Vol. 18 • Issue 2
• Page 20
CE Woman's Health
Continuing Education Offering: The goal of this article is to educate nurse practitioners about polycystic ovarian syndrome. Nurse practitioners may obtain 2 contact hours by reading this article and earning a passing score on the test that follows. For immediate test results, take the quiz online at www.advanceweb.com/NP. The author has completed a disclosure statement and stated no real or perceived conflicts of interest.
How to Obtain Contact Hours by Reading This Article
Instructions: Nurse practitioners may receive 2 contact hours by reading the article noted below and earning a passing score on the accompanying quiz. To obtain contact hours:
1. Read the article "Polycystic Ovarian Syndrome. Where Environment and Genetics Collide," carefully noting the tables and other illustrative materials provided to enhance your knowledge and understanding of the content.
2. Read each question, and record your answers on the registration form provided.
3. Fill out the evaluation portion completely. You will not receive CE credit if this section is not completed.
4. Type or print your full name and address in the space provided on the registration form.
5. Forward the completed registration form with your check or money order for $10.00 payable to Merion Publications, or provide your credit card information. Quizzes are accepted up to 24 months from publication.
Continuing Education Credit: Merion Publications Inc. is approved as a provider of continuing education in nursing (Provider #008-0-07) by the Pennsylvania State Nurses Association, which is accredited as an approver of continuing education in nursing by the American Nurses Credentialing Center Commission on Accreditation, the California Board of Registered Nursing (Provider #CEP 13230) and the Florida Board of Nursing (Provider #CEP 3298). California and Florida participants must retain certificates for 4 years.
You will be advised of your score within 30 to 60 days. A score of 70% or above is passing grade. A certificate will be awarded to participants who pass. Participants who score less than 70% can retest one time for no additional charge. No refunds.
Objectives: The purpose of this article is to educate nurse practitioners about polycystic ovarian syndrome. After reading this article, the nurse practitioner should be able to:
• explain the pathogenesis of PCOS
• identify diagnostic criteria for PCOS
• describe clinical manifestations associated with PCOS
• identify appropriate PCOS management principles.
Directions: On the registration form, check the box next to the best answer.
Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women, affecting 1 in 15 women of childbearing age. It has significant reproductive, metabolic and dermatologic consequences.1
The term PCOS first described the coexistence of amenorrhea, hirsutism, obesity and polycystic ovaries. A great deal of research has been conducted to determine the association among these symptoms.2
PCOS is known as a syndrome, not a disease.3A syndrome is a symptom complex with no known cause. It is associated with specific characteristics, and it is defined by its consequences.
Women with PCOS are at increased risk for chronic conditions including diabetes, coronary artery disease, hypertension, dyslipidemia, endometrial cancer, infertility and obesity.4PCOS symptoms affect quality of life, leading to a higher frequency of depression and psychosexual morbidity in affected patients.5
Pathophysiology
Multiple pathophysiologic mechanisms contribute to PCOS, but a comprehensive explanation is still lacking. Key features of the syndrome are abnormal pituitary function, abnormal steroidogenesis and insulin resistance.6Androstenedione is a steroid hormone produced in the adrenal glands and gonads that is converted to testosterone or estrogen. The enzyme 17-beta hydroxysteroid dehydrogenase is required for conversion to testosterone, and the enzyme aromatase is required for conversion to estrogen.
Studies suggest that ovarian theca cells in women with PCOS are more efficient than normal theca cells at converting the androgenic precursors to testosterone. In women, androstenedione is released into the blood by theca cells that provide androstenedione substrate for estrogen production in the granulosa cells. Theca cells lack aromatase, which is required to make estrogen. Theca cells and granulosa cells work together to form estrogen. Androgens are synthesized by the ovarian theca cells in response to stimulation by luteinizing hormone (LH). LH regulates the androgenic synthesis of theca cells, and follicle-stimulating hormone (FSH) regulates the aromatase activity of granulosa cells, determining the amount of estrogen synthesized from androgenic precursors. When the LH concentration is greater than that of FSH, the ovaries preferentially produce more androgens. Excessive LH secretion relative to FSH was the first laboratory abnormality identified in association with PCOS, but not all patients with PCOS have elevated LH levels.7 pproximately 40% of patients with PCOS have normal LH:FSH ratios.8The ratio of LH to FSH is partly determined by the frequency of hypothalamic gonadotropin-releasing hormone (GnRH) stimulation. Increased pulse frequency of GnRH increases the LH:FSH ratio, and decreased pulse frequency reduces the ratio. Women with PCOS appear to have increased LH pulse frequency, indicating an increased pulse frequency of GnRH. It is unclear whether this is due to an intrinsic abnormality in the GnRH pulse generator or is caused by low levels of progesterone from infrequent ovulatory events. The low circulating progestin levels in women with PCOS may cause a rise in the pulse frequency of GnRH, increasing levels of LH and of ovarian androgens.7Polycystic ovaries have two to six times more follicles than healthy ovaries.5In anovulatory women with PCOS, the antral follicle stops growing at the stage just before the emergence of a dominant follicle. Excessive stimulation of follicular cells by insulin, LH or both is related to follicular arrest. Arrested follicles show signs of premature luteinization. Androgen excess results in excessive growth of small ovarian follicles and inhibition of the follicular maturation and development of the dominant follicle, resulting in the polycystic appearance of the ovary. Polycystic ovaries also have a thickened thecal layer that secretes excessive androgens.5Insulin influences the pathogenesis of hyperandrogenemia in PCOS. Insulin enhances the androgen production of theca cells by working synergistically with LH. It also inhibits hepatic synthesis of sex hormone-binding globulin (SHBG), the main protein that binds to testosterone. This increases the bioavailability of testosterone. Women with PCOS often have hyperinsulinemia, which elevates free testosterone concentration.7Insulin may act directly on the hypothalamus or pituitary gland - or both - to regulate gonadotropin release.9Hyperinsulinemia causes the pituitary gland to hypersecrete LH, which results in anovulation and thickening of the ovarian theca. This leads to higher androgen levels, specifically testosterone. Elevated testosterone may cause many of the symptoms associated with PCOS.8 The ovarian enzymatic activity involved in the synthesis of testosterone precursors is most likely the main cause for increased testosterone levels. Elevated LH levels, together with hyperinsulinemia, lead to an increase in androgen production by ovarian theca cells.9The pathogenesis of PCOS suggests that it is a complex multigenic disorder. Both genetic and environmental factors are implicated in causation.5The popular understanding is that PCOS is the result of intrinsic ovarian genetic traits that interact with other congenital or environmental factors to cause dysregulation of steroidogenesis.6Diagnostic criteria are outlined in Table 1.
Clinical Manifestations
PCOS is usually identified as a disorder of ovarian androgen excess and is not diagnosed without evidence of clinical or biochemical hyperandrogenism. Clinical features of hyperandrogenism reflect a subjective assessment of manifestations of excessive androgen activity. Common features associated with PCOS include hirsutism, acne and androgenic alopecia.
Hirsutism is the most common of these symptoms, manifesting in about 60% of women with PCOS.3The most common sites are the upper lip, chin, chest, lower abdomen and inner thighs. Degrees of hirsutism vary depending on ethnicity. It is important to obtain a medication history because many drugs cause hirsutism.
Acne occurs in 15% to 25% of women with PCOS. Androgenic alopecia is more common in older women, affecting approximately 5% of women with PCOS.3,5Approximately 60% to 80% of patients diagnosed with PCOS have elevated serum androgen levels. Biochemically, hyperandrogenemia is most commonly assessed by measuring total testosterone and sex hormone-binding protein (SHBP), followed by calculation of free serum testosterone. Although radioimmunoassays to directly measure free testosterone are available, they are considered unreliable.5The mass action equation to calculate free serum testosterone is considered the method of choice, assuming reliable assays are used. The majority of abnormal values are in the form of free testosterone.5
Approximately 25% of patients with PCOS have supranormal levels of dehydroepiandrosterone sulfate (DHEAS), an androgen metabolite. Measurement of other serum androgens has limited diagnostic value. Reliable detection of biochemical hyperandrogenism is not straightforward, and the range for healthy women is broad. It may vary according to ethnicity, body weight and age. Therefore, DHEAS measurement should only be used as an adjuvant for the diagnosis of hyperandrogenic disorders and never as the sole criterion for diagnosis.3Between 20% and 40% of women diagnosed with PCOS have androgen levels within the normal range, so failure to detect hyperandrogenism should not exclude a diagnosis of PCOS in the presence of other clinical signs.5Approximately 75% of patients diagnosed with PCOS have clinically evident menstrual dysfunction.3The major clinical signs of chronic anovulation are oligomenorrhea and amenorrhea. Oligomenorrhea is defined as less than eight episodes of vaginal bleeding per year or cycles that are longer than 35 days. Amenorrhea is a lack of menstruation for at least 3 months without pregnancy. A menstrual history alone is not adequate; regular cycles do not exclude anovulation. To make a determination of menstrual dysfunction, serum progesterone concentration should be measured during the luteal phase of the menstrual cycle. If anovulation is present, the finding may be confirmed with serum prolactin and luteinizing hormone to exclude hypothalamic and pituitary diseases.
Before attributing anovulation to PCOS, consider any form of functional hypothalamic amenorrhea that may be caused by extreme dietary restrictions or exercise. Chronic anovulation is associated with unopposed estrogen stimulation of the endometrium, which can result in endometrial hyperplasia or carcinoma. PCOS is also the most common cause of infertility due to anovulation and often the primary reason a patient seeks medical advice.5Polycystic ovaries detected by transvaginal ultrasonography may be detected in approximately 75% of women diagnosed with PCOS.3Polycystic ovaries are identified when at least one ovary is greater than 10 mL or has 12 or more follicles measuring 2 mm to 9 mm in diameter, according to transvaginal ultrasound. Transabdominal ultrasonography with measurement of ovarian volume is only appropriate for adolescent girls because determining the number of follicles via transabdominal ultrasonography is much less reliable in women, especially when they are obese.
Measurement of anti-Müllerian hormone secreted by granulosa cells of developing follicles is emerging as an alternative to ultrasonography because values do not closely correlate with the number of antral follicles. This assay is not valid for women older than 35, but it may be helpful when ultrasonography is inappropriate or unavailable.5 he finding of polycystic ovarian morphology on ultrasound is not unique to the clinical disorder of PCOS. This morphology has been documented in association with other disorders - as well as in 16% to 25% of apparently healthy women with regular cycles.10
Approximately 10% to 30% of women diagnosed with PCOS do not have polycystic ovaries on ultrasound, and the definition of the diagnostic features for polycystic ovaries by ultrasound is controversial.3Other clinical features of PCOS include obesity, insulin resistance, hyperinsulinism, gonadotropic abnormalities, increased LH levels and increased LH:FSH ratio. These findings are not universally present and are not considered part of the diagnostic criteria for PCOS.3
besity is present in at least 30% of women with PCOS, and in some studies the prevalence is as high as 75%.7PCOS is characterized by an increase in waist circumference (greater than 35 inches), typically known as central obesity. This type of obesity is generally related to insulin resistance, glucose intolerance, dyslipidemia and decreased sex hormone-binding globulin, which increases circulating free testosterone.
Acanthosis nigricans, a hyperpigmentation of the skin, is common in patients who are insulin resistant. It often appears on the nape of the neck, the axilla and the area between the breasts.9
Fasting insulin and glucose levels are often normal in women with PCOS. However, they may have an exaggerated serum insulin response to oral glucose tolerance tests (OGTT). They may also exhibit elevated LH levels, low to normal FSH levels, and an LH:FSH ratio of 2:1 or higher. Patients can present with a range of symptoms and laboratory abnormalities. This underscores the importance of first excluding any other possible diagnoses associated with similar symptoms and laboratory values. A thorough family history, past medical history and focused physical exam are necessary to detect any signs of hyperandrogenism.8
Long-Term Health Risks
Women who have PCOS are at increased risk for metabolic and cardiovascular abnormalities similar to those that comprise metabolic syndrome. PCOS and metabolic syndrome share insulin resistance as a central pathogenic feature. Between 30% and 40% of women with PCOS have impaired glucose tolerance, and up to 10% develop type 2 diabetes in their 30s or 40s.
Whether all women with PCOS should be screened for glucose intolerance or insulin resistance - or both - is unclear. An increase in central fat, hyperinsulinemia, glucose intolerance, increased blood pressure and other features of metabolic syndrome are common in women with PCOS. In women, excess androgen is a risk factor for metabolic syndrome independent of obesity and insulin resistance.5Dyslipidemia with low serum HDL, high serum triglycerides and high serum LDL concentrations are common in women with PCOS. Therefore, a fasting lipid profile is suggested for newly diagnosed patients. A number of professional organizations recommend a baseline 2-hour OGTT in all women diagnosed with PCOS. If a 2-hour OGTT is too difficult to perform, obtain a fasting glucose along with a hemoglobin A1c11Cardiovascular risk factors are substantially increased in women with PCOS.7Recent studies have documented a higher incidence of obstructive sleep apnea and an increased prevalence of endometrial hyperplasia and carcinoma in women who have PCOS.7
Management Principles
Table 2? outlines core concepts in PCOS management. Hyperandrogenemia and hyperinsulinemia are fundamental features of PCOS and therefore are targeted in most treatment protocols. Therapeutic options are broad and range from lifestyle modifications to pharmacologic interventions. Early recognition and intervention may prevent or delay complications.12
Lifestyle modifications that result in a modest weight reduction (5% to 10%) can improve ovulatory function and reduce androgen levels in women with PCOS.12 xcess body weight can influence metabolic and reproductive features of PCOS and has significant implications for response to treatments for infertility, menstrual dysfunction and metabolic abnormalities.13Obesity may also influence pregnancy outcomes in PCOS. Lifestyle modifications to reduce the adverse effects of obesity on reproductive and metabolic features of PCOS are universally recommended.13 To achieve weight loss, a low-fat, high-fiber diet with low glycemic index carbohydrates is recommended. Glycemic index is a classification of carbohydrates based on blood glucose response over 2 hours. Low glycemic index foods include bran cereals, mixed grain breads, lentils and soy. High glycemic index foods include refined carbohydrates, potatoes and desserts with simple sugars.13Diets high in polyunsaturated fatty acids (PUFAs) alter plasma glucose and modulate levels of sex hormones. Therefore, encourage intake of foods high in PUFAs (e.g., nuts, nut butters, olive oil, canola oil and oily fish).14Moderate physical activity assists in the achievement and maintenance of weight loss. Muscle strengthening improves insulin sensitivity and, in combination with dietary intervention, strength training may limit loss of lean muscle mass.13
Treatment of Menstrual Dysfunction
For the patient who presents with oligomenorrhea or amenorrhea, an estrogen-progestin combination therapy or progestin alone are considered first-line treatment options when fertility is not a goal. Oral contraceptives (OCs) regulate the menstrual cycle and lower the risk for endometrial hyperplasia, which may result from infrequent menses and low levels of progestin that enable unopposed proliferation of the endometrium by estrogen.12Protecting the endometrium must therefore be a goal of treatment. Daily exposure to progestin in OCs counteracts the proliferate effects of estrogen. Patients with PCOS who have not had menstrual bleeding for a year or longer should undergo ultrasound to determine endometrial thickness.
Oral contraception provides the additional benefit of contraception, if desired, and may be of cosmetic benefit by reducing excess androgen effects. The estrogen component of oral contraception suppresses LH, reducing ovarian androgen synthesis. Estrogen also increases hepatic production of SHBG, reducing the amount of free testosterone.
The possible metabolic effects of oral contraception and progestin must be considered before initiating treatment. Studies in healthy populations of women show that combination OCs decrease insulin sensitivity, impair glucose tolerance and alter lipid profiles - but not to a degree that affects diabetes or cardiovascular disease risk. The metabolic effects of OCs in women with PCOS are unclear. The progesterone component is the main determinant of metabolic effects. Most progestins also have some degree of androgenic activity. Third-generation progestins such as norgestimate (Ortho-Cyclen, Ortho-Tricylcen) and desogestrel (Desogen, Ortho-cept) are nonandrogenic progestins and have a neutral effect.
Drosperinone (Yasmin, Yaz) possesses antiandrogenic activity that is potentially ideal for women with PCOS.12The progestins with higher androgenic activity weaken the effects of estrogen, suppressing sex hormone-binding globulin production.12They also lead to a greater degree of insulin resistance. OCs containing progestins with lower androgenic activity produce varying results on insulin sensitivity.12OCs may also have an effect on lipids, so caution should be exercised when prescribing them for women with dyslipidemia at baseline. Less androgenic progestins can have neutral or positive effect on LDL and HDL.12For patients who cannot tolerate combined OCs or who have contraindications to them, consider intermittent progestin such as medroxyprogesterone acetate (Provera) of 5 mg to 10 mg per day for 7 to 10 days every 1 to 2 months. This will help prevent buildup of the endometrial lining, but it will not provide contraception or reduce symptoms of hirsutism or acne.12
nsulin-lowering therapy can regulate menstrual abnormality.15Reducing insulin levels decreases ovarian androgen secretion and improves cyclic pituitary-ovarian function, which may reduce hair growth and restore menstrual regularity and, presumably, fertility.15Weight loss is one of the most studied therapies for improving insulin resistance. Weight loss in the overweight woman with PCOS has been associated with a reduction in serum testosterone concentration, restoration of normal ovulatory cycles, and pregnancy. Weight loss should be attempted before initiating ovulation induction, because ovulation can be restored with a modest amount of weight loss. If unsuccessful, a multistep approach to ovulation induction is recommended. Approximately 80% of women with PCOS ovulate in response to clomiphene citrate (Clomid), and approximately 50% conceive. The addition of insulin sensitizing agents to improve ovulation is controversial. Gonadotropin therapy and ovarian surgery are sometimes options if previous methods are unsuccessful.15
Treatment of Androgen Excess
Manifestations of hyperandrogenemia are a common complaint in women with PCOS, due to elevated levels of free testosterone. Hepatic production of sex hormone-binding globulin is inhibited by hyperinsulinemia, which increases unbound testosterone. Hirsutism can be treated with electrolysis or laser treatments; other methods (e.g., waxing, shaving) are often used, but they do not provide permanent hair removal.
Generally, OCs are considered first-line pharmacologic therapy for hirsutism and acne. In some cases, an oral antibiotic or a dermatologist-directed therapy is necessary. Estrogen suppresses LH secretion, decreasing ovarian androgen production. Estrogen increases hepatic production of sex hormone-binding globulin, decreasing the amount of free testosterone. Higher androgenic progestins may counteract those effects and have a negative effect on insulin; therefore, OC choice should be based on progestin component. Antiandrogens can be used alone or in combination with oral contraception to decrease the effects of androgen excess. Spironolactone (Aldactone) has antiandrogenic effects when administered in doses of 100 mg to 200 mg daily. Finasteride is a competitive inhibitor of the enzyme that converts testosterone to dihydrotestosterone, but studies show it is suboptimal for the treatment of hirsutism. Eflornithine (Vaniqa) is a topical treatment for facial hirsutism.12 Antiandrogens and OCs are often used to treat androgen excess. A starting dose of 30 mcg to 35 mcg of ethinyl estradiol combined with a progestin is recommended. If the patient is not satisfied after 4 to 6 months, a spironolactone may be added. When OCs are contraindicated, spironolactone may be used alone. Endometrial protection is necessary with intermittent progestin or metformin (Glucophage). An alternate form of contraception is necessary because spironolactone may cause abnormal development of external genitalia in male fetuses.15
Treatment of Insulin Resistance
Hyperinsulinemia plays a primary role in the pathogenesis of PCOS. Women with PCOS have increased rates of obesity, type 2 diabetes, impaired glucose tolerance and dyslipidemia. In addition to the metabolic risks, hyperinsulinemia contributes to hyperandrogenemia by decreasing hepatic production of SHBG and increasing free testosterone levels. Insulin also binds to ovarian theca cells to stimulate testosterone production and may act to enhance LH-stimulated testosterone by the ovary. Insulin-lowering therapy improves insulin resistance and regulates menstrual activity. It may also influence body weight and lipid metabolism.12Metformin and the thiazolidinediones (TZDs) are the two most common pharmacologic approaches to hyperinsulinemia. Metformin is a biguanide used in the treatment of type 2 diabetes. It is an antihyperglycemic agent that decreases hepatic glucose production, improves glucose utilization in peripheral tissue, reduces intestinal glucose uptake and decreases lipolysis. Some research suggests that it also acts directly to reduce ovarian steroidogenesis. In women with PCOS, metformin therapy can increase ovulation rates, decrease body mass index or waist-to-hip ratio and decrease fasting insulin and testosterone levels.
Some researchers have suggested using OCs together with metformin to minimize the unwanted side effects of oral contraception. OCs work well for hyperandrogenic symptoms and menstrual cycle regulation, but they may worsen insulin sensitivity and occasionally cause a small increase in weight. The addition of metformin produces a modest improvement in insulin sensitivity.12 ZDs such as pioglitazone (Actos) and rosiglitazone (Avandia) are other treatments for type 2 diabetes. These are insulin sensitizers believed to improve the action of insulin in the liver, skeletal muscle and adipose tissue. They may have a direct effect on the ovary by decreasing testosterone and estradiol production. Troglitazone (Rezulin) was removed from the market because it was associated with severe idiosyncratic hepatotoxicity. The FDA now recommends liver function tests prior to TZD therapy and occasionally during therapy.12Pioglitazone and rosiglitazone improve insulin sensitivity, hyperandrogenemia and menstrual cycles, but they can cause weight gain. TZDs have been studied less than metformin but appear to produce clinical improvements; they are not recommended in women with PCOS who are not diabetic.15Insulin sensitizing agents are associated with reduced serum androgen evels and gonadotropins and improvement in serum lipids nd in prothrombotic factor.16This therapy has lso been associated with a decrease in hirsutism and acne, regulation of menses and an improvement of ovulation nd fertility. Notable improvements in all these parameters ave also been described after a change in lifestyle approach, articularly in the presence of obesity. Lifestyle interventions hould therefore be combined with insulin sensitizers when obesity is present.16In women with PCOS, oral contraception is more effective than insulin sensitizing agents in improving menstrual pattern and reducing serum androgen levels.17Metformin is more effective in reducing fasting insulin levels and not increasing triglyceride levels.17Limited evidence supports the preferential use of insulin sensitizing agents or OCs in the treatment of hirsutism or acne, or in preventing the development of diabetes, cardiovascular disease or endometrial cancer.
A combination therapy is often needed to achieve optimal results, but no specific combination of medications is recommended for all patients diagnosed with PCOS. Each woman has different needs and goals. Encourage lifestyle modifications before any pharmacologic treatment when obesity is present. All studies show that weight oss improves endocrine and metabolic abnormalities and hat ovulation and fertility may be restored.16
b>Putting It Into Practice
Nurse practitioners have an important role in the evaluation and treatment of patients with PCOS. Appropriate management encompasses timely diagnosis, treatment of numerous physical problems, thorough patient education, and psychosocial support. NPs have the skills and ability to provide a holistic approach to care that will help patients with PCOS achieve good clinical outcomes and a better quality of life.8
Cheryl Lindenbaum is a women's health nurse practitioner at Genesis Fertility and Reproductive Medicine in Brooklyn, N.Y.
References
1. Azziz R. Diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab. 2006;91(3):781-785.
2. Lorenz LB, Wild RA. Polycystic ovarian syndrome: an evidence-based approach to evaluation and management of diabetes and cardiovascular risks for today's clinician. Clin Obstet Gynecol. 2007;50(1):226-243.
3. Azziz R, et al. Positions statement: Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):4237-4245.
4. Azziz R. Diagnostic criteria for polycystic ovary syndrome: a reappraisal. Fertil Steril. 2005;83(5):1343-1346.
5. Norman RJ, et al. Polycystic ovary syndrome. Lancet. 2007;370(9588):685-697.
6. Rosenfield RL. Definition, pathogenesis, and etiology of polycystic ovary syndrome in adolescents. UpToDate. Available with subscription at http://www.uptodate.com. Accessed Oct. 15, 2009.
7. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223-1236.
8. Barron AM, Falsetti D. Polycystic ovary syndrome in adolescents: a hormonal barrage and metabolic upheaval. ADVANCE for Nurse Practitioners. 2008;16(3):49-54.
9. King J. Polycystic ovary syndrome. J Midwifery Womens Health. 2006;51(6):415-422.
10. Adams JM, et al. Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab. 2004;89(9):4343-4350.
11. Barbieri RL, Ehrmann DA. Diagnosis of polycystic ovary syndrome in adults. UpToDate. Available with subscription at: http://www.uptodate.com. Accessed Oct. 15, 2009.
12. Dronavalli S, Ehrmann DA. Pharmacologic therapy of polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):244-254.
13. Hoeger KM. Obesity and lifestyle management in polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):277-294.
14. Snyder BS. The lived experience of women diagnosed with polycystic ovary syndrome. J Obstet Gynecol Neonatal Nurs. 2006;35(3):385-392.
15. Barbieri RL, Ehrmann DA. Treatment of polycystic ovary syndrome in adults. UpToDate. Available with subscription at: http://www.uptodate.com. Accessed Oct. 15, 2009.
16. Pasquali R, Gambineri A. Insulin-sensitizing agents in polycystic ovary syndrome. Eur J Endocrinol. 2006;154(6):763-775.
17. Costello M, et al. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovarian syndrome. Cochrane Database Syst Rev. 2007;1:CD005552.
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