Polycystic Ovarian Syndrome (PCOS) |
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Polycystic Ovarian Syndrome (PCOS) is a very common reproductive disorder effecting approximately 10% of women in their child bearing years. Women with PCOS frequently have irregular menstrual cycles (oligomenorrhea), excessive body hair (hirsutism), are overweight, and suffer from infertility.
Historically Polycystic Ovarian Syndrome was first described by Drs. Irving Stein and Michael Leventhal in 1935 and for many years bore their names as “Stein Leventhal Syndrome”. In their original 1935 article Drs. Stein and Leventhal described seven patients with infertility, very irregular menstrual periods and enlarged ovaries. They operated on these patients removing ½ to ¾ of each ovary and described the surgical procedure as a “bilateral ovarian wedge resection (BOWR)”. Remarkably all of the patients began to menstruate regularly and two achieved a spontaneous pregnancy. The procedure was never evaluated in a controlled study but nevertheless slowly entered the mainstream of gynecology. For many years was the therapy of choice although its exact mechanism of action was never fully understood. BOWR as a surgical treatment for PCOS has declined dramatically of the last 30 – 40 years. This decline is a consequence of the availability of non-invasive, effective medical treatments as well as the significant possibility of BOWR creating severe pelvic adhesions which can create an additional obstacle to pregnancy.
In 2003 criteria required for the diagnosis of PCOS were established by “The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group”. These criteria included: (1) absent or irregular ovulation, (2) the appearance of polycystic ovaries on ultrasound and (3) either clinical evidence or laboratory evidence of increased male hormones (androgens). When testing for elevated androgens free testosterone and DHEAS should be measured. In order to “officially” make the diagnosis of PCOS two of the three criteria need to be met and other disorders need to be excluded. Even after these criteria have been met, other causes of elevated androgens must be ruled out.
PCOS symptoms often have a gradual onset. Oligomenorrhea and hirsutism may begin to appear following the fist menstrual period (menarche). However, most women do not seek treatment of these symptoms until their early or middle 20’s Abnormal vaginal bleeding is also a common complaint. Some women with PCOS may stop menstruating (amenorrhea) and others may menstruate irregularly (oligomenorrhea). This irregular and often incomplete shedding of the uterine lining can lead to premalignant changes (endometrial hyperplasia with/without atypia) and if left untreated eventually lead to cancer of the lining of the uterus (endometrial carcinoma).
In addition to reproductive problems, women with PCOS have a higher risk of developing “Metabolic Syndrome” which is a characterized by a number of factors that increase the risk of cardiovascular disease. These risk factors include: elevated cholesterol and/or triglycerides, adult onset (Type 2)diabetes, hypertension and obesity. By the age of 40, up to 40% of PCOS patients develop impaired glucose tolerance or clinical diabetes. Treatment of PCOS is therefore not only directed at correcting reproductive problems but is also directed at decreasing these cardiovascular risk factors. These cardiovascular risk factors may be more of a problem for obese PCOS patients and less of a problem for lean PCOS patients.
The basic pathophysiological defect is unknown in PCOS. There is, however, a tendency for PCOS to cluster in families and therefore the cause is very likely to be genetic. A study reported in 2001 revealed that the rates of PCOS in mothers and sisters of women who have PCOS were 24% and 32%. Women with PCOS have a decreased sensitivity to insulin (insulin resistance) and as a consequence their bodies compensate by overproducing insulin. The resulting high level of insulin (hyperinsulinemia) contributes to excessive production of androgens (male hormones, such as testosterone) by the ovaries which results in hirsutism and also contributes to ovulatory and menstrual disorders.
Insulin Resistance, Hyperinsulinemia, Oligo-anovulation and PCOS A proposed pathway
Given the strong evidence that excess insulin plays a role in the development of PCOS, it is reasonable to assume that reducing circulating levels of insulin will help restore normal reproductive function and fertility. A reduction in the circulating levels of insulin may be accomplished with improved nutrition particularly with the reduction of carbohydrate intake, weight loss and exercise. These life-style changes, in addition to the use of insulin sensitizing agents, can be critical to the successful treatment of PCOS.
Dietary Recommendations for PCOS
Exercise Recommendations for PCOS
It is important that women with PCOS exercise regularly because exercise brings down insulin levels and can also help with weight loss. Exercise can be especially helpful in bringing down insulin levels after a meal. So, if possible, go for a walk after you eat a large meal. Any increase in exercise helps, so find an activity, sport, or exercise that you like to do. If you aren't doing a lot of exercise now, start slowly, and build up to your exercise goal. If you exercise sometimes, try to exercise regularly. Work towards exercising at least 5 days a week for 60 minutes. The more the better!
Options for the Medical Treatment of PCOS
There are multiple drug treatment options for PCOS and selection depends on the goals of therapy. Essentially treatment is either directed at symptoms of PCOS other than infertility such as irregular menstrual periods and hirsutism or at infertility.
Oral Contraceptive Pills: Oral contraceptive pills are often the first line of treatment for patients who are concerned about irregular menstrual periods and hirsutism and not interested in pregnancy. Oral contraceptive pills will regulate menstruation and insure complete shedding of the uterine lining thereby protecting against endometrial carcinoma. In addition oral contraceptive pills decrease the production of ovarian androgens and also increase the production of male Sex Hormone Binding Globulin by the liver which also decreases the level of circulating androgens.
Antiandrogens: Antiandrogens are drugs that are capable of preventing or inhibiting the biologic effects of androgens on normally responsive tissues in the body. Antiandrogens usually work by blocking the androgen receptors, competing for androgen binding sites on the cell's surface, or blocking the production of androgens. These medications are usually slow to produce results and improvement is often not seen for 6-9 months. Spironolactone in doses up to 200mg/day is the most widely used of these drugs. Spironolactone is antihypertensive drug and its use for hirsutism, although safe, is off label (prescribed for a particular indication even though the drug has not yet received approval from the Food and Drug Administration for that disease, condition, or symptom). Spironolactone is not safe in pregnancy and therefore should only be given to PCOS patients who are not interested in pregnancy and it is best given in combination with oral contraceptive pills. Flutamide and finesteride are two other antiandrogens occasionally used to treat hirsutism in PCOS patients. Their use is also off label and they are also contraindicated in pregnancy.
Ovulation Inducing Agents: Initially the use of ovulation inducing medication was the most common treatment of infertility in PCOS patient and clomiphene citrate (Clomid) was the gold standard. Clomid is an antiestrogen that stimulates the pituitary gland to increase the release of gonadotropins which in turn stimulates the ovaries. Approximately one-third to one half of patients who take Clomid will conceive. Conception generally will occur within 3-4 treatment cycles and at doses of 50mg/day or 100mg/day for 5 days. Clomid at these doses has minimal side effects but does increase the incidence of multiple pregnancy to 3%-5%. Other medications that can be used to induce ovulation are gonadotropins and letrazole. Gonadotropins are given as daily injections, usually for 7-10 days, and safe administration requires frequent monitoring to avoid over stimulation. The drugs themselves are costly as is the frequent monitoring with blood test and pelvic ultrasound studies that is required. In addition there is a 20% incidence of multiple pregnancy when these drugs are used. These drugs do however result in many pregnancies when Clomid has failed. Letrazole is a drug developed for the treatment of breast cancer and interferes with the production of estrogen. This in turn stimulates the pituitary gland to increase the release of gonadotropins in a manner similar to Clomid which in turn stimulates the ovaries. The use of letrazole for ovulation induction is off label. In addition there are some controversial studies suggesting that letrazole may increase the incidence of birth defects. For this reason many reproductive endocrinologists are reluctant to prescribe letrazole
Insulin-Sensitizing Agents: Drugs approved by the FDA for the treatment of Type 2 diabetes (adult onset diabetes) are very effective in the treatment of PCOS. These drugs, known as insulin sensitizing agents, have been shown to improve the body's response to insulin, thereby reducing the need for excess insulin and restoring the levels to normal.
Options for the Surgical Treatment of PCOS
Laparoscopic Ovarian Drilling: Laparoscopic ovarian drilling is the modern version of bilateral ovarian wedge resection first described by Stein and Leventhal in 1935. Although still major surgery it is less invasive and if done by a physician skilled in operative laparoscopy is less likely to result in significant pelvic adhesions. However it still carries with it the inherent risks associated with any surgical procedure and for this reason is generally not considered to be appropriate as the first treatment of choice. The premise of the surgery, just as is the case for BOWR, is that destruction of ovarian tissue leads to a decrease in androgen production by the ovaries which in turn leads to a decrease in LH released by the pituitary gland which in turn restores normal ovarian function. At best, results of ovarian drilling are the same as the same achieved with medical treatment, and therefore our feeling is that the procedure should be reserved for special situations.
The Treatment of PCOS
At the present time most, if not all, reproductive endocrinologists believe the insulin sensitizing agents represent the first line of therapy for PCOS patients interested in achieving pregnancy. These agents do need to be prescribed in conjunction with the implementation of a carbohydrate restricted diet as well as weight loss for those PCOS patients who are obese and increased exercise.
The best studied insulin sensitizing agent available in the United States for women with PCOS is metformin (Glucophage®), a biguanide that has been available for forty years. Metformin reduces circulating insulin and androgen levels and restores normal ovulation in some women with PCOS. Even if metformin alone does not restore regular ovulation, it often improves a woman's response to fertility drugs. Gastrointestinal irritation, especially diarrhea nausea/vomiting and flatulence and abdominal discomfort are common side effect. These symptoms usually improve after a few weeks particularly if patients start with a small dose of medication and gradually increase to the full dose. Lactic acidosis is a rare but serious adverse effect of metformin. Metformin is not recommended for patients with kidney, lung, liver, or heart disease.
Rosiglitazone (Avandia® 4mg twice daily) and pioglitazone (Actos® 15mg-30mg once daily), which belong to the thiazolidinedione group of antidiabetic agents, are also available in the United States to treat women with PCOS. Thiazolidinediones have been shown to reduce hyperandrogenism and restore ovulation in some PCOS patients. Rather than gastrointestinal side effects, liver toxicity is the main concern with these agents. Liver tests should be performed frequently for the first year and periodically thereafter. These medications should not be started in women with any evidence of liver disease.
The FDA use-in-pregnancy rating classifies metformin as a Class B drug (no evidence of risk in humans). The thiazolidinediones are classified as Class C drugs (risk in pregnancy cannot be ruled out). Therefore Metformin is the insulin sensitizing agent of choice. Thiazolidinediones may be considered if Metformin is ineffective or not tolerated by the patient. Metformin should be temporarily stopped several days prior to surgery or X-ray procedures that use intravenous contrast. Unlike ovulation inducing drugs, the use of insulin sensitizing agents is not associated with an increased risk of multiple pregnancies. Although results from all clinical studies have been very encouraging, the use of these medications in women with PCOS is still considered investigational and off label.
Present data clearly confirms that the use of insulin sensitizing agents for ovulation induction in PCOS patients who want to conceive is appropriate. Because these medications correct the underlying metabolic abnormalities associated with PCOS, it is more than likely that their long term use may delay the emergence or reduce the likelihood of developing Type 2 diabetes, elevated cholesterol, high blood pressure and cardiovascular disease. Since data are lacking, long-term use of insulin sensitizing agents for this purpose cannot be recommended at present however all indications from early studies are very encouraging.
Metformin (Glucophage®) is available in 3 strengths (500mg tablet, 850mg tablet and 1000mg tablet) and is generally prescribed in a dose ranging from 1500mg to 2000mg daily in a divided dose. Metformin is also available in an extended release form Metformin ER (Glucophage XR®) in 2 strengths (500mg tablet and 750mg tablet). Metformin ER is taken in a single dose and causes fewer gastrointestinal symptoms for some patients. Metformin ER must be swallowed whole and never crushed or chewed. Occasionally, the inactive component of Metformin ER may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way Metformin ER works. Your doctor will discuss the appropriate dose regimen with you.
Present data suggest that the continued use of Metformin during the first trimester of pregnancy decreases the slightly increased incidence of first trimester spontaneous abortion associated with PCOS. Therefore, once pregnant, patients are advised continue to take Metformin until instructed to discontinue its use. Emerging data also suggest that the continued use of Metformin throughout pregnancy may decrease the incidence of gestational diabetes.
Suggested Reading: Healing Syndrome O, R. Feinberg, MD, PhD
Suggested Web Sites: www.soulcysters.com www.pcostrategies.org www.pcosupport.org
Suggested Diet Books: Atkins Diet South Beach Diet Carbohydrate Addicts Diet Insulin Control Diet Protein Power Sugar Busters The Zone The New Glucose Revolution: The Authoritative Guide to the Glycemic Inde |
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