The polycystic ovary syndrome (POS) is a fairly common condition, affecting about 6% of women of reproductive age. It is characterized by anovulation, oligomenorrhea or amenorrhea, and hirsuitism. About half of the women with this syndrome are obese and some have diabetes mellitus. There are three hormones involved in POS: testosterone, luteinizing hormone (LH), and insulin. For years, medical scientists were aware that the local and systemic symptoms of POS were due to increased ovarian production of androgens, particularly testosterone, but only recently has the role of insulin in POS been carefully examined.
In the ovaries of normal women, progesterone is converted within the theca cells to 17alpha-hydroxyprogesterone, then to androstenedione, and finally to testosterone. Testosterone, in turn, is converted to estradiol in the granulosa cells. In women with polycystic ovaries, there is an increase in the enzyme cytochrome P450c17alpha that converts progesterone to androstenedione. Since androstenedione is rapidly converted into testosterone, the result is increased testosterone production. Some of the excess testosterone causes premature follicular atresia and anovulation, some of the excess reaches the circulation.
What causes the increase in ovarian enzyme activity? It appears that the culprit is insulin, or more to the point, insulin resistance with compensatory hyperinsulinemia. Insulin increases testosterone production by stimulating ovarian function, specifically, by stimulating the activity of cytochrome P450c17alpha. Insulin also decreases serum sex hormone-binding globulin by decreasing the hepatic production of the binding protein; with less binding capacity, there is more free testosterone in the serum. Finally, it appears that insulin increases LH production. Дuteinizing hormone (LH) contributes to POS by stimulating theca-cell growth and thus enhancing testosterone production.
Recently Nestler and Jakubowicz published a report in the New England Journal of Medicine describing the results of their study of an oral hypoglycemic agent – metformin (Glucophage/Bristol Myers Squibb) – on glucose tolerance and serum steroid concentrations in 24 obese women with polycystic ovary syndrome (POS). Metformin is a biguanide that reduces insulin resistance and secondarily inhibits insulin secretion. The subjects were given either placebo or metformin (500 mg three times daily) for 4-8 weeks. Compared with placebo, metformin reduced insulin secretion by about 50% and caused a reduction of approximately 50% in levels of basal and peak serum 17alpha- hydroxyprogesterone and serum free testosterone. Metformin also reduced serum LH about 75% and increased serum sex- binding globulin concentration about 75%. These values remained basically the same in the placebo group.
In some of the study participants, metformin actually induced ovulation. The fact that the reduction in insulin secretion caused a prompt drop in serum basal and stimulated-peak 17alpha-hydroxyprogesterone levels indicates that insulin has a direct effect on cytochrome P450c17alpha, enhancing the production of the hydroxyprogesterone. The effects of insulin on this enzyme are probably heritable, since not all women with insulin resistance and hyperinsulinemia have POS.
In an accompanying editorial in the New England Journal of Medicine, Robert Utiger said that POS is currently treated with weight loss and oral contraceptives and/or an antiandrogen such as spironolactone of cyproterone. The infertility is treated with clomiphene or assisted- reproduction procedures. However, if metformin can reduce androgen production, restore cyclic pituitary-gonadal function, and improve fertility, “it could represent a substantial advance in treatment for women with polycystic ovary syndrome.”