Disorders of Puberty in Girls.

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.

Obesity and Insulin Resistance, Not Polycystic Ovary Syndrome, Are Independent Predictors of Bone Mineral Density in Adolescents and Young Women.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders that affects females of reproductive age. The characteristic features of PCOS individually have opposing effects on bone mineral density (BMD); however, their cumulative effect on BMD has not been clearly defined. Adolescence and young adulthood span a crucial period in achieving peak bone mass. Thus, a better understanding of the impact of PCOS on BMD in this age group is needed. OBJECTIVES: To determine whether BMD is different between young females with PCOS and controls and to identify factors that influence BMD in this population. METHODS: Data from four cross-sectional studies with a total of 170 females aged 12-25 years with PCOS (n = 123) and controls (n = 47) with a wide range of BMIs (18.7-53.4 kg/m2) were analyzed. Participants had fasting glucose, insulin, and free and total testosterone concentrations measured. HOMA-IR was calculated. Whole-body BMD was assessed by dual-energy X-ray absorptiometry. Multiple regression analysis for predicting BMD included PCOS status, menstrual age, obesity, HOMA-IR, and free testosterone. RESULTS: HOMA-IR and total and free testosterone were significantly higher in PCOS compared to controls but there was no difference in BMD z-score between PCOS (0.8 ± 1.0) and controls (0.6 ± 1.0) (p = 0.36). Obesity (p = 0.03) and HOMA-IR (p = 0.02) were associated with BMD z-score. CONCLUSIONS: Obesity status and insulin resistance, but not PCOS status, were each independently associated with BMD in adolescents and young women who spanned a wide range of BMIs.

Deficits in Bone Geometry in Growth Hormone-Deficient Prepubertal Boys Revealed by High-Resolution Peripheral Quantitative Computed Tomography.

INTRODUCTION: Although growth hormone (GH) is essential for attainment of peak bone mass, bone health in prepubertal children with GH deficiency is not routinely evaluated. The objective of this study was to evaluate bone microarchitecture in GH-deficient (GHD) boys using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Fifteen control and fifteen GHD, GH naïve pre-pubertal boys were recruited for a case-control study at a major academic center. Subjects with panhypopituitarism, chromosomal pathology, chronic steroids, or stimulant use were excluded. Volumetric bone mineral density (vBMD; total, cortical, and trabecular), bone geometry (total, cortical and trabecular cross-sectional area, cortical perimeter), bone microarchitecture, and estimated bone strength of the distal radius and tibia were assessed by HR-pQCT. Areal BMD and body composition were assessed by DXA. Insulin-like growth factor 1 (IGF-1), osteocalcin, C telopeptide, and P1NP levels were measured. RESULTS: GHD subjects had a significantly smaller cortical perimeter of the distal radius compared to controls (p < 0.001), with the difference in cortical perimeter persisting after adjusting for height z score, age, lean mass, and 25-hydroxyvitamin D level (p < 0.05).No significant differences were found in vBMD. No significant differences were found in microarchitecture, estimated strength, areal BMD, body composition, or bone turnover markers. Analysis showed significant positive correlations between IGF-1 levels and cortical parameters. DISCUSSION/CONCLUSIONS: Prepubertal GHD boys had deficits in bone geometry not evident with DXA. Larger prospective/longitudinal HR-pQCT studies are needed to determine the extent of these deficits, the need for routine bone evaluation, and the timing of GH replacement for prevention or restoration of these deficits.

Alterations in Glucose Effectiveness and Insulin Dynamics: Polycystic Ovary Syndrome or Body Mass Index.

BACKGROUND/AIMS: To delineate the relationship of polycystic ovary syndrome (PCOS), obesity, and hyperandrogenism (HA) with glucose and insulin dynamics in adolescents across a broad body mass index (BMI). METHODS: Seventy-four PCOS subjects (aged 16 years) and 82 controls (aged 16 years) were evaluated by an oral glucose tolerance test. Subjects were categorized by BMI: normal weight (21 ± 0.4), overweight/obesity (OO; 33 ± 1.0), and severe obesity (SO; 48 ± 1.4). Indices of glucose and insulin dynamics were determined. Multiple linear regression analysis was used to evaluate the contribution of PCOS, HA, and BMI to these indices. RESULTS: BMI was significantly associated with systolic and diastolic blood pressure and insulin resistance. A significant interaction between BMI and PCOS and indices of post-glucose load was observed. The mean difference in peak glucose, early glucose response, area under the curve for glucose, and glucose effectiveness (SgIo) between PCOS and control subjects was significantly different between OO and SO. In PCOS subjects, testosterone was positively associated with BMI, fasting insulin, early insulin response, and diastolic blood pressure, and negatively associated with SgIo. CONCLUSIONS: Abnormal glucose dynamics in adolescents with PCOS is mainly due to SO. The combination of PCOS and SO has a synergistic effect on glucose dynamics when compared to all other groups.

Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents.

OBJECTIVES: This study aimed to [1] confirm that nonobese adolescents with polycystic ovary syndrome (PCOS) have higher anti-Mullerian hormone (AMH) than controls; [2] examine the relationship of AMH with PCOS features and hormonal profile; and [3] approximate an AMH value that discriminates between adolescents with PCOS and controls. DESIGN: Case-control study. SETTING: Subspecialty ambulatory clinic. PATIENTS: Thirty-one nonobese adolescent girls (age 13-21 years), 15 with PCOS diagnosed using the National Institutes of Health (NIH) criteria and 16 healthy control subjects. Subjects and controls were comparable for body mass index z-score, age and ethnicity. MAIN OUTCOME MEASURE(S): AMH in PCOS subjects and control groups, correlation of AMH with hormonal parameters. RESULTS: AMH was higher in PCOS subjects (4.4±3.4 ng/mL) than in controls (2.4±1.3 ng/mL), when adjusted for menstrual age. In the entire group (PCOS and controls), AMH correlated with androgens, ovarian size and the presence of polycystic ovary (PCO) appearance. There was no difference in average ovarian size between PCOS (7.1±2.6 cm³) and controls (6.7±1.8 cm³). PCOS subjects were 1.49 times more likely to have AMH >3.4 ng/mL (confidence interval 0.98-2.26 ng/mL). CONCLUSIONS: Our data suggest that AMH may be a useful adjunct in the diagnosis of PCOS in adolescents.

Diagnosis and challenges of polycystic ovary syndrome in adolescence.

Although the diagnostic criteria for polycystic ovary syndrome (PCOS) have become less stringent over the years, determination of the minimum diagnostic features in adolescents is still an area of controversy. Of particular concern is that many of the features considered to be diagnostic for PCOS may evolve over time and change during the first few years after menarche. Nonetheless, attempts to define young women who may be at risk for development of PCOS is pertinent since associated morbidity such as obesity, insulin resistance, and dyslipidemia may benefit from early intervention. The relative utility of diagnostic tools such as persistence of anovulatory cycles, hyperandrogenemia, hyperandrogenism (hirsutism, acne, or alopecia), or ovarian findings on ultrasound is not established in adolescents. Some suggest that even using the strictest criteria, the diagnosis of PCOS may not valid in adolescents younger than 18 years. In addition, evidence does not necessarily support that lack of treatment of PCOS in younger adolescents will result in untoward outcomes since features consistent with PCOS often resolve with time. The presented data will help determine if it is possible to establish firm criteria which may be used to reliably diagnose PCOS in adolescents.

Metabolic manifestations of polycystic ovary syndrome in nonobese adolescents: retinol-binding protein 4 and ectopic fat deposition.

OBJECTIVE: To determine whether nonobese adolescents with polycystic ovary syndrome (PCOS) have higher levels of retinol-binding protein 4 (RBP4) and ectopic fat than controls and whether RBP4 and ectopic fat correlate with comorbidities of metabolic disease. DESIGN: Cross-sectional case-control study. SETTING: Pediatric clinical research center based in a quaternary care medical center. PATIENT(S): Twenty-four nonobese adolescents between the ages of 13 and 21 years, 13 with PCOS and 11 controls. INTERVENTION(S): Measurement of RBP4, insulin resistance, lipids, and body composition. MAIN OUTCOME MEASURE(S): Retinol-binding protein 4, reproductive and adrenal hormones, insulin resistance, intrahepatic and intramyocellular lipid levels, and visceral adipose tissue. RESULT(S): Adolescents with PCOS had higher intrahepatic lipid content and a statistical trend for higher RBP4 compared with controls. Retinol-binding protein 4 correlated with body fat, triglycerides, insulin resistance, and androgens but not intrahepatic lipid content; however, when adjusted for body fat, the correlation between RBP4 and triglycerides weakened to a statistical trend and was no longer statistically significant for the other measures. CONCLUSION(S): This small preliminary study of nonobese adolescent girls suggests that RBP4 may be involved in the dyslipidemia associated with PCOS and that there may be an independent relationship between RBP4 and triglycerides but not between RBP4 and insulin resistance. Although intrahepatic lipid content was higher in PCOS, it did not correlate with RBP4, triglycerides, or insulin resistance.

Approach to the girl with early onset of pubic hair.

Premature pubarche, or the development of pubic hair before the age of 8 in girls or 9 in boys, is most commonly caused by premature adrenarche. Adrenarche is the maturation of the adrenal zona reticularis in both boys and girls, resulting in the development of pubic hair, axillary hair, and adult apocrine body odor. Although originally thought to be a benign variant of normal development, premature adrenarche has been associated with insulin resistance and the later development of metabolic syndrome and polycystic ovary syndrome. Although further studies are needed to confirm these relationships, the case presented herein argues for periodic assessment of children at risk. Indeed, recognition of these associations may allow for early preventive measures.

Bone age advancement in prepubertal children with obesity and premature adrenarche: possible potentiating factors.

Obesity and premature adrenarche (PA) are both associated with bone age (BA) advancement of unclear etiology, which may lead to earlier puberty, suboptimal final height and obesity in adulthood. Our objective was to understand the hormonal and anthropometric characteristics of BA advancement in a spectrum of prepubertal children with and without obesity and PA. In this cross-sectional study of 66 prepubertal children (35 PA, 31 control, 5-9 years), BMI z-score, hormonal values and response to an oral glucose tolerance test were the main outcome measures. Subjects were divided into tertiles by BA divided by chronological age (BA/CA), an index of BA advancement. Subjects in the top tertile for BA/CA had the highest dehydroepiandrosterone sulfate (DHEAS), free testosterone (%), hemoglobin A(1C), BMI z-score, and weight (P < 0.05). BMI z-score (r = 0.47), weight (r = 0.40), free testosterone (%) (r = 0.34), and DHEAS (r = 0.30) correlated with BA/CA (P < 0.02). Regression analysis showed greater BA/CA in PA compared to controls after controlling for weight (0.21 ± 0.56, P < 0.004). An exploratory stepwise regression model showed that weight, estradiol, and DHEAS were the strongest predictors of BA/CA accounting for 24% of its variance. Obesity was highly associated with BA advancement in this study of prepubertal children. In addition, children with PA had greater BA/CA at any given weight when compared to controls. These findings suggest a possible hormonal factor, which potentiates the effect of obesity on BA advancement in children with obesity and/or PA.