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Gender in health and disease

Sex and gender: modifiers of health, disease, and medicine

There are gender disparities in epidemiology, pathology, clinical manifestations, disease progression, and response to treatments.

Studies have consistently shown major sex- and gender-based genetic, cellular, biochemical, and physiological differences in cardiovascular health and disease.

Sex and gender differences exist in genetics, epigenomic modifiers, hormonal milieu, immune function, neurocognitive aging, vascular health, response to therapeutics and interaction with healthcare systems.

Gender disparities are related to a combination of biological 

 sex differences in chromosomes, reproductive organs, sex steroids, gender specific factors, and activities by social cultural and traditional roles along with associated comorbidities.

Gender differences are based on sociocultural environments and thus unique to humans, such as differences in socioeconomic position, social support, culture, health behaviors, or access and attitudes towards treatment and prevention.

There may be gender-based differences in communicating bodily discomfort, with women choosing more diverse, detailed, and emotional terms and a broader spectrum of presenting symptoms compared with men when expressing discomfort.

Sex differences result from differential effects of sex chromosomes and sex hormones in males and females. 

Eight of the ten prescription drugs withdrawn from the market between 1997 and 2000 posed greater health risks for women than for men.

In a 2019 study published in the Journal of Allergy and Clinical Immunology that analyzed cases of anaphylaxis after vaccination from 1990 and 2016 found that women made up 80% of all anaphylactic reactions to vaccines in adults.

Diseases are characterised by differences between women and men by epidemiology, pathophysiology, clinical manifestations, psychological effects, disease progression, and response to treatment.

There may be gender-based differences in communicating bodily discomfort, with women choosing more diverse, detailed, and emotional terms and a broader spectrum of presenting symptoms compared with men when expressing discomfort (referred to as gendered language).

The genetic differences between men and women result in differences in disease prevalence, manifestation, and response to treatment.

Genetic sex differences begin at conception when the ovum fuses with a sperm cell, resulting in an embryo carrying either XX or XY chromosomes. 

The differences in the chromosome complement generates ubiquitous sex differences in the molecular makeup of all male and female cells.

The Y chromosome carries genes that exhibit subtle functional differences from their X-linked homologues.

and also carries genes with no homologue at all.

Random inactivation of one of the X chromosomes in female cells, causes another degree of sex difference in gene expression. 

Some X-linked genes escape inactivation in women, and those genes are often expressed at higher levels in women than in men.

Sex-specific gene expression due to genomic imprinting extends to autosomes as well, and such imprinted genes exhibit sex-gmspecific and tissue-specific expression.

Sex differences deriving directly from genetic heterogeneity between the X and Y chromosome exist at the molecular level in all human cells. 

Sex  differences persist throughout life and are independent of sex hormones.

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 surge of testicular testosterone permanently masculinizes the reproductive tract and the organization of brain circuits affecting male behavior at puberty.

The first surge of testosterone occurs at the end of the first trimester of pregnancy,  and it alters cellular gene expression and tissue structure in multiple organs of men via epigenetic mechanisms.

The first surge of testosterone is also paramount in programming sex differences in physiology and susceptibility to diseases that will manifest in adulthood. 

After the 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 are affected differently in men and women. 

Sex differences 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

Gender is a determinant of patient and doctor behavior.

Gender is a modifier of health, disease, and medicine.

Gender refers to the social  norms that determine roles, relationships, and positional power for all people across their lifetime.

Gender interacts the biological and physical characteristics of sexuality that define women, men, and those with intersex identities.

Gender is not a binary term: includes the understanding that many people have traits of masculinity or femininity coexist and are expressed to different degrees. 

Gender is fluid, with more than two thirds of women and men report gender-related characteristics traditionally attributed to the opposite sex.

In transgender people, gender identity differs with the sex they were assigned at birth. 

Gender is an important variable as biological sex in human health, and influences the behavior of communities, clinicians, and patients.

Gender roles influence everyday actions, expectations, experiences, including diet, perceived stress, smoking, and physical activity, and can affect health and disease susceptibility. 

Gender identity describes how a person perceives oneself as a woman or a man, which affects feelings and behaviors, and how we interact with or are treated by people, on the basis of our ascribed gender. 

Gender reflects the distribution of power between men and women in the political, educational, and social institutions.

Gender shapes social norms that define, and often justify different expectations and opportunities for women and men.

Gender-related characteristics within populations of men and women can influence health differently than biological sex, and can determine access to health care, help-seeking behaviours, and individual use of the health-care system. 

Clinicians perception of  as a man or a woman patient triggers different responses, diagnoses and interventions differently according to gender. 

Women often underestimate their risk compared with men and seek consultation later than men in the clinic for treatment of myocardial infarction.

In the GENESIS-PRAXY prospective study, mortality 1 year after an acute coronary event was more strongly associated with gender than with biological sex.

Control of cardiovascular risk factors as hypertension, diabetes, depressive symptoms is better predicted by gender than by biological sex.

Cardiovascular risk factors including diabetes, smoking, and hypertension are more impactful in women compared with men.

Cardiovascular risk factors that predominantly affect women, are rheumatoid arthritis and systemic lupus erythematosus.

Specific cardiovascular risk factors in women have been established including estrogen deficiency due to premature ovarian failure, ovariectomy, polycystic ovarian syndrome, or hypothalamic amenorrhea. 

Hypertensive disorders of pregnancy, preterm delivery, and gestational diabetes indicate premature vascular dysfunction and are associated with increased cardiovascular risk later in life.

Gender intersects with race or ethnicity and age.

Sex and gender are reciprocally inter-related in biology and disease.

Sex influences behaviors.

Gender-related behaviors of smoking, lifestyle, stress and pain, and nutritional habits might produce epigenetic modifications that modulate gene expression and biological phenotypes. 

Heart disease is the leading cause of death, accounting for  24·2% of all deaths for men and for 21·8% of all deaths for women.

Heart failure disproportionately contributes to coronary heart disease mortality in women, potentially due to undiagnosed ischemic heart disease in women. 

The association with cardiovascular risk factors differ by sex: Systolic blood pressure hypertension, smoking, and diabetes are associated with higher hazard ratios for myocardial infarction in women than in men.

Compared with men, women with ischemic heart disease are older; believed to be due to the protection of endogenous estrogens.

Women suffering from ischemic heart disease are underdiagnosed, and less likely to have a prehospital diagnosis of myocardial infarction.

A total of 6,720,639 weighted hospitalizations for MI (79.8% NSTEMI, and 20.2% STEMI) were included in a study: The incidence rate of hospitalizations for MI was lower in women than men across all age groups. 

These differences were consistent across all age groups.

Compared with men, women have lower incidence of MI and less likelihood of undergoing invasive treatment regardless of age.

The negative impact of female sex on most outcomes was most pronounced in young and middle-aged women.

Men are more likely to develop obstructive coronary artery disease of large vessels than women.

Coronary microvascular dysfunction leading to chronic myocardial ischaemia without obstructive coronary artery disease has a higher prevalence in women than men.

The incidence rate of hospitalizations for MI was lower in women than men across all age groups. 

Women were less likely than men to undergo coronary angiography, revascularization, or to use circulatory-support devices. 

These differences were consistent across all age groups.

Compared with men, women have lower incidence of MI and less likelihood of undergoing invasive treatment regardless of age.

The negative impact of female sex on most outcomes was most pronounced in young and middle-aged women.

Acute myocardial infarction: both sexes most often present with chest pain, but compared with men, women were more likely to present with pain between the shoulder blades, nausea or vomiting, and shortness of breath.

Gender bias appears to be responsible for the absence of recognition of ischemic heart disease presentation in women.

Heart failure affects 10% of adults aged 65 years and older.

Heart failure affects more women than men in absolute numbers.

Heart failure occurs at an older age and with less ischemic causes in women than in men. 

Hypertension and diabetes predispose older women to heart failure to a greater extent than men. 

Exposing coronary arteries to ionizing radiation during breast cancer radiotherapy and/or administration of chemotherapy such as anthracyclines or trastuzumab increases cardiovascular risk even more than 10 years later in life.

Heart failure with preserved ejection fraction, a form of heart failure with normal systolic function, is twice as prevalent in women as in men. 

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. 

Estrogens produce anti-inflammatory actions on endothelial and immune cells, and promote cardioprotective effects in premenopausal women.

Premenopausal women’s hearts develop less inflammation, resulting in less fibrosis, than men’s hearts.

This protection might disappear after menopause.

In contrast, testosterone induces adverse cardiac remodelling in the male heart.

Compared with men, women suffering from ischemic heart disease are less likely to receive evidence-based treatment, and when suffering from acute myocardial infarction, they are less likely to receive reperfusion therapy.

ST-elevation myocardial infarction study,revealed that compared with men, women exhibit delayed reperfusion leading to higher mortality.

Women suffering from acute myocardial infarction treated by male emergency physicians have a higher mortality rate than those treated by female physicians.

Optimal survival in women occurs with lower doses of β blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors than in men.

Fewer women undergo heart transplantation than men, although women are more frequently donors.

Cancers are the second leading cause of death, accounting for 21·9% of deaths in men and 20·7% of deaths in women.

More men develop cancer than women.

Most cancers, of non-reproductive sites, there is 2:1 male predominance.

Some cancers: oropharynx, larynx, esophagus, and bladder, the male versus female incidence ratios can be higher than 4:1. 

Hypopharyngeal cancer is five times  more common in males than in females.

Tumors of the pyriform sinus and the posterior pharyngeal wall occur mainly in males, while post-cricoid carcinoma is more often occurs in females.

It is five times  ore common in males than in females and mainly occurs in the aged 50 to 70 years.

Meningioma, thyroid cancer, lung cancer in non-smokers cancers, have female predominance over males.

A male predominance in cancers that affect both sexes is evident around the world, in all races, and at all ages.

Survival for men is shorter than women across multiple cancer types. 

The higher cancer risk in men is partially explained by gender constructs like dietary habits or risk behaviors such as smoking and alcohol consumption.

A similar male bias in incidence and survival is seen in paediatric cancers before puberty and the adoption of high-risk cancer-promoting behaviors.

There is a fundamental role of sex, in addition to gender, in cancer biology. 

Sex-specific biology includes genetic differences (XX vs XY chromosomes), the incomplete X-inactivation in female individuals, Y chromosome-encoded oncogenes and the chromatin remodelling effects of in-utero testicular testosterone in male cells.

Above mechanisms influence cancer, including: metabolism, growth regulation, angiogenesis, and immunity, which all contribute to cancer predisposition.

There is a male predisposition to glioblastoma.

In glioblastoma, there is a cell-intrinsic predisposition of male astrocytes, a subtype of glial cell, to malignant transformation.

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 estrogens in female individuals.

Women have a lower overall incidence of colon cancer than men, but have a higher incidence of right-sided colon cancers, which have the worst outcomes.

Tumors from women with right-sided colon cancers exhibit a distinct molecular signature compared with those of women with left-sided colon cancers.

This molecular signature is not observed when comparing tumors from men with right-sided colon cancers to men with left-sided colon cancers. 

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 behaviorso to establish cancer risks.

Immune checkpoint inhibitors associated with an improved survival for men with advanced melanomas and non-small-cell lung cancers more than for women.

Women are overrepresented among individuals with chronic obstructive pulmonary disease.

COPD especially among those women with early-onset disease or those who have never smoked.

Women are also twice as likely to have chronic obstructive pulmonary disease with chronic bronchitis.

Women with severe chronic obstructive pulmonary disease have as much emphysema as men.

Women’s lungs are more susceptible  to chronic obstructive pulmonary disease than the male lungs.

Women develop symptoms of lung disease at a younger age with less tobacco exposure than men.

Early-onset chronic obstructive pulmonary disease might originate in utero in susceptible women from alterations in lung development, potentiated by maternal asthma and smoking, genetic factors, or hormonal influences. 

Chronic obstructive pulmonary disease exacerbation rates are higher in women than men, especially at a younger age.

Asthma is more prevalent in prepubertal boys than girls.

From puberty onwards, more female than male individuals have asthma.

Women have an increased severity of asthma in middle-aged women and a higher mortality rate.

Sex hormones have a major impact on female asthma symptoms and severity after puberty.

Asthma that worsens in women before menstruation and is known as premenstrual asthma.

Premenstrual asthma is more with severe asthma, with obesity and with a long rather than a short duration of asthma.

Premenstrual asthma may be due to a fall in progesterone.

Premenstrual asthma with severe disease,  responds to progestogens.

A third of patients with asthma in pregnancy show an improvement, and the remainder are unaffected.

The menopausal period  is associated with accelerated decline in lung function in women with chronic obstructive pulmonary disease, suggesting 

estrogens 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.

Women experience more improvement in quality of life than men after treatment of chronic obstructive pulmonary disease with a β2-adrenoreceptor agonist combined with an anticholinergic drug

Asthma control usually improves after menopause in women who don’t take hormone therapy.

In general, estrogens increase asthmatic inflammation, whereas androgens reduce it.

Females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.

Stroke is the fourth leading cause of death for women, but the fifth for men.

More women die from stroke (6·2% of all deaths) than men (4·3%), but this increase in mortality related to women living longer and the older age at which women experience their first stroke.

The risk of subarachnoid hemorrhage is 45% higher in women than men, and risk factors, especially smoking, have a stronger adverse effect in women than men.

Sex differences in ischemic stroke epidemiology vary over the lifespan.

Sex differences in ischemic stroke 

are influenced by risk factors that are unique to women, such as pregnancy.

In childhood and early adulthood, men have a higher incidence of ischemic stroke and poorer functional outcomes than women.

In middle-age, the rates of ischemic stroke begin to increase in women, with the onset of menopause and loss of female sex hormones.

After middle-age, stroke rates continue to increase in women.

Stroke prevalence is higher in older women (>80 years) than elderly men.

Hypertensive disorders of pregnancy-pre-eclampsia or eclampsia and pregnancy-induced hypertension, produce an increased risk of stroke in middle-aged women.

Maternal stroke, a complication of pregnancy, is the leading cause of maternal mortality in the USA

For other women risk factors for stroke include gestational diabetes and oral contraceptive use.

Hormone therapy can increase the risk of stroke if initiated late after menopause. 

The initiation of therapy early after menopause decreases stroke risk.

Hypertension, abdominal obesity, and adverse lipid profiles are the most impactful causes of stroke in women worldwide. 

Some stroke risk factors are more prevalent in women, including diabetes, hypertension, atrial fibrillation, migraine with aura, and depression.

Women with ischemic stroke have poorer outcomes than men: older age of first stroke in women, the higher pre-existing disability in elderly women, the larger strokes seen in women many from atrial fibrillation,and  post-stroke depression and social isolation experienced by elderly women.

Aspirin, provides greater benefit for women than men in the primary prevention of ischemic stroke.

A gender gap in the treatment of acute stroke exists for women: 

many are older and more frail and are thus seen as poor candidates for thrombolysis and thrombectomy, the only two therapies that are effective for the treatment of acute ischaemic stroke. 

Yet, data suggest that women benefit more from intervention than men.

Alzheimer’s disease is the most common form of dementia, and two thirds of individuals with Alzheimer’s disease in the USA are female.

Alzheimer’s disease ranks as the fifth leading cause of death for women (6·1% of deaths), whereas it is the seventh for men (2·6%.

 The greater longevity in women along with an earlier initiation of pathology during menopause contribute to their disproportionate burden of the disease. 

The apolipoprotein E epsilon 4 (APOE-ε4) genotype, however, is the strongest known genetic risk factor for late-onset Alzheimer’s disease.

The apolipoprotein E epsilon 4 (APOE-ε4) is related to increases in the deposition of β-amyloid,  which accumulates in amyloid plaques. 

The frequency of APOE-ε4 genotype does not differ by sex.

The risk of Alzheimer’s disease in carriers of APOE-ε4 is four times higher in women than men between the ages of 65 and 75 years.

Women with a single copy of APOE-ε4 are at greater risk of Alzheimer’s disease than men.

Women’s risk for AD is equivalent to men with two copies.

The increased APOE-ε4-related risk in women is associated with an increase in phosphorylated tau, a second pathological hallmark of Alzheimer’s disease. 

 

Tau protein accumulates in intracellular neurofibrillary tangles. 

Women, particularly APOE-ε4 carriers, are more vulnerable to tau accumulation in the presence of β-amyloid than men.

Among cognitively healthy individuals with evidence of β-amyloid burden, women show earlier tau accumulation in the entorhinal cortex, a site of early Alzheimer’s disease pathology, than men.

Conditions such as pregnancy disorders, early bilateral oophorectomy, early menopause, and late initiation of menopausal hormone therapy are also associated with an increased Alzheimer’s disease risk.

Menopause-related decrease in cerebral glucose metabolism also appears to represent a sex-specific pathophysiological mechanism of Alzheimer’s disease.

The clinical course of Alzheimer’s disease is faster in women than in men.

More men are diagnosed with mild cognitive impairment although more women are diagnosed with Alzheimer’s disease.

Women bear a greater burden of Alzheimer’s disease caregiving, which  carries its own risk to cognitive and physical health.

Female caregivers might experience higher levels of depression and anxiety than male caregivers.

Diabetes:

Women have higher rates of type 2 diabetes in youth than men.

Men have a higher prevalence of type 2 diabetes in midlife than women.

Rates of type 2 diabetes are fairly similar between the sexes in later life.

Gestational diabetes in women represents a sex-specific risk factor.

The prevalence of prediabetes differs by sex: 

impaired glucose tolerance reflects postprandial insulin resistance is more prevalent in women than men.

Impaired fasting blood glucose, reflecting fasting insulin resistance, more prevalent in men than women.

For screening or diagnosing type 2 diabetes, hemoglobin A1c is more appropriate than fasting plasma glucose or oral glucose tolerance test, as these tests might lack sensitivity in one sex or the other. 

Estrogen deficiency specifically predisposes menopausal women to type 2 diabetes, which is prevented by oestrogen therapy.

 In men with testosterone deficiency, testosterone replacement therapy prevents the progression from prediabetes to type 2 diabetes.

The absolute rates of cardiovascular disease are higher in men than in women.

In reproductive-age women, the presence of type 2 diabetes largely negates this protection from cardiovascular disease, and diabetic women are more severely affected than men.

In the prediabetes period, women have an earlier, greater, and more prolonged deterioration in cardiovascular disease risk factors than men. 

In prediabetic women cardiovascular disease risk factors includes central obesity and insulin resistance and is associated with endothelial dysfunction, inflammation, hypercoagulability, dyslipidaemia, and hypertension.

Gender bias occurs in the management of type 2 diabetes, suggesting undertreatment of type 2 diabetes and other cardiovascular disease risk factors in women compared with men.

Diabetes is a stronger risk factor for the onset of ischemic heart disease, heart failure, stroke, cancer, and dementia in women than in men.

Progress in reducing type 2 diabetes mortality has been more effective in men than in women.

Type 2 diabetes presents a greater risk for severe consequences of cardiovascular disease in women than in men, and that at the time of diagnosis, women with type 2 diabetes might have more advanced atherosclerosis than men at the same stage of disease. 

There is also a sex difference in the response to antidiabetic drugs. 

Lean men show greater glycemic reduction with sulfonylureas than lean women, whereas women with obesity show greater glycemic reduction with thiazolidinediones than men with obesity.

Severe seasonal influenza is more likely to affect young boys than young girls before puberty, and cause worse outcomes in adult women between puberty and menopause than in adult men.

During influenza outbreaks and pandemics, morbidity and mortality are higher for women than for men.

The pathogenesis of influenza is mediated not by virus replication, but by the immune responses it  initiates and maintains to control the infection. 

Pregnancy is a women-specific condition associated with more severe influenza A viruses infection outcome.

Because of different roles and occupations, such as caring for children, more common among women than men, or working in poultry facilities, more common among men, which increase the likelihood of coming into contact with different strains of influenza A virus.

Pneumonia predominantly affects men, with the greatest risk during infancy and in older age.

The manifestations of pneumonia are consistently more severe for men than for women, with prognosis being worse for men than for women during acute disease.

While the incidence of pneumonia is greater in males than in females, the total number of deaths due to pneumonia has been higher among females since the mid 1980s.

Men experience worse outcomes from either bacterial or viral pneumonia than women.

Men are significantly less likely to wash their hands or use soap with water than women.

This is true even among health-care workers.

Gender-associated factors associated with hygiene could contribute to the pathogenesis of infections that cause pneumonia.

Women develop higher antibody titers  than men following vaccination for influenza.

Pregnant women represent a target population for receiving the inactivated influenza vaccine.

Greater expression of X-linked genes in B lymphocytes and higher oestrogen concentrations in women are responsible for the generation of higher quality and quantity of antibodies in women than in men.

Influenza vaccine hesitancy is higher among women, and receipt of influenza vaccination is higher among men.

Chronic kidney disease is the ninth leading cause of death (1·8% of deaths) for women, but is not among the ten leading causes of death for men.

The prevalence of chronic kidney disease is higher in women (11·8%) than men (10·4%), although chronic kidney disease could be overestimated in women in part by assuming the same body surface area for both sexes in kidney function equations.

Autoimmune disease and infection (ie, pyelonephritis) are more common causes of chronic kidney disease in women than men, hypertension and diabetes prevail among men.

Pregnancy, is a specific risk factor for women, as hypertensive disorders of pregnancy predispose women for developing chronic kidney disease later in life.

In men with chronic kidney disease, testosterone deficiency is common, which increases men’s risk of cachexia and frailty.

Biological sex probably contributes to the more rapid rate of chronic kidney disease progression in men than women.

Testosterone can increase oxidative stress, activate the renin angiotensin system, and aggravate renal fibrosis.

Estrogens inhibit these pathological processes, noted above, in the diseased kidney.

The majority of patients that initiate dialysis are men (women:men ratio 4:6).

This male predominance in dialysis is attributed to men’s biological predisposition to faster rate of chronic kidney disease progression, and gender. 

Women more often donate kidneys and show similar transplantation survival benefits than men, women still receive fewer kidney transplants.

There are gender differences in prescription rates of cardiovascular drugs, with women being less aggressively treated with guideline-recommended medication than men: 

women with chronic coronary syndromes receive less antiplatelets, lipid-lowering drugs, inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and nitrates than men.

Women also preferentially choose conservative care, possibly because more elderly women than men live alone and without caregivers. 

Women are more likely to have difficulty with dialysis arteriovenous fistula functions.

Women on dialysis have higher hospitalization rates, lower reported quality of life, and greater symptom severity than men.

Excess dialysis, and erythropoietin-stimulating agent doses are given attributed to extrapolating men’s therapeutic dosing to women.

Chronic liver disease is the tenth leading cause of death for men, about 1·8% of deaths.

Chronic liver disease deaths are not in the top ten for women.

Men exhibit a higher risk of primary sclerosing cholangitis, chronic viral hepatitis, cirrhosis, and hepatocellular carcinoma.

Women exhibit a higher risk of primary biliary cholangitis and autoimmune hepatitis rates.

Alcoholic liver disease is more common among men because due to their higher alcohol consumption than women.

The threshold amount of alcohol that results in alcoholic liver disease in women is half that of men.

The effect of biological sex on ethanol metabolism results in women having higher blood ethanol concentrations than men after drinking the same amount of alcohol.

Premenopausal women are protected from non-alcoholic fatty liver disease, with an around 50% decreased risk compared with men.

Women of reproductive age with non-alcoholic fatty liver disease are also protected from hepatic fibrosis, hepatocellular carcinoma, and mortality.

With postmenopausal status women lose this protection, and premature menopause and bilateral oophorectomy is associated with a higher risk of non-alcoholic fatty liver disease and related complications among women.

Sex and sex hormones influence the non-alcoholic fatty liver disease in a multifaceted way: regional body fat distribution, gut microbiome, fibrosis, tumorigenesis, and determine sex-specific risk profiles.

Estrogens protect women from visceral obesity, insulin resistance, non-alcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma.

Androgen protects men from visceral obesity, insulin resistance, and non-alcoholic fatty liver disease.

Androgens increases the risk for women polycystic ovary disease.

Much greater weight loss is required for resolution of non-alcoholic fatty liver disease in women.

Unipolar depression is roughly twice as prevalent in women than men.

Post-traumatic stress and panic disorders, which are comorbid with major depressive disorder, occur more frequently in women than men and affect symptom presentation. 

Women are more likely than men to seek treatment for depression.

Women with depression are more likely to present with hyperphagia, weight gain, hypersomnia, anxiety, and greater illness severity.

Men with depression tend to present with symptoms that are not included in criteria for major depressive disorder: 

irritability, aggression, violence, substance abuse, risky behavior, and somatic complaints, which obscures underlying depression.

Rumination is a cognitive style with attention on symptoms of one’s distress as opposed to its solutions.

Rumination is more common among women than men and contributes to depression severity and relapse.

Suicide attempts are two times more common in women than men, they are more lethal in men.

Testosterone surges masculinize  the male brain neurochemistry, wiring, and function, and sets the stage for sex differences in mental health throughout life. 

X-linked genes are involved in structural brain development and volume. 

Women are at risk for depression during periods of hormonal fluxes such as during the menstrual cycle, peripartum period, and menopause, supports a role for gonadal hormones in depression pathophysiology among women. 

Estrogens and progesterone exert a profound and broad effect on brain neurochemistry and brain function and interact with early life stress and genetic risk for depression.

Working-age men suffer a two times higher mortality rate than working-age women, for nearly the whole spectrum of diseases.

Poor lifestyles and preventable risk factors account for half of premature deaths in men. 

Men are more likely to eat unhealthy diets, exercise less, consume alcohol, smoke, misuse drugs, or exhibit risky behavior. 

Men are more likely than women to die from unintended injuries. 

Men are socially conditioned to neglect pain and disease, resulting in a general underutilisation of health services and a lower likelihood to engage in routine checks compared with women.

 The rate of hospital admission is higher for men than for women for all of the diseases described above. 

Many men do not access health services and benefit from lifestyle modification resulting in premature mortality that is mostly preventable.

Autism spectrum disorders affect four times as many men as women.

Parkinson’s disease, the second most frequent age-related neurodegenerative disorder, is also more common in men than in women by a ratio of 2:1.192.

Most autoimmune diseases are characterized by an 80% female predominance,  and migraine and eating disorders are three times more prevalent in women than men. Anorexia nervosa and bulimia nervosa are more commonly found in females than males – thus hinting at a possibility of a linkage to the X-chromosome.

The severity of COVID-19, as measured by hospitalization, admission to intensive care units, intubation for mechanical ventilation, and death, has consistently been 1·5 to 2 times greater for men than for women around the world.

In contrast, biological sex contributes to the protection against COVID-19 death among women, because women exhibit a heightened immune response to viral infections compared with men, as discussed previously in the case of H1N1 influenza. In mice, infection with a related coronavirus (ie, severe acute respiratory syndrome coronavirus) produced more pulmonary damages and mortality in male than female mice.200 A greater attention on sex and gender outcomes will be useful to mitigating COVID-19 infection rates and outcomes.

Conclusions and perspectives for sex-based precision medicine

The evidence discussed in this Review highlights the robust sex and gender influences that exist across leading causes of death and morbidity globally (table). Despite policies in Canada, Europe, and the USA to include sex and gender in medical research, the medical establishment has not assimilated current evidence of sex differences, and the influence of sex and gender on human health and disease continues to be estimated, understudied, and underutilised in medical practice. The beliefs, attitudes, and knowledge of clinicians and researchers regarding the importance of sex and gender in biology, disease, and medicine are key barriers in addressing these pressing issues.201 Efforts to bring sex and gender into the mainstream of modern medical research, practice, and education are urgently needed, as the lack of appreciation for sex and gender differences harms both women and men. Several steps can be taken to promote gender equity at all levels of the biomedical enterprise, as described in the following sections

Ultraviolet radiation exposure is associated with an increased risk for herpes zoster in males but not in females.

Severe sunburn is associated with a high risk of herpes zoster in both men and women.

Women in general, have a more vigorous innate and adaptive immune response and all this susceptible to U R induced immunosuppression.

More women than men report side effects from Covid-19  vaccine.

More women report side effects from the vaccine, may be due to their immune system being more reactive.

More women report side effects from the  flu vaccine.

In a 2019 study published in the Journal of Allergy and Clinical Immunology that analyzed cases of anaphylaxis after vaccination from 1990 and 2016 found that women made up 80% of all anaphylactic reactions to vaccines in adults.

Female sex is an established risk factor for statin-associated muscle symptoms and new-onset diabetes.

Women who consume higher levels of vitamin D – particularly from dietary sources – have a reduced risk of developing early-onset colorectal cancer, compared with those who have lower levels.

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