“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

Abstract

Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

“…Sex/gender-related differences in cardiovascular disease (CVD) risk, clinical phenotype, and outcome have been discovered in the past two decades [1]. These new concepts have an important translational value as CVD is the leading cause of death in older people and there is a global increase in the elderly population.…”

“…Of particular relevance is the issue of heart failure, which is expected to double each decade of life and to grow significantly in the whole population due to the dramatic increasing trend of population aging, particularly in the developed countries [3]. Although several novel molecular markers and pharmacogenetic studies have been used to intensively investigate complex polygenic chronic or degenerative diseases [4][5][6][7][8][9][10][11][12][13] leading to the discovery of novel prognostic biomarkers or inherited predispositions [14][15][16][17][18][19], specific dedicated therapies to treat heart failure due to heart wall remodeling do not currently exist, and women experience the worst prognosis [1,20,21]. Epidemiological data highlight that CVD now represents the leading cause of mortality and hospital admission for women, accounting for one in three deaths worldwide and half of all deaths of women over 50 in developing countries [3].…”

“…Epidemiological data highlight that CVD now represents the leading cause of mortality and hospital admission for women, accounting for one in three deaths worldwide and half of all deaths of women over 50 in developing countries [3]. By contrast, breast cancer, considered in the past to be the leading cause of death in women, now accounts for just 3% of all deaths in the female adult population [1,22]. Several studies and reports have unequivocally demonstrated the key role of sex hormones in protecting women from CVD during the premenopausal state, providing an advantage over men that is lost when the hormonal profile changes at menopause transition.…”

“…In real practice, new therapeutic treatments useful to men have not led to a significant decrease in CVD fatality rates in women [1,24], supporting the key role of sex/gender differences in determining CVD risk, diagnosis, and prognosis and explaining the existing gap in the progress achieved to treat CVD in women compared to men [25]. The emerging view is that disparities in knowledge regarding CVD in women over men can be overcome through a sex/gender-based "holistic" approach to disease pathophysiology [1,20], spanning from clinical signs and manifestations up to risk establishment, diagnosis definition, and dedicated treatment design through appropriate clinical trials in which the role of sex and gender differences can be properly evaluated in terms of therapeutic response [22]. In fact, although milestone studies in the last few decades have allowed the development/optimization of actual standard care in the context of CVD by taking advantage of more accurate clinical tests that have allowed a better definition of the risks and benefits of effective prevention/therapies, the majority of these studies did not appropriately consider women.…”

“…It is now widely recognized that there is an incremental shift in how CVD should be treated in women. This has left healthcare professionals unprepared, mainly because of the poor understanding of sex/gender-specific differences in the pathophysiology of CVD, resulting in a dramatic absence/insufficiency of diagnostic and therapeutic guidelines to address personalized differences in women [1,3].…”