Metformin for the Treatment of Premature Pubarche in Girls
Metformin for the Treatment of Premature Pubarche in Girls
The primary objective of this study is to determine the safety and efficacy of metformin in
 lowering serum DHEAS levels in girls with premature pubarche and secondary, to observe
 changes in hormones associated with pubertal development including gonadotropins, sex
 steroids, insulin, adipocytokines, and growth factors.
Inclusion Criteria:

 1. Girls aged 4-10 with pubic hair prior to 8 years of age

 2. Elevated DHEAS level above age normal levels

 3. Informed consent from parents and assent from the girl

 Exclusion Criteria:

 1. Diagnosis of incomplete precocious puberty, peripheral precocious puberty, or evidence
 of any abnormal pituitary, hypothalamic, adrenal, thyroid, and gonadal function other
 than premature secretion of adrenal androgens.

 2. Chronic illness requiring treatment that may interfere with growth and development,
 i.e. chronic steroid use, renal failure, etc.

 3. 21-hydroxylase deficiency or other enzyme deficiency leading to the phenotype of
 congenital adrenal hyperplasia. 21-hydroxylase deficiency will be excluded in all
 patients by a fasting 17-hydroxyprogesterone (17-OHP) level < 2 ng/mL. In the case of
 elevated fasting 17-OHP levels, an ACTH stimulation test will be performed. A 1-hour
 stimulated value > 10 ng/mL will be an exclusion 82. As 21 hydroxylase deficiency is a
 congenital condition, any normal level in the past of 17-hydroxyprogesterone allows
 entry into this study.

 4. Uncorrected thyroid disease (defined as TSH < 0.2 mIU/ML or > 5.5 mIU/mL). A normal
 level within the last year is adequate for entry.

 5. Type I or Type II diabetes (defined as a fasting serum glucose > 125mg/dL on two
 occasions 83), or patients receiving anti-diabetic medications such as insulin,
 thiazolidinediones, acarbose, or sulfonylureas; patients currently receiving metformin
 XR for a diagnosis of Type I or Type II diabetes or for PCOS are also specifically
 excluded.

 6. Liver disease defined as AST or ALT > 2 times normal or total bilirubin > 2.5 mg/dL.

 7. Renal disease defined as BUN > 30 mg/dL or serum creatinine > 1.4 mg/dL.

 8. Significant anemia (Hemoglobin < 10 mg/dL).

 9. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident.

 10. Known heart disease (New York Heart Association Class II or higher).

 11. Enrolled simultaneously into other investigative studies that require medications,
 proscribe the study medications, or otherwise prevent compliance with the protocol.
 Patients who anticipate taking longer than a one month break during the protocol
 should not be enrolled.

 12. Concomitant use other medications known to affect reproductive function or metabolism.
 These medications include growth hormone, IGF-1, medroxyprogesterone acetate, oral
 contraceptives, GnRH agonists and antagonists, anti-androgens, gonadotropins,
 anti-obesity drugs, somatostatin, diazoxide, ACE inhibitors, and calcium channel
 blockers. The washout period on all these medications will be three months.

 13. Suspected adrenal or ovarian tumor secreting androgens or other ectopic steroid
 secreting tumor.

 14. Suspected Cushing's syndrome.

 15. Lactose intolerance (the placebo filler is lactose).

 16. Known hypersensitivity to study medication, including ACTH and GnRH, or their
 excipients.

 17. Any concomitant medical condition that in the opinion of the investigator, may expose
 a subject to unacceptable level of safety risk, or that affects subject compliance.

 18. Subjects who anticipate having any surgery associated with restricted intake of fluids
 or radiological studies with contrast dye during the study period.

 19. Any concomitant medical condition that in the opinion of the investigator, may expose
 a subject to unacceptable level of safety risk, or that affects subject compliance.