Attractiveness of women with rectovaginal endometriosis: a case-control study

Capsule:
Women with rectovaginal endometriosis were judged more physically attractive than women with peritoneal or ovarian endometriosis and than women with other benign gynecological conditions.

Authors:
Paolo Vercellini, M.D., Laura Buggio, M.D., Edgardo Somigliana, M.D., Giussy Barbara, M.D., Paola Viganò, Ph.D., Luigi Fedele, M.D.

Volume 99, Issue 1, Pages 212-218, January 2013

Abstract:

Objective:
To evaluate physical attractiveness in women with and without endometriosis.

Design:
Case-control study.

Setting:
Academic hospital.

Patients:
Three hundred nulliparous women.

Intervention:
Assessment of attractiveness by four independent female and male observers.

Main outcome measure:
A graded attractiveness rating scale.

Results:
A total of 31 of 100 women in the rectovaginal endometriosis group (cases) were judged as attractive or very attractive, compared with 8 of 100 in the peritoneal and ovarian endometriosis group, and 9 of 100 in the group of subjects without endometriosis. A higher proportion of cases first had intercourse before age 18 (53%, 39%, and 30%, respectively). The mean ± SD body mass index in women with rectovaginal endometriosis, in those with other disease forms, and in those without endometriosis was, respectively, 21.0 ± 2.5, 21.3 ± 3.3 and 22.1 ± 3.6. The median (interquartile range) waist-to-hip ratio and breast-to-underbreast ratio were, respectively, 0.75 [0.71-0.81], 0.76 [0.71-0.81] and 0.78 [0.73-0.83; P = .08], and 1.15 [1.12-1.20], 1.14 [1.10-1.17] and 1.15 [1.11-1.18; P = .044].

Conclusions:
Women with rectovaginal endometriosis were judged to be more attractive than those in the two control groups. Moreover, they had a leaner silhouette, larger breasts, and an earlier coitarche.

  • alawson@nmff.org

    The Executive Committee of the Mental Health Professional Group of ASRM would like to make you aware of our grave concerns regarding the publication of the research article “Attractiveness of women with rectovaginal endometriosis: a case control study” in the most recent issue of Fertility and Sterility. Unfortunately, there are multiple problems with the study, all of which should have resulted in the manuscript being promptly rejected for publication. We highlight several of our concerns below.

    1) The study is inherently deceptive in that female participants were not informed that they were being rated according to how attractive/pretty or unattractive/ugly they were. Given the large literature on women’s body image concerns, it is highly likely that many women would have refused to participate (rather than behaved seductively) in the study had they known that such ratings were to occur.

    2) The ratings of women’s attractiveness were in no way rigorous, were not operationally defined, and were completely subjective. It is also problematic that the raters were not apparently trained for consistency in rating attractiveness and raters were not consistent throughout the study.
    3) As the authors note on this forum, the study is not clinically useful. Physicians are not and would not be instructed to evaluate all future attractive female patients for rectovaginal endometriosis or to assume that ugly women carried some other diagnosis.

    4) The premise of the study is highly sexist in nature. Objectifying and ogling women’s bodies in the name of science is shameful.

    As scientists, we are concerned about the clear failure of the peer review process. We feel that the readers of Fertility and Sterility deserve both an explanation about how such a gross failure occurred as well as assurances of how these types of errors will be prevented in the future. As women, we are offended that such a study was conducted and published. The objectification of women’s bodies and beauty have clearly been shown in the literature to contribute to anxiety, depression, and eating disorders. That Fertility and Sterility and therefore, the American Society of Reproductive Medicine, condones such behavior and non-rigorous or useful research by the publication of this manuscript calls into question the integrity of the publication and the peer review process. We believe that this manuscript should be retracted from publication with an apology and assurances that such errors in judgment will be guarded against in the future.

    The ASRM’s Executive Committee of the Mental Health Professional Group
    Mary Riddle PhD, Claudia Pascale PhD, Piave Lake MD, and Angela Lawson PhD

    • Craig Niederberger

      We appreciate the interest in this article expressed by The Executive Committee of the Mental Health Professional Group of the American Society for Reproductive Medicine and would like to emphasize that statements and opinions expressed in articles and communications in the journal are those of the authors and not necessarily those of the the American Society for Reproductive Medicine or any organizations endorsing Fertility and Sterility. This article was subjected to the rigorous peer review process as are all submissions to Fertility and Sterility including review of the consent of the subjects and Institutional Review Board approval. Based on the opinions of the reviewers, it was our editorial judgment that this is a legitimate work of science and worthy of inclusion. We appreciate the discussion and have learned much from it, as we hope have the other readers of the journal.

      Craig Niederberger and Antonio Pellicer
      Editors in Chief, Fertility and Sterility

    • Paola Viganò, PhD

      To the
      Executive Committee of the ASRM’s Mental Health Professional Group,
      Mary Riddle PhD, Claudia Pascale PhD, Piave Lake MD, and Angela Lawson PhD

      Dear Dr Riddle, Dr Pascale, Dr Lake and Dr Lawson,

      As a woman, and thus not only as a co-author of the paper under discussion (1), I acknowledge with overwhelming sorrow, but also some perplexity, your negative comments concerning both the methodological aspects and the legitimacy itself of the assessment of attractiveness of women with and without endometriosis.

      Honestly, as a group, we did not think that our paper could have been received as an offense to women, and the possibility of conducting a highly sexist study was absolutely out of our perspective. Indeed, full respect of all women in general and of women with endometriosis in particular has always been our priority. We have fought for years to put the patients with endometriosis at the center of medical decisions and of the socio-political awareness (2) and I have been personally among the very few scientists on the side of the women’s associations sustaining the disease recognition as a social disease.

      With regard to methodology, I cannot exclude that your listed limits may have had an impact on the results. However, we have already explained and clarified in detail all these aspects both in the manuscript itself and in this online forum. With
      regard to the overall ethical aspects of the investigation and the accusation
      of highly sexist conduct, I would like to make some further considerations.

      According to our vision, the ethical legitimacy of our investigation was based on the observation that face and human attractiveness in both females and males has been the objective of vast research in several fields of medicine for a long
      time. In order to further clarify our line of thinking, I refer to another well
      known example of strict interaction between genetic/endocrine factors and
      expression of a particular phenotype, i.e., the complete androgen insensitivity
      syndrome (CAIS). The evidence for an attractive feminine phenotype of some
      subjects with CAIS is anecdotal, but apparently well radicated in gynecological
      knowledge. As an example, one of the most authoritative textbooks of gynecology
      reported ‘[…] is a phenotypic female who is usually somewhat tall, has excellent
      breast development […]. After puberty, the general habitus and distribution of
      body fat is entirely female in proportion and many of these women are
      strikingly attractive’ (3). Similar comments can be found in other
      gynecological textbooks (4). Also patients themselves seem to be aware of this phenotype, which is sometimes felt as a sort of compensation (‘She
      nevertheless, was acutely aware of her physical attractiveness and was recorded as saying: “At least I can take comfort in my femininity”’) (5).

      On a scientific basis, there are evident parallelisms between these two conditions, especially considering the novel genetic findings underlying endometriosis risk (6).
      Mutations or polymorphisms of genes critical for the fetal development and variations in the intrauterine endocrine milieu are likely to determine different phenotypes in the adult age (7). Indeed, the potential role of intrauterine life on endometriosis development has recently been suggested based on a series of observations indicating a modification of the risk among women exposed to specific factors in utero (8). Finally, evidence to suggest antiandrogenic or estrogenic effects for certain environmental toxins is an added factor which merits further consideration for the etiology and for the variable expression of the involved genes.

      As established concepts on feminine phenotype and attractiveness were already
      present in the literature, I and we all as a group did not expect that our investigation could have ignited such a great resentment and could have been
      received as a grave gender offence. We certainly did not imagine that reporting
      an excess of attractive women among the patients with a particular endometriotic lesion could have increased the risk of anxiety, depression, and eating disorders or that measuring physical variables could be interpreted as “objectifying women’s bodies”. In addition, and for sake of clarity, the raters encountered the women exclusively when they were completely dressed. Therefore, facial characteristics were the main factors influencing the determination of the assessment of overall attractiveness.

      Our study has been a long, strenuous, alternative temptative of unravelling a potential factor in the pathogenesis of a particularly distressing form of endometriosis, nothing else than this. If something different was happening, I, as a woman affected by deep endometriosis, should have realized it.

      Paola Viganò, Ph.D.
      Obstetrics and Gynecology Unit, San Raffaele Scientific Institute, Milano, Italy

      1. Vercellini P, Buggio L, Somigliana E, Barbara G, Viganò P, Fedele L. Attractiveness of women with rectovaginal endometriosis: a
      case-control study. Fertil Steril 2013;99:212-8.

      2. Bianconi L, Hummelshoj L, Coccia ME, Vigano P, Vittori G, Veit J, Music R, Tomassini A, D’Hooghe T. Recognizing endometriosis as a social disease: the European Union-encouraged Italian Senate approach. Fertil Steril. 2007;88(5):1285-7.

      3. Jones HW, Colston Wentz A, Burnet LS. Chapter 6. Congenital anomalies and intersexuality. In Novak’s Textbook of Gynecology, Baltimore, Williams & Wilkins, 11th ed, 1981:163-164.

      4. Parsons L, Sommers SC. Chapter 10. Delayed development. In Gynecology, Philadelphia, W.B.Saunders Company, 2nd ed., 1978:134-169.

      5. Conn J, Gillam L, Conway GS. Revealing the diagnosis of androgen insensitivity syndrome in adulthood. BMJ. 2005;331(7517):628-30.

      6. Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J, Lee SH, Lambert A, Zhao ZZ, Roseman F, Guo Q, Gordon SD, Wallace L, Henders AK, Visscher PM, Kraft P, Martin NG, Morris AP, Treloar SA, Kennedy SH, Missmer SA, Montgomery GW, Zondervan KT. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet.
      2011 ;43(1):51-4.

      7. Evans BA, Hughes IA, Bevan CL, Patterson MN, Gregory JW. Phenotypic diversity in siblings with partial androgen insensitivity syndrome. Arch Dis Child. 1997; 76(6):529-31.

      8. Viganò P, Somigliana E, Panina P, Rabellotti E, Vercellini P, Candiani M. Principles of phenomics in endometriosis. Hum Reprod Update. 2012;18(3):248-59.

    • alawson@nmff.org

      I would like to thank Dr. Niederberger and Dr. Pellicer for their reply. As previously stated in the post from the MHPG, we understand that the article made it through the peer review process. We feel peer review failed as this article should not have been published. We know that ours is not the only voice in the likely loud chorus that has expressed this opinion.

      I would also like to personally thank Dr. Vigano for her reply and I would like to respond to her statements. First, I am certain that you did not think this manuscript was sexist, or I would hope that you would not have conducted the study nor attempted to have it published. I am glad that your group has fought on behalf of your patients over the years. I also am aware that previous research and/or anecdotal information has been published which examines the interaction between genetic/endocrine factors and particular phenotypes. However, the simple fact that someone else has published an anecdote (or even rigorous research) on such subjects does not mean that those anecdotes are free of sexism nor does it mean that any later published study on such a subject is automatically exempted from being sexist because someone else published it first.

      Further, you misrepresented the wording of the original post regarding the risks of mental health disorders. The vast literature on women’s body image issues and psychological distress would suggest that additional experiences of sexism (such as I believe is evidenced in your study) contribute to a larger culture of sexism and women’s body image concerns and therefore increase the risk of psychological distress and disorder. Further, as described in your study, you did not merely measure physical variables. Had you only examined physical variables and not attractiveness, your study might have had more merit (though still inherently flawed). However, you asked your raters to look at women’s bodies to determine if they subjectively found them attractive. It does not matter that the participants in your study were clothed; their bodies (breasts, buttocks, etc.) were still ogled. If they were not, you would not have commented on whether or not they were clothed nor would you have excluded women with “congenital anomalies”, “acquired physical defect”, “esthetic or plastic surgery procedures, presence of tattoos or piercing, fixed orthodontic appliances, colored contact lenses, and completely dyed hair.” Your inclusion of such exclusion criteria was also evidence that you predetermined what was attractive which brings additional bias into your study. Your statement that “it has recently been demonstrated that standards for evaluating attractiveness are shared across cultures as different as Caucasian, Chinese, and Japanese” does not mean that such shared views (or research) are free of bias (racial, gender, disability, and otherwise). It also does not mean that such shared views of attractiveness should be used to define what is attractive. As a final example of sexism (as well as more evidence that the women were going to be visually judged as to how pretty or ugly they were) in your manuscript, I would point out that you were deceptive and hid from your study participants the fact that attractiveness was to be a measured variable. Why did you assume that women would behave in a “seductive” way? What research do you have to suggest that women behave this way? Or was this simply a sexist stereotype about women’s desire to be perceived as sexy? If this were a study of male participants, would you have assumed that they would also behave seductively and deceive them about the study’s purpose?

      Second, we agree that there are multiple limitations to the published work. Explaining your limitations however, does not justify the publication of the manuscript as the limits are so severe in my opinion that the manuscript does not warrant publication. Clearly we disagree on that point.

      Finally, although you may not have intended for your study to be sexist in nature, you now have a chorus of fellow researchers and clinicians who are telling you otherwise. If nothing else, I hope that going forward we will all think carefully about the ways in which our research can be interpreted and do our best to limit the furtherance of stereotypes and other harmful behaviors.

      Angela Lawson, Ph.D.

      • Paola Viganò, PhD

        Dear Dr Lawson,

        Your respectful opinions have generated an enriching debate among our study group and we have actually reconsidered some of our positions. However, be assured that, had we conducted the study on male subjects,
        our methodological approach, even with all the possible indicated limits, would have been exactly the same. There was really nothing in our methods that was specifically planned for a female rather than a male study population. Everything we did had the only aim of limit confounding.
        We are the first to be astonished by the fact that our findings could be
        interpreted from such different points of view. We are worried by your
        hypothesis that we might have caused psychological distress to some women. Indeed, assessment of attractiveness was performed the way we did also with the purpose of avoiding any type of distress to participants. Overall, we are willing to take into consideration your opinions and, for certain, in future studies the points raised by you will be given utmost priority.

        Viganò Paola, Ph.D, Somigliana Edgardo, M.D., Vercellini Paolo, M.D.

  • Jhumka Gupta

    I applaud the authors for working to advance the knowledge base of endometriosis. Clearly, scientific efforts to develop current understanding of this critical public health issue, including research surrounding phenotypes, are direly needed. However, there are some important issues pertaining to the methodology that I would like to receive further clarification on—thank you for this forum that gives us the opportunity to
    interact with the authors.

    1 Exposure variables (attractiveness)
    How were the raters trained? Were they given any particular instructions regarding how to assess attractiveness? How do the readers know that the assessments were conducted in a systematic manner? For instance, there may be variation in time spent on rating a patients’ attractiveness, which may in turn influence the actual rating.

    Where did the “attractiveness scale” come from? What are its psychometric properties? Was pilot work done? Has this scale been validated for use with the particular study population?

    Did the authors collect data on the raters to tease out any inherent biases, beyond gender? While I understand that there was “moderate” inter-rater reliability, it is important to note that while the ratings may be deemed reliable, the kappa measure does not tell us much about validity, thus presenting a threat to the exposure variable (attractiveness), and ultimately the association under study. I am not convinced of the strength of one, 5-item scale to assess a construct that is largely considered to be subjective.

    2. Unmeasured confounding:
    I am curious to learn more about the authors’ thoughts on unmeasured confounding as I am not convinced that the threat of unmeasured confounding was prevented, as suggested. Particularly, I am interested in learning if data on potential confounders such as use of hormonal contraceptives were collected. It seems having this information would be important to the suggested mechanism underlying the observed association as outlined by the authors. For instance, BCP use may impact estrogen level, and may also be a marker for DIE (as shown in prior work).

    As a next step for future research, I’m curious about the authors’ perspective on the replicability of current findings in other cultural contexts—–for instance, in specific cultures where low BMI isn’t necessarily viewed as attractive

    ·
    Regarding sexual behaviors, what is the authors’ conceptual framework? Was age at
    sexual debut conceptualized as an a priori covariate of the association under
    study? Did the authors conceptualize it as a potential confounder? Did the authors control for age of sexual debut in adjusted analyses? It seems that conceptually this variable may need to be accounted for. I whole-heartedly agree that more work is needed surrounding the significant finding surrounding age at sexual debut. Particularly because Sexual intercourse is not necessarily correlated to attractiveness nor is it necessarily a proxy for demand from men. Perhaps a better indicator may have been to ask women at what age were they first asked to engage in sexual activity, because women may have been in a position where they could have had sex, but did not engage in sexual intercourse. However, there are many complex, contextual factors that are also at play that influence age at sexual debut. Moreover, what are the authors’ thoughts on their use of earlier sexual debut as a proxy for attractiveness (when women were on
    average 18 years of age), when in the current study attractiveness was assessed
    while these women were in their 30s (on average).

    Lastly, I am curious to learn if any key informant discussions were done with endometriosis patient groups regarding the current study—or if there are any future plans to do qualitative work with endometriosis patients to help understand potential mechanisms that underlie reported findings (e.g. sexual risk)? My own research has only been enriched by close collaborations with community-based organizations serving the intended beneficiaries of my work and helps me to consider unintended consequences (e.g. further marginalizing a vulnerable group).

    Thank you again for taking this important step.

    Many thanks,

    Jhumka Gupta, ScD

    Department of Chronic Disease Epidemiology

    Yale School of Public Health

    • Edgardo Somigliana

      Dear Dr. Gupta,

      Thank you very much for your interest in our study and for your sound comments.

      1. I certainly agree that attractiveness remains highly subjective and it is clearly extremely difficult to force it into numbers. This point was extensively discussed among us at the time of the study design and we were aware of this difficulty.
      However, we did not want to give up because of this methodological difficulty.
      We ultimately decided for a classical 5 points Likert scale since this approach
      was used in previous papers aimed at evaluating attractiveness
      (Rozmus-Wrzesinska and Pawlowski, 2005; Zaidel et al., 2005). It is simple but I do not think it is simplistic.
      Since alternative tools are lacking, the simpler approach may be the most
      appropriate. For the same reason, evaluators were not trained and no particular
      instruction was given. No pilot study was done since a validated comparator was
      lacking. No analysis to tease out any inherent biases beyond gender was done.
      The evaluation was done in a systematic manner by requesting the evaluators to
      join the participating women informally and to judge after briefly looking at them.
      In fact, votes did not vary over time and there was a high concordance among
      evaluators thus supporting the overall validity of our approach. Moreover, the
      analysis of attractiveness was conducted pooling the scores and subdividing
      them into three categories from the original five. Substantially, this resulted
      in the definition of the study subjects as averagely, more than averagely, or
      less than averagely attractive. This should have further limited a potential
      effect of inter-rater variability. With regard to the comment on the kappa
      index, we believe this index is not a good tool when evaluating diagnostic
      tests (that requires faultless concordance), but appears of value in the
      context of a study aimed at identifying an association with attractiveness.

      2. We are not aware of data demonstrating a marked influence of hormonal contraceptives on attractiveness. Moreover, it has not been demonstrated that birth control pills may cause endometriosis development. In fact, the association between oral contraceptive use and endometriosis is generally explained based on treatment for pain caused by pre-existing endometriosis (Vercellini et
      al. Hum Reprod Update 2011;17:159-70. Somigliana et al. Fertil Steril 2011;95:431-433). For this reason, we did not decide to control for this potential confounder.

      3. I fully agree on your comment and I would be also highly interested in future studies investigating attractiveness in other cultural settings.

      4. I also fully agree that sexual debut may not be strictly related to attractiveness. Other factors may play a role. This item of our questionnaire only aimed at collecting some other indirect information that may at least in part indicate a potentially pathogenic factor in the development of vaginal endometriotic lesions. We did not have the idea to investigate the age when women were first asked to engage in sexual activity, but this seems a good suggestion for future studies. We did not use age at sexual debut as a co-variate because, as correctly pointed out, it is not expected to relevantly influence attractiveness. Judging attractiveness in all women at 18 years would be an optimal study design. However, this would have to be done in the context of a 20-30 years large cohort study.

      5. Our research was not aimed at obtaining information of clinical relevance. The
      findings of our study should be exclusively interpreted in a pathogenic perspective. In other words, they may suggest new lines of research aimed at disentangling the origin of endometriosis. Attractiveness is a topic of current high scientific interest and a legitimate area for research. More in general, we certainly agree with you that close collaboration with patient organizations is of utmost importance in order to define management strategies that fit women’s expectations. This last aspect has always been one of the priorities of our research group, and we were probably among the pioneers of patient-centeredness both in the clinical (shared decision-making), as well as in the research setting (patient-preference trials).

      Edgardo Somigliana, M.D.

      Milan, Italy

  • Lone Hummelshoj

    The authors have explained the premise behind the study in this press release: http://endometriosis.org/news/research/attractiveness-of-women-with-endometriosis/

  • I have read this paper and want to congratulate the authors. This article is not sexist. It is not chauvinistic. It is not a joke. This article is a valid expression of the scientific process. It is understandable that the lay media might emphasize the ‘attractiveness’ nature of the study, but the media is about packaging and selling news at any cost and in any way, usually in a sensational way. Therefore, media reaction should not be taken seriously by those who understand the scientific process. Likewise, apparently thoughtful and serious negative commentators might question and criticize the study simply because it focuses on the correlation of a certain phenotype with an important disease. Such detractors may unwittingly base their objections on long-held stereotypes of chauvinists judging the physical beauty of human females and concluding that this is something that is superficial, demeaning to women, and which should not be tolerated, especially in a scientific study. This type of reaction is sexist and should be recognized as such. Such a sexist reaction is not appropriate in a scientific discipline.

    This study is well-constructed and the conclusions are well-supported by data and relate directly to fundamental biological aspects of phenotype which accompany the disease. This correlation of phenotype with expression of disease helps open the door to understanding the origin of endometriosis as being related to something which begins in the embryo. For over a quarter of a century, I have recognized and published on the importance of the embryo in the origin of endometriosis. I therefore welcome the results of this study because, as the authors imply, embryonic and genetic factors seem to play a role in the origin of the disease. This will be increasingly obvious as time goes by. Acceptance of the embryonic origin of endometriosis is inevitable. This theory of origin will eventually supplant the theory of reflux menstruation which has limped along for too long, supported by an increasingly unsustainable system of unscientific patches seeking to prolong its zombie-like state of clinical and therapeutic irrelevance..

    On an anecdotal note, my first wife was very attractive and had endometriosis. My second wife is very attractive and apparently does not have endometriosis. So in my experience, the rate of endometriosis among attractive wives is 50%, which provides further support for the authors’ premise. Bravo and Brava!

    David Redwine, M.D.

    Bend, Oregon

    USA

    • Paola Viganò, PhD

      Dear Redwine,

      Thank you for your kind comments regarding our paper. Your interesting observations give us the opportunity to underline some findings derived from the recently published genome wide association studies (Uno et al., 2010; Painter et al, 2011) that may explain, at least in part, the association between endometriosis and specific phenotypic traits on a genetic basis. A genome-wide association study is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. Very few genes have been so far identified in association with endometriosis but it has to be considered that at least two of them, apart for their various functions at cellular level, are also very intriguing for
      their potential involvement in determining physical characteristics.
      Endometriosis has been found to be associated with a variant located on chromosome 9p21 in the CDKN2BAS gene also known as ANRIL, by Uno et al. (2010) at a genome level and the results were then confirmed by our group in the Caucasian population (Pagliardini et al., 2013).
      The ANRIL product is thought to be able to regulate the transcriptional repression of another molecule p16/CDKN2A which strongly contributes to nevus development, density and distribution. Therefore, an apparently unexplained phenotypic trait characteristic of patients with endometriosis, a high number of nevi, may simply be explained by the involvement of a “very busy” gene in its development. We are actually dedicating much effort to the study of this gene and the intricate routes through which this gene might affect endometriosis pathways represent a very exciting area of research.
      A second variant found to be associated with endometriosis by Painter et al (2011) at a genome level and then confirmed by our group (Pagliardini
      et al., 2013) lies in a region containing the Wnt4 gene. As already
      pointed out, this gene is specifically involved in reproductive tract development in both sexes and is likely to be involved in the expression of marked secondary
      sexual traits.
      Therefore, the idea that genetic factors, as you correctly mentioned, may account partially for both endometriosis development and specific pigmentary/physical traits may be plausible. On the other hand, a role of endocrine or environmental factors cannot be ruled out (Kvaskoff et al., 2010).
      In this context, it has to be considered that blue eyes and fair skin are also more common in autoimmune disorders (Coulthard et al., 2011), but vitamin D deficiency and sun exposure, and not genetic factors, have been claimed to be involved.
      In conclusion, our interest in the study of the phenotype of women with endometriosis is guided by the possible genetic implications underlying the expression of specific physical characteristics. As an example, it is accepted that some variables associated with facial attractiveness are determined by a genetic asset that has been modulated by phylogenetic processes, and that may have potential linkages also with gonadal hormones environment. If our findings will be confirmed, another piece in the jigsaw puzzle of the endometriosis phenome will be identified, thus opening a little bit more our window on the complex pathogenesis of a potentially dreadful disease.

      Vigano’ Paola, PhD

      Milano, Italy

  • Heather Guidone

    I would like to first acknowledge Professor Vercellini’s illustrious body of work in endometriosis, which has led to many advances. We owe a debt of gratitude to him and his colleagues for their lifetime contributions to this enigmatic illness.

    Indeed, better understanding of the disease may well be furthered if in fact an “endometriosis phenotype” could be firmly established. Investigation into specific relationships between endometriosis and select factors and establishing candidates even in absence of surgical confirmation cannot be undervalued, and can only lead to new perspectives. Likewise, there remains a critical need for development of valid prognostic tools for a disease which is indubitably a public health crisis.

    While provocative, the findings of this study were unfortunately lost on the public at large, which does not routinely include the principles of phenomics in their daily conversation. Endometriosis itself is rarely if ever “above the fold” news; likewise, much of society does not fully understand the far-reaching impact of this painful and life-altering ailment. Lay society for the most part does not have access to full research studies; even when they do, shareholders concerned with the illness may not fully understand the implications outlined therein. Likewise, professionals and others who do may dismiss the data out of hand even upon reading the full study. Such was clearly the unfortunate case in this instance.

    In that I, at least in small part, represent the community of those affected, the issue as I see it is not necessarily that the study was conducted, or even the findings – though admittedly the knee-jerk response was not altogether unexpected or even unwarranted – as I understand it to have value in targeting future research towards unlocking pathogenesis and hopefully leading to better treatments (and ultimately, the definitive cure for all affected). The problem, as it were, is that the media did not heed author’s behest to “exclude a spurious relation between attractiveness and rectovaginal endometriosis.” Often, the articles were also accompanied by images of outspoken celebrities who struggle with the disease, i.e. EFA Co-Founder Padma Lakshmi, known for her beauty, further compounding the issue.

    Sensationalized headlines immediately propagated to more than half a million websites and news outlets (and continue to multiply even as of this writing). For example, in typical unrestrained fashion, Cosmopolitan’s lead-in reads “We all know it takes a bit of pain to look good (plucking hurts!), but some new research takes the notion a bit too far.” Another article [Jezebel] opens with “Super Hot Women More Likely to Have Super Painful Endometriosis: Italian scientists have announced that they’ve discovered a positive correlation between women being remarkably good looking and the likelihood that she’ll have one of the worst kinds of lady pain. Leave it to the home of Silvio “Bunga
    Bunga” Berlusconi to commission a study that tracks the relationship between a woman’s f***ability and the occurrence of a painful gynecological condition.” Other responses [Skeptical Scalpel] read: “Attractiveness is based on how many beers I need to drink to find them attractive.” Yet another wrote [TheFrisky], “I am ordinary-looking. Average size, build and looks…[w]hat I don’t want is a study that correlates my disease with attractiveness. There is no known cause for endometriosis, and no known cure. What a colossal waste of time and resources!”

    Still another – this time a well-known, influential OB/GYN and author – wrote under the headline “[t]he journal Fertility and Sterility publishes misogyny”: “The title, so obscene I can barely type it, is: Attractiveness of women with rectovaginal endometriosis: a case-control study (Fertility Sterility, September 2012)…I will absolutely concede that studying attractiveness is important from a psychological standpoint and so I believe in studies that try to contribute to our understanding of what we like and why, what turns us on, and why we make the choices we do with our sexual partners etc. These studies should be done, but by psychologists, not by OB/GYNs. And so I fail to understand how a small group of Italian doctors rating attractiveness of women with different stages of endometriosis contributes anything to medical science…If some researcher asked me to participate in that study my first response would be, “F*** off.” My second would be to report them to the institutional ethics board.” [Jen Gunter, MD]

    These are just isolated examples of similar widespread response. It is this information by which the public forms their opinion – even erroneously – not the seven page study containing all the pertinent details. Obviously, such seemingly melodramatic coverage is going to lead to an unwelcome stereotype and leave the public slow to understand yet quick to criticize. Case in point; the result when one of my organizations shared this study months ago was a legion of overwhelmingly angry readers who felt trivialized, that the study focused on unimportant physical characteristics, lent no valid insight to endometriosis, and did not further the search for the elusive cure. In truth, at cursory glance, it is hard to convince otherwise. Lost as well was that specific disease type (rectovaginal) held a key role in findings. Finally, when stripped of mate selection factors, attractiveness still remains a subjective opinion (“beauty is in the eye of the beholder”) – at least in general perception. Thus at first glance, the overwhelmingly negative reaction cannot be considered an altogether gargantuan leap, particularly given the ensuing media coverage.

    Perhaps the problem is larger yet and not directly related to this study alone. Women and girls with endometriosis have long felt invalidated, dismissed, ignored and isolated as they battle the daily effects of this insidious illness. They want answers that will lead to real improvement in their disease experience. Indeed, at times it does feel as though endometriosis will forever remain the red-headed stepchild of gynecology. Obstetrics, reproductive malignancies, fertility and even ubiquitous, non-specific “pelvic pain” receive far more attention than our disease does; and yet, when endometriosis is mentioned at all, it is often done in the context of a highly scientific (and thus inaccessible) manner that seems too far distant to realize positive, real-time impact on shareholders, or, as in this case, trotted out as a perceived slight dressed in provocative wordsmithing. The issue again seems not so much to be with the findings, but rather, the limitations, misunderstandings and interpretations thereof. Whilst I acknowledge the significance of this study, our attempts to mitigate the crushingly negative response and elevate the article to a more productive platform have been somewhat akin to climbing a proverbial mountain. This is a frequent dilemma we share on both sides of the sector and one we should strive to solve together for the greater good of those who matter most: the women and girls who suffer.

    Nevertheless – critical shortfalls in research, treatment and support of women with this disease continue to exist, and any progress to that end is warranted and appreciated. It is our hope that additional, well-designed studies will eventually prove out these and other proposed theories related to pathogenesis, identification of specific genetic factors, and establishment of longitudinal data in ways that will ultimately benefit those who need (and deserve) it most. Please do continue these and related research efforts. We will strive on our side to make valid findings more accessible to and better understood by our constituency, to hopefully avoid fallout such as that which has occurred in this instance.

    Thank you for indulging me in the opportunity to share a perspective from the so-called “trenches”.

    Heather Guidone
    Surgical Program Director, Center for Endometriosis Care
    Senior Director, Endometriosis Research Center
    Member, ASRM EndoSIG

    *The opinions expressed herein represent my own and not those of my employer.

    • Paolo Vercellini, MD

      I greatly appreciate the thoughtful considerations of Heather Guidone that put
      our findings in a comprehensive and very sensible perspective. Indeed, we were
      shocked by the extremely negative reactions caused by the publication of our
      results (1). The hypothesis of trivializing a complex and severe condition such
      as endometriosis could not have been more remote from our thoughts when we
      discussed and designed our study.

      Our group, as other groups worldwide, is investigating several phenotypic
      characteristics associated with endometriosis since many years. Several
      relations have been demonstrated, including body mass index, hair color, skin
      pigmentation, and presence of nevi and freckles (2-12). We do not believe that these associations may per se have immediate clinical implications, but they may aid in better defining the focus of research, throwing more light on the pathogenesis of the disease. A simple example may help clarify the concept of the potential link between phenotypic characteristics and pathogenic pathways leading to specific disorders.

      People with brown eyes are more likely to experience hearing loss after exposure to cisplatin (13). However, subjects with dark eyes are less likely to develop
      hearing loss associated with noise (14). Moreover, people with light eyes are
      more likely to be deafened by meningitis than those with dark eyes (15). The
      results of a recent study demonstrate that blue eyes are associated with an
      increased risk of type 1 diabetes (16). Interestingly, the same finding was
      already reported more than eighty years ago (17), well before the advent of the
      “omics” era. Along the same line, the proportion of subjects with green-blue
      eyes among women with endometriosis has been observed to be statistically
      significantly higher that that of women without endometriosis (9). Does this
      mean that studying the eye color of women with endometriosis will lead to
      important or helpful clinical consequences? Probably not but, as in other
      fields of medicine, it could help identifying the underlining pathogenic
      mechanisms.

      The same could be true for several other phenotypic characteristics that have
      already been studied in women with endometriosis, and attractiveness does not
      seem to make an exception, as it is determined also by some of the above
      physical variables, and has profound genetic, endocrine, metabolic,
      immunologic, and evolutionary implications, in addition to the evident
      psychological, social, and cultural considerations. Face attractiveness has
      been studied also in male subjects, as it may be linked with cortisol and
      testosterone levels, as well as with immune response and current health (18).
      Facial femininity has been linked to health and to some aspects of disease
      resistance. Facial femininity and attractiveness correlate negatively with
      reported number of upper respiratory tract infections and with the frequency of
      antibiotic use in the preceding year (19).

      I could not agree more on the idiom written by Margaret Wolfe Hungerford, “beauty is in the eyes of the beholder”. This phrase epitomizes the dignity and intellectual freedom of each human being and synthesizes a multitude of factors, certainly not only physical, that eventually determines attraction between people. However, I was surprised when reading the available scientific evidence on this issue, and realized how much of what we believe is the result of an in-depth, purely mental selection process, could indeed be predetermined by genetic factors, in addition to, or in concomitance with, psychological mechanisms. Inter-pupillary distance, cheekbone prominence, jaw height, eyes, nose, and chin dimensions, eyebrow and lips shape, face height and width, waist-to-hip ratio, body mass index, and breast size, all concur in creating a subliminal biologic communication that may indicate various endocrine and immunological conditions and even different reproductive potentials (20-31). We most probably do not consciously care about symmetry, averageness, and sexual dimorphism, but our central nervous system apparently does at an unconscious level, because this visual information has biologic implications. Even infants of a few months of age gaze longer at faces that adults consider attractive (32), and this may indicate that the ideal of beauty as a subliminal biological information is innate.

      Phenotypic characteristics are acquiring increasing importance in medicine, due to their potential to be indicators of specific genotypic-environmental relationship
      (33-35). In this regard, attractiveness, being influenced by sex steroid, and
      genetic as well as environmental factors (e.g., nutrition and pollutants),
      represents a novel area of research. In fact, the biological basis of
      attractiveness are not only relevant for the understanding of the reproductive-oriented behavior, but may provide interesting clues for the association with specific gynecological disorders (36). Indeed, the present publication (1) does not
      constitute a debout of our group in this field, as we began studying phenotypic
      characteristics of women with endometriosis already some years ago (9). Review
      articles are available on the concept of phenomics of endometriosis (35) and on
      the biological implication of attractiveness (36). Therefore, this study is the
      result of a meditated process. Within the framework of this research concept,
      we are developing additional ideas, and another study is already underway. We
      are eager to verify whether a phenotypic difference will be confirmed between
      women with and without endometriosis, and if an expression gradient of the
      study characteristic will be ascertained in relation with the degree of
      severity of the condition.

      Involvement of psychologists would have certainly added value to our research. This could be true also for experts of digital technology for the study of face
      morphology, as well as for neurophysiologists using functional magnetic
      resonance imaging to investigate the effect of exposure to people with varying
      degrees of attractiveness. Unfortunately, these professional expertise, complex
      instrumentation, and adequate funds, were all unavailable when developing our
      project. However, we were not discouraged by these limitations, and thought
      that, even with no funds, by working on a voluntary basis, and without the
      participation of evolutionary psychologists and neurophysiologists, we could
      have tried to explore a novel area of research, adopt a completely different
      investigational approach, and obtain a new type of data that could have helped
      focus efforts where the cause (or at least an important co-factor) of
      rectovaginal endometriosis is hidden.

      One of the differences with most existing publications on female and male
      attractiveness is that here we were not dealing with the general population,
      with voluntary people, or paid subjects. We have taken the concept of
      attractiveness developed in a somewhat elitist and rarefied research
      environment, and applied it to a group of women with a specific disorder that
      can cause disabling pain, impede conception, and interfere with interpersonal,
      social, and work relations. We have investigated attractiveness in the
      “real world”, tried to use this instrument to uncover potential
      biological differences among women with diverse disease forms. Moreover, the
      results of the study have been published, probably for the first time, in a
      gynecological journal (1). We now realize that many readers were not prepared
      for this type of report, and that misunderstanding easily ensued.

      With regard to the reaction of part of the lay press, it is frustrating to note how
      the study message has been distorted and mislead. Maintaining tout court that patients with endometriosis are more attractive than women in the general population (let alone other offensive definitions) certainly increases the attractiveness of the newspaper that publishes such piece of news, but does not render a useful service to the readers. What do the data really show? The vast majority of women with endometriosis (90%) are as attractive as women without
      endometriosis. This simple figure clarifies how unfounded are the sensational
      titles. It is like maintaining that women with endometriosis have blue eyes
      just because there is an excess of blue irid in women with the disease compared
      with the general female population. The core finding is that, among women with
      endometriosis, the proportion of attractive subjects is significantly higher
      specifically in those with rectovaginal lesions (thus with a relatively
      infrequent disease form with particular anatomic characteristics), being 31% in
      this group versus 8% in women with peritoneal and/or ovarian endometriosis (and
      9% in women without endometriosis). The observation of an excess of very
      attractive or rather attractive women only in such a definite and limited study
      population, may expand our understanding on endometriosis, suggesting different
      pathogenic pathways for different lesions, and conveys a clear message towards
      genetic and possibly hormonal implications. Dr. Paola Viganò has already wrote
      in this forum on the interesting potential role of WNT4, a gene implicated in
      sexual differentiation, in the development of the genital tract segment where
      rectovaginal endometriotic lesions are found, and in the hormonal synthesis of
      gonadal steroids. Incidentally, WNT4 is among the few demonstrated true endometriosis risk loci (37, 38).

      There is a difference between looking and seeing. Many years ago, one of my closest collaborators, Dr Giorgio Aimi, commented about the higher frequency of
      endometriomas in the left ovary compared with the right one, considering that
      observation as obvious. After a multitude of ovarian endometriotic cyst
      excisions, certainly much more than those performed by Dr Aimi at that time,
      not the feeblest suspect of such an asymmetry had ever crossed my mind. Indeed very skeptical, I challenged that conviction and invited Dr Aimi to retrieve
      and analyze some preliminary data. The findings were indisputable and
      originated a formal study. The results were published almost 15 years ago (39),
      were followed by further demonstrations of the asymmetrical distribution of
      endometriotic lesions in bilateral structures (ureter, large bowel, sciatic
      nerve, inguinal region, pleura and diaphragm), and were confirmed by many
      independent research groups, leading to the rejection of the metaplasia theory
      for most of the above lesions (40). For a century, apparently nobody had
      noticed what was so evident and under the eyes of everybody.

      Likewise, when we became aware that women using oral contraceptives after excision of ovarian endometriomas very rarely showed cyst recurrences at periodic ultrasonographic evaluation, a formal investigation was planned. That study demonstrated an impressive risk reduction in oral contraceptive users compared with nonusers (41), and was followed by other trials and meta-analyses
      reporting consistent findings, thus supporting the crucial role of ovulation in
      the pathogenesis of ovarian endometriotic cyst formation.

      When we noticed that the frequency of attractive women in the group of patients with rectovaginal endometriotic lesions was unusually high, we pursued the same
      approach, i.e., from anecdotal observation, through formulation of a rationale
      based on the available scientific evidence, to conduction of a formal study in
      order to verify the hypothesis. Our findings suggest that the pathogenic
      mechanism leading to rectovaginal endometriosis may follow different pathways
      with respect to superficial peritoneal lesions and ovarian endometriomas. We
      hope that these results could be integrated within the ongoing research on subjective predisposition to development of aggressive disease forms, and contribute to the definition of the still evolving concept of endometriosis phenome (35).

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  • Micah Hill

    Thank you Dr. Vercellini for taking the time to so thoroughly address the questions I had. Your answers were very helpful for me!

  • Micah Hill

    I also had a difficult time with this article. The first is the biologic plausibility. The entire study seems based on the premise that one study has shown women with lower BMI have worse endometriosis. Other studies have correlated attractiveness with BMI. Therefore the authors sought to see if endometriosis was correlated with attractiveness. The authors talk in the introduction about disease being correlated with phenotypes, but I’m not sure why this would lead to a study about breast size and attractiveness in endometriosis. My main question to the authors is what clinical relevance they perceive this research leading to?
    As to the methods, I had a few other questions:
    1. if you perform multivariate regression analysis to control for weight, BMI, breast size, and hip size, is attractiveness still associated with severe endometriosis? In other words, if leaner is generally considered to be more attractive, and leaner women have more endometriosis, then the study is set up to find that endometriosis is associated with attractiveness.
    2. the 4 physicians grading attractiveness were blinded to pre-op diagnosis. However, group allocation was not made until after surgery. So was the person making group allocations blinded to the grade of the attractiveness given to the subject? Also, did all 4 physicians grade every patient’s attractiveness?
    3. was the decision to divide the patients into three groups completely prior to the study? or was it a post hoc decision to group patients by 1. deep endometriosis 2. peritoneal or ovarian endometriosis 3. other pelvic pathology. If you group all forms of endometriosis together then the results are similar to other pelvic pathology patients?
    Thank you for your consideration of these questions.

    • Paolo Vercellini, MD

      Dear Dr. Hill,
      Our study did not aim at revealing findings of clinical relevance. Physicians are
      obviously not supposed to suspect endometriosis based on the attractiveness of
      the patient. The study exclusively aimed at disentangling some phenotypic clues
      of women with endometriosis that may shed some new light on the pathogenesis of
      the disease. BMI was only one the phenotypic traits possibly linked to
      attractiveness that was previously reported to be associated with the disease.
      Other intriguing associations have been documented including those with skin
      pigmentation and body shape. Our investigation is thus not entirely new. It is
      within a line of research (namely the phenomics of endometriosis) that our
      group and others are currently following (Viganò et al., Human Reproduction Update, 2012). The new aspect of our study was to focus on attractiveness in general (mostly facial attractiveness given that the evaluation was performed in an informal manner without requesting the womento wear standardized dresses). We deem this outcome of great interest since it is plausible that endometriosis and attractiveness may share some common causal vectors. For instance, albeit the mechanisms are poorly clarified, sex steroids presumably play a role in both conditions.
      I briefly answer to the other specific questions.
      1. Even if some (but not all) studies reported an association between endometriosis and BMI, we failed to document a marked relationship in our study. The BMI was
      slightly lower in women with rectovaginal endometriosis compared to controls
      (21.0 ± 2.5 compared to 22.1 ± 3.6 Kg/m2, p=0.016) but this significance got lost when comparing the data using categorical analysis (p=0.30) (Table 3). For this reason, we did not deem necessary to adjust our results for this potential confounder. However, as requested, we now did the logistic regression analysis controlling for the suggested variables (weight, BMI, breast size, and
      waist-hip ratio) and the results remained highly statistically significant (p<0.001). The adjusted OR for being very or rather attractive in women with rectovaginal endometriosis compared to controls was 5.4 (95%CI:2.2-13.3).
      2. The person making group allocations was actually blinded to the grade of the
      attractiveness and all four physicians graded every patient's attractiveness.
      3. The decision to divide the patients into three groups was taken prior to start the
      study. It was not a post-hoc decision. This idea was based on the anecdotal
      observation of some highly attractive women in women with rectovaginal
      endometriosis. When grouping all women with endometriosis, the association
      persisted but its magnitude is less relevant. Using the previously suggested
      multivariate model, the adjusted OR for being very or rather attractive in
      women with endometriosis compared to controls was 2.6 (95%CI: 1.1-5.8)
      (p=0.023).

  • While any attempt at levity in a serious scientific journal is appreciated, this joke article is actually in poor taste. It IS a joke, right?

    • Paolo Vercellini, MD

      Dear Dr. Cain,
      This article is not a joke. We did a great effort to perform the study. I am sorry
      you do not share the potential new insights in terms of pathogenesis that may harbor behind our findings. Attractiveness is a topic of current great interest in the literature and the idea to associate clues linked to attractiveness to a specific disease is not new. Attractiveness is a complex but also intriguing argument with phylogenetic, social, physical, hormonal, psychological and genetics implications. The observation of a link between endometriosis and attractiveness may open new fascinating perspectives that can help us achieving our common goal, i.e. shedding more light on the pathogenesis of this enigmatic disease.

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