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POLYCYSTIC OVARY SYNDROME STEPHEN FRANKS, M.D.

P

OLYCYSTIC ovary syndrome — in its most typical form, the association of hyperandrogenism and chronic anovulation — is one of the most common endocrine disorders. The clinical and biochemical features are heterogeneous, and there has been much debate as to whether it represents a single disorder or several. In recent years, it has become apparent that the polycystic ovary syndrome not only is the most frequent cause of anovulation and of hirsutism, but is also associated with a characteristic metabolic disturbance (resistance to the action of insulin) that may have important implications for long-term health. DEFINITION The most widely accepted clinical definition of the polycystic ovary syndrome is the association of hyperandrogenism with chronic anovulation in women without specific underlying diseases of the adrenal or pituitary glands.1 Hyperandrogenism is characterized clinically by hirsutism, acne, and androgen-dependent alopecia and biochemically by elevated serum concentrations of androgens, particularly testosterone and androstenedione. Obesity is common but not universal.2-4 Typically, these features are associated with hypersecretion of luteinizing hormone and androgens but with normal or low serum concentrations of follicle-stimulating hormone.2,4-7 Ironically, although the early descriptions of the syndrome were based on ovarian morphology,1,2 this has not been considered an essential requirement for the diagnosis. The recent application of modern, high-resolution diagnostic ultrasonography has again tipped the balance toward a more morphologically based diagnosis8-15 (Fig. 1). Nevertheless, there is remarkable concordance between the results of studies wherein diagnoses have been based on ultrasonographic criteria and the results of those in which the polycystic ovary syndrome has been defined on the basis of clinical and biochemical criteria.13,14,16,17 PREVALENCE Although it has long been known that the polycystic ovary syndrome is an important cause of anovulation From the Reproductive Endocrinology Group, Department of Obstetrics and Gynaecology, St. Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine, University of London, London W2 IPG, United Kingdom, where reprint requests should be addressed to Dr. Franks.

and hirsutism, few studies have attempted to define its prevalence in women with these symptoms. In a study of 175 anovulatory women presenting consecutively to a reproductive endocrine clinic, 30 percent of those with amenorrhea and 75 percent of those with oligomenorrhea had ultrasonographic evidence of polycystic ovaries. More than 60 percent of these women were hirsute, and 90 percent had elevated serum concentrations of luteinizing hormone or androgens (or both).13,14 These findings are supported by a study in which clinical and biochemical, rather than ultrasonographic, criteria were used to make the diagnosis of polycystic ovary syndrome. In a series of women being treated at a regional infertility center in southwest England, 37 percent of those with amenorrhea and 90 percent of those with oligomenorrhea (overall, 73 percent of the cases of anovulatory infertility) were found to have the polycystic ovary syndrome.18 Subsequently, clinical and biochemical markers of the syndrome were correlated with ultrasonographic results, and a high degree of concordance was observed between the findings.16 Surprisingly, polycystic ovaries were detected by ultrasonography in 40 of 46 women (87 percent) presenting with hirsutism but with regular menses (i.e., “idiopathic hirsutism”).14 The recognition of polycystic ovaries in women with regular menstrual cycles is an important finding. First, it belies the idea that the polycystic morphology simply indicates a nonspecific response of the ovary to chronic anovulation. Second, the evidence that this group of women shares the biochemical, as well as the morphologic, characteristics of anovulatory women with polycystic ovaries suggests that the former group represents a particular presentation of the same underlying disorder. Third, it relegates the diagnosis of idiopathic hirsutism to the minority of women with hyperandrogenism alone. These findings have since been supported by the results of other studies,19,20 including an analysis of 350 hirsute women among whom polycystic ovaries were found by ultrasonography in over 50 percent of those with regular cycles.20 Polycystic ovaries are also common in women with hyperandrogenism — with or without menstrual disturbances or hirsutism — whose principal presenting symptom is acne, seborrhea, or malepattern alopecia.14,19,21,22 It is a moot point whether patients with polycystic ovaries, hyperandrogenism, and regular menses should be considered to have the polycystic ovary syndrome.1,15,16 They do not fit the classic definition of the syndrome, which includes anovulation, but there is clearly considerable overlap between this group and those with anovulation. For example, it is well recognized that women with the polycystic ovary syndrome and oligomenorrhea may occasionally have spontaneous ovulatory cycles.3,23 The high frequency of polycystic ovaries in patients with symptoms of hyperandrogenism or anovulation

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prompted my colleagues and me to investigate the prevalence of ultrasonographic features indicative of polycystic ovaries in the normal population.24 We found ultrasonographic evidence of polycystic ovaries in 22 percent of 257 volunteers, none of whom had found it necessary to seek medical attention for gynecologic symptoms. Nevertheless, even within this “normal” population, there was a striking correlation between clinical (and biochemical) features and ultrasonographic appearance. Seventy-five percent of the women with polycystic ovaries had irregular menses, whereas only 1 of the 115 women with normal ovaries had abnormal cycles. Likewise, objective evidence of hirsutism was observed more often in women with polycystic ovaries (45 percent) than in those with nonpolycystic morphologic features (7 percent). Overall,

A

B Figure 1. Ultrasonographic (Panel A) and Gross Histologic (Panel B) Appearance of a Typical Polycystic Ovary. The criteria for a diagnosis of polycystic ovaries based on ultrasonographic data include bilateral ovarian enlargement (9 cm in maximal diameter), 10 or more follicles 2 to 10 mm in diameter per ovary, and increased density and area of stroma.8-12

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94 percent of the normal women with polycystic ovaries had at least one symptom that could be considered to be a clinical marker of polycystic ovary syndrome. The effect of polycystic ovaries on the future reproductive function of these women remains unclear. CLINICAL PRESENTATION Typical clinical features of the polycystic ovary syndrome are summarized in Table 1. Hyperandrogenism presents as hirsutism, acne, or male-pattern alopecia. Anovulation manifests itself as menstrual disturbance — amenorrhea, oligomenorrhea, or dysfunctional uterine bleeding — and infertility. Obesity is common but not usually a presenting symptom. In many cases, a history of menstrual disturbance dates back to the menarche.23 Menarche may be delayed, and presentation with primary amenorrhea is uncommon but well recognized. Hirsutism and obesity may be present in adolescent girls, even before the menarche. At any institution, the relative frequencies of the various presenting symptoms will, of course, depend primarily on the particular interests of the referral centers. The degree of hirsutism can be assessed by the Ferriman–Gallwey score, a simple, semiquantitative method for recording the distribution and severity of excess body hair.25 Examination may also reveal, particularly in obese subjects,14,19,26 acanthosis nigricans, a cutaneous indicator of hyperinsulinemia. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of polycystic ovary syndrome is usually made on the basis of a combination of clinical, ultrasonographic, and biochemical criteria. A woman presenting with oligomenorrhea is likely to have the polycystic ovary syndrome if she has one or more of these three features: polycystic ovaries on ultrasonography, hirsutism, and hyperandrogenemia. Many women with the syndrome have hypersecretion of luteinizing hormone, although normal serum concentrations of luteinizing hormone do not rule out the diagnosis. The diagnosis of polycystic ovary syndrome in a woman presenting with hirsutism and regular cycles is more contentious, but the finding of polycystic ovaries on ultrasonography in association with moderate hyperandrogenemia (i.e., serum testosterone concentrations of 85 to 150 ng per deciliter [3 to 5 nmol per liter]) points to a benign, ovarian cause of the hirsutism, whether or not the term “polycystic ovary syndrome” is used. The differential diagnosis of polycystic ovary syndrome includes patients with menstrual disturbances and hirsutism in whom the primary diagnosis is of pituitary or adrenal diseases — for example, hyperprolactinemia, acromegaly, and classic or nonclassic congenital adrenal hyperplasia. These “polycystic-ovary– like” syndromes14,23 can be identified by the presence of other, specific, clinical and biochemical features. The need for further biochemical or radiologic investigations should be determined by the clinical context

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Table 1. Clinical Features of the Polycystic Ovary Syndrome.* FEATURE

DIAGNOSTIC CRITERIA HISTOLOGIC ULTRASONOGRAPHIC

ULTRASONOGRAPHIC

(FRANKS14)† (N  300)

(CONWAY ET AL.19) (N  556)

(GOLDZIEHER AND G REEN 3) (N  1079)

64 (34) 27 (9) 35 (10) 42 (41) 28 (23) 52 (38) 20

61 24 35 29 26 45 25

ovary syndrome are similar to those in the midfollicular phase of a normal menstrual cycle but are lower than those in the early follicular phase.7 This difference may contribute to the mechanism of anovulation, but is unlikely to be its principal cause. Androgens

percent frequency

Hirsutism Acne Obesity Infertility Amenorrhea Oligomenorrhea‡ Regular menstrual cycle

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69 — 41 74 51 29 15§

*Data were compiled from two recent studies in which ultrasonography was used as the primary method of diagnosis (Franks14 and Conway et al.19) and from the classic review by Goldzieher and Green,3 in which the diagnosis was based on proved histologic features of ovaries after wedge resection. Note the similarity in the distribution of symptoms in the three studies. †Values in parentheses indicate percentages of subjects in whom the feature was a presenting symptom. ‡These values include women with any abnormal pattern of uterine bleeding. §Percentage of patients with biphasic basal-body-temperature charts. Twenty-two percent of subjects in this series were noted to have a recent corpus luteum on histologic examination of the ovaries.

and the results of initial screening tests. The polycystic ovary syndrome can be distinguished from late-onset (nonclassic) congenital adrenal hyperplasia due to 21hydroxylase deficiency27 by measuring the 17a-hydroxyprogesterone response to corticotropin, but it is arguable whether such a test should be performed routinely in populations in which the frequency of congenital adrenal hyperplasia is low27,28 or in women whose serum testosterone concentrations are less than 150 ng per deciliter.20 The differential diagnosis of hirsutism includes androgen-secreting tumors of the ovary or adrenal gland. Although rare, it is important to consider this diagnosis in patients with a short history of hirsutism, those with severe hirsutism, and those whose serum testosterone concentrations are greater than 200 ng per deciliter (7 nmol per liter). The presence of acanthosis nigricans in a patient with marked virilization is a useful clinical marker, since this suggests the polycystic ovary syndrome and is not a feature of androgen-secreting tumors. ENDOCRINE ABNORMALITIES Gonadotropins

Elevated mean serum concentrations of luteinizing hormone are common in all reported series of women with the polycystic ovary syndrome,4,14 although the prevalence of frankly elevated hormone concentrations depends on both the criteria for diagnosis and the method of measurement. For example, if hypersecretion of luteinizing hormone is a sine qua non for diagnosis, all subjects will have elevated serum concentrations of luteinizing hormone,29-31 but the limitations of this approach are illustrated by recent data showing divergent results of different assays of luteinizing hormone.30,31 Serum concentrations of follicle-stimulating hormone in anovulatory women with the polycystic

Serum concentrations of testosterone and androstenedione are elevated in women with the polycystic ovary syndrome (the mean concentrations are 50 to 150 percent higher than in controls), but as with luteinizing hormone, there is variation among individual women.4,14,19 On the one hand, anovulatory but nonhirsute women with polycystic ovaries have levels of hyperandrogenemia similar to those in women with hirsutism.14,19 This presumably indicates variable sensitivity of the hair follicle to androgens.32,33 The most obvious example of this phenomenon is the difference among races in the prevalence of hirsutism in women with polycystic ovaries who have similar levels of hyperandrogenemia.34 On the other hand, hirsute women with polycystic ovaries may have normal serum androgen concentrations.14,19,33 The rate of androgen production has been demonstrated to be higher than normal in these subjects,35-37 whose normal serum concentrations reflect increased clearance of androgen by peripheral tissues. The clearance and bioavailability of testosterone (but not androstenedione) are affected by the serum concentration of sex hormone–binding globulin.38,39 Traditionally, sex steroids have been considered to be the major regulators of sex hormone–binding globulin,38 but recent data suggest that nutritional factors, probably mediated by insulin, are more important in determining the production of sex hormone–binding globulin and therefore the clearance of androgen.14,40-45 Obese subjects with marked hirsutism may have normal serum concentrations of total testosterone but, because of the suppression of sex hormone–binding globulin, have a greatly increased rate of androgen production. Nevertheless, the values for free testosterone (that not bound to sex hormone–binding globulin) in hirsute and nonhirsute women with elevated levels of total testosterone still overlap.14 Hirsute and nonhirsute subjects likewise cannot be reliably differentiated on the basis of their levels of conjugated 5a-reduced androgens in plasma — a reflection of the peripheral conversion of testosterone to the more bioactive 5adihydrotestosterone.14,46,47 These analytes remain of some scientific interest but are not useful in clinical practice. The relative importance of ovarian and adrenal contributions to hyperandrogenism is discussed in the section on pathogenesis. Estrogens

In women with the polycystic ovary syndrome, chronic anovulation is an important consequence of abnormal secretion of estrogen. Serum concentrations of estradiol (both total and free) lie within the normal

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ranges for the early follicular and mid-follicular phases of the cycle,48 but the pattern of secretion differs from that in the normal menstrual cycle because there is no preovulatory or midluteal increase in estradiol concentrations. Furthermore, the action of estradiol on the hypothalamic–pituitary axis and on the endometrium is unopposed because of a lack of cyclical progesterone secretion.14,23 These effects may be compounded in obese subjects by increased serum concentrations of estrone arising from the extraglandular conversion of androgens by adipose tissue.24,48 Both acyclical estrogen production and progesterone deficiency contribute to the mechanism of hypersecretion of luteinizing hormone.41 The effects of unopposed estrogen on the endometrium include episodes of unscheduled and heavy uterine bleeding and an increased risk, in the long term, of endometrial carcinoma.49 Prolactin and Growth Hormone

Less common biochemical features of the polycystic ovary syndrome include hyperprolactinemia14 and impaired secretion of growth hormone.50-52 The prevalence of hyperprolactinemia in women with polycystic ovaries has been reported to be between 5 and 30 percent.14,53-55 Its importance remains unclear. Impairment of the secretion of growth hormone has been noted but appears to be mainly a function of accompanying obesity rather than the polycystic ovary syndrome itself.52 Conversely, polycystic ovaries have been noted in patients with proved prolactinomas or acromegaly, but these diseases have characteristic clinical presentations and are unlikely to be confused with the polycystic ovary syndrome. METABOLIC ABNORMALITIES It has long been recognized that syndromes characterized by extreme insulin resistance are associated with ovarian hyperandrogenism. In the past decade, however, attention has focused on women who present with the polycystic ovary syndrome rather than on those with the typical phenotype of syndromes involving insulin resistance. Women with the polycystic ovary syndrome have a greater frequency and degree of both hyperinsulinemia26,56-62 and insulin resistance58,63-65 than weight-matched controls. Insulin resistance is independent of the effect of obesity; both lean and obese women with the polycystic ovary syndrome have evidence of decreased insulin sensitivity, but insulin resistance is most marked where there is an interaction between obesity and the syndrome.64,65 The nature of the complex interrelation of hyperandrogenism, the distribution of body fat, and insulin resistance remains unresolved,65-69 but insulin appears to affect androgen secretion and metabolism, rather than vice versa. Notably, insulin augments the androgen response to luteinizing hormone in human ovarian interstitial tissue in vitro,70,71 and positive correlations have been observed between circulating concentrations of androgens and insulin in some42,62,72,73 but not all74,75 studies. Insulin may also affect the expression of an-

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drogen by suppressing concentrations of sex hormone– binding globulin.43-45,74 Insulin resistance in women with the polycystic ovary syndrome is regarded by some investigators as a distinct etiologic entity.57,58 It is characterized by decreased sensitivity to insulin in peripheral tissues, notably muscle and adipose tissue,58 but not — in contrast to the insulin resistance of type II diabetes — hepatic resistance.58,64 Hyperinsulinemia in women with the polycystic ovary syndrome appears to reflect the hypersecretion of insulin itself, rather than of proinsulin and its split products.76,77 The cellular mechanism of insulin resistance in the polycystic ovary syndrome remains controversial. Results from studies of blood cells have suggested reduced binding of insulin to its receptor,78,79 whereas two recent studies80,81 using peripheral adipocytes (recognized target cells for insulin action) have shown normal binding but reduced insulin-mediated glucose transport, suggesting a postreceptor defect. The mechanism underlying this phenomenon has not been fully characterized,58 but decreased expression of the insulin-dependent glucose-transporter protein GLUT-4 has been described.82 Interestingly, insulin resistance is not a feature of all women with hyperandrogenemia and polycystic ovaries. It occurs in patients with the classic syndrome (i.e., those with menstrual disturbance), but hirsute women with hyperandrogenemia and polycystic ovaries who have regular menstrual cycles have serum insulin concentrations after fasting and after glucose stimulation that are indistinguishable from those in weight-matched normal subjects62,83 and have normal insulin sensitivity.83 It is unlikely that anovulation is the cause of impaired insulin sensitivity. Cyclical changes in insulin sensitivity have been reported, but these take the form of reduced sensitivity during the luteal phase of an ovulatory menstrual cycle.84 Furthermore, complete suppression of ovarian steroids does not alter insulin sensitivity.85-87 It is more likely that hyperinsulinemia and insulin resistance contribute to the mechanism of anovulation.85,88 The practical implication of these findings is that the polycystic ovary syndrome may be a marker of insulin resistance and dyslipidemia.89-92 Impaired glucose tolerance and frank type II diabetes mellitus are more prevalent in obese young women with the polycystic ovary syndrome than in weight-matched controls.26,63 Recently published long-term follow-up studies of women with the syndrome show that the prevalence of type II diabetes is seven times higher in that group than in the reference population.93 These women have hyperlipidemia and a greatly increased risk of cardiovascular disease.94 PATHOGENESIS Despite the heterogeneity of clinical presentations of women with polycystic ovaries, there is a common thread of biochemical features that links the spectrum of symptoms and signs. The endocrine hallmarks are hyperandrogenemia and, to a lesser extent, hyperse-

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cretion of luteinizing hormone.95 It seems likely, however, that abnormal gonadotropin secretion is a result, rather than the cause, of ovarian dysfunction.14,96 Although it is clear that hypersecretion of adrenal androgens may contribute to the hyperandrogenemia of women with the polycystic ovary syndrome,14,23 the weight of evidence favors the ovary as the principal source of excess androgen secretion. In particular, pituitary and ovarian suppression by long-acting analogues of gonadotropin–releasing hormone results in a decline in serum androstenedione and testosterone concentrations to within the range for menopausal women or those who have undergone ovariectomy.97-99 The biochemical basis of the putative disorder of ovarian androgen biosynthesis remains unclear. There is evidence, from both clinical and in vitro studies of human ovarian theca cells, of dysregulation of the ratelimiting enzyme in androgen biosynthesis, cytochrome P-450c17a, which catalyzes both 17a-hydroxylase and 17,20-lyase activities.100-103 Cytochrome P-450c17a is expressed in the adrenal glands as well as in the ovary, and recent data suggest that although the polycystic ovary syndrome is primarily a manifestation of ovarian hyperandrogenism, some women with polycystic ovaries also have an exaggerated response of androstenedione and 17a-hydroxyprogesterone to exogenous corticotropin.104 In other words, an intrinsic abnormality of P-450c17a activity could explain both ovarian and adrenal hyperandrogenism in the polycystic ovary syndrome.101,104 Genetic Basis of the Syndrome

The polycystic ovary syndrome is a familial disorder, but the genetic basis of the syndrome remains controversial.105-110 Determining the mode of inheritance of this syndrome is difficult because there has been no clearly described male phenotype and because it is a disorder that affects principally women of reproductive age. However, a recent study of 150 subjects in 10 families of women with the syndrome revealed evidence of an autosomal dominant mode of inheritance, with premature balding in men being the putative male phenotype.111 What is the role of insulin resistance in the pathogenesis of ovarian hyperandrogenism and the polycystic ovary syndrome? Full expression of the syndrome may require the interaction of an insulin abnormality with an underlying disorder of androgen biosynthesis,58,95,112 but an abnormality of insulin action alone is unlikely to cause hyperandrogenism.58,83,111 The precise nature of the interaction of androgens and insulin awaits identification of the gene (or genes) involved, but this interrelation provides a model that may begin to explain the heterogeneity of the polycystic ovary syndrome.95,103 MANAGEMENT The management of the polycystic ovary syndrome encompasses the differential diagnosis and treatment of two very common problems in reproductive endocri-

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nology — hirsutism and anovulation. The issues to be addressed are not only the symptoms but also the long-term consequences of the syndrome, including the metabolic sequelae. In effect, this means that the majority of patients with the polycystic ovary syndrome should be considered for treatment. Anovulation

In women with infertility, the treatment of first choice for the induction of ovulation in cases of polycystic ovary syndrome is an antiestrogen — most commonly, clomiphene citrate.113,114 However, treatment of the 20 to 25 percent of women who are resistant to clomiphene presents particular difficulties.115 Gonadotropin preparations, principally urine-derived, have been used for more than 30 years, but conventional regimens are associated with a low rate of pregnancy (30 percent), a high rate of multiple pregnancy (30 percent), and the ovarian hyperstimulation syndrome.116-118 Consequently, a number of investigators have adopted a low-dose schedule for the induction of ovulation with gonadotropins.119-123 The critical factors in this regimen are a low starting dose followed by small incremental increases, aiming for a threshold level of follicle-stimulating hormone124 that facilitates the maturation of a single preovulatory follicle. The results of such treatment have proved encouraging, particularly in achieving a relatively low rate of multiple pregnancy of 5 to 7 percent.115,122 Another method of achieving monofollicular ovulation is the pulsatile administration of gonadotropin-releasing hormone. This has proved highly effective in the management of hypogonadotropic hypogonadism but has been less successful in treating the polycystic ovary syndrome.125,126 Nevertheless, a case can be made for a trial of pulsatile gonadotropin-releasing hormone in lean (body-mass index [the weight in kilograms divided by the square of the height in meters], 25) women with the polycystic ovary syndrome who are resistant to clomiphene and who do not have excessively high concentrations of luteinizing hormone before treatment.126 Obesity has an adverse effect on rates of ovulation and miscarriage after treatment with low-dose gonadotropin or gonadotropin-releasing hormone.126,127 Calorie restriction is therefore an important part of infertility management. Indeed, weight reduction alone may result in spontaneous ovulation and pregnancy.88,128-130 Surgical management of anovulatory infertility has enjoyed a revival in recent years, after the demonstration that laparoscopic diathermy, or laser “drilling,” may restore ovulatory cycles.131-133 Although a number of studies have pointed to the efficacy of surgical treatment, only one controlled trial has compared surgery with exogenous gonadotropin treatment.133 There was no significant difference in outcome between the study groups. Furthermore, although laparoscopic surgery is less invasive than the traditional treatment of ovarian wedge resection, it may still result in pelvic adhesions.134 Dysfunctional uterine bleeding in women who do not

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desire pregnancy can in most cases be managed either by a low-dose oral contraceptive or by cyclical administration of progestins.113 Progestins that have intrinsic androgenic activity (such as norgestrel or norethindrone) should be avoided, since they may exacerbate symptoms of hyperandrogenism and abnormalities of glucose and lipid metabolism. Women with oligomenorrhea or amenorrhea who have neither infertility nor troublesome periods may prefer not to have treatment. They are, however, at risk for unscheduled episodes of heavy menstrual bleeding and, in the long term, may be vulnerable to endometrial cancer.49 My policy is therefore to advise such patients that if they are reluctant to receive hormonal treatment they should at least undergo regular ultrasonographic scanning to assess endometrial thickness. Hyperandrogenism

Hirsutism, if moderate and localized, may be treated simply by the removal of hair. In more severe cases (or when cosmetic treatment is undesirable or ineffective), antiandrogen therapy can be offered. In Europe, the most widely used antiandrogen is cyproterone acetate.135,136 It is also progestogenic, and when combined with ethinyl estradiol, it provides effective control of menses and contraception. Cyproterone acetate is not generally available in the United States, but spironolactone — a mineralocorticoid antagonist that is also an antagonist of androgen receptors — has been used extensively.137 Spironolactone may be associated with erratic vaginal bleeding and is therefore usually administered with a low-dose oral contraceptive. More recently there have been reports of the successful use of “pure” antiandrogens, such as flutamide.138,139 Side effects of antiandrogens include lethargy, mood changes, and loss of libido, and these may occasionally be severe enough to necessitate interruption of treatment. Liver dysfunction is a rare but serious complication of both cyproterone acetate and flutamide treatments, and liver function should therefore be monitored regularly during these therapies. Long-acting agonist analogues of gonadotropin-releasing hormone have also been used in the management of hirsutism. Such treatment is effective in suppressing androgen production by the ovaries,97-99 but it is expensive and cumbersome to manage on a long-term basis because of the need for concurrent estrogen and progestin therapy. Any medical therapy for hirsutism is likely to involve long-term treatment. A clinically obvious change in hair growth is unusual in the first 5 months of treatment, and the maximal effect may not be reached until after 18 months of treatment, or even longer. Antiandrogens are the treatment of choice for androgen-dependent alopecia,32 but a satisfactory cosmetic result is not often achievable and the complete reversal of symptoms is rare. Acne can be treated by broad-spectrum antibiotics in the first instance, but if these prove unsatisfactory, further options include ret-

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inoic acid derivatives and antiandrogens,135,140 both of which are effective. Management of Metabolic Aspects of the Syndrome

Because of the high prevalence of impaired glucose tolerance or type II diabetes in obese young women with the polycystic ovary syndrome, it is logical to perform a standard 75-g oral glucose-tolerance test routinely in such patients. Obtaining a lipid profile is advisable,89-92 as is surveillance of the blood pressure.93,94 Metabolic investigation of lean women with the polycystic ovary syndrome is more controversial. Few will be expected to have impaired glucose tolerance or diabetes, but as indicated previously, lean, anovulatory women with the syndrome may have marked hyperinsulinemia or insulin resistance and low levels of the HDL2 subfraction of high-density lipoprotein cholesterol.92 Though less vulnerable than their obese counterparts, these women may still be at risk for diabetes, cardiovascular disease, or both in the long term.93,94 In the absence of prospective data, however, it is not yet clear whether measurements of glucose, insulin, and lipids in lean women with polycystic ovaries have any more predictive value than the clinical presentation of hyperandrogenism and anovulation and a family history of type II diabetes. Nevertheless, it seems sensible to obtain a lipid profile (if only for future reference), even in lean subjects. Weight reduction in obese women with the polycystic ovary syndrome should be encouraged88,128-130 in an effort to limit the risk of type II diabetes and long-term cardiovascular disease. I am indebted to Ms. D.S. Kiddy for Panel A of Figure 1 and to Ms. H.D. Mason for Panel B of Figure 1.

REFERENCES 1. Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Oxford, England: Blackwell Scientific, 1992:377-84. 2. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181-91. 3. Goldzieher JW, Green JA. The polycystic ovary. 1. Clinical and histological features. J Clin Endocrinol Metab 1962;22:325-38. 4. Yen SSC, Vela P, Rankin J. Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 1970;30:435-42. 5. McArthur JW, Ingersoll FM, Worcester J. The urinary excretion of interstitial-cell and follicle-stimulating hormone activity by women with diseases of the reproductive system. J Clin Endocrinol Metab 1958;18:120215. 6. Gambrell RD Jr, Greenblatt RB, Mahesh VB. Inappropriate secretion of LH in the Stein-Leventhal syndrome. Obstet Gynecol 1973;42:429-40. 7. Holte J, Bergh T, Gennarelli G, Wide L. The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women. Clin Endocrinol (Oxf ) 1994;41:473-81. 8. Swanson M, Sauerbrei EE, Cooperberg PL. Medical implications of ultrasonically detected polycystic ovaries. J Clin Ultrasound 1981;9:21922. 9. Parisi L, Tramonti M, Derchi LE, Casciano S, Zurli A, Rocchi P. Polycystic ovarian disease: ultrasonic evaluation and correlations with clinical and hormonal data. J Clin Ultrasound 1984;12:21-6. 10. Adams J, Franks S, Polson DW, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 1985;2:1375-9. 11. Yeh HC, Futterweit W, Thornton JC. Polycystic ovarian disease: US features in 104 patients. Radiology 1987;163:111-6.

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New England Journal of Medicine

CORRECTION

Polycystic Ovary Syndrome Polycystic Ovary Syndrome . On page 854, the parenthetical phrase starting in the fourth line of the legend to Figure 1 should have read, ``>9 ml in volume,´´ not ``>9 cm in maximal diameter,´´ as printed. We regret the error.

N Engl J Med 1995;333:1435

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