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From: Contemporary Endocrinology: Androgen Excess Disorders in Women:
Polycystic Ovary Syndrome and Other Disorders, Second Edition Edited by: R. Azziz et al. © Humana Press Inc., Totowa, NJ
13
Definition and Epidemiology of the Polycystic Ovary Syndrome
Ricardo Azziz
SUMMARY
P
olycystic ovary syndrome (PCOS) is a heterogeneous disorder of functional androgen excess, although its definition remains fluid and controversial. PCOS is characterized by clinical and/or biochemical hyperandrogenism and is frequently accompanied by ovulatory dysfunction and polycystic ovaries. PCOS is a diagnosis of exclusion, with other androgen excess and related disorders to be excluded. Two principal defini- tions are in use today: one arising from an expert conference sponsored by the National Institutes of Health (NIH) in 1990 (NIH 1990 criteria) and the other from another expert conference sponsored by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine in 2003 in Rotterdam (Rotterdam 2003 criteria). The prevalence of PCOS among unselected reproductive-aged women is at least 6.5– 8.0% using the NIH 1990 criteria. Future studies must establish the prevalence of the disorder in different populations and using the various criteria proposed to define PCOS. Finally, studies on the long-term development of reproductive and metabolic abnormalities in women with the two new phenotypes of PCOS defined by Rotterdam 2003 are needed to determine whether these have risks similar to classic PCOS.Key Words: Epidemiology; polycystic ovary syndrome; phenotyping; diagnostic criteria.
1. INTRODUCTION
The polycystic ovary syndrome (PCOS) was first described by Stein and Leventhal in 1935 (1) and has since been recognized as one of the most common endocrine/metabolic disorders of women (2). PCOS is a heterogeneous disorder, whose principal features include androgen excess, ovulatory dysfunction, and/or polycystic ovaries. Although it is widely recognized that PCOS is a diagnosis of exclusion, the definition of PCOS remains controversial. Here, we review the definition and epidemi- ology of PCOS as it currently stands.
2. BACKGROUND 2.1. Defining PCOS
Although the disorder is relatively heterogeneous at present, we recognize that a relatively consis-
tent feature of PCOS is androgen excess, or hyperandrogenism (3). Hyperandrogenism is detectable
either by laboratory analysis, generally measuring circulating androgen levels, or by clinical exam,
primarily in the form of hirsutism. Two other features often considered fundamental to the diagnosis
include ovulatory dysfunction, often but not always associated with overt menstrual dysfunction, and
polycystic ovarian morphology, generally detectable by ultrasonography.
First we should note that PCOS is a diagnosis of exclusion, such that androgen excess disorders with clearly defined etiologies are to be excluded. One disorder that is difficult to distinguish clini- cally from PCOS is 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) (4), generally detected by a basal and/or ACTH-stimulated 17-hydroxyprogesterone level (5). Other disorders that can be suspected clinically include those resulting in Cushing’s syndrome with hyperandrogenic features, such as adrenocortical carcinomas, Cushing’s disease, and ovarian and other adrenal andro- gen-secreting neoplasms. The history may reveal use or abuse of anabolic drugs. Although still con- troversial, many investigators also consider patients with the hyperandrogenism, severe insulin resistance, and acanthosis nigricans syndrome as distinct from PCOS (see Chapter 11), because these women will have extreme degrees of hyperinsulinism and insulin resistance far greater than the vast majority of PCOS patients and may have other unique features, including lipodystrophy.
If ovulatory dysfunction is identified, other disorders that may result in this abnormality, such as thyroid dysfunction and hyperprolactinemia, will also need to be excluded. Nonetheless, recent studies suggest that the prevalence of these endocrine abnormalities in patients with apparent PCOS is rela- tively low, on the order of 1–3% (6–9). Likewise, investigators generally will also exclude those disor- ders that can result in polycystic-like ovarian morphology, such as hypothalamic amenorrhea (10,11).
Women with PCOS demonstrate a rate of obesity higher than the general population (30–60%, depending on country of origin) (9,12–14), insulin resistance and hyperinsulinism (present in 50–
70%) (15–18), and a luteinizing hormone (LH)–to–follicle-stimulating hormone (FSH) ratio of greater than 2 or 3 (in 30–50%) (19–24). However, these features have not generally been included in the diagnostic criteria, as they are either highly prevalent in disorders other than PCOS (e.g., obesity and insulin resistance) or are not observable in the majority of patients with routine laboratory assess- ments (e.g., an elevated LH-to-FSH ratio, because LH levels are lower in obese individuals, which accounts for a large fraction of women with PCOS).
To date, two major criteria have been proposed, with other investigators proposing modifications of these. We will review the criteria arrived at a National Institutes of Health (NIH)/National Institute of Child Health and Human Development (NICHD) expert conference sponsored in April 1990 and another co-sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) in May 2003, as well as a modifica- tion of these.
2.1.1. The 1990 NIH Criteria
The definition of PCOS most commonly used today arose from the proceedings of an expert con- ference sponsored by the NIH in April 1990 (Table 1). Participants were surveyed, and tabulation of the results indicated that most felt that the features of PCOS were (in order of importance) (1) hyperandrogenism and/or hyperandrogenemia; (2) chronic anovulation; and (3) exclusion of related disorders such as hyperprolactinemia, thyroid disorders, and congenital adrenal hyperplasia (25).
Conference participants felt that polycystic ovaries were suggestive, not diagnostic, of the syndrome.
Notwithstanding this omission, we should note that the results of this survey had the lucidity of identifying PCOS as an androgen excess disorder of exclusion, with ovarian consequences.
We should note that these proceedings did not provide clear guidelines as to how to define each criterion. Clinical hyperandrogenism has generally been interpreted as hirsutism, because more than 70% of hirsute women have PCOS (9). At a minimum, hyperandrogenemia generally is interpreted to be an elevated free testosterone (T) level, observable in approximately 70% (26) of affected women.
Measuring total T, dehydroepiandrosterone sulfate, and androstenedione levels will increase the num- ber of patients diagnosed as hyperandrogenemic (26,27). As noted in Chapter 5, close attention must be paid to the quality of the androgen assays.
Chronic anovulation is generally defined as menstrual cycles (or more accurately vaginal bleeding
episodes) at no less than 35-day intervals (28,29) or no more than10 bleeds per year (i.e., 365 days/35
days = 10.4). Although other investigators define oligomenorrhea as cycles at no less than 43-day intervals or no more than 8 bleeds per year (30), they also note that cycle length varies with age, such that women between the ages of 27 and 42 years (which includes most women with PCOS) usually have a maximum (within 3 standard deviations) cycle length of less than 35 days (31). Although most women with PCOS will have overt oligomenorrhea, about 15% will present with a history of regular menses, and oligo-ovulation in these women is only discoverable by monitoring the luteal (cycle day 20–24) progesterone levels. The disorders that may be considered for exclusion already have been discussed.
Three principal phenotypes of PCOS are recognized using the NIH 1990 criteria, including women with (a) hirsutism, hyperandrogenemia, and oligo-ovulation; (b) hyperandrogenemia and oligo-ovu- lation; or (c) hirsutism and oligo-ovulation. The overall prevalence of these phenotypes, at least in one large study, was approximately 50%, 30%, and 20%, respectively (26). There were no differ- ences in mean age, mean body mass index (BMI), mean waist-to-hip ratio, racial distribution, sever- ity of oligomenorrhea, or prevalence of family history for hyperandrogenism between the phenotypes.
The exception was the fasting insulin levels, which were highest in patients with hirsutism, hyperandrogenemia, and oligo-ovulation and lowest in those women with oligo-ovulation and hirsut- ism only. Whether different mechanisms underlie the development of these phenotypes remains to be demonstrated.
Overall, the NIH criteria have proven extremely useful to begin to define and understand, among other features, the high prevalence of the disorder (2,32,33), its high frequency of insulin resistance (18,34), and the considerable risk of these women for developing type 2 diabetes mellitus (DM) (16,35).
2.1.2. The 2003 ESHRE/ASRM (Rotterdam) Criteria
Another expert conference was organized in Rotterdam in May 2003 (Table 1), in part spon- sored by the ESHRE and the ASRM. The proceedings of the conference noted that PCOS could be diagnosed, after the exclusion of related disorders, by at least two of the following three features:
(a) oligo- or anovulation, (b) clinical and/or biochemical signs of hyperandrogenism, or (c) polycys- tic ovaries (36,37). It should be noted that these recommendations did not replace the NIH 1990
Table 1
Proposed Criteria for the Definition of PCOS NIH, 1990 (25):
To include all of the following:
1. Hyperandrogenism and/or hyperandrogenemia 2. Chronic anovulation
3. Exclusion of related disorders ESHRE/ASRM (Rotterdam), 2003 (36,37):
To include at least two of the following, in addition to exclusion of related disorders:
1. Oligo-anovulation
2. Hyperandrogenism and/or hyperandrogenemia 3. Polycystic ovaries
Modified NIH criteriaa(45):
To include all of the following:
1. Androgen excess (clinical and/or biochemical hyperandrogenism)
2. Ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology) 3. Exclusion of other androgen excess or ovulatory disorders
PCOS, polycystic ovary syndrome; NIH, National Institutes of Health; ESHRE, European Society for Human Reproduction and Embryology; ASRM, American Society for Reproductive Medicine.
criteria; rather they expanded the definition of PCOS. Additional phenotypes now to be considered as having PCOS included (1) women with polycystic ovaries with clinical and/or biochemical evidence of androgen excess, but no signs of ovulatory dysfunction, and (2) women with polycystic ovaries and ovulatory dysfunction, but no signs of androgen excess. Whether or not these additional pheno- types actually represent PCOS remains to be determined. However, it is useful to briefly review the current data supporting or refuting this argument.
One possible approach to determining whether these new phenotypes are part of the syndrome known as PCOS is to compare long-term morbidities. Ovulatory hyperandrogenic patients with poly- cystic-appearing ovaries appear to have features that approximate patients with PCOS defined by the NIH 1990 criteria, although of a milder nature. These include slight excess in circulating LH, insulin, and other markers for cardiovascular disease (38–41). Essentially, these patients can be considered to have “mild PCOS” and, in the absence of long-term follow-up studies, may not have the same degree of reproductive or metabolic consequences as women with the full PCOS phenotype.
Alternatively, it is even less clear that women with ovulatory dysfunction and polycystic ovaries, but without any evidence of hyperandrogenism, as a group have a similar morbidity to patients with PCOS (e.g., insulin resistance). For example, in a study of 235 women aged 40–42 years, polycystic- appearing ovaries were observed in 20.8% (42). Of women with polycystic ovaries, the differences in the prevalence of irregular cycles and infertility were not significantly different compared to subjects with normal ovaries (41 vs 27%, and 16 vs 15%, respectively). Only 14% of women with polycystic ovaries demonstrated hirsutism. These data would suggest that the prevalence of PCOS among women with polycystic ovaries might not be higher than 15–25%. In addition, the prevalence of polycystic- appearing ovaries does not appear to predict abnormalities in insulin sensitivity either in women with PCOS (43) or in their sisters (44). Finally, it is uncertain how patients with hypothalamic amenorrhea and polycystic ovaries will be differentiated from non-obese women with PCOS, an important co- nundrum considering the significant differences in long-term morbidity (e.g., bone loss for hypotha- lamic amenorrhea and increased bone mass for PCOS, increased risk of diabetes in PCOS but not hypothalamic amenorrhea patients). Overall, it may be prudent to withhold expanding the definition of PCOS much beyond that originally suggested by the NIH 1990 expert conference until more com- plete epidemiological and long-term data are available.
2.1.3. Modified NIH Criteria
In order to accommodate current epidemiological data, a modification of the NIH criteria has been proposed (Table 1 [45]). This definition suggests that PCOS should have three features: (1) androgen excess (clinical and/or biochemical hyperandrogenism), (2) ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology), and (3) exclusion of other androgen excess or ovulatory disorders (45). This definition then recognizes one additional phenotype to those noted by the NIH 1990 criteria, namely those women with polycystic ovaries, hyperandrogenism, and apparently nor- mal ovulation. This definition does not eliminate the possibility that future research may demonstrate that the subset of women with polycystic ovaries and ovulatory dysfunction and without overt andro- gen excess may actually have PCOS. However, expanding the definition of PCOS without good supporting data may have significant detrimental implications for research (e.g., increased heteroge- neity of the study populations), clinical practice (e.g., requiring that all these patients undergo ultra- sonography), and patient quality of life (e.g., requiring long-term monitoring for the development of associated metabolic morbidities and potentially adversely affecting health insurability).
2.2. Prevalence of PCOS
Clearly the prevalence of PCOS will depend to some degree on the criteria used to define this
disorder. The prevalence of PCOS has been determined primarily using the NIH 1990 criteria and in
populations of white or Caucasian women with a few exceptions. Studying 277 women seeking a
preemployment physical in the southeastern United States, we initially reported a prevalence of PCOS
of 4%, not significantly different between whites and blacks (27). In a subsequent and more intensive study of 400 unselected consecutive women ages 18–45 years in the same setting (223 black, 166 white, 11 of other races), the prevalence of PCOS was observed to be 6.6%, still not significantly different between blacks and whites (8 and 4.8%, respectively) (2). Nonetheless, the lack of a signifi- cant difference in the prevalence of PCOS between black and white women may solely reflect inad- equate sample size.
Also using the 1990 NIH criteria, a study of 192 Greek women on the island of Lesbos, recruited through the promise of a free medical exam, reported a prevalence of PCOS of 6.8% (32). Another study of 154 Caucasian blood donors in Madrid, Spain, found a similar prevalence (6.5%) (33). Among 230 volunteers (97% white) recruited from two Oxford universities and two general practice surgeries who agreed to participate in “a study of women’s health issues,” the prevalence of PCOS using the NIH 1990 criteria was 8% (46). These data indicate that the prevalence of clinically evident PCOS using the 1990 NIH criteria in unselected women of reproductive age ranges from 6.5 to 8.0%, affect- ing 1 in 13–15 unselected women. This translates to at least 5 million affected women in the United States and 105 million worldwide. Furthermore, as many women in the aforementioned studies were on hormonal contraceptives, it is probable that this figure underestimates the true prevalence.
A number of conditions are associated with increased prevalences of PCOS, including obesity (47,48), insulin resistance (48), type 1 or type 2 DM (49–51), and oligo-ovulatory infertility (40,52,53). The prevalence of PCOS also appears to be higher among Mexican-Americans than among white or black (African-American) women (54)
(Fig. 1). Finally, the prevalence of PCOSseems higher among populations reporting premature adrenarche (55), gestational diabetes (56,57), and logically, in first-degree relatives of PCOS patients (58,59).
The use of more expansive definitions for PCOS, such as the Rotterdam 2003 criteria, would logically raise the prevalence further. In their study, Michelmore and colleagues defined PCOS by the presence of polycystic ovaries on ultrasound plus one additional feature, including menstrual irregularity, acne, hirsutism, BMI greater than 25 kg/m
2, raised serum T, or raised LH (>10 IU/L) (46). Applying these criteria, 26% of the 224 women undergoing a transabdominal sonography had evidence of PCOS, compared with only 8% if the NIH 1990 criteria were used. However, these features also occurred frequently in women without polycystic ovaries, and 112 of the 150 women (75%) with normal ovaries had the presence of one or more of these attributes. We can only conclude
Fig. 1. Potential racial differences in the prevalence of PCOS in unselected women in the United States.Whether these data are confirmed in further studies and/or whether these differences are the product of differ- ences in the population prevalence of insulin resistance remains to be confirmed. (Adapted from refs.2 and 54.)
that the number of women diagnosable as having PCOS could possibly double or even triple if the Rotterdam 2003 criteria are used. Further studies comparing the prevalence of PCOS using the NIH 1990 and the Rotterdam 2003 criteria are needed.
3. CONCLUSIONS
PCOS is a heterogeneous disorder of functional androgen excess, detectable either by laboratory analysis or by clinical exam, with ovulatory dysfunction and polycystic ovarian morphology affect- ing a large proportion of patients. PCOS is a diagnosis of exclusion, with other androgen excess or related disorders to be ruled out. The first broadly used definition of PCOS arose from the proceed- ings of an expert conference sponsored by the NIH in 1990, which noted the features of PCOS to be (in order of importance) (1) hyperandrogenism and/or hyperandrogenemia; (2) chronic anovulation;
and (3) exclusion of related disorders such as hyperprolactinemia, thyroid disorders, and congenital adrenal hyperplasia. Another expert conference held in Rotterdam in 2003 expanded the NIH 1990 criteria for PCOS, noting that the disorder could be diagnosed by having at least two of the following three features: (1) oligo- or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, or (3) polycystic ovaries, after the exclusion of related disorders. This definition created two new phenotypes for PCOS: (1) women with polycystic ovaries and ovulatory dysfunction, but no signs of androgen excess, and (2) women with polycystic ovaries with clinical and/or biochemical evidence of androgen excess, but no signs of ovulatory dysfunction. Whether or not these phenotypes actually represent PCOS remains to be determined.
To accommodate current epidemiological data, a modification of the NIH criteria has been pro- posed, defining PCOS by three features: (1) androgen excess (clinical and/or biochemical hyperandrogenism), (2) ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphol- ogy), and (3) exclusion of other androgen excess or ovulatory disorders. Clearly the prevalence of PCOS will depend to some degree on the criteria used to define this disorder, although using the NIH 1990 criteria, most studies have observed 6.5–8.0% prevalence in unselected reproductive-aged women. The prevalence of PCOS is increased in the presence of obesity, insulin resistance, type 1 or type 2 DM, oligo-ovulatory infertility, premature adrenarche, prior gestational diabetes, and first- degree relatives of PCOS. Further investigation is required to better establish the definition of PCOS.
4. FUTURE AVENUES OF INVESTIGATION
Studies of the prevalence of PCOS in large populations of unselected women from different eth- nic, racial, and geographic groups is required and may yield important information that will assist in the elucidation of the respective roles of genetics and environment in the development of the disor- der. The prevalence of the disorder using the various criteria proposed to define PCOS must also be established. Finally, studies on the long-term development of reproductive and metabolic abnormali- ties in women with the two new phenotypes of PCOS defined by Rotterdam 2003 are needed to determine whether these have risks similar to classic PCOS.
KEY POINTS
• PCOS is a heterogeneous disorder of functional androgen excess, ovulatory dysfunction, and polycystic ovarian morphology.
• PCOS is a diagnosis of exclusion, with other androgen excess or related disorders to be ruled out.
• Two major definitions are in use: one established by an expert conference sponsored by the NIH in 1990, and the other from an expert conference held in Rotterdam in 2003 and sponsored by the ESHRE and ASRM.
• The NIH 1990 definition states that the features of PCOS are (in order of importance) (1) hyperandrogenism and/or hyperandrogenemia; (2) chronic anovulation; and (3) exclusion of related disor- ders such as hyperprolactinemia, thyroid disorders, and congenital adrenal hyperplasia.
• Rotterdam 2003 defines PCOS as having two of the following three features: (1) oligo- or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, and (3) polycystic ovaries, after the exclusion of related disorders.
• A modification of the NIH criteria has been proposed, defining PCOS by three features: (1) androgen excess (clinical and/or biochemical hyperandrogenism), (2) ovarian dysfunction (oligo-anovulation and/
or polycystic ovarian morphology), and (3) exclusion of other androgen excess or ovulatory disorders.
• While the prevalence of PCOS will vary according to the criteria used, using the NIH 1990 criteria, prevalences of 6.5–8.0% have been observed.
• The prevalence of PCOS is increased in the presence of obesity, insulin resistance, type 1 or type 2 DM, oligo-ovulatory infertility, premature adrenarche, prior gestational diabetes, and first-degree relatives of PCOS.
ACKNOWLEDGMENTS
Supported in part by NIH grants R01-HD29364 and K24-HD01346-01 (to RA).
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