Doi:10.1016/j.fertnstert.2003.10.004

FERTILITY AND STERILITY௡
VOL. 81, NO. 1, JANUARY 2004Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc.
Printed on acid-free paper in U.S.A.
Revised 2003 consensus on diagnostic
criteria and long-term health risks related
to polycystic ovary syndrome
The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003; revised andaccepted October 22,2003.
Since the 1990 National Institutes of Health–sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses a broader spectrum of signs and symptoms of ovarian dysfunction than those defined by the original diagnostic criteria. The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome, and as such no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations Scientific committee: J.
Chang (USA), R. Azziz may include menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events. (Fertil Steril௡ 2004;81:19 –25. 2004 by American Society for Repro- (Gr), B. Fauser (Nl).
Invited discussants: A.
Balen (UK), Ph.
Nearly 15 years have passed since the first PCOS is associated with an increased risk of Bouchard (Fr), E.
Dahlgren (Sw), L.
international conference on polycystic ovary syndrome (PCOS) was held. During that initial sponsored conference on PCOS, it has become meeting at the National Institutes of Health appreciated that the syndrome encompasses a (USA), M. Filicori (It), R.
Homburg (Is), L. Ibanez (NIH) in Bethesda, Maryland, there was con- broader spectrum of signs and symptoms of siderable discussion with little consensus, al- ovarian dysfunction than those defined by the though a questionnaire led to the current diag- Nestler (USA), R.
Norman (Aus), R.
recognized that women with regular cycles and Based on the majority opinion rather than clin- hyperandrogenism and/or polycystic ovaries ical trial evidence, the following diagnostic Tan (Can), A. Taylor(USA), R. Wild (USA), S.
criteria were put forth: clinical or biochemical also been recognized that some women with evidence of hyperandrogenism, chronic anovu- the syndrome will have PCO without clinical lation, and exclusion of other known disorders evidence of androgen excess but will display These criteria were an important first step toward standardizing diagnosis and led to a number of landmark randomized multicenter single diagnostic criterion (such as hyperandro- genism or PCO) is sufficient for clinical diag- and as outlined during a number of subsequent nosis. PCOS also remains a diagnosis of exclu- international conferences there has been a sion. Known disorders that mimic the PCOS gradually increasing awareness that the clinical expression of PCOS may be broader than that Diagnostic Criteria for Clinical
Rotterdam Consensus on Diagnostic
Trials and Familial Studies
Erasmus Medical Center,3015 GD Rotterdam, The Criteria for PCOS
PCOS is a syndrome of ovarian dysfunction.
may not be suitable for trials focusing on clin- Its cardinal features are hyperandrogenism and ical outcomes in women with PCOS. For in- stance, trials focusing on pregnancy as an out- manifestations may include menstrual irregu- doi:10.1016/j.fertnstert.2003.
10.004 larities, signs of androgen excess, and obesity.
anovulation as the identifying symptom, rather measurement of TSH in the hyperandrogenic patient need Revised diagnostic criteria of polycystic ovary syndrome.
The initial workup in women presenting with oligo/ anovulation may also include the assessment of serum FSH and E levels to exclude hypogonadotropic hypogonadism (i.e., central origin of ovarian dysfunction) or premature 2. Clinical and/or biochemical signs of hyperandrogenism ovarian failure characterized by low E and high FSH con- centrations, according to World Health Organization (WHO) classification PCOS is part of the spectrum of 2. Clinical and/or biochemical signs of hyperandrogenism, normogonadotropic normoestrogenic anovulation (WHO 2) It should be emphasized, however, that serum LH and exclusion of other etiologies (congenital adrenal hyperplasia,androgen-secreting tumors, Cushing’s syndrome) concentrations are frequently elevated in these patients, as Note: Thorough documentation of applied diagnostic criteria should be done (and described in research papers) for future evaluation.
Most participants felt that the routine measurement of 2003 Rotterdam PCOS consensus. Fertil Steril 2004. PRL in the evaluation of hyperandrogenic patients should beperformed to exclude hyperprolactinemia, with a caveat thatmany hyperandrogenic patients may have PRL levels in the than the presence of PCO or clinical hyperandrogenism.
upper normal limit or slightly above normal.
Similarly, trials seeking an improvement in hirsutism maydeemphasize baseline ovulatory function and require some Finally, syndromes of severe insulin resistance (e.g., for pathological terminal hair growth for entry. Moreover, the diagnosis of the hyperandrogenic-insulin resistant-acan- women with chronic anovulation and hyperandrogenism thosis nigricans, or HAIRAN, syndrome) Cushing’s and/or PCO appear to be at substantially greater risk for insulin resistance than those with hyperandrogenism and high-dose exogenous androgens should be excluded if regular cycles Accordingly, it is essential that studies of the metabolic features of PCOS stratify affected Hyperandrogenism
women according to ovulatory function (i.e., chronic oligo-/ Clinical phenotyping of PCOS involves determining the presence of clinical and/or biochemical androgen excess Family studies are critical for understanding the spectrum (hyperandrogenism), while excluding related disorders.
of phenotypes and for identifying susceptibility genes forPCOS. More narrow diagnostic criteria may be used in family studies to identify affected individuals, such as the the primary clinical indicator of androgen excess is the presence of PCO alone or hyperandrogenemia per se presence of hirsutism However, the following issues A rigid definition of PCOS based on the present or past proposed diagnostic criteria may hamper our understandingof this heterogeneous disorder.
● Normative data in large populations are still lacking.
● The assessment of hirsutism is relatively subjective.
Exclusion of Related Disorders
● Few physicians in clinical practice actually use standardized To establish the diagnosis of PCOS, it is important to exclude other disorders with a similar clinical presentation, ● Hirsutism is often treated well before the patient is ever such as congenital adrenal hyperplasia, Cushing’s syndrome, and androgen-secreting tumors. Exclusion of 21-hydroxylase ● Hirsutism may be significantly less prevalent in hyperandro- genic women of East Asian origin or in adolescence deficient nonclassic adrenal hyperplasia (NCAH) can beperformed using a basal morning 17-hydroxyprogesterone The sole presence of acne was also felt to be a potential level, with cutoff values ranging between 2 and 3 ng/mL marker for hyperandrogenism, although studies are some- Some participants felt that the routine screening of what conflicting regarding the exact prevalence of androgen hyperandrogenic patients for NCAH should take into ac- excess in these patients The sole presence of andro- count the prevalence of this autosomal recessive disorder in genic alopecia as an indicator of hyperandrogenism has been less well studied. However, it appears to be a relatively poor The routine exclusion of thyroid dysfunction in patients marker of androgen excess, unless present in the oligo- deemed to be hyperandrogenic was felt to have limited ovulatory patient Overall, the clinical evidence of hy- value, as the incidence of this disorder among these patients perandrogenism is an important feature of patients with is no higher than that in normal women of reproductive age.
PCOS, notwithstanding the above-mentioned limitations.
However, because screening for thyroid disorders may be advisable in all women of reproductive age, the routine PCOS have evidence of hyperandrogenemia, and recent ob- ESHRE/ASRM PCOS consensus workshop group
servations suggest that circulating androgen levels may also PCO are the following: “Presence of 12 or more follicles in represent an inherited marker for androgen excess each ovary measuring 2–9 mm in diameter, and/or increased However, it was clearly denoted that a proportion of patients ovarian volume (Ͼ10 mL)” (for a review, see The with PCOS may not demonstrate an overt abnormality in subjective appearance of PCO should not be substituted for this definition. The follicle distribution should be omitted as The limitations of defining androgen excess by the mea- well as the increase in stromal echogenicity and volume.
surement of circulating androgen levels were felt to be due in Although increased stromal volume is a feature of PCO part to the inaccuracy and variability of the laboratory meth- it has been shown that the measurement of the ovarian volume is a good surrogate for the quantification of stromalvolume in clinical practice This definition does not ● There are multiple androgens that may not be considered apply to women taking the oral contraceptive pill, since its ● There is wide variability in the normal population.
use modifies ovarian morphology in normal women and ● Normative ranges have not been well-established using well- putatively in women with PCO Only one ovary fitting this definition is sufficient to define PCO. If there is evidence ● Age and body mass index (BMI) have not been considered of a dominant follicle (Ͼ10 mm) or a corpus luteum, the when establishing normative values for androgen levels scan should be repeated during the next cycle. The presence of an abnormal cyst or ovarian asymmetry (which may Little normative data are present on adolescent and olderwomen.
suggest a homogeneous cyst) necessitates further investiga- ● Androgens are suppressed more rapidly by hormonal suppres- sion than other clinical features and may remain suppressed A woman having PCO in the absence of an ovulatory even after discontinuation of hormonal treatment.
should not be considered as having PCOS until more is Notwithstanding these limitations, it was felt that the mea- known regarding the clinical presentation In addition to surement of free T or the free T (free androgen) index its role in the definition of PCOS, ultrasound is helpful to were the more sensitive methods of assessing hyperandro- predict fertility outcome of clomiphene citrate and the genemia Recommended methods for the assess- risk of ovarian hyperstimulation syndrome (OHSS) and to ment of free T included equilibrium dialysis calcu- assist in deciding whether the in vitro maturation of oocytes lation of free T from the measurement of sex hormone– binding globulin and total T, or ammonium sulfateprecipitation It was the uniform impression that cur- It is recognized that the appearance of PCO may be seen rently available direct assays for free T have limited value, in women before undergoing ovarian stimulation for IVF in particularly in the evaluation of the hyperandrogenic woman.
the absence of overt signs of the PCOS. These ovaries, when It was noted that measurement of total T only may not be stimulated, behave like the ovaries of women with PCOS a very sensitive marker of androgen excess. A small fraction and are at increased risk for hyperstimulation and OHSS of patients with PCOS may have isolated elevations in dehydroepiandrosteronesulphate (DHEAS) levels. Some felt In addition, ultrasound provides the opportunity to screen that the measurement of total T and DHEAS had some value for endometrial hyperplasia in these patients. The following in detecting a patient with an androgen-secreting tumor technical recommendations should be highlighted: although more recent data suggest that the best predictor ofthese neoplasms is the clinical presentation ● State-of-the-art equipment is required and should be operated Finally, little data are available on the value of routinely measuring androstenedione in hyperandrogenic patients ● Whenever possible, the transvaginal approach should be used, although it was noted that it might be somewhat more elevated in patients with 21-hydroxylase– deficient nonclas- ● Regularly menstruating women should be scanned in the early sic adrenal hyperplasia than in patients with PCOS. None- follicular phase (cycle days 3–5). Oligo-/amenorrhoeic women theless, the paucity of normative and clinical data with should be scanned either at random or between days 3 and 5 androstenedione precluded its recommendation for the rou- after a progestin-induced withdrawal bleeding.
tine assessment of hyperandrogenemia.
● Calculation of ovarian volume is performed using the simpli- fied formula for a prolate ellipsoid (0.5 ϫ length ϫ width ϫ Polycystic Ovaries (PCO)
Workshop participants felt that PCO should now be con- ● Follicle number should be estimated both in longitudinal and sidered as one of the possible criteria for PCOS (see antero-posterior cross-sections of the ovaries. The size of According to the available literature the follicles Ͻ10 mm should be expressed as the mean of the criteria having sufficient specificity and sensitivity to define diameters measured on the two sections.
FERTILITY & STERILITY௡
Summary of 2003 polycystic ovary syndrome (PCOS) Criteria for the metabolic syndrome in women with consensus regarding screening for metabolic disorders.
polycystic ovary syndrome. (Three of five qualify for thesyndrome.) Summary of consensus1. No tests of insulin resistance are necessary to make the diagnosis of PCOS, nor are they needed to select treatments.
2. Obese women with PCOS should be screened for the metabolic syndrome, including glucose intolerance with an oral glucose tolerance 3. Further studies are necessary in nonobese women with PCOS to determine the utility of these tests, although they may be considered if additional risk factors for insulin resistance, such as a family history of 2003 Rotterdam PCOS consensus. Fertil Steril 2004. 2003 Rotterdam PCOS consensus. Fertil Steril 2004. Insulin Resistance
the 2-hour glucose level after a 75-g oral glucose challenge Insulin resistance is associated with reproductive abnor- for glucose intolerance (WHO criteria, impaired glucose malities in women with PCOS (see also Improving tolerance [IGT] Ͼ140 mg/dL to 199 mg/dL) IGT insulin sensitivity through both lifestyle and pharmacologi- has long been recognized as a major risk factor for diabetes cal intervention can ameliorate these abnormalities. Insulin and recent studies have shown that progression to resistance, defined as decreased insulin-mediated glucose diabetes in individuals with IGT can be delayed by lifestyle utilization, is commonly found in the larger population changes and pharmacological intervention Addi- (10%–25%) when sophisticated dynamic studies of insulin tionally, IGT identifies individuals at risk for excess mortal- action are performed However, the criteria for selecting ity, especially women Given the high prevalence of an abnormal cutoff point vary. Insulin resistance in women IGT and type 2 diabetes as diagnosed by the OGTT among with PCOS appears even more common (up to 50%), both in obese women with PCOS, it is prudent to screen obese obese and nonobese women Reports of the prevalence women (BMI Ͼ27 kg/m2) with PCOS with an OGTT on insulin resistance in women with PCOS vary depending Further studies of the prevalence of features of the metabolic on the sensitivity and specificity of the tests employed and syndrome are necessary in both lean and obese women with There is currently no validated clinical test for detecting insulin resistance in the general population. Dynamic inva- Currently, there are scant data to indicate that markers of sive tests such as the euglycemic clamp and frequently insulin resistance predict responses to treatment sampled glucose tolerance test are research procedures be- Therefore, the role of these markers in the diagnosis of cause of their intensive use of time and resources. Calculated PCOS, as well as in selecting specific treatments, is uncer- indices based on fasting levels of insulin and glucose corre- tain. Tests of insulin sensitivity are of greatest interest in late well with dynamic tests of insulin action. However, research studies of [1] the pathophysiology of PCOS, [2] there are multiple flaws that limit their widespread clinical young adolescents with a combined history of low birth use, including changes in beta-cell function with the devel- weight and excessive postnatal catch-up, [3] mechanisms of opment of diabetes (which alters the sensitivity of the tests), response to therapy, and [4] family phenotypes. Further normal physiologic fluctuation in insulin levels, and the lack studies to identify predictive factors or early response factors of a standardized universal insulin assay.
Other consensus conferences also recommended against Luteinizing Hormone
screening for insulin resistance in both the general popula- Both the absolute level of circulating LH as well as its tion and in high-risk populations because of these concerns relation to FSH levels are significantly elevated in women and concerns regarding the value of these tests to predict with PCOS as compared with controls This is due clinical events Instead, criteria have been developed for to an increased amplitude and frequency of LH pulses defining a metabolic syndrome, which includes components Elevated LH concentrations (above the 95th percentile of associated with the insulin resistance syndrome, including normal) can be observed in approximately 60% of women centripetal obesity, hypertension, fasting hyperglycemia, and with PCOS whereas the LH/FSH ratio may be elevated in up to 95% of subjects if women who have Other groups have recommended adding an oral glucose recently ovulated are excluded. LH levels may be influenced tolerance test (OGTT) to these fasting blood tests to evaluate by the temporal relation to ovulation, which transiently nor- ESHRE/ASRM PCOS consensus workshop group
malizes LH, by BMI (being higher in lean women with ● The risk is greater in anovulatory women with PCO, in obese PCOS), as well as by the assay system used.
subjects, and in those with a family history of type 2 diabetes.
● The risk of cardiovascular disease is uncertain at present The potential negative actions of LH on human reproduc- Limited epidemiological data have shown no increase in tion are highly controversial. Some investigators have sug- cardiovascular events, but two factors need to be borne in gested that high LH levels could have detrimental effects on mind: The young age of the cohorts studied so far (around 55 oocyte maturity and fertilization as well as result in years) and the possibility that unknown factors(s) may be lower pregnancy and higher miscarriage rates How- present in PCOS that protect the heart in the face of other risk ever, other studies have shown no untoward actions of LH on oocyte and embryo quality or on fertilization, implantation, More research is required to [1] assess the level of risk, and pregnancy rates Reduction of endogenous LH [2] enable identification of patients at risk, [3] provide lon- levels with GnRH agonists also provided conflicting results gitudinal follow-up of PCOS cohorts into their sixties and as some studies have suggested that this maneuver could beyond, and [4] determine the place, timing, and efficacy of reduce miscarriage rates while others have questioned this therapeutic effect LH levels or the administra- Although many questions remain to be answered, lifestyle tion of exogenous LH activity were not found to affect the changes (diet and exercise) should be strongly encouraged to chances of ovulation or achievement of pregnancy using reduce the risk of both type 2 diabetes and cardiovascular clomiphene citrate or exogenous gonadotropins Based on the aforementioned data, the panel felt that measurement of serum LH levels should not be considered References
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