The reported prevalence of LUT symptoms (LUTS) in patients with PD ranges from 38% to 71% [⁴³–⁴⁸]. However, it has been difficult to determine to what extent PD contributes to LUTS. Men older than 60 years of age may have bladder outlet obstruction due to prostate hyperplasia. Women may have stress urinary incontinence. “Idiopathic DO” [¹⁰] may occur in men and women older than 65 years due in part to latent brain ischemia [⁴⁹]. Some of the studies were published before the diagnosis of multiple system atrophy (MSA) [⁵⁰] was recognized. In recent studies of PD patients who were diagnosed according to modern criteria [⁵, ⁵¹–⁵³], the prevalence of LUTS was found to be 27–63.9% using validated questionnaires [⁵¹–⁵³], or 53% in men and 63% in women using a nonvalidated questionnaire that includes a urinary incontinence category [⁵], with all of these values being significantly higher than the incidence rates in healthy controls. The majority of patients had onset of bladder dysfunction after appearance of motor disorder. Correlations have been shown between bladder dysfunction in patients with PD and neurological disability [⁵¹], and bladder dysfunction and stage of disease [⁵], both suggesting a relationship between dopaminergic degeneration and LUTS. However, Campos-Sousa and colleagues did not find such a correlation [⁵³].

LUTS are divided majorly into two; storage symptoms and voiding symptoms. Storage symptoms are the most common of the LUTS symptom types in PD. Storage symptoms include nocturia (nighttime urinary frequency), which is the most prevalent symptom reported by patients with PD (>60%) [⁵, ⁵¹–⁵³]. Patients also complain of urinary urgency (33–54%) and daytime frequency (16–36%). Urinary incontinence was present in 26% of male and 28% of female patients with PD [⁵].

Although less common than storage symptoms, voiding symptoms also occur in PD patients. In the study by Sakakibara and colleagues, PD patients had significantly higher rates of retardation in initiating urination (44% of men only), prolongation/poor stream (70% of men only), and straining (28% of women only) compared with the control group [⁵]. Araki and colleagues noted a correlation between voiding symptoms and stage of disease [⁵⁴]. However, despite the voiding symptoms, PD patients have low postvoid residuals [⁵].

It is possible that levodopa and other antiparkinson medication may affect bladder function in PD. Aranda and Cramer [⁶⁶] studied the effects of 3–8 mg apomorphine injection on the storage function in 2 de novo PD patients, and found that the bladder capacity increased. They gave oral levodopa to one of the patients, and the bladder capacity increased. We compared the frequency of bladder dysfunction in de novo PD and PD with levodopa. In that study, LUTS was less frequent than in the treated group [⁵⁹]. In another study, after 3 months of treatment with levodopa, the storage urodynamic parameters were slightly improved in de novo PD [⁶⁷].

In contrast, in treated patients, studies concerning the effect of dopaminergic drugs on micturition have produced conflicting results. Regarding overactive bladder, some reports have shown a storage-facilitating effect of dopaminergic drugs [⁵]. In contrast, Kuno and colleagues showed that a change in medication from bromocriptine (D2 selective agonist) to pergolide (D1 < 2 agonist) brought lessening of nocturia [⁶⁸], and Yamamoto described improvement of DO by pergolide [⁶⁹]. Benson and colleagues [⁷⁰] gave 2000 mg of levodopa in 2 longstanding PD patients, and bladder capacity increased in both patients. After discontinuation of levodopa, the bladder capacity further increased in one of the patients, but decreased in the other. Other reports have shown a voiding-facilitating effect of dopaminergic drugs [⁷¹]. Fitzmaurice and colleagues [⁷²] have described that, in advanced PD with the on-off phenomenon, DO worsened with levodopa in some patients and lessened in others. Winge and colleagues [⁷³] found that the effect on micturition of treatment with dopaminergic drugs in PD was unpredictable. Recent studies have shown that in early PD [⁷⁴] and advanced PD with the on-off phenomenon [⁶], a single dose of levodopa exacerbates DO in the filling phase. We still do not know the exact reasons for the discrepancy.

There are several factors underlying the complex bladder behavior in treated PD patients [⁷⁵]. Postsynaptic dopamine D1 (excitatory) and D2 (inhibitory) receptors have a millimolar affinity to dopamine whereas dendritic D2 (inhibitory) autoreceptors have a picomolar affinity to dopamine [⁷⁶]. Therefore, levodopa may first stimulate dendritic D2 autoreceptors, which might suppress the dopaminergic cells and facilitate the micturition reflex. In cases of PD under long-term treatment with levodopa, dopamine receptors are downregulated and potential hypersensitivity might occur [⁷⁷]. The A11 dopaminergic cell group lies in the dorsal-posterior hypothalamus, which is affected in marmosets with MPTP-induced parkinsonism [⁷⁸]. This cell group descends as the sole source of spinal dopamine [⁷⁹], which might also involve in generating bladder overactivity [⁸⁰]. Peripheral dopamine D1 and D2 receptors also exist in the bladder [⁸¹], although their exact role has not been delineated.

Anticholinergics [⁸²] are generally used as a first-line treatment for overactive bladder. However, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects. When the dose of drug increases, postvoid residuals may appear [⁷⁵]. Dry mouth and constipation are common [⁸³]. Cognitive adverse events by anticholinergics are a concern particularly in the elderly. For example, trihexyphenidyl (for PD) and oxybutynin (for overactive bladder) have been shown to have central side effects [⁸⁴, ⁸⁵]. Factors contributing to the central effects of drugs may include blood-brain barrier (BBB) penetration [⁸⁶]. Among the factors of BBB penetration, diffusion is facilitated by lipophilicity [⁸⁷]. Particularly in elderly patients who have hallucinations or cognitive decline (PD with dementia/dementia with Lewy bodies) [⁶⁴, ⁶⁵], anticholinergics should be used with extreme caution.

When a first-line treatment fails or is contraindicated, a second-line treatment might be considered. The main action of central 5-hydroxytryptamine- (5-HT, or serotonin-) ergic neurons on the LUT is facilitation of urine storage [⁸⁸]. In PD, neuronal cell loss in the raphe nucleus has been documented [⁸⁹]. Therefore, serotonergic drugs, such as duloxetine and milnacipran [⁹⁰] can be a choice to treat overactive bladder in PD. Nocturnal polyuria should be distinguished from overactive bladder. In patients with PD, the imbalance between diurnal and nocturnal production of urine can be observed in the course of the disease [⁹¹]. Treatment with desmopressin proved to be effective in reducing nocturia in PD [⁹²], although this medication needs caution of water intoxication. The subthalamic nucleus (STN) is regarded as the key area in the indirect pathway, which is dominant in the parkinsonian state [⁹³]. Deep brain stimulation (DBS) in the STN inhibits many cells within the STN, probably due to depolarization block and release of GABA from activation of inhibitory afferent terminals [⁹⁴]. In the STN, neuronal firings related to the micturition cycle have been observed in cats [³⁹]. DBS in the STN proved to have an inhibitory effects on the micturition reflex in animals [³⁹, ⁴⁰] and in patients with PD [⁹⁵–⁹⁷]. DBS in the STN also increased bladder capacity and facilitated bladder afferent pathways in the brain of PD patients [⁹⁸, ⁹⁹].

In PD there is dysfunction along the entire length of the GI tract. Therefore, while we focus on the colon and rectum, we refer to stomach and small intestine when necessary. The reported prevalence of LGIT symptoms in PD is mostly more than half [¹⁴⁹–¹⁵¹]. However, it has been difficult to determine the extent to which PD is contributing to the LGIT symptoms. This difficulty occurs because not only PD but also idiopathic constipation may occur in the elderly due in part to dietary habit [¹⁵¹], exercise [¹⁵²], or age-related ENS degeneration [¹⁵³]. Controlled studies [⁵, ¹⁴⁹, ¹⁵⁴, ¹⁵⁵] could overcome these problems, in which the incidence rate of decreased stool frequency (<3 times a week) in PD patients ranges from 20% to 81%, that of difficulty in stool expulsion in 57–67%, and that of diarrhea in 21%. All of these values are significantly higher than in the normal population (range, decreased stool frequency, 0–33%; difficulty in stool expulsion, 26–28%; diarrhea, 10%) [⁵, ¹⁴⁹, ¹⁵⁴, ¹⁵⁵]. Fecal incontinence has been reported to be 10–24% in PD [⁵, ¹⁴⁹]. Therefore, constipation is the most prominent LGIT symptoms in patients with PD. Indeed, PD is a risk factor for elderly nursing home residents to have constipation [¹⁵⁶]. Of particular importance is that bowel dysfunction affects the quality of life in patients with PD [⁵].

There is no significant difference in the use of dopaminergic or anticholinergic drugs and bowel dysfunction [⁵, ¹⁴⁹]. Difficulty in expulsion, and diarrhea are more common in the higher grade of Hoehn and Yahr staging [⁵, ¹⁴⁹, ¹⁵⁰], suggesting a relationship between dopaminergic degeneration and LGIT symptoms. However, there are also studies in which no such relationship was found [¹⁵⁷]. Constipation in PD occurs commonly with a low coefficient of variation in electrocardiographic R to R intervals [¹⁵⁸]. The findings indicate that parasympathetic dysfunction might underlie these abnormalities. A recent epidemiological study revealed an association between the frequency of bowel movements and the future risk of developing PD [¹⁵⁹]. From a clinical perspective, it is of particular importance that patients with PD see gastroenterologists or physicians first because of their bowel dysfunction before a diagnosis of PD is made.

A more severe and often acute presentation of bowel dysfunction is intestinal pseudo-obstruction [¹⁶⁰], also called paralytic ileus. Yokoyama and Hasegawa [¹⁶¹] have recently reported the frequency to be 7.1% among 112 patients with PD. Radiographical features of intestinal pseudo-obstruction are dilatation of colon and small intestine [¹⁶⁰, ¹⁶²–¹⁶⁴]. True obstruction due to volvulus in PD also occur [¹⁶¹, ¹⁶³, ¹⁶⁴]. Intestinal pseudo-obstruction also occurs insidiously [¹⁶⁵, ¹⁶⁶]. In such patients, histology specimens may reveal Lewy body disorder.

LGIT function primarily consists of (1) colonic transport of the bowel content to the anorectum [¹⁰⁷, ¹⁰⁸], (2) transient anorectum reservoir, and (3) defecation from the anorectum with the aid of strain [¹⁰²]. In PD, constipation results primarily from decreased transport and/or disturbed anorectal evacuation. Fecal incontinence may result from disturbed anorectal reservoir, or overflow secondary to constipation.

Previous reports have shown that total CTT is increased beyond the normal threshold in 80% of PD patients [¹⁶⁷], which translates into an increased average CTT ranging from 44 hours to 130 hours in PD [¹⁶⁷, ¹⁶⁸], and in 89 hours in de novo PD patients [¹⁶⁷], all of which are significantly longer than those of controls (range, 20–39 hours) [¹⁶⁰, ¹⁶⁷, ¹⁶⁸]. Prolonged CTT has also been documented in PD patients without subjective constipation [¹⁶⁹]. Slow colonic transit is the major cause of decreased stool frequency. The slow colonic transit is likely to reflect a decrease in slow waves and spike activities of the colon, which may reflect the ENS pathology, and to a lesser extent, the CNS pathology in PD. Among right, left, and rectosigmoid segments of the CTT, the rectosigmoid CTT is significantly prolonged in PD patients [¹⁶⁰, ¹⁶⁷, ¹⁶⁹]. Several explanations for this finding can be hypothesized. It is possible that the ENS innervated by the sacral cord is more severely affected than that innervated by the DMV in PD [¹⁶⁰]. Oro-caecal transit time in PD is also prolonged [¹⁷⁰].

Pathological studies have demonstrated that PD affects the ENS [¹¹⁷–¹²¹]; showing decrease in dopaminergic myenteric neurons and the appearance of Lewy bodies along the proximal-distal axis, for example, they were most frequent in the lower esophagus, but scarce in the rectum. Presumably, degeneration of not only the inhibitory (dopaminergic) fibers, but also of facilitatory (cholinergic and serotonergic) fibers might contribute to the slow colonic transit in PD.

Rectoanal videomanometry measures functions of the anorectum reservoir and evacuation. During slow rectal filling, PD patients have a slightly but not significantly larger rectal volume at first sensation and a maximum desire to defecate compared with control subjects [¹⁶⁰, ¹⁷¹]. The PD patients had the same rectal compliance as control subjects using the slow-liquid-filling method [¹⁰², ¹⁶⁰], which is in accordance with the studies using the balloon-inflation method. However, the amplitude of the spontaneous phasic rectal contraction in the PD patients is significantly less than that in control subjects [¹⁰², ¹⁶⁰]. The decreased spontaneous phasic rectal contraction may share the same aetiology with the decrease in CTT.

In normal subjects, anal pressure not only varies during the storage phase, but also shows a close relation with spontaneous phasic rectal contraction, for example, when the rectal pressure increases, the anal pressure tends to decrease [¹⁰²]. The concurrent sphincter relaxation with the spontaneous phasic rectal contraction resembles the rectoanal inhibitory reflex [¹⁷⁶]. The concurrent sphincter relaxation might be appropriate for the following evacuation phase [¹⁰²]. However, in the PD patients, both rectal and anal pressures tend to increase together [¹⁶⁰]. This phenomenon during filling resembles the paradoxical sphincter contraction on defecation, as described below.

In addition to slow transit constipation, anorectal (outlet type) constipation is a common feature in PD. Indeed, most PD patients could not defecate completely and had postdefecation residuals, the volume of which were significantly larger than those in a control group [¹⁶⁰]. During defecation, it has remained a subject of controversy whether true rectal contraction occurs, since abdominal strain is large enough to mask the rectal contraction if present. Only a few studies have measured the differential rectal pressure component [¹⁷⁹] and not found rectal contraction on defecation. In recent studies, healthy control subjects had a moderate rectal pressure increase on defecation, for example, the healthy subjects utilized the final wave of spontaneous phasic rectal contractions for defecation [¹⁰²]. However, rectal contraction on defecation in PD patients is smaller than that in controls [¹⁶⁰].

The abdominal straining in PD patients is less than that in control subjects [¹⁶⁰]. Straining plays a physiological role in both coughing and defecation, which is achieved by cocontraction of the glottis, diaphragm, and abdominal wall [¹⁸⁰]. Straining is associated with activation in brainstem nuclei such as the Kolliker-Fuse nucleus and medullary respiratory neurons [¹⁸⁰]. However, PD patients show a less pronounced increase in abdominal pressure on coughing [¹⁶⁰, ¹⁸¹] and Valsalva maneuver [¹⁶⁰, ¹⁸²] before starting rectal filling, and in the defecation phase [¹⁶⁰, ¹⁸²], than do control subjects. The mechanism of the impaired straining in PD may include rigidity and reduced contractility of the axial muscles, and a failure of coordinated glottis closure [¹⁸¹]. However, neuronal degeneration in the CNS relevant to straining is yet to be clarified in PD.

During defecation, the anal pressure increase on defecation in patients is significantly larger than that in control subjects, with an increase in the sphincter electromyography (EMG) activity. This finding in PD has been described as paradoxical sphincter contraction on defecation (PSCD), or anismus [¹¹⁸, ¹⁶⁰, ¹⁶⁷, ¹⁷¹, ¹⁸², ¹⁸³]. During fictive defecation (straining), a lack of anal inhibition has also been reported in 65% of PD patients. Although PSCD can also be seen in patients with idiopathic constipation [¹⁸⁴], the frequent occurrence of PSCD in PD suggests that PSCD is a disease-related condition. The frequency of PSCD is almost the same in early and late PD [¹⁸⁵], indicating that PSCD is an early defecatory abnormality. Mathers and colleagues [¹⁸²] consider PSCD a focal dystonia. PSCD also occurs in spinal cord-injured patients [¹³⁶], suggesting that dysfunction in the suprasacral descending pathway to the external sphincter is a contributing factor. Apomorphine is shown to lessen PSCD [¹⁸², ¹⁸³]. This effect was not antagonized by domperidone, which did not penetrate the BBB, suggesting that the CNS pathology may produce PSCD. Both weak abdominal strain and PSCD seem to be the major causes of difficulty in stool expulsion in PD patients.

Although it is not certain whether exercise may facilitate bowel habit in PD, in the healthy population, moderate exercise is reported to shorten mouth-to-anus transit time [¹⁸⁶] and improve overall wellbeing [¹⁵²]. Water content is an important determinant to make stools normal (70% water) or hard (40–60% water) [¹⁸⁴]. PD patients are reported to have reduced water intake [¹⁸⁷]. Diet and laxatives are the first-line treatment for constipation [¹⁸⁸]. Dietary fibers such as psyllium produced an improvement in stool consistency and an increase in stool frequency in healthy population [¹⁸⁹] and PD [¹⁶⁹, ¹⁹⁰]. Polyethylene glycol 3350 [¹⁹¹], or bulking and highly hydrophilic agent polycarbophil [¹⁹²], improve constipation in PD.

A prior report has shown that pyridostigmine bromide, an acetylcholinesterase inhibitor, is effective in the amelioration of constipation in PD [¹⁹³].

Dopaminergic blockers (domperidone, etc.) are widely used as GI prokinetics by means of antagonizing dopamine's inhibitory effects on the GI motility, particularly D2 receptor blockade [¹⁹⁹]. The pharmacological profiles of the compounds differ in terms of their molecular structure, affinity at D2 receptors, and ability to interact with other receptor systems (5-HT3 and 5-HT4 receptors for metoclopramide; 5-HT4 receptors for levosulpiride). Since domperidone does not cross the BBB, it can be used as GI prokinetics for constipation in PD [²⁰⁰], although the effect of domperidone on constipation is minimal. In contrast, dopaminergic blockers that could penetrate the BBB (metoclopramide, levosulpiride, etc.) may potentially worsen extrapyramidal motor disorder in PD [¹⁹⁹]. Since levodopa is absorbed from the small intestine [²⁰¹], bowel dysfunction in PD may interfere with levodopa absorption, worsen the motor disorder, or even lead to malignant syndrome [²⁰², ²⁰³]. Gastric emptying of an isotope-labeled solid meal becomes significantly faster during domperidone therapy in PD [²⁰⁰]. In addition, domperidone pretreatment causes a mean 12% increase in peak plasma levodopa concentrations that occurs a mean of 10 min earlier than when levodopa is given alone [²⁰²]. Peak plasma levodopa concentrations are reported to be greater on levodopa-domperidone than on levodopa-carbidopa [²⁰⁴].

Cisapride, a selective 5-HT 4 receptor agonist, has significantly shortened CTT in PD [²⁰⁵], although after 1 year, only a small effect could be demonstrated [²⁰⁶]. Of particular importance is that cisapride add-on therapy improved the “on-off” phenomenon in advanced PD [²⁰³]. However, some reports indicated cisapride's D2 dopaminergic receptor blocking property [²⁰⁷]. Cisapride also blocks K⁺ channels and leads to cardiotoxicity. Mosapride is a novel selective 5-HT 4 receptor agonist that lacks a D2 receptor or K⁺ channel blocking property [²⁰⁸]. Mosapride is shown to ameliorate delayed gastric emptying [²⁰⁹] as well as constipation in PD [²¹⁰], by shortening of total CTT (particularly the caudal segment), and by augmenting the amplitude in rectal contraction during defecation [²¹⁰]. Improvement of parkinsonism is more significant with pergolide-mosapride than with pergolide-domperidone [²¹¹]. Tegaserod, a selective 5-HT 4 agonist, is also effective in ameliorating constipation in PD [²¹²].

Although prior reports have indicated the effectiveness of motilides (erythromycin, etc.) [²¹³], neurotrophin-3 [²¹⁴] and colchicine [²¹⁵] on constipation in PD, their use remains limited. Type A botulinum toxin injection into the puborectalis muscle [²¹⁶, ²¹⁷] and biofeedback [²¹⁸] ameliorates anismus in PD.

The reported prevalence of sexual symptoms in men with PD ranges from 37% to 65% [²³⁴–²³⁹]. Only few previous studies have looked at sexual symptoms in PD and control subjects. Jacobs et al. [²⁴⁴] studied 121 men with PD (mean age 45 years) and 126 age- and sex-matched community male controls. Patients were more dissatisfied with their present sexual functioning and relationship whereas no differences were found for the frequency of sexual intercourse itself. Erection and ejaculation were not inquired. Sakakibara et al. [⁵] analyzed sexual function of 46 men with PD (age 35–70 years old) and 258 healthy male control subjects (age 30–70 years old) [⁵]. As compared with the control group, the frequency of dysfunction in PD patients was significantly higher for decrease of libido (84%), decrease of sexual intercourse (55%), decrease of orgasm (87%), and decrease of erection (79%) and ejaculation (79%). Therefore, sexual dysfunction is significant in PD. The majority of patients had onset of the sexual dysfunction after the appearance of the motor disorder. This is in contrast to patients with MSA, who often have sexual dysfunction before the onset of motor disorder.

Comparing the results between four age subgroups (subjects in their 30s, 40s, 50s, and 60s) in the control group, the frequencies of sexual intercourse and of orgasm were significantly lower in older individuals [⁵]. In the PD group, only the frequency of orgasm was lower in older men (P < 0.05). Comparing the results between both sexes in the control group, decrease of libido and orgasm were more common in women (P < 0.01). In the PD group, there was no significant difference in sexual function items. Bronner et al. [²⁴⁵] reported that use of medications (selective serotonin reuptake inhibitors used for comorbid depression), and advanced PD stage contributed to the development of ED.

In healthy men, sexual intercourse is thought to be carried out by integrating affective, motor, sensory, autonomic, and other factors. In male patients with PD, depression, motor disorder, and pain inevitably lead to sexual dysfunction. In contrast, it has been difficult to determine to what extent autonomic factors contribute to the sexual dysfunction in PD. However, erectile dysfunction often precedes motor disorder in MSA, and abnormal NPT is not uncommon in PD. These findings strongly suggest that the disorder does in fact contribute to sexual dysfunction in PD. Rigiscan is an objective measure for erectile dysfunction, which allows both tumescence and rigidity measurement, and is suitable for assessing NPT.

Only few data have been available concerning the relationship between NPT and dopamine. However, in experimental animals, administration of levodopa elicited erection and yawning together. Animals with experimental parkinsonism showed fewer REM stages during sleep than control animals did.

As compared with men, few studies are available concerning female sexual dysfunction in PD. Further, only few previous studies have looked at female sexual symptoms in PD and control subjects. Sakakibara et al. [⁵] analyzed sexual function of 38 women with PD (age 35–70 years old) and 98 healthy control women (age 30–70 years old) [⁵]. As compared with the control group, the frequency of dysfunction in women with PD was significantly higher for decrease of libido (83%) and decrease of sexual intercourse (88%) while decrease of orgasm was not different between women with PD and control. The majority of patients had onset of the sexual dysfunction after the appearance of the motor disorder. Welsh et al. [²⁴⁶] studied 27 women with PD (mean age 67 years) and community healthy controls, and in both group 50% were sexually active. As compared with control, women with PD had more common decrease of libido, vaginal tightness, involuntary urination, and dissatisfaction in sexual intercourse. There was no difference in terms of sexual arousal, sexual intercourse, and orgasm. Without control, in young PD patients (36–56 years) women had more common sexual problems (decrease of libido, 70%, decrease of sexual intercourse, 80%) than men (40%, 33.4%, resp.) [²⁴⁷, ²⁴⁸]. Other domains, such as loss of lubrication and pain, are not clearly known.

There is no established regimen to treat sexual dysfunction in women with PD. PDE5 inhibitors, such as sildenafil, tadalafil, and vardenafil, has become the first choice in the treatment of erectile dysfunction in men. Whereas sildenafil facilitated clitorial engorgement in women with sexual dysfunction [²⁶⁰], clinical efficacy of this drug in women with PD awaits further clarification [²⁶¹]. Bremelanotide, a melanocortin receptor agonist, is applied to female sexual dysfunction, and is reported to be effective [²⁶²].