Relative Desirability of Metformin vs. Birth Control Pill in Treating PCOS in Women of Later Reproductive Age

Inclusion Criteria:

• Women with PCOS aged 40-49 years. Subject is considered to have PCOS if she hascurrent or verifiable history of: a) clinical and/or biochemical evidence ofhyperandrogenism plus b) oligomenorrhea or irregular menstruation (substantiallyinconsistent menstrual cycle length). Subjects with fewer than 10 menses/year oraverage menstrual cycle length >35 days are allowed to participate if they have acompelling past history of oligomenorrhea (average menstrual cycle length >45 days orfewer than 9 menses/year) or irregular menstruation.
• Screening safety labs within normal reference ranges although mild abnormalities thatare common in obesity and/or hyperandrogenism will not be grounds for exclusion (seeexclusion criteria).
• Subjects must be willing and able to provide written informed consent.
• Willingness to strictly avoid pregnancy (using non-hormonal methods) during the timeof the study
• Willingness and ability to comply with scheduled visits and study procedures

Exclusion Criteria:

• Postmenopausal status (i.e., absence of periods for previous year plus elevatedfollicle stimulating hormone [FSH] level)
• Biochemical evidence for perimenopause as defined by an anti-Mullerian hormone <0.5ng/mL. As an alternative, cycle day 3 FSH > 9 IU/L (with concomitant estradiol level >80 pg/mL), if this testing is available, will serve as evidence of perimenopausestatus. NOTE: If FSH >9 IU/L on screening (but it is not cycle day 3), FSH andestradiol will be repeated on cycle day 3
• History of hysterectomy and/or bilateral oophorectomy
• BMI ≥ 40 kg/m2
• Inability to comprehend what will be done during the study or why it will be done.
• Being a study of older women with PCOS, children and men will be excluded.
• Pregnancy or lactation within the past 6 months. Subjects with a positive pregnancytest will be informed of the result by the screening physician.
• Prisoners.
• History of (or clinical evidence for) Cushing's syndrome or adrenal insufficiency.
• History of congenital adrenal hyperplasia or 17-hydroxyprogesterone (17-OHP) >200ng/dL, which suggest the possibility of congenital adrenal hyperplasia. 17-OHP will becollected during follicular phase. NOTE: if a 17-OHP >200 ng/dL and is confirmed onrepeat testing, an ACTH-stimulated 17-OHP <1000 ng/dL will be required for studyparticipation.
• Total testosterone >150 ng/dL, which suggests the possibility of virilizing neoplasm.
• DHEA-S greater than 1.5 times the upper limit of normal range (mild elevations may beseen in PCOS, so elevations < 1.5 times the upper limit of normal will be accepted inthese groups).
• Virilization
• Diagnosis of diabetes mellitus (DM), fasting glucose ≥ 126 mg/dL, or a hemoglobin A1cof ≥ 6.5%.
• Abnormal thyroid stimulating hormone (TSH). Subjects with stable andadequately-treated hypothyroidism, reflected by normal TSH values, will not beexcluded.
• Moderate to severe hyperprolactinemia. Mild prolactin elevations may be seen in PCOS,and elevations < 1.5 times the upper limit of normal will be accepted in this group.
• Persistent liver abnormalities, with the exception that mild bilirubin elevations willbe accepted in the setting of known Gilbert's syndrome. Mild transaminase elevationsmay be seen in women with obesity, so elevations <1.5 times the upper limit of normalwill be accepted in this group.
• Persistent hematocrit <36% and hemoglobin <12 g/dL.
• Abnormal sodium, potassium, or bicarbonate concentrations or elevated creatinineconcentration.
• Significant history of pulmonary dysfunction (e.g., asthma or COPD requiringintermittent systemic corticosteroid, pulmonary hypertension, etc.).
• History of known or suspected congestive heart failure.
• History of known or suspected ischemic heart disease or cerebrovascular disease.
• History of hypertension.
• History of uncontrolled/untreated dyslipidemia. Subjects with stable and adequatelytreated dyslipidemia reflected by normal lipid panel values will not be excluded.
• History of complicated valvular heart disease (e.g. pulmonary hypertension, risk ofatrial fibrillation, history of subacute bacterial endocarditis)
• History of stroke
• History of smoking
• History of severe cirrhosis or liver tumor (e.g. hepatocellular adenoma or malignanthepatoma).
• Use of anticonvulsants, rifampicin or rifabutin therapy. The interaction of thesedrugs with OCs will not be harmful to the subjects, but it will reduce theeffectiveness of OCs.
• History of venous thromboembolism (e.g. deep venous thrombosis (DVT), pulmonaryembolism (PE)).
• Personal history of blood clotting disorders (e.g., protein C, protein S, positiveantiphospholipid antibodies).
• First-degree relative history of blood clotting disorder, unless the same disorder hasbeen formally excluded for the study subject.
• History of migraine headaches.
• History of breast, ovarian, or endometrial cancer.
• Note: If endometrial thickness on transvaginal ultrasound is >8 mm in theproliferative (follicular) phase or >14 mm in the secretory (luteal) phase, thesubject will be referred to a gynecologist for further evaluation (38). Theseparticular subjects will be required to obtain a clearance from their gynecologist toparticipate in this study.
• Note: Any abnormal labs may be repeated to exclude a lab error.
• No medications known to affect the reproductive system can be taken in the 2 monthsprior to screening and in the 3 months prior to the study. Such medications includeoral contraceptive pills, metformin, progestins, glucocorticoids, anti-psychotics,and/or mood stabilizers that are known to cause hormone abnormalities.