Randomized Study of Decreased Hyperinsulinemia on the Ovulatory Response to Clomiphene Citrate in Women With Polycystic Ovary Syndrome

PROTOCOL OUTLINE: This is a randomized, double blind, placebo controlled, multicenter study. Patients are randomized to one of two treatment arms.

Patients receive oral metformin or oral placebo three times daily for 7 weeks. Patients remaining anovulatory by day 49 receive metformin or placebo plus escalating doses of oral clomiphene citrate daily for 5 consecutive days, beginning on days 50, 80, and 110. Following ovulation, treatment with clomiphene citrate and metformin or placebo continues until 6 ovulatory cycles occur, pregnancy occurs, or anovulation persists. Patients receiving the placebo arm who have not ovulated on the highest dose of clomiphene citrate may be crossed over to receive metformin after a 6 week washout.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Patients with chronic anovulation due to polycystic ovary syndrome (PCOS) who have failed clomiphene citrate

Must have oligoovulation and hyperandrogenemia

--Prior/Concurrent Therapy--

Endocrine therapy: At least 2 months since prior clomiphene citrate

Other:

• At least 2 months since prior standard therapy (including over the counter drugs)
• At least 2 months since prior investigational drugs
• Prior multi/prenatal vitamins allowed

--Patient Characteristics--

Hematopoietic: Hematocrit greater than 38%

Hepatic:

• Liver function normal
• No clinically significant hepatic disease

Renal:

• No clinically significant renal disease
• Creatinine less than 1.4 mg/dL
• No proteinuria

Cardiovascular: No clinically significant cardiac disease

Pulmonary: No clinically significant pulmonary disease

Hormonal:

• Thyroid function normal
• Prolactin normal
• Estradiol normal
• Fasting 17 alpha-hydroxy progesterone less than 200 ng/dL OR No late onset adrenal hyperplasia 21 alpha-hydroxylase deficiency

Other:

• Not pregnant
• Negative pregnancy test
• Male partner must have a normal semen analysis by WHO criteria
• Must be in acceptable health by interview, medical history, physical exam, and laboratory tests
• No diabetes mellitus
• No clinically significant neurologic, psychiatric, infectious, neoplastic, or metabolic disease
• No clinically significant malignant disease except nonmelanomatous skin cancer
• At least 1 year since any prior drug abuse or alcoholism