The Search for the Causes of Common Hyperandrogenism, 1965 to circa 2015.

From 1965-2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology; insulin resistance, hyperinsulinism, type 2 diabetes mellitus; folliculogenesis; androgen secretion; obesity; phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicates that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and pro-inflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in one-quarter of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

Evaluation of cardiac electrophysiological features in patients with premature adrenarche.

OBJECTIVES: This study aimed to analyze the cardiac effects of hyperandrogenism in premature adrenarche (PA) and evaluate the risk of arrhythmia development. METHODS: Fifty patients with PA and 50 healthy children from a pediatric endocrinology outpatient clinic were included in the study. The patients underwent echocardiography and electrocardiographic evaluations. Conventional echocardiography, tissue Doppler echocardiography, repolarization time, and repolarization dispersion time were evaluated. RESULTS: The median age in the PA and control groups was 7.91 years (5.83-9.25), 8.08 years (5.75-9.33), respectively. Thirty percent of patients in the PA group were male. While mitral early diastolic velocity deceleration time (DT), isovolumetric relaxation time (IRT), and E/e' ratio were significantly higher in the PA group than in the control group, mitral lateral annulus tissue Doppler early diastolic velocity was significantly lower (p=0.0001, 0.0001, 0.003, 0.0001). While P wave dispersion (PWD), Tpe, and QT-dispersion (QT-d) values were significantly higher in the PA group than in the control group, the P minimum value was significantly lower in the PA group (p=0.0001, 0.02, 0.004, and 0.0001, respectively). CONCLUSIONS: Early subclinical diastolic dysfunction was observed in the PA group. There was an increased risk of atrial arrhythmia with PWD and an increased risk of ventricular arrhythmia with increased Tpe and QT-d. There was a correlation between testosterone levels and diastolic function parameters. The increased risk of atrial arrhythmia is closely related to diastolic function.

Update on Adrenarche - Still a Mystery.

CONTEXT: Adrenarche marks the timepoint of human adrenal development when the cortex starts secreting androgens in increasing amounts, in healthy children at age 8-9 years, with premature adrenarche (PA) earlier. Because the molecular regulation and significance of adrenarche are unknown, this prepubertal event is characterized descriptively, and PA is a diagnosis by exclusion with unclear consequences at long-term. EVIDENCE ACQUISITION: We searched the literature of the past five years including original articles, reviews, and meta-analyses from PubMed, ScienceDirect, Web of Science, Embase, and Scopus, using search terms "adrenarche", "pubarche", "DHEAS", "steroidogenesis", "adrenal", and "zona reticularis". EVIDENCE SYNTHESIS: Numerous studies addressed different topics of adrenarche and PA. Although basic studies on human adrenal development, zonation and zona reticularis function enhanced our knowledge, the exact mechanism leading to adrenarche remains unsolved. Many regulators seem involved. A promising marker of adrenarche (11-ketotestosterone) was found in the 11-oxy androgen pathway. With current definition the prevalence of PA can be as high as 9-23% in girls and 2-10% in boys, but only a subset of these children might face related adverse health outcomes. CONCLUSION: New criteria for defining adrenarche and PA are needed to identify children at risk for later disease and spare children with a normal variation. Further research is therefore required to understand adrenarche. Prospective, long-term studies should characterize prenatal or early postnatal developmental pathways that modulate trajectories of birth size, early postnatal growth, childhood overweight/obesity, adrenarche and puberty onset, and lead to abnormal sexual maturation, fertility, and other adverse outcomes.

Dose inhibin B or anti-Müllerian hormone relate to precocious puberty in girls? result of a systematic review and meta-analysis.

BACKGROUNDS: Existing studies have investigated the relationship between the levels of serum inhibin B (INHB), anti-müllerian hormone (AMH) and precocious puberty in girls, but the results are inconsistent. OBJECTIVE: The aim of this meta-analysis was to assess whether the INHB and AMH levels changed in girls with precocious puberty relative to healthy controls. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched through June 2022. We included observational clinical studies reporting the serum levels INHB and AMH in girls with precocious puberty. Conference articles and observational study abstracts were included if they contained enough information regarding study design and outcome data. Case series and reports were excluded. An overall standard mean difference (SMD) between precocious puberty and healthy controls was estimated using a DerSimonian-Laird random-effects model. RESULTS: A total of 11 studies featuring 552 girls with precocious puberty and 405 healthy girls were selected for analysis. The meta-analysis showed that the INHB level of precocious puberty [including central precocious puberty (CPP) and premature the larche (PT)] were significantly increased. While there was no significant association between precocious puberty [including CPP, PT, premature pubarche (PP) and premature adrenarche (PA)] and the level of serum AMH. CONCLUSION: Scientific evidence suggested that the INHB level, but not the AMH level, altered in girls with precocious puberty compared with healthy controls. Through our results we think that INHB level might be a marker for the auxiliary diagnosis of precocious puberty (especially CPP and PT). Therefore, it is important to evaluate and thoroughly investigate the clinical indicators (e.g., INHB) in order to ensure early diagnosis and medical intervention, and the risk of physical, psychological and social disorders in immature girls with precocious puberty is minimized.

Cardiorespiratory Fitness in Young Adult Women With a History of Premature Adrenarche.

Context: Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict overall health, but no data exist on the CRF of women with a history of PA. Objective: To study if hyperandrogenism in childhood resulting from PA leads to a measurable difference in CRF between young adult PA and control women. Methods: A total of 25 women with PA and 36 age-matched controls were followed from prepubertal age until adulthood. Anthropometric measurements, body composition, biochemical, and lifestyle factors were assessed. The main outcome measure was maximal cycle ergometer test result at the mean age of 18.5 years. We also assessed prepubertal predicting factors for CRF with different linear regression models. Results: Though prepubertal children with PA were taller and heavier than their non-PA peers, there were no significant differences in height, body mass index, body composition, or physical activity in young adulthood. We observed no significant differences in any of the parameters of the maximal cycle ergometer test, including maximal load (P = .194) or peak oxygen consumption (P = .340). Hemodynamic responses of the groups were similar. None of the examined models or prepubertal factors significantly predicted CRF at adult age. Conclusion: This study suggests that hyperandrogenism in childhood/adolescence resulting from PA does not have a significant impact on adulthood CRF.

High frequency of autoimmune thyroiditis in euthyroid girls with premature adrenarche.

Objective: The purpose of this study was to investigate the frequency of autoimmune thyroiditis (AT) among euthyroid prepubertal girls presenting with premature adrenarche (PA). We also aimed to identify the clinical, metabolic, and endocrine profile of girls with AT and concurrent PA and compare them to girls with AT without PA, PA alone and healthy controls. Methods: Ninety-one prepubertal girls aged 5-10 years, who attended our department for AT, PA and normal variants of growth and puberty were recruited for the study: 73 girls had PA, 6 AT without PA and 12 were referred for investigation of growth. All girls underwent clinical examination, detailed biochemical and hormonal screen. Standard dose Synachten stimulation test (SDSST) and oral glucose tolerance test (OGTT) were performed in all girls with PA. The whole study population was divided in 4 groups: Group PA-/AT+ included 6 girls with AT without PA; Group PA+/AT- PA subjects without AT; Group PA+/AT+ girls with PA and concomitant AT; Group PA-/AT- twelve healthy girls without PA nor AT (controls). Results: Among 73 girls presenting with PA 19 had AT (26%). BMI, systolic blood pressure (SBP) and the presence of goiter significantly differed between the four groups (p = 0.016, p = 0.022 and p < 0.001, respectively). When comparing hormonal parameters among the four groups significant differences were found in leptin (p = 0.007), TSH (p = 0.044), anti-TPO (p = 0.002), anti-TG (p = 0.044), IGF-BP1 (p = 0.006), Δ4-Α (p = 0.01), DHEA-S (p = <0.001), IGF-1 (p = 0.012) and IGF-BP3 (p = 0.049) levels. TSH levels were significantly higher in Group PA+/AT+ compared to PA+/AT- and PA-/AT- (p = 0.043 and p = 0.016, respectively). Moreover, girls with AT (Groups PA-/AT+ and PA+/AT+) had higher TSH levels than those in Group PA+/AT- (p = 0.025). Girls in Group PA+/AT + showed higher cortisol response at 60 min post-SDSST than girls in Group PA+/AT- (p = 0.035). During the OGTT, insulin concentrations at 60 min were significantly higher in Group PA+/AT + compared to Group PA+/AT- (p = 0.042). Conclusion: A high frequency of AT among euthyroid prepubertal girls with PA was observed. The combination of PA with AT even in euthyroid state may be associated with a greater degree of insulin resistance, than PA alone.

Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.

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.

The Relationship Between Premature Adrenarche and Platelet Aggregation

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.

Premature adrenarche in Prader-Willi syndrome is associated with accelerated pre-pubertal growth and advanced bone age.

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 (R2=0.12 and 0.30) compared to healthy controls (R2=0.89 and 0.88) in a pattern unrelated to BMI-SDS (adjusted R2=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 R2=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.

Role of 11-oxygenated androgens in the diseases of pediatric hyperandrogenism / 国际儿科学杂志

Previously the diseases of pediatric hyperandrogenism were mainly diagnosed and evaluated by testing traditional androgens such as testosterone and androstenedione.However, clinical application has revealed a poor correlation between traditional androgens and the clinical manifestations of hyperandrogenism in some patients.It has been proposed that adrenal-derived 11-oxygenated androgen may also be involved in the course of this type of disease.The concentrations of 11-oxygenated androgen are elevated in androgen excess diseases, and they fulfill a variety of roles in human physiology and disease.This article discusses three aspects of the synthesis process, activity and content of 11-oxygenated androgen and their application in three androgen excess diseases: congenital adrenocortical hyperplasia, premature adrenarche and polycystic ovary syndrome, in order to help clinicians expand their clinical understanding and investigative thoughts on 11-oxygenated androgen.

NMR-based metabolic profiling of children with premature adrenarche.

INTRODUCTION: Premature adrenarche (PA) for long time was considered a benign condition but later has been connected to various diseases in childhood and adulthood which remains controversial. OBJECTIVE: To investigate the effect of premature adrenarche on the metabolic phenotype, and correlate the clinical and biochemical data with the metabolic profile of children with PA. METHODS: Nuclear magnetic resonance (NMR)-based untargeted and targeted metabolomic approach in combination with multivariate and univariate statistical analysis applied to study the metabolic profiles of children with PA. Plasma, serum, and urine samples were collected from fifty-two children with Idiopathic PA and forty-eight age-matched controls from the division of Pediatric Endocrinology of the University Hospital of Patras were enrolled. RESULTS: Metabolomic results showed that plasma and serum glucose, myo-inositol, amino acids, a population of unsaturated lipids, and esterified cholesterol were higher and significantly different in PA children. In the metabolic profiles of children with PA and age-matched control group a gradual increase of glucose and myo-inositol levels was observed in serum and plasma, which was positively correlated their body mass index standard deviation score (BMI SDS) values respectively. Urine 1H NMR metabolic fingerprint of PA children showed positive correlation and a clustering-dependent relationship with their BMI and bone age (BA) respectively. CONCLUSION: This study provides evidence that PA driven metabolic changes begin during the childhood and PA may has an inductive role in a BMI-driven increase of specific metabolites. Finally, urine may be considered as the best biofluid for identification of the PA metabolism as it reflects more clearly the PA metabolic fingerprint.

Adult Height in Girls With Idiopathic Premature Adrenarche: A Cohort Study and Design of a Predictive Model.

Introduction: Idiopathic premature adrenarche (IPA) is considered a normal variant of puberty, presenting more commonly in female patients. There are concerns as to whether IPA alters the final height of these girls. Our main objectives were to (a) compare the adult height of girls with IPA against their target height and (b) design a mathematical model to predict adult height at diagnosis in female patients with IPA. Materials and Methods: A cohort study of girls with IPA was conducted from the time of IPA diagnosis until adult height. The following data were collected: target height, perinatal history, anthropometric and biochemical variables and bone age at diagnosis, age at Tanner stage 2 and menarcheal age, and adult height. First, we performed a univariate statistical analysis after which we carried out a multiple linear regression analysis using adult height as the dependent variable. Results: We obtained data from 79 female patients diagnosed with IPA with a mean adult height of 164.6 cm (95% CI: 163.36-165.85 cm). The mean follow-up time was 6.60 years. Average age at Tanner stage 2 was 9.71 years. Mean menarcheal age was 11.64 years. There were no significant differences between target height and adult height. Of the several predictive models designed for these patients, one of them, which included bone age, obtained an R2 value of 71%. Conclusions: Although slightly advanced puberty was observed among the girls with IPA, their adult height was preserved. The use of predictive models of adult height on diagnosis of IPA could facilitate closer follow-up of girls at risk of reduced adult height.

Investigation of early puberty prevalence and time of addition thelarche to pubarche in girls with premature pubarche: two-year follow-up results.

We aimed to determine the prevalence of early puberty in girls with premature pubarche and analyze the time interval between their pubarche and succeeding thelarche. This study included 60 female children with premature pubarche. We retrospectively collected clinical, laboratory, and radiological findings from all participants. We investigated the time interval between pubarche and thelarche in cases wherein premature pubarche was followed by thelarche. The mean age at onset of pubarche was 6.93 ± 0.79 yr old. Among the participants, 16.7% were preterm, 20% were small for gestational age (SGA), and 55% were overweight or obese. The mean time interval between pubarche and thelarche was 11.20 ± 7.41 mo. The mean serum DHEA-S level was higher in the preterm group (p = 0.016), and DHEA-S levels were generally higher in the SGA group (p = 0.004). This study documented the presence of being overweight or obese and having more advanced growth than their genetic potential in half of the patients who had premature pubarche. In addition to these identified risk factors, obesity-independent DHEA-S levels were observed to be higher in patients who had early puberty with the first six months of their follow-up considered to be the most critical time in predicting early puberty.

Pelvic and breast ultrasound abnormalities and associated metabolic disturbances in girls with premature pubarche due to adrenarche.

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 (R2 = 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.

Evaluation of metabolic parameters and aortic elasticity in normotensive children with premature adrenarche.

OBJECTIVES: Premature adrenarche may be associated with an intrauterine programmed metabolic syndrome which should be considered as a warning sign for coronary heart disease due to accelerated atherosclerosis, hypertension, type 2 diabetes mellitus (DM), and polycystic ovary syndrome. METHODS: Seventy-three patients with premature adrenarche were evaluated for metabolic parameters and aortic elasticity to evaluate the susceptibility to atherosclerosis and compared with a control group. The patients were examined in two groups as overweight and nonoverweight, and metabolic and cardiac parameters were also compared among these groups. Strain, distensibility, and stiffness index parameters were used to evaluate aortic elasticity. RESULTS: Biochemical parameters and cardiac measurements were not statistically different between patients and controls. They also did not differ between patients with normal weight and overweight groups. Atherogenic index and insulin resistance were closely related and a positive correlation between cholesterol and triglyceride, and ascending aortic stiffness was found. CONCLUSIONS: The results may suggest that cholesterol and triglyceride-related arterial involvement is more involved in the pathogenesis of arterial stiffness. It can be considered that 'being overweight' or 'having metabolic profile characterized by insulin resistance and dyslipidemia' are the major coexisting factors influencing the vascular structure, rather than increased androgens and premature adrenarche itself.

Polycystic Ovary Syndrome: Ontogeny in Adolescence.

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.

Premature Adrenarche in Children with Prader-Willi Syndrome Treated with Recombinant Human Growth Hormone Seems to Not Influence the Course of Central Puberty and the Efficacy and Safety of the Therapy.

Puberty in children with Prader-Willi syndrome (PWS) is usually delayed and/or incomplete but in some patients premature/early adrenarche is observed. We assessed the premature adrenarche (PA) in PWS patients during the recombinant human growth hormone (rhGH) therapy and influence of PA on the course of central puberty (CP), rhGH efficacy and safety, and patients' metabolic state. Forty-nine PWS patients were treated with rhGH, 11 presented with PA (group 1) and 14 had normal course of adrenarche (group 2). PA was observed in 22.5% of the PWS children treated with rhGH. The mean time between the rhGH start and the adrenarche, the rhGH dose, the growth velocity and the insulin-like growth factor 1 SD (IGF1 SD) during the treatment, as well as the time of CP, final height SD and BMI SD were similar in both groups. There were also no significant differences in the metabolic assessment-the oral glucose tolerance test (OGTT) and lipid profile results. PA may be a part of the clinical picture of PWS, apart from hypogonadotrophic hypogonadism and it seems to have no influence on CP in PWS patients. The rhGH efficacy and safety were comparable in the patients with PA and the normal course of adrenarche.

Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood.

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 (P < 0.05). In the combined PCOS plus female control group, GCSI correlated negatively with cortisol and testosterone (P < 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.

Premature Adrenarche in Girls Characterized By Enhanced 17,20-Lyase and 17ß-Hydroxysteroid Dehydrogenase Activities.

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 17ß-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3ß-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.