Re: Manuscript number: Polycystic ovary syndrome controversy: are expanding disease definitions unnecessarily labelling women with PCOS?

Transcription

1 Friday, 26 May 2017 Helen Macdonald, Clinical Editor. British Medical Journal Re: Manuscript number: Polycystic ovary syndrome controversy: are expanding disease definitions unnecessarily labelling women with PCOS? Dear Dr Helen Macdonald, Thank you very much for the opportunity to resubmit our paper to the BMJ. We have read the comments of the reviewers and editors with great interest, and have revised our paper in light of the reviewers comments and the relevant editorial points. We have addressed each of the reviewer s and editor s comments, and provide full details of our response below. Reviewer An excellent review. It reflects opinion that I have long held on which my clinical practice has been based. I might take the review further and ask if PCOS reflects an abnormality or a variation of normal? The pathologists that analysed the ovaries that Stein provided could find no diagnostic morphological features and I think that this view remains. There is no evidence that the eggs that result from the PCO have a reduced potential for normal fertility once ovulated. There is a variation in the number of primordial follicles laid down in the ovary in fetal life (there may be a genetic basis for this). I argue that women with PCO simply have more than average. Based on the gonadostat theory, this results in the typical fixed setting of the pituitary ovarian axis (1,2). Each follicle produces androgens so with more follicles this results in higher systemic androgen concentrations. RESPONSE: Thank you for taking the time to review our paper. We agree that PCOS is on a continuum of normality, particularly as symptoms improve in the peri-menopausal phase, even in women with severe symptoms and the classic phenotypes. Due to word restraints, we have not expanded on this in the main manuscript but have added in a sentence in Table 4 (How to communicate to women about PCOS to increase transparent conversation) to acknowledge that although assistance may be needed for ovulation, women with PCO do not have reduced fertility: Increased ovarian reserve associated with PCOS is an indicator of high fertility, and is an important positive message that can be communicated to women. See page 10, Table 4 of the revised paper. 1.2 In relation to the metabolic changes, our research suggested that the insulin impairment was likely to be the consequence not the cause of anovulation and thus not specific to PCOS. ( ) Weight reduction in all cases is essential but obesity in PCOS is due to overeating (not hormones). The metabolic

2 consequences of obesity are generic. RESPONSE: Thank you for highlighting this debate in the literature. Insulin impairment may be the result of anovulation and thus not specific to PCOS, research finding that ovulation reduces insulin resistance in women with PCOS (Marsden et al., 1999). However, insulin has been found to increase androgen synthesis in the theca cells and result in impaired follicle growth (Franks et al., 2006). Regarding obesity, a meta-analysis found that women with PCOS are at an increased risk of IGT, type 2 DM and Metasyn, independent of weight (Moran et al., 2010), however the relationship with PCOS and obesity is unclear. We agree that women who are overweight should be given lifestyle advice, irrespective of whether they have PCOS or not. Given the mixed findings and limited word space, we have decided not to elude to this further in the manuscript Hirsutism is partly due to the genetics of the hair follicle (racial variation) but is often underestimated. Not much is worse for a 16 year old girl than having to shave twice daily? This review says little about the psychological consequences or management of hirsutism. RESPONSE: Thank you for highlighting this important issue. We have added a sentence to the manuscript acknowledging the impact of hirsutism on psychological wellbeing (see page 8 of revised paper): A recent meta-analysis found that reduced psychological wellbeing in women with PCOS is weakly associated with symptoms that are particularly distressing, such as hirsutism (Cooney et al., 2017) The medical career benefits of creating a disease syndrome PCOS are clear (me too in the past). But the psychological consequences of creating a disease, from the patient perspective, and giving that label to the woman can be devastating. ( PCOS = fat, hairy, spotty, can t have babies and likely to get diabetes ). Consequently, I tell women that they do not have bad ovaries but that they have super-ovaries. Their ovaries are too good, contain lots of eggs, and that has made their hormone regulation out of balance. Turning women from the Bearded circus lady into Superwoman at least gives a better chance that they will respond to symptomatic treatment. I would support a stronger reference to this under Harms for over diagnosis. RESPONSE: Thank you for sharing your clinical experience regarding communication of what it means to have PCOS. We agree that labelling women with PCOS can be highly distressing. We have added a sentence about how PCOS is a profoundly stigmatising condition (page 8): Qualitative research also emphasises that PCOS is a deeply stigmatising condition, and added in the results of a recent study examining the impact of the PCOS label, which found that those who were given the label PCOS in a hypothetical scenario had lower self-esteem, higher perceived severity of their hypothetical condition and higher interest in further medical investigation (page 8): A recent study found that

3 when given the PCOS disease label in a hypothetical scenario, young women had higher intention to have an ultrasound, perceived their condition to be more severe and lower self-esteem than women not given the disease label (Copp et al., 2017). We have also added a point in Table 4 (How to communicate to women about PCOS to increase transparent conversations) about how women with PCOS have increased ovarian reserve, as estimated by ultrasound and AMH levels, which healthcare providers can review positively with women (page 10): Increased ovarian reserve associated with PCOS is an indicator of high fertility, and is an important positive message that can be communicated to women. Reviewer This paper is well-written and describes the current state of knowledge surrounding PCOS diagnosis. Specifically, the authors provide an overview and definition of PCOS as a condition, concerns for over diagnosis and potential harms, and recommendations for future work to improve PCOS diagnosis and associated conditions. The latter incorporated both clinical and research suggestions for improving approaches to PCOS. While the paper is wellorganized and informative, I had several major concerns and minor comments: The authors call for more research on a number of PCOS-related issues ranging from long-term follow-up to increased work in adolescents and under-diagnosed populations. However, they do not offer plausible options for research in the area. Of particular concern is that these types of research efforts may require classifications similar to what the authors argue against clinically. I would encourage the authors to separate their research recommendations from their clinical recommendations. In research, schemas are typically needed to identify groups in order to analyze data. Could authors say more about how this work could be done, in the context of issues raised? RESPONSE: Thank you for your comments on our paper and for highlighting this important issue in the manuscript. We have removed specific recommendations about more research in adolescent populations, as we recommend delaying diagnosis of PCOS during adolescence and treating the individual manifestations of PCOS without the label, as there is evidence that treating the individual manifestations of PCOS (without the label) adequately targets the underlying metabolic and reproductive changes associated with PCOS (Morris et al., 2015). We have now also separated the research recommendations from the clinical recommendations in the How to move forward section (see page 9 of the revised paper) While well-organized, could the authors consider grouping the recommendations instead of integrating them throughout the manuscript? Alternatively, they could provide a summary from both a clinical and a research

4 perspective toward the end of the manuscript. RESPONSE: Thank you for this suggestion. The formatting of the paper has now been reordered. All recommendations are grouped in the How to move forward section (page 9), rather than integrated throughout the manuscript. We hope the recommendations are now clearer Why do the authors use populations based in China for both of their illustrations? Is it possible these are lower-risk populations? Might there be alternative data sources that could provide more insight into higher-risk and medium-risk populations for PCOS? RESPONSE: We have only been able to find three studies that examined PCOS prevalence by age group (the one in China, one in Denmark and another in Iran). The study in Denmark examined PCOS prevalence by diagnostic criteria and age, and found that prevalence decreases with age: for women under 30 years, prevalence was 33.3%, women aged years was 14.7%, and women aged 35 and over was 10.2% (Lauritsen et al., 2014). Likewise, the crosssectional study in Iran found that prevalence of PCOS was 26.7% for women under 25 years, 14.7% for women aged years, and 7.5% for women aged years (Tehrani et al., 2014). We have now added in both these studies, along with the Chinese study under the subheading Diagnosis during young adulthood (see page 6 of revised paper): Three studies in different populations examining PCOS prevalence by age found that prevalence rapidly decreased after 25 years of age, suggesting that the symptoms and signs of PCOS may be transitory for many women (Zhuang et al., 2014; Tehrani et al., 2014; Lauritsen et al., 2014). We have also removed Figure 1, as we believe that Figure 2 using the Chinese data (now Figure 1 in revised paper) is more appropriate in communicating this age-related trend (page 7) Would the authors consider using "physician-diagnosis" instead of the term "label" throughout the manuscript? RESPONSE: Thank you for your suggestion. Although physician-diagnosis may be more precise, we would prefer to keep the term label so that the paper aligns with the current body of literature regarding the disease labelling effect. No changes have been made to the manuscript in this regard Page 3, lines 36-38: awkward revision needed RESPONSE: This paragraph has since been altered by the editor Either Figure 1 is mislabeled or is missing from the version of the manuscript that I have. RESPONSE: Thank you for notifying us of this error, the one remaining figure is now appropriately labelled with the correct reference in the text (see Figure 1,

5 page 7 of revised paper) On page 6, line 30: change second occurrence of reduce to decrease RESPONSE: We have now changed the sentence to say (page 4): The diagnosis may also enable medication, such as oral contraceptive pills to regulate menstrual cycle, decrease hirsutism and reduce the risk of endometrial cancer, or metformin to improve insulin sensitivity and potentially decrease risk of impaired glucose tolerance (IGT) and diabetes On page 7, line 5: is scepticism the appropriate spelling for skepticism RESPONSE: Thank you for highlighting this mistake. This subheading has now been removed due to suggested edits from the editor On page 7, line 48, cofounders should be confounders RESPONSE: Thank you for finding this error. In align with suggestions from the editor, this sentence has since been removed due to repetition with the way forward section (page 9) On page 9, line 22: "women" should be "woman" RESPONSE: Thank you for finding this mistake. We have changed it to woman (page 9). Editor Comments E.1. Needs fully formatting for the series i.e. putting under the headings. RESPONSE: Thank you very much for your help with reformatting the paper under the correct headings. We agree with your suggested formatting and changes, and have added in the missing headings and revised the paper to fit with the required template. E.2. A stronger steer in the evidence of OD section on whether there is evidence of rising diagnosis over time coupled with static or falling adverse outcomes which has often been the hallmark of this series. In this case I wonder if it is too confounded - in which case this could merely be explained. It doesn't overwhelm/make their view point untenable. RESPONSE: This is an important point. At this stage, the data on health outcomes in women diagnosed with PCOS is not available, and perhaps it would be too confounded to depict clearly like in other diseases. We have added in a sentence stating there is no data comparing prevalence of adverse effects over time (page 5): Although overdiagnosis in other conditions tends to result in increased identification of milder cases, it is unknown which PCOS phenotypes are rising as there is currently no longitudinal data. Consequently, the impact of increasing prevalence on the frequency of adverse outcomes is unknown.

6 E.3. Tails off towards the end and needs a stronger way forward section which speaks to clinicians as well as just laying out research priorities and a section on what you could say to a woman in a box would help this. RESPONSE: Thank you for this very helpful suggestion. We agree with your suggestions and have incorporated them into a table for what clinicians can communicate to women about PCOS (see Table 4, page 10 of revised paper). E.4. HM has done a track change edit on this to facilitate transformation into the template, reduce a bit of repetition and soften some of the most academic sounding patches of language towards something a little more conversational whilst maintaining its power. RESPONSE: Thank you for your help with improving the readability and approachability of the paper. We have taken on-board your suggestions and worked from your clean version (please see changes in tracked version of manuscript). External Advisor EA.1. This is an excellent paper that outlines the different diagnostic criteria for polycystic ovary syndrome and their derivation and changes over time. The paper explains how overdiagnosis may be harmful, and the issues in applying a one-size-fits-all diagnostic criteria to different variations of a disease that may have heterogeneous presentations. The one thing that could be improved in this paper would be a better explanation of how these issues occur with every disease, namely that improving sensitivity results in decreased specificity and vice versa. RESPONSE: Thank you very much for your comments. We agree that the issues in applying a one-size-fits-all diagnostic criteria are relevant not only in PCOS but other diseases as well. We have added this into the manuscript (see page 9): The issue of widening disease definitions has also been raised as a concern for many other conditions, such as osteoporosis, gestational diabetes and hypertension, where widened definitions mean that people with lower risk of consequences are receiving permanent disease labels and lifelong treatments that may cause more harm than benefit (Moynihan et al., 2012; Doust et al., 2017). We have also emphasised the issues with applying a one-size-fits-all criteria (page 9): Clinically, more transparent conversations with women are needed so that they understand the limitations in current evidence on this condition (see Table 4), and the issues with applying a one-size-fits-all diagnostic criteria to heterogeneous presentations of symptoms. EA.2. The other issue thing that is touched upon but not expanded on greatly in this paper is that the ultimate utility of a diagnostic is that it should improve

7 patient outcomes, not merely categorize more people into a syndrome. The initial categorization with the NIH criteria seemed to be solely for categorization to allow further study but diagnostic criteria may need to change over time if there are heterogeneity of treatment effects based on evidence. There is a little benefit to patients and in fact the paper clearly states there may be increased harm to patients not only physically but mentally by labeling them with the diagnosis. It appears that in polycystic ovary syndrome like many other diseases, that evidence of benefit is extrapolated from other situations and or based on changes in biomarkers not patient centered outcomes. This all too common scenario in clinical medicine leaves both patient and clinicians at a loss to know whether interventions are beneficial or not. It can also result in the unfortunate consequence of declaring interventions beneficial, with the consequences that future research is then declared on ethical without ever answering the more important patient centered questions. RESPONSE: Thank you for emphasising this crucial point. As we currently only discuss biochemical markers versus patient relevant outcomes in Table 5 about PCOS guidelines, we have added this in the main manuscript to make it more salient (page 9): Better understanding and research is also needed to characterise the benefit and harm of treatment for women with both severe and milder symptoms. For example, with double-blinded RCTs of long duration with placebo-controlled arms in community settings, to investigate the value of early intervention and treatment benefit on improving patient centred outcomes (e.g. menstrual regularity and hirsutism), not just biochemical markers (e.g. androgen assays or insulin levels). We hope that our adjustments make the paper suitable for publication in the BMJ, and we look forward to your final decision. Sincerely, Tessa Copp and Dr Jesse Jansen On behalf of all authors