Abstract
Background:
Sexual dysfunction (SD) is one of the least studied non-motor symptoms in Parkinson’s disease (PD).
Objectives:
To assess sexual function in a cohort of patients with early-onset PD (EOPD) and compare it to a group of healthy controls.
Methods:
In this cross-sectional multicenter study, SD was assessed with gender-specific multi-dimensional self-reported questionnaires: The Brief Male Sexual Function Inventory (BSFI-M) and the Female Sexual Function Index (FSFI). Scores between patients and controls were compared and associations between SD and demographical and clinical variables were studied.
Results:
One hundred and five patients (mean age 47.35±7.8, disease duration 6 (3–11) years, UPDRS part III 17 (10–23) and 90 controls were recruited. The BSFI-M total score was lower in EOPD men than in controls, and specific items were also significantly lower, such as drive, erections, ejaculation, and satisfaction. EOPD women had lower scores than controls in total
FSFI, and certain domains such as lubrication and pain. SD was present in 70.2% of patients and 52.5% of controls. Sexual satisfaction in 35.2% of patients and 81.2% of controls. By gender, male and female patients had more SD than controls but only male patients had more dissatisfaction than controls. Gender, higher depression scores and urinary dysfunction were associated with SD in multivariate analysis; and gender, UPDRS and urinary dysfunction with sexual satisfaction
Conclusion:
In this Spanish cohort, SD and sexual dissatisfaction was more prevalent in EOPD patients than in the general population. Gender and urinary disfunction were associated with SD and sexual dissatisfaction.
INTRODUCTION
Non-motor symptoms (NMS) are highly prevalent in Parkinson’s disease (PD) [1]. They occur across all stages of PD and have a substantial impact on quality of life (QoL) [2]. Sexual dysfunction (SD) is one of the least studied NMS in PD and prevalence rates are likely to be underestimated, considering the reluctance of patients and doctors in discussing these symptoms. Only two questions regarding sexually related symptoms are included in the NMS-questionnaire and in the NMS-scale while these symptoms are not considered in the most widely used questionnaire about health related QoL in PD (PDQ-39) [3]. Sexual function in humans represents a complex process that requires adequate functioning of the autonomic, sensory, and motor systems [4]. SD in PD patients may be secondary to motor dysfunction, pharmacological treatment, psychological, and social factors. However, few studies have addressed the issue of sexual function in PD patients and reported data shows conflicting results [5–14]. Most studies have methodological limitations such as the use of incomplete instruments for accurate assessment of sexual function, the absence of a control group, or the inclusion of only one gender [7, 8]. A recently published systematic review and meta-analysis of the association between PD and the risk of SD substantiated a hazardous effect of PD for the development of SD only in men [9]. However, PD duration has been identified as a source of substantial heterogeneity in meta-regression analysis so these results call for further investigation.
The threshold of early-onset Parkinson’s disease (EOPD) has been established at age 45 years old, although 40 and 50 years of age have also been used in some studies. EOPD patients are affected by this neurodegenerative disease at an age at which they expect to be sexually active, and they may develop SD due to a range of vulnerability factors including depression, motor disabilities such as tremor or dyskinesias, and disruption of family life [10, 15]. Two controlled studies, exploring SD have been published in EOPD patients, one comparing them to the general population and the other to their spouses [12, 13]. They showed that patients were more dissatisfied with their sexual life, but sexual function results were contradictory.
The aim of this study was to comprehensively assess sexual function in a Spanish cohort of EOPD patients using gender-specific multi-dimensional instruments and to compare results to a healthy control (HC) group. Secondary objectives were to identify demographical or clinical factors related to SD and to study the effect of SD on QoL.
METHODS
Subjects
Patients were recruited from 14 hospitals in the greater Madrid area in two time-periods: between March 2010 and November 2011 and from January to November 2017. PD was defined according to the United Kingdom PD Society Brain Bank criteria [16], with the exception that PD family history was not regarded as exclusion criteria, and early onset was defined as before the age of 45 years old. All patients were evaluated and followed by Movement Disorder specialists. Patients with other types of parkinsonism, cognitive impairment (defined by a score below 24 on the Mini-Mental State Examination) or those unable to complete the questionnaires were excluded from the study. Controls were subjects with no neurological complaints recruited among hospital personnel and friends of patients but not family members. They were paired by age and gender to the patient group. The study received the approval of all hospitals’ ethics committees and all participants provided their written informed consent.
Evaluations
Assessments were conducted on the same day of the neurological evaluation. Demographic and clinical data were collected, and motor function was evaluated by the Hoehn and Yahr scale and the MDS Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III during the “ON” condition after the first morning dose of medication. The presence of dyskinesias and motor fluctuations were registered. All treatments were recorded and L-dopa equivalent daily dose (LEDD) was calculated [17]. The presence of depression was assessed through the Beck Depression Inventory (BDI) [18], whereby patients with a score of at least 13 points (maximum of 63) were diagnosed as depressed. The QoL of all subjects (patients and controls) was assessed with the generic EuroQol-5D scale [19] and PD patients also completed the PDQ-39 [20]. Autonomic dysfunction was assessed with the Scale for Outcomes in Parkinson’s disease Autonomic symptoms (SCOPA-AUT), a questionnaire consisting of 25 items, including urinary dysfunction items and two items on SD concerning erectile dysfunction and ejaculation in men and vaginal dryness and orgasm in women [21]. Frequency of sexual intercourse was registered and categorized in three tiers: <1 per week, 1 or 2 per week and >2 per week. Hypersexuality was assessed using the short form of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP). A positive response in the items of sexual behavior was considered as hypersexuality. SD was studied through the Brief Sexual Function Inventory (BSFI) in men [22] and through the Female Sexual Function Index (FSFI) in women [23]. Both tests are brief multi-dimensional self-reported questionnaires and are two of the most widely used instruments for evaluation of SD. Sexual satisfaction items are included in these questionnaires.
The BSFI-M is an 11-item self-administered questionnaire in which the first 10 items cover functional aspects of male sexuality like sexual drive (two items), erection (three items), ejaculation (two items) and three items focus on how problematic these aspects are for the patients. The last item covers overall sexual satisfaction. Every item is scored from 0 (most problematic) to 4 (no problem). It has shown an internal consistency of 0.62–0.95 and retest coefficients of 0.79–0.90. The total score is the sum of all items divided by ten (range 0–4). For ages 40–50 years old, a score of more than 3.42 (0.59) indicates normal sexual function [22].
The FSFI is a multidimensional self-reported instrument with 19 items to assess female sexual function over the past 4 weeks, and yields domain scores in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain [23]. Individual scores for each question range from a minimum of 0 or 1 to a maximum of 5. Domain scores are obtained by adding individual question scores and multiplying these by a specific factor. The full-scale score is obtained by adding the six domain scores and ranges from 2 to 36, with higher scores reflecting a better sexual function. This questionnaire is accepted as a valid tool to measure female sexual function and has good internal consistency (Cronbach’s alpha 0.791 to 0.914). A cut-off score of <26.5 has been proposed to indicate SD.
In this study, sexual dysfunction was defined as a score <3.42 in the BMFI-M for men and a score of <26.5 in the FSFI for women. Sexual satisfaction was defined in men as a score of >2 on item 11 of the BMFI-M and in women as a score of >3 on item 16 of the FSFI.
Statistical analysis
All statistical analyses were carried out using version 18 of the Statistical Package for the Social Sciences (SPSS) for Windows. Quantitative results are showed as the mean and standard deviation (SD), or median and interquartile range (IQR) if the data did not follow a normal distribution. Qualitative data were expressed as counts and percentages. To analyze differences between patients and controls the Chi-squared test or Fisher exact test were used in case of qualitative variables and Student’s t-test or the Mann-Whitney U test were used in case of quantitative data. A univariate analysis was developed to study factors associated with SD and sexual satisfaction in EOPD patients. Univariate and multivariate logistic regression models were adjusted to estimate factor’s odds ratio (OR). All p-values were two tailed and values <0.05 were considered significant. If >10% of the data from a questionnaire or a scale were missing for any subject, data was excluded from the statistical analysis.
RESULTS
The study included 105 EOPD patients and 90 control subjects. Demographic and clinical features of all participants are shown in Tables 1 and 3.
Demographic and clinical variables in EOPD and in healthy controls
SD, standard deviations; BDI, Beck Depression Inventory; SCOPA-AUT, Scales for Outcomes in Parkinson’s disease Autonomic; VAS, Visual Analogue Scale, QUIP, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease.
Brief Sexual Function Inventory (BSFI) and Female Sexual Function Index (FSFI) scores in EOPD patients and healthy controls
Total BISF-M was significantly lower in male patients than in male controls (mean difference 0.85, CI 95%,0.57–1.12, p < 0.001). Every aspect of sexual functioning: drive, erections, ejaculation, problem assessment and overall satisfaction were lower in patients than in controls. Women with EOPD had lower scores than controls in total FSFI (mean difference 3.56, CI95%, 0.56–6.56, p = 0.021). They also had less lubrication (p = 0.017) and more pain (p = 0.03) during intercourse. There were no differences in desire, arousal, orgasm and satisfaction between woman patients and controls (Table 2). Most EOPD patients 70.2 % had SD (Table 3). Stratifying by gender, 80.6% of male patients had SD vs 41.2% of controls (p < 0.001) and 54.8% of female patients had SD vs 27% of controls (p = 0.013). In the EOPD group, 52.5% reported sexual satisfaction vs 81.5% of the controls (p < 0.001). This difference was driven by male EOPD patients, since only a third (33.9%) of them reported sexual satisfaction vs 74.5% of controls (p < 0.001) while female patients and controls reported similar sexual satisfaction scores (82.1 % and 91.9% (p = 0.311)).
Demographic, clinical variables and treatment in patients with and without sexual dysfunction
UPDRS, Unified Parkinson’s Disease Rating Scale; PDQ-39, Parkinson’s Disease Questionnaire –39; LEDD, Levodopa Equivalent Daily Dose.
Concerning SD in EOPD patients, 68.5% of males and 54.8% of females had SD. Patients with SD were significantly older (p = 0.047) and had higher BDI scores (p = 0.01) (Table 3).
In multivariate logistic regression analysis, including gender, age, depression score, H&Y, SCOPA Urinary score, SD was related to male gender (OR 6.71, CI95%, 2.02–22.4, p < 0.002), higher depression scores (OR 1.11, CI95%, 1.01–1.22, p < 0.038), and higher SCOPA Urinary score (OR: 1.2, CI95% : 1.02–1.41, p = 0.031).
Sexual satisfaction was higher in female patients than in males (82.1% vs 33.9%). It was related to lower UPDRS part III (p = 0.02) and BDI scores (p = 0.046) (Table 4). In multivariate logistic regression analysis, including gender, UPDRS III, depression score, SCOPA urinary score and age, satisfaction was related to female gender (OR:31.5, CI95% :6.1–162.56, p < 0.001), lower UPDRS III score (OR: 0.92, CI95% : 0.86–0.99, p = 0.017) and lower SCOPA Urinary score (OR: 0.85, CI95% : 0.74–0.99, p = 0.035).
Demographic, clinical variables and treatment in patients with and without sexual satisfaction
PDQ-39 was similar in patients with and without SD and in patients with and without sexual satisfaction (Tables 3 and 4). Frequency of sexual intercourse was similar in EOPD patients than in controls, in women (p = 0.81) and men (p = 0.082).
DISCUSSION
To the best of our knowledge, this is the first controlled study approaching sexuality in EOPD female and male patients using instruments specifically developed to assess sexual function in both genders. Most previous studies have included only one gender, incomplete instruments for sexual dysfunction assessment or PD patients of all ages [5–8, 13]. Furthermore, the number of controlled studies assessing sexual dysfunction in PD is strikingly scarce and there are only two studies in patients with EOPD [12, 13].
Sexual function typically declines with advancing age [24]. Most conditions associated with SD, like hypertension, diabetes and hormonal dysfunction, are age-correlated [4]. In our study, the confounding effect of advancing age was mitigated by focusing on early-onset patients to provide a clearer insight into the PD-specific aspects of the problem. Even in our sample, PD patients with SD were older than patients with normal sexual function. However, age was not an independent determinant of SD according to our multivariate logistic regression analysis. Previous studies, using different methodologies, have revealed conflicting results. While most studies [5, 25] concluded that SD was more prevalent in late-onset PD (LOPD) than in EOPD, especially in males, another study found no differences between age groups [24]. On the other hand, a Chinese study revealed that SD were more prevalent in EOPD than in LOPD [26]. In a recently publish meta-analysis [9] men with PD were more likely to experience SD than those without PD, while female patients showed similar results to healthy controls. Only Wermuth et al.’s study, limited by its small sample, concluded that changes in libido and sexual function occur especially in women [10].
In our cohort, patients with EOPD, both men and women, reported SD and this was significantly higher than in healthy controls of the similar age and gender. Our data suggests that SD is a prevalent NMS among EOPD patients that may be underestimated due to personal, social and cultural factors. In a time-limited consultation, patients rarely bring up these very personal and sensitive issues and their doctors rarely question them, possibly due to discreetness, shyness, lack of knowledge or disregard of its importance.
All sexual function domains were significantly worse in male patients than in controls (drive, erections, ejaculation and overall satisfaction). While in women, only lubrication and pain during vaginal penetration were reportedly worse than in controls. This discrepancy between genders could be related to sex-related differences in the nigrostriatal or extranigral dopaminergic pathways. In fact, it has been suggested that the striatum in male patients is more dopaminergically denervated than in females [27]. Gonadal hormones may influence the nigrostriatal system and their production may, at least in part, explain sex-differences in the pathogenesis and clinical manifestations of PD [28]. Of note, while testosterone is the hormone most closely associated with sexual drive in male individuals, female sexual drive may be more dependent on changes in estradiol [29]. Evidence suggests that estrogen might serve as a neuroprotective factor that might play a role in minimizing toxicity on the dopaminergic neuron population [30, 31].
Erectile and ejaculatory function are importantly affected in EOPD male patients. Erectile dysfunction is the most studied feature of SD in PD, even in young PD patients [13, 32]. In recent years, clinical studies suggest that erectile dysfunction may be one of the pre-motor features of PD, appearing several years before motor symptoms. A large epidemiological study found that men with erectile dysfunction had a fourfold higher risk of developing PD over the 16 year follow-up than those who reported very good function [32]. Authors concluded that erectile dysfunction was associated with a higher risk of developing PD. A recent study focusing on prevalence and duration of non-motor symptoms in prodromal PD found that males reported more SD than females [33].
Nevertheless, even if EOPD male patients have more SD than females, 54% of female patients had SD. Total FSFI scores, lubrication and pain domains were lower than in controls. We used the same methodology as Varanda’s study, who found a much higher proportion of SD in PD women (86.9%) than in controls (79.0%). These high rates are probably due to the older age of the participants in this study had, about twenty years older than ours. The authors concluded that older age was a predictor of SD [7].
In addition to male gender, our study showed that higher depression scores were associated with SD, in agreement with previously reported data [7, 34]. Likewise, our data suggests that SD may be independent of PD related clinical and pharmacological variables, in concurrence with other studies [7, 13].
Sexual satisfaction has been assessed with different methods in previous studies. We used the question about sexual satisfaction included in the questionnaires. In this cohort, satisfaction was lower in patients than in controls, mainly driven by male patients. Sexual dissatisfaction in our patients (men and women) was associated with higher BDI scores. Jacobs and colleagues studied an EOPD cohort that was demographically similar to our sample, although clinically more advanced (longer disease duration and higher UPDRS III and Hoehn & Yahr scores) [12]. Using a multiple-choice questionnaire, they found that patients, especially men (36% men vs 20% women, p = 0.01) were less satisfied with their current sexual life than controls [12]. They found that depression was relevant to sexual dissatisfaction. Likewise, Brown et al. assessed sexual satisfaction with a single question (“overall, how satisfactory to you is your sexual relationship with your current partner?”) in 34 young patients (23 males and 11 females) and their spouses, and found that 59% of PD males and 34% of PD females were dissatisfied. They found that these problems were associated with a range of variables relating to the disease, psychological and social factors [14].
Previous studies have noted that lack of sexual interest is a common complaint reported by PD patients [10, 35] and is correlated with reduced general satisfaction in life [35, 36]. While lack of sexual interest may reflect coexistent or undiagnosed psychiatric comorbidities, it can exist independently [37]. A recent prospective longitudinal study involving a large cohort of PD patients suggested that sexual activity is associated with better health related QoL as well as with lower motor and non-motor disability [38]. Our study did not find a relationship between SD and QoL as assessed by a generic scale (EuroQol) and a disease specific scale (PDQ-39), in line with a previous study [2].
In our cohort, urinary dysfunction is associated with sexual dysfunction. Interestingly, male PD patients have been reported to suffer more sexual problems and more severe urinary symptoms than female patients [26], suggesting that the same pathophysiological process may underlie both sexual and urinary dysfunction in males. Furthermore, autonomic symptoms, such as urinary problems, may inhibit sexual drive [35, 37].
SD is a complex NMS that may be affected by biopsychosocial factors, including mood problems, autonomic and motor dysfunction. Thus, SD in EOPD should be managed by neurologists actively questioning about sexual function, as an integral part of the neurological assessment involving patients and their partners. Adequate intervention should be offered, optimally within a multidisciplinary team, where treatment of sexual issues can be handled comprehensively by dedicated professionals [39]. The availability of effective treatments for SD, particularly those for erectile dysfunction and female lubrication, provide powerful justification for a comprehensive assessment of sexual functioning in PD patients [39].
This study has some strong points such as the high number of participants, both patients and controls, recruited from many centers and the use of multi-dimensional generic instruments to assess SD, as disease specific instruments that comprehensively assess sexual function are lacking in PD. However, this study has some limitations. Most importantly, controls filled out the questionnaires without an interview, and many of them did not register the drugs they took. Several drug classes, especially antidepressants, are known to influence sexual function [40]. Some controls were recruited from hospital personnel. This is a selection bias but we tried to minimize it by making responses completely anonymous (sealed envelope given to the PI in a different hospital. Another limitation was that none of the patients reported hypersexuality as a problem in the interview, although 25.5% had hypersexuality according to the QUIP. We did not have spouse reports to check. Furthermore, we have not taken into consideration the presence of sleep disorders such as REM sleep behavior disorder, which may promote bed separation, thus reducing the opportunities for sexual intercourse.
Conclusions
In this Spanish EOPD cohort, SD (as measured by the BSFI-M and FSFI) is more common in patients than in the general population. All sexuality domains were decreased in EOPD male patients while total FSFI were lower in EOPD females along with decreased lubrication and increased pain during intercourse. Sexual dissatisfaction was more prevalent in EOPD male patients than in the general population. Among EOPD patients, male gender and urinary dysfunction were associated with SD and sexual dissatisfaction. SD was related to depression. SD should be investigated as an integral part of the neurological assessment in EOPD since it is a prevalent symptom and effective treatments are available.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Financial disclosures
Lydia Vela-Desojo reports compensated advisory services, consulting or speaker honoraria from AbbVie, Bial, Italfarmaco, Teva, Krka and Zambon.
Monica Kurtis-Urra - reports compensated consulting or speaker honoraria from Bial and Zambon.
Pedro J Garcia Ruiz received research support from Allergan and UCB, personal compensation as a consultant/scientific advisory board from Italfarmaco, Britannia, Bial, and Zambon and speaking honoraria from Italfarmaco, UCB, Zambon, Allergan, and Abbvie.
Lydia Lopez-Manzanares reports compensated advisory services, consulting, research grant support, or speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Roche, Teva, UCB, and Zambon.
Marina Mata has received speaking honoraria from Abbvie, Italfarmaco, Zambon, Bial, Alter, and has participated in Advisory Board of Zambon, Italfármaco and Abbvie.
JC Martínez-Castrillo has received honoraria for speaking at meetings sponsored by AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB, and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB, and Zambon; and has participated in Advisory Boards of AbbVie, Allergan, Eisai, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orin, UCB, and Zambon.
Daniele Urso, Elia Perez-Fernandez, Ignacio Posada-Rodriguez, Eva Lopez-Valdes, Carmen Borrue, Maria del Valle, Isabel Ybot, Cristina Ruiz- Huete –They do not have any disclosures
Footnotes
ACKNOWLEDGMENTS
We thank Dr. Yolanda Macias for her help with data collection. We also thank Dr. Francisco Vivancos, Dr Ana Rojo and Dr Miriam Eimil for recruiting patients for our study. We are sincerely grateful to the patients and subjects who participated in the study.