Pregnancy in Polycystic Ovary Syndrome II

Inclusion Criteria: Key Inclusion Criteria (Must have ovulatory dysfunction and either hyperandrogenism or PCO)

1. Chronic anovulation or oligomenorrhea: defined as spontaneous intermenstrual periodsof ≥45 days or a total of ≤8 menses per year, or for women with suspected anovulatorybleeding, a midluteal serum progesterone level < 3 ng/mL is indicative of chronicanovulation. For women who have been on ovarian suppressive therapy or otherconfounding medication (i.e. insulin sensitizing agents) within the last year prior tothe study, a history of ≤8 menses per year prior to the initiation of this priortherapy will qualify as evidence of oligomenorrhea. For women with more regularbleeding patterns, but who are suspected to be experiencing anovulatory bleeding, amidluteal progesterone level < 3ng/mL will be evidence of ovulatory dysfunction andqualify as anovulation. Undiagnosed persistent vaginal bleeding should be diagnosedand treated prior to enrollment.

2. Hyperandrogenism (either Hirsutism or Hyperandrogenemia) or Polycystic Ovaries onUltrasound:

3. Hirsutism is determined by a modified Ferriman-Gallwey Score >8 at screening exam (Hatch, Rosenfield et al. 1981 Aug 1). Subjects who have hirsutism do not needlocal or core labs documenting elevated androgen levels.

4. Hyperandrogenemia can be determined from local labs. Local cutoffs will bepre-determined by each site prior to study initiation. Hyperandrogenemia will bedefined as an elevated total testosterone, or free androgen index (FAI)(in ourlab at Penn State College of Medicine a total T > 50 ng/dL or a free androgenindex >5) will allow entry into the study (Legro, Driscoll et al. 1998). The FAIis calculated from measurable values for total T and SHBG, as previouslydescribed (Miller, Rosner et al. 2004), using the following equation: (FAI =Total testosterone in nmol/L / SHBG in nmol/L) X 100. Outside lab values obtainedwithin the last year documenting elevated T or FAI levels are sufficient to meetcriteria of hyperandrogenemia.

5. Polycystic Ovaries on Ultrasound: We will use the revised Rotterdam criteria fordiagnosing polycystic ovaries (Balen, Laven et al. 2003). PCO will be defined aseither an ovary that contains 12 or more follicles measuring 2-9 mm in diameter,or an increased ovarian volume (> 10 cm3) on one ovary for entry into the study.If there is a follicle > 10 mm in diameter, the scan should be repeated at a timeof ovarian quiescence in order to calculate volume and area if the subject doesnot otherwise qualify for the study. The presence of a single polycystic ovary (PCO), either by volume or morphology, is sufficient to provide the diagnosis.

Exclusion Criteria: We will exclude subjects with medical conditions that represent contraindications to CC,aromatase inhibitors and/or pregnancy or who are unable to comply with the studyprocedures. We will exclude subjects with poorly controlled Type I or Type II diabetes;undiagnosed liver disease or dysfunction (based on serum liver enzyme testing); renaldisease or abnormal serum renal function; significant anemia; history of deep venousthrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hypertension,known symptomatic heart disease; history of or suspected cervical carcinoma, endometrialcarcinoma, or breast carcinoma; undiagnosed vaginal bleeding, and use of other medicationsknown to affect reproductive function or metabolism (e.g., OCP, GnRH agonists andantagonists, antiandrogens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACEinhibitors, and calcium channel blockers). As in PPCOS we will allow a 2 months washoutperiod for subjects who desire to participate and discontinue exclusionary medications (most commonly OCP, but also possibly metformin), and a period of observation or treatmentfor correctable conditions. Couple Inclusion Criteria

1. Sperm concentration of 14 million/mL in at least one ejaculate within the last year,with at least some motile sperm.

2. Ability to have regular intercourse during the ovulation induction phase of the study.

3. At least one patent tube and normal uterine cavity as determined by sonohysterogram,hysterosalpingogram, or hysteroscopy/laparoscopy within the last 3 years. Anuncomplicated intrauterine non-IVF pregnancy and uncomplicated delivery and postpartumcourse resulting in live birth within the last three years will also serve assufficient evidence of a patent tube and normal uterine cavity as long as the subjectdid not have, during the pregnancy or subsequently, risk factors for Asherman'ssyndrome or tubal disease or other disorder leading to an increased suspicion forintrauterine abnormality or tubal occlusion.

4. No previous sterilization procedures (vasectomy, tubal ligation) that have beenreversed. The prior procedure may affect study outcomes. Specific Exclusion Criteria

5. Current pregnancy.

6. Patients on oral contraceptives, depo-progestins, or hormonal implants (includingImplanon). A two month washout period will be required prior to screening for patientson these agents. Longer washouts may be necessary for certain depot contraceptiveforms or implants, especially where the implants are still in place. A one-monthwashout will be required for patients on oral cyclic progestins.

7. Patients with hyperprolactinemia (defined as two prolactin levels at least one weekapart > 30 ng/mL or as determined by local normative values). The goal of eliminatingpatients with documented hyperprolactinemia is to decrease the heterogeneity of thePCOS population. These patients may be candidates for ovulation induction withalternate regimens (dopamine agonists). A normal level within the last year or ontreatment is adequate for entry.

8. Patients with known 21-hydroxylase deficiency or other enzyme deficiency leading tothe phenotype of congenital adrenal hyperplasia. 21-hydroxylase deficiency will beexcluded in all patients by a fasting 17-hydroxyprogesterone (17-OHP) level <2 ng/mL (Azziz, Hincapie et al. 1999 Nov). If relevant, this level should be determined in thefollicular phase, because the 17-hydroxyprogesterone level is likely to be elevatedbeyond this range if the patient is in the luteal phase of an infrequent ovulatorycycle. In the case of elevated fasting 17-OHP levels in the follicular phase, an ACTHstimulation test will be performed. A 1-hour stimulated value > 10 ng/mL will be anexclusion (Moran, Knochenhauer et al. 1998). As 21-hydroxylase deficiency is acongenital condition, any normal level in the past of 17-hydroxyprogesterone allowsentry into this study.

9. Patients with menopausal levels of FSH (> 15 mIU/mL). A normal level within the lastyear is adequate for entry.

10. Patients with uncorrected thyroid disease (defined as TSH < 0.2 mIU/mL or >5.5mIU/mL). A normal level within the last year is adequate for entry.

11. Patients diagnosed with Type I or Type II diabetes who are poorly controlled (definedas a glycohemoglobin level > 7.0%), or patients receiving antidiabetic medicationssuch as insulin, thiazolidinediones, acarbose, or sulfonylureas likely to confound theeffects of study medication; patients currently receiving metformin XR for a diagnosisof Type I or Type II diabetes or for PCOS are also specifically excluded.

12. Patients with liver disease defined as AST or ALT > 2 times normal or total bilirubin >2.5 mg/dL.

13. Patients with renal disease defined as BUN > 30 mg/dL or serum creatinine> 1.4 mg/dL.

14. Patients with significant anemia (Hemoglobin < 10 g/dL).

15. Patients with a history of deep venous thrombosis, pulmonary embolus, orcerebrovascular accident.

16. Patients with known heart disease that is likely to be exacerbated by pregnancy.

17. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, orbreast carcinoma. A normal Pap smear result within ACOG guidelines for Pap smearfrequency will be required for women 21 and over.

18. Patients with a current history of alcohol abuse. Alcohol abuse is defined as > 14drinks/week or binge drinking.

19. Patients enrolled simultaneously into other investigative studies that requiremedications, proscribe the study medications, limit intercourse, or otherwise preventcompliance with the protocol. Patients who anticipate taking longer than a one monthbreak during the protocol should not be enrolled.

20. Patients taking other medications known to affect reproductive function or metabolism.These medications include oral contraceptives, GnRH agonists and antagonists,antiandrogens, gonadotropins, anti-obesity drugs, anti-diabetic drugs such asmetformin and thiazolidinediones, somatostatin, diazoxide, ACE inhibitors, and calciumchannel blockers. The washout period on all these medications will be two months and alist is found in the appendix.

21. Patients with a suspected adrenal or ovarian tumor secreting androgens.

22. Patients with suspected Cushing's syndrome.

23. Couples with previous sterilization procedures (vasectomy, tubal ligation) which havebeen reversed. The prior procedure may affect study outcomes, and patients with both areversed sterilization procedure and PCOS are rare enough that exclusion should notadversely affect recruitment.

24. Subjects who have undergone a bariatric surgery procedure in the recent past (<12months) and are in a period of acute weight loss or have been advised againstpregnancy by their bariatric surgeon.

25. Patients with untreated poorly controlled hypertension defined as a systolic bloodpressure ≥ 160 mm Hg or a diastolic ≥ 100 mm Hg obtained on two measures obtained atleast 60 minutes apart.