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Current Perspectives in Polycystic
Ovary Syndrome
MARILYN R. RICHARDSON, M.D., University of Kansas Medical Center, Kansas City, Kansas
Polycystic ovary syndrome has been viewed primarily as a gynecologic disorder requiring
medical intervention to control irregular bleeding, relieve chronic anovulation, and facil-
itate pregnancy. A large body of evidence has demonstrated an association between
insulin resistance and polycystic ovary syndrome. The former condition has an estab-
lished link with long-term macrovascular diseases such as type 2 diabetes mellitus, hyper-
tension, and atherosclerotic heart disease, consequences that also are observed in
women with polycystic ovary syndrome. In addition, chronic anovulation predisposes
women to endometrial hyperplasia and carcinoma. The purpose of this review is to
examine the clinical course of this syndrome, which spans adolescence through
menopause, and suggest a simple and cost-effective diagnostic evaluation to screen the
large numbers of women who may be affected. Therapy, which should be individualized,
should incorporate steroid hormones, antiandrogens, and insulin-sensitizing agents.
Weight loss by way of reduced carbohydrate intake and gentle exercise is the most
important intervention; this step alone can restore menstrual cyclicity and fertility, and
provide long-term prevention against diabetes and heart disease. Treatment alternatives
should be directed initially toward the most compelling symptom. Longitudinal care is of
paramount importance to provide protection from long-term sequelae. (Am Fam Physi-
cian 2003;68:697-704. Copyright 2003 American Academy of Family Physicians.)
are well placed to make early diagnoses ofPCOS and to help patients avoid the long-term consequences.
is the most common endocri-nopathy among women of repro-ductive age and is estimated to Clinical Course
Young women of reproductive age most fre- quently seek attention initially because of irreg- described masculinized women with amenor- ular menses, hirsutism, or infertility, but PCOS rhea, sterility, and enlarged ovaries containing has a long prodrome with detectable abnor- multiple cysts. The syndrome was placed in malities throughout the life cycle of affected the gynecologic realm for control of chronic women. The earliest manifestations of PCOS anovulation, abnormal menstrual bleeding, are discernible in the peripubertal years.
resistance develop with increased frequency in impaired glucose tolerance.3,4 The connection arche.11,12 In the early reproductive period, to an insulin post-receptor defect was isolated chronic anovulation results in reduced rates of in women with PCOS in the early 1990s.5 As a conception. When pregnancy is achieved, it result of these recent associations, attention is frequently terminates in spontaneous, first- now focused on treating the central deficits trimester loss or is associated with gestational diabetes.6 Approximately 25 to 30 percent of these women show impaired glucose tolerance lipid levels, and obesity that have broader by the age of 30, and 8 percent of women with health implications (Table 1).3,6-10 This new PCOS develop frank type 2 diabetes mellitus information profoundly alters our view of the gravity of this condition. Family physicians tension, and coronary artery disease compared with con- trol patients. PCOS appears to follow a familial distribu- Intermediate and Long-Term Consequences
tion; 40 percent of the sisters and 20 percent of the moth- Associated with PCOS
ers of affected women also have the syndrome to varyingdegrees.15 Clinical Features
In many women the symptoms are easily recognizable, but ethnicity influences the extent of symptoms, especially with regard to hirsutism and obesity. Therefore, taking a diligent history with regard to menstrual patterns is cru- cial to help establish the diagnosis. The National Institute of Child Health and Development16 held a consensusmeeting to develop the following diagnostic criteria for NOTE: These abnormalities may be identified in women with PCOS PCOS: (1) clinical or biochemical evidence of hyperan- at various life stages. Listed in order from most common to leastcommon. drogenism; (2) oligo-ovulation; and (3) exclusion of otherknown disorders, such as congenital adrenal hyperplasia PCOS = polycystic ovary syndrome; LDL = low-density lipoprotein;HDL = high-density lipoprotein. Information from references 3, and 6 through 10. HYPERANDROGENISM
The wide spectrum of manifestations ranges from mild acne and increased terminal (coarse) hair growth in midline cerebrovascular disease are prevalent. Women with poly- structures (face, neck, abdomen), to android changes in cystic ovaries are seen to have more extensive coronary body habitus, with waist-to-hip ratios of more than 1. Vari- artery disease by angiography.8 In two case-control stud- ations are influenced by ethnicity,17 as well as coexisting con- ies,9,10 women in their 40s had greater intima-medial thick- ditions (such as hyperthyroidism) that alter androgen ness of the carotid vessels, and more atherogenic lipid pro- biosynthesis. For example, Asian women with PCOS are files: increased total and low-density lipoprotein (LDL) rarely hirsute, but hirsutism is a frequent finding in black cholesterol and triglyceride levels, and decreased high-den- women with PCOS. Yet the actual incidences of hyperan- sity lipoprotein (HDL) cholesterol levels.9,10 drogenemia and insulin resistance do not show a racial These metabolic abnormalities are compounded by the prevalence of obesity, which occurs in more than 65 per- In addition, nonhirsute women with oligo-ovulation cent of women with PCOS.3 Abnormal androgen produc- may have laboratory evidence of hyperandrogenism.
tion declines as menopause approaches (as it does in Frank or rapid “virilization” involving clitoromegaly, vocal women without PCOS), and menstrual patterns somewhat chord thickening, or male-pattern baldness is rare in normalize. However, in retrospective cohort studies,13,14 patients with PCOS and, when present, suggests another perimenopausal and postmenopausal women with a his- cause of hyperandrogenism, such as adrenal disorders or tory of PCOS had increased rates of type 2 diabetes, hyper- androgen-producing tumors (Table 2).18 OLIGO-OVULATION
Oligo-ovulation manifests as menstrual irregularity and Diagnostic criteria for polycystic ovary syndrome occurs in 70 percent of women with PCOS. Among include (1) clinical or biochemical evidence of women with more regular menses, many have variable hyperandrogenism, (2) oligo-ovulation, and (3) degrees of ovulatory dysfunction. Often the menstrual for- exclusion of other known disorders, such as mula (i.e., three to five days of menstrual flow every 28 to adrenal hyperplasia or hyperprolactinemia. 35 days) occurs for the first one to two years after menar-che (which occurs at the normal age), but menses then become less frequent, occurring every 45 to 365 days.
Because the estrogen from ovarian and adipose tissues Bleeding can be unpredictable, heavy, and pro- stimulates proliferation of endometrium that is not stabi- longed, and chronic endometrial proliferation can lized by post-ovulatory progesterone, bleeding can be unpredictable, heavy, and prolonged. Chronic endometrialproliferation can result in carcinoma.
SYMPTOMS WITH VARIABLE FREQUENCY
Diagnostic Evaluation
Obesity. More than 65 percent of women with PCOS Although there is no consensus as to which laboratory have a body mass index exceeding 27. The fat distribution tests should be used to diagnose PCOS, most physicians often is abdominal/visceral, similar to that frequently asso- agree that the evaluation should screen for hyperandro- ciated with metabolic abnormalities (e.g., hypertension, genemia as well as for abnormalities that have serious dyslipidemia, insulin resistance, glucose intolerance). Most health consequences. Often, the clinical picture is readily women deny childhood obesity and describe normal apparent from the history and physical findings. Thus, test- weight until after menarche. Significant weight gain ing for parameters known to be abnormal in women with appears in the mid-teens and accelerates in the later teens PCOS, such as luteinizing hormone (LH) and follicle- stimulating hormone (FSH) ratios, is unnecessary, redun- The presence of obesity also is influenced by ethnicity. It is most common in Hispanic, black, and white women, less In the author’s opinion, the evaluation should follow striking in women of Mediterranean descent, and rare in these principles: exclude other etiologies of amenorrhea, Asian women.17 Obesity is likely to facilitate the metabolic such as prolactin or thyroid abnormalities; exclude other abnormalities of PCOS, as evidenced by the reduction in causes of hyperandrogenism; exclude glucose intolerance; insulin resistance and restoration of cyclic menses follow- and detect insulin resistance and lipid abnormalities.
ing weight loss.19 A 1982 study,20 which has been con-firmed by later research, showed that a 10 to 15 percent LABORATORY EVALUATION
weight reduction resulted in spontaneous conception in Normal testosterone determinations in the hirsute patient more than 75 percent of obese patients with PCOS.
can be misleading, partially because of inherent variation in Acanthosis Nigricans. These velvety, raised skin deposits in intertriginous areas are associated with insulin resis-tance and result from insulin stimulation of the basal lay- ers of the epidermis. When found in conjunction with Differential Diagnosis of Hyperandrogenism
hyperandrogenism, the condition is termed HAIR-ANsyndrome (hyperandrogenic-insulin resistant–acanthosis nigricans); it occurs in 2 to 5 percent of hirsute women.21 The majority of women with PCOS (70 percent) are insulin resistant, but hyperinsulinemia is far more severe inwomen with HAIR-AN syndrome.
Polycystic Ovaries. Ovaries with multiple, small (less than 10 mm) follicular cysts surrounding the ovarian stroma are found in 16 to 25 percent of normal women and in female patients with ammenorrhea caused by other etiologies.22Nearly 80 percent of women with hyperandrogenism have PCOS = polycystic ovary syndrome; HAIR-AN = hyperandrogenic- polycystic ovaries,23 but these may not be present at the time insulin resistant—acanthosis nigricans. of evaluation in women who have used oral contraceptive Adapted with permission from Azziz R. Hirsutism. In: Droege- pills (OCPs), insulin-sensitizing agents, or other forms of mueller W, Sicarra JJ, eds. Gynecology and obstetrics.Vol 5. ovarian suppression. Therefore, the presence of polycystic Philadelphia: Lippincott, 1994:1-22. ovaries on ultrasonography is not a diagnostic essential.
TABLE 3
Laboratory Investigation of PCOS
0.5 to 4.5 µU per mL (0.5 to 4.5 mU per L) 600 to 3,400 ng per mL (1.6 to 9.2 µmol per L) 0.4 to 2.7 ng per mL (1.4 to 9.4 nmol per L) Follicular phase < 2 µg per L (6.1 nmol per L) 65 to 119 mg per dL (3.6 to 6.6 mmol per L) Exclude type 2 diabetes or glucose intolerance 35 to 85 mg per dL (0.9 to 2.2 mmol per L) 80 to 130 mg per dL (2.1 to 3.4 mmol per L) NOTE: Diagnosis of PCOS established by exclusion of other causes of oligomenorrhea or hyperandrogenism. Other tests may be of benefitin monitoring therapy. PCOS = polycystic ovary syndrome; ␤-hCG = beta subunit human chorionic gonadotropin; TSH = thyroid-stimulating hormone; DHEAS =dehydroepiandrosterone sulfate; NCAH = nonclassic adrenal hyperplasia; HDL = high-density lipoprotein; LDL = low-density lipoprotein. commercial testing methods.24 However, bioavailable (free) Both free testosterone and sex hormone-binding globu- testosterone levels may support the diagnosis, especially in a lin may be useful in monitoring the efficacy of androgen nonhirsute woman with other signs and symptoms of suppression therapy. Total testosterone levels greater than PCOS. Hyperandrogenemia also might be established by 20 ng per dL (0.7 nmol per L) or DHEAS levels greater elevated serum levels of dehydroepiandrosterone sulfate than 700 ng per mL (1.9 µmol per L) are suggestive of androgen-secreting tumors; these patients should bereferred for gynecologic investigation.25 Morning 17␣-hydroxyprogesterone (17-OHP) determi- nation is important to exclude nonclassic adrenal hyperpla- sia secondary to 21-hydroxylase deficiency, which is present MARILYN R. RICHARDSON, M.D., is clinical assistant professor of in 1 to 8 percent of hirsute women.26 When elevated 17- obstetrics and gynecology in the Division of Reproductive Endocrinol- OHP is discovered, the next step should be a short adreno- ogy and Infertility at the University of Kansas Medical Center, KansasCity, Kan. She received her medical degree from the University of corticotropic hormone stimulation test to further delineate Kansas School of Medicine, Kansas City, and completed a residency in the enzymatic defect. The ratio of LH to FSH is greater than obstetrics and gynecology at the University of Missouri–Kansas City 3:1 in about 30 percent of women with PCOS and may be School of Medicine, Truman Medical Center, Kansas City, and a fellow-ship in reproductive endocrinology and infertility at the University of diagnostically helpful in nonhirsute women with mild ovu- Texas Health Science Center at Dallas.
latory dysfunction, but this determination is not routinely Address correspondence to Marilyn R. Richardson, M.D., University of necessary if the clinical picture is otherwise clear.
Kansas Medical Center, Department of Obstetrics and Gynecology, Divi- Because nearly 30 percent of women with PCOS have sion of Reproductive Endocrinology and Infertility, 3901 Rainbow Blvd., impaired glucose tolerance, determinations of glucose tol- Kansas City, KS 66160 (e-mail: [email protected]). Reprints arenot available from the author. erance and insulin resistance are of paramount impor- TABLE 4
Medical Treatment Options in PCOS
PCOS = polycystic ovary syndrome; FSH = follicle-stimulating hormone; LH = luteinizing hormone. *—1 = Suppression of hyperandrogenism; 2 = restore menstrual cyclicity; 3 = prevent endometrial hyperplasia; 4 = induce/facilitate ovu-lation; 5 = facilitate weight loss; 6 = reduce hyperinsulinemia. †—Estimated cost to the pharmacist for one month of therapy based on average wholesale prices in Red book. Montvale, N.J.: MedicalEconomics Data, 2002. Cost to the patient will be higher, depending on prescription filling fee. tance. One approach is to perform standard oral glucose choices should be based on the woman’s most pressing tolerance testing with insulin levels. Peak levels of insulin concern and her stage of reproductive life (Figure 1). Given that exceed 100 µU per mL (718 pmol per L) are suggestive the current awareness of the long-term consequences asso- of insulin resistance. This test may be unnecessarily cum- ciated with PCOS, the physician carries the responsibility bersome and expensive for general screening, however, and of tailoring therapy to add preventive benefits. In addition, the author’s practice is to reserve this test for use in women cosmetic alterations can result in depression and with- with a family history of glucose intolerance, morbid obe- drawal from social and career pursuits. Thus, the physician sity, or other symptoms suggestive of diabetes.
should be armed with information about removal of A more efficient assessment may be to use the ratio of unwanted hair. Shaving and depilation are the most effi- fasting levels of glucose to insulin. When less than 4.5, this cient short-term means for terminal hair removal while ratio has a significant correlation with insulin resistance and initiating androgen suppression using some of the modal- has been studied for use as a screening test in obese patients with PCOS. It combines sensitivity (95 percent) and speci-ficity (84 percent) for insulin resistance, with positive and STEROID HORMONES
negative predictive values of 87 percent and 97 percent in OCPs are the most efficient means of androgen sup- obese patients with PCOS.27 This predictive capacity may pression (ovarian as well as adrenal), and nearly any com- not hold true in nonobese women with PCOS.
bination OCP is effective in treating PCOS. This therapy The author includes assessments of total, HDL, and LDL results in lower and static LH levels without surges. The cholesterol levels as well as triglyceride levels to help in estrogen component stimulates hepatic production of sex planning and follow-up of recommended dietary modifi- hormone-binding globulin that reduces bioavailable cations to reduce obesity and cardiovascular risk. Finally, androgen and can reduce hirsutism and acne. The prog- endometrial biopsy is helpful to rule out endometrial estin component provides competitive antagonism to hyperplasia in patients with prolonged amenorrhea (morethan five months). A list of laboratory tests that may helpto identify patients with PCOS is provided in Table 3. A ratio of less than 4.5 of fasting glucose to Treatment
insulin levels correlates significantly with insulin The primary goal of all forms of therapy is to suppress resistance and has been studied for use as a insulin-facilitated, LH-driven androgen production.
screening test in obese patients with polycystic Although numerous medications (Table 4) and protocols are effective in reducing insulin and androgen levels, the Management of Polycystic Ovary Syndrome
FIGURE 1. Management of polycystic ovary syndrome. After the primary concern is identified, the patient can decide ifcontraception or fertility is preferred. Lifestyle modification is a central measure in either case. androgen at its receptors, reducing the action of testos-terone at the target organ.
ANTIANDROGENS
Newer formulations contain progestins of lower andro- Therapy with spironolactone (Aldactone) has a direct genicity, such as norgestimate, desogestrel, and gestodene.
suppressive effect on enzymes in the androgen biosynthetic OCPs can be used alone or in conjunction with antiandro- pathway. Because of its structural similarity to testosterone, gens, gonadotropin-releasing hormone agonists, or it can competitively inhibit androgen receptor binding and insulin-sensitizing agents. Restoration of the menstrual is useful in the treatment of hirsutism. Three of six open cycle and prevention of endometrial hyperplasia are addi- clinical trials showed improvement in hirsutism, but results of double-blind placebo-controlled trials were not as posi- Hirsute women should be counseled that regression of tive.28 One study29 has shown that spironolactone can terminal hair growth during OCP therapy is a slow reduce the caliber and growth rate of terminal hair. Dosages process, requiring up to eight months for noticeable bene- as high as 200 mg per day are tolerated, and menses some- fits. It is appropriate to institute permanent methods of times resume. This agent is most effective when combined hair removal by way of electrolysis or laser ablation after with OCPs; some form of contraception is advisable when suppression of hyperandrogenism has been achieved.
it is used alone. A newly released formulation of OCP con- Because these women are highly estrogenized (as a result tains an analog of spironolactone, drospirenone. Drospire- of peripheral conversion of androgenic precursors), none combined with ethinyl estradiol (Yasmin) is indicated menses can be induced by administration of progesta- tional agents for approximately 10 days. Women should beadvised that their cycles are not re-established by this treat- ASSISTED FERTILITY
ment, and that if it is not repeated at two- or three-month Clomiphene citrate (Serophene) or gonadotropins can intervals, unchecked endometrial growth can result in be used to establish menses but should be reserved for use endometrial hyperplasia. If menstrual bleeding does not in patients who wish to become pregnant. Because the occur within 14 days of completion of progesterone woman with PCOS is uniquely sensitive to these agents and administration, another etiology for amenorrhea rather risks higher rates of ovarian hyperstimulation and multiple than PCOS should be sought. Progesterone administration gestation,30 specialty referral for this therapy is recom- does not provide relief from any other symptoms or pre- mended. Clomiphene administration will result in ovula- vent any of the long-term conditions. It is useful on a tion in 50 to 60 percent of cases, in pregnancy in 30 percent, scheduled basis only for menstrual regulation.
and in multiple gestation (twins or greater) in 3 percent.
Although the body of data is limited, it is suggested that excessive or prolonged exposure to clomiphene citrate Lifestyle modifications with weight loss have (more than 12 months) could increase the risk of ovarian achieved pregnancy rates as high as 60 percent cancer.31 When clomiphene fails, gonadotropin administra- tion frequently is successful in helping women to achievepregnancy (70 percent), but it requires self-injection, iscostly, and carries an even higher rate of hyperstimulationand multifetal pregnancy (as high as 30 percent).32 it brings about the greatest global improvement in car-diovascular risks, insulin sensitivity, and menstrual pat- INSULIN REDUCTION
terns; it is most difficult because of the compliance issue.
Metformin (Glucophage), a biguanide and insulin-sen- Weight loss should not be rapid or drastic but should be sitizing agent, has been used to restore menstrual cyclic- achieved through consistent lifestyle modification that ity and induce ovulation in PCOS without the use of includes gentle exercise, intake of dietary carbohydrates additional fertility drugs. Use of this agent is associated with a low glycemic index, and a reduced intake of fats with reductions in serum levels of bioavailable androgen, and simple sugars. Severe dietary deprivation is uni- LH, and atherogenic lipids. Levels of plasminogen activa- tor inhibitor I and Lp(a) lipoprotein also were reduced.33 No single food plan is recommended, but frequent feed- There are no data to show a benefit in women who are ings (four to six times per day) are important to avoid not insulin resistant, but a few physicians support its hypoglycemia and hunger. Hypoglycemia leads to cravings and poor food choices that, in turn, result in simple sugar Metformin is presently classified as a category “B” risk in intake and reactive hyperinsulinemia. In the experience of pregnancy, which indicates that there are no apparent fetal the author, most women respond well to the admonition defects associated with its use in the late trimester of preg- to eat more food more frequently to lose weight.
nancy, based on animal studies. Because the human effects In addition to the metabolic improvements, successful of first-trimester use are unknown, discontinuation of weight loss has the benefit of improving body image, therapy at the onset of pregnancy confirmation has been reducing depression, and restoring a sense of control. Pro- standard. However, a recent prospective study of women grams that have targeted this issue alone have achieved with PCOS who continued metformin therapy through pregnancy rates as high as 60 percent without medical the first trimester of pregnancy showed no evidence of intervention.35 There are no data to support the use of fetal harm, calling into question this recommendation.34 lipid-lowering drugs in women younger than 40 years, but The rate of early spontaneous abortion was reduced dietary regulation should be encouraged. Family physi- from 73 percent without metformin to 10 percent. In our cians should monitor blood pressure elevations and smok- clinical setting, the initial dosage of 500 mg is given at bed- ing cessation for further cardiovascular protection.
time each night for one week to reduce the occurrence of Knowledge gained over the past 60 years has carried gastrointestinal side effects and is increased by 500 mg per PCOS beyond the realm of gynecology and infertility, and week to a total dosage of 1,500 mg per day in divided doses.
warrants heightened attention from physicians who will Insulin, glucose, and androgen levels are retested after eight focus on the functional abnormalities that have serious weeks. If improvement is not shown, the dosage is long-term consequences. It is important to recognize that increased to 2,550 mg. Menses often will occur within this PCOS is an entity with a long lifespan, requiring “control” treatment time. If fertility is desired, ovulation induction rather than “cure,” and that therapies will change with the agents can be added. Metformin therapy is associated with stage of life (Figure 1). A considerable armamentarium of a slight risk of lactic acidosis and is not used in patients therapies exists for the family physician, using specialty with impaired liver or renal function.
referral for patients with intractable vaginal bleeding,infertility, or dermatologic problems.
LIFESTYLE MODIFICATION
The most successful but difficult therapy to “adminis- The author indicates that she does not have any conflicts of inter- ter” is weight loss. Weight loss is most successful because est. Sources of funding: none reported. nicity influence the prevalence of adrenal hyperandrogenism andinsulin resistance in polycystic ovary syndrome? Am J Obstet 1. Hull MG. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 18. Azziz R. Hirsutism. In: Droegemueller W, Sicarra JJ, eds. Gynecol- ogy and obstetrics. Vol 5. Philadelphia: Lippincott, 1994:1-22.
2. Stein IL, Leventhal ML. Amenorrhea associated with bilateral poly- 19. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed cystic ovaries. Am J Obstet Gynecol 1935;29:181-91.
MJ, et al. Improvement in endocrine and ovarian function during 3. Ehrmann DA. Obesity and glucose intolerance in androgen excess.
dietary treatment of obese women with polycystic ovary syn- In: Azziz R, Nestler JE, Dewailly D, eds. Androgen excess disorders drome. Clin Endocrinol 1992;36:105-11.
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20. Bates GW, Whitworth NS. Effect of body weight reduction on 4. Dunaif A, Hoffman AR, Scully RE, Flier JS, Longcope C, Levy L J, et plasma androgens in obese, infertile women. Fertil Steril 1982; al. Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstet 21. Azziz R. The hyperandrogenic-insulin-resistant acanthosis nigri- cans syndrome: therapeutic response. Fertil Steril 1994;61:570-2.
5. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin 22. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries— receptor serine phosphorylation in cultured fibroblasts and in a common finding in normal women. Lancet 1988;1:870-2.
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24. Boots LR, Potter S, Potter D, Azziz R. Measurement of total serum 7. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and pre- testosterone levels using commercially available kits: high degree dictors of risk for type 2 diabetes mellitus and impaired glucose toler- of between-kit variability. Fertil Steril 1998;69:286-92.
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