Should Exercise Be Prescribed Differently Between Women and Men? An Emphasis on Women Diagnosed With Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease caused by a reduction in dopaminergic neurons in the substantia nigra (Dexter and Jenner, 2013). Individuals can exhibit muscle tremors, rigidity, and bradykinesia, leading to posture and gait abnormalities (Dexter and Jenner, 2013). Although the incidence ratio of males to females is ~1.46 (Taylor et al., 2007), the prevalence of PD among men is doubled when compared to women (Elbaz et al., 2002). A lower mortality rate has traditionally been associated with PD in women due to the overall longer life expectancy when compared to men in the general population (Xu et al., 2014; Pinter et al., 2015). However, a diagnosis of PD was found to be associated with a two-fold increased risk for all-cause mortality in a recent study with 396 older women (Winter et al., 2016). This value is similar to that reported among older men (Xu et al., 2014). Males may have a greater predisposition to develop PD (Gillies et al., 2014). This bias may be due to the molecular pathology of PD. Gene expression profiles in dopaminergic neurons are sex-specific, and the survivability of these neurons are dependent on molecular pathways that are very different in men and women (Gillies et al., 2014). In healthy brain tissue, genes involved in signal transduction and neuronal growth are up-regulated more in women (Cantuti-Castelvetri et al., 2007). In men, genes with specific mutations (e.g., α-synuclein, PINK-1) that may contribute to the pathogenesis of PD are upregulated more often (Simunovic et al., 2010). A downregulation of genes that provide for oxidative phosphorylation, and synaptic and nerve impulse transmission, is also more prevalent in older males (Simunovic et al., 2010). Therefore, women are thought to have greater protection from PD when compared to men, which may also be due to estrogen concentrations (Gillies et al., 2014). Estrogen influences dopamine synthesis and release while inhibiting dopamine uptake (Shulman, 2007). The higher concentrations of estrogen are a possible reason for the more benign phenotype in women when compared to men, particularly before a course of medication has begun (Haaxma et al., 2007; Miller and Cronin-Golomb, 2011; Cereda et al., 2013). Estrogen may play a role in preventing toxins from possibly degrading neurons in the substantia nigra (Shulman, 2007). Exogenous or endogenous estrogen administration may therefore play a crucial role in the pathogenesis of PD (Lv et al., 2017). There are several factors, including medicinal options, surgical interventions, dietary strategies, and lifestyle habits that may alter estrogen levels in women with PD. Oral contraceptive (OC) use may increase the risk of PD among women (Nicoletti et al., 2011), with a 20% increased risk of developing PD for every five years of OC use (Simon et al., 2009). However, the use of OCs has been also been shown to be inversely associated with PD risk (Greene et al., 2014), with continuous use for more than 10 years determined to even be a protective mechanism against developing PD (Liu et al., 2014). Following an ovariectomy, a decrease in the concentration of estrogen receptor-α and an increase in angiotensin, NADPH-oxidase activity, and the expression of neuroinflammatory markers was observed in the substantia nigra of menopausal rats (Rodriguez-Perez et al., 2015). Smoking may increase levels of estrogen and serum sex hormone-binding globulin, and may also be protective against PD, as an inverse correlation between smoking and PD risk has been shown (Ritz et al., 2007; Breckenridge et al., 2016). Proper intake of vitamin D may increase glial derived neurotrophic factor (Smith et al., 2006) and reduce activated microglial cells (Kim et al., 2006), therefore acting as a neuroprotectant with estrogen and reducing inflammation. The protective effect of estrogen is not always evident, particularly in women who report a more rapid onset of motor symptoms upon diagnosis (Sato et al., 2006; Colombo et al., 2015; Bjornestad et al., 2016). With regard to motor symptoms, women typically present more with tremors and bradykinesia, but not rigidity, when compared to men (Haaxma et al., 2007; Martinez-Martin et al., 2012). Non-motor symptoms, such as constipation, restless legs, pain, nervousness, anxiety, and sadness, are more prevalent in women (Martinez-Martin et al., 2012; Solla et al., 2012; Picillo et al., 2013; Szewczyk-Krolikowski et al., 2014). A reduction in visuospatial cognition also occurs more frequently in women (Miller and Cronin-Golomb, 2011). To treat the motor and non-motor symptoms of PD, individuals are often presented with a variety of options. Medications and surgical procedures are available but are often unsuccessful at treating all symptoms of PD, can be expensive and invasive, and may lead to unwanted side effects (Bloem et al., 2004). Exercise may therefore be an inexpensive and complementary option to other interventions to treat symptoms of PD. Performing regular exercise may improve numerous functional outcome measures and quality-of-life, particularly in higher-functioning individuals diagnosed with neurodegenerative diseases, including PD, multiple sclerosis, and dementia (Dodd et al., 2011; Brienesse and Emerson, 2013; Morley et al., 2015). Gait speed is slower in older women, possibly due to observed increases in muscle strength and standing balance ability in men (Bohannon, 1997). When compared to men with PD, women with PD exhibit increased cadence and decreased stride length and frequency (Kokko et al., 1997; Pedersen et al., 1997). To improve gait, motor performance, and quality-of-life, aerobic exercise on a motorized treadmill may be effective intervention for those with PD (Herman et al., 2007). Treadmill exercise can improve motor function, stride and swing time variability, and gait speed in adults with mild to moderate PD (Herman et al., 2007). This in turn may allow for greater mobility during...