Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (PCOS) Women

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility among
women, and women with PCOS are at increased risk for pregnancy complications such as
gestational diabetes and pre-eclampsia. Both hyperandrogenism (HA) and obesity exacerbated
insulin resistance (IR) are characteristics of the syndrome, and are targets for treatment,
but which should be the predominant focus is still unknown. Phase 1 of this study will be a
randomized trial of three preconception interventions in infertile women with PCOS. The
first arm will be a combined intervention of medication, meal replacements, and lifestyle
modification to improve IR. Orlistat is a gastric lipase inhibitor that reduces the
absorption of fat contained in a meal by about 30%. The second arm will be the use of a
continuous OCP for 4 months to improve HA. Lo-Estrin 1/20 will be used in a continuous
method for 4 months to suppress the ovary. The third arm is the combination of both to
improve HA an IR. Phase II of this study will involve ovulation induction with clomiphene
citrate with hopeful outcome of pregnancy. Finally, Phase III involve following the
pregnancies for outcomes and complications.

Couples Inclusion Criteria:

- Partner with sperm concentration of >=14 million/mL in at least one ejaculate with
motile sperm.

- Ability to have regular intercourse 2-3 times per week during the ovulation induction
phase of study.

- At least one patent tube and normal uterine cavity as determined by sonohysterogram,
hysterosalpingogram, or hysteroscopy/laparoscopy within the last 3 years, or
confirmation of a intrauterine pregnancy within the past 2 years.

- No previous sterilization procedures(vasectomy, tubal ligation) that have been
reversed.

- Wanting to seek pregnancy.

Inclusion Criteria:

- Chronic anovulation or oligomenorrhea defined as intermenstrual periods of >= 45 days
or a total of <=8 periods per year.

- Hyperandrogenism will be an elevated total testosterone >=50 ng/dL.

- Hirsutism determined by a modified Ferriman-Gallwey Score >8.

- PCO on ultrasound (12 or more follicles measuring 2-9 mm in diameter).

- BMI >=27 to <=42.

- Normal EKG to rule out any abnormalities with the heart.

Exclusion Criteria:

- Current pregnancy.

- Patients on oral contraceptives, depo progestins, or hormonal implants.

- Patients with hyperprolactinemia defined as two prolactin levels at least one week
apart >30 ng/mL.

- Patients with known 21-hydroxylase deficiency by a fasting 17-hydroxyprogesterone
(17-OHP) level <2 ng/mL and ACTH stimulation test as needed, or other enzyme
deficiency.

- Patients with menopausal FSH levels >20 mIU/mL.

- Patients with uncorrected thyroid disease (TSH <0.45 mIU/ML or >4.5 mIU/ML).

- Patients diagnosed with Type1 or Type II diabetes.

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

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

- Patients with significant anemia (Hemoglobin <10 mg/dL).

- Patients with a history of deep venous thrombosis, pulmonary embolus, or
cerebrovascular accident.

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

- Patients with a history of , or suspected cervical carcinoma, endometrial carcinoma,
or breast carcinoma. A normal PAP smear or reassuring colposcopy based on current
ACOG guidelines will be required.

- Patient with current history of alcohol abuse.

- Patients enrolled simultaneously into other investigative studies.

- Patients taking other medications know to affect reproductive function or metabolism.

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

- Patients with suspected Cushing's syndrome.

- Patients who have undergone a bariatric surgery procedure in the recent past (<12
months).

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

- Patients with medical conditions that represent contraindications to orlistat, OCP,
clomiphene, and/or pregnancy.

- Patients currently participating in lifestyle intervention program (Weight Watchers,
Atkins Diet, Curves) or lost more than 5% body weight within the last 6 months.