Context: Polycystic ovary syndrome (PCOS) is defined most commonly according to the proceedings of an expert conference sponsored by the National Institutes of Health (NIH) in April 1990, which noted ...the disorder as having 1) hyperandrogenism and/or hyperandrogenemia, 2) oligoovulation, and 3) exclusion of known disorders. Alternatively, another expert conference held in Rotterdam in May 2003 defined PCOS, after the exclusion of related disorders, by two of the following three features: 1) oligo- or anovulation, 2) clinical and/or biochemical signs of hyperandrogenism, or 3) polycystic ovaries. In essence, the Rotterdam 2003 expanded the NIH 1990 definition creating two new phenotypes: 1) ovulatory women with polycystic ovaries and hyperandrogenism, and 2) oligoanovulatory women with polycystic ovaries, but without hyperandrogenism.
Objective: The objective of this study was to ascertain the validity of using the Rotterdam 2003 criteria rather than the NIH 1991 criteria for the diagnosis of PCOS.
Intervention(s): Interventions included the use of the Rotterdam 2003 criteria for diagnosing PCOS and, in particular, the proposal to define two new phenotypes as PCOS.
Positions: Available data suggest that hyperandrogenic ovulatory women with polycystic ovaries tend to have mild insulin resistance and mild evidence of ovarian dysfunction, although significantly less than women with anovulatory PCOS. However, whether these women will have an increased risk of infertility or metabolic complications, such as type 2 diabetes, remains to be determined. Alternatively, the risk of insulin resistance and long-term metabolic risks of oligoovulatory women with polycystic ovaries is even less well characterized and may be nonexistent.
Conclusions: Because of the paucity of data on the two new phenotypes and their long-term implications and the potential negative impact on research, clinical practice, and patient insurability, the adoption of the Rotterdam 2003 criteria for defining PCOS should be considered premature. However, because polycystic ovaries are a frequent feature of PCOS, a modification of the NIH 1990 criteria is proposed. Additional research characterizing the phenotypes and associated morbidities of PCOS is urgently required.
Polycystic ovary syndrome (PCOS) is a highly prevalent disorder effecting reproductive-aged women worldwide. This article addresses the evolution of the criteria used to diagnosis PCOS; reviews ...recent advances in the phenotypic approach, specifically in the context of the extended Rotterdam criteria; discusses limitations of the current criteria used to diagnosis, particularly when studying adolescents and women in the peri- and postmenopause; and describes significant strides made in understanding the epidemiology of PCOS. This review recognizes that although there is a high prevalence of PCOS, there is increased variability when using Rotterdam 2003 criteria, owing to limitations in population sampling and approaches used to define PCOS phenotypes. Last, we discuss the distribution of PCOS phenotypes, their morbidity, and the role that referral bias plays in the epidemiology of this syndrome.
To review all available data and recommend a definition for polycystic ovary syndrome (PCOS) based on published peer-reviewed data, whether already in use or not, to guide clinical diagnosis and ...future research.
Literature review and expert consensus.
Professional society.
None.
None.
A systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, to identify studies evaluating the epidemiology or phenotypic aspects of PCOS.
The Task Force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the Androgen Excess and PCOS (AE-PCOS) Society AE-PCOS Board of Directors. No section was finalized until all members were satisfied with the contents, and minority opinions noted. Statements were not included that were not supported by peer-reviewed evidence.
Based on the available data, it is the view of the AE-PCOS Society Task Force that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders. However, a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism, but recognized that more data are required before validating this supposition. Finally, the Task Force recognized and fully expects that the definition of this syndrome will evolve over time to incorporate new research findings.
Abstract
STUDY QUESTION
What are the best practices for undertaking epidemiologic and phenotypic studies in polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
Best practices for the undertaking of ...epidemiologic and phenotypic studies in PCOS are outlined.
WHAT IS KNOWN ALREADY
Currently methodologies used for studies of PCOS epidemiology and phenotypes vary widely, and the comparability of studies is low, reducing the ability to harmonize studies.
STUDY DESIGN, SIZE, DURATION
The Androgen Excess and PCOS (AE-PCOS) Society established a Task Force to draft a research resource for epidemiologic and phenotypic studies in PCOS, with the aim of providing guidelines on study design and execution, insights into the limitations and alternatives and protocols to be used, taking into consideration a global perspective.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A targeted review of the literature was carried out as necessary.
MAIN RESULTS AND THE ROLE OF CHANCE
High level recommendations include the following:
(i) Before initiating the study, a number of critical factors should be addressed including selecting the population and diagnostic criteria (which should ideally align with the recommendations of the International Guidelines), the type of observational study to be undertaken and the primary and secondary endpoint(s) of the study.(ii) To assess the ‘natural’ or true phenotype and epidemiology of PCOS, the least medically biased, broadest and most generalizable population, and the broadest definition of PCOS, should be used.(iii) Four PCOS phenotypes (Phenotypes A through D), based on the presence or absence of three general features (oligo-anovulation, hyperandrogenism and polycystic ovarian morphology), should be ascertained.(iv) In epidemiologic and phenotypic studies, the detection of PCOS rests on the accuracy and sensitivity of the methods used for assessing the individual features of the disorder, and how ‘normal’ is defined.(v) Although an assessment algorithm that minimizes the use of certain measures (e.g. androgen levels and/or ovarian ultrasonography) can be devised, when possible it is preferable to uniformly assess all subjects for all parameters of interest.
(vi) The inclusion of subjects in epidemiologic studies who do not appear to have PCOS (i.e. ‘non-PCOS’) will provide the necessary cohort to establish population-specific normative ranges for the various features of PCOS.
(vii) Epidemiologic studies of PCOS in unselected populations will yield relatively limited numbers of PCOS subjects available for genetic study; alternatively, large population-based epidemiologic studies of PCOS will potentially generate large numbers of unaffected individuals that may serve as genetic controls.
(viii) Epidemiologic studies of PCOS will benefit from a clear governance structure and should begin by informing, educating and engaging both the formal and informal leaders of the populations targeted for study.
(ix) In designing their study investigators should, in advance, establish statistical power and recognize, manage and account for inherent biases.
(x) Subjects suspected of having PCOS but who do not/cannot complete their evaluation (i.e. have ‘possible PCOS’) can be included by imputation, assigning them a ‘diagnostic weight’ based on those subjects of similar clinical phenotype that have completed the study.
(xi) In obtaining, storing and retrieving subject data, subjects should be assessed consecutively using a uniform data collection form; providing as complete and in depth data as possible.
(xii) Maintenance of both paper and electronic medical records should focus on ensuring data quality, accuracy and institutional ethical compliance, and familiarity with country-dependent laws, including biobanking-specific laws, tissue laws and research laws.
(xiii) In obtaining and biobanking study samples, these should be ideally collected at the time of the first assessment.
(xiv) Access to stored data sets should ideally be granted to other bona fide researchers conducting research in the public interest.
(xv) SOPs detailing the exact method of each of the activities for handling the data and the samples are necessary to ensure that all methods are performed uniformly.
(xvi) Epidemiologic studies of PCOS must be resourced adequately.
LIMITATIONS, REASONS FOR CAUTION
As with all reports involving expert interpretation of experiential and published data, inherent individual biases are possible. This risk is minimized in the present study by including experts from varying fields of study, aligning with recent international evidence-based guidelines and obtaining consensus approval of the recommendations from the Task Force and the board of the AE-PCOS.
WIDER IMPLICATIONS OF THE FINDINGS
These guidelines should encourage investigators worldwide to undertake much needed epidemiologic studies of PCOS, increasing the validity, integrity and comparability of the data.
STUDY FUNDING/COMPETING INTEREST(S)
The study received no funding. R.A. serves as consultant for Medtronic, Spruce Biosciences and Ansh Labs; has received research funding from Ferring Pharmaceuticals; and is on the advisory board of Martin Imaging; R.L. has received research funding from MSD Pharmaceuticals; J.L. has received fees and/or grant support from the Dutch Heart Association, The Netherlands Organisation for Health Research and Development (ZonMw), Ferring Pharmaceuticals, Danone, Euroscreen/Ogeda and Titus Health Care; H.T. receives grant funding from the National Health and Medical Research Council; K.K., L.M.-P., S.S.M. and B.O.Y. have no potential conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A
The polycystic ovary syndrome (PCOS) is recognized as one of the most common endocrine abnormalities of humans, with global prevalences so far generally 5%-15%. Overall, the disorder appears to be an ...ancient complex genetic trait, perhaps dating at least 50,000 years ago. The phenotype of PCOS can be subdivided into four different types. Phenotype A and B (hyperandrogenism + ovulatory dysfunction, with A and without B polycystic ovarian morphology PCOM, respectively) can be considered to represent the "classic" form of the disorder. Phenotype C is the so-called "ovulatory" PCOS (hyperandrogenism + PCOM only). And phenotype D is often referred to as "nonhyperandrogenic" PCOS (ovulatory dysfunction + PCOM only). The different phenotypes vary in the degree to which they are associated with an increased risk for metabolic dysfunction and reproductive complications. There are a number of determinants of the epidemiology (prevalence) and presentation (phenotype) of PCOS, including environmental (e.g., socioeconomic, geographic, toxicologic, life-style, and dietary) and genetic (e.g., gene variants, epigenetic, and race/ethnicity) factors. Finally a better understanding of the evolutionary determinants of PCOS has the potential for providing additional insight into those factors determining the etiology, prevalence, and persistence of a disorder that appears to be, superficially at least, an evolutionary paradox.
To compare the prevalence of polycystic ovary syndrome (PCOS) phenotypes and obesity among patients detected in referral versus unselected populations.
Systematic review and meta-analysis.
Not ...applicable.
Thirteen thousand seven hundred ninety-six reproductive-age patients with PCOS, as defined by the extended Rotterdam 2003 criteria.
Review of PUBMED, EMBASE, and Cochrane Library, 2003-2016. Only observational studies were included. Data were extracted using a web-based, piloted form and combined for meta-analysis.
PCOS phenotypes were classified as follows: phenotype A, clinical and/or biochemical hyperandrogenism (HA) + oligo-/anovulation (OA) + polycystic ovarian morphology (PCOM); phenotype B, HA+OA; phenotype C, HA+PCOM; and phenotype D, OA+PCOM.
Forty-one eligible studies, reporting on 43 populations, were identified. Pooled estimates of detected PCOS phenotype prevalence were consequently documented in referral versus unselected populations, as 1 phenotype A, 50% (95% confidence interval CI, 46%-54%) versus 19% (95% CI, 13%-27%); 2 phenotype B, 13% (95% CI, 11%-17%) versus 25% (95% CI, 15%-37%); 3 phenotype C, 14% (95% CI, 12%-16%) versus 34% (95% CI, 25-46%); and 4 phenotype D, 17% (95% CI, 13%-22%) versus 19% (95% CI, 14%-25%). Differences between referral and unselected populations were statistically significant for phenotypes A, B, and C. Referral PCOS subjects had a greater mean body mass index (BMI) than local controls, a difference that was not apparent in unselected PCOS.
The prevalence of more complete phenotypes in PCOS and mean BMI were higher in subjects identified in referral versus unselected populations, suggesting the presence of significant referral bias.
Stein and Leventhal: 80 years on Azziz, Ricardo, MD, MPH, MBA; Adashi, Eli Y., MD, MS
American journal of obstetrics and gynecology,
02/2016, Volume:
214, Issue:
2
Journal Article
Peer reviewed
Eighty years ago a publication in the Journal proved to be seminal and transformative. The report by Irving Freiler Stein and Michael Leventhal titled, “Amenorrhea associated with polycystic ...ovaries,” has proven to be a remarkably lasting and influential publication. The growth in related literature has been increasing exponentially: the 50 years between 1950 and 2000 saw a little more than 8000 publications on the topic, whereas the 15 year period between 2001 and 2015 (so far) has seen more than 20,000 related publications, a greater than 8-fold increase in the publication rate after 2000. As we commemorate the 80th anniversary year of the publication of the report by Stein and Leventhal, it is important to ask ourselves, “Was this publication truly as seminal as it is generally assumed to be? And why did it gain such a strong foothold on the medical psyche?” To the first question, a review of the antecedent medical literature makes it clear that the report of Drs Stein and Leventhal in 1935, although not flawless, was both seminal and transformative. In fact, it was the first report to describe a series of patients, rather than isolated cases, who demonstrated the triad of polycystic ovaries, hirsutism, and oligo/amenorrhea, connecting what had previously been disparate features of polycystic ovaries and menorrhagia, and hirsutism and oligo/amenorrhea. Second, the facts that Dr Stein and his collaborators were relatively prolific writers, consistent and clear in their message and descriptions; that a possible therapy (bilateral ovarian wedge resection) had been conveniently included in the report; and that the disorder was (is) relatively prevalent, permitted what would eventually be called the Stein-Leventhal syndrome to gain a strong foothold in contemporary medical practice. Overall, we in the field of medicine have much to celebrate, as we commemorate the 80th anniversary of the publication of the report by Stein and Leventhal in 1935, for a new disorder was described, one that we know today affects, in its various forms, 1 in every 7-17 women worldwide.
Objective: We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH).
Participants: The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines ...Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration.
Consensus Process: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society’s CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.
Conclusions: We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing’s syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients’ quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.
Presented is The Endocrine Society Guideline for the evaluation and management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Polycystic ovary syndrome (PCOS) is a prehistoric complex genetic trait, perhaps dating back at least 50,000 years. The disorder also represents an evolutionary paradox, demonstrating clear ...reproductive disadvantages (i.e., lack of evolutionary fitness), albeit persisting tens of thousands of years. Here we examine possible explanations for this paradox. We evaluate a variety of possible benefits accruing to women in ancestral populations who possessed this trait, including considerations of whether dramatic changes in environment and lifestyle from the ancestral past to the contemporary present have altered the selection dynamics operating on the trait. Putative benefits include metabolic functioning, immune system dynamics, patterns of child-rearing and mothering, reproductive longevity, in utero or childhood survival, and musculoskeletal advantages. However, there is limited evidence that the persistence and relative homogeneity in the prevalence of PCOS can be accounted for by direct positive selection. Rather, PCOS evolution has likely been driven by nonadaptive evolutionary mechanisms, including genetic drift due to a serial founder effect and population balance due to sexually antagonistic selection. Ultimately, insights into the evolutionary origins of PCOS will emerge through the study not only of unique characteristics of affected individuals and their environments butalso through a broad consideration of the potential adaptive and beneficial aspects of vulnerability to the disorder, importantly including examination of populations whose fertility, disease load, and diet resemble those of ancestral humans.
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