Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone
Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone
Many, but not all, girls with high levels of the male hormone testosterone go on to develop
 polycystic ovary syndrome (PCOS) as adults. Women with PCOS often have irregular menstrual
 periods, excess facial and body hair, and weight gain. PCOS is also a leading cause of
 difficulty becoming pregnant. The investigators do not understand why some girls with high
 hormones develop PCOS and others do not. In a previous study by our group, some girls with
 high levels of male hormones had abnormalities in the secretion of another hormone, called
 luteinizing hormone (LH), that are often seen in women with PCOS. However, another group had
 normal LH secretion. The girls with the abnormal LH secretion had higher levels of another
 hormone, called insulin, than the girls with normal LH secretion. The investigators will test
 whether metformin, an insulin-sensitizing agent, changes the effects of high male hormone
 levels in adolescent girls, specifically by looking at their LH secretion response following
 metformin treatment.
A better understanding of the factors that make adolescent girls more or less susceptible to
 the adverse neuroendocrine effects of elevated androgens will hopefully lead to improved
 prevention and treatment strategies for PCOS. In this study, we propose to explore the role
 of hyperinsulinemia on neuroendocrine function in hyperandrogenic adolescent girls by
 assessing the effect of the insulin sensitizer Metformin on hypothalamic progesterone
 sensitivity. Other differences between the progesterone sensitive and progesterone
 insensitive subgroups, including racial and ethnic differences between the two populations
 and a trend towards older gynecologic age in the progesterone insensitive population, are
 being pursued through other ongoing studies (IRB-HSR# 8588 and 12160).
Inclusion Criteria:

 -  Girls ages 10 to 17

 -  Hyperandrogenemic (free testosterone greater than 2.5 standard deviations above the
 mean for normal control subjects of the same Tanner Stage)

 -  Creatinine clearance > 90 ml/min as calculated by the Cockcroft-Gault equation

 -  Hemoglobin > 12 mg/dL or Hematocrit > 36%

 -  Normal screening labs (with exception of the expected hormonal abnormalities inherent
 in hyperandrogenemia)

 -  Sexually active subjects must agree to abstain or use double barrier contraception
 during the study

 -  Subjects must agree not to take any other medications during the course of the study
 without approval by the study investigators.

 Exclusion Criteria:

 -  Abnormal screening labs (with the exception of the expected hormonal abnormalities
 inherent in hyperandrogenemia)

 -  Creatinine clearance less than 90 ml/min as calculated by Cockcroft-Gault equation

 -  Hemoglobin <12 mg/dL or hematocrit < 36%

 -  Abnormal liver function tests, including Aspartate Aminotransferase (AST), Alanine
 Aminotransferase (ALT), Bilirubin, Albumin, and Alkaline Phosphatase

 -  Weight < 34 kg

 -  History of renal dysfunction, liver dysfunction, congestive heart failure, deep venous
 thrombosis, breast cancer, endometrial cancer, or cervical cancer

 -  Pregnant or breast feeding

 -  On medications known to affect the reproductive axis within 3 months of the study
 (including oral contraceptive pills, metformin, and spironolactone)

 -  Are currently participating in another study or have been in one in the last 30 days.

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