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Try out PMC Labs and tell us what you think. Learn More. Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity.
We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.
What clinicians know about the diagnosis, treatment, and prevention of disease originates from studies mostly done on male cells, male mice, and men. As a result, medical research and care have been centred on male physiology. The assumption was that male and female cells and animals were biologically identical, and evidence-based medicine was defined by clinical trials done predominantly in men.
Preclinical research and drug development studies have also predominantly used male animal models and cells. Essential for the success of clinical care and translational science is awareness by clinicians and researchers that the diseases they are treating and studying are characterised by differences between women and men in epidemiology, pathophysiology, clinical manifestations, psychological effects, disease progression, and response to treatment. This Review explores the role of sex biological constructs and gender social constructs as modifiers of the most common causes of death and morbidity, and articulates the genetic, biological, and environmental determinants that underlie these differences.
We aim to guide clinicians and researchers to better understand and harness the importance of sex and gender as genetic, biological, and environmental modifiers of chronic disease. Ultimately, it is a necessary and fundamental step towards precision medicine that will benefit women and men. Sex differences in disease prevalence, manifestation, and response to treatment are rooted in the genetic differences between men and women. Genetic sex differences start at conception when the ovum fuses Woman seeking sex Roberta a sperm cell carrying an X or a Y chromosome, resulting in an embryo carrying either XX or XY chromosomes.
This fundamental difference in chromosome complement eg, genes outside the testis-determining SRY gene generates ubiquitous sex differences in the molecular makeup of all male and female cells. In addition, in men, the X chromosome carries only maternal imprints—ie, epigenetic modifications made by the parent in generating the sex cells—which alter the expression of genes in the offspring. As women have X chromosomes from both parents, they carry maternal and paternal imprints, which target a different set of genes. Random inactivation of one of the X chromosomes in female cells, which prevents sex differences in X chromosome gene dosage, causes another degree of sex difference in gene expression.
As some of these X-linked genes escape inactivation in women, those genes are often expressed at higher levels in women than in men. These sex differences persist throughout life and are independent of sex hormones figure 1. A Genetic sex differences start with cells carrying either XX Woman seeking sex Roberta XY chromosome complement eg, genes outside the testis-determining SRY genewhich generates ubiquitous sex differences in the molecular makeup of all male and female cells.
B Random inactivation of one X chromosome in female cells causes another level of sex differences in gene expression. Some X-linked genes escape inactivation in female individuals and have a higher expression in female than male individuals.
C The Y chromosomal SRY gene directs the development of a testis in male individuals, which produces a surge of testicular testosterone at the end of pregnancy. The testosterone surge programmes cellular gene expression and tissue structure in multiple organs of male individuals via epigenetic remodelling.
The combination of these genetic and developmental events programmes sex differences in physiology and susceptibility to diseases that will manifest in adulthood. Arguably the greatest source of differences between men and women comes from the Y chromosomal SRY gene, which directs the development of a testis in men.
The ensuing developmental surge of testicular testosterone permanently masculinises the reproductive tract and the organisation of brain circuits affecting male behaviour at puberty. Because it alters cellular gene expression and tissue structure in multiple organs of men via epigenetic mechanisms, this testosterone surge is also paramount in programming sex differences in physiology and susceptibility to diseases that will manifest in adulthood.
After this initial testicular testosterone surge, gonadal hormone concentrations remain low until puberty, which triggers lasting sex differences in circulating oestrogens and testosterone concentrations. After puberty, cells with androgen or oestrogen receptors will Woman seeking sex Roberta affected differently in men and women. The combination of all genetic and hormonal causes of sex differences aforementioned culminates in two different biological systems in men and women that translate into differences in disease predisposition, manifestation, and response to treatment.
Therefore, sex is an important modifier of physiology and disease via genetic, epigenetic, and hormonal regulations figure 1. It includes the understanding that in many people, traits of masculinity or femininity coexist and are expressed to different degrees. Gender attributes are fluid; more than two thirds of women and men report gender-related characteristics traditionally attributed to the opposite sex. So far, transgender people have generally been underrepresented in clinical studies to date, although this underrepresentation is changing.
Gender is an equally important variable as biological sex in human health, and influences the behaviour of communities, clinicians, and patients. Gender identity describes the fluidity of how a person perceives oneself as a woman or a man, which affects feelings and behaviours. Gender relations refer to how we interact with or are treated by people, on the basis of our ascribed gender. Institutionalised gender reflects the distribution of power between men and women in the political, educational, and social institutions in society and shapes social norms that define, perpetuate, and often justify different expectations and opportunities for women and men.
Together, these gender constructs determine access to health care, help-seeking behaviours, and individual use of the health-care system. Being perceived as a man or a woman triggers different responses from clinicians who might diagnose and suggest interventions differently according to gender. As such, gender largely determines the use of preventive measures and referral for or acceptance of invasive therapeutic strategies. Gender-related behaviours contribute to risk exposure and preventive behaviour in several diseases.
This postulation is well exemplified in the cardiovascular field, in which women often underestimate their risk compared with men and seek consultation later than men in the clinic for treatment of myocardial infarction. On the other hand, gender-related behaviours eg, smoking, lifestyle, perceived stress and pain, and nutritional habits might produce epigenetic modifications that modulate gene expression and biological phenotypes.
Figure 2 summarises how sex and gender are inter-related in biology and disease. Biological sex causes sex differences through genetic and hormonal influences in disease pathophysiology, clinical manifestations, and response to treatment. Sex also influences behaviours towards more aggressive or caring phenotypes. On the other hand, gender-related behaviours eg, smoking, lifestyle, Woman seeking sex Roberta stress, and nutritional habits produce epigenetic modifications that modulate the expression of biological sex.
Gender constructs determine patients' perception of disease, help-seeking behaviour, and individual use of health care. Gender constructs also influence decision making and trigger different therapeutic responses from providers, biased by gender.
Having established the importance of sex and gender in disease, we will summarise their influences on the most common causes of death and debilitating diseases in the USA as an example figure 3. Because current knowledge about pathophysiology, diagnosis, and treatment Woman seeking sex Roberta disease is primarily based on men as representative of the human species, this Review focuses on how women differ from men.
We discuss some key aspects regarding the dimensions of men in a dedicated section. Adapted from Heron. Heart disease is the leading cause of death in the USA. For example, heart failure disproportionately contributes to coronary heart disease mortality in women, 27 Woman seeking sex Roberta due to undiagnosed ischaemic heart disease in women. The strength of the association with cardiovascular risk factors differ by sex. Systolic blood pressure and hypertension, smoking, and diabetes are associated with higher hazard ratios for myocardial infarction in women than in men. Ischaemic heart disease is the most recognised example for integrating the concept of gender and sex, which shape divergent or distinct disease outcomes.
Compared with men, women suffering from ischaemic heart disease are older; this difference is historically believed to be due to the protection of endogenous oestrogens, 29 although contemporary study refutes this simplistic explanation 30 and associations cannot be inferred to be causation.
Still, women suffering from ischaemic heart disease are underdiagnosed 3132 and less likely to have a prehospital diagnosis of myocardial infarction. First, biological sex differences exist in the pathogenesis of ischaemic heart disease. Whereas men are more likely to be affected by obstructive coronary artery disease of large vessels than women, coronary microvascular dysfunction 36 leading to chronic myocardial ischaemia without obstructive coronary artery disease has a higher prevalence in women than men.
Second, a gender bias appears to be responsible for the absence of recognition of ischaemic heart disease presentation in women. However, hypertension and diabetes predispose older women to heart failure to a greater extent than men. Heart failure with preserved ejection fraction, a form of heart failure with normal systolic function, is twice as prevalent in women as in men.
By contrast, heart failure with reduced ejection fraction affects more men than women. Women who have heart failure with preserved ejection fraction have smaller and stiffer hearts than men. Inflammation and the resulting fibrosis play a sex-specific role in the pathogenesis of heart failure with preserved ejection fraction. Under stress, premenopausal women's hearts develop less inflammation, resulting in less fibrosis, than men's hearts.
Compared with men, women suffering from ischaemic heart disease are less likely to Woman seeking sex Roberta evidence-based treatment 3132 and when suffering from acute myocardial infarction, they are less likely to receive reperfusion. Guidelines for the treatment of heart failure are similar for women and men.
A male predominance in cancers that affect both sexes is evident around the world, in all races, and at all ages. The higher cancer risk in men is partially explained by gender constructs like dietary habits or risk behaviours such as smoking and alcohol consumption.
After appropriate adjustment for these risk factors, adult men still have a higher cancer risk than women. The universal male predominance in cancer incidence and differential outcomes argues for a fundamental role of sex, in addition to gender, in cancer biology. Sex-specific biology includes genetic differences XX vs XY chromosomesthe incomplete X-inactivation in female individuals which in bi-allelic expression of X-encoded tumour suppressors in female cells54 Y chromosome-encoded oncogenes such as the RNA-binding motif on Y chromosome in male cells55 and the chromatin remodelling effects of in-utero testicular testosterone in male cells.
In glioblastoma, there is a cell-intrinsic predisposition of male astrocytes, a subtype of glial cell, to malignant transformation. For example, the increased frequency and aggressive phenotype of hepatocellular carcinoma in male individuals has been linked to the stimulatory effects of androgens in male individuals, and the protective effects of oestrogens in female individuals.
Thus, the interaction between sex, gender, and cancer mechanisms cannot be expected to be constant. Take colon cancer, the second leading cause of cancer-related death, for example. Although women have a lower overall incidence of colon cancer than men, they have a higher incidence of right-sided colon cancers, which have the worst outcomes. Thus, overall, the male predisposition to cancer is probably the consequence of genetic programming of male cells and the effect of sex hormones after puberty, interacting with gender-specific behaviours to establish cancer risks. In the future, cancer prevention and treatment will be improved by sex-specific and gender-specific approaches.
For example, immune checkpoint inhibitors can improve survival for men with advanced melanomas and non-small-cell lung cancers more than for women. Cellular nutrient partitioning is sexually dimorphic, so approaches such as ketogenic diets or glutaminase inhibition might be associated with substantial sex-specific responses. Chronic obstructive pulmonary disease is characterised by irreversible airflow limitation and is associated with exposure to smoking or air pollutants.
Women are overrepresented among individuals with chronic obstructive pulmonary disease, especially among those with early-onset disease or those who have never smoked. Future studies should focus on the contribution of maternally inherited factors such as mitochondrial and X chromosome genes to understand disease pathogenesis.
It is important to consider gender constructs as well. Smoking advertising campaigns targeting women rose in the s, and the resulting higher smoking rates influenced women's risk for developing chronic obstructive pulmonary disease. Therefore, physicians should consider chronic obstructive pulmonary disease in the differential diagnosis of women with pulmonary symptoms, regardless of tobacco or pollutant exposure histories.
Asthma, characterised by variable airflow obstruction and chronic airway inflammation, also affects men and women differently. Asthma is more prevalent in prepubertal boys than girls. Regarding asthma, both male biological sex lung development and atopy and male Woman seeking sex Roberta constructs related to outdoor play and indoor pet exposure are factors contributing to the development of asthma, and sex versus gender contributions could be difficult to separate.
However, biological sex plays a crucial role in asthma, and sex hormones have a major impact on female asthma symptoms and severity after puberty. Premenstrual asthma is more common in women with severe rather than mild asthma, obesity rather than normal weight, and a long rather than a short duration of asthma. The menopausal transition represents a pivotal time of accelerated decline in lung function in women with chronic obstructive pulmonary disease, and thus represents a sex-specific window for treatment intensification.
These observations also suggest that oestrogens protect from chronic obstructive pulmonary disease. Women exhibit greater expression of M2 over M3 muscarinic receptors and accordingly show greater improvements in lung function than men in response to the muscarinic anticholinergic bronchodilator ipatroprium. Unlike chronic obstructive pulmonary disease, asthma control usually improves after menopause in women who don't take hormone therapy. Stroke is the fourth leading cause of death for women, but the fifth for men figure 3.
Sex differences in ischaemic stroke epidemiology vary over the lifespan, and can be influenced by risk factors that are unique to women, such as pregnancy.
However, initiation of therapy early after menopause decreases stroke risk.Woman seeking sex Roberta
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Dyspareunia is Associated with Decreased Frequency of Intercourse in the Menopausal Transition