Depakene

Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance in women of reproductive age, affecting 5% to 10% of women in this age group. Seventy-five percent of women with secondary amenorrhea meet the diagnostic category for PCOS.

Stein and Leventhal first described an association between amenorrhea and polycystic ovaries in 1935.1From an infertile population observed at laparotomy, they described obese women with amenorrhea, hirsutism, and enlarged, cystic ovaries (defined as thickened capsule, multiple, subcortical cysts in a necklace pattern, and increased stromal density). Originally only described in obese women, the condition is now known to occur in all body types.

Stein and Leventhal's initial description of the ovaries led to the current, classic ultrasonographic findings and an overemphasis on morphologic ovarian findings as a key component to PCOS diagnosis. Other conditions associated with polycystic ovaries (defined as > 10 2-8 mm cysts on ultrasound examination) are Cushins's syndrome, coneeni-tal adrenal hyperplasia, and ovarian or adrenal tumors.2,3 The identification of polycystic ovaries on ultrasound is clearly not specific for PCOS diagnosis.

In 1963, Goldzieher and Axelrod4 further characterized this syndrome by determining the incidence of signs and symptoms in a PCOS population (see Table: "Signs and Symptoms of PCOS"). An understanding of the heterogeneous na-ture of the syndrome began to emerge. Understanding and appreciating the heterogeneous aspect as it relates to the clinical presentation, workup, and treatment, as well as an interpretation of published studies, is a key point in this article.

The Normal Menstrual Cycle

Knowledge of hypothalamic, pituitary, ovarian, and endometrial events of the normal menstrual cycle is essential to understand the aberrations associated with PCOS (see Figure: "The Normal Menstrual Cycle").5 Briefly, pulsatile release of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus of the medial basal hypothalamus stimulates pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary.

Every menstrual cycle begins when FSH levels rise in response to decreasing estrogen and progesterone levels at the end of the previous luteal phase. Responding to rising FSH, a cohort of follicles begins to grow and develop. The theca cells within the follicles respond to LH and produce androgens (androstenedione and testosterone), which are con-verted to estrogens (estrone and estradiol) in the granulosa cells influenced by FSH. As estrogen levels rise, FSH secretion from the pituitary is inhibited, and most follicles undergo atresia. The single, dominant follicle that emerges has increased FSH receptors on the granulosa cells and is therefore able to maintain growth even as central FSH concentrations decline. The rising estrogen level triggers the onset of a mid-cycle LH surge, resulting in ovulation 34 to 36 hours later. The granulosa cells, influenced by estrogen, acquire LH receptors as the cycle progresses.

Following ovulation, LH stimulation of the granulosa cells results in progesterone production. Rising estrogen levels during the first half of the cycle (the proliferative phase) stimulate increased endometrial thickness and vascularity. Progesterone production following ovulation (the secretory phase) stimulates increased glandular secretion and vessel tortuosity within the endometrium. In the absence of pregnancy, progesterone and estrogen levels fall after about 14 days, the en-dometrium is sloughed, and a new cycle begins.

* Pathogenesis of PCOS

A complete understanding of PCOS pathogenesis is still elusive. The syndrome heterogeneity reinforces its multifactorial nature. The endocrine, reproductive, and metabolic consequences of PCOS, in varying degrees, include increased circulating LH levels, with normal-to-low FSH secretion leading to increased ovarian and adrenal androgen production and resulting in acne and hirsutism. Other problems are the failure of a dominant follicle to mature and ovulate, resulting in menstrual cycle irregularities and infertility, and insulin resistance, which has been associated with acanthosis nigricans.

As many as 40% to 50% of young, obese women with PCOS and 8% to 10% of lean women with the disorder have either impaired glucose tolerance (IGT) or diabetes mellitus (DM),6-8 as compared with 5% of age-matched controls in the general population.9 IGT and DM are defined as a fasting blood sugar (FBS) level of 110-125 mg/dl and > 126 mg/dl, respectively. The 2-hour glucose tolerance test (GTT) values for IGT and DM are 140-199 mg/dl and > 200 mg/dl, respectively.10 Current research focuses on the hypothesis that insulin resistance and accompanying hyperinsulinemia observed in obese and non-obese women with PCOS is the result of a genetic defect." This defect may also be responsible for the increased LH pulse amplitude and frequency leading to the hyperandrogenism observed with PCOS. The heterogeneous clinical expression may be related to the variation in penetrance of a single, or multiple, genetic defect.

* Clinical Manifestations

Menstrual Dysfunction

PCOS-associated menstrual dysfunction usually extends beyond the typical irregularity associated with the first 1-2 years following menarche, and varies from subtle irregularity to amenorrhea. The endometrium is in an unopposed estrogen state caused by antral follicle atresia and the resulting anovulation, leading to endometrium proliferation. Bleeding, often unpredictable and heavy, represents the sloughing of only the top layer of the endometrium that can no longer be sustained by estrogen production. In women of reproductive age, PCOS explains 85% to 90% of oligomenorrhea and 30% to 40% of amenorrhea.12

Hirsutism and Acne

Approximately 70% of women with PCOS are hirsute. It is important to remember that hirsutism is the accumulation of terminal hairs in a male distribution pattern, not the general increase of vellus hair (hypertrichosis) that can vary among ethnic groups. PCOS-associated hirsutism is dependent on overall androgen levels, sex hormone-binding globulin (SHBG) levels, individual skin androgen metabolism, and ethnic and genetic factors and their effects on the pilosebaceous unit (PSU).13

For biologic effect, androgens must be peripherally metabolized. Dehydroepiandrosterone, (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione are converted to testosterone. Testosterone is then metabolized to the more potent dihydrotestosterone (DHT), which is mediated by 5[alpha]-reductase activity in the hair follicle. The anagen (growth) phase of the hair cycle is prolonged in hyperandrogenic states, resulting in increased terminal hair.13 These effects are more noticeable in women with darker hair.

Increased PCOS-associated androgen levels also stimulate sebaceous gland cell division,13 which leads to increased sebum production and the resulting acne frequently seen in patients with PCOS. SHBG levels also influence the biologic effects of testosterone. When SHBG levels are decreased, as is often the case in PCOS, a greater percentage of testosterone is free or unbound and, therefore, biologically active.

Obesity

Although obesity was traditionally associated with PCOS, about 50% of women with PCOS are not obese,14 an important fact to remember when evaluating women with anovulation and hyperandrogenism. The obesity commonly observed in PCOS is characterized by an increased waist-to-hip ratio, referred to as android obesity,15,16 as opposed to the truncal obesity associated with Cushing's syndrome. The cause of PCOS obesity has not been fully delineated. Obesity appears to have a synergistic, deleterious effect on glucose tolerance in women with PCOS, as noted by the increased incidence of IGT and DM in obese women compared to lean women.

Infertility

Goldzieher and Axelrod17 found that approximately 75% of women with PCOS experience infertility. This was a fact observed in obese women with PCOS, and the incidence of infertility in lean women with PCOS may be less. An estimated 40% of all female infertility can be attributed to ovulatory dysfunction.18

* Diagnosis

PCOS diagnosis should be considered when women present with complaints such as menstrual cycle dysfunction, hirsutism, and infertility. The development of a diagnostic category has been difficult because of the heterogeneous nature of PCOS. Endocrinologists disagree over the appropriate criteria required for diagnosis, and varying inclusion criteria complicates reviews of PCOS studies.

A generally accepted, clinically useful definition established at a National Institutes of Health consensus conference in 1990 includes irregular menstrual bleeding (> every 35 days or

History

A careful and thorough history is important in patients presenting with menstrual dysfunction, signs of androgen excess, and infertility. A family history of oligomenorrhea, amenorrhea, hirsutism, and infertility is suggestive of PCOS. A positive family history of diabetes is associated with a higher incidence of IGT or frank diabetes in the patient with PCOS.

It is important to ask the patient about the timing of symptom onset and progression as it relates to menstrual irregularity and hirsutism. Patients with PCOS commonly complain of menstrual irregularity beginning with menarche, and are not limited to the common 1-2 years of irregularity until the hypo-thalamic-pituitary-ovarian axis matures and regular ovulation ensues.20 For certain women, the irregularity may not begin until they are in their late teens or early twenties. PCOS bleeding episodes often lack preceding symptoms, such as breast tenderness or bloating, suggesting anovulatory bleeding.

Hirsutism and acne, when present, have a gradual onset. Rapid onset and signs of virilization are more suggestive of an ovarian or adrenal androgen-producing neoplasm. A careful medication history is important because many drugs have been associated with hirsutism, including antiepileptics such as phenytoin (Dilantin),valproate(Depakote),valproic acid (Depakene), corticosteroids such as betamethasone (Betnelan, Celestone), cortisone (Cortone), dexamethasone (Decadron), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol), and prednisone (Deltasone), and androgens and anabolic agents such as danazol (Danocrine, Cyclomen), testosterone (Andro 100, Androderm, Testoderm), and minoxidil (Loniten, Rogaine).

Physical Examination

The physical examination should include a search for terminal hair in areas uncommon in women, such as the upper lip, chin, chest, upper and lower back, upper and lower abdomen, and upper arms and thighs. The Ferriman-Gallwey scoring system has been used extensively for objective evaluation; a score of 8 or higher is diagnostic of hirsutism.21 Alopecia (especially temporal) should be noted, as well as the presence and severity of acne. Obesity, if present, should be characterized (android obesity is characteristic of PCOS).

The patient should be evaluated for signs of Cushing's syndrome, including truncal obesity, striae, moon face, hypertension, spontaneous ecchymosis, buffalo hump, and muscle weakness. Signs of virilization, such as a deepened voice and clitoromegaly, should be assessed, as well as signs of galactorrhea. Acanthosis nigricans, if present, usually presents on the nape of the neck or in intertriginous areas of the body, such as the axillae, under the breasts, or the medial aspect of the thighs.

Laboratory Findings and Differential Diagnosis PCOS remains largely a diagnosis of exclusion (see Table: "Differential Diagnoses and Biochemical Markers in Menstrual Irregularity and Hirsutism"). DHEA-S should be measured because of its longer half-life; DHEA levels are too variable to be useful. Androgen level measurements rule out tumor. There is no need to measure free testosterone, androstenedione, or SHBG, as these are not beneficial to the evaluation.

There is no consensus regarding insulin resistance testing in women suspected of PCOS. Al-though frank diabetes testing is appropriate when suspected, it is not currently known if identifying insulin resistance predicts response to insulin-sensitizing medications for treating infertility, or if treating insulin resistance decreases the incidence of developing diabetes.

A 2-hour oral GTT may provide prognostic value as epidemiologic evidence supports IGT as a risk factor for developing diabetes. The clinician must decide which laboratory values are pertinent based on the prevalence of the suspected disorder, cost, patient and family history, and the findings of the physical examination.

Imaging Studies

Imaging studies are not generally helpful for establishing a PCOS diagnosis. On ultrasound, 20% of normally ovulating women will have evidence of polycystic ovaries. However, if the DHEA-S level is > 700 mcg/dl and an adrenal tumor is suspected, a computed tomography (CT) scan with contrast of the adrenals is recommended. If total testosterone is significantly elevated, an ultrasound may identify an ovarian tumor.

* Management of Associated Disorders and Health Consequences

Treatment goals include suppression of hyperandrogenism to improve hirsutism and acne, resumption of reproductive function in those desiring fertility, protection of the endometrium, and reduction of long-term risks of type 2 diabetes and cardiovascular disease. No monotherapy treats all aspects of PCOS and, in fact, many treatments are mutually exclusive.

Hirsutism and acne

Hirsutism and acne, two clinical signs of hyperandrogenism, can be distressing to patients. The goals of therapy are to lower androgen levels, increase SHBG to allow less bioactive circulating testosterone, and if necessary, hair removal. There are two hirsutism therapy categories-cosmetic hair removal and pharmacotherapy, which can either reduce androgen production or decrease the effects on the skin. Cosmetic therapies include plucking or tweezing, waxing, shaving, depilatories, electrolysis, and laser treatments. These therapies do not affect the rate of hair growth and are only temporary measures, however electrolysis and laser treatments may provide more permanent results. A 6-12 month pretreatment with medical therapy to allow for new hair growth suppression may help avoid re-treatment.

Medical therapies limit new hair growth, but do not affect existing hair. Therefore, it may take 6-12 months of therapy before an effect is appreciated, and 18 months or longer to see a full effect. Pharmacotherapy is also a temporary measure and the benefits are lost when the treatment is discontinued.

The FDA has not approved oral contraceptive treatment of hirsutism, and only OrthoTri-Cyclen and Estrostep received an PDA-approved indication for acne. No one oral contraceptive has proven to be a better treatment for hirsutism and acne, although individual responsiveness exists. Topical benzoyl peroxide, retinoids (topical or systemic), and antibiotics (topical or systemic) are sometimes used when oral contra-ceptives are not effective. Pregnancy must be prevented with retinoid use because of the teratogenic effects.

Long-acting gonadotropin-releasing hormone agonist (Lupron) therapy is not indicated for hirsutism because it induces a hypoestrogenic state. The use of glucocorticoids, such as dexamethasone, in the absence of 21-hydroxylase deficiency is not warranted therapy for hirsutism, as PCOS hyperandrogenism is a result of ovarian androgen production. The association of glucocorticoids and increased insulin resistance would be an additional concern in this patient population.

Spironolactone, an aldosterone antagonist and androgen receptor competitor, can be beneficial in hirsutism treatment,22 but does not have FDA approval for this indication. Spironolactone is best used with a combination oral contraceptive because of its association with menstrual irregularity in up to 50% of patients (as a result of mild progestational activity) and possible teratogenic effect.23 Dosing should begin at low levels and gradually increased (25 mg q.d. for 2 weeks, followed by 50 mg q.d. for 2 weeks, then increased to 50-100 mg b.i.d.) to avoid mild diuretic effects. Spironolactone should be discontinued 3 months prior to conception attempts.

Flutamide, a 5[alpha]-reductase inhibitor indicated for prostate cancer, has been proposed as an alternative to spironolactone for hirsutism treatment, however, conflicting data exist regarding its effectiveness compared with spironolactone.24,25 Flutamide may have a slower return of symptom rate once discontinued. Finasteride, a type II 5[alpha]-reductase specific inhibitor indicated for androgenic alopecia, has potential liver toxicity and shows no clear advantage over spironolactone.26 Vaniqa is a topical cream for facial hair removal, but there is no published data on clinical trials.

Obesity

Obesity is a well-recognized risk factor for developing type 2 diabetes, and 50% of PCOS patients are obese. The cause of obesity or how it is involved in developing diabetes is not clear.

Research shows that the endocrine and ovarian function of obese women with PCOS can be improved (decreased insulin levels, increased SHBG, and spontaneous resumption of menses) with as little as a 5% weight loss.27 As with any weight loss therapy, the challenge is to maintain the loss.

Weight reduction can be encouraged as a first-line solo therapy and should be included with medical treatment for androgen reduction, menstrual regulation, and ovulation induction for those desiring fertility. Weight reduction is expected to reduce the risk of hypertension and dyslipidemia associated with obesity. The insulin resistance of PCOS does not confer additional risk, other than the obesity alone, for developing hypertension and dyslipidemia,28 although long-term, prospective, controlled studies are needed to confirm this.

* Hyperinsulinemia and Dyslipidemia

IGT is a known risk factor for type 2 diabetes and is associated with PCOS. Data from the Diabetes Prevention Program,29 a large study of both men and women with IGT, demonstrated a 29% conver-sion to type 2 diabetes over 3 years when only standard lifestyle interventions were employed. A 58% reduction in developing type 2 diabetes was seen with intensive lifestyle interventions alone (aimed at a 7% weight reduction and 150 minutes of physical activity per week). Only a 31% reduction was seen when the insulin-sensitizing drug metformin (Glucophage) was combined with standard lifestyle interventions.

No large-scale prospective studies have followed well-defined PCOS women into menopause to characterize their progression of glucose tolerance. These studies are needed before we can determine the best use of these drugs in this population.

Wild et al reported that women with hirsutism have a statistically significant decrease in HDL cholesterol and a statistically significant increase in triglycerides and cholesterol/HDL ratios.30

Subsequently, Legro et al31 studied a well-characterized group of non-Hispanic, nondiabetic, white PCOS women ages 18 to 45 years old. After adjusting for age, alcohol use, smoking, and activity level, higher total cholesterol and LDL-C levels were found in both obese and non-obese PCOS women compared to their controls.

Obese PCOS women had higher HDL-C levels compared to obese controls. Triglycerides were similar among groups. Although obese women had cholesterol/HDL-C ratios in the highest quartile, the ratios were lower in obese PCOS women, possibly reducing their risk of cardiovascular disease (CVD) compared to other obese women. Previous studies in PCOS women did not adjust for weight and ethnicity. The findings of this study were not consistent with the elevated triglyceride and low HDL-C levels associated with non-PCOS insulin resistant states, so it remains unclear what additional risk of CVD disease exists in PCOS women independent of obesity.

In a retrospective cohort, long-term follow-up study of PCOS women in the UK,32 an increased prevalence of cardiovascular risk factors was demonstrated, but no excess of cardiovascular disease was found in middle-aged women. Large-scale prospective trials of PCOS women are needed to help us elucidate the etiology of heart disease in this population and if PCOS actually confers protection from CVD through yet unclear mechanisms.

Currently, there is no standard regarding routine screening for dyslipidemia in women with PCOS. Screening for lipid abnormalities may be warranted, how-ever, if IGT or diabetes is discovered.

* Menstrual Dysfunction

The endometrium can be protected from unopposed estrogen and regular, scheduled, withdrawal bleeding can be accomplished with combination oral contraceptives or cyclic progesterone. The standard contraindications and precautions for oral contraceptive use apply to this population. Medroxyprogesterone acetate in dosages of 5-10 mg p.o. every day for 5-10 days, Prometrium 400 mg p.o. every day for 10 days, and Crinone vaginal cream 4-8% every other day for 6 doses all have FDA indication for secondary amenorrhea.

* Infertility

To reduce pregnancy complications, weight reduction should be the first-line treatment for all obese patients seeking fertility. When this is not successful, pharmacotherapy should be implemented.

Clomiphene citrate (CC) has been the mainstay of ovulation induction for women with PCOS in the United States since 1967. Because the focus of treating PCOS patients with CC is correction of the anovulatory state while keeping multiple birth risk low, treatment should be started with the lowest available dose (50 mg), with 50 mg increments of increased dosage if ovulation is not detected. There is no advantage to increasing the dose if ovulation occurs on a lower dose. Of oligomenorrheic women, 93% to 95% ovulate with CC.33,34

Approximately 50% of women will conceive at the 50 mg 5-day dosage. An additional 20% of women conceive at the 100 mg dose. The majority of pregnancies (84.5%) occur during the first 3 ovulatory cycles. Increased body weight is associated with a need for increased dosage to achieve ovulation. If the patient has remained anovulatory after doses of 150 mg or has not conceived after 3 ovulatory cycles, refer her to a reproductive endocrinology practice for further assessment and treatment, which may include insulin-sensitizing agents (to treat insulin resistance), gonadotropin injections, or laparoscopic ovarian drilling (to reduce androgen levels).

An increasing number of reports review the use of insulin-sensitizing drugs for the treatment of PCOS. Metformin (Glucophage) has been best studied in this regard, including its effectiveness in restoring regular menstrual cycles, initiating ovulation induction, reducing rates of spontaneous miscarriage and gestational diabetes, and correcting metabolic abnormalities associated with PCOS.35,36 Guidelines are being established for its use in the treatment of infertility in PCOS women.37 It is already FDA approved for the treatment of type 2 diabetes.

Treatment with metformin is aimed at lowering the hyperinsulinemia associated with PCOS, thereby reducing androgen production and facilitating ovulation. The reduced insulin levels would theoretically lower the risk of developing DM or cardiovascular disease.

Although studies evaluated in the review articles demonstrated a 60% return to normal menstrual cycles and ovulation after 3 to 6 months of treatment using metformin alone in an unselected population of PCOS women (PCOS women not shown to be CC-resistant), there were no good data available on pregnancy rates. In this population of women, the addition of CC to metformin for a total duration of 8 to 9 months resulted in an approximate 66% ovulation and 34% pregnancy rate. This compares to an ovulation and pregnancy rate using CC alone as first-line therapy for ovulation induction in PCOS women of 70-80% and 33-45% respectively. Not all studies showed universal beneficial effects on androgen levels, insulin levels or body mass index.

In CC-resistant PCOS women, the ovulation and pregnancy rates were 40% and 25% respectively in both metformin alone and metformin plus CC groups.

These studies must be viewed with caution and as preliminary results since there are a limited number of studies, many were small in numbers and observational, and most were performed on obese PCOS women, leaving the effec-tiveness of metformin on lean PCOS women unclear. Additionally, there are no published large-scale clinical trials demonstrating metformin's impact on live birth rates in PCOS women, nor do any head-to-head randomized trials exist comparing metformin to CC as initial therapy for ovulation induction.

Summary

PCOS is common among women of reproductive age, with endocrine, reproductive, and metabolic consequences. Although not fully understood, research indicates that the cause is the unique and intrinsic insulin resistance associated with the syndrome. Treatment should focus on reduction of androgen-associated symptoms, protection of the endometrium, weight loss if obese, reducing long-term risk of diabetes and cardiovascular disease, and resumption of fertility, if desired.

After a careful history, physical examination, and laboratory testing to rule out metabolic causes for the symptoms, NPs can manage most of the common complaints and health maintenance issues associated with PCOS. If non-PCOS causes of oligomenorrhea or hirsutism, such as Cushing's syndrome, adult onset congenital adrenal hyperplasia or adrenal or ovarian tumors are found during the workup, the patient should be referred to an endocrinologist for treatment. If fertility is desired, a reproductive endocrinologist should be consulted.

ACKNOWLEDGEMENTS

The author would like to thank Laura H Greenberg, MD, and Michael McClung, MD, for their assistance in reviewing the manuscript.

REFERENCES

1. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181-91.

2. Polson DW, Adams J, Wadsworth J, et al.: Polycystic ovaries-A common finding in normal women. Lancet 1988;1:870-72.

3. Franks S: Polycystic ovary syndrome. N Engl J Med 1995;333:853-61.[Erratum: N Engl J Med 1995;333:1435.]

4. Goldzieher JW, Axelrod LR: Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963;14:631.

5. Katzung B. Basic and Clinical Pharmacology. 6th edition. New York, N.Y.: McGraw-Hill, 1995;609.

6. Dunaif A, Finegood DT: Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942-47.

7. Legro R, Finegood D, Dunaif A: A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:2694-98.

8. Legro RS, Kunselman AR, Didson WC, et al.: Prevalence and predictors for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165-69.

9. Harris MI, Hadden WC, Knowler WC, et al.: Prevalence of diabetes and impaired glucose tolerance levels in US population aged 20-74 years. Diabetes 1987;36:523-34.

10. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183-97.

11. Dunaif A: Insulin resistance and the polycystic ovary syndrome: Mechanisms and implications for pathogenesis. Endocr Rev 1997;18:774-800.

12. Franks S, White DM: Prevalence of and etiological factors in polycystic ovarian syndrome. Ann N Y Acad Sci 1993;687:112.

13. Lobo RA: Androgen excess. In: Daniel RM Jr, Val D, Rogerio L, eds. Infertility, Contraception and Reproductive Endocrinology. 3rd edition. New York, N.Y.: Blackwell Scientific, 1991:422-46.

14. Pasquali R, Antenucci D, Casimirri F, et al: Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68:173-79.

15. Evans DJ, Barth JH, Burke CW: Body fat topography in women with androgen excess. Int J Obes 1988;12:157-63.

16. Franks S: Polycystic ovary syndrome. N Engl J Med 1995;333:853-61.

17. Goldzieher JW, Axelrod LR: Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963; 14:631.

18. Female infertility. In: Speroff L, Glass RH, and Kase NG, eds. Clinical Gynecologic Endocrinology and Infertility. 5th edition. Baltimore, Md.: Williams and Wilkins, 1994;809-39.

19. Dunaif A, Segal KR, Shelley DR, et al: Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41:1257-66.

20. Yen SSC: The polycystic ovary syndrome. Clin Endocrinol 1980:12:177-208.

21. Ferriman D, Gallwey JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961:21:1440-47.

22. Barth JH, Cherry CA, Wojinarowska F, Dawber RP: Spironolactone is an effective and well tolerated systemic antiandrogen therapy for hirsute women. J Clin Endocrinol Metab 1989;68:966-70.

23. Chapman MG, Dorwsett M, Dewhurst CJ, Jeffcoate SL: Spironolactone in combination with an oral contraceptive: An alternative treatment for hirsutism. Br J Obsetet Gynaecol 1985;92:983-85.

24. Cusan L, Dupont A, Gomez JL, et al: Comparison of flutamide and spironolactone in the treatment of hirsutism: A randomized controlled trial. Fertil Steril 1994:61:281-87.

25. Erenus M, Gurbuz O, Durmusoglu F, et al: Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertil Steril 1994:61:613-16.

26. Wong IL, Morris RS, Ghang L, et al: A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 1995:80:233-38.

27. Kiddy DS, Hamilton-Fairley D, Bush A, et al: Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 1992;36:105-11.

28. Graf MJ, Richards CJ, Brown V, et al: The independent effects of hyperandrogenism, hyperinsulinemia, and obesity on lipid and lipoprotein profiles in women. Clin Endocrinol 1990;33:119-31.

29. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346: 393-403.

30. Wild RA, Alapovic P, Parker J: Lipid and apolipoprotein abnormalities in hirsute women. The association with insulin-resistance. Am J Obstet Gynecol 1992;166:1191-97.

31. Legro RS, Kunselman AR, Dunaif, A: Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001;111:607-613.

32. Wild S, Pierpoint T, McKeigue P, et al; Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol 2000;52:595-600.

33. Gysler M, March CM, Mishell DR, et al: A decade's experience with an individualized clomiphene treatment regimen including its effect on the post-coital test. Fertil Steril 1982;37:161-67.

34. Lobo RA, Gysler M, March CM, et al: Clinical and laboratory predictors of clomiphene response. Fertil Steril 1982;37:168-74.

35. Costello MF, Eden JA: A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003;79:1-13.

36. Haas, DA, Carr BR, Attia, GR: Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003;79:469-481.

37. Nester JE, Stoval D, Akhter N, et al: Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002;77:209-215.

Kathryn M. Hill, RNC, WHCNP, MS

ABOUT THE AUTHOR

Kathryn M. Hill is a Women's Health Care Nurse Practitioner with the reproductive endocrinology practice of Laura H. Greenberg, MD, in Portland, Ore.

Copyright Springhouse Corporation Jul 2003
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