Outlook PCOS: a diagnostic challenge

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1 RBMOnline - Vol 8. No Reproductive BioMedicine Online; on web 5 April 2004 Outlook PCOS: a diagnostic challenge Dr Ricardo Azziz Dr Azziz is currently Chairman of both the Helping Hand of Los Angeles in Obstetrics and Gynecology, and the Department of Obstetrics and Gynecology at Cedars-Sinai Medical Center, Los Angeles, California, USA. He also holds positions at The David Geffen School of Medicine at UCLA. Dr Azziz is a Fellow of both The American College of Surgeons (FACS) and The American College of Obstetricians and Gynecologists (FACOG). He is a current member of the Reproductive Endocrinology Study Section of the National Institutes of Health. Dr Azziz has published over 200 original articles, book chapters, and reviews. His research interests include the study of the polycystic ovary syndrome (PCOS), the nonclassic adrenal hyperplasias (NCAH); the role of the adrenal gland in hyperandrogenic disorders; the genetics of hyperandrogenic disorders; the treatment of hirsutism; the regulation and physiology of adrenal androgens; and operative endoscopy for pelvic reconstruction. Ricardo Azziz Department of Obstetrics and Gynecology, Cedars-Sinai Medical Centre and Department of Obstetrics and Gynecology and Department of Medicine, The David Geffen School of Medicine at UCLA, 8635 West Third Street, Suite 160W, Los Angeles, CA 90048, USA Correspondence: Tel: ; Fax: ; azzizr@cshs.org Abstract Useful research and diagnostic criteria for PCOS arose from a conference in 1990, whereby PCOS could be defined by: (i) clinical and/or biochemical hyperandrogenism, (ii) chronic anovulation, and (iii) exclusion of related disorders. The presence of polycystic ovaries was not included in this definition, which created significant concern since many women with PCOS have polycystic ovaries on ultrasound, and conversely women with this ovarian morphology have a higher prevalence of androgen excess and insulin resistance. More recently, at an expert meeting in 2003 in Rotterdam, it was recommended that PCOS be defined when at least two of the following three features were present, after exclusion of other aetiologies: (i) oligo- or anovulation, (ii) clinical and/or biochemical hyperandrogenism, or (iii) polycystic ovaries. These newer criteria effectively create additional phenotypes of PCOS (e.g. women with hyperandrogenism and polycystic ovaries but normal ovulatory function, and women with ovulatory dysfunction and polycystic ovaries but no clinical or biochemical evidence of hyperandrogenism). It remains to be demonstrated whether these phenotypes actually represent patients with PCOS. Nonetheless, the trend towards the use of uniform diagnostic criteria in studies of PCOS will increase the comparability and potentially the value of published research. Keywords: hirsutism, hyperandrogenaemia, ovulatory dysfunction, polycystic ovary 644 General considerations Polycystic ovary syndrome (PCOS) is truly a diagnostic challenge. In 1935, Drs Stein and Leventhal reported their findings of seven cases in which they describe patients with oligo- or amenorrhoea with bilaterally polycystic ovaries (Stein and Leventhal, 1935). Only three of these patients were obese, while five were hirsute. One of the hirsute patients was obese and one was thin with acne. A wedge resection in this small series resulted in two pregnancies and regular cycles in the remainder. Hence, the disorder to be later called PCOS, or as, it was initially termed, the Stein Leventhal syndrome, was recorded. PCOS is a heterogeneous disorder of unknown aetiology. Many features have been associated with the disorder, including ovulatory dysfunction, polycystic ovaries on either ultrasonographic or histopathological examination, hirsutism, hyperandrogenaemia, abnormal gonadotrophin concentrations, and most recently insulin resistance and hyperinsulinaemia. A number of investigators have determined the value of ultrasonography in diagnosing PCOS. Adams and colleagues in 1985 noted that polycystic ovaries are characterized by the excessive number of follicles, also termed multifollicularity, and by stromal hypertrophy. They defined polycystic ovaries by the presence of >10 cysts measuring 2 8 mm in diameter arranged peripherally around a dense core of stroma or scattered through an increased amount of stroma (Adams et al., 1986). However, subsequent reports have not supported the specificity or sensitivity of polycystic ovaries for the diagnosis of the endocrine syndrome PCOS. For example, among 257 normal volunteers, 23% were found to have polycystic ovaries, and of the patients with polycystic ovaries, only about 50% had PCOS (Polson et al., 1988). Alternatively, of those women with PCOS, approximately 70% have polycystic ovaries on ultrasound (Carmina et al., 1992). Ethnicity may also influence the prevalence of adrenal hyperandrogenism in insulin resistance in the polycystic ovary syndrome (Carmina

2 et al., 1992; O Driscoll et al., 1994). Therefore, while many women with PCOS have polycystic ovaries, the two conditions are not the same. An abnormal concentration of gonadotrophins, namely an elevated LH:FSH ratio, have been observed in many patients with PCOS. However, even in the original studies of Rebar and colleagues, up to 30% of women with PCOS actually had normal concentrations of LH on a single sample (Rebar et al., 1976). Consequently, the LH:FSH ratio, although increased to ratios over 2:1 or 3:1 in many women with PCOS, is not a universal feature and is not currently used for the differential diagnosis of PCOS. Insulin resistance has been another feature associated with PCOS. PCOS patients are also usually insulin resistant (Dunaif et al., 1989; Carmina et al., 1992; Legro et al., 1998). That the insulin resistance of PCOS patients underlies many of the features of this disorder is highlighted by the finding that insulin directly stimulates androgen secretion by ovarian theca (Barbieri et al., 1986; Nestler et al., 1998) and suppresses sex hormone-binding globulin (SHBG) (Plymate et al., 1988; Nestler et al., 1991), thereby enhancing circulating free testosterone. In addition, the administration of insulinsensitizing agents, principally metformin, troglitazone and rosiglitazone, have been found to improve the clinical and endocrine features of many of these patients (Nestler et al., 1989, 1998, 1999; Ehrmann et al., 1997; Diamanti-Kandarakis et al., 1998; Azziz et al., 2001). However, insulin resistance is not a universal feature of PCOS. Overall, between 50 and 70% of PCOS patients demonstrate this metabolic abnormality (Dunaif et al., 1989; Legro et al., 1998). Specific reports In view of the heterogeneity of the disorder, and the prevailing conflicts in published studies, an expert meeting was held in 1990 sponsored by the National Institute of Child Development and Health (NICHD). At this conference, a survey was conducted of those attending and the survey results were summarized in the conference proceedings (Zawadzki and Dunaif, 1992). These data concluded that the most common features of PCOS were (in order of importance): (i) clinical (e.g. hirsutism) and/or biochemical (i.e. hyperandrogenaemia) hyperandrogenism, (ii) chronic anovulation, and (iii) exclusion of related disorders, such as congenital adrenal hyperplasia, androgen secreting tumours, hyperprolactinaemia, and thyroid disorders. At the time of this survey, most participants felt that the presence of polycystic ovaries by ultrasound was suggestive, but not diagnostic, of PCOS. While these criteria were not reached by consensus, the survey data have been very useful for those conducting research in the area of PCOS. For example, it was possible to use this definition to determine the prevalence of PCOS, observing that about 5% of unselected reproductive-aged women undergoing a pre-employment physical in the southeastern United States suffered from the disorder (Knochenhauer et al., 1998). Further studies from Spain and Greece report these same observations (Diamanti-Kandarakis et al., 1999; Asuncion et al., 2000). How does one proceed with identifying patients with PCOS? As noted, there appear to be significant variations in the features associated with PCOS. However, until further data are made available, the single consistent feature of PCOS is probably the presence of androgen excess, whether biochemical or clinical (Azziz et al., 2004). Consequently, the first step is to confirm the presence of androgen excess-related clinical features, such as hirsutism. Other features may suggest androgen excess, although the association with hyperandrogenism is less strong than hirsutism, including androgenic acne, alopecia, and ovulatory dysfunction. In patients with these latter features, androgen excess is primarily confirmed by the measurement of circulating androgen concentrations. Once the presence of androgen excess is suspected or confirmed, patients are then divided into two general categories. The first category includes those patients with specific identifiable disorders. These are diagnoses of inclusion, such as non-classic and classic congenital adrenal hyperplasia, androgen-secreting tumours, the hyperandrogenic-insulin resistant-acanthosis nigricans (HAIRAN) syndrome, and drug-induced hyperandrogenism. The second category is patients with disorders of exclusion, which are defined as functional androgen excess (FAE) disorders, such as patients with PCOS and idiopathic hirsutism (IH). Based on the 1990 NICHD criteria and the concept that androgen excess must be a part of PCOS, a phenotype grid has been devised for patients with FAE (Table 1), The grid uses three features, ovulatory dysfunction, hyperandrogenaemia, and hirsutism, to define eight phenotypes. Consequently, it is possible to identify three different phenotypes of PCOS, as follows: (i) patients with all three features (ovulatory dysfunction, hyperandrogenaemia, and hirsutism), (ii) patients with ovulatory dysfunction and hyperandrogenaemia, but no hirsutism, or (iii) patients with ovulatory dysfunction and hirsutism, but no detectable hyperandrogenaemia. There are two FAE phenotypes that are less clear, namely patients with IH and patients with hirsutism, hyperandrogenaemia, but apparently regular ovulation. The definition of IH is very specific, such that patients should have documented proof of regular ovulation, normal androgen concentrations, and of course hirsutism. Using these strict criteria, the subgroup of normo-ovulatory women who are hirsute and hyperandrogenaemic are not defined as having IH, but there is still some doubt as to whether these individuals actually represent a variant of PCOS. Further studies will be needed to better define the aetiology of this subgroup of patients. In a recent report of experience with over 1000 consecutive patients, 7% had definable disorders (e.g. HAIRAN syndrome or NCAH) and the remainder had FAE (Azziz et al., 2004). The vast majority of patients with FAE (82%) had PCOS, while only 5% of patients had IH, defined strictly. About 7% of patients had hirsutism and hyperandrogenaemia, with normal ovulation (Azziz et al., 2004). Examining the phenotypes of 654 consecutive untreated PCOS, about half had all three features (hirsutism, hyperandrogenaemia, and oligo-ovulation), onethird were oligo-ovulatory and hyperandrogenaemia, and the remainder had oligo-ovulation with hirsutism, but no detectable hyperandrogenaemia (Knochenhauer and Azziz, 2001). Initial analysis indicated that there was no difference in body mass index (BMI), waist-to-hip ratio (WHR), or glucose and insulin 645

3 ratio, and minimal difference in age between in these three PCOS phenotypes, suggesting that the phenotypes are very much related and probably manifestations of the same syndrome (Knochenhauer and Azziz, 2001). To study this further, family studies are currently being undertaken to determine the degree of heterogeneity of these phenotypes within families of patients who have PCOS. In 2003, an expert conference held in Rotterdam and sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) suggested new and broader criteria for PCOS, and to include the finding of polycystic ovaries on ultrasonography (Geisthovel, 2003; Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group, 2003). The meeting proceedings recommended that PCOS be defined when at least two of the following three features were present, after exclusion of other aetiologies: (i) oligo- or anovulation, (ii) clinical and/or biochemical hyperandrogenism, or (iii) polycystic ovaries. These newer criteria for PCOS give rise to new questions. For example, two new phenotypes of PCOS are defined, namely patients who have hirsutism and/or hyperandrogenaemia with polycystic ovaries, but who have normal ovulation, and women who have polycystic ovaries and irregular ovulation, but no sign of androgen excess. The key is, and will be in the future as more research into this area is carried out: are these phenotypes truly PCOS, or is the definition simply more expansive without being more exact? Limitations of PCOS definition There are a number of concerns regarding potential limitations of defining PCOS based on the features of hirsutism, hyperandrogenaemia, and ovulatory dysfunction. One of the principal limitations with using hirsutism as a clinical feature is the fact that the visual scale on which the degree of excess terminal hair growth is scored is subjective. In addition, hirsutism appears primarily to be a continuous psychosocial variable, with an unclear cut-off value. In addition, it is often the first symptom to be treated, so years of laser and electrolysis procedures diminish the ability to detect the presence of hirsutism. Hirsutism is also less prominent in adolescents and older women, as it develops with time and begins to regress as women age. Finally, it is much less prominent among Asian individuals (Carmina et al., 1992) (Figure 1). Consequently hirsutism cannot be considered a universal feature of PCOS, although over 80% of hirsute patients have PCOS. When androgen concentrations are used to define PCOS, a series of limitations must be kept in mind. Androgen concentrations fall very rapidly following hormonal suppression (Table 2), and may take an extended amount of time to return to normal after the medication has been discontinued. The laboratory methods currently used to detect androgen concentrations are often inaccurate or variable (Boots et al., 1998). There is also a wide variance of values in the normal population. The high degree of inter-subject variability in androgen concentrations is primarily due to the fact that androgens in women are not tightly regulated, such that there is no endocrine counter-regulatory mechanism controlling their concentrations, much as thyroid stimulating hormone normally reflects the circulating concentrations of free thyroxine, and vice versa. Finally, androgen concentrations are altered by many factors; for example concentrations of dehydroepiandrosterone are altered by age, and obesity alters the concentrations of SHBG and consequently free testosterone, variables that often are not considered in interpreting androgen values. Many investigators use menstrual dysfunction as a surrogate for oligo-ovulation. While there is little argument that, in the absence of anatomical defects of the uterine cavity, oligomenorrhoea reflects oligo-ovulation, the same cannot be said for the presence of regular menses. In hirsute women who report regular episodes of vaginal bleeding, ~40% may be oligo-ovulatory (Azziz et al., 1998; Carmina and Lobo, 1999). Therefore, a hirsute patient who affirms that she is experiencing regular periods is not necessarily making a reliable statement about her ovulatory function, and ovulatory function should be confirmed in these patients by measuring progesterone concentration days after the onset of vaginal bleeding in one or two consecutive cycles. The presence of premenstrual molimina (swelling, breast tenderness, mood changes) is helpful, but the sensitivity and specificity of these signs are in confirming normal ovulatory function is not clear. Table 1. Phenotypes of functional androgen excess (FAE). Reprinted with permission from Kahsar-Miller and Azziz (1999). Features Phenotypes A B C D E F G H Oligo-ovulation Y Y Y N N Y N N Hyperandrogenaemia Y Y N Y N N Y N Hirsutism Y N Y Y Y N N N PCOS ** IH Oligo NL? NL FAE Non-HA Oligo Normal 646 Y = yes; N = no; IH = idiopathic hirsutism; HA = hyperandrogenic; oligo = oligo-ovulation; NL = normal; FAE = functional androgen excess. No. of phenotypes possible = 2 n ; where n = no. of features considered. **Hirsutism + HA + normo-ovulation.

4 Figure 1. Prevalence of obesity, cystic ovaries and hirsutism in US Hispanic, Japanese, and Italian PCOS patients (modified from Carmina et al. (1992). Table 2. Prevalence of PCOS among mothers and sisters of PCOS patients, comparing relatives who were premenopausal and not on hormonal therapy with those who were either post-menopausal or were receiving hormonal therapy. This comparison illustrates one of the limitations of using androgen concentrations to define PCOS (adapted from Kahsar-Miller et al., 2001). Values in parentheses are percentages. Conclusion Pre-menopause/ Post-menopause/ Total untreated treated Mothers 13 (35) 6 (16) 19 (40) Sisters 14 (40) 2 (13) 16 (32) PCOS has proven to be a diagnostic challenge. Whereas useful research and diagnostic criteria for PCOS arose from a conference sponsored by the National Institutes of Health (NIH) in 1990, the presence of polycystic ovaries was not included in this definition, creating significant concern for many investigators. More recently, the proceedings from an expert meeting held in May 2003 in Rotterdam recommended that PCOS be defined when at least two of the following three features were present, after exclusion of other aetiologies: oligo- or anovulation, clinical and/or biochemical hyperandrogenism, or polycystic ovaries. However, these newer criteria effectively create additional phenotypes of PCOS (e.g. women with hyperandrogenism and polycystic ovaries but normal ovulatory function, and women with ovulatory dysfunction and polycystic ovaries but no clinical or biochemical evidence of hyperandrogenism). It remains to be demonstrated whether these phenotypes actually represent patients with PCOS. Furthermore, a number of limitations exist and must be accounted for when using the presence of hirsutism, hyperandrogenaemia, ovulatory dysfunction, or polycystic ovaries by ultrasonography to establish the PCOS phenotype. Nonetheless, the trend towards the use of uniform diagnostic criteria in studies of PCOS will increase the comparability and potentially the value of published research. References Adams J, Polson DW, Franks S 1986 Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. British Medical Journal 293, Asuncion M, Calvo RM, San Millan JL et al A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. Journal of Clinical Endocrinology and Metabolism 85, Azziz, R, Waggoner WT, Ochoa T et al Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama. Fertility and Sterility 70, Azziz,R, Ehrmann D, Legro RS et al Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. 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