Many women present to their physician for management of symptoms of androgen excess and/or menstrual irregularity. In general medical treatment is designed to lower serum androgens and thereby improve symptoms. There are several pharmaceutical agents that are used for polycystic ovarian syndrome although there is no specific FDA-approved medication for the treatment of polycystic ovarian syndrome. Table Treatment options for PCOS summarizes the main clinical treatments in polycystic ovarian syndrome.
Table Treatment options for PCOS
|Treatment||Presumed Mechanism of Action||Impact||Possible Disadvantages|
|Combination oral contraceptives||Decreases LH secretion
Suppresses ovarian testosterone production
Reduced serum testosterone
|Possible adverse impact on lipids
Variable progestin component with variable androgen impact
|Cyclic progestins||Endometrial stabilization and induces secretory changes||Induction of menses||No androgenic improvements|
Inhibits DHT binding to receptor
Pregnancy Category C
|Flutamide||Blocks action of DHT on receptor||Reduced hirsutism||Hepatocellular dysfunction
|Finasteride||Inhibits 5-a reductase||Reduced hirsutism||No impact on alopecia
|Eflornithine hydrochloride||Inhibits ornithine decarboxylase||Topical cream that slows rate of facial hair growth||Does not prevent new hair growth
Does not impact androgens
|Metformin||Reduces hepatic glucose output
Decreases insulin levels
|Improved ovulatory rates
Improved menstrual cycles
|Gastrointestinal side effects common|
|Pioglitazone/ Rosiglitazone||Improves skeletal and hepatic insulin sensitivity||Improved ovulatory rates
Effective insulin sensitizer
|Possible weight gain
Pregnancy category C
Oral Contraceptives and Progestins
One first line agent that is used for the control of menstrual irregularity is also the predominant treatment for androgen suppression. Use of combination oral contraceptives will significantly reduce circulating free testosterone. Oral contraceptives contain ethinyl estradiol which will suppress luteinizing hormone secretion from the pituitary and decrease luteinizing hormone-driven production of testosterone from the ovary. Additionally, estrogenic compounds increase SHBG production in the liver which will reduce the circulating component of free testosterone. The progestin component of the oral contraceptive will also contribute to luteinizing hormone suppression. The type of progestin varies in different combination oral contraceptives. Progestins can have variable androgenic activity as they are derived from an androgenic base. Drosperinone, an analog of spironolactone with unique anti-androgenic activity, also has progestin activity and is now available in an oral contraceptive. At this time, it has not yet been studied for its effects to reduce androgenic symptoms more than other oral contraceptive formulations, but it is a promising agent in the treatment of androgen excess disorders.
Cycle control is significantly enhanced when using oral contraceptives. Most women with polycystic ovarian syndrome are oligo-ovulatory at best, and continuous estrogenic exposure of the endometrium without exposure to progesterone enhances the potential for erratic breakthrough bleeding which can be heavy, as well as increasing the risk for development of endometrial hyperplasia and cancer of the endometrium. The progestin component in oral contraceptives will significantly reduce this risk.
Cycle control with intermittent use of oral progestins such as medroxyprogesterone acetate will also result in regular withdrawal bleeding. Used on a regular basis this will also decrease endometrial hyperplasia and cancer risks. However, oral progestins alone will not significantly reduce androgenic symptoms and are often inadequate as a single agent for the control of all the symptoms of polycystic ovarian syndrome.
The metabolic effects of oral contraceptives have raised some concerns about the use of these agents in insulin resistant women. Some but not all studies indicate worsening of insulin resistance in polycystic ovarian syndrome women on oral contraceptives. They have not, however, been shown to increase the rate of type 2 diabetes. Effects of oral contraceptives on vascular reactivity and inflammation in polycystic ovarian syndrome are yet not well studied, and it should be recognized that there may be potential adverse effects when considering these agents for polycystic ovarian syndrome treatment.
Spironolactone is an anti-mineralocorticoid agent that also acts as an anti-androgen. It is a potassium sparing diuretic that in high doses (100-200 mg/ day) demonstrates significant anti-androgenic properties. Spironolactone interferes with testosterone biosynthesis by reducing 17-hydroxylase activity and thus lowers plasma testosterone. It also inhibits dihydrotestosterone’s binding to the androgen receptor. It is not FDA-approved for treatment of androgenic symptoms but in many studies has been shown to be an effective agent in this regard. It is often combined with oral contraceptives to reduce testosterone action and production.
Menstrual cycle irregularity can be seen with the use of spironolactone alone. Typically it is combined with oral contraceptives, thereby reducing this concern. Additionally it is a pregnancy category C drug so should be used with contraception to avoid pregnancy while taking it.
Flutamine and finasteride can improve androgenic symptoms in polycystic ovarian syndrome. In general potential serious side-effects have limited their use in the United States. Flutamide is a nonsteroidal, nonhormonal antiandrogenic drug, which has been demonstrated to block the action of dihydrotestosterone (DHT) on androgen receptors. It has been associated with hepatocellular dysfunction. Finasteride is a 4-aza analog of testosterone and is a competitive inhibitor of both tissue and hepatic 5-alpha reduc-tase. This results in inhibition of the conversion of testosterone to dihydrotestosterone. In small mostly uncontrolled studies it has been shown to be effective in the treatment of hirsutism. It does not seem to treat androgenic alopecia in women however, unlike the effect seen in male pattern baldness in men.
Eflornithine hydrochloride is an inhibitor of ornithine decarboxylase in skin. It is available as a topical cream that can slow the rate of hair growth and has been shown to have some effect in the treatment of facial hirsutism.
Insulin Sensitizing Agents
Given the prevalence of insulin resistance seen in PCOS, a number of insulin-sensitizing agents have been studied in the treatment of symptoms. Currently metformin, a biguanide, and pioglitazone and rosiglitazone, thiazolidinediones, are available clinically, and all have been studied in polycystic ovarian syndrome. The single most common agent for use in polycystic ovarian syndrome is metformin. Metformin appears to work by reducing hepatic glucose output thereby reducing the demand for insulin. A meta-analysis of thirteen studies of metformin in polycystic ovarian syndrome concluded that metformin significantly enhanced the rate of ovulation. There was also evidence for improved insulin levels and reduced cholesterol. There is conflicting evidence that metformin’s effects are partially mediated through weight reduction. Metformin has been noted in several studies to be associated with weight reduction in the initial phase of treatment, but this is not consistently seen. The effects of metformin on pregnancy loss and gesta-tional diabetes have been studied only in small uncontrolled trials. Current evidence is not sufficient to conclude a consistent positive effect.
The thiazolidinedione therapies are associated with improved insulin action at the level of skeletal muscle and liver. The largest available study involved troglitazone, which is no longer on the market due to hepatotoxicity However, significant improvements in ovulation were noted in a 48-week trial. Both pioglitazone and rosiglitazone have been shown to improve ovulatory rates in polycystic ovarian syndrome in small trials. Both are pregnancy category C agents and have not been studied in pregnancy. No association with weight reduction is noted with these agents. Several studies indicate slight increases in weight with use although metabolic improvements are noted.
Weight reduction, of as little as 3-5%, has been associated with improvements in ovulation rates in polycystic ovarian syndrome women who are overweight or obese. Although studies are consistent in this regard, no large scale controlled trials are available to assess improvements in pregnancy rates. There are no specific dietary regimens that target polycystic ovarian syndrome and effective weight reduction has been demonstrated with a wide variety of approaches.
Achieving and maintaining permanent weight reduction is a challenge that is often met with repeated failures and relapse. Severely restrictive diets have not been shown to improve outcomes over modest changes in diet that result in slow weight reduction. Metabolic parameters are also consistently improved with lifestyle modification that includes weight reduction. Exercise, although not a significant tool in initial weight reduction, is associated with better maintenance of weight reduction over time and should be encouraged. Significant support is needed to encourage women with polycystic ovarian syndrome who are overweight or obese to consider lifestyle modification as the first line of therapy.