DISEASE IN THE CONTEXT OF BIOLOGIC AND SOCIAL GENDER

Right from the point of conception, male and female biology diverge at the cellular level, resulting in almost completely separate biologic systems in the body. While many decades were spent studying male physiology in order to enhance medical treatment, studies have been far more inclusive in the last 2-3 decades. The world of difference between the sexes is only just beginning to be deciphered, having mass implications for the future of healthcare.

The below discussion describes how biologic gender affects health and well-being, summarizing key differences between men and women that contribute towards disease outcomes. Sex-specific characteristics are also reviewed within the context of 9 common diseases, highlighting unique presentations, prognosis and treatment responses.

The diseases discussed include obesity, cancer, autoimmune diseases, Alzheimer’s Disease, diabetes, asthma, chronic kidney disease, COVID-19 and chronic liver disease. The first 3 are discussed in this article, while the remaining 6 are continued in part 2.

The Difference between Gender and Sex

Gender usually refers to the psychological construct of masculinity and femininity, referring to these traits in the makeup of one’s identity. It’s also sometimes referred to as gender identity.

Biologic sex refers to the physical gender traits of a person’s body and biologic makeup. It describes a person’s reproductive, hormonal and genetic position all of which contribute towards defining their physiology.

For the purpose of this discussion, gender is going to be used interchangeably with biologic sex. Gender identity in the context of disease is discussed in brief under the social constructs section.

How Gender Differences Impact Health

Gender can refer to both social constructs and physiological differences that both may have a substantial impact on health and well-being. They also typically influence one another.

Are There Any Medical Conditions that remain unaffected by gender?

Aside from diseases affecting gender-specific organs, the brief answer is no. States of disease tend to have multiple biological components, of which metabolism, genetics and sex hormones are prime factors that also influence each other.

Diseases with higher prevalence rates in a specific gender tend to embody a unique hormonal profile, which influences either sex uniquely, leading to separate disease expressions. Hormonal imbalance places one at a greater risk of disease, often with a worse prognosis.

Physiological Differences

The following physiologic differences have arisen from a relatively new sphere of gender-based research and are to be interpreted with caution. Biologic gender influences disease progression, prognosis, and response to treatment; yet much remains to be determined before firm conclusions can be drawn.

XX vs XY

It’s outdated to think that the sex-specific chromosomes are there merely to program the production of sex hormones. These chromosomes have shown to have interactions with the other genetic material in the cell and change many aspects of biological functioning in men and women.

While the interactions of hormones play a substantial role in the biology of gender, the X and Y chromosomes have been shown to govern a wide array of cellular processes, including those pertaining to metabolism and immune function.^[1]

The Y chromosome carries gene analogues that are different to that seen on the X chromosome. Examples include UTX and UTY as well as ZFX and ZFY. Polymorphisms or genetic alterations to these genes can predispose men and women to an increased risk of disease.

The second X chromosome has many genes on it which become silenced very early on in embryonic development. This serves to avoid redundancy and to promote feminine biologic traits, as the second X chromosome is derived from the father and is influenced by his biology.

In females, some of these genes may escape silencing, and increase the risk of various auto-immune diseases. Other gene sets on the X chromosome reveal increased protection against tumor formation. As a result, researchers have found that if all the genes are silenced, women will have a higher risk of various cancers. By contrast, men tend to have a lower risk for auto-immune diseases and an increased risk of cancer compared to women.

Hormonal Actions and Cell Receptors

The Y chromosome encodes for genes that promote the development of male testis, which already begin to produce testosterone and masculinize the fetus in utero. At puberty, the reproductive system increases the production of sex hormones and begins to alter cellular interactions in a sex-specific manner, having lifelong biological implications.

Sex hormones and their receptors promote either pro- or anti-inflammatory immune responses when interacting with immune cells. In either sex, the ratio of these hormones is unique for optimal health and so is the strategy of the immune system.

• Estrogens typically exert an anti-inflammatory effect and tend to enhance cellular repair (autophagy). Women tend to succumb to more male-predominant diseases after menopause due to a sharp decline in estrogen levels and a rise in androgen.
• Androgens are known to exert pro-inflammatory effects and tend to enhance cellular turnover through programmed cell death (apoptosis).

The above hormone effects may be inverted depending on the hormone type, receptor type, cell type, ratio and sex of the organism they are found in.

Immune Parameters

The reproductive hormones are implicated in shifting the immune profile in both sexes after puberty. Prior to that, there are minor differences in the immune profiles between children of different genders. In childhood, boys display increased levels of inflammation compared to girls, which changes after puberty when reproductive hormone levels increase.^[2]

Females have elevated levels of CD4+ T cells, B cells, immunoglobulins and bigger immune responses, resulting in higher levels of T cells in response to a threat. Females express lower interferons than males, with higher numbers of prostanoids and interleukins. Higher numbers of these cells suggest that antigens are detected swiftly by the female immune system and can also explain the elevated autoimmune risk.

Males have an increased number of CD8+ T cells, natural killer cells, and regulatory T cells. CD8+ T cells and natural killer cells express more interferon gamma on average and are more pro-inflammatory than other immune cell types. Regulatory T cells help to balance inflammation and support sustained immune activity.

Mental-Emotional Cognition

More advanced research is revealing that, unlike previously thought, men and women have unique physiological responses to stress. While the ‘fight-or-flight’ model has been used as the basic model of the stress response, some research suggests that this is more accurate of a masculine stress response. The feminine response to lesser stressors is known as the ‘tend and befriend’ response. ^[3]

In the context of this theory, a female is more likely to try and repatriate a harmful situation with a compromising solution instead of fighting it or running from it. Feminine conflict is often more subtle in this regard.

Women also appear to be more sensitive to the effects of stress hormones than men and major stressors tend to have a worse effect on the health of women. In spite of this, female sex hormones slow down the stress response by comparison to men, either reducing it or delaying its onset.^[4]

Social Constructs

Gender identity influences many aspects of health and is an important consideration to make when looking at disease. Social constructs largely shape gender identity and have made an impact on health outcomes in both men and women.

Medical Research Disparity

In line with history, even medical science and research emulated gender inequality until the turn of the 21^st century. It was previously thought that cells from either sex functioned similarly and as a result, the majority of modern medicine was founded on the study of male physiology. Male mice and cell cultures were the only subjects used in laboratories until the late 90’s and even then, many labs did not make the transition to account for female biology. Today it is regarded as a specialized area of biologic research in spite of efforts to make it mandatory.^[5]

As it turns out, the cellular differences between men and women are substantial enough to affect disease prevention and treatment and nearly all aspects of biology. The baseline genetic coding of both male and female cells has far-reaching implications beyond sex hormone production.[1] 

Social Roles Affect Medical Treatment

Patients and doctors are not immune to the effects of gender roles and these roles are able to influence treatment. Following up from a long history of such, many prefer to seek medical help from doctors of the same gender to avoid stereotypical misunderstandings.

A doctor of the same sex may have a better affinity for treating patients of their gender, being particularly pertinent in the surgical arena. Studies show that doctors who have more friends and colleagues of the opposite sex are better equipped at treating patients of that sex. Doctors have likewise been subject to difficult interactions with patients, which can hamper progress.

Nonetheless, professionalism does away with much of these underlying attitudes. A good doctor is able to treat any patient, regardless of their gender, ethnicity or age.

Gender Identity, Physiological Sex and Disease Outcomes

A very new field of research has begun to show that gender identity may influence disease risk and mortality irrespective of biologic sex. This is because of the way in which gender influences behavior, preferences and how likely one is to seek medical care.

Females and those with more feminine characteristics are less likely to seek medical attention when symptoms first make themselves apparent, which can delay timely treatment. As a result, risk factors for acute coronary syndrome were associated with feminine gender irrespective of sex.^{[6] [7]}

On the other hand, men and those with more masculine traits tend to live a higher risk lifestyle in terms of smoking, drinking, consuming a less healthy diet and participating in high risk activities that predispose them to accidents and injuries more often.

Many of these preferences are linked to underlying aspects of biology and psychology that guide behavioral patterns and play a large role in defining gender identity. Thus the concept of sex and gender are intimately linked.

This review is only going to hone in on biological gender, as it is easier to study and there is more available data on the subject in the context of disease.

9 Diseases Affected by Sex and Gender

The majority of disease is affected by sex-specific factors. The following reviews 9 common diseases in the context of biologic gender, highlighting how sex affects presentation, prognosis and response to treatment.

1. Obesity

Obesity refers to excessive or abnormal fat accumulation that presents a risk to health. Those with a BMI of 30 or higher tend to be obese; however, body composition testing is the most accurate way to tell.

Presentation

Obesity tends to have a female bias due to the role of estrogen in the biology of fat. Healthy women typically carry more fat on average than men and traditionally find losing weight more difficult^[8].

Due to the differences in hormones and metabolism, fat is distributed differently in either sex and the deleterious effects of obesity are sex-specific. Females tend to gain weight on the thighs, buttocks and hips, while men tend to gain belly fat.

Prognosis

While obesity is more common in females, it tends to increase the risk of cardiometabolic disease in males due to the area in which it accumulates.^{[9] [10]} The excessive abdominal fat is accompanied by increased fasting glucose and insulin levels and higher blood pressure, having negative consequences on cardiovascular and digestive function.^[11]

On this note, obese females with a masculine weight distribution profile are susceptible to the same risk as obese males. The same cannot be said of men that gain weight in a feminine fashion.

Females appear more susceptible to the negative stigma associated with being overweight.

Treatment Response

Females have been placed under more pressure societally to manage their weight and as a result may engage in risky dieting fads in order to lose some pounds here and there. In many instances, this ironically results in more weight gain after rapid weight loss^[12]. The most optimal way to lose weight would be partaking of a balanced diet plan consisting of healthy wholefoods, in tandem with consistent exercise that improves fitness levels. For women, weight loss is slower and patience is warranted.^[13]

Men tend to lose weight quicker than women when engaging in physical activity, as well as displaying better health outcomes in response to exercise^[14]. Nevertheless, adherence to a healthy diet plan may be low and it may be more difficult for men than women to lower the intake of fat-promoting foods. These include unhealthy high-fat and high-sugar foods as well as alcohol.

In extreme cases of obesity, bariatric surgery is employed and has different outcomes for men and women. 78-80% of patients that opt for the surgery are female^[15]. Male candidates tend to be older, more obese, and have more complications in response to the surgery. However, in spite of better physical outcomes, women were more prone to post-surgical depression, dissatisfaction and reduced psychological well-being.

These results also indicate that women are prescribed the surgery more often than men, which may highlight that men suffer the consequences of severe obesity for longer. Women appear to be a priority for weight loss, reflecting societal views regarding female body image. These may contribute towards the higher rate of depression and the increased urgency of obese women to opt for surgery at younger ages and for lesser BMI’s. Counselling and patience may be of more value to these women before surgery is prescribed, particularly given the drastic life-long side effects.^[16]

2. Cancer

Cancer refers to a number of complex diseases in which cells of any tissue type transform into cancerous cells, becoming malignant, and displaying abhorrent and excessive growth. A collection of these cells is called a tumor. Tumor formation is believed to depend on immune suppression, chronic inflammation, and carcinogenic genetic mutations which promote chronic unregulated growth.^[17]

Presentation

In the vast majority of cancer types, males show a higher prevalence than females. Thyroid cancer is one exception, where females contract this type more often than males.

Reproductive cancers are more common than other types in both sexes, with a 2:1 male to female ratio. Cancers of the throat, kidneys and bladder display above-average prevalence in males compared to other types^[18]. This is thought to be related to occupational hazards and increased chemical exposure.

Males engage in more high risk activities than women on average, such as increased drinking and smoking. In spite of this difference, males are still at an increased risk.

Prognosis

The lower incidence of female cancer is attributed to hormonal and genetic differences which influence cellular metabolism, growth and immune function differently between the sexes. The X chromosome confers tumor suppressor genes, with women having a spare set that occasionally escape gene inactivation and remain active^[19]. Other studies reveal that total silencing of these genes predisposes some women to cancer.

While the X chromosome may offer protection against cancer, generational studies show that reproductive cancers may be transmitted via the X chromosome. The mother can confer an increased risk of breast cancer in children of either sex, however fathers with breast cancer only pass on the risk to the daughter^[20].

The Y chromosome appears to have in-built oncogenes and growth processes in males are heightened in response to testosterone. This is a result of both its hormonal actions and the way it remodels male chromatin in-utero, changing fundamental cellular biology. 

While not involved in the formation of all types of cancer, androgens are renowned for stimulating growth, which contributes towards the male predominance. Estrogens by contrast are often associated with preventing tumor formation, with the exception of estradiol-17-beta.

Thyroid cancer prevalence in women is currently unexplained. Thyroid tumors are noted to express unique estrogen receptors that may be related to the higher prevalence in women.^[21]

Mortality rates are similar between the sexes when diagnosed with cancer, with men being at a slightly higher risk than women.

MicroRNA’s located on the X chromosome may also protect against tumor formation, with women naturally having a higher number than men. Some of these microRNA’s were also associated with the formation of cancer, such as hormone-responsive cancers, including those of the reproductive system, thyroid and melanoma, as well as gastric cancers.^[22]

Interestingly, women displayed differing tumor metabolic signatures in tumors on either side of the gut, a correlation that was not observed in men.^[23] All these results suggest a unique expression of cancer in women to men, which may also explain why women with it tend to live longer.

Treatment Response

Due to the wide variety of chemotherapy and limited studies examining the efficacy between the sexes, it is difficult to ascertain how treatment might affect the outcome for men and women. Precision medicine is beginning to make use of an accurate combination of therapeutics per patient. Treatment is anticipated to be greatly improved over the next decades, with a more refined understanding of tumor biomarkers and sex-specific factors.

Limited available evidence is highlighted below:

• Immune checkpoint inhibitors are anticancer therapies that block tumor growth by inhibiting specific mechanisms in cancerous cells. There have been a few studies highlighting that these therapies tend to show improved efficacy in male patients vs female patients. For instance, in non-small cell lung cancer, immune checkpoint inhibitors increased overall survival in both sexes, however females required additional therapy to enhance treatment outcomes. Men still had better results in response to therapy overall.^[24] Other studies revealed marginal differences.^[25]
• Radiation Therapy appears to be more beneficial in female pediatric patients than males for reducing the size of pediatric brain tumors and subsequently improving IQ.^[26]
• Immunotherapy may produce more robust responses in females, however this cannot apply to therapies that treat sex-specific tumor targets. ^[27] As some tumor types, while being the same, express unique mechanisms in either sex; it is thus possible that current immunotherapies will show little to no efficacy, unless specific biomarkers are tested for and accuracy can be guaranteed.

3. Auto-Immune Diseases

Auto-immune diseases encompass a very wide variety of conditions from digestive disorders to demyelinating diseases. They are characterized by a persistent immune reaction wherein the immune system loses tolerance towards self-proteins and proceeds to attack its own tissues. Examples of auto-immune diseases include multiple sclerosis, rheumatoid arthritis, type 1 diabetes and irritable bowel disease. Some diseases are not classified as auto-immune, but may have an auto-immune component to them.

Presentation

According to current statistics, autoimmune diseases display a trend of up to 80% female predominance on average^[28].

Not all auto-immune conditions are indicative of the same immune reactions, with varying immune profiles being able to perpetuate states of auto-immunity. Precision medicine reveals that even amongst patients with the same diagnosis, auto-immune biomarkers can vary in a spectrum and conspire to produce similar symptoms between people.

Classifications have been divided into systemic and organ-specific auto-immune diseases, with an emphasis on abhorrent antibody responses and/or inflammatory immune reactions.

Women appear to be at a higher risk for systemic autoimmune diseases such as systemic lupus erythematosus, with varying risk in both sexes for organ-specific autoimmunity.^[29] Other conditions females are more prone to contracting include Sjogren’s syndrome, multiple sclerosis, endocrine conditions such as hashimoto’s thyroiditis, rheumatoid arthritis, primary biliary cirrhosis, and celiac’s disease.

Interestingly, autoimmune condition prevalence may change depending on one’s environmental exposures and location^[30], as illustrated below:

• Myasthenia gravis and Guillain-Barre syndrome (neurological auto-immune diseases) tend to show a roughly equal male to female ratio of distribution, however in China, Japan and India, men are more commonly affected by these auto-immune diseases.
• Type 1 diabetes prevalence is also nearly equal between the sexes, with the exception of male dominance in the US and Denmark, and female dominance in Japan and Australia.
• Ankylosing spondylitis appears to favor males in many countries including the US, China, Australia, India and the UK.

Prognosis

The severity of autoimmune diseases is difficult to predict according to biologic gender. In general, women are more likely to acquire an auto-immune condition than men, yet also typically have a better prognosis.

Some exceptions include Crohn’s Disease, type 1 diabetes, lupus erythematosus, primary biliary cirrhosis and autoimmune hepatitis in which men display better prognosis than women. It is speculated that a higher degree of comorbidities worsen prognosis for women with these conditions.

Women typically produce more antibodies than men do, have reduced levels of inflammation (when estrogen is balanced) and have higher number of T and B lymphocytes^[31] with the potential for autoimmune reactivity. T helper lymphocytes, which specialize in helping to control inflammatory immune responses, are also seen to be lower in females and higher in males.^[32]

Men tend to be younger than women when diagnosed with an autoimmune condition, and the result tends to be far more inflammatory. Testosterone may have a protective effect as it can suppress immune reactivity. In some autoimmune conditions, such as multiple sclerosis, testosterone levels are seen to be reduced.

Other factors affecting prognosis include:

• Genes that escape silencing on a female’s second X chromosome may also predispose women as this has been linked to gene switches pertaining to faulty antigen presentation, loss of self-tolerance and increased immune cell responses^[33].  The hormonal profile of women is likely what makes the prognosis better in spite of the higher prevalence.
• The menstrual cycle has been linked with fluctuations in symptoms and severity; with increased estrogen levels generally acting as a protective factor.
• Pregnancy may cause remission of autoimmune symptoms due to the potency of estriol. Increased estrogen activity is known to be a key anti-inflammatory mechanism that promotes immune tolerance towards the developing fetus. Aggressive inflammatory autoimmune conditions and/or low estrogen levels are associated with miscarriage and/or fetal abnormalities. Systemic lupus erythematosus is a non-inflammatory autoimmune disease that typically worsens during pregnancy and is considered one of the rare exceptions.
• Aging can promote the loss of Y chromosomes as seen in ±20% of men over the age of 80, which also predisposes them to a greater risk of disease^[34], including autoimmunity. While inactive X chromosome loss occurs in a subset of aging women as well^[35], it likely does not pose a substantial risk for autoimmunity.^[36]
• Environmental and lifestyle factors may also increase the risk, many of which include chronic infection and/or chemical exposure. Men and women are affected uniquely by many of these factors, such as the amount of time spent in the sun, the use of cosmetic products, mercury exposure (increased in pads and tampons) and solvents.
• Assisted reproductive technology is known to overstimulate the ovaries to enhance fertility. However in women with autoimmune conditions, it may also promote disease during pregnancy and worse outcomes for the infant.
• Hormone replacement therapy may confer benefit in menopausal and postmenopausal women with an autoimmune disease. However synthetic estrogens, such as diethylstilbestrol, are associated with increasing symptoms.

Treatment Response

Currently, there is no known cure for autoimmune diseases. Research is highlighting how personalized medicine is one of the few promising treatment strategies, given the large degree of variability between patients and the complexity of autoimmune conditions^[37].

Some common treatment options for symptoms include anti-inflammatories, immune suppressants and in some cases, interferon therapy.

• Interferon-beta therapy is a common treatment option for multiple sclerosis patients. However the pathways it affects are unique to men and women respectively^[38], highlighting how it may require additional sex-specific modifications in unresponsive individuals. Further research suggests that late-stage disease may increase the risk of adverse effects in either sex.^[39]
• Anti-inflammatories and Immune Suppressants also display sex-specific efficacy, however more data is required to clarify current observations. In general, most of these drugs are more effective for men, and that women tend to suffer more adverse effects on average with lesser benefit. ^[40]

A low vitamin D status has recently been associated with a substantial risk of autoimmunity.

Some research has begun to make connections between reproductive hormone synthesis, vitamin D3 and immune function; highlighting that vitamin D may be a large regulating factor and that there are sex-specific differences in vitamin D metabolism that likely affect the disease course^[41]. Both men and women with low vitamin D were shown to produce less reproductive hormones on average.^{[42] [43]}

Women may require more vitamin D than men in the context of autoimmunity; however more research is needed to assess sex-specific differences in Vitamin D metabolism.^[44]

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