Background

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disease behind only Alzheimer’s disease. The multitude of potential motor and nonmotor symptoms of PD include resting tremor, bradykinesia, rigidity, multifactorial gait impairments, autonomic dysfunction, cognitive impairment, and sleep disorders, among others. The sequelae of the motor and nonmotor symptoms of PD can negatively affect quality of life, increase fall risk, impair mobility and functional independence, and affect social, emotional, and medical well-being. ^, By 2037, the total US economic burden of the disease is estimated to reach US$79.1 billion. The exact cause of PD is unknown, but it is believed to be influenced by genetics, age-related changes in neurons, and the presence of abnormal proteins called Lewy bodies, resulting in the main pathology of a deficiency of dopamine in the substantia nigra of the brainstem.

Discussion

The role of biological sex has gained increasing attention as an important component in the development and impact of PD. Generally speaking, the prevalence of PD is twice as high in men compared to women. Sex-related differences exist in some motor manifestations of the disease process. Women are more likely than men to present with tremor as their initial symptom. Women have a slightly older age of onset and have a shorter time to and higher likelihood of developing levodopa-induced dyskinesias. ^, Women also tend to have a lower likelihood of rigidity but a higher likelihood to develop postural instability.

Sex also appears to play a role in the prevalence of multiple nonmotor symptoms. Women more often present with depression, fatigue, lack of motivation, nervousness, constipation, pain, and restless legs and report worse disability and quality of life. ^, Compared to women, men appear to have more common and severe symptoms of daytime sleepiness, drooling, and sexual dysfunction, which includes altered interest in sex as well as increased frequency of compulsive sexual behavior. ^,

Health care disparities between men and women also appear to exist. A retrospective observational cohort study of Medicare beneficiaries with PD published in 2011 revealed that women were statistically significantly less likely than men to obtain care from a neurologist, even after the adjustment for comorbid disease and socioeconomic barriers to specialty care. There is evidence that sex is a strong, independent predictor of receiving a deep brain stimulator (DBS), with women being disproportionately less likely than men to receive a DBS for reasons that remain unclear. In a retrospective cohort study of over 133,000 Medicare beneficiaries diagnosed with PD and followed through 2008, compared to men, women had higher utilization of advanced nursing care (skilled nursing facility, home health, and hospice) and lower utilization of direct physician contact. A 2018 study of 7209 patients at 21 centers in the United States, Canada, the Netherlands, and Israel, revealed that women were less likely than men to receive caregiver support from a spouse, family, or friends and utilized paid caregiver services less often than men.

Response to treatment can vary between sexes. Multiple studies have demonstrated that compared to men and controlling for other factors, women have higher blood levels and bioavailability of levodopa following oral carbidopa–levodopa administration. One review article presented interesting findings for patients with PD following DBS implantation; women tended to report more improvement in activities of daily living, while motor improvement appeared to be equal between both sexes.

Estrogens also appear to play a potential protective role in both the risk of PD development and symptom reduction. A prospective cohort study concluded that women with a higher cumulative exposure to both endogenous and exogenous estrogens throughout life had a significantly reduced PD risk. In a double-blind, placebo-controlled, crossover study and a double-blind, parallel-group, prospective study, both among postmenopausal women, estrogen replacement therapy reduced levodopa-induced dyskinesias. Furthermore, in this study by Tsang and colleagues, estrogen replacement also improved “on/off” times and motor symptoms as measured by the Unified Parkinson’s disease rating scale subscale III.

A 2020 cross-sectional case–control research study revealed important findings relating to osteoporosis in PD, 2 age-related diseases that can affect mobility and disability. Women with PD were compared to age-similar women without PD. Women with PD had lower bone mineral density of the lumbar spine, femoral neck, distal radius, and total body compared to women without PD. The frequency of history of osteoporotic fractures in women with PD was higher compared to women without PD, at 51.7% versus 11.3%, respectively. Additionally, the future 10 year probability of major osteoporotic and hip fractures were higher in women with PD compared to women without PD, as projected by FRAX (Sheffield, UK), a well-known calculator for the assessment of fracture risk. The authors thus conclude that with lower bone mineral density indices, higher rates of osteoporosis and fractures, and higher risk of future low-energy fractures, this osteoporosis and fracture risk should be taken into consideration with the clinical management of women with PD.

Background

MS is an autoimmune disease that affects the central nervous system (CNS) and involves a pattern of demyelination, inflammation, and neuronal insult. Colloquially characterized as disseminated in time and space, lesions that develop within the CNS often present in different areas and at different times. Initial presentations have a wide range, including visual deficits, sensorimotor effects, cognitive implications, and bowel/bladder problems. Wherever a lesion is present, downstream symptoms can be seen. Progression of MS can be gradual or rapid based on MS subtypes, including relapsing-remitting, primary progressive, secondary progressive, and progressive relapsing. Worldwide, 2.5 million individuals live with MS, with an overall prevalence of 1 in 1000 in populations of European ancestry. Notably, MS has a predilection for women, with a woman:man prevalence ranging from 2:1 to 3:1, with numbers as high as 3.2:1 in patient populations below the age of 20 years.

Discussion

The immune system and the CNS are closely linked, with implications of the immune system commonly seen in many CNS disorders. MS specifically is thought to be an autoimmune disorder of TH1 cell-mediated immunity, similar to rheumatoid arthritis and psoriasis. ^, Autoreactive CD4 ⁺ T cells go on to attack myelinated proteins found on neurons, which leads to the development of plaques and astrocytic scars. ^, Gender differences of the immune system have been observed in humans and also experimentally in mice, with one disease being studied at the forefront—experimental autoimmune encephalomyelitis (EAE). Within the confines of this disease, which is akin to MS, special attention was paid to peroxisome proliferator-activated receptor-α, which is involved in gender differences of lipid metabolism. This receptor also exerted gender-specific effects in EAE, indicating a potential interaction between sex-related factors and diet in autoimmunity. Further gender differences can be stratified as related to incidence and progression.

Between 65% and 70% of new MS diagnoses are in women, with this trend steadily increasing in recent years. Many mechanisms may be behind this pattern, with the Y chromosome offering a level of protection by way of the SrY gene. If this SrY gene is transposed to the X chromosome, disease progression has been witnessed to worsen. Additionally, physiologic testosterone is protective, where castration of mice worsens established EAE and places the mice at higher risk of disease onset and incidence. Looking further into hormonal impacts, pregnancy has often shown a consistent and profound beneficial impact on nearly all aspects of MS.

From an overarching stance, pregnancy modifies disease most significantly in the third trimester; MS has the lowest relapse risk during this time, with an overall reduction of nearly 70%. Important shifts at this time period include peak levels of estradiol, estriol, and progesterone, which are all thought to be protective modulating factors. This is further drawn home by an increased presence of relapse at 6 months postpartum, where many of these hormones either normalize or downregulate considerably. In fact, 2 recent pilot studies examined the use of oral estriol in women with MS with definitively positive impacts. Current MS treatment regimens diminish relapse risk by an average of 30% to 60%, thereby indicating that pregnancy confers even higher protection than current pharmacologic modulations. On a more macroscopic level, the previously noted increase in new diagnoses among women could be explained by a waning tendency of many young women in society today to be multiparous, therein evading the summative protection of multiple pregnancies in the context of MS.

Beyond the above gender-specific differences on incidence and in the context of pregnancy, specific differences were also seen in MS effects on men and women, both clinically and radiologically. Despite women receiving MS diagnoses more often, men with the disease tend to progress differently than women, and often more rapidly especially in the context of gray matter volumes. A recent examination conducted by Antulov and colleagues looked at 763 total patients with MS, 171 of which were men (22%), and identified considerably less gray matter volumes within the men of this group. Interestingly, women had less white matter volumes in comparison, yet many of MS sequelae are related directly to gray matter changes that may explain why men develop more rampant symptoms at times and more often are implicated in the progressive variants of the disease. ^, Gray matter atrophy has also been shown to correlate stronger with permanent disability than does white matter atrophy. Transdermal testosterone has been utilized in men that suffer from MS similarly to the regimen of oral estriol in women, with similarly positive outcomes. Hormonal fluctuations of testosterone may potentially play a role in pathogenesis of MS, with perhaps a diminished level of protection compared to estrogens. Estrogen and testosterone levels thus could affect clinical outcomes in men compared to women based on hormonal differences.

Background

Alzheimer’s disease (AD) has had a profound, multifaceted impact on the world. Examining just the United States, approximately 5.2 million Americans carry the diagnosis, with 5 million of these individuals being older than 65 years. This number is expected to nearly triple by 2050, with a high burden on morbidity and mortality as well, with AD currently being the sixth leading cause of death in the United States. Fiscal cost and opportunity cost revolving this disease are dramatic, with Medicare estimates in congruence with the 17.7 billion hours of care given to family members affected leading to a cost of nearly US$214 billion for the former and US$220 billion for the latter. The aim of this review is to dive deeper into the discrepancies of men and women who are diagnosed with AD.

Discussion

On the surface, women appear to be further affected by this disease in particular, as women are more likely to develop the disease and also twice as prevalent in caregiver roles compared to men. Several mechanisms may be at play but all boil down to a simple concept—longevity.

Two-thirds of novel cases of AD are women, with a common explanation being offered of dementia risk correlating with age. Swedish twin studies from the 1960s and stratified studies from the 1980s both concluded that men overall are not expected to live as long as women, with a significant dichotomy observed in the incidence of AD above the age of 85 years in particular. ^, These studies, thus, did not identify sex-specific rationales for the differences in incidence and prevalence, rather attributing it all to age and life expectancy. ^,

More recent investigations have added some components to the argument beyond longevity, albeit supporting the notion that a difference in age remains the primary culprit of discrepancies. Sporadic AD is strongly linked to the APOE4 allele (apolipoprotein E4), with statistically stronger evidence of gene conversion in women compared to men. For instance, one copy of this allele in a woman increases the risk of developing AD 4 fold, while only marginally increasing the risk in a man with only one copy of this allele. Beyond simply the genetic background, some experts consider AD a subset of an autoimmune condition, which women are at greater risk for, because one of the first actual signs of damage seen pathologically in the brain was microglial infiltration of macrophages. ^, This inflammatory component has several downstream implications for those actually afflicted with the disease, as Irvine and colleagues identified that women tend to demonstrate a more profound cognitive decline compared to men. A reduction in estrogen in postmenopausal women has been posited as a potential explanation for this phenomenon, as estrogen has been shown to serve a protective factor in numerous neurologic and autoimmune conditions. However, more consistent with principles discussed initially, perhaps cognitive performance is swayed simply by a greater number of women diagnosed with AD who continue to live longer than their male counterparts. Yet another study saw an explanation revolving around brain anatomy, as men tended to have up to 10% larger brain volumes than women, which therefore may lend itself to a greater resilience of a gradual degeneration. This concept was later reinforced by an autopsy study declaring women are much more likely to be clinically diagnosed with AD compared to men at similar levels of actual brain pathology.

Another interesting parallel uniquely seen in women involves the relation of menopause and eventual Alzheimer’s dementia risk. As a review, following menopause, certain sex hormones begin to rapidly decline—most notably 17 beta-estradiol and progesterone. If a bilateral oophorectomy is indicated and performed for a female patient prior to menopause, similar rampant declines are witnessed in these patients, along with testosterone and the totality of the hypothalamic-pituitary-ovarian axis. The Mayo Clinic Cohort Study of Oophorectomy and Aging examined patients longitudinally to try and understand how this significant change could impact the remaining lifespan of patients moving forward. An almost doubled risk of all-cause dementia was seen in this population; yet, if women began hormone replacement therapy after their oophorectomies until the age of expected natural menopause, the risk of AD was synonymous with the general female population.