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.

Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents.

Approximately half of all women with polycystic ovary syndrome (PCOS) are overweight or obese, and studies have reported endocrine and metabolic differences between lean and obese women with PCOS. PCOS has not been as extensively investigated in the adolescent population. The objectives of our study were to further characterize early endocrine and metabolic alterations in adolescents with PCOS and to determine whether differences between nonobese and obese women with PCOS are present early in its course. We studied an ethnically heterogeneous group of 48 adolescents: 11 nonobese with PCOS [age, 16.1 +/- 1.9 yr; body mass index (BMI), 22.5 +/- 1.5 kg/m(2)], 22 obese with PCOS (age, 15.5 +/- 1.4 yr; BMI, 35.9 +/- 6.2 kg/m(2)), and 15 obese controls (age, 14.4 +/- 1.5 yr; BMI, 35.8 +/- 7.1 kg/m(2)). Fasting levels of glucose, insulin, proinsulin, hemoglobin A1c, testosterone, SHBG, Delta4-androstenedione (Delta4-A), dehydroepiandrosterone sulfate (DHEAS), LH, FSH, IGF-I, IGF binding protein-1, free IGF-I, and lipids were measured. Six of the 11 nonobese PCOS subjects, 11 of the 22 obese PCOS subjects, and six of the 15 controls underwent standard oral glucose tolerance testing. The insulin response to the oral glucose tolerance test was measured by the insulin area under the curve (I(AUC120)). Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. The nonobese adolescents with PCOS demonstrated higher levels of LH, SHBG, Delta4-A, DHEAS, dihydrotestosterone, free IGF-I, and high-density lipoprotein, and lower low-density lipoprotein, compared with the obese PCOS group. Fasting levels of insulin and proinsulin, I(AUC120), and log I(AUC120) were higher, and the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index were lower in the obese compared with the nonobese PCOS subjects. Greater levels of LH and androgens, including total and free testosterone, Delta4-A, and DHEAS, and lower SHBG levels were found in the obese PCOS group compared with the obese controls. Adolescents with PCOS manifest clinical, metabolic, and endocrine features similar to those of adult women, and differences between nonobese and obese women with PCOS may be detected in adolescence. Our findings indicate a more pronounced alteration in the hypothalamo-pituitary-adrenal axis in nonobese adolescents with PCOS and a more marked dysregulation of insulin levels and impairment of insulin sensitivity in their obese counterparts. Our data also suggest differences in the IGF system between nonobese and obese adolescents with PCOS.

Generalized acanthosis nigricans in an otherwise healthy young child.

Acanthosis nigricans in children is usually a benign condition most commonly associated with obesity. Generalized acanthosis nigricans is a very rare condition, especially in childhood. We report a 6-year-old boy with a 4-year history of generalized hyperpigmentation and velvety thickening of the skin. Despite an extensive examination, no evidence for an underlying neoplastic or endocrinologic disease was found.

Insulin sensitivity and the insulin-like growth factor system in prepubertal boys with premature adrenarche.

Girls with premature adrenarche (PA), similar to women with polycystic ovarian syndrome, display alterations in the IGF system, may have impaired insulin sensitivity, and demonstrate unfavorable lipid profiles. Girls with PA are also at increased risk for functional ovarian hyperandrogenism. Metabolic studies in boys with PA, however, are limited. The objective of this study was to determine whether boys with PA show alterations in insulin sensitivity and the IGF system. We studied an ethnically heterogeneous group of 19 prepubertal boys: 11 with PA (age, 8.2 +/- 0.7 yr; body mass index (BMI)-Z score, 1.8 +/- 1.1) and 8 controls (age, 7.9 +/- 0.8 yr; BMI-Z score, 1.2 +/- 1.0). Fasting levels of glucose, insulin, proinsulin (P(0)), hemoglobin A1c, testosterone, SHBG, delta4-androstenedione, dehydroepiandrosterone sulfate, LH, FSH, IGF-I, IGF-binding protein-1, IGF-binding protein-3, free IGF-I, and lipids were measured. Ten of 11 boys with PA and six of eight controls underwent standard oral glucose tolerance testing. The insulin response to this test was measured by the insulin area under the curve. Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. All values were adjusted for BMI-Z score. Total IGF-I, P(0), ratio of P(0) and fasting insulin level, and log insulin area under the curve were higher, and SHBG was lower in the boys with PA, compared with controls. Decreased insulin sensitivity was suggested by decreased composite insulin sensitivity index. A trend toward greater triglycerides was observed in the boys with PA, compared with the controls. Prepubertal boys with PA show differences in the IGF system and decreased insulin sensitivity, independent of obesity, as observed in girls with PA. These findings suggest that both boys and girls with PA should be monitored for the development of insulin resistance and associated complications, including diabetes mellitus and cardiovascular disease.

5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activity in prepubertal Hispanic girls with premature adrenarche.

Girls with idiopathic premature adrenarche, characterized by the early appearance of pubic hair and adrenal hyperandrogenism, may be at an increased risk for polycystic ovarian syndrome and its associated complications. Alterations of peripheral metabolism of adrenal steroids, specifically increased 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activities, have been documented in patients with polycystic ovarian syndrome and proposed as an underlying mechanism for the adrenal hyperandrogenism in this syndrome. We sought to investigate whether alterations in 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activities are present in girls with premature adrenarche, suggesting a possible role in the pathogenesis of the hyperandrogenism of this condition. We studied C19 and C21 urinary steroid metabolites, 5 alpha/5 beta and 11 oxo/11 hydroxy metabolite pairs as well as the ratios of the total 5 alpha/total 5 beta and total 11 oxo/total 11 hydroxy metabolites in 24-h urine samples from 17 prepubertal Hispanic girls with premature adrenarche and seven controls. We found no differences in the 5 alpha-reductase or 11 beta-hydroxysteroid dehydrogenase activities in the prepubertal girls with premature adrenarche, compared with the controls. When age and body mass index Z-score were controlled for in the statistical analysis, the results did not change. Total cortisol metabolites were not different in the girls with premature adrenarche, compared with the controls. In conclusion, we did not demonstrate a difference in the peripheral steroid metabolism, specifically 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activities, in prepubertal Hispanic girls with premature adrenarche, compared with controls. Therefore, in this group of young girls, alterations in 5 alpha-reductase or 11 beta-hydroxysteroid dehydrogenase activities do not appear to contribute to their early pubic hair development.

Proinsulin in girls: relationship to obesity, hyperinsulinemia, and puberty.

In adults with impaired glucose tolerance (IGT) and obesity (OB), an elevated proinsulin (PI) is predictive of type 2 diabetes mellitus (DM) and precedes the diagnosis by 5-20 yr. In type 2 DM, the PI is disproportionately elevated, i.e. increased PI/insulin ratio (PI/I). Few studies have evaluated PI in children at risk for type 2 DM. In the face of the current epidemic, we evaluated the relationship of PI and PI/I to IGT, insulin resistance (IR) defined by homeostasis model of assessment (HOMA), degree of OB, and stage of puberty in 70 girls (mean age 10.8 yr; body mass index z-score 3.5; ethnicity 64% Hispanic, 19% white, 16% African-American, and 1% other). Family history of DM was reported in 83%, and acanthosis nigricans was present in 80%. Subjects underwent a 2-h oral glucose tolerance test with glucose, insulin, and PI determinations every 30 min. All had normal hemoglobin A1c and fasting glucose. Five had IGT. With higher HOMA-IR, PI increased (P < 0.05), yet the ratio of fasting PI/I was lower (P < 0.05). Girls with body mass index z-score greater than 4 (n = 29) had higher PI than nonobese girls (n = 19, P < 0.05), but PI/I ratios were not different. PI-0 was increased in late puberty (n = 29), compared with prepuberty (n = 26, P < 0.05), but PI/I ratios showed no statistical difference. We found PI increased with increasing IR and OB in girls. Overall, PI/I was not different, suggesting the elevated PI reflects increased beta-cell output proportional to the elevated insulin in these groups and not a defect in PI processing or secretion. In fact, the lower fasting PI/I of the highest HOMA-IR quartile vs. the lowest HOMA quartile indicates more efficient conversion of PI to I in the presence of increasing IR in these girls.

Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity.

Girls with premature adrenarche (PA) (the onset of pubic hair before the age of 8 yr associated with elevated levels of adrenal androgens and no evidence of true puberty or adrenal dysfunction) may be at increased risk for development of polycystic ovarian syndrome (PCOS). Alterations in the IGF system, including elevated free IGF-I, have been demonstrated in PCOS and may be involved in its pathogenesis. Hyperinsulinemia, elevated total IGF-I, and decreased IGF-binding protein-1 (IGFBP-1) have also been reported in PA. Dysregulation of the IGF system may be involved in the pathogenesis of PA and its progression to PCOS. We compared the insulin/IGF system in 17 prepubertal girls with PA and nine prepubertal controls. Both groups were predominantly obese. Total and free IGF-I were elevated in the premature adrenarche group. No differences in basal insulin, insulin area under the curve in response to an oral glucose tolerance test, or IGFBP-1 were noted. These effects persisted when adjusted for adiposity using body mass index-Z score. Total and free IGF-I were positively correlated, and IGFBP-1 was negatively correlated with Delta4-androstenedione, but not with dehydroepiandrosterone sulfate. Free IGF-I trended toward higher levels in the insulin-resistant subgroup, compared with the insulin-sensitive subgroup. These results suggest altered regulation of the insulin/IGF system in prepubertal girls with PA and a possible role for free IGF-I in the pathogenesis of the hyperandrogenism of PA as well as its progression to PCOS.