Etiological Factors of Obesity-Associated Hyperandrogenemia in Peripubertal Girls
Etiological Factors of Obesity-Associated Hyperandrogenemia in Peripubertal Girls
The purpose of this study is to learn if obese pre- and early pubertal girls with
 hyperandrogenemia (HA) are more insulin resistant (i.e., have lower insulin-stimulated
 glucose disposal) compared to obese peripubertal girls without HA; and that overnight mean
 luteinizing hormone (LH) concentration is also an independent predictor of free testosterone
 concentrations, especially in mid- to late pubertal girls.
A number of pathophysiological mechanisms underlie the polycystic ovary syndrome (PCOS).
 Neuroendocrine abnormalities play a significant role in most women with PCOS, and PCOS is
 associated with relative resistance of the gonadotropin releasing hormone (GnRH) pulse
 generator to negative feedback by progesterone and estradiol. This hypothalamic resistance to
 negative feedback appears to be a result of hyperandrogenemia (HA), and can also occur in
 adolescents with HA. We have hypothesized that peripubertal HA (which can represent a
 forerunner of adult PCOS) can promote the development of PCOS in part via induction of
 hypothalamic resistance to negative feedback. However, the cause of peripubertal HA remains
 largely unknown. Obesity is a well-recognized pathophysiological factor in the HA of adult
 PCOS; and recent data demonstrate that peripubertal obesity is associated with HA. However,
 the mechanisms underlying the relationship between peripubertal obesity and HA-and the marked
 variability of androgen levels observed among obese girls-are unknown. We have gathered
 preliminary data that suggests that obese pre- and early pubertal girls with high androgen
 levels also exhibit greater degrees of insulin resistance compared to obese girls with lower
 androgens.

 The primary goal of this pilot project is to begin to establish the relationship between
 insulin resistance (as determined by insulin clamp studies) and free testosterone
 concentrations in obese peripubertal girls. Secondarily, the aim is to assess the
 contributions of elevated luteinizing hormone (determined by frequent blood sampling for LH)
 in obesity-associated HA across puberty.

 Subjects will be admitted to the General Clinical Research Center at 1600 h after 4 hours of
 fasting. We will measure luteinizing hormone every 10 minutes from 1800 h to 0900 h; other
 hormones (e.g., testosterone) will be assessed as well. Measurements of insulin and glucose
 will occur before and after a standardized mixed meal (eaten at 1900 h) and while fasting the
 following morning. A standard hyperinsulinemic euglycemic clamp procedure will be performed
 from 0900-1100 h.

 Characterization of the factors underlying peripubertal HA may permit prediction of which
 pre- and early pubertal girls will subsequently go on to develop symptoms of PCOS. Data
 generated by this project will prompt novel future studies to investigate the complex
 interactions among metabolic and classical endocrine pathways that lead to PCOS.
Inclusion Criteria:

 -  Peripubertal (Tanner stage 1 to 5) girl, age 8-16 years

 -  Obesity (BMI-for-age ≥ 95th percentile)

 -  Generally healthy (save for exogenous obesity)

 -  Ability and willingness of subject/parents to provide informed assent/consent

 Exclusion Criteria:

 -  Age < 8 or > 16 y

 -  Greater than 4 y post-menarche

 -  Obesity associated with a diagnosed (genetic) syndrome (e.g., Prader-Willi syndrome,
 leptin deficiency), obesity related to medications (e.g., glucocorticoids), etc.

 -  Pregnancy or lactation

 -  Virilization

 -  Total testosterone > 150 ng/dl, which suggests the possibility of a virilizing
 neoplasm

 -  DHEAS greater than twice upper limit of age-appropriate normal range

 -  17-OHP greater than 250 ng/dl, which suggests the possibility of congenital adrenal
 hyperplasia (if postmenarcheal, the 17-OHP will be collected during the follicular
 phase, or > 60 if oligomenorrheic) NOTE: If a 17-OHP > 250 ng/dl is confirmed on
 repeat testing, an ACTH stimulation test will be offered, with a post-ACTH 17-OHP <
 1000 ng/dl being required for study participation

 -  History of premature adrenarche (i.e., appearance of pubic and/or axillary hair before
 age 8)

 -  Fasting glucose > 125 mg/dl or hemoglobin A1c > 7.0%

 -  Abnormal TSH or prolactin

 -  Evidence of Cushing's syndrome by history or physical exam (e.g., history of impaired
 growth, striae)

 -  Hematocrit < 36% or hemoglobin < 12 g/dl

 -  Significant and current cardiac or pulmonary dysfunction (e.g., known or suspected
 congestive heart failure; asthma requiring systemic intermittent corticosteroids;
 etc.)

 -  Abnormal liver enzymes, age-specific alkaline phosphatase, or a bilirubin > 1.5 times
 upper limit of normal

 -  Abnormal sodium, potassium, bicarbonate concentrations, or elevated creatinine
 concentration

 -  Weight less than 34 kg is an exclusion criterion (to ensure safe blood withdrawal)

 -  Subjects using restricted medication (see restrictions below) are excluded unless the
 subject's primary care provider approves stopping the medication