Metformin and PCOS Therapy

Polycystic Ovarian Syndrome (PCOS), with insulin resistance, is one of the most common endocrine disorders in women of reproductive age. Classic symptoms consist of elevated male hormone levels leading to excess body hair (hirsuitism), acne, a classic "pear" body shape, and anovulation (lack of ovulation).

Recent research has found that PCOS is associated with hyperinsulinemia (elevated insulin levels) , insulin resistance, dyslipidemia, and hypertension. Risks of developing type 2 diabetes (noninsulin-dependent) and possibly premature cardiovascular disease is higher in patients with insulin resistance.

Insulin resistance, characterized by a decrease in the ability of insulin to stimulate glucose uptake to muscle and fat cells, as well as to inhibit glucose production by the liver, is a common feature in women with PCOS. Up to 40% of women with PCOS demonstrate some degree of impaired glucose tolerance as a result of insulin resistance.

It appears likely that an inherent, probably genetically determined, ovarian defect is present in women with PCOS which makes the ovary susceptible to insulin stimulation of androgen (male-like hormone) production. The insulin resistance and hyperinsulinemia are primary events in PCOS that somehow lead to hyperandrogenism and the subsequent reproductive endocrine abnormalities.

Metformin (Glucophage) is an oral hyperglycemic (elevated blood sugar) agent which acts primarily by improving the cells response to insulin. Metformin is one of a unique class of drugs that exerts direct effects on insulin resistance without affecting insulin secretion. Once the insulin sensitivity is improved ovulation will resume.

Metformin is known to increase peripheral glucose uptake with some reduction in basal hepatic glucose production. Its effects help lower the elevated insulin levels in the blood stream of patients with insulin resistance.

Metformin has only been shown to exert its antihyperglycemic effect in the presence of insulin. Because of its insulin-dependent mechanism of action, Metformin is approved by the FDA for the management of type II diabetes (non insulin dependent diabetes mellitus (NIDDM)) also known as adult onset diabetes.

Metformin treatment has been reported to decrease fasting insulin levels in non diabetic obese women. Clinical studies have specifically examined changes in ovulatory function in women with PCOS on Metformin (Glucophage 500 mg three times per day with meals) and confirmed increased frequency of spontaneous ovulation, resumption of menstrual cyclicity, and an improved ovulatory response to clomiphene.

Several previously infertile women with PCOS who were treated with Metformin for six months conceived and delivered healthy infants. The advantage of Metformin over traditional therapies for the treatment of PCOS is twofold; 1) it corrects both metabolic and endocrinologic aberrations; and 2) it permits resumption of normal endogenous ovulatory function, with little or no risk of ovarian hyperstimulation or multiple gestation.

Metformin has been in clinical use in the United States since 1995. It can produce gastrointestinal symptoms which are dose-related and tend to resolve after several weeks. In the first few weeks of taking Metformin, many patients will experience anorexia (loss of appetite), nausea, diarrhea or abdominal discomfort which usually resolves during continued treatment. (See the Bristol Myers Squibb Web site for a full discussion of potential side effects)

Pretreatment testing at the initial screening- Hyperinsulinemic insulin resistance will be determined by obtaining a blood sample after a 12 hour fast for insulin, glucose and C-peptide levels. A glycosolated hemoglobin (HbA1C), CBC with differential and platelets, and urinalysis will also be evaluated. A glucose/insulin ratio of < 7.0 will be used to define insulin resistance. A comprehensive metabolic panel profile will be monitored at monthly intervals to follow renal and liver function.

The correction of hyperandrogenism in women with PCOS may also be achieved by interventions which improve insulin sensitivity and reduce circulating insulin. Such measures include, but are not limited to weight loss, dietary modifications and insulin-sensitizing medications. The use of anti-diabetic drugs in PCOS represents a novel use of these agents.

The management of PCOS should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the insulin resistant patient with PCOS. This is not only important in the primary treatment of PCOS but in maintaining efficacy of drug therapy.

MORE INFORMATION ON METFORMIN, INSULIN RESISTANCE, AND PCOS

 

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