Sex and Gender Differences in Parkinson’s Disease and the Conclusions We Should Draw

Marita F. Thiel^* and Wolfgang H. Jost
^*Correspondence: Marita F. Thiel, Parkinson Klinik, Ortenau, Germany, Email:

Keywords

Gender differences • Parkinson’s disease • Alzheimer’s • Neurodegeneration

Introduction

Parkinson’s disease is worldwide the second most frequent neurodegenerative disease, second only to Alzheimer’s disease. It has been estimated that as of the year 2030 more than nine million persons will have contracted the disease [1]. We can readily assume that this will involve an ever-increasing burden for health economics, especially if calls for individualized therapies expand. The cardinal symptoms of the disease consist of rigor, tremor and akinesia, all of which can be accompanied, at any of the stages of the disease, by non-motor symptoms, that is, autonomic and/or neuropsychiatric symptoms. In the advanced stages, late motor complications such as fluctuations in the efficacy of medication and dyskinesias occur frequently. The individual patients’ symptoms, the course of their disease and their response to medication are characterized by a high degree of heterogeneity. We aim at developing individually tailored treatment therapies which necessitate recognizing the possible variations of the disease well ahead of any individualized treatment. For a considerable length of time there has been a lively discussion of such topics as sex-specific as well as gender-specific differences in the incidence, the symptomatology, the response to medication and the course of idiopathic Parkinson’s syndrome. Could this discussion signalize the beginning of individualized treatments in the future? Or: Are we really just not advanced enough to understand the basic underlying pathophysiology of Parkinson’s disease and thus cannot yet adequately fathom gender-specific differences?

Methods

Do we need a sex and gender-associated focus for treating Parkinson’s disease?

Cardiology has been demonstrating for years now that infarction in females can be reliably distinguished from those in men as regards symptoms, pathophysiological mechanisms and the outcome. As a result attention has grown for female infarction, thus improving its diagnosis, and the incidence rate in women increased correspondingly [2]. We now have preliminary indications, and the real hope, that similar progress is slowly developing for neurodegenerative diseases and particularly for Parkinson’s disease. In addition to the idea of gender-specific differences, another concept has taken on similar relevance: That of socio-cultural imprinting, in the sense of a fundamental gender definition. But within the framework of medical studies, the full influence of the gender aspect is quite complex and thus difficult to fully appreciate. As a result it is often neglected. Because we are only just starting to research the question of sex and gender-specific differences in idiopathic Parkinson’s disease, and because so many intriguing questions remain, one ideal starting point entails the analysis of defined and replicable data and criteria. The American National Institute of Health (NIH) emphasized in May 2014 that in preclinical research Sex as a Biological Variable (SABV) must be given consideration [3]. From the viewpoint of a feministic, gender-oriented medicine, the simple binary distinction between the two sexes fully neglects the impact of social sexual norms, sex-based behavior and powerful gender-associated influences on biology and health [4], but, in our view, being aware of this distinction opens the door at the same time for a medical science in which women are not just forgotten by being automatically integrated into the category of "70 kilogram heavy, standard male patient". Precisely because men diagnosed with Parkinson’s are overrepresented in the population, their involvement in studies is consistently higher and women are thus underrepresented which means that most study data describe male pathophysiology. Furthermore, studies which do permit for equal male and female participation routinely summarize their results as a single overall average. A separate treatment of the male versus the female data is more the exception rather than the standard procedure.

As a case in point: For centuries children were simply treated as small versions of adults until the physician Paul Grosser did ground-breaking post-doctoral research in 1919 at the University of Frankfurt on the topic of pediatrics. More than 120 years later the field of pediatrics has become a large-scale and accepted field of study in its own right. Women and men, on the other hand, are still subsumed into a "one size fits all" type of approach in research. One task for our future work will be to ask whether that approach is really appropriate. Similarly, treating transgender persons deserves proper attention: They possibly need a special level of sensitivity on our part, in particular when metabolic processes have been altered exogenously.

In the pharmacological treatment of Parkinson’s disease it has become more and more standard procedure to calculate dosages according to the patients’ sex and weight. For women this entails 5 mg of levodopa per kilogram of bodyweight, and for men preferably 7 mg of levodopa per kilogram. This allows for an approximate evaluation for the maximum dose. In their study from 2005 Zappia and coworkers were able to demonstrate that female patients tend more towards peak-dose dyskinesias than male patients do. The authors identified female sex and higher levodopa dosages as a risk factor [5]. But there are to date yet no studies as to whether women, whose levodopa dose has in fact been selected on the basis of their weight and their sex, do have less tendency to peak-dose dyskinesias. In addition to levodopa we have a number of other pharmacological treatment strategies for Parkinson’s syndrome, including the groups of MAO-B and COMT inhibitors as well as the class of dopamine agonists. A further important medication is seen in amantadine. But at the present status of research we cannot judge at all whether the dosage of these agents should be decided in dependence on sex and weight considerations. This question is further complicated by the fact that some of these drugs are only available on the market in a single dosage, thus precluding any readjustment of the dosage.

Results

Data from our clinic

We analysed data from 200 patients, 100 males and 100 females, relying on standard data routinely surveyed for all in-patient treatments at our hospital: Age, stage of the disease according to Hoehn and Yahr and the duration of the disease. In addition we compared data from all examinations then regularly performed during the patients’ stay. This analysis showed an average begin of the disease for men to be at 70 years (70.42 years), while the women rather became ill at the age of 73 (72.64). As to the distribution among the different types (akinesia-rigor (AR), equivalence (ART) and tremor dominance types (T) we found no significant differences between the sexes (Figure 1).

The distribution according to Hoehn and Yahr failed to show any significant differences according to sex. A bias in favor of Stages III and IV is typical for our clinic: Patients in these stages on the one hand strongly require pharmacological adjustments and activating interventions (such as physical, occupational and speech therapies) and on the other they are also sufficiently stable for a hospitalization which highlights such training (Figure 2).

A significant difference was found for the Levodopa Equivalent Dose (LED) between men and women at the time of their dismissal. Compared to the LED at the time of admission, the pharmacological dopaminergic dosage at dismissal is meant to substantially improve the motor and non-motor symptoms. For the purpose of comparing the different doses we make use of the conversion table from Nyholm and coworkers (Tables 1and 2) [6].

A further difference appeared for the frequency of depression: Our analyses revealed a significantly higher occurrence in female patients at a small effect. This corresponds to the tendency seen in currently available studies (see Table 8: Motor and Non-motor symptoms) (Figure 3) (Tables 3 and 4).

Female patients had significantly lower equivalent doses (average effect) compared to male patients. Various reasons can be given for this: Possibly, the sex and weight-adapted levodopa dose (which in clinical everyday life is the standard strategy for appropriate treatment) might be playing a role here. Or: Differences in the degree of disease severity, the extent of symptoms, or even potential differences in metabolism of the dopaminergic medication in men and women may be implicated here. On this point we find it interesting to compare the serum levels for vitamin B12 (Tables 5 and 6).

Here there were no significant differences between the sexes. Likewise there were no significant results for either the sonographic determination of residual urine or the results of the testing for orthostatic hypotension (Table 7).

What does the pertinent literature reveal?

Incidence and disease onset: Are there differences between the sexes? Males suffer from Parkinson’s syndrome more than women do. In 2000 Baldereschi and coworkers reported an incidence two times higher in men than in women [7]. Admittedly, in an extensive metaanalysis, Wooten and coworkers found a slightly smaller incidence rate for male patients, but the risk of contracting Parkinson’s was still 1.5 times higher for men compared to women [8]. The imbalance was thus still in favor of the women. Georgiev and coworkers analyzed patient data for the period of 1990 until 2016 and identified a larger accumulation for males than for females. They also showed that in the course of the disease the symptoms occurred earlier in the men [9]. The analysis of a small cohort of 253 patients gives support to these observations: Haaxma and coworkers found that the women received their initial diagnosis on the average two years later than the men [10]. On the other hand, Baba and coworkers could not confirm any demographic differences concerning disease outset in their study population of over 1,200 patients [11]. An analysis of 1,741 US-American patients also could not find any differences (1) in disease outset of men compared to that of women or (2) in the time interval between the inaugural symptom and the date of the official diagnose [12]. The same finding was given in an analysis of 681 Spanish patients [13].The findings to date establish a tendency for more men to contract the disease than women, but it appears improbable that any other demographic difference exists, although it cannot be reliably ruled out at the present.

Motor and non-motor symptoms

The symptoms that are recognized as being pathognomonic for Parkinson’s (rigor, tremor, bradykinesia) can of course be found in both male and female patients, but on this issue there are discrepancies and incomplete data in the current literature. Motor symptoms appear to be less severe in women compared to men (n=415) [14]. These rather more mild symptoms in female patients are reflected in the lower number of points given in the UPDRS Motor Score (n=415) [15]. However, female patients complain more about lower quality of life than male patients do. Fatigue and depression may very well be contributing factors here [16]. While Solla and coworkers found more tremor among females in their sample of 156 Sardinian patients [17], Liu and coworkers identified more tendency for tremor among men in a larger cohort [18] Postural instability belongs to the most obvious of symptoms in the disease, and is characterized by the inability to maintain balance under either static or dynamic conditions [19]. Up to now, the symptom has been attributed to later, more advanced stages of the disease, but Pérez-Sánchez and coworkers have doubts whether this holds true categorically: They describe instances in which this symptom has very well been observed in early stages of idiopathic Parkinson’s [20], but it remains to be seen whether their observations can be confirmed in further studies. Our present discussion here clearly shows that there are still a good many basic questions that have to be solved in Parkinson’s syndrome. This situation might cause a certain amount of consternation and poses the question of just how fundamental our present-day knowledge is to be considered valid knowledge, or, vice versa, how many new ideas can shake up our idea of the fundament? How much do we actually know about the disease? And so, a challenging question is just how much we actually know about the disease. Assigning the symptom of postural instability to just one sex has just simply not been conclusively resolved. The studies from Liu and Colombo, from the same year of publication, appear to confirm the doubts since their results are so dissimilar [21].The topic of sex and gender aspects in idiopathic Parkinson has been the subject of study, analysis and discussion for some time now, but we are still far off from any consensus whatsoever. In a retrospective analysis in 2018, Kim and coworkers came to the conclusion that freezing occurred in women somewhat earlier in the course of the disease than in men [22]. On the other hand, Ou and coworkers found camptocormia to occur earlier in male patients than in females [23]. In two extensive data analyses [24,25] the authors, independently of each other, reached the conclusion that falling events occur more often in women. Chou and coworkers found a larger number of falls in male patients after the age of 70. Work by Accolla and coworkers and by Zappia and coworkers [26,27] found dyskinesias to occur more frequently in their female patients. The results from Gao and coworkers [28] and from Silverdale and coworkers [29] show a similar picture: They addressed the theme of pain in idiopathic Parkinson’s, a frequent complaint that does not often receive the appropriate attention, although it clearly impacts the quality of life in afflicted patients. The causes of pain are usually multifactorial [30]. Goa and coworkers analyzed the data of 200 patients, Silverdale and coworkers did the same for 1,957 patients. Both studies came to the conclusion that pains were more often diagnosed in female patients and the same was true for anxiety and depression. These neuropsychiatric symptoms appear more often attributed to the female sex [31,32].

Impulse control disorders, which occur more often under medication with dopamine agonists, were observed occurring more often in male than female patients [33,34]. Likewise, cognitive deficits (mild cognitive impairment) have been attributed more to male gender: This was shown in two smaller studies from 2014 and 2018 [35,36]. In addition, one multicente r study with 585 patients analysed the occurrence of non-motor symptoms in men and women with Parkinson’s: The women had a higher rate of depression and bladder dysfunction, whereas men generally had significantly more nonmotor symptoms [37]. Rodriguez-Blazquez and coworkers [38,39] also came to the conclusion that depression occurs more frequently in the women patients: They also examined non-motor fluctuations and described for their collective a rate of 41%. A sex-specific difference was not observed in their data [40]. During earlier stage of the disease there is rather no difference in the occurrence of depressive symptoms between the sexes [40]. Furthermore, women in the prodromal phase of the disease may experience not only the known prodromal symptoms but also a subjective sense of cognitive decline also presaging the later outbreak of the disease [41]. A further study on non-motor fluctuations [42] likewise found essentially more such fluctuations in the female patients.

On the occurrence of motor and non-motor symptoms within the different sexes, the available studies currently show selective conformities, but just as well discrepancies. What is thus yet missing is a solid, reliable basis to draw final conclusions on sex and gender-associated criteria. Relying on a review of the literature to date, Cerri and coworkers attempted a preliminary description of the "typical" male and the "typical" female Parkinson patient [43]. This approach is indeed intriguing, although a reliable fundament is missing, and thus intensive discussion and targeted studies are much needed in the future (Table 8).

The role of neurosteroids

The general agreement on men being more often afflicted with Parkinson’s than women brings up the question of the possible causes. Different hypotheses are being discussed here: Genetic dispositions and sex-specific metabolic processes could be playing a role, as well as gender-associated risk factors. Among these latter factors are, for example, a higher incidence of traumatic brain injury and also a statistically increased exposure to harmful substances in men [8].

In recent discussions, the observation that women have a lower level of incidence and less-pronounced symptoms at outset suggests a possible correlation with the estrogen status [44]. The duration of the estrogen exposition could possibly be associated with the reduced incidence in women. In spite of the fact that the study from Benedetti and coworkers failed to achieve statistical significance, they took this hypothesis into consideration [45]. Since then this estrogen hypothesis has been subject to considerable discussion and a number of studies have specifically examined the effect of pharmacologically applied estrogen on Parkinson patients [46,47].The assumption here is that estrogens could be activating a neuroprotective effect in astrocytes. While estrogen is preferentially seen as having a neuroprotective effect, male testosterone might possibly have a negative effect on the course of the disease [48]. In a review from 2016 Villa and coworkers already outlined potential neuroprotective effects of estrogen and drew the preliminary conclusion that premenopausal women have a reduced risk for Parkinson’s [49]. This would hint at the idea that the course of neurodegenerative diseases such as Parkinson’s or Alzheimer’s might be positively influenced through estrogens. A few studies point in this direction [50], so that hopes of treatment with the use of estrogen substitution have been raised [51]. Using information from a survey of patients by the Michael J. Fox Foundation, Mathur and coworkers analyzed the data of more than 2,600 women with Parkinson’s. Their focus was on the personal self-image of the afflicted women. 61% of the participants indicated that they had a negative self-image due to the disease. In their conclusion, the authors identified a greater risk for depression and mental disorders in the women [52]. A further aspect of their analysis addressed the age factor and the resultant hormone status of the women in pre, peri and post-menstrual stages. Altogether, they examined 18 categories including weight, motor behavior, speech, disturbance in bladder functions, sialorrhea and bodily appearance. The results supported the suggestion that there is in fact an association between hormonal status and the estrogen hypothesis mentioned above. But, given the current status of research, the actual relevance of estrogen and its potential therapeutic effect remain uncertain.

In a review, Tansey and coworkers directly addressed the pathophysiology of the disease: They in no way doubted the prevailing view of the pathophysiology in Parkinson’s disease that the neurodegenerative processes stem from misfolded proteins which accumulate within neurones as so-called Lewy bodies. They consider the possibility that immunological processes might possibly be implicated in the etiology of the d isease [53].

This then re-focuses attention on so-called neuroactive steroids, specifically steroids produced in neurones, glia cells and endocrine glands, including estrogen, testosterone and progesterone and their metabolites. The aspects of particular concern here would include the positive, immune-modulating effect of progesterone in the course of ovulation [54], which could possibly be associated with the reduced incidence of Parkinson’s disease in women. Experimental work, including animal models of the disease, has succeeded in demonstrating neuroprotective and anti-inflammatory effects [55]. If positive effects do accrue to estrogen, the question comes up as to whether the masculine hormone testosterone possibly might have a major influence, of whatever kind, but the current status of our research is inconclusive here. A few, smaller studies, usually dating back considerably, have postulated that men afflicted with Parkinson’s have a demonstrably lower blood level of testosterone compared to healthy cohorts of similar age [56]. One topic which by far has not been conclusively clarified in its relevancy for Parkinson’s is the role of a receptor expressed in the pars compacta of the substantia nigra: The retinoic acid receptor-related orphan receptor alpha-RORA. Since the role of RORA has become the subject of extensive scientific research over recent years in such disorders as the autism spectrum (which also show clear differences in the sexes) [57], its relevancy for Parkinson’s disease has been given considerable attention. RORA has been attributed with a neuroprotective efficacy, and, because its expression is regulated by sexual hormones, the receptor might very well constitute an important mosaic stone for solving questions of sex differences in Parkinson’s. Al-Zaid and coworkers highlighted this issue in a study on human brains postmortem. Interestingly he did the first study that succeeded in showing, at least in vitro, a profit in the form of neuroprotection through use of RORA agonists. This is clearly a ´very promising approach which will provoke further work along this line [58].

The relevancy of genetics

In general, gene expression on either the X or the Y chromosome is decisive for a person’s predisposition to diseases and its course. Technological advances in gene sequencing and genetic typing over recent years have provided major new findings for our understanding of basic genetics for the idiopathic and the genetically determined Parkinson’s disease. For this genetically determined disease, altogether 20 gene variations have been identified by now as risk factors, and for sporadic Parkinson’s 90 variants have so far been tagged as such. Their possible effects on the organism are numerous and have effects all the way up into signal-transduction pathways [15]. Parkinson’s disease in women is apparently associated with a modified variant of the gene coding for glucocerebrosidase (GBA) [59]. The GBA variant as well as the LRRK2 gene (leucine-rich repeat kinase 2) have both been examined comparatively well. Several studies suggest that mutations of this gene may have relevancy in Parkinson’s in females. The LRRK2 G2385R variant has been implicated in the sex-related extent of motor and non-motor symptoms, for example: Cui and coworkers directly associated the LRRK2 variant in explaining that women patients show fewer reductions in everyday activities, present with fewer autonomic dysfunctions and have fewer affective disorders than male patients [60]. A further role was possibly identified for the G2019S subgroup which has a higher incidence in women than men [61,62]. Pelzer and coworkers showed that three subgroups of the dopamine receptor D (2) DRD2 Taq1A (rs1800497) occurred at different frequencies between the sexes [63], and were associated with differences in responsivity to levodopa. But it has not yet been clarified as to whether concrete symptoms are in fact associated with all the identified gene loci or just which mechanisms are playing a role here. But there are preliminary indications confirming a sexual differentiation along these lines. Confirmation has recently been found connecting changes in the ANKK1 (dopamine receptor D (2) (DRD2)/ANKK1) and BDNF (brainderived neurotro-phic factor) gene loci with levodopa-induced dyskinesias (LiD) [64]. In addition, female sex, early onset of the disease and anxiety disorders were found to be risk factors for LID [65]. Likewise, a number of gene types of the dopamine receptors have been identified as risk factors for the development of impulse control disorders [66]. Since males suffer from this symptom complex more than females, it would be very advantageous if we could find out whether the gene types under discussion are in fact less often expressed in women.

Discussion and Conclusion

Our analysis of the data from 100 male and 100 female hospitalized Parkinson patients shows that the majority of the women became ill somewhat later than the men did and that they were being treated with a lower dosage. We found a further significant distinction in the frequency of the diagnosis depression which was more frequently given for female patients. It would, however, be premature to attribute that merely to the primary disease, Parkinson’s, as depression is diagnosed even in otherwise healthy men less often. As a result sociocultural differences, that is, gender aspects cannot be ignored and the association between women, the more frequent diagnosis of depression and Parkinson’s has to be discussed with caution. Interestingly, although the empirical literature to date associates rigor and tremor more frequently with male sex, our data does not find corroboration for this difference. We are likewise somewhat critical on our finding of a lower equivalence dose for women: It is standard clinical practice to take both the patients’ sex and weight into consideration in determining the levodopa total dose which automatically entails a lower dose for females patients. That men more often contract Parkinson’s is indisputable today, and there are some indications that their symptoms are not identical with those of female patients. However, the present status of research is inconsistent and is in need of further detailed work directly addressing the topic.

The gold standard in medical treatment is still levodopa. For so-called late complications such dyskinesias, a strong levodopa daily dose and female sex can be viewed as a risk factor, and such a factor would strongly suggest sex-specific levodopa dosages. Here further studies are necessary. In the present state of our studies, we still do not know to what extent neuroactive steroids influence the pathophysiology of the disease and what their therapeutic use would effect. There is thus a crucial need for targeted, prospective and longitudinal studies which analyse the data from females, males and trans-gender persons with Parkinson’s disease separately. In clinical routine work the awareness has to be improved on for the different genders whose course of the disease, symptoms and responsivity to medication can very well be substantially different: We will only be able to perceive and appreciate what we have already conceptualized in our minds.

Acknowledgement

None.

Conflict Of Interest

The authors declared no conflict of interest.

References

1. Kowal, SL, Dall TM, Chakrabarti R and Storm MV, et al. "The Current and Projected Economic Burden of Parkinson's Disease in the United States." Mov Disord 28(2013):311-318.

   [Crossref] [Google Scholar]

2. Mehta, LS, Beckie TM, DeVon HA and Grines CL, et al. "Acute Myocardial Infarction in Women: A Scientific Statement from the American Heart Association." Circulation 133(2016):916-947.

   [Crossref] [Google Scholar]

3. Clayton, JA. "Studying both Sexes: A Guiding Principle for Biomedicine." FASEB J 30(2016):519-524.

   [Crossref] [Google Scholar]

4. Shai, A, Koffler S and Hashiloni-Dolev Y. "Feminism, Gender Medicine and Beyond: A Feminist Analysis of Gender Medicine". Int J Equity Health 20(2021):177.

   [Crossref] [Google Scholar]

5. Zappia, M, Annesi G, Nicoletti G and Arabia G, et al. "Sex Differences in Clinical and Genetic Determinants of Levodopa Peak-dose Dyskinesias in Parkinson Disease: An Exploratory Study." Arch Neurol 62(2005):601-605.

   [Crossref] [Google Scholar]

6. Nyholm, D and Jost WH. "An Updated Calculator for Determining Levodopa-equivalent Dose." Neurol Res Pract 3(2021):58.

   [Crossref] [Google Scholar]

7. Baldereschi, M, Di Carlo A, Rocca WA and Vanni P, et al. "Parkinson's Disease and Parkinsonism in a Longitudinal Study: Two-fold Higher Incidence in Men. ILSA Working Group. Italian Longitudinal Study on Aging." Neurology 55(2000):1358-1363.

   [Crossref] [Google Scholar]

8. Wooten, GF, Currie LJ, Bovbjerg VE and Lee JK, et al. "Are Men at Greater Risk for Parkinson's Disease than Women?" J Neurol Neurosurg Psychiatry 75(2004):637-639.

   [Crossref] [Google Scholar]

9. Georgiev, D, Hamberg K, Hariz M and Forsgren L, et al. "Gender Differences in Parkinson's Disease: A Clinical Perspective." Acta Neurol Scand 136(2017):570-584.

   [Crossref] [Google Scholar]

10. Haaxm,a CA, Bloem BR, Borm GF and Oyen WJ, et al. "Gender Differences in Parkinson's Disease." J Neurol Neurosurg Psychiatry 78(2007):819-824.

    [Crossref] [Google Scholar]

11. Baba, Y, Putzke JD, Whaley NRA and Wszolek ZK, et al. "Gender and the Parkinson's Disease Phenotype." J Neurol 252(2005):1201-1205.

    [Crossref] [Google Scholar]

12. Augustine, EF, Perez A, Dhall R and Umeh CC, et al. "Sex Differences in Clinical Features of Early, Treated Parkinson's Disease." PLoS One 10(2015):e0133002.

    [Crossref] [Google Scholar]

13. Santos-Garcia, D, Laguna A, Hernandez-Vara J and Fonticoba T, et al. "Sex Differences in Motor and Non-motor Symptoms among Spanish Patients with Parkinson's Disease." J Clin Med 12(2023):1329.

    [Crossref] [Google Scholar]

14. Kang, KW, Choi SM and Kim BC. "Gender Differences in Motor and Non-motor Symptoms in Early Parkinson Disease." Medicine 101(2022):e28643.

    [Crossref] [Google Scholar]

15. Tolosa, E, Garrido A, Scholz SW and Poewe W. "Challenges in the Diagnosis of Parkinson's Disease." Lancet Neurol 20(2021):385-397.

    [Crossref] [Google Scholar]

16. Yoon, JE, Kim JS, Jang W and Park J, et al. "Gender Differences of Non-motor Symptoms Affecting Quality of Life in Parkinson Disease." Neurodegener Dis 17(2017):276-280.

    [Crossref] [Google Scholar]

17. Solla, P, Cannas A, Ibba FC and Loi F, et al. "Gender Differences in Motor and Non-motor Symptoms among Sardinian Patients with Parkinson's Disease." J Neurol Sci 323(2013):33-39.

    [Crossref] [Google Scholar]

18. Liu, R, Umbach DM, Peddada SD and Xu Z, et al. "Potential Sex Differences in Non-motor Symptoms in Early Drug-Naive Parkinson Disease." Neurology 84(2015):2107-2115.

    [Crossref] [Google Scholar]

19. Schoneburg, B, Mancini M, Horak F and Nutt JG. "Framework for Understanding Balance Dysfunction in Parkinson's Disease." Mov Disord 28(2013):1474-1482.

    [Crossref] [Google Scholar]

20. Perez-Sanchez, JR and Grandas F. "Early Postural Instability in Parkinson's Disease: A Biomechanical Analysis of the Pull Test." Parkinsons Dis 2019(2019):6304842.

    [Crossref] [Google Scholar]

21. Colombo, D, Abbruzzese G, Antonini A and Barone P, et al. "The "Gender Factor" in Wearing-off among Patients with Parkinson's Disease: A Post Hoc Analysis of Deep Study." Scientific World Journal 2015(2015):787451.

    [Crossref] [Google Scholar]

22. Kim, R, Lee J, Kim Y and Kim A, et al. "Presynaptic Striatal Dopaminergic Depletion Predicts the Later Development of Freezing of Gait in de novo Parkinson's Disease: An Analysis of the PPMI Cohort." Parkinsonism Relat Disord 51(2018):49-54.

    [Crossref] [Google Scholar]

23. Ou, R, Liu H, Hou Y and Song W, et al. "Predictors of Camptocormia in Patients with Parkinson's Disease: A Prospective Study from Southwest China." Parkinsonism Relat Disord 52(2018):69-75.

    [Crossref] [Google Scholar]

24. Chou, KL, Elm JJ, Wielinski CL and Simon DK, et al. "Factors Associated with Falling in Early, Treated Parkinson's Disease: The NET-PD LS1 Cohort." J Neurol Sci 377(2017):137-143.

    [Crossref] [Google Scholar]

25. Parashos, SA, Bloem BR, Browner NM and Giladi N, et al. "What Predicts Falls in Parkinson Disease? Observations from the Parkinson's Foundation Registry." Neurol Clin Pract 8(2018):214-222.

    [Crossref] [Google Scholar]

26. Accolla, E, Caputo E, Cogiamanian F and Tamma F, et al. "Gender Differences in Patients with Parkinson's Disease Treated with Sub-thalamic Deep Brain Stimulation." Mov Disord 22(2007):1150-1156.

    [Crossref] [Google Scholar]

27. Zappia, M, Annesi G, Nicoletti G and Arabia G, et al. "Sex Differences in Clinical and Genetic Determinants of Levodopa Peak-dose Dyskinesias in Parkinson Disease: An Exploratory Study." Arch Neurol 62(2005):601-615.

    [Crossref] [Google Scholar]

28. Gao, L, Yang Y, Cai L and Xiong Y. "Gender Differences in Pain Subtypes among Patients with Parkinson's Disease." J Integr Neurosci 21(2022):120.

    [Crossref] [Google Scholar]

29. Silverdale, MA, Kobylecki C, Kass-Iliyya L and Martinez-Martin P, et al. "A Detailed Clinical Study Ofpain in 1957 Participants with Early/Moderate Parkinson's Disease." Parkinsonism Relat Disord 56(2018): 27-32.

    [Crossref] [Google Scholar]

30. Buhmann, C, Kassubek J and Jost WH. "Management of Pain in Parkinson's Disease." J Parkinsons Dis 10(2020):S37-S48.

    [Crossref] [Google Scholar]

31. Broen, MPG, Leentjens AFG, Hinkle JT and Moonen AJH, et al. "Clinical Markers of Anxiety Sub-types in Parkinson Disease." J Geriatr Psychiatry Neurol 31(2018):55-62.

    [Crossref] [Google Scholar]

32. Wissel, BD, Dwivedi AK, Merola A and Chin D, et al. "Functional Neurological Disorders in Parkinson Disease." J Neurol Neurosurg Psychiatry 6(2018):566-571.

    [Crossref] [Google Scholar]

33. Kon, T, Ueno T, Haga R and Tomiyama M. "The Factors Associated with Impulse Control Behaviors in Parkinson's Disease: A 2-Year Longitudinal Retrospective Cohort Study." Brain Behav 8(2018):01036.

    [Crossref] [Google Scholar]

34. Weintraub, D, Koester J, Potenza MN and Siderowf AD, et al. "Impulse Control Disorders in Parkinson Disease: A Cross-Sectional Study of 3090 Patients." Neurol 67(2010):589-595.

    [Crossref] [Google Scholar]

35. Szewczyk-Krolikowski, K, Tomlinson P, Nithi K and Wade-Martins R, et al. "The Influence of Age and Gender on Motor and Non-motor Features of Early Parkinson's Disease: Initial Findings from the Oxford Parkinson Disease Center (Opdc) Discovery Cohort." Parkinsonism Relat Disord 20(2014):99-105. 

    [Crossref] [Google Scholar]

36. Cholerton, B, Johnson CO, Fish B and Quinn JF, et al. "Sex Differences in Progression to Mild Cognitive Impairment and Dementia in Parkinsonâ??s Disease." Parkinsonism Relat Disord 50(2018):29â??36. 

    [Crossref] [Google Scholar]

37. Nicoletti, A, Vasta R, Mostile G and Nicoletti G, et al. "Gender Effect on Non-motor Symptoms In Parkinson's Disease: Are Men More at Risk?" Parkinsonism Relat Disord 35(2017):69-74.

    [Crossref] [Google Scholar]

38. Rodriguez-Blazquez, C, Schrag A, Rizos A and Chaudhuri KR, et al. "Prevalence of Non-motor Symptoms and Non-motor Fluctuations in Parkinson's Disease Using the MDS-NMS." Mov Disord Clin Pract 8(2020):231-239.

    [Crossref] [Google Scholar]

39. Martinez-Martin, P, Falup Pecurariu C, Odin P and van Hilten JJ, et al. "Gender-related Differences in the Burden of Non-motor Symptoms in Parkinson's Disease." J Neurol 259(2012):1639-1647.

    [Crossref] [Google Scholar]

40. Picillo, M, Amboni M, Erro R and Longo K, et al. "Gender Differences in Non-motor Symptoms in Early, Drug Naive Parkinson's Disease." J Neurol 260(2013):2849-2855.

    [Crossref] [Google Scholar]

41. Flores-Torres, MH, Bjornevik K, Hung AY and Healy BC, et al. "Subjective Cognitive Decline in Women with Features Suggestive of Prodromal Parkinson's Disease." Movement Disorders 38(2023):1473-1482

    [Crossref] [Google Scholar]

42. Donzuso, G, Cicero CE, Vinciguerra E and Sergi R, et al. "Gender Differences in Non-motor Fluctuations in Parkinson's Disease." J Neural Transm 130(2023):1249-1257.

    [Crossref] [Google Scholar]

43. Cerri, S, Mus L and Blandini F. "Parkinson's Disease in Women and Men: What's the Difference?" J Parkinsons Dis 9(2019):501-515.

    [Crossref] [Google Scholar]

44. Picillo, M, Nicoletti A, Fetoni V and Garavaglia B, et al. "The Relevance of Gender in Parkinson's Disease: A Review." J Neurol 264(2017):1583-1607.

    [Crossref] [Google Scholar]

45. Benedetti, MD, Maraganore DM, Bower JH and McDonnell SK, et al. "Hysterectomy, Menopause, and Estrogen Use Preceding Parkinson's Disease: An Exploratory Case-control Study." Mov Disord 16(2001):830-837.

    [Crossref] [Google Scholar]

46. Tsang, KL, Ho SL and Lo SK. "Estrogen Improves Motor Disability in Parkinsonian Postmenopausal Women with Motor Fluctuations." Neurology 54(2000):2292-2298. [Crossref]

    [Google Scholar]

47. Nicoletti, A, Arabia G, Pugliese P and Nicoletti G, et al. "Hormonal Replacement Therapy in Women with Parkinson Disease and Levodopa-induced Dyskinesia: A Crossover Trial." Clin Neuropharmacol 30(2007):276-280.

    [Crossref] [Google Scholar]

48. Bovenzi, R, Sancesario GM, Conti M and Grillo P, et al. "Sex Hormones Differentially Contribute to Parkinson Disease in Males: A Multimodal Biomarker Study." Eur J Neurol 30(2023):1983-1990.

    [Crossref] [Google Scholar]

49. Villa, A, Vegeto E, Poletti A and Maggi A. "Estrogens, Neuroinflammation and Neurodegeneration." Endocr Rev 37(2016):372-402.

    [Crossref] [Google Scholar]

50. Song, YJ, Li SR, Li XW and Chen X, et al. "The Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Post-menopausal Women: A Meta-Analysis." Front Neurosci 14(2020):157.

    [Crossref] [Google Scholar]

51. Guo, H, Liu M, Zhang L and Wang L, et al. "The Critical Period for Neuroprotection by Estrogen Replacement Therapy and the Potential Underlying Mechanisms." Curr Neuropharmacol 18(2020):485-500.

    [Crossref] [Google Scholar]

52. Mathur, S, LaMonica K, Matthews H and Hill K. "Self-Image in Women with Parkinson's Disease." J Parkinsons Dis 13(2023):329-332.

    [Crossref] [Google Scholar]

53. Tansey, MG, Wallings RL, Houser MC and Herrick MK, et al. "Inflammation and Immune Dysfunction in Parkinson Disease." Nat Rev Immunol 22(2022):657-673.

    [Crossref] [Google Scholar]

54. Zwahlen, M and Stute P. "Impact of Progesterone on the Immune System in Women: A Systematic Literature Review." Arch Gynecol Obstet 18(2023):1-10.

    [Crossref] [Google Scholar]

55. Bassani, TB, Bartolomeo CS, Oliveira RB and Ureshino RP. "Progestogen-mediated Neuroprotection in Central Nervous System Disorders." Neuroendocrinology 113(2023):14-35.

    [Crossref] [Google Scholar]

56. Bourque, M, Soulet D and Di Paolo T. "Androgens and Parkinson's Disease: A Review of Human Studies and Animal Models." Androg Clin Res Ther 2(2021):294-303.

    [Crossref] [Google Scholar]

57. Hu, VW, Sarachana T, Sherrard RM and Kocher KM. "Investigation of Sex Differences in the Expression of RORA and its Transcriptional Targets in the Brain as a Potential Contributor to the Sex Bias in Autism." Mol Autism 6(2015):7.

    [Crossref] [Google Scholar]

58. Al-Zaid, FS, Hurley MJ, Dexter DT and Gillies GE. "Neuroprotective Role for RORA in Parkinson's Disease Revealed by Analysis of Post-mortem Brain and a Dopaminergic Cell Line." NPJ Parkinsons Dis 9(2023):119.

    [Crossref] [Google Scholar]

59. Li, Q, Jing Y, Lun P and Liu X, et al. "Association of Gender and Age at Onset with Glucocerebrosidase Associated Parkinson's Carriers and Non-carriers in Parkinson's Disease. BMC Neurosci 22(2021):22.

    [Crossref] [Google Scholar]

60. Cui, SS, Fu R, Du JJ and Lin YQ, et al. "Sex Effects on Clinical Features in LRRK2 G2385R." BMC Neurosci 22(2021):22

    [Crossref] [Google Scholar]

61. Cilia, R, Siri C, Rusconi D and Allegra R, et al. "LRRK2 mutations in Parkinson's Disease: Confirmation of a Gender Effect in the Italian Population." Park Relat Disord 20(2014):911-914.

    [Crossref] [Google Scholar]

62. Chen, W, Yan X, Lv H and Liu Y, et al. "Gender Differences in Prevalence of LRRK2-Associated Parkinson Disease: A Meta-analysis of Observational Studies." Neurosci Lett 715(2020):134609.

    [Crossref] [Google Scholar]

63. Pelzer, EA, Sturmer S, Feis DL and Melzer C, et al. "Clustering of Parkinson Subtypes Reveals Strong Influence of DRD2 Polymorphism and Gender." Sci Rep 12(2022):6038.

    [Crossref] [Google Scholar]

64. Gatto, EM and Aldinio V. "Impulse Control Disorders in Parkinson's Disease. A Brief and Comprehensive Review." Front Neurol 10(2019):351.

    [Crossref] [Google Scholar]

65. Martinez-Carrasco, A, Real R, Lawton M and Iwaki H, et al. "Genetic Meta-analysis of Levodopa Induced Dyskinesia in Parkinson's Disease." medRxiv 2023.

    [Crossref] [Google Scholar]

66. Swetlitz, N. "Depression's Problem with Men." AMA J Ethics 23(2021):E586-589.

    [Crossref] [Google Scholar]