Metformin for Ectopic Fat Deposition and Metabolic Markers in Polycystic Ovary Syndrome (PCOS)

PCOS subjects will be screened by questionnaire for eligibility with the goal of recruiting
40 subjects who are 14 to 25 years, BMI between the 10th and 95th percentile for age (<20
years) and 18.5 - 29.9 kg/m2 (20 years or older), and at least two years post-menarche.
Oligomenorrheic subjects will complete the protocol during the early follicular phase of the
menstrual cycle (days one through seven) and amenorrheic subjects will complete the protocol
on any day. The protocol will comprise: a) History and physical exam: Height, weight, body
mass index (BMI) (percentile and z-score for <20 years), blood pressure, physical exam,
Ferriman-Gallwey hirsutism scoring, smoking, alcohol and family history; b) Laboratory
evaluation will be between 0800 and 0900 after an overnight fast via a 21 gauge intravenous
catheter for: 1) General endocrine panel: Thyroid function, prolactin,
17-hydroxyprogesterone; 2) PCOS panel: luteinizing hormone (LH), follicle stimulating
hormone (FSH), estradiol, sex hormone binding globulin, testosterone, free testosterone,
androstenedione, dehydroepiandrosterone; 3) Liver panel: Liver enzymes (alanine
aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl-transpeptidase
(GGT)), apoptosis markers (Fas, cytokeratin-18 fragments, M30), pancreatic polypeptide; 4)
Cardiovascular risk panel: Cholesterol, triglycerides, HDL, LDL, free fatty acids,
c-reactive protein; 5) IR evaluation: hemoglobin A1C, glucose, insulin, c-peptide and
two-hour oral glucose tolerance test (OGTT) after a 75 gram glucose challenge with
measurement of glucose and insulin at 30, 60, 90 and 120 minutes. IR will be determined by
age- and BMI- specific homeostatic measure of insulin resistance (HOMA-IR) cutoffs based on
a National Health and Nutrition Examination Survey (NHANES) study of 1,164 nonobese
adolescents 12 to 19 years old. Other IR indices that will be evaluated are whole body
insulin sensitivity (WBIS) and insulin area under the curve; 6) Genetic evaluation: A blood
sample for the PNPLA3 I148M allele (baseline only). c) Magnetic resonance spectroscopy (MRS)
of the liver for intrahepatic lipid content acquired using standard point resolved
spectroscopy sequence (PRESS). Percentage liver fat will be calculated. d) Total body
magnetic resonance imaging (MRI) with 10 mm slices and 40 mm interslice gaps for total body
adipose tissue and VAT. e) Dual-energy x-ray absorptiometry (DXA): Total body DXA will be
performed for total body lean and fat mass and percentage body fat. f) Randomization:
Subjects whose liver fat is 4.8% or greater (n≈20) will be randomized to placebo or
extended-release metformin 1000 mg (2 tablets) daily. Randomization will be double-blind and
will be performed by randomly selected permuted size 2 and size 4 blocks determined by the
Columbia University Medical Center (CUMC) Research Pharmacy with the guidance of a
statistician. g) Intervention: All subjects will receive identically appearing pill bottles
labeled "Study Medication" containing their first three-month supply of either metformin or
placebo. Subjects will be instructed to take pills with dinner and to take one pill once a
day for one week and subsequently two pills once a day for the remainder of the first three
months. Subjects will be asked to call with any side effects that they may experience. They
will receive weekly calls from a research coordinator and will be asked to bring their empty
pill bottles to their follow-up studies do to ensure compliance. h) Brief interim
evaluation: After three months of the intervention phase, subjects will be seen for a
general health assessment, which includes weight, blood pressure and a physical examination,
and will receive their second three-month supply of their assigned intervention. i)
Follow-up exam: At the end of six months, subjects will undergo laboratory and body
composition testing identical to those performed in the baseline testing.

Inclusion Criteria:

- Healthy adolescent girls and young women 13 - 25 years old

- At least 2 years postmenarche

- With clinical hyperandrogenism and/or hyperandrogenemia, menstrual dysfunction
(oligomenorrhea or amenorrhea) and exclusion of other known disorders. PCOS will be
diagnosed using NIH 1990 criteria.

Exclusion Criteria:

- Past or present history of a medical disorder or medication known to affect body
composition

- Insulin secretion and sensitivity, or the GH-IGF-I axis (e.g. steroid hormone or
thyroid replacement)

- Any diseases affecting bone metabolism (collagen disorders, primary
hyperparathyroidism, nephrolithiasis, untreated hyperthyroidism) indwelling hardware

- History of current or past pregnancy

- Hormonal contraceptive or metformin use within 3 months of enrollment

- Nonclassical congenital adrenal hyperplasia (CAH) - early morning
17-hydroxyprogesterone level less than 200 ng/dL