Hyperandrogenemia in Obese Peripubertal Girls: Correlates and Potential Etiological Determinants

Abstract

IntroductIonPolycystic ovary syndrome (PCOS) may be the most common endocrine disorder of young women, affecting ~7% of women in their reproductive years (1). Hallmarks of PCOS include ovarian hyperandrogenemia (HA) and ovulatory dysfunction (2,3). The etiology of PCOS remains unclear, but hyperinsulinemia, neuroendocrine abnormalities (e.g., exaggerated luteinizing hormone (LH) secretion), and primary abnormalities of ovarian steroidogenesis have all been proposed as causes (4-6).Manifestations of PCOS often begin soon after menarche, and HA during adolescence can be a precursor of adult PCOS (7,8). However, the cause(s) of adolescent HA is (are) unclear. Obesity is a well-recognized factor in the HA of adult PCOS (9); and some (10-12) but not all (13) studies suggest that obesity is linked to HA in peripubertal girls. Therefore, obesity during the pubertal transition may be an important factor contributing to adolescent and adult PCOS (14). Although mechanisms underlying the relationship between peripubertal obesity and HA remain uncertain, early data suggest that differences of insulin and LH contribute to free testosterone (T) differences between obese and nonobese girls (11,12).Of special interest, not all peripubertal obese girls demonstrate elevated free T (12,13), suggesting that obesity per se is not sufficient to produce HA. Herein we present data that demonstrates marked variability of free T among obese girls. Furthermore, to assess potential determinants of free T elevations in obese girls, we evaluated the relationship between free T and both fasting insulin and morning LH, while simultaneously adjusting for differences in age, pubertal development, and gender-specific BMI z-score. Our primary hypotheses were that insulin and LH would be independent predictors of free T levels in obese girls. Methods and Procedures subjectsOur collaborative group collected hormonal and anthropometric data from obese girls across the pubertal spectrum. Volunteers were recruited from Endocrinology Clinics and via local advertisements and evaluated at the University of Virginia (n = 61), the University of California at San Diego (n = 8), and Yale (n = 23). Gender-specific BMI-for-age percentile (BMI%) and BMI z-score was calculated for each participant using a SAS program incorporating normative data from the National Health and Nutrition Examination Surveys

Reproductive alterations in hyperinsulinemic but normoandrogenic MSG obese female rats

“…It has been reported that LH is the main inductor of ovarian androgen production (Knudsen et al 2010), whereas hyperinsulinemia contributes to roughly 20% of serum testosterone levels (Azziz et al 2001, Norman et al 2002, Creanga et al 2008. In humans (Tosi et al 2012) and animal MetS models (Newell-Fugate et al 2014, Wu et al 2014b, hyperinsulinemia is able to cause elevation of LH secretion with consequent hyperandrogenemia, as hypothalamic nuclei structures are intact.…”

Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys

“…Like adults with PCOS, obese girls with HA have increased levels of LH and decreased sensitivity to P 4 negative feedback (22,49). In late puberty, girls with obesity reportedly have increased frequency of pulsatile LH release compared with nonobese girls (57).…”

The Ratio of Parathyroid Hormone to Vitamin D Is a Determinant of Cardiovascular Risk and Insulin Sensitivity in Adolescent Girls

“…36 The association between free testosterone and insulin resistance in the lean cohort (on correlation analysis) and the combined cohort (on regression modeling) is a relatively novel finding in adolescent girls without phenotypic features of polycystic ovary syndrome (PCOS). In female obesity and PCOS, associations between hyperinsulinism, elevated androgen, and decreased SHBG are well known, 37,38 but the relevance of androgen levels to glucose homeostasis in lean girls without PCOS has not been investigated comprehensively. Lean hyperandrogenic young women have higher measures of insulin resistance than lean normoandrogenic women, and it is possible that positive associations of androgens with measures of insulin resistance exist even when androgens are in a normal range.…”