Fertility problems are due to many possible reasons, including structural defects in the reproductive tract, hormonal imbalances and problems with sperm; all of these can affect the successful fertilization of the egg and implantation of the embryo. One of the more common causes of infertility, estimated to affect 5 to 7 percent of reproductive age women, is ovulatory dysfunction due to polycystic ovarian syndrome (PCOS). PCOS is characterized by irregularities in menstruation and persistent anovulation due to excessive amounts and effects of androgenic, or masculinizing, hormones. The symptoms of PCOS are obesity, hirsuteness and acne. While PCOS derives its name from the multiple ovarian cysts seen in this condition, not all cases of PCOS will have cysts and not all ovarian cysts are PCOS.
Ovulatory Dysfunction in PCOS
Two of the causes of ovulatory dysfunction in PCOS are insulin resistance and hyperinsulinemia. Insulin is secreted by the pancreas to lower the blood glucose levels. Insulin resistance develops if the reduction in blood glucose is less than expected for a given amount of insulin. It is thought that insulin resistance is due to resistance in target tissues, reduced clearance in the liver or increased pancreatic sensitivity. Since typical amounts of insulin fail to bring blood glucose down, the pancreas secretes more insulin to the bloodstream to compensate. Increased levels of insulin, or hyperinsulinemia, together with insulin resistance are responsible for the increase in androgens observed in PCOS.
When there is an increase in the levels of circulating insulin, excess insulin binds to receptors in theca cells in ovarian follicles and induces them to synthesize more androgens. In addition, insulin reduces the liver’s production of sex hormone-binding globulin (SHBG), a protein that normally sequesters excess estrogens and androgens in the blood. With less SHBG, there is an increase in the levels of free, active estrogens and androgens. Studies have shown that weight loss and reduction in insulin levels can reduce androgen levels.
Metformin in Treating PCOS
Since hyperinsulinemia and insulin resistance are central to PCOS manifestations, including hyperandrogenism and infertility, treatments that reduce insulin resistance and ultimately reduce insulin levels should be able to restore cyclic menstruation and regular ovulation. Reductions in insulin resistance can be achieved through lifestyle modifications that include weight loss, improved nutrition and exercise. If these modifications fail, medications that can improve the insulin sensitivity of peripheral tissues can be used.
One of the medications available for this indication is metformin, an oral antidiabetic drug that belongs to the biguanide class. The medication can reduce insulin resistance and insulin levels by increasing the glucose utilization of muscle and fat even at normal insulin levels and by decreasing the liver’s production of new glucose molecules. By addressing hyperinsulinemia, treatment with metformin also reduces androgen levels in the blood.
The usual dose of metformin is 500 mg every eight hours. Four to six months of metformin treatment is required before resumption of regular menses and ovulation occurs. Evidence from good studies indicates that when metformin is taken with pro-ovulatory drugs, such as clomiphene and gonadotropins, the likelihood of ovulation and a successful pregnancy is increased.