Hyperandrogenemia In Girls Research Articles

OR15-1 Obesity is Associated with Adolescent Hyperandrogenemia in Girls Aged 6-18, National Health and Nutrition Examination Survey (NHANES) 2013-2016

Abstract Background Peripubertal hyperandrogenemia (HA) often represents a forerunner to adolescent/adult polycystic ovary syndrome (PCOS), but risk factors for peripubertal HA are unclear. Studies have associated obesity with HA throughout puberty (e.g., McCartney, JCEM 2007;92: 430-436, Knudsen, Obesity 2010;18: 2118-2124). However, these studies were performed in academic centers and could have been influenced by recruitment bias. We therefore investigated if there was a difference in calculated free testosterone (T) levels between girls with healthy weight and those with obesity in a nationally-representative U.S. sample. Methods We analyzed data for 1,196 girls aged 6–18 years from the National Health and Nutrition Examination Survey (NHANES) 2013-2016 databases, utilizing a cross-sectional study design. We calculated free T from total T and sex hormone-binding globulin (Vermuelen equation). We divided girls into 3 groups by age, based on presumed pubertal stages: "Pre-/Early" (6–9 years), "Middle" (10–14 years), and "Late" (15–18 years). Each individual was also categorized as healthy-weight (BMI-for-age percentile 5-85) or obese (BMI-for-age percentile ≥95). We analyzed mean free T concentrations by weight status (healthy-weight vs. obese) for each age group by calculating population estimates. We also performed survey-weighted regression analysis to assess the relationships between weight status and age category (independent variables) and free T (outcome). Results Among Pre-/Early girls, free T was 0.33 pg/ml (0.28-0.38) [mean (95% CI)] for healthy-weight vs. 0.86 pg/ml (0.67-1.05) for obese. Among Middle girls, free T was 2.53 pg/ml (2.27-2.78) for healthy-weight vs. 4.35 pg/ml (3.75-4.95) for obese. Among Late girls, free T was 3.33 pg/ml (2.96-3.70) for healthy-weight vs. 5.64 pg/ml (4.93-6.36) for obese. (Notably, in each age group, the 95% CIs for free T did not overlap between healthy-weight vs. obese subgroups). Mean free T increased with advancing age in both healthy-weight and obese groups, especially between Pre-/Early and Middle age ranges (Pre-/Early-to-Middle differences were 2.20 pg/ml for healthy-weight and 3.49 pg/ml for obese). Our regression model accounted for 45% of the variance in free T (R2=0.45). Both weight status (obese vs. healthy-weight) and age group were independent predictors of free T concentrations (p<0.0001 for both). When adding an age-in-months-by-BMI-percentile interaction term, the model R2 value was 0.47, with age category, weight category, and the interaction term all being independent predictors of free T (p<0.001 for all). Conclusion We conclude that obesity is associated with higher free T levels in U.S. girls aged 6–18 years. Age also predicts free T, likely reflecting increases related to pubertal maturation, and free T differences according to weight status are more prominent in older girls. This study in a nationally-representative sample of U.S. girls supports previous analyses of girls studied at academic centers, further suggesting an important relationship between obesity and peripubertal androgen excess. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Ambient Circulating LH, but Not Insulin, Predicts Rise in Testosterone Levels After Recombinant hCG in Girls With Obesity

Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance. Adolescent hyperandrogenemia (HA) may precede adult PCOS. Androgen production in females occurs in both the adrenals and the ovaries, but the relative contribution of each to adolescent HA is unknown. Both luteinizing hormone (LH) and insulin contribute to HA in adult PCOS, and both correlate with HA in obese girls, but detailed assessments of LH and insulin in combination with ovarian and adrenal androgen responses to stimulation (in the same individual) have not been described. To assess the relative roles of stimulatory factors (LH and insulin) and end organ (adrenal, ovarian) responsiveness to stimulation, we have studied 16 girls with obesity: age 13.4 (10.5–15.9) y (median [range]); Tanner 5 (2 girls 2-3; 14 girls 4-5); BMI Z 2.2 (1.7–2.7); free testosterone (T) 17.7 (6.6–88.3) pmol/L. Subjects underwent a detailed study including (a) frequent blood sampling for LH (6p–9a), to estimate mean 24-h LH; (b) sampling for insulin from 1 h before to 2 h after a standardized mixed meal (7p) and while fasting (7a–9a), to estimate mean 24-h insulin; (c) an adrenal stimulation protocol (dexamethasone [DEX] given at 10p, with 17-OHProgesterone [17OHP], T, and androstenedione (∆4A) drawn before plus 30 and 60 min after synthetic ACTH [250 mcg iv] given at 7a); and (d) an ovarian stimulation protocol (after the 8a sample above, recombinant hCG [r-hCG, 25 mcg iv] given, DEX given at 10p, with 17OHP, T, and ∆4A drawn the next morning at 8a). Responses to ACTH and r-hCG stimulation were defined as the mean value 30 and 60 min post-ACTH and the value 24 h post-hCG, respectively, minus the post-DEX morning value. Relationships between such responses and estimated mean 24-h LH and 24-h insulin were assessed using Spearman partial correlation (correcting for differences in 24-h insulin and 24-h LH, respectively). Estimated 24-h LH was 3.7 (1.8–21.5) mIU/mL in the group, while estimated 24-h insulin was 61.4 (23.2–175) uIU/mL. After correcting for differences in 24-h insulin, estimated 24-h LH predicted hCG-stimulated changes in T (r = 0.61, p = 0.02), but did not predict ACTH-stimulated changes in T. When corrected for 24-h LH, there were no significant relationships between estimated 24-h insulin and T responses to either r-hCG or ACTH. Estimated 24-h LH and 24-h insulin were not correlated with ACTH- or hCG-stimulated changes in either 17OHP or ∆4A. These data suggest that, in pubertal girls with obesity, either that ovarian T responses to stimulation are influenced by ambient LH concentrations, but not by insulin, or that ovarian hyperresponsiveness leads to increased LH. Similar relationships with 17OHP or ∆4A were not evident, for either ambient LH or insulin. Simultaneous detailed assessments of LH, insulin, and end organ (adrenal, ovarian) responsiveness to stimulation may help discriminate the determinants of HA in girls with obesity.

The role of LCPUFA-ω3 on the obesity-associated hyperandrogenemia of pubertal girls: secondary analysis of a randomized clinical trial.

Introduction Hyperandrogenism (HA), either clinical or biochemical, is associated with obesity in adolescent girls. Long chain polyunsaturated fatty acids ω3 (LCPUFA-ω3) play protective roles in some obesity-associated morbidities, but their contribution to preventing HA is unclear. Our aim was to examine the potential positive relationships between erythrocyte LCPUFA-ω3, with or without supplementation, and hyperandrogenemia. Methods Secondary analysis of a clinical trial that was conducted previously to analyze the effect of LCPUFA-ω3 on insulin resistance and body weight. Here, we present a cross-sectional analysis of 180 girls with obesity, and a longitudinal analysis of 117 girls who completed a 3-month supplementation period (57 LCPUFA-ω3 [DO3] and 60 placebo [DP)]). Dehydroepiandrosterone sulfate (DHEAS), total testosterone (TT) and steroid hormone binding globulin (SHBG) were measured with chemiluminescence; free testosterone (FT) was calculated. Erythrocyte fatty acids were determined by gas chromatography. Non-parametric statistics was used for analysis. Results In cross-sectional analysis, age (odds ratio [OR] = 1.35; 95% confidence interval [CI] = 1.03, 1.78; p = 0.027), insulin (OR = 1.05; 95% CI: 1.00, 1.10; p = 0.018), and erythrocytes eicosapentaenoic acid (EPA) (OR = 0.04; 95% CI: 0.01, 0.65; p = 0.012) were predictors of hyperandrogenemia (FT >0.63 ng/mL). In longitudinal analysis, EPA, adiponectin and SHBG increased, while FT decreased, in the DO3 group (p < 0.05). The risk of hyperandrogenemia at the end of follow-up was predicted by basal hyperandrogenemia (OR = 18.16, 95% CI: 5.37, 61.4; p < 0.001) and by increases in EPA (OR = 0.40; 95% CI: 0.01, 0.65; p = 0.06 marginal significance). Conclusions Our results suggest a preventive role of EPA on the risk for hyperandrogenemia in girls with obesity, but further studies are needed to demonstrate a benefit.

What is adolescent polycystic ovary syndrome?

The diagnostic criteria for adolescent polycystic ovary syndrome (PCOS) has been derived from adult criteria, which makes diagnosis challenging as criteria include normal physiological events that occur during puberty such as acne, hirsutism, menstrual irregularities, high androgen levels and polycystic ovarian morphology on pelvic ultrasound. The only criteria that applies from the adult criteria is exclusion of other conditions that mimic PCOS. Clinical findings consistent with hyperandrogenaemia during adolescence include inflammatory acne, hirsutism, alopecia and/or menstrual irregularities, which are severe and present 2 years after menarche. The measurement of androgen levels during adolescence should take into account age, puberty, type of androgen measured, assay used and diurnal rhythm. Multiple measurements are useful to demonstrate hyperandrogenaemia. The combination, severity and persistence of the hyperandrogenic symptoms and hyperandrogenaemia in girls 2 years or more post-menarche support the diagnosis of adolescent PCOS. Adolescent girls with these findings should be followed up into adulthood.

High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles

To compare the pubertal development, the hormonal profiles and the prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus (T1DM). Data were collected from 96 obese adolescent girls and 78 adolescent girls with T1DM at Tanner stage IV or V, whose ages ranged between 11.9 and 17.9 years. High prevalence of hirsutism and menstrual disorder was found in the obese adolescent girls (36.5 and 42% respectively) and the adolescent girls with T1DM (21 and 44% respectively). The obese girls were significantly younger at pubarche, thelarche and menarche than the girls with T1DM. Hirsutism in the obese girls and those with T1DM was associated with hyperandrogenaemia and a raised free androgen index (FAI). When the cause of the raised FAI was investigated in both the groups of girls with hirsutism, the raised FAI in the obese girls was due to low serum sex hormone-binding globulin (SHBG) levels. In contrast, the raised FAI of the girls with T1DM and hirsutism was due to hyperandrogenaemia. Menstrual disorders in the T1DM girls were associated also with hyperandrogenaemia unlike obese girls. Hirsutism and menstrual disorders are common in obese adolescent girls and adolescent girls with T1DM. Although hyperandrogenaemia is present in both groups of girls, the androgenic profiles of the two groups differ. The hyperandrogenaemia in the obese girls is primarily due to their decreased serum SHBG levels, whereas the hyperandrogenaemia in the girls with T1DM is due to their increased androgen production.