The goal of this three-armed randomized controlled trial is to establish the relative roles of treatment of hyperandrogenism versus obesity (as the largest modifiable factor contributing to insulin resistance) in treating infertility and improving pregnancy outcomes among obese PCOS women. The investigators hypothesize that the key to restoring ovulation leading to live birth is to correct hyperandrogenism with oral contraceptive pills, but the key to avoiding later pregnancy complications is to improve insulin sensitivity with weight loss.
Full Title of Study: “Treatment of Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: March 2014
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.
- Drug: Orlistat/Meal Replacement/Lifestyle Modification
- Orlistat will be given at 60 mg three times per day (1 tablet 3 times a day) before meals, i.e., breakfast, lunch, and dinner.
- Drug: Loestrin 1/20
- Patients will be started on a low dose containing OCP for a continuous 4 month period.
- Drug: Combination of treatments
- Medications will be administered as described for the other 2 arms.
Arms, Groups and Cohorts
- Active Comparator: Lifestyle intervention
- Orlistat/Meal Replacement/Lifestyle Modification
- Active Comparator: Oral Contraceptives (OCP)
- Loestrin 1/20
- Active Comparator: Lifestyle/OCP Combined
- Combination of treatments
Clinical Trial Outcome Measures
- Live Birth Rate
- Time Frame: Participants were followed for 4 months of attempted conception and those who conceived were then followed for the duration of their pregnancy, approximately 9 months.
- Ovulation Rate
- Time Frame: Up to 4 months
- Change in Weight
- Time Frame: Baseline, 4 months
- Change from baseline to end of the 4-month intervention.
- Prevalence of Metabolic Syndrome
- Time Frame: Baseline, 4 months
Participating in This Clinical Trial
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.
Gender Eligibility: Female
Minimum Age: 18 Years
Maximum Age: 40 Years
Are Healthy Volunteers Accepted: Accepts Healthy Volunteers
- Lead Sponsor
- Milton S. Hershey Medical Center
- University of Pennsylvania
- Provider of Information About this Clinical Study
- Principal Investigator: Richard S. Legro, M.D., Professor, Obstetrics and Gynecology and Public Health Sciences – Milton S. Hershey Medical Center
- Overall Official(s)
- Richard S Legro, M.D., Principal Investigator, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center
- Christos Coutifaris, M.D., Ph.D., Principal Investigator, Universtiy of Pennsylvania, Department of Obstetrics and Gynecology
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