Measurement of 11-Oxo-Androgens, A Novel Biomarker, in Females with Clinical Signs of Premature Adrenarche.

Introduction: Premature adrenarche in girls is defined biochemically by an increase in adrenal androgen (DHEAS) levels above the age-specific reference range before age 8 years. Recently, increased levels of 11-oxyandrogens have also been reported in girls with premature adrenarche. Epigenetic modifications, specifically CpG methylation, may affect gene expression and/or activity of steroidogenic enzymes during developmental changes in adrenal androgen secretion. Objective: The aim of the study was to determine whether circulating 11-oxyandrogen levels in post-menarcheal girls are associated with the methylation status of genes involved in 11-oxyandrogen steroidogenesis. Methods: Ninety-seven healthy girls followed since the age of 3 years were classified, according to DHEAS serum concentration at age 6–7 years, as normal DHEAS (<42 μg/dL [75th percentile for population]) or high DHEAS (≥42 μg/dL). At Tanner stage 2, the methylation status of CpG sites located in CYP11B1 and HSD11B2 genes was analyzed in genomic DNA from peripheral blood leukocytes by the melting curve analysis methylation assay. Eleven-oxyandrogen concentrations were assessed at 4 years post menarche. Results: Significantly lower methylation levels were detected in the CYP11B1 gene in girls with high versus normal serum DHEAS levels, with no differences found in HSD11B2 gene. Additionally, CYP11B1 methylation status correlated inversely with 11β-hydroxy-androstenedione and 11-ketotestosterone levels. Furthermore, CYP11B1 methylation in the full cohort correlated inversely with insulin concentration at Tanner 1 and with body mass index at Tanner stage 1 and 2. Conclusion: This pilot study proposes the hypothesis that a lower methylation of CYP11B1 may be a mechanism contributing to increased concentrations of 11-oxyandrogens in premature adrenarche and its associated metabolic risk.

Premature adrenarche (PA) is linked to prematurity, small for gestational age (SGA), and rapid weight gain. Understanding these factors is important for early identification and management of PA. To evaluate the impact of prematurity, SGA, obesity, and rapid weight gain on the development of PA in Turkish girls. A retrospective review of medical records from girls diagnosed with PA between 2015 and 2020. A total of 104 girls diagnosed with PA were included. Clinical data, including birth weight, gestational age, body mass index (BMI), and hormone levels (DHEA-S), were analyzed. The relationships between PA and prematurity, SGA, obesity, and rapid weight gain (delta weight SDS) were assessed. Of the 104 patients, 14.4% were born prematurely, 28.8% were SGA, and 30.5% were overweight or obese. A positive correlation was observed between delta weight SDS and DHEA-S levels (r=0.523, p<0.01). While obesity was not significantly associated with elevated DHEA-S levels, rapid weight gain was a key factor. Prematurity and SGA are significant risk factors for PA, with rapid weight gain playing a critical role. Monitoring weight gain in SGA and premature infants is essential to mitigate PA-related risks.

ObjectiveThe 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.MethodsNinety-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).ResultsAmong 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).ConclusionA 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.

Association between 2D:4D digit ratios and metabolic markers and hormonal parameters in children with premature adrenarche: A cross-sectional study from Türkiye.

Premature adrenarche is a condition characterized by precocious development of pubic and/or axillary hair, due to early onset of adrenal androgen secretion. Girls with premature adrenarche may later develop menstrual irregularities, hyperandrogenism, and the classic polycystic ovary syndrome. As leptin is thought to modulate the onset of pubertal development, we measured plasma leptin levels in 7 girls with premature adrenarche, and 8 age-matched comparison girls. Because leptin, the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-gonadal axes are functionally interrelated, we also determined salivary and plasma cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, estradiol, and estrone. Finally, since IGF-I may play a role in adrenocortical function, we determined plasma levels of IGF-1, and IGF-BP1. Plasma was collected by an intravenous catheter at times 0, 20, and 40 min, starting at 1.30 p.m. Girls with premature adrenarche had a higher body mass index (BMI) and an over two-fold elevation of their plasma leptin than comparison girls. This group also had elevated levels of salivary and plasma cortisol, and increased levels of DHEA, DHEA-S, androstenedione, estradiol and estrone. Plasma IGF-1 and the ratio of IGF-1/IGF-BP1 were elevated. We propose that girls with premature adrenarche may represent an overlapping group characterized by both features of increased adiposity and HPA axis activity, which together, and depending on the genetic/constitutional background of the individual, may account for the development of adrenal hyperandrogenism, and, later, the polycystic ovary syndrome.

Although premature adrenarche (defined as precocious appearance of pubic or axillary hair) is more common in African-American girls, ethnic differences in adrenal androgen secretion in normal prepubertal girls have not been described. We examined ethnic differences in circulating serum levels of DHEA-S, IGF-1, IGFBP-1 and -3, and insulin in healthy prepubertal [Tanner stage I] Caucasian, African-American and Hispanic girls. Body fat was determined by dual-energy x-ray absorptiometry. Forty-seven girls (19 Caucasian, 9 African-American, 19 Hispanic) between the ages of 7.5 and 9 yr were enrolled. Age, weight, height, insulin, glucose-insulin ratios, and IGFBP-3 levels were not statistically different among groups. Body mass index and% fat were higher in Hispanic girls (p<0.017; p<0.004, respectively) but not different between African-Americans and Caucasians. Despite similar insulin levels among groups, IGFBP-1 levels were higher in Caucasian than in Hispanic (p<0.002) and African-American (p<0.0001) girls. DHEA-S levels in the African-Americans were twofold higher than in the Caucasians(p<0.004), despite the fact that African-Americans and Caucasians were equally lean (16.1% vs 19.4% body fat; p=0.138), whereas those of Hispanics were intermediate. Plasma IGF-I levels also were higher in African-Americans than in Caucasians (319 ng/ml vs 219 ng/ml; p<0.02) while no significant difference was seen between the Caucasians and Hispanics. Conclusions: (1) In African-American girls, DHEA-S concentrations are higher than those of Caucasian girls, even without clinical evidence of premature adrenarche; (2) These ethnic differences are unrelated to body fat or insulin resistance; (3) Elevated DHEA-S and IGF-I levels in African-American girls may be indicative of an influence not only of gonadal but also of adrenal steroids on the GH/IGF-I axis.

21 The adrenocortical hormone Dehydroepiandrosterone (DHEA) represents not only a precursor for sex steroids but mediates also anabolic, antiglucocorticoid, antidepressive and immunoregulatory effects. Recently, Wiesniewski et al. reported on a correlation between DHEA-S serum levels and CD4 T-cell counts in HIV-infected patients. There was an inverse relation between disease progression and DHEA-S levels. Therefore, we were interested in the regulation of DHEA-S serum levels in long-term transplant patients. We speculated that low DHEA-S levels may be associated with a strong immunocompromised situation and, as a result of this, with a good graft function. DHEA-S levels were determined in the plasma of 89 renal and 8 renal/pancreas long-term transplant patients (mean: 59 months post Tx) by a commercially available immunoassay (DPC-Immulite). Additionally, plasma cortisol, ACTH and surface expression of T-cell activation markers on peripheral blood lymphocytes were investigated in a subgroup of 18 patients. Beside the known influence of age and sex we have found diminished DHEA-S levels in nearly all patients with a mean of 1.60 µmol/l (normal range: 0.95-15.6) which was correlated with the time post-Tx (r= -0.23, p<0.05). To exclude the influence of age and sex we have transformed absolute DHEA-S levels to percent of the expected value. In contrast to our hypothesis, there was a statistically significant negative correlation between DHEA-S levels and both serum creatinine (r= -0.34, p<0.01) and urea (r= -0.32, p<0.01) levels. Interestingly, we could not see any relation between levels of DHEA-S and plasma ACTH/cortisol which were normal in the majority of patients. Furthermore, there was no relation between flowcytometric signs of T-cell activation (high expression of CD25, CD71, HLA-DR) and DHEA-S levels. Our results indicate that diminished levels of DHEA-S in long-term renal transplant patients are not due to adrenocortical insufficiency. The association between low DHEA-S levels and poor graft function may result from chronic (intragraft) inflammation-induced or stress-induced downregulation of DHEA-S secretion. However, the pathophysiological relevance of diminished DHEA-S levels for long-term outcome remains unknown.

The magnitude of adrenal versus ovarian or peripheral contributions to the hyperandrogenemia of polycystic ovarian syndrome (PCOS) is controversial. Evidence for an adrenal origin of circulating androgens has been studied in prepubertal, adult, and postmenopausal women who will have, do have, or have had PCOS. Many girls who have premature adrenarche with increased circulating levels of adrenal steroid DHEA-S or those diagnosed with precocious puberty go on to develop PCOS in adolescence. Some adults with PCOS demonstrate increased DHEA and DHEA-S levels after ACTH stimulation test. Alternatively, or in addition, in many women with PCOS who have elevated DHEA or DHEA-S, these steroids may be suppressed by exogenous corticosteroid administration. In some PCOS women (20 %), long-term suppression of ovarian steroidogenesis to castrate levels with the use of GnRH agonists fails to suppress hyperandrogenemia, suggesting an adrenal source. Approximately 30–50 % of PCOS patients can be shown by these maneuvers to be producing excessive amounts of adrenal androgens. Increased activity of P450C17α can contribute to excessive production of both adrenal (DHEA) and ovarian (androstenedione) androgens. Alternatively, excess androgen production may occur as an ancillary phenomenon during processes that can result in cortisol overproduction (e.g., Cushing syndrome) or increased degradation of cortisol. The normal decline in adrenal androgen production with menopause is blunted in women who have PCOS and postmenopausal women with a history of PCOS demonstrate an exaggerated androgen response to exogenous ACTH. While the exact mechanisms remain unclear, these observations suggest that adrenal steroidogenesis may be under different control in women with PCOS.

Study ObjectiveDehydroepiandrosterone (DHEA) and its sulfated form (DHEAS)—jointly referred to as DHEA(S)—are neurosteroids known to regulate brain development and function that have been found to be positively correlated with cognitive function. It is unknown whether prechemotherapy plasma DHEA(S) levels are associated with the onset of cancer‐related cognitive impairment (CRCI). The objective of this study was to evaluate whether an association exists between prechemotherapy plasma DHEA(S) levels and onset of CRCI in patients with breast cancer receiving chemotherapy.DesignMulticenter, prospective cohort study.SettingTwo specialized cancer centers in Singapore.PatientsEighty‐one patients with early‐stage breast cancer (stages I–III) who had no prior exposure to chemotherapy and/or radiotherapy and were scheduled to receive anthracycline‐based or taxane‐based chemotherapy treatment with curative intent.Measurements and Main ResultsPatients completed assessments for self‐perceived and objective cognitive function at three time points: prechemotherapy (T1), during chemotherapy (T2), and after chemotherapy (T3). Plasma samples were collected prior to chemotherapy, and DHEA(S) levels were quantified by using ultra–high‐performance liquid chromatography–tandem mass spectrometry. Multivariable logistic regression was used to adjust for clinically important factors and to evaluate the association between prechemotherapy plasma DHEA(S) levels and CRCI. Mean ± SD age was 48.9 ± 9.3 years, with 27.8% of patients experiencing clinically significant cognitive impairment based on global Functional Assessment of Cancer Therapy–Cognitive Function scores. The mean ± SD prechemotherapy plasma DHEAS and DHEA levels were 1.61 ± 0.91 μmol/L and 19.21 ± 13.13 nmol/L, respectively. Prechemotherapy DHEAS levels were found to be associated with impairment in the self‐perceived cognitive domains of verbal fluency (adjusted odds ratio [OR] 0.27, 95% confidence interval [CI] 0.08–0.96) and mental acuity (adjusted OR 0.25, 95% CI 0.08–0.74). Conversely, DHEA levels were not associated with impairment in any cognitive subdomains.ConclusionOur findings suggest that patients with higher prechemotherapy DHEAS levels had lower odds of developing self‐perceived cognitive impairment. Future studies are required to further investigate the effect of DHEA(S) on specific cognitive domains and to validate our findings in independent cohorts.

Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.

Background: Premature adrenarche (PA) is characterized by presence of isolated pubic and/or axillary hair, acne and body odor before age 8(9) in girls (boys). These individuals are at increased risk of developing insulin resistance, metabolic syndrome and polycistic ovarian syndrome. Irisin seems to have an active role in the metabolism of carbohydrates and lipids, however little is known about this hormone in PA.Objective: To analyze irisin levels in children diagnosed with PA and its relationship with their body composition.Methodology: Exploratory cross-sectional study that evaluated 15 children with PA and 15 matched controls (C). Anthropometric data were measured: height, weight, waist circumference (WC) and triceps skinfold. Fasting blood glucose(G), insulin(I), 17OHP, total cholesterol, LDL, HDL, triglycerides, DHEA-S, 25(OH)D and irisin levels were determined.Results: The levels (mean±SEM) of triglycerides [99±14, 8mg/dl (C); 68±9, 1mg/dl (AP)] and 25(OH) D [26±0, 9ng/ml(C); 30.2±1.6ng/ml (AP)] were significantly different between the groups. WC above p90 and G/ I&lt;7 were found in 6.7% of the C group versus 33.3% and 20% of the PA group, respectively.Conclusions: PA children presented a lower G/I and a higher waist WC compared to the C group, suggesting an increased risk of metabolic disease. Irisin levels were not different between the groups. The significantly higher levels of TGs from the C group may be related to their reduced levels of 25(OH) D, which may also have masked differences in irisin levels. This study suggests that determination of vitamin D levels may be necessary to evaluate metabolic data, based on the significant frequency of this hormone insufficiency/deficiency in the pediatric population.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by dysmorphic features, obesity, hypogonadism, hypotonia and mental retardation. Obesity has been linked to insulin resistance and the latter has also been associated with premature adrenarche. Since up to date a controlled study to investigate adrenarche and its hormonal regulation was lacking in PWS, our aim was to assess whether prepubertal PWS patients develop premature adrenarche and its relationship with markers of insulin sensitivity. Fourteen prepubertal children with PWS (6 M, 8 F) and 10 non-syndromal simple obese matched controls (5 M, 5 F) participated (mean age: 7.62 ± 1.84 years). A fasting blood sample was obtained for adrenal and ovarian androgens, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1, leptin, adiponectin and a lipid profile. Thereafter an oral glucose tolerance test was performed. PWS patients were smaller at birth and a higher proportion displayed premature pubarche. No differences were found in testosterone, androstenedione, sex hormone binding globulin, free androgen index, homeostatic model assessment-IR, 2-hour insulin, leptin or adiponectin levels. 17-hydroxyprogesterone and DHEAS levels however, were significantly higher in PWS. IGF-I levels were significantly lower in PWS and correlated significantly with height SDS (p < 0.05). In conclusion, a higher proportion of premature adrenarche in our PW patients was observed, which was not explained by differences in insulin sensitivity or plasma levels of adipokines and IGF-I.

Disclosure: V.M. Figueredo: None. T. Seeherunvong: None. Background: Precocious puberty is typically associated with a speed up in growth, risk of premature growth plate closure and reduced adult height. Serum alkaline phosphatase (ALP) is a biochemical indicator of bone turnover and studies have shown greater serum ALP levels in pubertal individuals compared to prepubertal controls. We examined serum ALP levels among children with various form of early puberty. We investigated whether serum ALP levels were significantly different between children with premature thelarche or premature adrenarche compared to those with central precocious puberty (CPP). Methods: We conducted a retrospective chart review of patients with early pubertal development attending a pediatric endocrinology clinic between 2017 and 2023. Information on height, weight, serum ALP levels and bone age was obtained. Patients were considered to have CPP based on the results on a GnRH test. Patients with diagnosis of premature adrenarche or premature thelarche were included as controls. This study was approved by Institutional Review Board (IRB). Analysis of data was performed using IBM SPSS Statistics version 29.0.1.0 (171). Results: Among 72 patients included in the study, 22 patients had progressive CPP whereas 50 patients had premature adrenarche or premature thelarche. The prevalence of abnormally elevated serum ALP levels was greater among patients with CPP (22.7%) than among patients with premature adrenarche or premature thelarche (6%). Using logistic binomial regression analysis, serum ALP levels were significantly elevated (p=0.042) in subjects with progressive CPP compared to patients with premature adrenarche or premature thelarche. Both groups had similar BMI values. BMI z-scores and advanced bone age were positively correlated. BMI (p=0.08) and advanced bone age were not significantly different (p=0.12) in the group with CPP compared with the group comprising patients with either premature adrenarche or premature thelarche. Conclusion: These findings suggest that serum ALP levels are helpful as a tool to help distinguish CPP from premature adrenarche or premature thelarche in the evaluation of patients with initial early pubertal development. Presentation: 6/1/2024

The relationship between biochemical premature adrenarche (PA) in girls and metabolic alterations during puberty it is well described. A part of these circulating androgens undergoes aromatization in peripheral tissues to estrogens. This raises the question whether the metabolic effects are due to the action of androgens or estrogens. Our aim was to assess whether levels of urinary estrogens are associated with metabolic risk at late stages of puberty in girls with and without PA. This prospective observational study included 321 girls from the Growth and Obesity Chilean Cohort Study (GOCS). Anthropometric and biochemical variables included in metabolic syndrome score (MetS) were measured along with urinary estrogens at Tanner stage B4, 1-year (M1) and 4-years after menarche (M4). Relationships between urinary estrogens and metabolic syndrome were analyzed during these periods. Furthermore, we analyzed whether metabolic disturbances in patients with biochemical PA (based on DHEA-S levels at age ~7) were mediated by androgens or estrogens. In multilevel analysis urinary estrone correlated positively with anthropometric variables (BMI, WC and fat percentage) and MetS score in adolescent girls. In contrast, urinary estradiol was not associated with metabolic risk. Interestingly, urinary estrogens were not associated with metabolic score in patients with biochemical PA. Our investigation suggests that metabolic risk in patients without biochemical PA are mostly associated with estrone levels. In contrast, in patients with biochemical PA, androgens are associated with MetS. Therefore, metabolic disturbances throughout puberty might be generated by different pathways in girls with and without biochemical PA.

Aetiological factors affecting the phenotype of adrenarche are largely unknown. This study investigated the phenotypic variability of premature adrenarche. In this cross-sectional retrospective registry study, data on 91 mainly Caucasian children diagnosed with premature adrenarche were retrieved from patient records. Hormonal and growth-related variables were analysed, and the data were further divided into subgroups to explore variations in different phenotypes of premature adrenarche. We studied 91 children with premature adrenarche (23% boys) with median ages of 7.5 years (range 4.5-8.9) for boys and 6.8 years (4.3-8.0) for girls. They displayed increased height and weight, elevated androgen levels, and clinical signs of androgen action. Bone age was advanced by approximately 1 year, with overweight children showing more advanced bone age and linear growth. Adult heights predicted with bone age were comparable to mean parental heights. Girls with more advanced bone age had higher dehydroepiandrosterone sulfate (DHEAS) levels. Interestingly, early (< 6 years) diagnosed children exhibited higher height standard deviation scores but lower DHEAS levels compared to those diagnosed later (≥ 6 years). Despite advanced bone age, predicted adult heights remained normal in premature adrenarche. Subgroup differences suggested the heterogeneity of aetiological factors in premature adrenarche.