A practical approach to the diagnosis of polycystic ovary syndrome

American Journal of Obstetrics and Gynecology (2004) 191, 713 7 www.elsevier.com/locate/ajog CLINICAL OPINION A practical approach to the diagnosis of polycystic ovary syndrome R. Jeffrey Chang, MD Department of Reproductive Medicine, University of California, San Diego, School of Medicine, La Jolla, Calif Received for publication April 27, 2004; accepted April 29, 2004 KEY WORDS Polycystic ovary syndrome Hirsutism Androgens The diagnosis of polycystic ovary syndrome (PCOS) is primarily achieved through clinical history and physical findings. The principle features are hirsutism or biochemical evidence of excess androgen production and irregular menstrual bleeding caused by the chronic anovulation. Associated findings include insulin resistance with compensatory hyperinsulinemia and obesity. Ultrasound imaging of the ovary has facilitated the diagnosis. It is important to exclude conditions that may mimic PCOS, such as hyperthecosis, congenital adrenal hyperplasia, 21- hydroxylase deficiency, Cushing s syndrome, and androgen-producing neoplasms. These disorders are usually revealed by appropriate laboratory assessment. Screening tests include measurement of serum total testosterone, DHEA sulfate, and 17-hydroxyprogesterone. In addition, in the obese individual, determinations of glucose and insulin levels, as well as a lipid profile, are highly recommended. Ó 2004 Elsevier Inc. All rights reserved. Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy of women during their childbearing years, with a reported prevalence of 4% to 8%. 1,2 Classic symptomatology is a result of excessive ovarian androgen production and chronic anovulation. In addition, the ovaries display a typical morphologic pattern that appears to be unique to the disorder. Other associated clinical features include obesity and insulin resistance. While the diagnosis is generally indicated by the clinical presentation, laboratory testing is necessary to exclude other possible conditions that may mimic PCOS. Symptomatology of PCOS In general, the diagnosis of PCOS is largely based on clinical history. The most distinctive and visible clinical Reprints not available from the author. feature is hirsutism, the degree of which is variable from mild to severe. The rate of hair growth is important clinically because gradual and progressive growth indicates a functional etiology, whereas the rapid appearance of thick, pigmented hair often suggests a neoplastic source of androgen production. The areas of hirsutism usually involve the face and chin, as well as an extension of pubic hair growth in the midline towards the umbilicus. In addition, it is not unusual to document some degree of temporal balding and acne formation as a result of androgen overproduction. However, extreme expression of androgen excess, such as virilization and clitoromegaly, are not typical findings in this functional syndrome. In women with PCOS, menstrual dysfunction is primarily characterized by irregular, infrequent, or absent menstrual bleeding. In particular, episodes of irregular bleeding are not typically preceded by premenstrual 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.04.045

714 Chang symptomatology, and thus, not predictable. This important clinical observation is highly suggestive of anovulation. Typically, the inception of irregular bleeding in PCOS can be traced to menarche and the postpubertal phase of ovarian activity, during which time there is lack of monthly menstrual cyclicity. Thus, in the postpubertal adolescent with PCOS, irregular bleeding may be indistinguishable from the inconsistent bleeding pattern that accompanies the emergence of regular ovulatory function following menarche in normal girls. In some cases, the onset of chronic anovulation is encountered beyond adolescence, but this is unusual. A small percentage of women will present with amenorrhea. The disruption of regular menstrual bleeding is not uniform in all women with PCOS. It is now recognized that some affected individuals will have normal ovulatory function, which implies that the presence of regular menses does not preclude the possibility of PCOS. Obesity has been reported to occur in about half of PCOS patients. 3 However, of recent note, the rate of obesity associated with PCOS has not been corroborated, and there is a growing impression that the incidence may be greater, at least in the United States, than that previously described. The obesity of PCOS is characterized by an increased waist-to-hip ratio, or android appearance as opposed to truncal obesity. The presence of obesity compounds clinical risk in PCOS for several reasons. First, obesity is correlated to decreased sex hormone-binding globulin, which increases circulating free testosterone and estradiol. Second, the likelihood of dyslipidemia is increased in obese individuals, which raises concern for cardiovascular risk. 4 Third, obesity is associated with insulin resistance, which may progress to diabetes mellitus in PCOS patients. 5,6 Improvement in these abnormalities with weight loss underscores the role of obesity in PCOS. It has been well-documented that women with PCOS, independent of obesity, are insulin resistant and have compensatory hyperinsulinemia as a result of their disorder. 7 Generally, the degree of insulin resistance is mild, although the prevalence of glucose intolerance and subsequent diabetes has been reported to be as high as 31% and 7.5%, respectively. 8 Notwithstanding the increased risk for diabetes, there is indirect evidence to indicate that insulin resistance may worsen the clinical manifestations of PCOS. Administration of insulin-lowering drugs has been shown to improve insulin sensitivity, reduce androgen levels, and restore ovulation in some, but not all patients with this disorder. 9,10 Insulin resistance may also contribute to metabolic dysfunction in PCOS, including an increased likelihood of lipid abnormalities. Acanthosis nigricans is common in obese PCOS, and often may be found on the nape of the neck, the axilla, the area beneath the breasts and other intertrigenous areas, as well as on exposed surfaces such as the elbows and knuckles. While the skin appears to be pigmented, the involved areas of skin do not exhibit increased number of melanocytes or melanin deposition. Actually, the lesion arises from epidermal hyperkeratosis and dermal fibroblast proliferation. The factors responsible for these findings have not been identified, although the close association of acanthosis nigricans with marked insulin resistance suggests a causative relationship. Increased insulin sensitivity following dietary or pharmacologic intervention is associated with a lessening of the hyperplastic process and cosmetic improvement. Women with PCOS may experience increased skin oiliness resulting from excessive stimulation of the pilosebaceous unit by increased androgen production. However, increased sebaceous gland activity in PCOS is neither associated with acne, nor does acne correlate with increased ovarian androgen production. Therefore, as an isolated symptom, acne should not be considered a sign of PCOS. Differential diagnosis Ovarian hyperthecosis Hyperthecosis refers to an unusual proliferative condition in which the ovary contains nests of luteinized theca cells scattered throughout the stroma. 11 The ovary is enlarged and of an extremely firm texture resulting from extensive and dense fibroblast growth. The absence of follicle formation provides a clear morphologic distinction from the PCOS ovary. Because of markedly high serum androgen concentrations, these individuals suffer from severe hirsutism, and a significant percentage of patients exhibit virilizing signs, such as clitoromegaly, temporal balding, a male body habitus, and a deepening of the voice. There usually is marked insulin resistance with substantial elevations of circulating insulin levels. In addition, these patients are often obese and exhibit acanthosis nigricans. Congenital adrenal hyperplasia (CAH) This disorder of adrenal steroidogenesis is comprised on several enzymatic defects, the most common of which is 21-hydroxylase deficiency. Compared with the infrequent occurrence of classic CAH-21-hydroxylase deficiency, which is recognized at birth and is notable for its severity of clinical presentation, the nonclassic or adult-onset form may simulate the features of PCOS. The symptoms of adult-onset CAH-21-hydroxylase deficiency reflect the accumulation of serum 17-hyroxyprogesterone (17-OHP), which leads to abnormal elevations of the hormone compared with circulating values found in the follicular phase of the menstrual cycle. Because 17-OHP is an androgen precursor, expression of this defect is associated with increased production of androstenedione and testosterone with

Chang 715 resultant hyperandrogenism. While the clinical presentation may be indistinguishable from that of PCOS, there are several aspects of CAH-21-hydroxylase deficiency which may suggest the diagnosis. These include severe hirsutism, clitoromegaly, regular menses, familial tendency, and short stature. The condition is transmitted by an autosomal-recessive inheritance pattern, while an explanation for regular menses and short stature is unknown. Morphologically, the ovaries have been reported to appear similar to those of PCOS. 12 The second most common enzyme deficiency is 11-b-hydroxylase, which may also give rise to mild hirsutism in association with increases in 17-OHP and 11-deoxycortisol, the immediate precursor for this enzyme. The accompanying hypertension often distinguishes this disorder from the 21-hydroxylase form of CAH. Cushing s syndrome The clinical features of Cushing s syndrome primarily result from excessive cortisol production by an adrenal neoplasm or from excessive adrenocorticotropin (ACTH) production. In most cases, ACTH overproduction is caused by a pituitary tumor, although rarely, ectopic sources of ACTH may be encountered, such as in adenocarcinoma of the lung. The preponderant findings are obesity, hirsutism, acne, and menstrual irregularity. These suggest the diagnosis of PCOS. However, additional evidence of moonlike facies, buffalo hump, hypertension, muscle wasting, abdominal striae, and osteoporosis indicates a primary problem of cortisol excess. While circulating androgen levels are elevated, there is also abnormal cortisol secretion characterized by increased urinary free cortisol excretion, loss of circadian rhythm, and failure of suppression in response to dexamethasone. In contrast to CAH, careful examination of the ovaries does not reveal changes typical of PCOS in the vast majority of cases. Fortunately, Cushing s syndrome occurs rarely. Androgen-producing neoplasms While seldom encountered, androgen-producing tumors may arise from the ovary and the adrenal gland. In contrast to the gradually evolving clinical presentation associated with functional hyperandrogenism, the neoplastic process can be quite dramatic. Within a matter of months, these lesions may induce severe hirsutism, a male body habitus, and virilization with clitoromegaly. In addition, there may be acne and a lowering of the voice. Despite the severity of androgenic manifestations, the early stages of development of these tumors can mimic PCOS or other functional hyperandrogenic syndromes. Disruption of menstrual cycles varies from irregular bleeding to amenorrhea. The rapid onset of symptoms provides an important clue to the diagnosis. In some instances, a pelvic or abdominal mass can be palpated, which suggests an ovarian tumor. Imaging studies In women with PCOS ultrasound imaging of the ovaries has revealed ovarian enlargement, 10 or more antral follicles ranging from 2 to 10 mm in diameter arranged in a peripheral distribution, and increased central stroma of greater than 25% of the ovarian area. 13 This rather specific description of the polycystic ovary is distinct from the ultrasound appearance of the multifollicular ovary, which is associated with spontaneous ovarian follicular activity in a woman recovering from hypogonadotropic hypogonadism or ovarian stimulation as a result of ovulation induction. The multifollicular ovary has been described as being normal sized or slightly enlarged, containing 6 or more follicles without peripheral displacement, and having no increase in central stroma. 14 Nevertheless, addition of the ultrasound description of polycystic ovaries has not necessarily enhanced the ability to make the diagnosis of PCOS or impact therapy. In the situation of a suspected ovarian neoplasm, pelvic ultrasound may provide evidence of an ovarian lesion. Similarly, MRI or CT has been useful in the detection of an adrenal tumor. Laboratory evaluation Patients suspected of having PCOS on a clinical basis should undergo a minimum endocrine evaluation consisting of serum total testosterone, DHEA-sulfate, and, as indicated, 17-OHP. The primary reason for obtaining measurements of testosterone and DHEA-S is to exclude the rare possibility of an androgen-producing tumor of the ovary or adrenal gland, respectively. Threshold values beyond which a neoplasm should be considered are 200 ng/dl for testosterone and 7,000 ng/ ml for DHEA-S. Determination of serum 17-OHP is useful for the detection of CAH caused by 21-hydroxylase deficiency. A circulating level less than 3 ng/ml obtained during the follicular phase in patients with regular menstrual cycles excludes the diagnosis. Values in excess of 3 ng/ml warrant further evaluation by an ACTH stimulation test. If Cushing s syndrome is a consideration, then the 24-hour urinary free cortisol provides the most sensitive measure. A value in excess of 3 times the normal upper limit for the laboratory performing the test assumes the diagnosis. Intermediate values warrant a repeat of the test. As part of the assessment of oligoamenorrhea caused by anovulation, measurements of prolactin and thyroidstimulating hormone (TSH) have been advocated in some, but not all instances. In PCOS serum elevations in prolactin have been reported to be as high as 35% in patients and probably relates to lactotrope stimulation by chronic estrogen exposure. 15 Coexistence of

716 Chang a prolactinoma and PCOS is uncommon. Disorders of thyroid secretion have been associated with irregular menstrual bleeding. Usually there are other accompanying clinical features that suggest the diagnosis. Some comment is deserved regarding the measurement of serum gonadotropin levels and free testosterone concentrations. Despite the widespread practice of measuring serum luetinizing hormone (LH) and follicle-stimulating hormone (FSH), the circulating levels of these glycoproteins really do not contribute significantly to the diagnosis of PCOS. Increased pituitary LH secretion cannot always be determined by measurement of the serum concentration because approximately one third of patients will have circulating levels of LH in the normal range. Accordingly, the LH to FSH ratio also fails to provide additional useful information. The role of free testosterone in women suspected of having androgen excess is slowly evolving. In women with obvious hirsutism, there is little diagnostic value. By comparison, in anovulatory women without excessive hair growth, an elevated free testosterone may forecast incipient hirsutism. However, the cost/benefit of obtaining this measurement in this group of women remains to be determined. The principle utility of free testosterone may be to monitor the efficacy of treatment to reduce androgen production. The observation that women with PCOS are insulin resistant and have compensatory hyperinsulinemia raises the question of whether assessment of glucose metabolism and insulin secretion should be evaluated in these patients. Unfortunately, at the present time the ability to determine insulin resistance is limited by tests that lack sensitivity or are impractical for implementation. Based on fasting levels of glucose and insulin, a variety of indices have been designed to establish insulin resistance. 16-18 While a reasonable correlation exists between each model and provocative glucose tolerance tests, normal values do not preclude the presence of insulin resistance. However, the fasting level of glucose may be used to distinguish glucose intolerance (110 to 125 mg/dl) or diabetes (O125 mg/dl), and an elevated fasting insulin level will confer insulin resistance. Because of significant variability in methodologic techniques of measuring insulin, one should be mindful of the normal reference range for the laboratory in which the test was preformed. In the presence of obesity, it may be prudent to perform an oral glucose tolerance test, particularly if there is a family history of diabetes. Whether determination of insulin resistance is essential to the diagnosis of PCOS seems unlikely. While not pertinent to the diagnosis of PCOS, dyslipidemia is a concern given the existence of hyperandrogenemia, insulin resistance with hyperinsulinemia, and obesity, each of which may independently exert adverse effects on lipid metabolism. As a result, in the obese patient with PCOS, a lipid profile should be obtained. Summary recommendation The diagnosis of PCOS is primarily dictated by the development of hirsutism and anovulation, which is consistent with the majority recommendation of the 1990 PCOS conference held at the NIH. 19 Ultrasound imaging revealing polycystic ovaries combined with these features is essentially confirmatory. Recently, an attempt was made to revise the diagnostic criteria for PCOS based on discussions conducted at the 2003 Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop, which were published in Fertility and Sterility and Human Reproduction in 2004. 20,21 It was recommended that the diagnosis of PCOS may be fulfilled when 2 of the following 3 clinical features were present: clinical or biochemical evidence of hyperandrogenism, chronic anovulation, and imaging of polycystic ovaries. While the new guidelines are more flexible and address the problem of heterogeneous presentations, they also pose additional confusion. For example, according to these criteria, a woman with irregular menstrual bleeding and polycystic ovaries may be designated as having PCOS without any clinical or biochemical evidence of androgen excess. That PCOS could be diagnosed without hyperandrogenism is inconsistent with the original description of the syndrome and difficult to reconcile. Nevertheless, the conclusions of the workshop represent a credible first step to account for the patient that exhibits some, but not all of the previous criteria established for this disorder. It may well be that a better understanding of the heterogeneity of PCOS is necessary before these revised diagnostic criteria are embraced in clinical practice. Moreover, it is likely that this topic will undergo further debate and discussion until the time when uniform and definitive criteria or subclasses of criteria are achieved. For women suspected of having PCOS, the laboratory screening tests include measurement of a serum total testosterone, DHEA-S, and 17-OHP. Measurement of serum gonadotropins is not necessary for diagnosis. In patients who exhibit moderate to severe hirsutism associated with a rapid onset of symptoms, assessment should be directed toward determining the presence of an androgen-producing neoplasm. Serum total testosterone and DHEA-S are essential. Should these values exceed the threshold levels for tumor, then imaging studies such as ultrasound and MRI or CT are warranted to locate the lesion. Occasionally, high circulating androgen levels may not be associated with a distinct lesion, but rather bilateral noncystic ovarian enlargement. If accompanied with a gradual onset of symptoms, this presentation would suggest the diagnosis of hyperthecosis. The diagnoses of adrenal disorders include CAH, primarily 21-hydroxylase deficiency, Cushing s syndrome, and adrenal tumors. CAH-21-hydroxylase

Chang 717 deficiency is suspected in patients with an elevated 17- OHP level beyond 3 ng/ml, and an ACTH stimulation test should be done. Serum 17-OHP responses to ACTH that exceed 10 ng/ml are indicative of the enzyme defect. Laboratory screening for Cushing s syndrome is best achieved with a 24-hour urinary free cortisol. Abnormal responses require further testing, including low-dose, high-dose dexamethasone suppression tests, as well as imaging studies, to determine the existence of adrenal hyperplasia, Cushing s syndrome, adrenal adenoma, or an ectopic ACTH production site. References 1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner M, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998;83: 3078-82. 2. Farah L, Lazenby AJ, Boots LR, Azziz R. Prevalence of polycystic ovary syndrome in women seeking treatment from community electrologists. Alabama Professional Electrology Association Study Group. J Reprod Med 1999;44:870-4. 3. Goldzieher JW, Green JA. The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab 1962;22:325-38. 4. Guzick DS. Cardiovascular risk in women with polycystic ovarian syndrome. Semin Reprod Endocrinol 1996;14:45-9. 5. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499-507. 6. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk 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;84:165-9. 7. Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 1983;57:356. 8. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141-6. 9. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 2001;86: 1626-32. 10. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-54. 11. Culiner A, Shippel S. Virilism and theca cell hyperplasia of the ovary syndrome. J Obstet Gynaecol Br Commonw 1949;56: 439. 12. Barnes RB, Rosenfield RL, Ehrmann DA, Cara JF, Cuttler L, Levitsky LL, et al. Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab 1994;79:1328-33. 13. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J Clin Res Ed 1986;293:355. 14. Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N, Tucker M, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 1985;2:1375-9. 15. Corenblum B, Taylor PJ. The hyperprolactinemic polycystic ovary syndrome may not be a distinct entity. Fertil Steril 1982;38: 549-52. 16. Legro RS, 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;83:2694-8. 17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9. 18. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402-10. 19. Zawadski JS, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: toward a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, editors. Polycystic ovary syndrome. Boston: Blackwell Scientific; 1992. p. 377-84. 20. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 2004;81:19-25. 21. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Hum Reprod 2004;19:41-7.