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Understanding the dopaminergic pathway relative to men’s sexual dysfunction in patients with Parkinson’s disease: a narrative review with implications for future research (2022)
Nicholas A. Deebel, Kim Thai, Ranjith Ramasamy, and Ryan P. Terlecki
Parkinson’s disease (PD) is often most recognized for motor symptoms but associated non-motor symptoms such as sexual dysfunction can significantly impact the quality of life. This condition involves a hormonal disruption and has a predilection for male patients, yet there are no formal guidelines for screening or management of sexual health pathology in these patients. While prior publications have addressed the presence of sexual dysfunction (SD) among men with PD, there has been a paucity of work examining the hypothalamic-pituitary-gonadal (HPG) axis and the interplay between dopamine, prolactin (PRL), and testosterone. This review provides an overview of data extracted from the existing peer-reviewed literature regarding hormonal and sexual health changes in men with PD and the impact of dopaminergic and/or androgen replacement therapy. Furthermore, while some research suggests that PD patients are at higher risk for prolactin elevation and testosterone deficiency, heterogeneity of the data limits extrapolation. Additionally, data related to pharmacologic optimization of the HPG axis in this patient population is similarly limited. Prospective studies are needed to better characterize the hormonal pathophysiology of PD as it relates to sexual dysfunction such that men at risk can be effectively identified so as to offer interventions that may improve quality of life.
INTRODUCTION
Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder that stems from the progressive loss of dopaminergic neurons within the substantia nigra [1]. The clinical manifestations are often grouped into motor (e.g., tremor, bradykinesia) and nonmotor categories with the nonmotor elements often less emphasized in the literature [2]. Dopamine is both a neurotransmitter and a hormone, such that PD can also be viewed as a hormonal disorder [3]. Axis disruptions have relevance to both overall health and quality of life [4, 5].
60,000 people in the United States are diagnosed with PD annually with an anticipated prevalence of 1.2 million people living with PD by the year 2030 [6]. PD has a predilection for affecting males more than females, a discrepancy attributed to the neuroprotective properties of estrogen against dopaminergic neuron degradation [2, 7]. Relative to controls, men with PD have nearly twice the risk of sexual dysfunction, most commonly involving erectile dysfunction (ED), premature ejaculation, orgasmic dysfunction, and decreased libido [2]. Each of these components may be related to hormonal axis disruption.
Unfortunately, sexual dysfunction is often overlooked among PD patients, possibly due to tunnel vision relative to motor symptoms. However, a study by Politis et al. found sexual dysfunction (classified as loss of libido and/or ED) to be the 12th most bothersome symptom (out of 24) in this population [1]. Another cross-sectional study of 113 men with PD found the prevalence of sexual dysfunction to be 68%, but the rate increased to 75% when considering only those patients, not on pharmacotherapy [8]. The majority of subjects self-reported PD as having a negative impact on their sexual health.
Although reports document the noteworthy existence of sexual dysfunction among men with PD, there is a paucity of data relative to the disruption of the hypothalamic-pituitary-gonadal (HPG) axis and the interplay between dopamine, prolactin (PRL), and testosterone (Fig. 1).
Likewise, there have been insufficient efforts to fully characterize the hormonal response from PD-related medications and the role of androgen replacement therapy (ART) in men with PD. Thus, we chose to review the peer-reviewed literature relevant to investigations into the underlying pathophysiology and the efforts to optimize the hormonal underpinnings of sexual health among men with PD. In doing so, we hope to create a basis upon which to build working relationships between clinicians and researchers within both urology and neurology, with the ultimate goal of improving understanding of disease and patient quality of life.
The dopaminergic pathway to testosterone deficiency
Dopamine is known to inhibit PRL production and release [9]. Thus, degradation of dopaminergic neurons can lead to a rise in serum PRL, which can subsequently inhibit pulsatile GnRH release, resulting in decreased production of luteinizing hormone (LH) and testosterone (Fig. 2).
The role of prolactin
It has been demonstrated that PD patients have higher nocturnal PRL levels compared to age-matched controls [16].
Sexual quality of life in men with PD
Rates of sexual dysfunction among men with PD range from 41–82% [25–27]. However, the etiology is likely multifactorial considering the potential for neurological, vascular, and endocrine pathophysiology among these patients. Additionally, psychogenic factors may stem from self-perception/self-esteem issues relative to motor symptoms, emotional state, and partner status [28]. Thus, there are many targets for meaningful research in order to improve upon the reportedly high incidence of poor libido, erectile and orgasmic dysfunction, and avoidance of intercourse [29].
Sexual health following dopaminergic therapy
Based on the pathophysiology, dopaminergic agonists are the mainstay of therapy in patients with PD [31, 32]. Following the initiation of therapy, patients have reported improvement in sexual dysfunction, and even hypersexuality [33–35]. . Bronner et al. investigated this further and noted 8.8% of patients reported increased sex drive, 3.5% developed compulsive sexual behavior, and 2% demonstrated hypersexuality [28]. However, a concrete explanation to tie these symptoms to the use of dopaminergic agonists has not been put forth. A case study by Ivanco et al. discussed that lowering dopaminergic drug doses was of minimal behavioral benefit for the reduction of hypersexuality [36]. Perhaps conversely, a separate report described fluctuating erections with “peak” doses of levodopa [37]. Finally, other reports have noted that therapy such as Pergolide may improve IIEF metrics in young males with PD [38, 39]. Thus, due to the limited data, it is unknown if there is a dose-dependent effect of dopaminergic-agonist relative to the causation of hypersexuality.
Symptoms of TD can mimic non-motor symptoms of PD, which may prevent men from receiving potentially valuable hormonal therapy (Table 1 [10, 40, 41]). In a survey of men with PD, 93% answered positively to 3 or more questions on ADAM, despite only 35% having serum levels to support TD [12, 13]. Among men with PD and TD, the use of ART has been shown to significantly improve motor and nonmotor symptoms [13, 42]. However, when ART has been applied to men with PD whose testosterone levels did not quite meet the criteria for TD (i.e., “borderline”), the symptomatic improvement did not reach statistical significance, but the therapy was well tolerated [43]. To draw an interesting parallel from another area of research, multiple authors have looked at the risk of the development of PD in the setting of androgen deprivation therapy for prostate cancer. The data, however, is mixed as some studies suggest an increased risk whereas others do not [13, 44–46].
Future directions
Considering the number of individuals affected by PD (both patients and their loved ones), the male predilection, a clear hormonal pattern, and the detriment to the quality of life from sexual dysfunction, well-designed research, and organized collaboration are required. Men’s health providers should work with colleagues within the neurosciences to develop multidisciplinary pathways for men with PD. New and existing patients should be screened for signs and symptoms of sexual dysfunction and/or testosterone deficiency. Future research efforts should consider (1) establishing the prevalence of TD among men with PD, with efforts to define the natural progression over time, (2) evaluating the impact of ART upon sexual dysfunction and other PD-related symptoms in these patients, and (3) examining the hormonal and sexual health impact of dopaminergic agonists, and whether any such effects are dose-related.
CONCLUSIONS
In addition to the classic motor impairments, men with PD are at increased risk of sexual dysfunction. The loss of dopaminergic suppression of PRL appears to place patients at a potentially greater risk of low testosterone. This hormonal pathology has numerous implications for both sexual health and overall wellness, and symptoms can unfortunately be misinterpreted or ignored. Better data to guide clinical practice is required. Effective collaboration between providers specialized in PD and those in men’s health may create meaningful clinical algorithms to identify men at risk and optimize their quality of life and longevity.
Nicholas A. Deebel, Kim Thai, Ranjith Ramasamy, and Ryan P. Terlecki
Parkinson’s disease (PD) is often most recognized for motor symptoms but associated non-motor symptoms such as sexual dysfunction can significantly impact the quality of life. This condition involves a hormonal disruption and has a predilection for male patients, yet there are no formal guidelines for screening or management of sexual health pathology in these patients. While prior publications have addressed the presence of sexual dysfunction (SD) among men with PD, there has been a paucity of work examining the hypothalamic-pituitary-gonadal (HPG) axis and the interplay between dopamine, prolactin (PRL), and testosterone. This review provides an overview of data extracted from the existing peer-reviewed literature regarding hormonal and sexual health changes in men with PD and the impact of dopaminergic and/or androgen replacement therapy. Furthermore, while some research suggests that PD patients are at higher risk for prolactin elevation and testosterone deficiency, heterogeneity of the data limits extrapolation. Additionally, data related to pharmacologic optimization of the HPG axis in this patient population is similarly limited. Prospective studies are needed to better characterize the hormonal pathophysiology of PD as it relates to sexual dysfunction such that men at risk can be effectively identified so as to offer interventions that may improve quality of life.
INTRODUCTION
Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder that stems from the progressive loss of dopaminergic neurons within the substantia nigra [1]. The clinical manifestations are often grouped into motor (e.g., tremor, bradykinesia) and nonmotor categories with the nonmotor elements often less emphasized in the literature [2]. Dopamine is both a neurotransmitter and a hormone, such that PD can also be viewed as a hormonal disorder [3]. Axis disruptions have relevance to both overall health and quality of life [4, 5].
60,000 people in the United States are diagnosed with PD annually with an anticipated prevalence of 1.2 million people living with PD by the year 2030 [6]. PD has a predilection for affecting males more than females, a discrepancy attributed to the neuroprotective properties of estrogen against dopaminergic neuron degradation [2, 7]. Relative to controls, men with PD have nearly twice the risk of sexual dysfunction, most commonly involving erectile dysfunction (ED), premature ejaculation, orgasmic dysfunction, and decreased libido [2]. Each of these components may be related to hormonal axis disruption.
Unfortunately, sexual dysfunction is often overlooked among PD patients, possibly due to tunnel vision relative to motor symptoms. However, a study by Politis et al. found sexual dysfunction (classified as loss of libido and/or ED) to be the 12th most bothersome symptom (out of 24) in this population [1]. Another cross-sectional study of 113 men with PD found the prevalence of sexual dysfunction to be 68%, but the rate increased to 75% when considering only those patients, not on pharmacotherapy [8]. The majority of subjects self-reported PD as having a negative impact on their sexual health.
Although reports document the noteworthy existence of sexual dysfunction among men with PD, there is a paucity of data relative to the disruption of the hypothalamic-pituitary-gonadal (HPG) axis and the interplay between dopamine, prolactin (PRL), and testosterone (Fig. 1).
Likewise, there have been insufficient efforts to fully characterize the hormonal response from PD-related medications and the role of androgen replacement therapy (ART) in men with PD. Thus, we chose to review the peer-reviewed literature relevant to investigations into the underlying pathophysiology and the efforts to optimize the hormonal underpinnings of sexual health among men with PD. In doing so, we hope to create a basis upon which to build working relationships between clinicians and researchers within both urology and neurology, with the ultimate goal of improving understanding of disease and patient quality of life.
The dopaminergic pathway to testosterone deficiency
Dopamine is known to inhibit PRL production and release [9]. Thus, degradation of dopaminergic neurons can lead to a rise in serum PRL, which can subsequently inhibit pulsatile GnRH release, resulting in decreased production of luteinizing hormone (LH) and testosterone (Fig. 2).
The role of prolactin
It has been demonstrated that PD patients have higher nocturnal PRL levels compared to age-matched controls [16].
Sexual quality of life in men with PD
Rates of sexual dysfunction among men with PD range from 41–82% [25–27]. However, the etiology is likely multifactorial considering the potential for neurological, vascular, and endocrine pathophysiology among these patients. Additionally, psychogenic factors may stem from self-perception/self-esteem issues relative to motor symptoms, emotional state, and partner status [28]. Thus, there are many targets for meaningful research in order to improve upon the reportedly high incidence of poor libido, erectile and orgasmic dysfunction, and avoidance of intercourse [29].
Sexual health following dopaminergic therapy
Based on the pathophysiology, dopaminergic agonists are the mainstay of therapy in patients with PD [31, 32]. Following the initiation of therapy, patients have reported improvement in sexual dysfunction, and even hypersexuality [33–35]. . Bronner et al. investigated this further and noted 8.8% of patients reported increased sex drive, 3.5% developed compulsive sexual behavior, and 2% demonstrated hypersexuality [28]. However, a concrete explanation to tie these symptoms to the use of dopaminergic agonists has not been put forth. A case study by Ivanco et al. discussed that lowering dopaminergic drug doses was of minimal behavioral benefit for the reduction of hypersexuality [36]. Perhaps conversely, a separate report described fluctuating erections with “peak” doses of levodopa [37]. Finally, other reports have noted that therapy such as Pergolide may improve IIEF metrics in young males with PD [38, 39]. Thus, due to the limited data, it is unknown if there is a dose-dependent effect of dopaminergic-agonist relative to the causation of hypersexuality.
Symptoms of TD can mimic non-motor symptoms of PD, which may prevent men from receiving potentially valuable hormonal therapy (Table 1 [10, 40, 41]). In a survey of men with PD, 93% answered positively to 3 or more questions on ADAM, despite only 35% having serum levels to support TD [12, 13]. Among men with PD and TD, the use of ART has been shown to significantly improve motor and nonmotor symptoms [13, 42]. However, when ART has been applied to men with PD whose testosterone levels did not quite meet the criteria for TD (i.e., “borderline”), the symptomatic improvement did not reach statistical significance, but the therapy was well tolerated [43]. To draw an interesting parallel from another area of research, multiple authors have looked at the risk of the development of PD in the setting of androgen deprivation therapy for prostate cancer. The data, however, is mixed as some studies suggest an increased risk whereas others do not [13, 44–46].
Future directions
Considering the number of individuals affected by PD (both patients and their loved ones), the male predilection, a clear hormonal pattern, and the detriment to the quality of life from sexual dysfunction, well-designed research, and organized collaboration are required. Men’s health providers should work with colleagues within the neurosciences to develop multidisciplinary pathways for men with PD. New and existing patients should be screened for signs and symptoms of sexual dysfunction and/or testosterone deficiency. Future research efforts should consider (1) establishing the prevalence of TD among men with PD, with efforts to define the natural progression over time, (2) evaluating the impact of ART upon sexual dysfunction and other PD-related symptoms in these patients, and (3) examining the hormonal and sexual health impact of dopaminergic agonists, and whether any such effects are dose-related.
CONCLUSIONS
In addition to the classic motor impairments, men with PD are at increased risk of sexual dysfunction. The loss of dopaminergic suppression of PRL appears to place patients at a potentially greater risk of low testosterone. This hormonal pathology has numerous implications for both sexual health and overall wellness, and symptoms can unfortunately be misinterpreted or ignored. Better data to guide clinical practice is required. Effective collaboration between providers specialized in PD and those in men’s health may create meaningful clinical algorithms to identify men at risk and optimize their quality of life and longevity.
