Review papers

Ten authors have been requested to write a review about the integration of gender in their field of expertise.

Ten reviews have been commissioned which together cover various methodological aspects of paying attention to sex and gender in research as well as six health areas where attention to sex and gender issues is urgently called for. The methodological reviews address basic, translational, clinical and public health research. The identified health area's are: anxiety disorders, asthma, metabolic syndrome, nutrigenomics, osteoporosis, and work-related health.

The reviews are meant to provide the state of the art as regards specific problems and opportunities (challenges) and at proposing widely supported solutions. The reviews, referee comments and discussions will contribute to answering the following questions:


These ten papers were peer reviewed, presented and discussed at the GenderBasic Expert Meeting.

The GenderBasic Reviews have now been published:
Gender Medicine, Volume 4, Supplement B, 2007. GenderBasic: Promoting Integration of Sex and Gender Aspects in Biomedical and Health-Related Research.

  1. Integrating the dimension of sex and gender into basic life sciences research: methodological and ethical issues in research. A review of the problems and solutions in experimental studies. (pdf) Anita Holdcroft
  2. Gender differences in asthma development and progression. (pdf) Dirkje S. Postma
  3. Methodological ramifications of paying attention to sex and gender differences in clinical research. (pdf) Martin H. Prins , Kim M. Smits & Luc J. Smits
  4. Integrating a gender dimension in osteoporosis and fracture risk research. (pdf) Piet P.M.M. Geusens & GeertJan Dinant
  5. Sexually dimorphic gene expression in somatic tissues. (pdf) Jörg Isensee & Patricia Ruiz Noppinger
  6. The metabolic syndrome - sex and gender related issues. (pdf) Vera Regitz- Zagrosek , Elleke Lehmkuhl & Shokufeh Mahmoodzadeh
  7. Methodological and ethical ramifications of paying attention to sex and gender differences in public health research. Prevention, health care delivery; focus on health inequalities with particular examples from Austria. (pdf) Anita Rieder & Kitty Lawrence
  8. Anxiety disorders: a gender test case within mental health (care) research. (pdf) Marrie H.J. Bekker & Janneke van Mens- Verhulst
  9. A tool for distinguishing gender research from gender difference research – examples from work-related health. (pdf) Anne Hammarström
  10. Gender, a major player in the crosstalk between genes, environment and health. (pdf) Jose M. Ordovas


Paper 1: Integrating the dimension of sex and gender into basic life sciences research: methodological and ethical issues in research. A review of the problems and solutions in experimental studies. (pdf)

Anita Holdcroft, MB ChB MD FRCA, Clinical Reader in Anaesthesia and Honorary Consultant Anaesthetist
Department of Anaesthetics, Pain Medicine and Intensive Care
Division of Surgery, Oncology, Reproductive Biology and Anaesthetics (SORA)
Faculty of Medicine
Imperial College London
Chelsea and Westminster Hospital
369 Fulham Road, London, SW10 9NH , United Kingdom
Phone: +44 (0)20 8746 8816
Fax: +44 (0)20 8237 5109

The research process, from study design, selecting a species and its husbandry, through the experiment and analysis, publication and peer review, is rarely subject to questions about sex or gender differences in mainstream life sciences research. However, the impact of sex and gender on these processes has been recognised to be important in explaining biological variations and presentation of symptoms and diseases. The mechanisms for these effects lie not only in biological differences but also in environmental, social and psychological interactions. Unfortunately, laboratory research often imposes restrictions that are not present in a normal population. These are particularly related to ageing, socializing and reproduction and, although present in humans, are not systematically studied in the laboratory.

Methodological approaches to this present lack of a gender dimension in research include actively reducing variations through attention to physical factors, biological rhythms and experimental design. The hormonal milieu is another factor and although their genomic activity is well recognised, the more acute non-genomic effects of hormones may play a role in the development of small sex differences that can compound during the course of an acute pathological event. In addition there are now many exogenous sex steroid hormones and their congeners used in medicine, for example in contraception and cancer therapies, and these may further alter cellular activity.

Having determined that sex and gender are determinants of many outcomes in life science research then in order to embed the gender dimension into basic science research, it has to be broadly applied. One approach may be externally through animal ethical review boards and peer review of manuscripts where standardised questions can be asked about study design and analysis. In addition the relevance of laboratory models should be questioned in order to determine how best they can represent the age-related changes, co-morbidity and variations experienced by different genders in clinical medicine.

Paper 2: Gender differences in asthma development and progression. (pdf)

Dirkje S. Postma, MD PhD, Professor of Pulmonology
Department of Pulmonary Medicine
University Medical Center Groningen
University of Groningen
Hanzeplein 1
9713 GZ Groningen, the Netherlands
Phone: +31 50 361 3532

Asthma is an inflammatory, chronic airway disease that has a higher prevalence in boys before puberty and a higher prevalence in females in adulthood. Due to the complexity of the disease, no straightforward single mechanism can explain gender differences found in asthma. It is likely that hormonal changes and genetic susceptibility both contribute to the change in prevalence around puberty. Intriguingly severe asthma is also more predominant in females. It has to be established whether this is a social, cultural, hormonal and/or genetic issue. Topics requiring further research are:


Paper 3: Methodological ramifications of paying attention to sex and gender differences in clinical research. (pdf)

Martin Prins, MD PhD, Professor of Clinical Epidemiology
Faculty of Health, Medicine and Life Sciences
Department of Epidemiology
Maastricht University
P.O. Box 616
6200 MD Maastricht, the Netherlands

Essential in studies on differences in effect based on sex is the evaluation of effect or accuracy estimate differences between patient groups based on sex, i.e. the analysis of effect modification. The use of absolute risk differences to illustrate differences in treatment effect size between sexes should be preferred to facilitate decisions on diagnostic and /or treatment strategies separately for sexes. Confounding can be introduced by an unequal distribution of potential effect modifiers of prognostic variables associated with sex or gender. Therefore, differences in the distribution of presumed effect modifiers or prognostic variables should be presented and, if possible, taken into account. The choice of a statistical model for analysis should be based on the effect measure that was chosen to measure treatment effect. If risk ratios were used, analyses should be based on a multiplicative model. In addition, due to a possible association between sex, gender and prognosis, interactions between treatment and sex should be analysed by calculating the effect of treatment within each of the sexes and subsequently comparing these effect sizes with each other. For the use of results in meta-analyses, point estimates and their 95% confidence intervals should be presented for each sex separately.


Paper 4: Integrating a gender dimension in osteoporosis and fracture risk research. (pdf)

Piet P.M.M. Geusens, MD PhD, Professor of Medicine
Biomedical Research Institute
University Hasselt
Agoralaan gebouw A
B-3590 Diepenbeek, Belgium
Phone: +32 11 269375
Fax: +32 11 269376

GeertJan Dinant, MD PhD, Professor of Clinical Research in General Practice
Faculty of Health, Medicine and Life Sciences
Department of General Practice
P.O. Box 616
6200 MD Maastricht, the Netherlands

Sex (referring to its strict biological sense) and gender (referring to the socio-cultural dimension) are major determinants of health and disease. The aim of this review is to examine differences between sexes in the prevalence of osteoporosis and fractures and their risks in terms of bone- and fall-related factors and to review differences between genders in relation to the perception of fracture risk and the possibilities of prevention of fractures.

The incidence of fractures differs between women and men: it is higher in boys than in girls and the burden of fractures in adults increases with age, and is higher in adult women than in adult men. With life expectancy growing the yearly number of fractures is likely to increase substantially. Vertebral, hip and other non-vertebral fractures in adults result in increased mortality (more in men than in women), increased morbidity (equal in women and men) and high costs (more in women than in men).

The reasons for the differences in incidences of fractures between men and women are multiple. They are related to the many factors that determine fracture risk: those related to bone and those related to falls. Such differences, but also similarities, have been documented from the molecular and cellular level up to the organ level. Sex hormones play a central and essential role in the physiology of bone. Sex hormones have a wide array of functions and influences on bone, cartilage and muscle cells by direct and indirect mechanisms. Differences in sex hormones therefore directly and indirectly contribute to sex differences in fracture risk.

Adult men fracture less because they build up structurally stronger bones than women and which they are able to maintain longer. Men build up larger bones during growth with better micro architecture and thereafter have less increase in bone remodelling. Furthermore, they develop later bone loss and fewer older men are hypogonadic than women.

Case finding strategies for patients at risk for fracture, including bone densitometry, is much better documented at the population level in women than in men.

Drug therapies that reduce the risk of a broad spectrum of fractures, even within short term, are more clearly demonstrated in randomised controlled studies in women than in men. Drug therapy is more widely available for women with osteoporosis, but only scarcely for men with osteoporosis.

In how far perception of osteoporosis could be different between genders is less well documented. In general, osteoporosis is under diagnosed and under treated both in women and men, and related to limits in patient's and doctor's awareness at all clinical stages, from case finding to compliance and persistence of therapy.


Paper 5: Sexually dimorphic gene expression in somatic tissues. (pdf)

Jörg Isensee, MSc
Center for Cardiovascular Research (CCR)
Max-Planck-Institut für Molekulare Genetik
Campus Charité Mitte
Charité, Universitätsmedizin Berlin
Hessische Strasse 3-4
10115 Berlin, Germany
Phone: +49 - 30 - 450 578 727
Fax:+49 - 30 - 450 525 901

Patricia Ruiz Noppinger, PhD
Center for Cardiovascular Research, Charité Universitätsmedizin &
Max-Planck Institute for Molecular Genetics, Dept. Vertebrate Genomics
Hessische Str. 3-4, 10115 Berlin, Germany
Tel. +49 - 30 - 450 578 744
Fax. +49 - 30 - 450 525 901

The sexually dimorphic differentiation of the bipotential gonad into testis or ovary initiates the sexually dimorphic development of mammals and leads to divergent hormone levels between sexes for the entire lifetime. However, despite the fact that anatomical and hormonal differences between genders are well described, only a few studies investigated the manifestation of these differences at the transcriptional level in somatic tissues. More recently, the application of microarray technology enabled the systematic evaluation of sex-biased gene expression on transcriptome level indicating that the regulatory pathways underlying sexual differentiation are giving rise to extensive differences in gene expression in adults. A sustainable annotation of sex-biased gene expression represents a key towards the understanding of basic physiological differences between males and females in the healthy as well as diseased condition. This review focuses on basic regulatory mechanisms of sex-specific gene expression and discusses recent gene expression profiling studies to outline basic differences between sexes on transcriptome level in somatic tissues


Paper 6: The metabolic syndrome - sex and gender related issues. (pdf)

Vera Regitz-Zagrosek, PhD, Elleke Lehmkuhl; Shokufeh Mahmoodzadeh
Center for Gender in Medicine and Cardiovascular Disease in Women and Cardiovascular Research Center Berlin
Charité and Deutsches Herzzentrum Berlin
CCR, Hessische Str. 3 – 4
10115 Berlin, Germany
E- mail:

The combination of the risk factors abdominal obesity, disturbed glucose homeostasis, dyslipidemia and hypertension are believed to represent a distinct entity that leads to a greater increase in cardiovascular risk than the sum of its components and has therefore been defined as an own entity - the metabolic syndrome. In the recent years, the prevalence of the syndrome was greater in men but rose particularly in young women where it is mainly driven by obesity. Diagnostic criteria for the metabolic syndrome vary for the cut-off points and definition of its components in a gender specific manner. Based on the definition of impaired glucose homeostasis, pathological abdominal circumference or waist/ hip ratios, more or less women are included. Glucose and lipid metabolism are directly modulated by oestrogen and testosterone with induction of insulin resistance and a proatherogenic lipid profile by a lack of oestrogen or a relative increase in testosterone. Hypertension is a strong risk factor in both sexes and increases steeper in aging women than in men. Menopause and polycystic ovarian syndromes contribute to the development of metabolic syndrome by the direct effects of sexual hormones. Some components of the metabolic syndrome carry a greater risk for cardiovascular disease in women, such as hypertension and diabetes. Future gender related clinical and research activities should focus on the identification of sex and gender specific criteria for risk management in patients with the metabolic syndrome. We propose small focussed mechanistic studies on sex specific surrogate endpoints and sex-specific studies in animal models for diabetes and aging.

Keywords: metabolic syndrome, menopause, cardiovascular disease, gender differences


Paper 7: Methodological and ethical ramifications of paying attention to sex and gender differences in public health research. Prevention, health care delivery; focus on health inequalities with particular examples from Austria. (pdf)

Anita Rieder, MD, Professor of Social Medicine
Centre for Public Health, Institute of Social Medicine,
Medical University of Vienna
Rooseveltplatz 3
A-1090 Vienna
Phone: 01/4277-64 680

Kitty Lawrence, BEng. DipION, MPH
Association Altern mit Zukunft
A-1090 Vienna, Austria
Phone: +43 1 409 5201 11
Fax: +43 1 409 6295 15

Much progress has been made in recent years towards achieving a more “gender conscious” approach to research and health promotional and preventive intervention. The profile of gender specific medicine has been further heightened by initiatives, statements and guidelines from, for example, the WHO, the Beijing platform for action and gender mainstreaming “Gender Good Practices” and the EU framework programme. Increasingly countries are paying more attention to gender issues, developing strategies and setting up projects to incorporate gender mainstreaming and gender equity, not only in medicine, but also in all walks of life. However, no country has yet managed to completely eliminate the gender gap. There is much work still to be done and much to be considered in terms of the ethical and methodological implications of gender orientated public health research and practical application. The question Does sex matter ? has long since been answered with yes. It is time now to examine what we know and how we can best utilise and implement this knowledge in effective public health research and strategy.

As a multifaceted determinant of health, gender is inextricably linked with public health which assumes illnesses and health problems are influenced by physical factors, the social/cultural and health political environment. Inequities between men and women in terms of health, access to public health programmes and medical treatments have in part stemmed from the past lack of gender-differentiated research. This paper looks at the implications that incorporation of gender in public health research has for methodology and public health ethics. It aims to identify where potential disparities lie starting with education at medical school through to inequalities in access to health care and health care delivery and further discusses implications for policy. Finally some practical examples have been cited from Austria such as the compilation and use of gender specific health reports, which have proved an invaluable tool in the development of public health policy.

Only through gender-based research and public health planning and intervention can we achieve health promotion and prevention tailored to the specific needs of men and women in the 21 st century.

Gender Specific public health strategies have a major responsibility to meet the societal needs and to contribute to the societal value of health research.


Paper 8: Anxiety disorders: a gender test case within mental health (care) research. (pdf)

Marrie Bekker, PhD, Associate Professor in Clinical and Health Psychology and Diversity
Department of Psychology and Health
Tilburg University
P.O. Box 90153
NL-5000 LE Tilburg, the Netherlands
Phone: +31 13 466 2366

Janneke van Mens-Verhulst, PhD, Former Professor of Women's (Mental) Health Care
University for Humanistic Studies, Utrecht & Associate Professor in Health Psychology, Department of Health Psychology
Kastanjelaan 24
1214 LH Hilversum, the Netherlands.
Phone/fax +31-35-6246850 (or phone +31-30-2534924, fax 2534718)
E-mail: .

Anxiety disorders are more prevalent among women than among men. The present paper is aimed at investigating to what degree current theories and treatment of anxiety disorders pay attention to gender. To that end, we systematically scrutinized the literature, mainly the Psycinfo and Pubmed databases, but also performed several additional searches. The main themes in our searches were current prevalence figures of the several types of anxiety disorders, and co-morbidity; theories explaining anxiety disorders; and studies on treatment effects.

Our main conclusion is, first, that more attention should be given to gender-relevant individual differences leading to anxiety disorders via learning processes. Attachment experiences and resulting affective-cognitive conditions in terms of attachment styles and autonomy-connectedness seem promising but firmer empirical evidence has to be established, also concerning possible processes between these conditions and phobic fears and avoidance. Secondly, large discrepancies are observed between the attention paid to the sex differences in prevalence of anxiety disorders and their possible background on the one hand, and the scarce attention given to these differences when it comes to treatment, at the other hand. Prevention and treatment might gain efficiency if the available knowledge on sex- and gender specificity of aspects of anxiety disorders would be implemented into practice. Simultaneously, treatment effect studies should be improved by paying more attention to sex and gender throughout the research process.


Paper 9: A tool for distinguishing gender research from gender difference research – examples from work-related health. (pdf)

Anne Hammarström, MD PhD, Professor of Public Health
Dept of Public Health and Clinical Medicine
Division of Family Medicine
Umeå University
901 85 UMEÅ, Sweden
Phone: +46 (0)90 - 785 35 47

Background: The awareness of gender research is low in academic medicine and the concepts of ‘sex' and ‘gender' are often used synonymously. The number of medical articles with focus on gender and women is increasing, while the number of articles based on gender research is still quite small.

Aim: The aim of this paper is to identify possible problems and /or challenges with regard to the concepts of ‘sex' and ‘gender' in work-related research as well as to propose a tool to implement the theoretical insights. The tool will be used to distinguish gender research from gender or sex difference research in relation to the public health consequences of unemployment and labour market position.

Results: Gender research differs from sex/gender difference research in several important ways. While gender research questions the dominating epistemology of medicine, sex/gender difference research is performed within the dominating paradigm. While gender is an analytic category and structural analyses of gender relations are central in medical gender research, the level of analyses in sex/gender is often as a variable on the individual level in gender difference research. Masculinity research constitutes a dynamic part of gender research. However, in sex/gender difference research men, as well as women, are analysed as one of several variables. Through questioning the existing field of knowledge, gender research – with its base in power analyses and theoretical development – can lead to new knowledge about men and women. There is vigilance in gender research with regard to the risk of exaggerating differences between men and women; these differences are either biomedical or socio-cultural in nature. In gender difference research there is a risk for essentialism, i.e. the tendency to regard differences between men and women as constant, general and unimpressionable.

Conclusion: In this paper I have developed a model which may be used to distinguish gender research from gender difference research. The model may become a practical tool for making such comparisons. However, the questions in the tool need to be refined and further developed in an active dialogue with gender researchers.

Paper 10: Gender, a major player in the crosstalk between genes, environment and health. (pdf)

Jose M. Ordovas, PhD, Senior Scientist and Director, Nutrition and Genomics Laboratory
Jean Mayer USDA HNRCA at Tufts University
711 Washington Street
Boston , MA 02111-1524
Phone: (617) 556-3102
FAX: (617) 556-3103

Men and women share most of the genetic information; however, they have dramatically different disease susceptibilities which go well beyond the expected gender-specific diseases (i.e., cervical or prostate cancer). Sex influences susceptibility to nearly all common diseases that affect both men and women, including atherosclerosis and diabetes and their preceding risk factors, such as hyperlipidemia, insulin resistance and obesity. These are all known to be highly complex and multifactorial in their origin, involving genetic factors but also a myriad of environmental and behavioural factors which interact with the genetic component, which, in itself, is highly polygenic. This complexity underlies the poor replication obtained for most candidate gene association studies examining common diseases and their predisposing risk factors. There is already evidence about the different pharmacogenetic response to lipid-lowering drugs in men and women. However, pharmacogenetic knowledge deals with the population that is already diseased or at high risk of developing disease. Parallel developments are taking place in the area of nutrigenomics aimed to the health of the entire population. In this regard, information exists regarding significant gene-gender interactions for risk of diet-related diseases (i.e., obesity) as well as more complex gene-gender-diet interactions (i.e., perilin). However, we are still lagging behind in terms of replication of preliminary interesting findings as well as on the definition of the functional basis for these gender-specific effects.

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