Comparing the Effects of Oral Contraceptive Pills Versus Metformin

The intervention will consist of randomizing subjects to one of three arms. Subjects will
either be assigned to OCP + Placebo, Metformin + Placebo or OCP + Metformin. Metformin will
be initiated in a step-up fashion on cycle day 1-3 of spontaneously or induced menses.
Extended release pills will be utilized as they are associated with fewer gastrointestinal
side effects. Subjects will begin with one tablet of metformin every night for 5 days,
eventually building up to 4 tablets every night, with the maximum dose of metformin being
2000 mg. In regards to OCP, previous randomized clinical trials (RCTs) have shown that 20mcg
ethinyl estradiol/norethindrone 1.0 mg was well tolerated. The study will utilize a 20mcg OCP
but a less androgenic third generation progestin (desogestrel 0.15mg) with potentially lesser
impact on lipids and insulin sensitivity. The OCP will be started on the first Sunday after
spontaneous or induced menses. All subjects with no menses the 4 weeks before randomization
will be given medroxyprogesterone acetate after a negative pregnancy test (in order to induce
menses). Placebo pills will be administered to individuals randomized to OCP or metformin
only in order to maintain study blinding. Subjects will undergo 6 in person study visits and
life style modification counseling regarding diet and exercise. Phone contact will be made 2
weeks after randomization and at the end of each month when there is no in person visit to
ensure study compliance with medications, keeping study logs and to review side effects

Inclusion Criteria:

1. Women ≥ 18 to ≤ 40 years of age (at the time of screening), with hyperandrogenic PCOS.

2. Subjects will be diagnosed with PCOS defined by the Rotterdam criteria 20 based on:

1. A history of chronic anovulation (8 or fewer periods per year)

2. androgen excess (defined as an elevated serum T level or hirsutism, based on a
Ferriman Gallwey score > 8 (note: > 2 for women of Asian descent)

3. +/- polycystic ovaries.

3. BMI ≥ 25 kg/m² to ≤ 45 kg/m² obtained at screening visit.

4. In good general health.

5. Willing to avoid pregnancy for the duration of the study.

Exclusion Criteria:

1. Current pregnancy or desire of pregnancy during course of study

2. Currently breastfeeding

3. Known 21 hydroxylase deficiency

4. Untreated thyroid disease (TSH <0.45 mlU/mL and > 4.5 mlU/mL)

5. Untreated hyperprolactinemia (2 Levels>30 ng/ml at least one week apart)

6. Type 1 or type 2 Diabetes Mellitus (elevated fasting serum glucose >126mg/dL on two
occasions, poorly controlled diabetes (HgbA1C>6.5%), currently receiving anti-diabetic
agents, or currently receiving metformin for treatment of diabetes

7. Liver disease (AST/ALT>2 times normal or a total bilirubin >2.5 mg/dL)

8. Renal disease (BUN>30 mg/dL or serum creatinine >1.4 mg/dL)

9. Anemia (hemoglobin <10 mg/dL)

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

11. Current history of alcohol abuse (>14drinks/week)

12. Poorly controlled hypertension defined as average systolic blood pressure >= 150 mm Hg
or average diastolic >=100 mm Hg obtained on three measurements obtained 5 minutes
apart. If treated, average systolic blood pressure >=140 mm Hg or average diastolic
>=90 mm Hg

13. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or
breast carcinoma

14. TG>200mg/dl

15. Use of lipid lowering or weight loss agents (subjects may wash out from weight loss
agents)

16. Current use of oral contraceptives, depo progestin, or hormonal implants

17. Participation in any study of an investigational drug or device or biological agent
within 30 days

18. Suspected adrenal or ovarian tumor secreting androgens

19. Suspected Cushing's syndrome

20. Bariatric surgery procedure in the recent past (<12 months)

21. Absolute contraindications to the use of hormonal contraceptives or metformin,

23. Subjects who are unable to comply with the study procedures, for instance due to mental
illness, substance abuse, or participation in other studies.