DISEASE IN THE CONTEXT OF BIOLOGIC AND SOCIAL GENDER (CNTD.)

The following article is part 2 of a discussion describing how biological gender affects health and well-being. Sex-specific characteristics are reviewed within the context of 9 common diseases, highlighting unique presentations, prognosis and treatment responses.

The diseases discussed below include Alzheimer’s Disease, diabetes, asthma, chronic kidney disease, COVID-19 and chronic liver disease.

4. Alzheimer’s Disease

Alzheimer’s Disease is a neurodegenerative disorder wherein patients suffer progressive cognitive decline, often precipitated by dementia.^[1] It is a complex disease by nature and is associated with amyloid-beta plaque deposition, neurofibrillary tangle formation, problems with maintaining tau protein and chronic inflammation.

Presentation

Nearly 70% of those with AD in the US are women. Women are at a much higher risk for developing AD than men. Furthermore, female AD presents with worse features than male AD.

The rate of cognitive decline and brain atrophy occurs at faster rates in females compared to males. Males are not susceptible to many factors that promote AD progression, even if they are unfortunate enough to acquire it. In this sense, females are more likely to show signs earlier and have more severe problems with memory and cognition than males on average.

Men may present with different symptoms pertaining to white matter atrophy, which includes difficulty concentrating, and other neurologic problems, such as reduced vision or motion. In animal studies, males with AD appear to develop behavioral inhibition more than female counterparts. Some men may develop AD without classic signs of dementia, which may give rise to a delayed diagnosis. It is also speculated that many male AD patients are misdiagnosed and that the incidence in men is far less than previously thought.^[2]

Prognosis

While women acquire Alzheimer’s Disease more commonly on average, men that get it tend to have reduced mortality. It is unclear whether this is a result of advanced aging and comorbidities in men with AD.

Age-matched control studies reveal that women tend to have many more contributing factors at the cellular level than men. These all highlight an increased risk and a worse disease course in women, as well as a better survival rate. The better survival may be related to increased female longevity as women tend to outlive men on average. The size of the male brain is typically larger than the female brain as well, and this lends itself to slowing the progression of male AD and speeding the progression of female AD.

Aging women and men tend to have lower levels of reproductive hormones, which affect immune processes pertaining to neurodegeneration. The brain is a very sensitive organ that demands a lot of anti-inflammatory activity in order to maintain functionality. The male brain has a higher level of estrogens than the female brain, which has less estrogen and more progesterone than the male brain.

In aged individuals, men tend to have an advantage, unless hormone production is completely suppressed as a result of comorbidity. Aged females see an increase in estradiol and androgens, while other hormones decrease; a trend that is not observed in healthy aging men. Men with AD have reduced testosterone levels as compared to men that don’t have it in the same age cohort.

White matter degeneration was the main feature predisposing men to AD risk, which typically manifests in relation to other disease states that promote inflammation and lower hormonal status in the brain.

Cholesterol metabolism also plays a role in some cases of AD, particularly in those with genetic changes in the ApoE E4 allele. ApoE (apolipoprotein) causes more cholesterol to be transported into the brain^[3] and ApoE E4 is associated with increased amyloid-beta plaque build-up seen in AD^[4].

Over-activation of estrogen receptor alpha (ER-a) increases ApoE production^[5] and those genetically predisposed thus produce more of the E4 type. Estrogen receptor beta, on the other hand, decreases ApoE E4 expression and both ER’s are required to maintain healthy neurologic functioning. Estradiol, especially estradiol-17-beta, activates ER-a but not ER-b.^[6] Excessive levels are connected to AD, female aging^[7], reproductive diseases and cancer; revealing potential insight into why AD is a female predominant disease.

Other factors affecting female morbidity include excessive stress and lowered brain-derived neurotropic factor (BDNF). BDNF and cortisol have an intimate relationship and work together to coordinate optimal cognition, memory, learning and concentration whilst engaging in mental activities. If cortisol is too elevated, it can reduce BDNF levels and detract from cognitive function.

In many areas of the world, women tend to lead more stressful lives on average than men. Excessive cortisol metabolism has been linked with early stage AD, as has lower levels of BDNF.

Treatment Response

There is little information on sex-specific outcomes for currently approved AD treatments^[8], which include the following drugs^[9]:

• Cholinesterase inhibitors, including donepezil, galantamine, and Rivastigmine, have been approved for treating AD. They work by blocking the breakdown of acetylcholine, which may enhance cognition.^[10] Adverse reactions are more severe in women on average and it was shown that women require lesser amounts for the same efficacy.^[11] Other studies also stipulate that these drugs are more efficacious for treating men than women.^[12]
• Glutamate receptor antagonists such as Memantine work by blocking specific glutamate receptors known as N-methyl-D-aspartate receptors. This increases brain concentrations of glutamate and lowers the risk of excito-toxicity which is known to promote neurodegeneration. Little is known on the sex-specific effects of Memantine in AD treatment, however as women with AD have fewer glutamate receptors than male counterparts, adverse effects may be greater in women and dosages may need to be lower.^[13]
• Amyloid-beta immunotherapy involves the use of a monoclonal antibody that attacks amyloid beta proteins and thus may help halter disease progression. Aducanumab is currently approved for this use, showing promise in clinical trials by reducing amyloid plaque deposition by up to 22%. However it is known to have side effects, some of which are severe (e.g. brain hemorrhages)^{[14] [15]}. It is unclear if there are gender differences in response to this treatment.

Hormone replacement may promote a decreased AD risk in women who opt for the treatment during perimenpause. Postmenopause, however, this may increase the risk and severity of AD.

5. Diabetes

Diabetes is a disease in which glucose metabolism is impaired. There are two main types.^[16]

Type I diabetes is an autoimmune disease that usually expresses in children and adolescents, wherein the beta cells of the pancreas become damaged.

Type II diabetes is the result of chronic insulin resistance, whereby insulin can no longer be utilized properly, resulting in low insulin and erratic glucose levels.

Presentation

Diabetes type I is a male predominant disease^[17] Type II Diabetes is female predominant during youth, with the ratio shifting towards male predominance from mid-life onwards. All-in-all, diabetes is generally seen as a masculine disease.

The way diabetes expresses is unique between the sexes. Diabetic men tend to suffer from hyperglycemia more often than women. Women with pre-diabetes display a reduced tolerance to glucose release after a meal than men, and men display higher glucose levels while fasting than women.

Prognosis

Adult men acquire diabetes more often than adult women, however women with the condition are at an increased risk of mortality. Cardiovascular disease increases the risk of diabetes substantially and is regarded as the prime risk factor between both sexes. This is one of the main reasons that men are at a higher risk of diabetes, as overall cardiovascular disease rates have a male bias.

Women with diabetes have a higher cardiovascular disease risk than men with diabetes, as well as an increased risk for stroke, heart failure, cancer and dementia. Atherosclerosis is more prevalent in women with the condition, being more advanced than men in the same disease phase. Females also tend to remain undertreated for diabetes and cardiovascular disease by comparison to men. This may pertain to using fasting glucose levels as a biomarker to test for the disease.

Hypogonadism (low sex hormone levels) significantly increases the risk of diabetes in both men and women. These hormones decrease with aging, chronic stress, and states of disease; all to which women are the more vulnerable^[18]. Some studies have highlighted the role of testosterone in aiding glucose regulation and promoting resistance towards cardiovascular disease in men. In women, estrogens appear to reduce the hyperglycemic response to fats. Females tend to be more sensitive towards insulin and glucose than men in general, as well as being able to secrete more insulin on average.^[19]

Pregnancy also increases the risk of diabetes, in some cases by as much as 70%. Some studies imply that women are at a higher risk of gestational diabetes when carrying a male fetus.

Treatment Response

In response to insulin administration, diabetic women tended to suffer more severe hypoglycemia than men with diabetes. This suggests women with the condition need less insulin for enhancing glycemic control.^[20]

Women are less responsive than men towards other drugs that control for blood sugar levels. Sex-specific efficacy of common anti-diabetic drugs are listed below:

• Metformin was more efficacious in men and produced more adverse effects in women on average.
• Sulfonylureas reduce hyperglycemia in lean men better than in lean women with diabetes.
• Thiazolidinediones promote better insulin sensitivity in obese females than males with diabetes. Other studies show that it is more effective in treating female diabetes, which may be due to increased uptake and higher systemic levels of the drug in women.^[21]

Men appear to require limb amputation more often than women. Blood pressure and increased body mass increased the risk of diabetic foot syndrome in men while increased uric acid levels and insulin therapy increase the risk for women.

Kidney disease is a more common comorbidity in male diabetic patients, showing a speedier progression and more often resulting in dialysis therapy. Women that undergo dialysis are at an increased risk of mortality than men.

Men and women respond differently to managing diabetes. While women may do better at following a healthy diabetic diet plan, they may also suffer additional stress due to social obligations^[22] which may detract from successful disease management. Women with diabetes are also at a higher risk for suffering depression, anxiety and fatigue than men, however all with the condition experience these symptoms more often than that of the general population.

6. Asthma

Asthma is a respiratory disease, characterized by chronic episodes of acute allergic responses in the airways that constrict breathing.

Presentation

Asthma affects more males before puberty, with the bias shifting towards females during adulthood. Adult women are more likely to experience more severe symptoms and an increased sensitivity to potential triggers of asthma, such as nicotine and environmental pollutants. Obesity affects the severity of asthma in women, but not in men.^[23]

Prognosis

In adulthood, the female immune response shifts due to the change of steroidal hormones. Increases can be seen in female B cells, dendritic cells and CD4+ T cells involved in a type 2 immune response.^[24] This is the same response that drives both asthma^[25] and allergies. While both sexes can contract asthma, the response is generally worse in females for these reasons.^[26]

Interestingly, many women experience an intensification of symptoms just before and during menstruation, during the first trimester of pregnancy, as well as during menopause. More studies are needed to understand why this appears to be the case; however it likely pertains to the mucus-stimulating properties of estradiol^[27] and increased bodily water retention that occur during the menstrual cycle.

In contrast, limited research indicates that testosterone and DHEA are protective against asthma, supporting the trend seen in adult men.

It is not clear why boys have a higher incidence of asthma than girls until puberty onset. Several theories have been proposed, including delayed growth of airways in boys. Immune responses appear to favor the type 2 reaction in boys until puberty as well, for reasons that have yet to be elucidated.

It is possible that the X chromosome plays a role as it contains 10% of the genes pertaining to microRNA expression, while the Y chromosome merely contains 2 genes that serve the same function^[28]. MicroRNA’s have been shown to regulate allergic inflammation, potentially giving females an advantage until their reproductive hormones kick in later on.

Treatment Response

Conventional asthma treatment involves the use of corticosteroids, often administered via an inhaler pump. These are known to block the inflammatory pathways involved in the allergic reaction and the results do not appear to be sex-specific. Aging is associated with a decrease in the effectiveness of treatment^[29], as is excessive corticosteroid use which may simultaneously block innate anti-inflammatory mechanisms^[30].

Oral contraceptives may reduce asthma risk and severity in women; however they are associated with endocrine disrupting effects. Hormone replacement therapy may increase asthma risk in menopausal women, particularly in those with a low BMI.

7. Kidney disease

Chronic kidney disease is characterized by kidney damage and/or a reduced filtration rate for a period of longer than 3 months. Diabetes and hypertension are the most common causes of kidney disease.^[31]

Presentation

Chronic Kidney Disease prevalence is nearly equal between men and women, with women showing a slightly higher bias in some studies^[32] and men in others. The diagnosis in females may also be overestimated due to using male references.

Infection and systemic autoimmune diseases are common risk factors for kidney disease in women; while in men, hypertension and diabetes are more common.

Women are at a lower risk of acquiring glomerular impairment in kidney disease compared to men.

Prognosis

The disease progresses slower in women than in men, once again due to the anti-inflammatory nature of estrogens.^[33] Postmenopausal women appear to progress as quickly as men, presumably due to lower hormonal status. Animal studies highlight that women may be at an advantage during disease course as a result of more swift antioxidant defense mechanisms early on^[34].

Women have an increased mortality rate in spite of having a slower disease progression than men. This may be due to delayed treatment and a potentially higher incidence of complications with regard to dialysis. Men have a higher mortality rate before starting on dialysis treatment.^[35]

Pregnancy may increase the risk of kidney disease, particularly if it induces diabetes or hypertension.

Treatment Response

Women may be treated too late and are at a higher risk of insufficient treatment, which may affect outcomes. In some studies, dialysis therapy is seen to produce more complications in women than men, while in others it does not.^[36] Dialysis is associated with a poorer quality of life in women than in men.^[37]

While females more often donate kidneys, they also less often receive them when in need of transplantation.^[38]

8. COVID-19

COVID-19 is the disease induced by infection with the novel coronavirus, SARS-COV-2. Symptoms include pneumonia, fatigue, and a variety of individualized complications, potentially reflective of blood-clotting, fibrosis and low oxygen status. Some cases are asymptomatic.

Presentation

The symptoms of COVID-19 are similar for both sexes, however males are at a slightly higher risk and may present with increased disease severity. Viral shedding seems to be longer for men on average, leading to a longer disease course.^[39]

Prognosis

Mortality rates are higher in males by as much as 61% and the chance of recovery is lower. This contradicts statistics regarding pneumonia and influenza, for which women suffer a higher risk of mortality.

Nonetheless, the sex-specific difference with regard to COVID-19 is thought to be a result of the advantages females have with respect to fighting viral infections. As compared to men, female biology is indicative of lower inflammation levels, additional anti-inflammatory estrogens and enhanced innate immune function due to having an extra X chromosome. Females are also noted to have an increased capacity for viral clearance.^[40]

Treatment Response

Common treatments for acute severe COVID-19 include hospitalization, oxygen administration, anticoagulant therapy, anti-inflammatory drugs and/or some form of antiviral medication. Vaccines are the best currently known form of prevention.

There is very limited information on sex-specific responses to COVID-19 treatments^[41]. Some non-covid studies indicate that women suffer more complications when undergoing antiviral treatment than men, in spite of being better immunologically equipped to handle them.

Women respond to anticoagulant therapy differently than men. Heparin is commonly used intravenously for this therapy. Studies show that heparin levels in women are much higher than in men in response to treatment, even when a lower dose is administered, suggesting a greatly increased risk of bleeding^[42]. In terms of COVID-19, this is likely a life-saving phenomenon that improves survival and prognosis in the face of severe blood clotting.

Men may have less immunity post vaccination due to making fewer antibodies than women in general. They may also require a longer quarantine period after receiving the vaccine due to a slower shedding rate. However, higher levels of adverse reactions to vaccination are reported in women on average^[43].

Convalescent plasma transfusions, rich with antibodies, are known to cause an increase in adverse reactions in men (e.g. dermatitis), particularly if the donor was a woman with a history of pregnancy in which estrogen content is increased. This highlights the need for sex-specific blood transfusions when used in the context of fighting off infectious illness.

9. Liver Disease

Chronic liver disease refers to liver deterioration that lasts longer than 6 months. The liver may succumb to chronic damage as a result of familial genetics, infection, alcoholism, autoimmunity, and/or cardiometabolic diseases, such as diabetes and metabolic syndrome.^[44]

Presentation

On average, men tend to suffer more from chronic liver diseases than women. Amongst the various types of liver disease, men are more susceptible than women to hepatic cancer^[45], fatty liver diseases, primary sclerosing cholangitis and infections precipitated by hepatitis B virus^[46]. Women are more susceptible to liver adenomas, autoimmune primary biliary cirrhosis and hepatitis C virus infections than men.

Women can process fats better than men due to elevated estrogens and tend to be healthier with their diets, potentially making men more vulnerable to non-alcoholic fatty liver disease as well. After menopause, women are more susceptible to liver diseases than men due to hormonal reductions. Males and postmenopausal females are also more likely to suffer hyperuricemia than younger women with liver disease, implicating testosterone in this profile.

Aside from obesity, many cardiometabolic diseases have a male predominance, which also increases the risk for chronic liver disease. Obese men are likely to have a higher risk than obese women, in spite of obesity being more prevalent amongst females.

Prognosis

Obese women are at an increased risk of liver fibrosis in fatty liver disease, however in non-obese patients, men and postmenopausal women appear to be at a higher risk. Computational genetic models suggest that women still process fats better than men do^[47]however they are at a risk of dumping excessive fat into fat mass as opposed to visceral fat.

Females may suffer worse inflammation, swelling and injury during disease progression than men, while men may suffer worse abhorrent liver growth. While men consume more alcohol than women on average and are at a higher risk of liver disease, the livers of women are twice as sensitive to the effects of alcohol.

Men with liver disease are prone to developing hepatic cancer at a faster rate than women and are also at an increased risk of mortality.

Treatment Response

There is little information on sex-specific responses to treating symptoms of liver disease. This is likely due to the fact that most treatments are multi-model.

Men are at a higher risk of drug-induced liver injury, making treatment for liver disease a bit more complex. Furthermore, men take longer to recover from drug-induced liver injuries^[48] and in some cases, are at a higher risk of morbidity and mortality. While females are at a lesser risk, they are more sensitive to medications more often than men, more often subject to worse adverse effects and often require less for better efficacy.

Liver transplantation studies reveal that success depends on matching the sex of the donor to the sex of the recipient^[49]. Interestingly, men who received a female liver or liver graft suffered a great degree of complications as compared to any other combination. Both males and females appear to do better with male liver transplants, and females appear prone to a slightly higher degree of complication when receiving a female liver transplant.^[50]

Conclusion

All-in-all, sex-specific differences in health are exceedingly complex and further research will be required before this aspect of biology can be incorporated fully into practice.

Current evidence highlights that women have increased immune reactivity as well as enhanced immune efficiency, leaving them more vulnerable on average towards allergic and autoimmune conditions. Men by contrast are affected more often by diseases constituted by suppressed immunity and warped cellular growth, making them susceptible towards cancer and viral infections.

Women tend to receive delayed treatment and may be more sensitive towards treatment on average. Prognosis is generally worse in either men or women that contract diseases with a higher prevalence in the opposite sex.

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