Pauliina Utriainen

Girls with Premature Adrenarche Have Accelerated Early Childhood Growth

OBJECTIVE To evaluate the effect of premature adrenarche (PA) on prepubertal growth. STUDY DESIGN The prepubertal growth of 54 girls with PA and 52 control girls was analyzed retrospectively. Birth measures were noted, and childhood length/height and weight were measured annually until age 5 years and at the current visit (at a median age of 7.6 years). The growth variables were correlated with serum insulin-like growth factor (IGF)-1, dehydroepiandrosterone sulfate, and insulin concentrations. RESULTS There were no significant differences in birth length or weight standard deviation scores (SDSs) between the 2 study groups. The girls with PA demonstrated a significant length SDS increment during the first 2 years of life (median +1.0 SDS; P < .001). Compared with controls, they were taller (median current height 1.2 vs 0 SDS; P < .001) and gained more weight throughout childhood. The difference in weight-for-height became significant at a later age compared with the difference in height. Median serum IGF-1 concentration adjusted for both age and body mass index SDS was higher in the PA group (24 vs 19 nmol/L; P < .031). CONCLUSIONS PA was not associated with small birth size in our population. Girls with PA had enhanced growth already in early childhood, which was not explained by weight gain. Enhanced IGF-1 production may contribute to the prepubertal growth acceleration in PA.

Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche

CONTEXT There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA). OBJECTIVES We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA. DESIGN AND PATIENTS We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). MAIN OUTCOME MEASURES AR gene methylation-weighted CAG(n)(mwCAG(n)) via CAG(n) length and X-chromosome inactivation analysis and clinical phenotype were determined. SETTING The study took place at a university hospital. RESULTS PA subjects had significantly shorter mwCAG(n) than controls [mean difference (95% confidence interval); 0.76 (0.14-1.38); P = 0.017]. AR gene mwCAG(n) did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAG(n) correlated positively with body mass index (BMI) (tau = 0.19; P = 0.02). The mean of mwCAG(n) was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI sd score < 0.79, n = 35, vs. BMI sd score > 0.79, n = 36; 1.13 (0.38-1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004). CONCLUSIONS The AR gene CAG(n) polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.

Premature Adrenarche - A Common Condition with Variable Presentation

Adrenarche refers to a maturational increase in the secretion of adrenal androgen precursors, mainly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In premature adrenarche (PA), clinical signs of androgen action appear before the age of 8/9 years in girls/boys, concurrently with the circulating DHEA(S) concentrations above the usually low prepubertal level. The most pronounced sign of PA is the appearance of pubic/axillary hair, but also other signs of androgen effect (adult type body odor, acne/comedones, greasy hair, accelerated statural growth) are important to recognize. PA children are often overweight and taller than their peers, and the higher prevalence of PA in girls than in boys is probably explained by higher female adiposity and peripheral DHEA(S) conversion to active androgens. PA diagnosis requires exclusion of other causes of androgen excess: congenital adrenal hyperplasia, androgen-producing tumors, precocious puberty, and exogenous source of androgens. PA has been linked with unfavorable metabolic features including hyperinsulinism, dyslipidemia, and later-appearing ovarian hyperandrogenism. Although this common condition is usually benign, PA children with additional risk factors including obesity should be followed up, with the focus on weight and lifestyle. Long-term follow-up studies are warranted to clarify if the metabolic changes detected in PA children persist until adulthood.

Continuum of phenotypes and sympathoadrenal function in premature adrenarche.

OBJECTIVES Premature adrenarche (PA), the early rise in adrenal androgen (AA) production, can manifest with different clinical signs of androgen effect. Premature pubarche defined as appearance of pubic hair before the age of 8/9 years in girls/boys, is the most prominent clinical sign of PA and often erroneously described as a synonym of PA. Our aim was to determine the association of circulating AA concentrations with different prepubertal signs of androgen action (SAA). Secondly, we tested whether adrenomedullary function is altered in children with SAA, as it is in congenital adrenal hyperplasia (CAH) also causing adrenal hyperandrogenism. DESIGN AND METHODS We examined 73 Finnish prepubertal children with any hyperandrogenic sign(s) having appeared before the age of 8/9 years (girls/boys) (35 with pubic and/or axillary hair=PAH; 38 without=nonPAH), and 98 age- and sex-matched controls. Circulating adrenal steroid and catecholamine concentrations were measured and correlated with clinical parameters. RESULTS None of the children with SAA had CAH or virilizing tumor. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione concentrations overlapped between the SAA and control children, and they were lower in the nonPAH than PAH group (P<0.01). SAA children had similar plasma epinephrine but higher norepinephrine (NE) concentrations than their controls (mean (95% confidence interval) 1.61 (1.44, 1.77) versus 1.39 (1.30, 1.49) nmol/l, P=0.03). CONCLUSIONS PA forms a continuum with more pronounced increase in circulating androgens in children with PAH than in those without. Some children show SAA with fairly low androgen concentrations. The clinical significance of elevated NE concentrations associated with SAA needs to be confirmed in further studies.

ACTH receptor promoter polymorphism associates with severity of premature adrenarche and modulates hypothalamo-pituitary-adrenal axis in children.

The genetic mechanisms underlying the regulation of adrenarche are unknown. The aim of the study was to find out whether ACTH receptor (MC2R) promoter polymorphism associates with premature adrenarche (PA) and its characteristics. DNA samples of 74 prepubertal children with PA and their age- and gender-matched 97 healthy controls were genotyped for the −2 bp T/C diallelic MC2R promoter polymorphism (MC2R −2 T>C) All children were examined clinically, and hormonal measurements after an overnight fast and a low-dose ACTH stimulation test were performed. In controls, the baseline ACTH/cortisol ratio was significantly higher (p = 0.002) in subjects with the polymorphism than in the T/T group indicating decreased ACTH sensitivity. The frequency of the MC2R −2 T>C polymorphism was significantly higher in PA children with premature pubarche than in those with milder signs of PA or in control children (p = 0.04). In children with PA, the polymorphism associated with higher baseline serum dehydroepiandrosterone (p = 0.03), androstenedione (p = 0.02), plasma ACTH (p = 0.03) levels and with lower birth weight (p = 0.02). Our study provides evidence that the MC2R promoter polymorphism modulates the hypothalamo-pituitary-adrenal axis in children and may play a role in altered regulation of adrenarche.

Body Composition and Bone Mineral Density in Children with Premature Adrenarche and the Association of LRP5 Gene Polymorphisms with Bone Mineral Density

CONTEXT Precocious increase in adrenal androgen production is the hallmark of premature adrenarche (PA). Adrenal androgens have anabolic properties. OBJECTIVE The objective of the study was to test whether body composition and bone mineral density (BMD) are altered in PA and study whether genetic variation in low-density lipoprotein receptor-related protein 5 (LRP5) affects BMD in PA. DESIGN This was a cross-sectional study. SETTING The study was conducted at a university hospital. SUBJECTS AND MEASURES The study included 126 prepubertal children (64 with PA, 10 boys; 62 non-PA controls, 10 boys). Femoral neck and lumbar spine areal and calculated volumetric BMD (dual energy X-ray absorptiometry), body composition (bioimpedance), serum 25-hydroxyvitamin D, and markers of bone turnover and calcium homeostasis were compared between the PA and control groups. Single-nucleotide polymorphisms of LRP5 were determined and associated with BMD. RESULTS Children with PA had higher femoral neck and lumbar spine BMD(areal) than the controls (Z-score 0.56 vs. -0.09, P < 0.001, and 0.20 vs. -0.31, P = 0.009, respectively). However, the mean BMDs did not differ significantly between the groups when adjusted for height or bone size. BMD(areal) correlated strongly with height sd score in both groups. Among the PA children, LRP5 single-nucleotide polymorphism E644E minor variant was associated with lower and F549F minor variant with higher BMD. Total body fat mass, fat percent, serum PTH, and alkaline phosphatase concentrations were higher and 25-hydroxyvitamin D lower in the PA group. CONCLUSIONS Prepubertal children with PA had higher BMD(areal) compared with healthy controls. This was mainly explained by their increased height. LRP5 polymorphisms may contribute to bone mass accrual in prepubertal PA children.

LRP5 in premature adrenarche and in metabolic characteristics of prepubertal children

Objective  Premature adrenarche (PA) is associated with unfavourable metabolic characteristics. We hypothesized that genetic variation in low density lipoprotein (LDL) receptor‐related protein 5 (LRP5), which is involved in Wnt signalling in the adrenal cortex and in cholesterol metabolism, plays a role in the pathogenesis of PA.

Blood Erythrocyte and Hemoglobin Concentrations in Premature Adrenarche

CONTEXT Premature adrenarche (PA) is characterized by an earlier than normal increase in adrenocortical androgen production, and it is associated with increased serum IGF-I concentrations. Both the GH-IGF system and androgens, particularly testosterone, are known to enhance erythropoiesis. OBJECTIVE Our objective was to test the hypothesis that blood erythrocyte count and blood hemoglobin (B-Hb) concentration are increased in PA. DESIGN, PARTICIPANTS, AND SETTING Sixty-four prepubertal children (10 boys) with clinically and biochemically defined PA and 62 healthy prepubertal controls (10 boys) participating in our Premature Adrenarche study were examined, and a fasting blood sample was drawn at a university hospital. MAIN OUTCOME MEASURES We evaluated B-Hb and erythrocyte, thrombocyte, and leukocyte counts and their association with serum dehydroepiandrosterone sulfate (DHEAS), testosterone and IGF-I concentrations. RESULTS Children with PA had higher mean blood erythrocyte count (4.74 vs. 4.64 × 10(12)/liter, P = 0.04; significant difference in girls but not in boys) and a tendency toward higher B-Hb (130 vs. 128 g/liter, P = 0.06) than their controls. No difference was observed in leukocyte or thrombocyte counts between the study groups. In linear regression models including age, sex, body mass index SD score, IGF-I, and DHEAS or testosterone, B-Hb was associated with serum DHEAS (P = 0.04), testosterone (P = 0.01), and IGF-I (P ≤ 0.003) concentrations in the entire study cohort and with IGF-I separately in girls (P ≤ 0.02). Similar models showed a significant association of blood erythrocyte count with serum IGF-I concentration (P = 0.003-0.049) but not with DHEAS or testosterone. CONCLUSIONS Increased erythrocyte count in PA girls suggests that relatively small increases in serum androgen or IGF-I concentrations during adrenarche may associate with enhanced erythropoiesis.

Impact of childhood obesity treatment on body composition and metabolic profile

BackgroundChildhood obesity is associated with adverse changes in cardiometabolic risk factors. A family-oriented group program stressing a health-promoting lifestyle has been more effective than routine counselling in the treatment of obesity in school children. The aim of the present study was to compare the impact of group program and routine councelling on body composition and metabolic profile, and to evaluate the associations of changes in adiposity with levels of cardiometabolic risk factors.MethodsSeventy obese prepubertal children were randomized into family-oriented group program (15 sessions for parents and children) and routine counselling (2 appointments for children). Body mass index (BMI), body composition and different metabolic risk factors were assessed before and after the 6-month intervention.ResultsWaist/height decreased more in the children attending the group treatment, but there were no significant differences between treatment arms in the changes of metabolic risk factors. When the arms were analyzed as combined, serum triglycerides decreased significantly if BMI standard deviation score (BMI-SDS) decreased ≥0.5. Serum fasting insulin decreased if BMISDS decreased ≥0.25.ConclusionsObesity-related metabolic risk factors reduced in prepubertal children if BMI-SDS decreased substantially. This result was not dependent on which intervention, family-oriented group program or routine counselling, was used.

Serum Anti-Müllerian Hormone Concentrations in Prepubertal Girls with and without Premature Adrenarche: The Influence of Body Mass Index

Background: A connection between premature adrenarche (PA) and polycystic ovary syndrome (PCOS) has been proposed. We investigated whether anti-müllerian hormone (AMH) production is increased in prepubertal girls with PA, as it is in women with PCOS and in their prepubertal daughters. Methods: Fifty-two prepubertal girls with PA and 48 prepubertal age-matched controls were studied. Serum AMH concentrations were determined by a specific ELISA assay and correlated with baseline steroid hormone, GnRH-stimulated LH and FSH, and glucose and insulin concentrations during an oral glucose tolerance test (OGTT). Results: Girls with PA had lower serum AMH concentrations than their controls (2.65 vs. 3.43 ng/ml, p = 0.035). This difference between the study groups vanished when adjusted for BMI SDS score (SDS) or body fat percentage. In the entire cohort, serum AMH concentration was negatively correlated with BMI SDS (r = –0.23, p = 0.019) and androstenedione (r = –0.22, p = 0.03), but not with age, GnRH-stimulated LH or FSH, baseline or OGTT insulin concentrations. Within the control group only, there was an inverse relationship of serum AMH with DHEAS (r = –0.32, p = 0.028) concentrations. Conclusions: Unlike prepubertal daughters of PCOS women, PA girls do not have abnormalities in serum AMH concentrations at prepubertal age.