The operationalization of gender in Parkinson’s research Under (de)construction Irene Göttgens
UNDER (DE)CONSTRUCTION THE OPERATIONALISATION OF GENDER IN PARKINSON’S RESEARCH IRENE GÖTTGENS
ISBN: 978-94-6483-508-3 Cover design and layout: © evelienjagtman.com Cover design inspired by: Armstrong MJ, Okun MS. Time for a New Image of Parkinson Disease. JAMA Neurol. 2020 Print: Ridderprint | www.ridderprint.nl Copyright © Irene Göttgens 2024 The research presented in this thesis was conducted at the Radboud University Medical Centre; Department of Primary and Community Care; Nijmegen, The Netherlands, and the Radboud University Medical Centre; Department of Neurology; Centre of Expertise for Parkinson & Movement Disorders; Nijmegen, The Netherlands. This research is part of the collaborative Proactive and Integrated Management and Empowerment in Parkinson’s Disease (PRIME Parkinson) project, which is a healthcare innovation project in selected areas of the United Kingdom and the Netherlands. The PRIME Parkinson project is financed by the Gatsby Foundation and co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. For reasons of consistency within this thesis, terminology have been standardized throughout the text, and therefore might slightly differ from the original publications. All rights reserved. No part of this publication may be reproduced in any form or by any means, electronically, mechanically, by print or otherwise, without the written permission of the copyright owner.
UNDER (DE)CONSTRUCTION THE OPERATIONALISATION OF GENDER IN PARKINSON’S RESEARCH Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. J.M. Sanders, volgens besluit van het college voor promoties in het openbaar te verdedigen op maandag 3 juni 2024 om 14:30 uur precies door Irene Louise Elisabeth Göttgens geboren op 6 november 1986 te Nijmegen
Promotoren Prof. dr. S. Oertelt-Prigione Prof. dr. B.R. Bloem Copromotor Dr. S.K.L. Darweesh Manuscriptcommissie Prof. dr. I.E. van der Horst-Bruinsma Prof. dr. J.A.M Kremer Dr. B. van Harten (Medisch Centrum Leeuwarden)
Table of Contents Chapter 1 General introduction and outline of the thesis 7 Part I Understanding the impact of gender on health outcomes and illness experiences Chapter 2 The impact of sex and gender on the multidisciplinary management of care for people with Parkinson’s Disease. 23 Chapter 3 The impact of multiple gender dimensions on healthrelated quality of life in people with Parkinson’s disease – an exploratory study. 43 Chapter 4 The salience of gender in the illness experiences and care preferences of people with Parkinson’s disease. 71 Part II Advancing the study of gender in medical research Chapter 5 The application of human-centered design approaches in health research and innovation: a narrative review of current practices. 101 Chapter 6 Gender-Aware Parkinson’s Care: A design-based analysis of patient perspectives on gender norms and gender sensitive care. 147 Chapter 7 Moving beyond gender identity: the need for contextualisation in gender-sensitive medical research. 197 Part III Discussion and summary Chapter 8 General discussion 205 Chapter 9 English Summary 225 Chapter 10 Dutch summary | Nederlandse samenvatting 231 Addendum A1 Research data management 239 A2 List of publications 243 A3 Acknowledgement 249 A4 About the author 255
Chapter 1 General introduction and outline of the thesis
General Introduction 9 1 General introduction and outline of the thesis The roots of sex- and gender-sensitive medicine The roots of sex- and gender sensitive medicine (SGSM) trace back more than 50 years to the feminist movements in the US and Europe. The focus on women’s health originated from the Women’s Health movement during the ’60 and ‘70s with its goals to improve care for all women through physical and sexual self-determination, and to gain control of their own reproductive rights.1 This first wave was followed in the ‘80s by the entry of larger numbers of women into the medical profession, which contributed to a broader awareness within- and outside medicine of the longstanding lack of research in women’s health. This coincided with a growing focus on differences in clinical signs and symptoms in women and men affected by the same condition, for numerous medical conditions.2 By the ’90s, ‘gender-specific’ research emerged as an innovative area of biomedicine, with an initial focus on filling the gap in knowledge about female symptoms and needs in a medical world that historically focused on male standards and on the identification of sex-linked differences in disease development and progression.3 Although it is beyond the scope of this introduction to include a comprehensive history of policies and initiatives that progressed the field of SGSM, some key initiatives are worth mentioning. With the adoption of the Health Revitalization Act in the US in 1993, the National Institutes of Health (NIH) established the first guidelines for the inclusions of women and underserved populations in clinical research.4 A decade later, in 2003, the EU Parliament resolution on gender mainstreaming offered a first blueprint on how to integrate sex and gender analysis into basic science.5 With this resolution, the EU required grantees to address “whether, and in what sense, sex and gender are relevant in the objectives and methodology of the research project”.6 Although the interest in- and attention towards the field of SGSM has increased in the past two decades, there is still a lack of robust and systematic instruments for the analysis of sex and, particularly, gender in (bio)medical research.7 The field of SGSM aims to differentiate between the incorporation of “information about how biological sex characteristics and sociocultural aspects of gender dimensions affect health and illness of people”.8,9 In the study of human subjects, the term ‘sex’ is used as a classification system based on biological attributes that are generally associated with male, female and intersex organisms (sex characteristics). From this perspective, individuals are often classified through the analysis of genes, gonads, and genitals (3G sex-system). This includes a focus on chromosomes, gene expression, hormone levels and function, and reproductive/sexual anatomy.10 The term ‘gender’ is used as an overarching concept that includes multiple sociocultural ideas, behaviours
Chapter 1 10 and characteristics generally associated with a individuals’ gender identity (gender dimensions). This includes a focus on gender identities, gender expressions, gender roles and norms, and gender relations (Box 1).8 From this perspective, gender identities can match or differ from people’s sex assigned at birth. Box 1. Gender dimensions and descriptions Gender dimension Description Gender identity Refers to and individual’s sense of self (i.e. identifying as a woman, man, non-binary person etc.) Gender expression Refers to the way an individual presents themselves to the world (i.e. how people present their body and identity through self-expression in e.g. clothing, hair, make-up, body language) Gender roles and norms Refer to social expectations associated with being a man, woman or non-binary person in a given society (i.e. societal structures that lead to shared ideas about what constitute e.g. masculinity and femininity) Gender relations Refers to ways in which power, authority and resources are distributed between sexes in a given society (the impact of gender on e.g. power dynamics in relationships) Investigating gender in medical research Researchers in social sciences already differentiated between the concepts of sex and gender in health in the 1970s. The constructivist perspective in social sciences holds the view that sex characteristics have a biological basis whereas gender dimensions are socially constructed and not natural phenomena. This position arose from the women’s movement of the 1960’s, when feminists argued that socially constructed gender differences have historically been mobilised to create and enforce inequalities between men and women in society and that these gender norms can be redefined to equalise the sexes. The constructivist perspective includes both ‘sex as biological variables’ (SABV) and ‘gender as sociocultural variables’ (GASV) paradigm in SGSM research.11 Currently, both the Canadian Institute of Health Research (2010) and the European Commission (2014) have endorsed the inclusion of both SABV and GASV in biomedical research, whereas the US National Institute of Health (2016) tends to focus more on the inclusion of SABV.12–14
General Introduction 11 1 While the importance of the inclusion of SABV and GASV in biomedical research is increasingly acknowledged in research policies, the introduction of gender in the (bio) medicine research practices has encountered difficulties and resistance in the past and present. First attempts at introducing ‘gender’ in (bio)medical research and education frequently meant an interchangeable use with the term ‘sex’, and often without specification how ‘sex’ was being operationalised.15 Efforts to address this practice in medical education revealed an initial lack of interest among medical students, as well as faculty, about the topic of gender, scepticism regarding the relevance of gender in medicine and a lack of time or willingness to learn about gender.16–19 While SABV is gaining popular and preferential interest in biomedical research, critics of SABV in both social and precision medicine argue that an intensive focus on solely documenting differences in biological sex characteristics risks producing decontextualised results with limited relevance to human health and clinical practice.20–22 Treating sex characteristics as binary (male/female) biological variables, uncoupled from research context, social environment, intersecting demographics and lifestyle variables, lacks the precision evidence-based medicine claims to seek.23 Differences and similarities in sex characteristics reflect both biological and sociocultural influences and (bio)medical researchers should be careful to address observed differences between men and women solely as biological sex-related differences, regardless of their causes.24 Investigating gender as socialisation characteristics allows us to contextualise observed sexrelated similarities and differences and to reflect upon societal realities and developments within and between patient populations. However, for the investigation of gender in medicine, there is currently no clear consensus on terminology or standards how to operationalise this construct. This makes gender-sensitive studies in medicine currently difficult to operationalise, let alone replicate. Furthermore, biomedical and health researchers are still developing their own understanding of gender as a dynamic multidimensional sociocultural construct. Operationalising gender dimensions in medical research This thesis is informed by the theoretical concepts of ‘doing gender’ (West and Zimmerman 1987) and ‘gender performativity’ (Butler 1988).25,26 Both theories view gender as a performative accomplishment compelled by social norms and sanction. Gender includes behavioural and psychological traits that are stereotypically associated with one of the sexes and are facilitated and restricted by social consequences. Gender ascribes similarities within one sex and differences between sexes. Based on these differences and similarities, cultural ideas describe what is regarded as normative behaviours for each of the sexes and which roles and responsibilities are socially (performatively) desired. From this perspective, cultural comprehension of what e.g. a ‘man’ or a ‘woman’ is, evolves from what is understood as both differences and sameness. This process of
Chapter 1 12 ‘gendering’ is embedded in our daily lives by means of social cues and responses through which gendered performances are constructed and reproduced. This social process is a central part in the development of social identities and senses of self and facilitates the development of cognitive gender schemas through which behaviours and social interactions are interpreted and (self-)regulated. Best practice in the study of gender in medicine is to consider gender as a multidimensional performative concept, covering, at least, gender identities, gender norms and gender relations.27 As (bio)medical knowledge is mostly constructed through empirical research based on a positivist inquiry paradigm, it relies heavily on quantitative methodologies.28 The availability of survey-based instruments to measure gender in medicine has increased in the last 20 years, however, most of them have been developed with a restricted study population of US-American students and in the field of psychology, focusing on binary representations of masculinity and femininity.29 Furthermore, the underlying assumptions of the concepts under investigations are often not defined. For example, when researchers ask about participant’s ‘gender’, they often imply ‘gender identity’ while offering two mutually exclusive possible response options: “man/male” or “woman/female” .30 This operationalisation lags behind the current thinking in biological and social sciences, as both sex and gender are considered multi-layered, variable and non-binary.30–32 While continued and valuable efforts are being made to quantitatively measure gender dimensions in (bio)medicine, a prerequisite for all these endeavours remains a thorough understanding of social theory on how gender is performed. Because gender is relational, constructed through human interaction and social processes, gender negotiations can be seen as situated performances.33 To understand and measure gender as a situational, multi-layered construct, its analysis requires careful focus and contextualisation and therefor one-size-fits all measures might be less suitable to capture the impact of gender on people’s health. There is a need to understand what role gender plays in the illness experiences and disease expressions of particular patient populations to help inform the design of gender-sensitive measures and interventions in medicine that are contextually relevant and capable to inform population and personalised care management. Investigating the impact of gender in the context of Parkinson’s disease Parkinson’s Disease (PD) provides a valuable model condition for chronic (neurological) disorders to study the impact of different gender dimensions because the disease is common, with an incidence and prevalence that are rising due do demographic changes and possibly other factors.34 The clinical phenotype of PD encompasses a wide range of non-motor and motor features and neuropsychiatric features for which sex/gender differences are reported but the concrete and interrelated impact of specific sex- and
General Introduction 13 1 gender related features is still far from being fully elucidated.35 Furthermore, PD has a long duration, spanning up to decades for affects patients and its management requires a multidisciplinary approach that includes complex pharmacotherapy, neurosurgical procedures, and various non-pharmacological interventions.36 The challenges and consequences of the progression and long-term treatment of PD can disrupt existing gender roles and norms in family and community settings. Gender roles and norms affect attitudes, opportunities, experiences and behaviours of individuals, with important health consequences throughout the life course.37 In this thesis, I investigate the impact of gender in the context of PD with the broader intention to extrapolate insights for the operationalisation of gender in medical research at large. Parkinson’s Disease Parkinson’s Disease is a chronic and progressive neurological movement disorder that is characterized by impairment of movement, cognitive functioning and behavioural and emotional regulation.38 The disease is named after dr. James Parkinson, who first described the symptoms and signs in 1817.39 The main underlying pathological factor is a loss of dopamine producing neurons in the midbrain (substantia nigra), which leads to a range of motor symptoms such as tremor, rigidity, bradykinesia (slowness of movement) and changes in axial mobility (gait, balance, posture). In addition to these clearly observable motor symptoms, PD can also cause a wide range of non-motor symptoms such as anxiety, depression, sleep disturbances, pain, autonomic dysfunction, and cognitive impairments. Since there is currently no cure or even a disease-modifying intervention for PD, and the treatment of PD is largely focused on the management of symptoms and the improvement of quality of life for people living with the disease. Box 2 provides an overview of both the motor and non-motor symptoms related to PD. There is emerging evidence of PD becoming the fastest growing neurological disorder worldwide. The global number of people with PD is projected to exceed 12 million by 2040.40 In observational studies, PD tends to affect men more frequently than women in most countries in the world (Japan being an example of a country where this is different), however, the reasons for this are largely unclear and sex/gender differences in PD prevalence may not be as pronounced as previously assumed.41–43 While gender is considered an important determinant of health in PD research, studies that have investigated the impact of gender on PD have almost exclusively focused on self-reported gender identity; often as a proxy for sex characteristics and rarely included other dimensions of gender. This results in a limited and incomplete picture of the role of gender as contextual and multidimensional social construct and its impact on clinical outcomes and individual illness experiences of people with PD. The aim of this thesis was, therefore, to apply a multiphase investigation to study the impact of gender and its multiple dimensions in the context of PD.
Chapter 1 14 Box 2. Motor and non-motor symptoms in Parkinson’s Disease Motor symptoms Non-motor symptoms • Resting tremor Rhythmic muscle contraction and relaxation of mainly extremities, but also lips, chin, and jaw • Rigidity Stiffness and inflexibility of limbs, neck, or trunk • Bradykinesia Slow movement, decrementing amplitude, problematic fine motor control • Postural instability Loss of postural reflexes, poor balance, falls • Gait disturbances Freezing of gait, gait asymmetry, reduced arm swing • Masked face • Dysphagia, contributing to drooling • Dysarthria • Flexed posture and other postural abnormalities • Neuropsychiatric changes Anxiety, apathy, depression, hallucinations, impulse control disorders • Cognitive impairments Impaired judgement and other frontal dysexecutive symptoms, bradyphrenia, dementia • Autonomic symptoms Orthostatic hypotension, urogenital problems, sexual dysfunction, sweating • Gastrointestinal dysfunction Constipation, delayed gastric emptying, small intestinal bacterial overgrowth • Sensory problems Pain, reduced smell (hyposmia) • Sleep disorders Rapid eye movement (REM) sleep behaviour disorder, sleep fragmentation, nightmares, excessive daytime somnolence, vivid dreaming • Other non-motor symptoms Fatigue, visual dysfunction, weight changes Outline of the thesis This thesis encompasses several studies and publications on the impact of gender on health outcomes and illness experiences of people with Parkinson’s Disease. An overview of the chapters and methodological approaches included in this thesis, is presented in figure 1. Part I – Understanding the impact of gender on health outcomes and illness experiences The first part of the thesis focuses on understanding the impact of several gender dimensions on health outcomes and illness experiences of people with PD. In Chapter 2, I provide a perspective on the current knowledge base regarding the impact of sex and gender on the multidisciplinary management of care for people with PD. Subsequently, I performed a rapid review of the literature to identify state-of-the-art options for the
General Introduction 15 1 operationalisation of multiple gender dimensions and investigated their impact on PD specific quality of life domains, which is described in Chapter 3. To investigate if and how gender is situationally performed by people with PD and how PD related symptoms could impact their gendered illness experience, I performed a qualitative study in Chapter 4 to explore the role of gender in the illness experiences of people with PD. Figure 1. Overview of the included chapters and methodological approaches. Part II – Advancing the study of gender medical research The second part of the thesis focuses on ideas to advance the study and analysis of gender in medical research from a human-centred perspective. Human-centred approaches recognize the importance of behavioural, emotional, and environmental contexts and adopt a systems approach towards human needs. I explored how multimethod human-centred design approaches are being used in health research and innovation in Chapter 5. This study formed the basis for the conception of a novel design-based study, described in Chapter 6, to explore patient perspectives on the
Chapter 1 16 presence of gender norms and stereotypes in PD illness experiences and care delivery and to formulate recommendations for gender-sensitive PD care, using participatory design methods. In Chapter 7, I emphasize the need for contextualisation of gender in medical research to overcome the reproduction of ingrained preconception and stereotypes related to gender that can stand in the way of equitable and personalised care. For the empirical studies in this thesis (Chapter 3, Chapter 4 and Chapter 6), a stepwise explanatory approach was used to collect and analyse quantitative, qualitative, and design-based data separately on the phenomena of gender and PD.44 Traditional explanatory mixed-method approaches explain or build upon initial quantitative results with an in-depth qualitative study. In this thesis, we added an additional designbased study to build upon the quantitative and qualitative findings (figure 2). The methodological consideration for operationalising and studying gender in PD research are discussed in Chapter 8. Part III – Summary and discussion In Chapter 8 the main findings are discussed, as well as the implications for gendersensitive Parkinson’s and medical research and the future development of gender transformative care interventions. In the final part of this thesis, Chapter 9 and Chapter 10, provide a summary of the results in English and Dutch.
General Introduction 17 1 Figure 2. Explanatory multimethod approach applied in this thesis.
Chapter 1 18 References 1. Nichols, F. H. History of the Women’s Health Movement in the 20th century. J. Obstet. Gynecol. Neonatal Nurs. 29, 56–64 (2000). 2. McGregor, A. J., Templeton, K., Kleinman, M. R. & Jenkins, M. R. Advancing sex and gender competency in medicine: sex & gender women’s health collaborative. Biol. Sex Differ. 4, 11 (2013). 3. Legato, M. J. Beyond women’s health the new discipline of gender-specific medicine. Med. Clin. North Am. 87, 917–37, vii (2003). 4. NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. https:// grants.nih.gov/grants/funding/women_min/guidelines_update.htm (2000). 5. Klinge, I. & Bosch, M. Transforming Research Methodologies in EU Life Sciences and Biomedicine: Gender-Sensitive Ways of Doing Research. European Journal of Women’s Studies 12, 377–395 (2005). 6. Policy Timeline. Gendered Innovations http://genderedinnovations.stanford.edu/policy/timeline.html (2021). 7. Becher, E. & Oertelt-Prigione, S. History and development of sex- and gender sensitive medicine (SGSM). Int. Rev. Neurobiol. 164, 1–25 (2022). 8. Oertelt-Prigione, S. Putting gender into sex- and gender-sensitive medicine. EClinicalMedicine 20, 100305 (2020). 9. Madsen, T. E. et al. Sex- and Gender-Based Medicine: The Need for Precise Terminology. Gender and the Genome 1, 122–128 (2017). 10. Joel, D. Genetic-gonadal-genitals sex (3G-sex) and the misconception of brain and gender, or, why 3G-males and 3G-females have intersex brain and intersex gender. Biol. Sex Differ. 3, 27 (2012). 11. Fisher, J. A. Gender and the Science of Difference: Cultural Politics of Contemporary Science and Medicine. (Rutgers University Press, 2011). 12. Government of Canada & Canadian Institutes of Health Research. How to integrate sex and gender into research. https://cihr-irsc.gc.ca/e/50836.html (2018). 13. Renewed commitment, A. Fact sheet: Gender equality in horizon 2020. https://genderedinnovations. stanford.edu/FactSheet_Gender_091213_final_2.pdf (2013). 14. NOT-OD-15-102: Consideration of Sex as a Biological Variable in NIH-funded Research. https://grants. nih.gov/grants/guide/notice-files/NOT-OD-15-102.html. 15. Peters, S. A. E. & Norton, R. Sex and gender reporting in global health: new editorial policies. BMJ Glob Health 3, e001038 (2018). 16. Zelek, B., Phillips, S. P. & Lefebvre, Y. Gender sensitivity in medical curricula. CMAJ 156, 1297–1300 (1997). 17. Ruiz, M. T. & Verbrugge, L. M. A two way view of gender bias in medicine. J. Epidemiol. Community Health 51, 106–109 (1997). 18. Risberg, G., Johansson, E. E. & Hamberg, K. “Important… but of low status”: male education leaders’ views on gender in medicine. Med. Educ. 45, 613–624 (2011). 19. Verdonk, P., Benschop, Y. W. M., De Haes, J. C. J. M. & Lagro-Janssen, A. L. M. Making a gender difference: case studies of gender mainstreaming in medical education. Med. Teach. 30, e194-201 (2008). 20. Shansky, R. M. & Murphy, A. Z. Considering sex as a biological variable will require a global shift in science culture. Nat. Neurosci. 24, 457–464 (2021). 21. McCarthy, M. M., Woolley, C. S. & Arnold, A. P. Incorporating sex as a biological variable in neuroscience: what do we gain? Nat. Rev. Neurosci. 18, 707–708 (2017).
General Introduction 19 1 22. DiMarco, M., Zhao, H., Boulicault, M. & Richardson, S. S. Why “sex as a biological variable” conflicts with precision medicine initiatives. Cell Rep Med 3, 100550 (2022). 23. Sapir-Pichhadze, R. & Oertelt-Prigione, S. P32: a sex- and gender-sensitive model for evidencebased precision medicine: from knowledge generation to implementation in the field of kidney transplantation. Kidney Int. (2023) doi:10.1016/j.kint.2022.12.026. 24. Eagly, A. H. & Wood, W. The Nature-Nurture Debates: 25 Years of Challenges in Understanding the Psychology of Gender. Perspect. Psychol. Sci. 8, 340–357 (2013). 25. West, C. & Zimmerman, D. H. Doing Gender. Gender and Society 1, 125–151 (1987). 26. Butler, J. Performative Acts and Gender Constitution: An Essay in Phenomenology and Feminist Theory. Theatre Journal 40, 519–531 (1988). 27. Klinge, I. Best Practices in the Study of Gender. Curr. Top. Behav. Neurosci. (2022) doi:10.1007/7854_2022_306. 28. Park, Y. S., Konge, L. & Artino, A. R., Jr. The Positivism Paradigm of Research. Acad. Med. 95, 690–694 (2020). 29. Horstmann, S., Schmechel, C., Palm, K., Oertelt-Prigione, S. & Bolte, G. The Operationalisation of Sex and Gender in Quantitative Health-Related Research: A Scoping Review. Int. J. Environ. Res. Public Health 19, (2022). 30. Johnson, J. L. & Repta. Sex and Gender: Beyond the Binaries. in Designing and Conducting Gender, Sex, & Health Research 7–38 (SAGE Publications, Inc., 2012). 31. Bolte, G. et al. Integrating Sex/Gender into Environmental Health Research: Development of a Conceptual Framework. Int. J. Environ. Res. Public Health 18, (2021). 32. Blackless, M. et al. How sexually dimorphic are we? Review and synthesis. Am. J. Hum. Biol. 12, 151–166 (2000). 33. Järviluoma, H., Moisala, P. & Vilkko, A. Performing and Negotiating Gender. Gender and Qualitative Methods 1–26 (2012). 34. Dorsey, E. R. & Bloem, B. R. The Parkinson Pandemic-A Call to Action. JAMA Neurol. 75, 9–10 (2018). 35. Russillo, M. C. et al. Sex Differences in Parkinson’s Disease: From Bench to Bedside. Brain Sci 12, (2022). 36. Bloem, B. R. et al. Integrated and patient-centred management of Parkinson’s disease: a network model for reshaping chronic neurological care. Lancet Neurol. 19, 623–634 (2020). 37. Weber, A. M. et al. Gender norms and health: insights from global survey data. Lancet 393, 2455–2468 (2019). 38. Bloem, B. R., Okun, M. S. & Klein, C. Parkinson’s disease. Lancet 397, 2284–2303 (2021). 39. Parkinson, J. An Essay on the Shaking Palsy. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002). 40. Dorsey, E. R., Sherer, T., Okun, M. S. & Bloem, B. R. The Emerging Evidence of the Parkinson Pandemic. J. Parkinsons. Dis. 8, S3–S8 (2018). 41. Zirra, A. et al. Gender Differences in the Prevalence of Parkinson’s Disease. Mov Disord Clin Pract 10, 86–93 (2023). 42. Picillo, M. et al. The relevance of gender in Parkinson’s disease: a review. J. Neurol. 264, 1583–1607 (2017). 43. Georgiev, D., Hamberg, K., Hariz, M., Forsgren, L. & Hariz, G.-M. Gender differences in Parkinson’s disease: A clinical perspective. Acta Neurol. Scand. 136, 570–584 (2017). 44. Creswell, J. W. & Plano Clark, V. L. Designing and Conducting Mixed Methods Research. Sage Publications Inc https://us.sagepub.com/en-us/nam/designing-and-conducting-mixed-methodsresearch/book241842 (2023).
Part 1 Understanding the impact of gender on health outcomes and illness experiences
Chapter 2 The impact of sex and gender on the multidisciplinary management of care for persons with Parkinson´s disease This chapter is based on the following publication: Göttgens I, van Halteren AD, de Vries NM, Meinders MJ, Ben-Shlomo Y, Bloem BR, Darweesh SKL and Oertelt-Prigione S (2020) The Impact of Sex and Gender on the Multidisciplinary Management of Care for Persons With Parkinson’s Disease. Front. Neurol. 11:576121. doi: 10.3389/fneur.2020.576121
Abstract The impact of sex and gender on disease incidence, progression and provision of care has gained increasing attention in many areas of medicine. Biological factors–sex–and sociocultural and behavioural factors–gender–greatly impact on health and disease. While sex can modulate disease progression and response to therapy, gender can influence patient-provider communication, non-pharmacological disease management and need for assistance. Sex and gender issues are especially relevant in chronic progressive diseases, such as Parkinson´s disease (PD), because affected patients require multidisciplinary care for prolonged periods of time. In this perspective paper, we draw from evidence in the field of PD and various other areas of medicine to address how sex and gender could impact PD care provision. We highlight examples for which differences have been reported and formulate research topics and considerations on how to optimise the multidisciplinary care of persons with PD.
Sex and Gender in Multidisciplinary PD Care 25 2 Introduction Sex and gender impact disease incidence, progression and provision of care in different medical disciplines.(1) “Sex” differences are based on biological variations due to differences in genetics, hormones and physiology. “Gender” differences are rooted in different expressions of identity, adherence to norms and socially defined behaviours. (2) Sex can impact the biological bases of disease progression, response to diagnostics and therapies, while gender can influence access to healthcare, coping with disease, compliance with therapies and patient-provider communication. Taken together, these aspects warrant consideration in the provision of care to people living with a disease. The influences of sex and gender on care delivery are especially relevant for chronic diseases that are characterized by a heterogeneous and progressive spectrum of clinical features. A prime example of such a disease is Parkinson’s disease (PD), which is the second most common neurodegenerative disease worldwide and which demonstrates a rapidly rising prevalence.(3) PD is partially characterized by motor features, but affected persons typically also experience a highly variable combination of non-motor features. Given the multifaceted and heterogenous nature of the disease, care delivery to people with PD typically involves healthcare professionals from a wide range of different professional disciplines to accommodate the specific clinical features, needs and coping styles of a person with PD.(4–7) Ideally, any person with PD should be treated by a diverse, multidisciplinary team, consisting of a general practitioner, neurologist, PD nurse specialist, physiotherapist, occupational therapist, speech- and language therapist, neuropsychologist, dietician or other healthcare professionals, depending on the needs of the patient.(7) At the time of clinical diagnosis, differences in the prevalence of motor and non-motor features might exist between men and women with PD. For instance, men might experience more rigidity and women more tremor.(8) As the disease progresses, sex and gender differences can emerge in the incidence of clinical features, such as postural instability or depressive symptoms (8,9). In addition to these differences in clinical phenotype, coping styles may also vary between men and women with PD.(10) Given this broad spectrum of potential differences, the consideration of sex- and genderspecific problems and needs of people with PD appears to be essential to provide personalised care. However, to date, empirical insight on the influence of sex and gender on disease progression and care for people with PD remains scarce. This perspective paper addresses how sex and gender may impact care for people with PD, drawing from both the PD literature as well as from other fields of medicine. We will specifically focus on the following domains: 1) motor features, 2) non-motor features,
Chapter 2 26 3) lifestyle and 4) coping and informal care. To illustrate the potential impact of sex or gender, we highlight examples for which differences have been reported in PD, although the level of evidence varies substantially. For each section, the reviewed data on sex and gender differences in PD are summarized, and considerations for multidisciplinary and sex- and gender-sensitive care for people with PD are highlighted.
Sex and Gender in Multidisciplinary PD Care 27 2 Sex and gender aspects in PD Sex and gender aspects in motor features PD is primarily known as a clinical syndrome described as ‘Parkinsonism’, which entails bradykinesia in combination with at least one of the following: resting tremor, rigidity or postural instability.(11,12) As the disease progresses, people with PD are prone to develop fluctuations in motor impairments related to dopaminergic therapy, as well as to freezing of gait.(13) Several differences in motor features between men and women with PD have been reported and have been summarized elsewhere.(8,14,15) However, the relevance of these differences for care provision to people with PD remains largely unknown. The potential impact of sex or gender differences on multidisciplinary care for mobility impairments comes from other fields of medicine, such as recent recommendations for osteoporosis screening guidelines based on underlying sex differences.(16) Osteoporosis predominantly affects postmenopausal females(17) but also impacts many elderly males.(18,19) Given the higher mortality of men with bone fractures, several osteoporosis and endocrinology societies now recommend screening in all men above 65 or 70 years (19,20), but this recommendation is not routinely implemented in clinical practice.(16) Similarly, it is possible that sex or gender differences in the prevalence of common motor features in PD may influence clinical recommendations in the future. Now, however, several gaps in empirical evidence hamper development of such sex- and gender-sensitive guidelines. In Table 1, we highlight key questions that, once addressed, could guide the implementation of sex- and gender-sensitive approaches to care for people with PD. An illustration of the current gaps in knowledge is the recent observation that postural instability appears to be more common among women with PD than among men.(8,21) This observation is based on a few relatively small studies, rendering uncertainty on whether this reflects a true sex difference in the prevalence of this feature. If larger studies replicated this finding, it would encourage preferential referral of women with PD to a physiotherapist for preventive and symptomatic interventions, such as technology-assisted balance training. But for this selective referral to be effective, we also need insight on whether the effectiveness of symptomatic interventions differs between men and women with PD. Future studies should be adequately powered to examine clinically meaningful effect modification by gender, which requires larger sample sizes.
Chapter 2 28 Furthermore, knowledge about the impact of gender-specific differences in activities of daily living (ADL) among people with PD is relatively scarce. The available literature, however, suggests that causal influences on ADL may differ substantially by gender. For instance, women report greater difficulty shopping and cleaning compared to men with PD, highlighting not only the practical consequences of mobility impairment, but also its gendered dimension.(22) If these differences are replicated in other studies, this would encourage the development of gendersensitive targeted occupational therapy interventions for ADL impairment.(23) Taken together, empirical evidence for targeted care interventions which consider sex and gender differences in mobility impairment could eventually influence clinical guidelines for people with PD. An additional area of potential sex- or gender-related influences on care revolves around interactions between patients and healthcare professionals. In the field of surgery, two gender-related factors have affect the indication for total joint arthroplasty(24): less referral of women by their primary care physician, i.e. reflecting a potential bias on the side of the physician; and less requests by women to undergo surgery, i.e. bias on the side of the patient. A recent study suggests that women with PD are less likely to undergo Deep Brain Stimulation (DBS) surgery than men with PD.(25,26) This is of particular note given that the current literature suggests that women may experience a greater improvement in quality of life after DBS than men.(9,27) This imbalance needs to be further investigated to remove potential referral or request bias through targeted interventions on the provider or patient side. (26,28) Sex and gender aspects in non- motor features Although PD is widely (and inadvertently) perceived as being primarily characterized by motor symptoms, non-motor symptoms are actually at least as common, and importantly, these can have a considerable impact on quality of life in persons with PD. In this section, we discuss two examples that highlight the potential impact of sex and gender differences on multidisciplinary care for people with PD: impulse control disorders and depressive symptoms. Impulse control behaviours (ICBs) are associated with dopamine replacement therapy in PD. Overall, ICBs are generally more common in men compared to women with PD.(29) However, the direction of these differences might differ by the specific type ICB: hypersexuality and gambling are more common in men, while compulsive buying is more common in women.(30) Analogous differences have been reported for compulsive disorders in people without PD, with women
Sex and Gender in Multidisciplinary PD Care 29 2 presenting more contamination/cleaning symptoms or eating disorders whereas men more commonly present with sexual and aggressive symptoms.(31,32) It remains to be investigated if these differences are due to different disease entities or simply to socially-acceptable gendered behaviours (Table 1). Depressive symptoms and anxiety are among the most common non-motor symptoms in people with PD.(33,34) Depressive symptoms and anxiety in PD are likely to be multifactorial, related to the influence of PD pathology and the indirect impact of impaired mobility and social isolation.(35,36) Sex differences in depression have been linked to differences in expression of susceptibility genes and hormonal influences as well as gender-related differences in reporting.(37,38) Although females and males with PD experience similar physical symptoms, the associated psychological burden appears to differ. Men primarily report difficulties in self-presentation, whereas women report greater psychological burden and larger impact on their intimate relationships.(39,40) This associates with a significant reduction in quality of life in women with PD.(41) Also, higher anxiety levels have been reported in women with PD, especially in the early clinical phase of the disease.(42–44). However, to date, the impact of sex and gender differences in anxiety and depressive symptoms on care provision for people with PD has remained limited. Again, the field of PD is not unique in this regard. In 2008, the masculine depression scale (MDS) was developed to facilitate diagnosis of masculine depressive symptoms.(45) A recent study found that men and women who endorse a masculine gender role are relatively more likely to display externalising symptoms (e.g., anger, somatic symptoms, using substance or sex to feel better) in response to negative life events, and less likely to report typical, internalising depressive symptoms, as measured by, e.g., the widely used Beck Depression Inventory (e.g., depressed mood or crying).(46) Therefore, clinicians should be aware that individuals who strongly adhere to masculine gender roles, whether they be men or women, might display different signs and symptoms and may respond differently to behavioural interventions for depression and anxiety than individuals who adhere more strongly to a feminine gender role (Table 1). Gender aspects in lifestyle Few differences in lifestyle between men and women with PD have been reported. In this section, we discuss two examples that highlight the potential impact of such differences on multidisciplinary care for people with PD: weight loss and physical activity. Progressive weight loss is common among people with PD , likely due to a combination of physical inactivity (causing muscle loss), lower intake of solid foods due to oropharyngeal dysphagia and a catabolic state.(15,47) A decreased intake of solid foods
Chapter 2 30 may result in less consumption of fresh foods and vegetables, which leads to a risk of malnutrition.(47) Researchers in other fields consistently reported healthier food choices among women compared to men, including increased consumption of fresh fruit and vegetables and reduced consumption of processed food and alcohol.(48,49) Encouragement by nutritionists of the consumption of healthy, solid, foods should consider these gender norms, as well as direct assessment of the ability to prepare and consume foods due to disease-related physical limitations. Again, this is an area in which a gender-sensitive care intervention for people with PD could be informed by data from other fields. However, to our knowledge, no studies have examined the effectiveness of gender-sensitive approaches to nutrition among people with PD to date. Once validated, gender-sensitive approaches may also help to better understand differences in body weight related impairments between men and women with PD. A useful example here comes from the field of cardiometabolic diseases, in which the observation of body fat distribution differences between women and men led to the identification of the hip-to-waist ratio as a better predictor of risk than BMI, especially for women.(50) Among people with PD, weight loss generally associates with higher mortality and worse quality of life.(51) While unexplained weight change is reported more commonly in women with PD (52,53), clinically significant weight loss is reported to be associated with lower 1-year survival rates in men, compared to women with PD.(54) Future studies should examine the sex-specific prognostic utility of weight loss among people with PD. Gender considerations are also relevant in the context of physical activity. Women worldwide appear to engage less frequently in physical activity compared to men.(55) Different drivers can modulate the uptake of physical activity in women and men with PD. Women appear to rely on enjoyment as the primary motivator while men describe self-efficacy as the primary driver for physical activity.(56) In different regions, genderrelated factors might also be at play. For example, in a qualitative study in Jordan, women with PD reported family commitment and support as important elements to initiate and maintain an exercise program. However, gender norms acted as barriers as unequal division of household tasks and childcare limited the time available for exercise.(57) Different motivation strategies might be needed for women and men with PD and gender norms should be made explicit to reduce barriers to exercise (Table 1). Examples could be drawn from gender-sensitive programs to increase physical activity and promote healthy weight such as WISEWOMAN in the United States and Football Fans in Training (FFIT) in the UK.(58,59)
Sex and Gender in Multidisciplinary PD Care 31 2 Gender aspects in coping and informal care Several differences in care management between men and women with PD have been reported. In this section, we discuss two examples that highlight the potential impact of such differences on multidisciplinary care for people with PD: coping strategies and informal care. Gender can influence individual coping strategies and should be taken into account in systematically measuring differences in distress and coping.(43) General studies on gender differences coping strategies are conflicting. Some authors report that women use more emotion-focused coping strategies while men prefer focusing on avoidant coping.(60,61) However, a study targeting coping strategies among people with PD reported the opposite, with women reporting more problem-focused coping strategies compared to males.(10) Interestingly, less polarized gender roles might associate with better quality of life in women. Specifically, androgynous women with PD, expressing masculine and feminine personality traits equally, scored significantly better on quality of life than androgynous men with PD.(62) Similar to the impact of gender roles on the response to negative life events in the context of depression, clinicians should be aware of the potential impact of gender roles on (in)effective coping strategies. Additionally, researchers should continue to explore the impact of different gender dimensions on coping strategies and health-related quality of life in people with PD. In the context of informal care, women with PD report less social support and less informal caregiving resources compared to men.(8) Women worldwide are still more frequently active caregivers than men, although this is changing in younger generations.(63) Previous studies describe fewer negative outcomes and less impaired quality of life in male caregivers.(64,65) Women caregivers reported exhaustion, social constraints and time limitations more frequently than men and women report more adverse consequences from the progression of the disease of their partners, such as feelings of manipulation, excessive demands and lack of freedom.(38) One study noted that women caregivers appeared to experience a higher incidence of depression and dysfunctional fear of progression compared to men caregivers(66), but another failed to find any gender differences in psychological, social and health outcomes.(67) Progression of disease and the potentially associated cognitive decline, which is higher in men with PD compared to women, also places a higher burden on caregivers with potential impact on their health.(14,68–71)
Chapter 2 32 Table 1. Considerations for sex- and gender sensitive multidisciplinary PD care. Domain Feature (s) Reported to be more common in Motor Features Poor balance Women Dyskinesia Women Non-motor features Impulse control disorders Men Episodes of depression and anxiety Women Lifestyle Weight loss related impairment Men Limited physical activity Women Care Support Less informal care resources Women Higher caregiver strain Women
Sex and Gender in Multidisciplinary PD Care 33 2 Possible sex- and gender sensitive care intervention(s) for this feature Key questions that could guide sex- and gender-sensitive approaches • Referral to (technologyassisted) balance training interventions • Are differences between men and women considered when assessing the effectiveness of balance training intervention? • Do men and women prefer different features in technologyassisted balance training interventions? • Deep brain stimulation • What are the underlying reasons for delayed access to deep brain stimulation surgery, on average, in women compared to men? • Do underlying gender-biases influence the shared decisionmaking process concerning deep brain stimulation surgery? • Reduction or discontinuation of dopaminergic therapies • Cognitive behaviour therapy • Are gender differences in ICBs due to different disease entities or socially accepted gender behaviours? • How are patients addressed and informed about sex differences in response to dopamine replacement therapies? • Do sex or gender predict outcome in psychotherapy interventions such as cognitive behaviour therapy? • Referral for coping skills training e.g.: mindfulnessbased interventions • Social support interventions • Do screening measures for depression and anxiety take differences in gender roles into account? • Do gender traits predict or affect the responsiveness to depression and anxiety care interventions? • Regular weight selfmonitoring • Development and regular review of diet plan • Are differences in food choices and practices between men and women considered in weight monitoring? • Do sex and gender aspects contribute to differences in food intake and processing? • Exercise enhanced by motivational app elements • Physical exercise interventions • Do exercise apps take different drivers and motivations for exercise between men and women into account? • Do exercise apps take gender-specific triggers and rewards into account in their design? • Proactive identification of social network and care capacities of the patient • Referral to social support interventions/ cognitive behavioural therapy • Are social support interventions taking gender-specific drivers and motivators into account? • Are there gender differences in social support needs and social support perception and how are these considering? • Regular screening of caregiver burden • Care giver education about disease progress, symptoms, and experiences • Do screening measures of caregiver burden take gender differences in caregiver experiences into account? • Are there gender differences in information and education needs about disease progression and (advanced) care planning?
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