Women & Parkinson’s: it’s all in your brain, not in your head

I had the pleasure of sitting down with my colleague and friend, Dr. Jill Farmer, to discuss Parkinson’s disease (PD) in Women. This important topic is gaining more press recently. Why is this important? The classic “picture” of PD is of an elderly, white gentleman. But we know PD affects both sexes and all races and ethnicities. For a variety of reasons, women experience PD differently than men. These differences include:

• Most common symptoms (what patients report)
• Signs (what physicians see on exam)
• Risk factors
• Getting a Diagnosis
• Treatments that are offered and responses to those treatments
• Involvement in research

Over the past few decades, research has shown, when compared to men, women have lower incidence and prevalence of PD, later age at onset, and better motor scores in the Unified PD Rating Scale. However, there are some differences that disfavor women. Some are attributable to sex-related biological and environmental differences, diagnosis and treatment bias, or differences in health care–seeking behaviors.

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Symptoms and Signs of PD in Women

When most people think of PD, the common motor symptoms come to mind: stiffness, slowness, and tremors. Later symptoms include postural instability and gait difficulty. But PD isn’t just motor symptoms. Thus, we spent quite a bit of time discussing the different types of signs and symptoms women experience. Dr. Indu Subramanian and colleagues provide a great summary of these in their 2022 paper that highlights a wide variety of unmet needs in this area including:

Motor Symptoms

• Women are more likely to present with the tremor-predominant subtype of PD as opposed to the other two subtypes: akinetic-rigid (slow and stiff) or postural instability gait disorder (PIGD).
• Women are more likely to have associated features such as facial masking, restless leg syndrome, and dyskinesias due to drug therapy.
• Disease progression is often slower in women.

Nonmotor Symptoms

• Women are more likely to have mood and sleep disturbances, anxiety, depression, fatigue, apathy, pain and urogenital symptoms.
• Women are less likely to have cognitive impairment, hallucinations, and gastrointestinal symptoms.
• Historically, researchers reported that women were less likely to report sexual dysfunction. Unfortunately, many discussions around sexual dysfunction focus more on difficulties men experience but the American Parkinson Disease Association just had a fantastic webinar that was inclusive of women here. A recent study from Italy showed a high frequency of sexual dysfunction in female PD patients, which indicates a need for further investigation to provide an adequate therapeutic approach and potentially improve quality of life.

Psychosocial factors

• Women are more likely to report psychological distress, disability and feeling that they are not being heard.
• They are also more likely to downplay symptoms, and have a negative or destructive self-image.
• Women more often report feeling a loss of femininity and impaired sexual intimacy.
• They are less likely to have social support.

Some of these psychosocial issues are especially important. As women often spearhead social activities in their families and are often the primary caregivers, they often feel lost when they need help. Who cares for the caregiver?

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Risk Factors

In general, the risk of PD is higher in men with a ratio of about 1.5-to-1 of men to women. Anytime we acknowledge differences based on biological sex, we have to consider hormones. There is evidence that estrogen may be protective because the difference in risk of PD between men and women narrows as women become postmenopausal. Does this mean women should go on hormone replacement therapy, you might ask? Not so fast - at least not solely for PD. There is conflicting evidence whether hormone replacement therapy can increase or decrease the progression of PD in peri- and postmenopausal women. This may be related to the duration of therapy, when it is started, whether it is estrogen only or also includes progesterone, and if it is a systemic treatment versus a local treatment (e.g. intravaginal only). There is even less data on the effect of hormone therapies used by individuals to affirm their gender when it conflicts with their sex assigned at birth. It is agreed though that we do NOT recommend starting hormone replacement therapy for the sole purpose of possible protection against developing PD or slowing its progression.

Interestingly, there are differences in genetic forms of PD. In men and women with the same mutation in LRRK2, a genetic risk factor for PD, one study showed that the risk of developing PD is higher in women. More research is needed to understand why this is the case.

There are other differences too. Based on a study of nearly seven million Koreans, men appear to have more “protection” against PD from smoking than women despite equal smoking intensity and duration. On the contrary, when comparing equal alcohol intake, the risk of PD was lower in females than males. Caffeine is long known to reduce the risk of PD, but only in men, based on a study by Alberto Ascherio and colleagues.

Other exposures may play a role as well. During my recent webinar with Dr. Ray Dorsey discussing the potential role of trichloroethylene (TCE) in the development of PD. He hypothesized that men have an increased risk in the US because they have higher occupational exposure to TCE in manufacturing or mechanical occupations, and to pesticides/herbicides in agricultural occupations. But in Asian countries where women were more involved in agriculture, the prevalence of PD in women was higher. Additionally, another study found that higher exposures to polychlorinated biphenyls (PCBs) in female factory workers was associated with higher rates of amyotrophic lateral sclerosis (ALS), PD, and dementia diagnoses.

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Getting a Diagnosis

There is evidence that women experience delays in getting the initial diagnosis of PD despite being more likely to have tremor-predominant subtype which usually helps with earlier diagnosis. Furthermore, there is evidence to suggest it takes women 61% longer to be referred to a movement disorders specialist. In part, this may be related to milder disease and slower progression often seen in women. We know that some of the most common symptoms in women with PD early on include depression, anxiety, sleep disturbances, and fatigue. If a woman does not display clear motor signs, and is not seeing a specialist trained in the subtleties of movement disorders, the diagnosis can be missed. 

More troubling, women – especially younger women – may be told their symptoms are related to underlying psychiatric issues. In this story in Womens’ Health, this woman in her early 40s shared a common story of a several-year delay in getting a diagnosis. Eventually, although she failed all the motor skill tests, one general neurologist told her:

My symptoms were likely all in my head…. I was probably just stressed out from being a full-time working mother and I needed to see a psychiatrist, get some therapy, and consider working fewer hours…. This was one of the few times I felt like I was losing my mind.

Her experience exemplifies the importance of being seen by a movement disorder specialist.

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Treatment Differences

There are differences in both the treatments offered to women and the adverse effects they may experience with antiparkinsonian therapies. Women have a higher risk of developing levodopa-induced dyskinesias. While both men and women can experience different impulsive or compulsive behaviors with dopaminergic medications (especially dopamine agonists), the behaviors exhibited are often different. As the disease progresses, less than 25% of referrals for deep brain stimulation (DBS) are women though at least some of this may be due to less women electing for the procedure. This may be due to real or perceived difficulty in giving up other caretaking duties, more risk aversion, or other factors. It is important that the medical community continue to offer this and make an effort to understand why women decline the referral as they may reap greater benefit following DBS. We also need to understand how symptoms and treatments may be different throughout a woman's reproductive cycle - pregnancy, pre/peri/post-menopausal. Hormone levels fluctuate and may confer different risks and protection against PD, different responses to treatments, and different symptomatology. In addition, medications may be absorbed or metabolized differently in women.

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Research

In 1977, the Food and Drug Administration (FDA) banned women of child-bearing years from participating in clinical trials. Although the National Institutes of Health (NIH) changed that policy in 1993, the underrepresentation of women in clinical trials still exists. Ultimately, in 2015, the (NIH) released a policy to consider sex as a biological variable in clinical trials and research yet there are no repercussions if a trial doesn’t equally recruit women. Today, women of childbearing years are still excluded from clinical trials or are commonly required to use two methods of birth control. This presents a problem in PD. If PD has a hormonal connection, chemical forms of birth control could affect the outcomes of the studies. 

Additionally, women are often the family's primary caretakers. Thus, trial participation may also be impacted by their familial obligations that prohibit them from traveling to trial sites or giving up precious family time.

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Summary

While we have appreciated for quite some time that there truly are differences in the lived experiences of men and women with PD, collecting data helps us provide objective information to drive future research, drug development, and more targeted treatments based on each individual’s constellation of biological factors and preferences.