The influence of sex on the incidence of Parkinson disease (PD) has been well established, as the disease is reported to occur at a rate of 1.37 to 3.7 times more frequently in men than in women.¹ Recently, several studies have begun to uncover sex-dependent variations in the symptomatic manifestations of PD, as well as in the response to dopamine therapies. One of the first clinical features observed was that the age of onset is approximately 2 years later in women than in men and was generally accompanied by a milder disease course.^1,2 The most common presenting symptom in women was tremor, whereas men were more likely to have initial symptoms of bradykinesia and rigidity.^1,2

Early Symptoms by Sex

The sex differential in PD seems to predominantly affect 3 areas, including nonmotor symptoms (NMS), cognition, and response to dopamine.

Sex differences were shown in a number of studies to influence NMS in clinical disease patterns of PD, but not the primary motor symptoms involving movement.^1-5 These differences tended to emerge after initial diagnosis, whereby women developed a higher prevalence of mood changes, including nervousness, sadness, and depression, as well as constipation, fatigue, and pain, whereas men were more likely to suffer from daytime sleepiness, dribbling, and sexual dysfunction.¹ Rapid eye movement behavior disorder was also more frequently reported in men than in women with PD.⁴

In a study published in 2013, Picillo et al⁵ assessed the frequency of NMS in 200 patients with early PD and 93 healthy control patients, using the Non-Motor Symptoms Questionnaire (NMSQ). Compared with women, men were more likely to complain of sexual difficulties and disturbances of smell and taste. This study showed specific sex-related patterns of NMS in drug-naive PD that emerged in the early, premotor stages of the disease. In contrast to previous data, female patients did not demonstrate a higher prevalence of mood symptoms compared with male patients, which may have been a result of treatment responses in the earlier studies.^2-5

When compared with healthy control patients, men with PD reported a higher frequency of dribbling, sadness/blues, loss of interest, anxiety, acting out during dreams, and taste/smell disturbances, whereas women with PD expressed an increased sense of anxiety and a greater loss of interest in daily activities compared with women without PD.⁵

In contrast, a 2015 study by Augustine and colleagues⁶ did not find any differences among sexes in age at onset or diagnosis, or in early motor signs, which, according to the investigators, may suggest an “equalizing effect” over time in their larger scale cohort of 1741 participants, although distinct differences in NMS, including cognition, were observed.⁶

Cognition

Contradictions in the divergence of cognitive symptoms between men and women are also common in the literature. Women in the Augustine study performed better on multiple measures of cognition compared with men, including the Scale for Outcome of Parkinson Disease Cognition, which measures learning, memory, attention, executive function, and visuospatial function, and the Symbol Digit Modality Test for cognition.⁶ The investigators pointed out that the influence of sex-based differences in PD varies during the course of the disease, and that cognitive differences appear later. “The difference in cognition scores between men and women may represent an important finding. Increasing cognitive impairment correlates with overall disability, and PD with dementia is associated with lower quality of life and a higher degree of caregiver burden compared to PD without dementia,” they wrote.

Other studies identified greater deficits in facial recognition and verbal fluency in men with PD, whereas women experienced greater losses in visuospatial function^.4 Liu and colleagues³ found evidence that cognitive impairment may actually begin in the early stages of PD, particularly in men. They suggested the importance of early evaluations of cognitive performance in predicting later decline in NMS and dementia.³

Hormonal Influences

“In terms of brain function and cognition, some behavioral tests, both in humans and animals, show some sex differences that imply genuine underlying biological differences or/and socioeconomic external factors (stereotypical male or female behaviors),” Glenda Gillies, PhD, a professor emeritus at the Imperial College of London, United Kingdom, told Neurology Advisor. Although some studies indicate no sex differences in behavioral endpoints, she said, “real-time brain imaging [eg, positron emission tomography scans, functional magnetic resonance imaging] reveal sex differences in the underlying brain activity patterns, suggesting that male and female brains achieve the same goal or performance, but by different processes.”

Response to dopamine therapy in PD seems to be significantly hormonally mediated, although there have been conflicting results across studies here as well.^1,3,4 In general, women have demonstrated a lesser response to dopamine for symptoms of bradykinesia and are more likely to develop dyskinesias, the latter of which seems to be dose-related.⁴ Of note, responses to deep brain stimulation for PD have not been differentiated by sex, also pointing to hormonal influences of estrogen.⁴

Male sex is the most prominent risk factor for the development of PD. Gillies and colleagues¹ suggested that intrinsic hormonal differences in the nigrostriatal dopaminergic pathway (which plays a substantial role in regulating fine motor control) “may underlie these differences in vulnerability, and could also account for the sexually dimorphic actions of estradiol, which protects females against striatal DA loss in experimental PD, but fails to protect, or may even worsen, striatal lesions in males.”

“From the basic research from my own and other labs, I believe that sex differences are present in many brain regions and, although this may not necessarily translate into readily discernable differences in function, they may well underpin sex differences in patterns of malfunction or degeneration, which occur in most brain disorders,” Dr Gillies explained.

The implications of these investigations points to a clear need to elucidate these differences further and to develop sex-specific treatment strategies (including varying therapies and dosages by sex) for targeted therapies that may have disease-modifying potential. “We need to understand these differences better if we are to achieve optimal treatment and preventative strategies for both sexes,” Dr Gillies said.

References

1. Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Front Neuroendocrinol. 2014;35:370-384.
2. Haaxma CA, Bloem BR, Borm GF, et al. Gender differences in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78:819-824.
3. Liu R, Umbach DM, Peddada SD, et al. Potential sex differences in nonmotor symptoms in early drug-naive Parkinson disease. Neurology. 2015;84:2107-2115.
4. Miller IN, Cronin-Golomb A. Gender differences in Parkinson’s disease: clinical characteristics and cognition. Mov Disord. 2010;25:2695-2703.
5. Picillo M, Amboni M, Erro R, et al. Gender differences in non-motor symptoms in early, drug naïve Parkinson’s disease. J Neurol. 2013;260:2849-2855.
6. Augustine EF, Pérez A, Dhall R, et al. Sex differences in clinical features of early, treated Parkinson’s disease. PLoS One. 2015;10:e0133002.