Treatment Options for Polycystic Ovary Syndrome

Drug Therapy for Polycystic Ovary Syndrome

When weight loss, diet and exercise do not adequately improve the symptoms of polycystic ovary syndrome (PCOS), drug therapy is usually initiated. There are several types of medications for the treatment of PCOS. Drugs may be given alone or in combination, may require readjustment of dosages, or may require adjustments of the particular combinations over time or with varying circumstance, (e.g., when trying to conceive).

Drugs used for the treatment of symptoms of PCOS include:

• Antiandrogens
• Oral contraceptives
• Insulin sensitizing drugs
• Glucocorticoids
• Gonadotropin releasing hormone (GnRH) agonists
• Ovulation-inducing drugs

Antiandrogens

Antiandrogens are a class of drugs that block the actions of androgens (male sex hormones such as testosterone) by preventing androgens from binding to androgen receptors on cells or by inhibiting the enzyme that converts testosterone to androgen.

Antiandrogens may be prescribed with oral contraceptives. Some of the reasons for combining them include:

• Antiandrogens may be teratogenic (may cause deformities to the fetus) and so they must be given in conjunction with birth control pills in women who are at risk of becoming pregnant.

• Each drug works differently and their combined effect is greater than either alone.

• Oral contraceptives can prevent irregular bleeding which is often a side effect of antiandrogens.

There are several antiandrogen drugs that may be used for symptoms of PCOS:

• Spironolactone (Aldactone, Spitonol)
• Flutamide (Eulexin)
• Finasteride (Proscar)
• Cyproterone acetate (Cyprostat)
• Ketoconazole

Spironolactone

Spironolactone (Aldactone, Spitonol) is a diuretic and is used to treat hypertension. Spironolactone is also active at the level of the hair follicle where it blocks the effect of androgen, thereby reducing excessive hair growth. It is usually stopped approximately 3 months before a woman plans to conceive. Spironolactone is one of the most widely used antiandrogens in the U.S.

Side effects include:

• Menstrual irregularity
• Hypotension
• Lethargy
• Increased urinary frequency
• Headache
• Mood swings
• Gastrointestinal disturbances
• Dry skin

Flutamide

Flutamide (Eulexin) is a non-steroidal antiandrogen and is used to treat prostate cancer. However, it is also very effective for hirsutism and acne. The effects of flutamide include:

• Reducing circulating androgens
• Reducing overall ovarian size
• Restoring ovulatory cycles

The efficacy of flutamide is considered to be comparable to that of spironolactone and, in addition, may have the advantage of not affecting kidney function. It is a highly effective antiandrogen, however, patients must be monitored carefully for signs of hepatotoxicity (liver toxicity) since it is metabolized by the liver.

Side effects of flutamine include:

• Dry skin
• Decreased libido
• Increased appetite
• Amenorrhea

Finasteride

Finasteride (Proscar) is used to treat benign prostatic hyperplasia (enlarged prostate) in men. Finasteride inhibits the activity of 5-alpha reductase, an enzyme that binds androgens at the level of the hair follicle.

Side effects of finasteride are rare but may include decreased libido. Since it may be teratogenic, caution must be exercised when the patient may be trying to conceive.

Cyproterone Acetate

Cyproterone acetate (Cyprostat) is a strong progestin that is very effective as an antiandrogen since it increases the metabolic clearance of androgens from the body. It is usually given with estrogen in order to prevent uterine bleeding. Liver function should be monitored for hepatotoxicity. This drug is currently not available in the United States.

Side effects include:

• Fluid retention
• Mood swings
• Weight gain
• Headaches
• Nausea
• Fatigue

Ketoconazole

Ketoconazole is an antifungal agent that inhibits androgen biosynthesis. It is toxic to the liver) and, therefore, is not a first-line antiandrogen therapy.

Oral Contraceptives

Oral contraceptives are synthetic hormones that mimic the natural hormones produced by the body. They consist of synthetic estrogen and progestin (alone or combined). Oral contraceptives reduce gonadotropin stimulation of the ovary and by doing so, reduce the production of androgen. They also raise the SHBG concentrations, thereby reducing the level of free testosterone in the blood. In addition, by manipulating the amount of these synthetic hormones, it is possible to cause the build up of the endometrium to a sufficient level so that if there is no conception, it will slough off in a menstrual cycle. Thus the oral contraceptive can be used also to regulate the menstrual cycle.

There are few studies that have compared different types of oral contraceptives. Responses to oral contraceptives are very individualized and can vary from woman to woman. Since the oral contraceptives contain different progestogens with different androgen potencies, it is reasonable to prescribe one with a low androgenic profile, such as drospirenone. The effect of oral contraceptives on obesity is not clear.

Oral contraceptives are often given together with other types of medication since they seem to enhance the effects of other drugs and the combined action of both drugs is sometimes greater than for each drug separately.

Limitations of oral contraceptive may include:

• Reappearance of symptoms when treatment is stopped
• No effect on the metabolic aspects of PCOS (insulin resistance)

Side effects of oral contraceptives include:

• Stroke
• Blood clots
• Liver cancer

These side effects are rare but the risk of stroke is elevated if the woman smokes cigarettes while taking oral contraceptives.

Insulin Sensitizing Drugs

Whereas many medications treat the symptoms of PCOS, insulin-sensitizing drugs are given to correct the underlying metabolic dysfunction of insulin resistance and do so at a relatively low risk and low cost. They are effective in decreasing hyperinsulinemia and thereby improving almost all symptoms, including reproductive function.

There is ongoing debate regarding whether treatment of women with PCOS who are insulin resistant reduces the risk of developing type II diabetes.

There are two types of insulin sensitizing agents - biguanides and glitazones. Neither has been approved by the FDA specifically for use in women with PCOS.

Biguanides

Metformin (Glucophage) was approved by the FDA for the treatment of Type II diabetes and insulin resistance that could not be adequately controlled by diet. It has not received FDA approval for treatment of PCOS though it is widely used. Metformin is considered a first-line drug therapy of the various insulin sensitizing agents. It lowers insulin levels by inhibiting hepatic (liver) glucose production, reduces the amount of glucose absorbed from food, and enhances the effect of insulin to reduce blood glucose.

Benefits of reduced glucose include:

• Increase in ovulatory rates
• Resumption of menstrual cycle
• Reduced waist:hip ratio
• Lower levels of androgens

Metformin is often combined with other drugs such as antiandrogens and oral contraceptives since it works differently than the others and appears to boost their effectiveness. It is usually initiated at low doses and is increased in graduating amounts as needed. It appears that even women who do not show signs of insulin resistance benefit from metformin for most other symptoms of PCOS.

Research reported in the British Medical Journal indicated that women with high blood pressure who were treated with metformin experienced a significant reduction in blood pressure. In a study published in the Journal of Clinical and Endocrinological Metabolism, adolescents treated with metformin experienced a significant improvement of hirsutism, hyperandrogenism, improved glucose tolerance, as well as regulation of menstrual cycles.

Side effects of metformin include:

• Gastrointestinal symptoms - diarrhea, nausea and anorexia)
• Lactic acidosis - the buildup of lactic acid in the body. This is a rare side effect and may be associated with alcohol use
• Poor absorption of vitamin B12

Metformin is not recommended for patients with renal (kidney) disease.

Glitazones

The glitazones are a relatively new class of insulin sensitizing drug used to control type II diabetes. They have been shown in studies to be very effective in reducing hyperandrogenism and improving ovulation. Glitazones improve the glucose uptake in muscle and peripheral tissue and also inhibit the production of glucose by the liver. The use of glitazones is often accompanied by weight gain.

There are three types of glitazones:

• Troglitazone - this drug has been shown to decrease testosterone, decrease fasting insulin levels and improve ovulation rates. However, troglitazone was removed from the market in 1999 due to liver toxicity.
• Pioglitazone (Actos)
• Rosiglitazone (Avandia)

The latter two drugs seem to improve glycemic control and show promise for the treatment of symptoms of PCOS. They may be given either individually or together with metformin or other medications. However, more testing is required before their efficacy and safety can be clearly established.

Glucocorticoids

If spironolactone and oral contraceptives do not adequately suppress levels of testosterone or DHEA-S, low doses of a glucocorticoid called dexamethasone may be given in order to decrease the adrenal production of these hormones. Glucocorticoids may also help in the establishment of ovulatory cycles.

Glucocorticoids are not used often since they cause many other undesirable side effects including:

• Water retention
• Osteoporosis
• Increased susceptibility to infection
• Insomnia
• Mood swings

Glucocorticoids can also affect blood sugar levels so that careful monitoring is required while taking these drugs.

Gonadotropin Releasing Hormone (GnRH) Agonists

GnRH agonists (e.g., Lupron, Zolodex and Synarel) are often used for severe ovarian hyperandrogenism since they cause almost complete suppression of ovarian function. This can lead to menopausal symptoms, including hot flashes and bone mineral loss, which are usually reversible with concurrent use of oral contraceptives. Due to the adverse side effects, as well as being expensive, GnRH agonists are not often used for the treatment of PCOS.

Ovulation Inducing Drugs

Drugs used to induce ovulation in women with anovulatory infertility associated with PCOS include:

• Clomiphene citrate (Clomid, Serophene) - Clomiphene citrate stimulates the release of gonadotropins that stimulate the follicular development of the ovaries.

• Synthetic gonadotropins (Humegon, Repronex) - Synthetic gonadotropins act directly on the ovary and are identical to those produced by the body. They induce follicular development and ovulation thereby increasing the likelihood of conception. The most common gonadotropins used for ovulation induction for women with PCOS include:

  • synthetic FSH
  • human menopausal gonadotropin - contains both synthetic FSH and LH
  • human chorionic gonadotropin (hCG)

Adverse side effects of gonadotropins include:

• Bloating
• Pelvic or stomach pain
• Swelling or rash at the site of injection
• Risk of ovarian hyperstimulation syndrome (OHSS) - a potentially serious condition caused by excessive stimulation (overstimulation) of the ovaries. This can result in blood clots, kidney damage, ovarian twisting (torsion), and buildup of fluid in the chest and abdomen. Women receiving gonadotropins must be monitored very carefully. Ovarian hyperstimulation syndrome is more likely to occur with this type of therapy than with clomiphene citrate.

Disadvantages of gonadotropin therapy include:

• Administered by injection
• Expensive
• Elevated risk of multiple gestations
• Increased risk of OHSS