| PCOS is the #1 cause of infertility. Elevated levels of insulin play an important role in the underlying cause of PCOS. As we will see, several treatment options are available, and the choice of treatment depends on the woman's symptoms and fertility status. Polycystic Ovarian Syndrome (PCOS) Also known as Stein-Leventhal syndrome Overview of Disease PCOS, also known as hyperandrogenic chronic anovulation (inability to ovulate long-term) is a benign disorder that commonly results in infertility. PCOS is characterized by irregular ovulation and menses, obesity, insulin resistance, acne, and hirsutism (excessive hair growth). Most women with PCOS also have ovaries filled with multiple benign cysts.1 PCOS is relatively common and seen in approximately 6-10% of all females. This equates to almost 5 million American women.2 Between 5 and 30% of women have some characteristic of PCOS. This is one of the most common hormonal abnormalities in women of reproductive age and is a leading cause of infertility. Often in PCOS patients, menarche (periods) starts at the usual age of 12-13, while some start menstruating earlier. Interestingly, there appears to be variabilities of PCOS clinical manifestations among races. For example, obesity and hirsutism are not prominent among Japanese people, whereas they are much more common among Caucasians.3 How does PCOS contribute to Infertility? Impaired fertility is a prominent feature of PCOS. This is believed to result from elevated insulin levels that stimulate excess androgen production by the ovaries. The androgens cause premature follicular wasting which causes inconsistent or absent ovulation, which is associated with infertility. {See Pathophysiology} Pathophysiology It is important to evaluate the usual hormonal events leading to ovulation in order to see how PCOS causes impaired fertility. Normally, estrogen levels reach their lowest point when a women is menstruating. At this same time, LH (luteinizing hormone) and FSH (follicle stimulating hormone) levels begin to rise and stimulate the development of an ovarian follicle, which contains the egg. The mature follicle produces androgens (male hormones, like testosterone), which are released into the circulation. Some of these androgens will bind to a circulating protein in the blood known as sex-hormone binding globulin (SHBG). These bound androgens do not affect the body and are referred to as "inactive". The unbound or free androgens are active and may be converted in the body's fat tissue into the hormone estrogen. This conversion causes the body's estrogen levels to rise, which in turn causes LH and FSH levels to fall. Moreover, as estrogen continues to increase, it will eventually cause the LH surge, which stimulates the egg to be released from the follicle, i.e. ovulation.4 In PCOS, this cycle is disrupted. There are several theories as to what causes PCOS. First, women with PCOS usually have an increase in LH secretion from the brain. An elevated LH promotes secretion of androgens from the ovaries. In turn, the increased androgen production causes wasting of the developing ovarian follicles and interferes with the production of a dominant follicle. This results in a disruption of normal estrogen production by the ovaries and the absence of a mid-cycle LH surge. Normally, an egg is released from the dominant follicle, but in PCOS, the follicles do not mature properly and instead, develop into ovarian cysts. Another theory regarding the cause of PCOS is believed to be associated with insulin resistance (the cells cannot normally utilize insulin for glucose uptake). Insulin is the hormone that regulates the body's sugar (glucose) levels. With insulin resistance, cells are not as sensitive to insulin and it accumulates in the bloodstream resulting in a condition called hyperinsulinemia. In PCOS, hyperinsulinemia contributes to excess androgen production within the ovary which causes follicular wasting and anovulation. The elevated androgen levels also contribute to common symptoms of PCOS like acne and hirsutism. Causes The cause of PCOS is unclear at this time, but is believed to be strongly associated with insulin resistance, a condition in which the cells of the body become less sensitive to the hormone insulin. Insulin is responsible for controlling the body's level of sugar. When cells cannot use insulin, it begins to accumulate in the blood and leads to various symptoms including obesity and a disruption in the normal menstrual cycle. This disruption frequently results in anovulation, and therefore infertility. Symptoms Common signs and symptoms of PCOS include the following: Irregular or absent periods Lack of ovulation Weight gain Hirsutism (excessive hair growth) Insulin resistance Acne Male-pattern balding Multiple small ovarian cysts-these may be seen by an ultrasound examination Ancthosis nigrans (darkening of the skin at the nape of the neck and under the arms and breasts) Note: Not all of these symptoms need to be present to diagnose PCOS (see below). There are three different ways to make the diagnosis of PCOS: 1. Symptoms: Irregular or absent menstrual cycles-PCOS patients may report to a physician for lack of menses or extremely variable menstrual cycles. Hyperandrogenic symptoms-Acne and hirsutism are the hallmark symptoms of PCOS 2. Blood Work/Hormonal Testing: Laboratory testing is important for diagnosis but it is crucial to look at multiple values collectively. Blood testing is performed by a clinician and the results are compared with known normal levels. 3. Ultrasound: Ultrasound of the pelvis is typically performed when the clinician suspects PCOS. If >10 cysts are found in either ovary that are less than 10mm, this meets the ultrasound criteria for PCOS. Furthermore, polycystic ovaries are typically 1.5 to 3 times the normal size. Just the presence of polycystic ovaries, without symptoms and/or consistent blood work, does not confirm a diagnosis of PCOS.3 Some individuals will have abnormal findings in all three categories, some in only two, and others in just one. The classic findings for PCOS are menstrual cycle abnormalities, increased hair growth, and obesity. Patients typically seek medical care for the menstrual cycle irregularities, infertility, problems of self-esteem and appearance arising from obesity, and excess hair growth. PCOS may be a risk factor for the development of Type II diabetes (non-insulin dependent), heart disease, and elevated cholesterol (hypercholesterolemia). Therefore, proper diagnosis along with effective treatment options is essential to prevent further complications.3 Treatment Various treatment options are available. The treatment will be chosen based on the woman's symptoms and fertility status. Weight Loss -Improved diet and exercise may decrease insulin levels, which may cause menses to return. Progestins -These medications mimic the action of progesterone. Progestins may be used to regulate the menstrual cycle and reduce blood levels of LH. Unfortunately, they are of little benefit in reducing hair growth or metabolic abnormalities. Examples include medroxyprogesterone (Provera®, Cycrin®) and norethindrone acetate (Aygestin®).3 Oral Contraceptives -The "pill" is an effective treatment for PCOS patients not wanting to become pregnant. Oral contraceptives decrease LH and regulate menses. The pill is also used to decrease symptoms associated with high androgen levels (acne and hirsutism). Anti-Androgens -These can only be used in women using adequate contraception because these medications pose a risk to the developing fetus. The value for use in PCOS is to improve skin conditions and to decrease other symptoms such as male-pattern baldness and hirsutism. Examples include spironolactone (Aldactone®), flutamide (Eulexin®), finasteride (Proscar®).3 GnRH agonists -Gonadotropin-releasing hormone (GnRH) agonists are synthetic versions of the natural GnRH and are up to 60 times more potent. They are similar in structure to the natural hormone. They cause release of LH and FSH from the pituitary gland in the brain, but with prolonged use, will deplete the pituitary gland of LH and FSH. This is important because women with PCOS usually have an increase in LH, which eventually leads to menstrual irregularities and/or infertility. Side effects of the GnRH agonists are like those experienced by menopausal women, including bone loss, hot flashes, decreased libido (sexual drives), and vaginal dryness. Loss of bone mass can be reversed after the women stops taking the medication. Examples of GnRH agonists include leuprolide acetate (Lupron®), goserelin (Zoladex®) and nafarelin acetate (Synarel®). Fertility drugs -In PCOS, normal follicular growth and ovulation are disrupted. Fertility drugs may be used in order to induce ovulation. Clomiphene citrate (Clomid®) is typically the first agent prescribed to stimulate ovulation. If clomiphene is unsuccessful, more potent medications along with AI or ART procedures may be recommended. Surgical therapy -2 surgical therapies are available: a) Ovarian wedge resection In ovarian wedge resection, a portion of the ovary is removed and then sewn back together. This procedure has been effective in decreasing LH and androgen production, and reestablishing regular menses in over 75% of patients. Pregnancy rates following ovarian wedge resection vary, but have been reported to be as high as 60%. Unfortunately, a major complication of this procedure is the formation of pelvic adhesions in 30% of patients.3 b) Laparoscopic ovarian drilling Laparoscopic ovarian drilling is another surgical alternative for PCOS. This procedure involves making small holes with a laser into the ovary. Ovarian drilling can be performed during the time of a laparoscopy and is very effective in reducing androgenic hormone production. Laparoscopic ovarian drilling may be an effective treatment in clomiphene-resistant anovulatory women with PCOS.5,6 Alternative treatment for PCOS Treating the insulin resistance associated with PCOS targets the cause rather than the symptoms of the disorder. Approximately 75% of obese patients with PCOS are insulin resistant and have elevated amounts of insulin in their bloodstream. These patients have an increased incidence of Type II diabetes, hypertension, and atherosclerosis (hardening of the arteries which could lead to a heart attack or stroke). Insulin-sensitizing therapy enhances the body's sensitivity to insulin and therefore, helps to normalize the hormonal abnormalities associated with PCOS. The following medications have shown promise in the treatment of PCOS when hyperinsulinemia is present: Metformin (Glucophage®) Metformin is mainly used in non-insulin dependent diabetes and helps enhance the body's sensitivity to insulin. It does not cause hypoglycemia (low blood sugar) which is important to prevent unwanted side effects. Some patients have experienced weight loss, improved lipid profiles, lowered blood pressure, return of menstruation, and achieved pregnancy while taking metformin. This drug is considered relatively safe. The most frequently occurring side effect is gastrointestinal upset (diarrhea or more frequent bowel movements). Stomach upset occurs more frequently after a fatty meal or dessert.7 Pioglitazone (Actos®): Pioglitazone works by allowing the body to utilize insulin more efficiently. Some common side effects with this drug include edema (swelling), weight gain, and headache.7 Rosiglitazone (Avandia®): Rosiglitazone is in the same class of insulin-sensitizers as Actos, so it works in a similar manner. Common side effects of Avandia include slight weight gain and headache.7 Please refer to our feature section "PCOS and Insulin Sensitizers" for a closer look at the use of these medications in PCOS. References Adolescent Medicine. "Polycystic Ovary Syndrome (PCOS)." Vanderbilt Medical Center. Retrieved May 2000 from www.mc.vanderbilt.edu/peds/pid1/adolesc/polcysov.htm. General Information About PCOS. Retrieved May 2000 from http://pcos.freeservers.com/general.html. The Center for Applied Reproductive Science. Polycystic Ovarian Syndrome (PCOS). Retrieved May 2000 from www.ivf-et.com/pcosstate.html. Franks S. Medical progress: Polycystic Ovary Syndrome. NEJM 1995;333(13):853-861. Dawood MY. "Laparoscopic Surgery of the Fallopian Tubes and Ovaries." Semin Laparosc Surg 1999;6(2):58-67. Felembam, Alaf et al. "Laparoscopic Treatment of Polycystic Ovaries with Insulated Needle Cautery: a reappraisal." Fertility and Sterility 2000;73(2):266-9. Micromedex drug monographs for metformin, rosiglitazone, and pioglitazone. Retrieved May 2000. |
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