Gynecological Endocrinology ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: https://www.tandfonline.com/loi/igye20 The pressing need for standardization in epidemiologic studies of PCOS across the globe Michael Ntumy, Ernest Maya, Daria Lizneva, Richard Adanu & Ricardo Azziz To cite this article: Michael Ntumy, Ernest Maya, Daria Lizneva, Richard Adanu & Ricardo Azziz (2019) The pressing need for standardization in epidemiologic studies of PCOS across the globe, Gynecological Endocrinology, 35:1, 1-3, DOI: 10.1080/09513590.2018.1488958 To link to this article: https://doi.org/10.1080/09513590.2018.1488958 Published online: 16 Jan 2019. Submit your article to this journal Article views: 380 View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=igye20 GYNECOLOGICAL ENDOCRINOLOGY 2019, VOL. 35, NO. 1, 1–3 https://doi.org/10.1080/09513590.2018.1488958 PCOS EPIDEMIOLOGY The pressing need for standardization in epidemiologic studies of PCOS across the globe Michael Ntumya, Ernest Mayab, Daria Liznevac, Richard Adanub and Ricardo Azzizd,e,f aDepartment of Obstetrics and Gynaecology, School of Medicine and Dentistry College of Health Sciences, University of Ghana, Accra, Ghana;; bSchool of Public Health College of Health Sciences, University of Ghana, Accra, Ghana; cDepartment of Medicine Division of Endocrinology Diabetes and Bone Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA; dDepartment of Obstetrics and Gynecology Medical College of Georgia, Augusta University, Augusta, GA, USA; eDepartment of Health Policy, Management, and Behavior School of Public Health, University at Albany, SUNY Rensselaer, NY, USA; fDepartment of Obstetrics and Gynecology, Albany Medical College, Albany, NY, USA ABSTRACT ARTICLE HISTORY The polycystic ovary syndrome (PCOS) is a common and important complex endocrine metabolic disorder Received 23 May 2018 affecting women mainly in the reproductive age. The prevalence of the disorder varies depending on the Accepted 12 June 2018 epidemiologic design and criterion used to study the disease. This variation in methodology and subse- Published online 15 January quent effect on epidemiologic estimate makes it difficult to compare prevalences and phenotypes across 2019 geographical areas and assess the effect of cultural and racial variations on PCOS phenotypes. Overall, KEYWORDS there is an urgent need for a globally accepted standardized protocol for epidemiologic studies of PCOS, PCOS; epidemiology; which will maximize the comparability of studies around the globe. To address this issue the Androgen prevalence; hirsutism; Excess and PCOS Society, Inc. has designated an expert Task Force to draft recommendations to guide androgen excess epidemiologic research worldwide. Once completed, the use of such recommendations will enable epi- demiologists to the effects of geographical and cultural variations of PCOS prevalence and assist in deter- mining the phenotype–genotype associations in the disorder. Further, it will assist in developing informed, and thus effective, public health policy. In essence, the need to standardize epidemiologic stud- ies across the globe is pressing and urgent. Introduction PCOS prevalence is affected by variations in methodology and research design Polycystic ovarian syndrome (PCOS) is a common endocrine meta- bolic complex genetic trait affecting women and is most apparent Globally, the reported prevalence of PCOS varies from 5% to in the reproductive age. The syndrome is characterized by chronic 20% in various studies, depending on which diagnostic criterion oligo-anovulation (OA), biochemical and/or clinical hyperandro- was used (or more precisely which phenotypes were included, genism (HA) and polycystic ovarian morphology (PCOM). PCOS see below), how the study population was identified, the methods impacts negatively reproductive function (infertility, recurrent preg- used to define each feature of the criterion, how complete were nancy loss, etc.) and predisposes to adverse obstetric outcomes, the phenotypic assessments, and the recruitment process of the such as gestational diabetes mellitus, pre-eclampsia, fetal macroso- study population [1]. Of note, most if not all studies of PCOS mia, and perinatal morbidity and mortality. There is also a direct prevalence are from North America, Europe, the Middle East, link between PCOS and endometria carcinoma, type-II diabetes Southern Asia, and Australia; there is no significant data as of mellitus (T2DM), and several other metabolic disorders and pos- yet from South America, Russia (i.e. Northern Asia), the island sibly cardiovascular disease in later years. Dyslipidemia is more countries of Oceania (Melanesia, Micronesia, and Polynesia) and common in women with PCOS, with patients demonstrating higher Africa [2]. In fact, our group is working to address the paucity levels of low-density lipoprotein (LDL)-cholesterol and triglycer- of data arising from the African continent. These variances in ides, and lower levels of high-density lipoprotein (HDL)-cholesterol methodology create great degree of uncertainty around preva- compared with women without the disorder. lence and phenotype of PCOS, hampering the comparability of While PCOS is most obvious clinically in reproductive age studies; the interpretation of genetic analyses; the ability to detect women, emerging evidence suggests that prepubertal girls and the impact of race/ethnicity, environment, socioeconomics, and postmenopausal women may also have related symptoms. diet and nutrition, among other factors; the estimation of eco- Postmenopausal women are at increased risk of T2DM and pos- nomic burden; and the development of informed and effective sibly cardio-metabolic complications though symptoms attribut- public health policy. able to excess androgen may improve or even disappear. PCOS Where it has been studied so far, the prevalence of the disease in children may manifest as premature pubarche while menstrual has been fairly constant at 5–9% in most parts of the world irregularity and clinical evidence of hyperandrogenemia may be when using the stricter 1990 NIH Criterion, which includes two the main signs and symptoms in the adolescent group. of the PCOS phenotypes (Phenotype A: OAþHAþPCOM and CONTACT Ricardo Azziz Ricardo.azziz@suny.edu Office of Academic Health and Hospital Affairs, The State University of New York System Administration, State University Plaza, S-423, Albany, NY 12246, USA  2019 Informa UK Limited, trading as Taylor & Francis Group 2 M. NTUMY ET AL. Phenotype B: OAþHA) [1]. When the 2006 Androgen Excess & visual scale, the modified Ferriman-Gallwey (mFG) score [2]. PCOS (AE-PCOS) society diagnostic criterion is used (which, in Less certain is the exact cutoff value to use. In White or Black addition to Phenotypes A and B, includes Phenotype C, i.e. women, hirsutism has been defined by a value of 6–8 or greater, HAþPCOM) prevalence rates for PCOS of 10–15% are representing the 95th percentile of the populations studied. reported. The use of the European Society for Human However, a question we should ask is why is a biological vari- Reproduction and Embryology (ESHRE)/American Society for able such as hirsutism being determined by a strict percentile? A Reproductive Medicine (ASRM) definition, more commonly measure that indicates that 5% of women studied are ‘abnormal’ known as the 2003 Rotterdam Criteria (which in addition to and the rest are not. Implying that, by definition, one in every PCOS Phenotypes A, B and C, includes Phenotype D, i.e. 20 women has hirsutism. The use of this percentile stems per- OAþPCOM), increased the reported prevalence rate for the dis- haps from confusion between what we commonly use as an order to as high as 20% in some studies. We should note that acceptable degree of statistical error (i.e. 5% or a p< .05) and phenotypically Rotterdam 2003 and AE-PCOS Society 2006 defi- what should be defined as ‘abnormal’. Or perhaps it stems from nitions are effectively expansions of the NIH 1990 criterion. an assumption that hirsutism follows a normal Gaussian curve Regardless, the diagnostic criterion chosen affects the prevalence distribution (which it does not) where mean plus two standard of the disorder observed. deviations encompasses 95% of all measures –but which actually How the study population is identified plays an important would mean that ‘abnormal’ on the high side would be defined role in determining prevalence. For example, the phenotype of as the upper 2.5%. As if we would define ‘abnormal’ fasting glu- the disorder observed in a population is under significant referral cose. Blood pressure, cholesterolemia, or body mass using per- bias and there is evidence that PCOS phenotype identified in centiles . clinical (referred) cohorts disproportionately represent for more In a large study of unselected black and white women we severe forms of the disorder compared with the phenotypes iden- used cluster analysis and associated symptom to define tified from studies of medically unselected populations. For ‘abnormal’, which our data indicated to be a cutoff value of 3 or example, Ezeh et al compared two cohorts from the same geo- more [4]. A study in Han Chinese women found a comparable graphical area, the first consisting of cases seeking medical care cutoff value using a similar approach [5]. So should we define and the second consisting of patients identified through a rou- hirsutism by an mFG score value greater than 3? Or 6 or 8 (or tine pre-employment medical screening [3]. They found that 10, as some investigators prefer to use)? Obviously, the number referred cases had a higher prevalence of the more complete of women detected as having clinical HA will vary according to PCOS phenotypes (phenotype A), were more hirsute, had higher cutoff (the lower the cutoff the more subjects will be discovered). serum androgen levels and were more obese compared with the And even more difficult may be defining HA biochemically. medically unselected cohort. This bias, at least in part is drive by Should we assess total Testosterone (T), free T, DHEA, andro- the negative impact of the disorder on quality of life, principally stenedione (A4), dihydrotestosterone (DHT)? Others? One, some around obesity and features of HA and ability to access medical or all? Evaluating a cohort of PCOS patients diagnosed by the care [3]. A subsequent meta-analysis of all published studies NIH 1990 criterion, total T alone (using a high-quality assay) demonstrated the same results [2]. Thus populations used to detected some 33% of patients, the addition of free T measures study the prevalence of PCOS should be medically unselected as increased the detection rate to 60%, and the addition of DHEA possible. These may include the study of randomly selected and A4 increased the detection rate by approximately 7–10% women from community-based cohorts or, less optimally, each. And speaking of androgen measures, the quality of assays women undergoing an assessment for non-medical reasons. vary widely. Total T is the mainstay of androgen measures in women, alone and in the estimation of free T and the standard for total T assay is either a high quality radio-immunoassay fol- Methodologic issues in defining each feature of the criterion lowing sample extraction and column chromatography or, better The methods used to define each feature of the criterion are crit- still, mass spectrometry. Yet the quality of total T varies widely ical in ensuring the complete detection of the disorder. How OA, in studies of PCOS and many investigators use total T (generally HA and PCOM is defined will play a significant role in deter- alone) measured by direct platform immunoassays. In fact, mining the prevalence of PCOS observed. For example, should Lizneva and colleagues observed in their meta-analysis that the OA be defined by the menstrual dysfunction only? Should the weakest areas of reporting were related to insensitive androgen degree of oligomenorrhea be defined as cycles (vaginal bleeding measures [2]. So which assays and hormones or prehormones episodes) at greater than 35 day intervals, or 45 day intervals should be assessed in detecting PCOS? And as androgens change (equivalent to 8 or less cycles per year)? Using older epidemio- with age should age-related cutoff values be used? logic data, it seems that cycles >35 days in length are abnormal, Finally, while PCOS is usually detected by ultrasonography, which is equivalent to 10 or less cycles per year. However, many what exact cutoffs should be used? The Rotterdam criterion studies use <8 cycles per year as the definition of oligomenor- defined PCOS by an ovarian volume of 10 cm2 (ml) and/or an rhea, equivalent to cycles >45 days in length. Furthermore, some antral follicle (reflected by cysts 2–9mm in diameter) count of the OA may not be detected by overt menstrual dysfunction, (AFC) of 12 or more (Rotterdam, 2004). Finding in one ovary and may present as polymenorrhea or eumenorrhea. These suffices. However, as technology has improved, the ability to oligo-ovulatory patients can be detected only if their late luteal detect small follicles has increased. So it is likely that AFC of 12 (day 22–24) progesterone levels are assessed. is too low, and investigators have suggested that AFCs of 18–22 Even more controversy exists around the definition of HA. should be used as the lower limit for the diagnosis of PCOS [6]. Clinically HA is often defined by the presence of hirsutism, but Alternatively, ovarian volume does not seem to change much how does the presence of acne and androgenic alopecia fit in to with improved transvaginal probe frequency. And what about the definition? And how is hirsutism defined? Today the most those patients in whom a transvaginal approach cannot be used? common method of detecting hirsutism is through the assess- And does age matter? Some investigators have used similar ment of terminal hair growth in male-like body areas using a methods (i.e. cluster analysis) to identify women with ‘abnormal’ GYNECOLOGICAL ENDOCRINOLOGY 3 ovarian morphology as has been used for determining ‘abnormal’ studies around the globe. To address this issue the Androgen facial or body terminal hair growth or androgen levels in the cir- Excess & PCOS Society, Inc. has designated an expert Task culation [6]. Force to draft recommendations to guide epidemiologic research And not only do epidemiologic studies of PCOS suffer from worldwide. Once completed, the use of such recommendations the use of different criteria, different recruitment schemes, and will enable epidemiologists to the effects of geographical and cul- even more variability in phenotyping, but the diagnostic scheme tural variations of PCOS prevalence, and assist in determining for PCOS itself advocates against a complete assessment of these the phenotype–genotype associations in the disorder. Further, it subjects. ‘Healthy controls’ in a population are often diagnosed will assist in developing informed, and thus effective, public simply by the absence of a history of irregular menstruation and health policy. In essence, the need to standardize epidemiologic medical problems, and the absence of clinical signs of HA on studies across the globe is pressing and urgent. physical exam. Alternatively, diagnosing a woman with PCOS requires many more tests. It requires that subjects undergo blood testing to exclude thyroid dysfunction and hyperprolactinemia, Disclosure statement and 17-hydroxyprogesterone to exclude 21-hydroxylase deficient nonclassic adrenal hyperplasia. It may even require additional R. A. consults for Ansh Labs, Longitude Capital, Spruce Biosciences, tests to exclude Cushing’s syndrome, congenital adrenal hyper- and Medtronics. He serves on the advisory board of Martin PET plasia, or androgen-secreting neoplasms. As mentioned, full phe- Imaging. No potential conflicts of interest was reported for any of notyping may also require measurement of luteal progesterone the remaining authors. levels and/or transvaginal ultrasonography. Hence, there is a much higher likelihood that subjects with PCOS will not be less willing to complete their evaluation, which may take multiple References visits and invasive tests, than controls, yielding many more [1] Bozdag G, Mumusoglu S, Zengin D, et al. The prevalence and pheno- ‘incompletely assessed’ subjects with PCOS than controls (and typic features of polycystic ovary syndrome: a systematic review and consequently biasing against the PCOS diagnosis). For example, meta-analysis. Hum Reprod. 2016;31:2841–2855. in a large population-based study of medically unselected women [2] Lizneva D, Kirubakaran R, Mykhalchenko K, et al. Phenotypes and body mass in women with PCOS identified in clinical vs. unselected of reproductive age in Tehran, Iran, Tehrani et al reported that, populations: systematic review and meta-analysis. Fertil Steril. 2016; more than a third of their cases would have been undiagnosed 106:1510–1520. or misdiagnosed had they not assessed the participants for sub- [3] Ezeh U, Yildiz BO, Azziz R. Referral bias in defining the phenotype clinical menstrual dysfunction or biochemical hyperandrogenism and prevalence of obesity in polycystic ovary syndrome. J Clin [7]. We have addressed this evaluation bias by including all sub- Endocrinol Metab. 2013;98:E1088–E1096. jects in our analysis, whether completely or incompletely eval- [4] deUgarte CM, Bartolucci AA, Woods KS, Azziz R. Distribution of facial and body terminal hair in unselected black and white women: uated, and assigning those women who were incompletely Towards a populational definition of hirsutism. J Clin Endocrinol evaluated a ‘weight’ for the diagnosis of PCOS based on the Metab. 2006;91:1345–1350. results in similarly phenotyped individuals who were completely [5] Zhao X, Ni R, Li L, et al. Defining hirsutism in Chinese women: a assessed [8]. cross-sectional study. Fertil Steril. 2011;96:792–796. [6] Dewailly D, Alebi M, Duhamel A, Stojanovi N. Using cluster analysis to identify a homogeneous subpopulation of women with polycystic Conclusions ovarian morphology in a population of non-hyperandrogenic women with regular menstrual cycles. Hum Reprod. 2014;29:2536–2543. Overall, these issues strongly indicate that epidemiologic studies [7] Tehrani FR, Simbar M, Tohidi M, et al. The prevalence of polycystic of PCOS worldwide vary greatly in methodology and outcome, ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol. 2011;9:39. and comparisons can only be inferred. Overall, there is an urgent [8] Azziz R, Yildiz B, Woods KS, et al. The prevalence of polycystic need for a globally accepted standardized protocol for epidemio- ovary syndrome among unselected consecutive premenopausal logic studies of PCOS, which will maximize the comparability of women. J Clin Endocrinol Metab. 2004;89:2745–2749.