to bone age Z-score were analyzed with multiple regression.
RESULTS
DHEAS levels rose earlier and were less strongly correlated with age in males and females with PWS (R=0.12 and 0.30) compared to healthy controls (R=0.89 and 0.88) in a pattern unrelated to BMI-SDS (adjusted R=0.076, p=0.10 for age, and 0.29 for BMI-SDS). Mid-childhood height velocity was increased in males and preserved in females with PWS before declining at the age of expected puberty (p<0.0001). Peri-adrenarchal bone age was advanced in a manner associated with DHEAS but not BMI-SDS (p<0.0001; adjusted R=0.48, p=0.0014 for DHEAS, and 0.78 for BMI-SDS).
CONCLUSIONS
An obesity-independent increase in adrenal androgens is associated with accelerated mid-childhood growth and bone maturation in PWS.
Topics: Child; Female; Humans; Male; Adrenarche; Androgens; Hypothalamo-Hypophyseal System; Obesity; Pituitary-Adrenal System; Prader-Willi Syndrome; Puberty, Precocious
PubMed: 36458449
DOI: 10.1515/jpem-2022-0468 -
Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.Epigenetics Dec 2023Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its...
Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 μg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 μg/dL] and High DHEAS (HD) [≥42 μg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.
Topics: Female; Humans; Child; Adrenarche; Androgens; Pilot Projects; DNA Methylation; Dehydroepiandrosterone Sulfate; Obesity
PubMed: 37053179
DOI: 10.1080/15592294.2023.2200366