Relative Desirability of Metformin vs. Birth Control Pill in Treating PCOS in Women of Later Reproductive Age
Relative Desirability of Metformin vs. Birth Control Pill in Treating PCOS in Women of Later Reproductive Age
The goal of this study is to determine the relative desirability of metformin vs. oral
 combined hormonal contraceptives (OCs) in treating Polycystic Ovary Syndrome (PCOS) in women
 of later reproductive age. Polycystic Ovary Syndrome Questionnaire (PCOSQ) score will be used
 as a proxy for patient satisfaction. In light of their respective effects on the classic and
 metabolic facets of PCOS, metformin will provide non-inferior patient satisfaction compared
 to OCs in later reproductive age women with PCOS.
This is a randomized, controlled, double-blinded, crossover study. The investigators will
 recruit women with PCOS in ages 40-49 yo. Subjects will be randomized to either receive
 metformin (2000 mg daily) or low dose oral contraceptives (OCs: 20 mcg ethinyl
 estradiol/norethindrone acetate 1mg) for a total of 6 months, and they will crossover to the
 other treatment for the following 6 months. Subjects will have the following assessed at
 baseline and 6 months after each study medication: blood pressure, weight, waist-to-hip ratio
 (WHR), average intermenstrual cycle length (in the previous 3 months), Ferriman-Gallwey score
 (as a measure of hirsutism), total testosterone (T), sex hormone binding globulin, calculated
 free T, fasting insulin, fasting glucose, 2-h glucose (during oral glucose tolerance test),
 Matsuda index, HgA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, estimated
 cardiovascular risk (Framingham risk score), health-related quality of life using both PCOS
 questionnaire (PCOSQ) and the Short-Form Health Survey (SF-36), and severity of anxiety using
 Generalized Anxiety Disorder-7 (GAD-7) questionnaire. For safety surveillance, the
 investigators will measure electrolyte levels, renal function, liver function, and pregnancy
 tests immediately before study mediation initiation and every 3 months. For statistical
 analysis, per PCOSQ domain, the post-treatment QoL scores will be analyzed via a linear mixed
 model (LMM), in which the LMM will be specified in accordance with a 2 treatment by 2 period
 crossover design. The investigators determined that if 73 subjects complete the study, the
 investigators expect to have at least an 80% chance of rejecting the null hypothesis that QoL
 is inferior with metformin therapy vs. OCs.
Inclusion Criteria:

 -  Women with PCOS aged 40-49 years. Subject is considered to have PCOS if she has
 current or verifiable history of: a) clinical and/or biochemical evidence of
 hyperandrogenism plus b) oligomenorrhea or irregular menstruation (substantially
 inconsistent menstrual cycle length). Subjects with fewer than 10 menses/year or
 average menstrual cycle length >35 days are allowed to participate if they have a
 compelling past history of oligomenorrhea (average menstrual cycle length >45 days or
 fewer than 9 menses/year) or irregular menstruation.

 -  Screening safety labs within normal reference ranges although mild abnormalities that
 are common in obesity and/or hyperandrogenism will not be grounds for exclusion (see
 exclusion criteria).

 -  Subjects must be willing and able to provide written informed consent.

 -  Willingness to strictly avoid pregnancy (using non-hormonal methods) during the time
 of 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 elevated
 follicle stimulating hormone [FSH] level)

 -  Biochemical evidence for perimenopause as defined by an anti-Mullerian hormone <0.5
 ng/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 perimenopause
 status. NOTE: If FSH >9 IU/L on screening (but it is not cycle day 3), FSH and
 estradiol 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 pregnancy
 test 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) >200
 ng/dL, which suggest the possibility of congenital adrenal hyperplasia. 17-OHP will be
 collected during follicular phase. NOTE: if a 17-OHP >200 ng/dL and is confirmed on
 repeat testing, an ACTH-stimulated 17-OHP <1000 ng/dL will be required for study
 participation.

 -  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 be
 seen in PCOS, so elevations < 1.5 times the upper limit of normal will be accepted in
 these groups).

 -  Virilization

 -  Diagnosis of diabetes mellitus (DM), fasting glucose ≥ 126 mg/dL, or a hemoglobin A1c
 of ≥ 6.5%.

 -  Abnormal thyroid stimulating hormone (TSH). Subjects with stable and
 adequately-treated hypothyroidism, reflected by normal TSH values, will not be
 excluded.

 -  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 will
 be accepted in the setting of known Gilbert's syndrome. Mild transaminase elevations
 may be seen in women with obesity, so elevations <1.5 times the upper limit of normal
 will be accepted in this group.

 -  Persistent hematocrit <36% and hemoglobin <12 g/dL.

 -  Abnormal sodium, potassium, or bicarbonate concentrations or elevated creatinine
 concentration.

 -  Significant history of pulmonary dysfunction (e.g., asthma or COPD requiring
 intermittent 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 adequately
 treated dyslipidemia reflected by normal lipid panel values will not be excluded.

 -  History of complicated valvular heart disease (e.g. pulmonary hypertension, risk of
 atrial fibrillation, history of subacute bacterial endocarditis)

 -  History of stroke

 -  History of smoking

 -  History of severe cirrhosis or liver tumor (e.g. hepatocellular adenoma or malignant
 hepatoma).

 -  Use of anticonvulsants, rifampicin or rifabutin therapy. The interaction of these
 drugs with OCs will not be harmful to the subjects, but it will reduce the
 effectiveness of OCs.

 -  History of venous thromboembolism (e.g. deep venous thrombosis (DVT), pulmonary
 embolism (PE)).

 -  Personal history of blood clotting disorders (e.g., protein C, protein S, positive
 antiphospholipid antibodies).

 -  First-degree relative history of blood clotting disorder, unless the same disorder has
 been 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 the
 proliferative (follicular) phase or >14 mm in the secretory (luteal) phase, the
 subject will be referred to a gynecologist for further evaluation (38). These
 particular subjects will be required to obtain a clearance from their gynecologist to
 participate 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 months
 prior to screening and in the 3 months prior to the study. Such medications include
 oral contraceptive pills, metformin, progestins, glucocorticoids, anti-psychotics,
 and/or mood stabilizers that are known to cause hormone abnormalities.