Gender Differences as a Factor in Parkinson’s

“Men are from Earth, women are from Earth. Deal with it.” George Carlin

“You can either be a victim of the world or an adventurer in search of treasure. It all depends on how you view your life.” Paulo Coelho

Précis: ~10% of Parkinson’s cases are linked to familial genetic mutations; whereas the vast majority of cases have an unknown cause and are labeled sporadic.  Epidemiological studies have recently shown that the male sex is an adverse factor for developing the sporadic form of Parkinson’s. Presented here is a brief overview that suggests female gonadal substances offer resilience to the loss of dopamine in Parkinson’s.

The nigrostriatal dopaminergic neural pathway:  Parkinson’s begins when dopamine-producing neurons die in the substantia nigra region in the mid-brain. There are four dopamine-dependent neural pathways that originate from the substantia nigra/ventral tegmental area (VTA); most likely, the nigrostriatal dopaminergic pathway has an important role in Parkinson’s (the figure below highlights the brain and dopaminergic pathways; modified from  The nigrostriatal dopaminergic pathway is the connection between the substantia nigra and the striatum (the caudate nucleus and putamen).  This pathway has an important function in supporting and regulating fine motor control (i.e., movement).

Loss of dopamine in the substantia nigra is somewhat analogous to a car engine running without oil; loss of oil (dopamine) eventually leads to engine seizure (stiffness, loss of fine movement control). Loss of dopamine-generating neurons in the substantia nigra is one of the main pathological features of Parkinson’s. The symptoms of the disorder typically do not evolve until a majority of dopamine production has been lost.

Although the loss of dopamine-producing neurons may seem to be a relatively simple process; in reality, Parkinson’s is a complex disorder. As described in detail over the past decade in the scientific literature (and described in various postings in this blog), Parkinson’s cause (etiology) is likely due to complex interactions between numerous genetic factors, changes in the cellular micro-environment, detrimental effects of inflammation, innate and possibly adaptive immune systems, and advanced aging (In a future blog, I will more fully describe the impact of advanced aging and how it contributes to the development of Parkinson’s).  After aging, epidemiological studies have shown that being male is an additional risk factor for developing Parkinson’s (see below).

Nigrostriatal.pathway“It would be possible to describe everything scientifically, but it would make no sense; it would be without meaning, as if you described a Beethoven symphony as a variation of wave pressure.” Albert Einstein

Parkinson’s and being male as a risk factor: Here’s a brief summary of many different studies regarding gender discrepancies in Parkinson’s.
•Parkinson’s appears to have both a greater prevalence and a younger age of onset in men than in women.
•Public health studies indicate that male gender is a bigger risk factor for developing Parkinson’s than female gender at most ages.
•Van Den Eeden et al. (2003) was an early study that noted gender differences; they showed that the incidence of Parkinson’s in men after 60 years of age was greater by 90% then in women.
•As with most public health studies using diverse groups of people, varied by gender, age, race/ethnicity and country of residence, the trends/results described above were similar in many but not in all studies.
Collectively, these studies show that men have both a higher prevalence and a younger age of onset of Parkinson’s than in women.

“Parkinson’s is my toughest fight. No, it doesn’t hurt. It’s hard to explain. I’m being tested to see if I’ll keep praying, to see if I’ll keep my faith.” Muhammad Ali

Men and women with Parkinson’s have different clinical profiles: Summarized below are some of the different clinical features found in women compared to men with Parkinson’s.
•Age of onset in women is later by ~2 years.
•Women typically present with a milder phenotype (observed traits) with a slower disorder progression and less motor decline.
•Women present more often with a tremor.
•Women have more nervousness, sadness, depression and constipation; in contrast, men experience more daytime sleepiness, dribbling and sex-related symptoms.
•Women, compared to men, show differences in Parkinson’s drugs efficacy and pharmacokinetics (what the body does to a drug).
Collectively, these clinical studies suggest that sex influences the nigrostriatal dopaminergic pathway to alter the degenerative processes that promote development of Parkinson’s.  These results imply that the female sex hormone estrogen likely serves a key role in this protective process.

gender4““A woman needs a man like a fish needs a bicycle.” I really hate this expression. I bet fish would totally want bicycles.”  Meg Cabot

The neuroprotective effect of estrogen: There have been many clinical studies on sex differences affecting the brain and linked to Parkinson’s susceptibility; here are some highlights.
•17β-estradiol (E2) is the most abundant estrogen in non-pregnant mammals; E2 is known to have a neuroprotective function.
•E2 may explain why women generally fare better with the neurodegenerative aspects of Parkinson’s.
•Women who had their ovaries (the source of E2) surgically removed (oophorectomy) before menopause have an increased risk of developing Parkinson’s.
•Parkinson’s symptom severity may increase in women at menses when estrogen levels are lowest,
•Estrogen-based hormone replacement therapy (HRT) (a) relieves symptoms in the early stages of Parkinson’s, (b) decrease the risk of developing Parkinson’s, and (c) on cessation of HRT Parkinson’s symptoms may worsen.
•Interestingly, sex differences in Parkinson’s remain following menopause, which suggests that it is more complex than just E2 providing neuroprotection.
These results imply a neuroprotective role for E2 during normal function of the nigrostriatal dopaminergic pathway; furthermore, E2 somehow enables a female to delay developing Parkinson’s. By contrast, male gonadal substances offer little protection to dopamine loss.

“The truth is you don’t know what is going to happen tomorrow. Life is a crazy ride, and nothing is guaranteed.”  Eminem

Concluding thoughts:  Sex matters.  Your sex affects and influences the biology and incidence of many disorders, including Parkinson’s. Women are seemingly protected from both progression and severity of Parkinson’s compared to men.  However, it is important to continue to delineate the molecular details to these sex differences in Parkinson’s. Scientists in this field are hopeful that hormone-specific therapies could be developed to treat and possibly delay the progression of Parkinson’s.
Sex matters.  Yes, sex matters and it is a factor to influence Parkinson’s. You still matter. Male or female. Stay hopeful, positive, persistent, mindful, educated, and keep going, keep going strong. You still matter.

“If you want to identify me, ask me not where I live, or what I like to eat, or how I comb my hair, but ask me what I am living for, in detail, ask me what I think is keeping me from living fully for the thing I want to live for.” Thomas Merton

Van Den Eeden, SK, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity Am. J. Epidemiol., 157 (2003), pp. 1015–1022

Miller IN, Cronin-Golomb A. GENDER DIFFERENCES IN PARKINSON’S DISEASE: CLINICAL CHARACTERISTICS AND COGNITION. Movement disorders: official journal of the Movement Disorder Society. 2010;25(16):2695-2703. doi:10.1002/mds.23388.

Haaxma CA, Bloem BR, Borm GF, et al. Gender differences in Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 2007;78(8):819-824. doi:10.1136/jnnp.2006.103788.

Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Frontiers in Neuroendocrinology. 2014;35(3):370-384. doi:10.1016/j.yfrne.2014.02.002.

Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson’s Disease. Sub-cellular biochemistry. 2012;65:389-455. doi:10.1007/978-94-007-5416-4_16.

Ngun TC, Ghahramani N, Sánchez FJ, Bocklandt S, Vilain E. The Genetics of Sex Differences in Brain and Behavior. Frontiers in neuroendocrinology. 2011;32(2):227-246. doi:10.1016/j.yfrne.2010.10.001.

Augustine EF, Pérez A, Dhall R, et al. Sex Differences in Clinical Features of Early, Treated Parkinson’s Disease. Nazir A, ed. PLoS ONE. 2015;10(7):e0133002. doi:10.1371/journal.pone.0133002.

Smith KM, Dahodwala N. Sex differences in Parkinson’s disease and other movement disorders. Exp Neurol. 2014 Sep;259:44-56. doi: 10.1016/j.expneurol.2014.03.010. Epub 2014 Mar 28.

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