Effect of Metformin on Adrenal or Ovarian Androgen Production in Overweight Pubertal Girls With Androgen Excess

Inclusion Criteria:

• Overweight(>85th BMI%) females
• Early to late puberty (expected age range 7-18)
• Hyperandrogenemic (free testosterone greater than 2.5 standard deviations above themean for normal control subjects of the same Tanner Stage)
• Screening labs within age-appropriate normal range, with the exception of a mildly lowhematocrit (see below) and the hormonal abnormalities inherent in obesity which couldinclude mildly elevated luteinizing hormone (LH), lipids, testosterone, prolactin,DHEAS, E2, glucose, and insulin; and decreased follicle-stimulating hormone (FSH)and/or sex hormone-binding globulin (SHBG)

Exclusion Criteria:

• Age < 7 or > 18 y
• Inability to comprehend what will be done during the study or why it will be done
• BMI-for-age < 5th percentile
• Positive pregnancy test or lactation.
• Abnormal laboratory studies will be confirmed by repeat testing to exclude laboratoryerror.
• Morning cortisol < 3 µg/dL or history of Cushing syndrome or adrenal insufficiency
• History of congenital adrenal hyperplasia or 17-hydroxyprogesterone > 300 ng/dL, whichsuggests the possibility of congenital adrenal hyperplasia (if postmenarcheal, the 17-hydroxyprogesterone will be collected during the follicular phase, or ≥ 40 dayssince last menses if oligomenorrheic). NOTE: If a 17-hydroxyprogesterone >300 mg/dL isconfirmed on repeat testing, an ACTH-stimulated 17-hydroxyprogesterone <1000 ng/dLwill be required for study participation.
• Total testosterone > 150 ng/dL, which suggests the possibility of a virilizingneoplasm
• DHEAS greater than the upper limit of age-appropriate normal range (mild elevationsmay be seen in polycystic ovary syndrome (PCOS) and adolescent hyperandrogenemia (HA),and elevations < 1.5 times the age-appropriate upper limit of normal will be acceptedin these groups)
• Virilization
• Previous diagnosis of diabetes, fasting glucose ≥126 mg/dL, or a hemoglobin A1c ≥6.5%
• Abnormal thyroid stimulating hormone (TSH) for age. Subjects with stable andadequately treated hypothyroidism, reflected by normal TSH values, will not beexcluded.
• Abnormal prolactin. Mild elevations may be seen in overweight girls, and elevations <1.5 times the upper limit of normal will be accepted in this group.
• Persistent hematocrit <36% and hemoglobin <12 g/dL. Subjects with a mildly lowhematocrit (33-36%) will be asked to take iron in the form of ferrous gluconate for upto 60 days. Subjects weighing ≤ 36 kg will take one 300-325 mg tablet oral ferrousgluconate daily (containing 36 mg elemental iron);subjects weighing >36 kg will taketwo 300-325 mg tablets oral ferrous gluconate daily (containing 36 mg elemental ironeach). They will return to the Clinical Research Unit (CRU) after 30-60 days of irontherapy to have their hemoglobin or hematocrit rechecked and will proceed with theremainder of the study if it is ≥12 g/dL or ≥36%, respectively.
• Persistent liver test abnormalities, with the exception that mild bilirubin elevationswill be accepted in the setting of known Gilbert's syndrome. Mild elevations may beseen in overweight girls, so elevations <1.5 times the upper limit of normal will beaccepted in this group.
• Significant history of cardiac or pulmonary dysfunction (e.g., known or suspectedcongestive heart failure; asthma requiring intermittent systemic corticosteroids;etc.)
• Abnormal sodium, potassium, or bicarbonate concentrations, or elevated creatinineconcentration (confirmed on repeat)
• No medications known to affect the reproductive system or glucose metabolism can betaken in the 3 months prior to the study. Such medications include oral contraceptivepills, progestins, metformin, glucocorticoids, and psychotropics.