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7400 Fannin St., Suite 1180
Houston, Texas 77054 Phone (713) 790-9900 Fax (713) 790-9901 |
Robert
B. McWilliams, MD
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INFERTILITY MALE
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Use of ACTOS in the Treatment of PCOS with Insulin Resistance.1. PCOS and Insulin Resistance Polycystic Ovarian Syndrome is one of the most common endocrine disorders of women of reproductive age. Classic symptoms consist of hyperandrogenism (hirsutism, acne) together with symptoms of anovulation (infertility and oligomenorrhea). Recent research has found growing concern that this syndrome is also associated with hyperinsulinemia, insulin resistance, dyslipidemia, and hypertension. Risks of developing type 2 diabetes (noninsulin-dependent) and possibly premature cardiovascular disease is higher in these 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 of 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. 2. Nature of the Drug ACTOS (pioglitazone HCl), an oral hyperglycemic (elevated blood sugar) agent that acts primarily by improving the cells response to insulin, is manufactured by Takeda Pharmaceuticals. It is one of a unique class of drugs called thiazolidinedione antidiabetic agents that exerts direct effects on insulin resistance. Furthermore, it appears to enhance insulin action without directly stimulating insulin secretion or affecting glucose levels. Its effects help lower the elevated insulin levels in the blood stream of patients with insulin resistance. ACTOS has only been shown to exert its antihyperglycemic effect in the presence of insulin. Because of its insulin-dependent mechanism of action, ACTOS is approved by the FDA for the management of type 2 diabetes (non insulin dependent diabetes mellitus (NIDDM)) also known as adult onset diabetes. It is important to understand that only a few small studies concerning the use of ACTOS in PCOS have been published or presented, and conclusive data regarding outcome, patient risks and complications, while currently being collected, is not yet available. For this reason, this information is intended to help inform you about this medication.
3. Potential Benefits Clinical studies demonstrate that ACTOS improves insulin-sensitivity in insulin-resistant patients. The effects occur without weight loss. Treatment of PCOS patients with pioglitazone led to improvement of insulin resistance and hyperinsulinemia, with the concomitant reduction of elevated testosterone and LH levels toward the normal range. In some of these women, ovulation also occurred during the period of drug therapy. The advantage of ACTOS over traditional therapies for the treatment of PCOS is two-fold; 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. Furthermore, patients with lipid abnormalities showed a mean decrease in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. Patients with these types of abnormalities are appropriate candidates for therapy if they demonstrate Insulin Resistance and the need for an insulin-sensitizing agent. 4. Method of Administration ACTOS is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. It is absorbed rapidly after oral administration, the time for maximum plasma concentration occurs within 2 to 3 hours. Food does not alter the extent of absorption, thus ACTOS should be taken without regard to meals. Pioglitazone has other unique advantages, including once-a-day administration, a low incidence of minor side effects, no known drug interactions, hepatic metabolism and secretion, and potent antioxidant properties 5. Risks and/or Side Effects Pioglitazone is contraindicated in women with certain underlying medical disorders. Because pioglitazone is structurally related to another drug of the thiazolidinediones, troglitazone (Rezulin) which has been associated with elevated liver function tests as a result of an idiosyncratic hepatotoxicity, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Therefore, serum liver function tests are to be followed every 2 months for the first year of therapy, and periodically thereafter. ACTOS will not be initiated if there is any evidence of liver disease. In premenopausal anovulatory patients with insulin resistance, Actos treatment may result in resumption of ovulation. The use of Actos can cause resumption of ovulation in women taking oral contraceptives (OC). Therefore, a higher dose of OC or an alternative method of contraception should be considered. These patients may be at risk for pregnancy. Another concern with this drug is possible teratogenic effects. Although this medication has no known human teratogenic effects, this reflects the lack of substantial experience in reproductive-aged women with troglitazone. A prospective registry is now in place to monitor birth outcomes following troglitazone exposure. 6. Pre-treatment Testing At the initial screening, hyperinsulinemic insulin resistance will be determined by obtaining a blood sample after a 12 hour fast for fasting insulin, fasting glucose and C-peptide levels. A glycosolated hemoglobin (HbA1C) will also be determined. A glucose/insulin ratio of < 7.0 will be used to define insulin resistance. A hepatic profile will be monitored at monthly intervals to follow liver function. 7. Alternative Therapy The correction of hyperandrogenism in women with PCOS may 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. Infertility and Women's Health Care Articles
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