Etiology and Treatment of Urogenital Dysfunction in Individuals with Parkinson Disease

Urogenital dysfunction is a common nonmotor symptom associated with Parkinson disease (PD). Urogenital symptoms can impair quality of life (QoL)¹ and should be addressed with care. This article highlights common urogenital symptoms associated with PD and treatments for these symptoms, as well as a brief review of the pathophysiology and etiology of urogenital dysfunction.

Urinary Dysfunction in PD
The lower urinary tract (LUT) consists of the bladder and urethra. The pathogenesis of LUT dysfunction in PD involves complex pathways. Autonomic dysfunction is one of the most common nonmotor symptoms observed in individuals with PD and is the basis for the development of LUT dysfunction.² Several regions of the brain have been studied in relation to LUT symptoms in PD. The frontal cortex, basal ganglia, thalamus, and anterior cingulate gyrus are territories involved in the development of bladder dysfunction.³ Bladder dysfunction (in particular, urinary urgency and frequency) is caused by disruption of the basal ganglia afferents to the pontine micturition center (PMC). The PMC receives afferent input from the lumbosacral spinal cord based on bladder distension and from the prefrontal cortex, which regulates behaviors by helping individuals determine if it is socially acceptable to void.⁴ The PMC projects excitatory signals to the spinal parasympathetic preganglionic neurons innervating the bladder and inhibitory interneurons regulating the Onuf nucleus, which supplies control of the external urethral sphincter.⁵ After receiving appropriate afferent stimulus, the PMC removes inhibition of the Onuf nucleus, which permits voiding. In PD, the reduction of dopamine in the substantia nigra, which normally inhibits the micturition reflex, causes disruptions in voluntary control and uninhibited bladder contractions.⁵

The prevalence of reported LUT dysfunction in people with PD ranges from 27% to 71%, which is significantly higher than in healthy age-matched individuals.^6,7 Most people with PD have onset of LUT dysfunction after the onset of their motor symptoms.⁶ Urinary dysfunction, including urinary urgency and frequency, is believed to be caused by changes in the dopamine–basal ganglia pathway, which normally suppresses the micturition reflex. Bladder dysfunction in PD has been shown to be correlated with neurologic disability,⁸ as well as the stage of disease,¹ suggesting a relationship between dopaminergic degeneration and LUT dysfunction. The latter point is controversial, however, as some authors have reported that dysfunctional urinary symptoms correlate only with age and not severity or duration of PD.⁹

Bladder storage symptoms are the most common LUT dysfunctions reported in people with PD, with nocturia being the most prevalent (>60%),^1,8,10 followed by urinary urgency (33%–54%), daytime frequency (16%–36%), and urinary incontinence (26%–28%).^1,11 Although not as prevalent as storage symptoms, problems with voiding also occur in PD. These include difficulty initiating urination, a prolonged or weak stream, and straining.¹

Treatment of Urinary Dysfunction in PD
When addressing urinary symptoms, clinicians should first exclude other common causes, such as urinary tract infection. If there is suspicion of a urinary tract infection, a urine culture and sensitivity test should be performed. 

After an infectious etiology has been excluded, conservative management with lifestyle modification strategies may be beneficial for managing urinary dysfunction. People with PD who have urinary dysfunction can be educated to use a bedside commode, urinal, or external (condom or wick) catheter. These tools may be preferable to attempting to walk to the bathroom, which may be difficult given motor impairments that may pose a threat for falls. Avoiding certain foods and drinks that exacerbate overactive bladder symptoms (eg, caffeine, alcohol, carbonated drinks, acidic foods, spicy foods), decreasing overall consumption before bedtime, and targeting fluid intake to times when there is easy access to a restroom are effective measures for managing urinary dysfunction. Other conservative methods include bladder training, pelvic floor physical therapy, and biofeedback training.⁵ People with urge incontinence can receive biofeedback training for detecting when they have an involuntary detrusor contraction and contracting their sphincter musculature to prevent episodes of incontinence. 

Anticholinergic medications (eg, oxybutynin, tolterodine, trospium), which diminish parasympathetic effect on the bladder, are generally considered first line treatments for overactive bladder and urge incontinence. The adverse effect profiles of anticholinergic medications, which may include dry mouth, constipation, and cognitive difficulties, must be considered. Given that many individuals with PD experience these challenges, the risk-to-benefit ratio of treatment should be considered carefully. The Table lists some pharmacologic options for different genitourinary symptoms.

Postvoid residual (PVR) volumes should be obtained throughout treatment.¹² If PVR is >100 mL, clean intermittent catheterization (CIC) is needed. CIC has shown benefit, especially when used in conjunction with an anticholinergic medication. People who performed CIC while taking oxybutynin reported better socially acceptable continence, improved QoL, and enhanced sexuality.¹³

Levodopa and other dopaminergic medications have shown mixed results in studies investigating their benefit in improving LUT dysfunction in individuals with PD. Levodopa, dopaminergic agonists, catechol-O-methyltransferase inhibitors, and selegiline were associated with increased bladder capacity in a cohort of participants with a Danish Prostatic Symptom Score >10, indicating moderate to severe LUT symptoms (difference +47.1 mL [95% CI, 0.88 to 93.25]; P=.04).¹⁴ Apomorphine infusion has been shown to improve bladder function in some people with PD.¹⁵ More studies are needed to evaluate the extent of nonmotor improvement with dopaminergic therapy.

Nocturnal polyuria, which is defined as “nighttime urine product consisting of greater than one-third of total daily urine output,” can also be observed in people with PD.⁶ Desmopressin, a vasopressin V2 receptor agonist, has been shown to be effective in reducing PD-related nocturia.¹⁶ Individuals receiving treatment with desmopressin should be closely monitored for hyponatremia and fluid retention.

If initial treatments fail or if PVR volumes are consistently high, a urologic consultation is recommended. Urodynamic studies, including cystometry, may be helpful in revealing an underlying urologic diagnosis. 

Intravesical botulinum toxin improves detrusor sphincter dyssynergia and has been used to treat involuntary detrusor contractions.⁵ Botulinum toxin A, the most studied serotype, resulted in chemical denervation of the detrusor muscle for up to 9 months.² Use of botulinum toxin has been shown to decrease urinary frequency, improve QoL scores in individuals with detrusor overactivity related to PD,¹⁷ and improve urinary urgency.¹³

Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been shown to increase bladder capacity, facilitate bladder afferent pathways,¹⁸ and inhibit micturition reflex in people with PD.¹⁹ In a questionnaire study evaluating subjective improvement among people with PD receiving different therapies (oral medications, STN-DBS, or apomorphine infusion) for LUT dysfunction, the DBS cohort reported significantly less nocturia (P=.007) compared with the 2 other groups.²⁰

With regard to voiding symptoms due to detrusor hypoactivity, benign prostatic hyperplasia may play a role in men. α1 adrenergic receptor antagonists may be tried to decrease tone in the bladder neck.²¹ These agents, such as tamsulosin and doxazosin, should be used with caution as they may worsen orthostatic hypotension. In women, voiding symptoms may be related to genital prolapse or urethral diverticulum.⁵

Sexual Dysfunction in PD
The pathogenesis of sexual dysfunction in PD is unknown but postulated to be related to hypothalamic dysfunction from changes in dopamine-oxytocin pathways, which normally promote libido and erection.²¹ The reported prevalence of sexual dysfunction in people with PD varies from 37% to 65%.⁶ Compared with healthy controls, people with PD have reported decreased libido, decreased frequency of sexual intercourse, decreased orgasm, decreased erection, and decreased ejaculation.¹

Treatment of Sexual Dysfunction in PD
Management of sexual dysfuntion in individuals with PD should begin with a review of current medications to look for causative agents, such as β-adrenergic blockers, α1 antagonists, thiazide diuretics, anxiolytics, and some antidepressants. 

Phosphodiesterase-5 inhibitors, such as sildenafil and vardenafil, are the first-line agents used to treat erectile dysfunction (ED) in people with PD. They prevent degradation of cyclic guanosine monophosphate, leading to relaxation of the vascular smooth muscle, vasodilation, and increased penile blood flow.²² Sildenafil has been shown to improve ED in individuals with PD.²² However, this class of medications should be used with caution in people with PD with orthostatic hypotension.

Levodopa and other antiparkinsonian medications may affect sexual function in individuals with PD, although it remains unclear to what extent levodopa helps with sexual dysfunction in people with PD.⁶ Apomorphine in a sublingual form has been shown to improve ED in the general population,²³ and treatment with subcutaneous apomorphine has been shown to induce penile erections.²⁴ STN-DBS has been reported to improve sexual functioning and satisfaction in men with PD.²⁵

Conclusion
Urogenital dysfunction, a common nonmotor symptom observed in people with PD, negatively affects QoL, and clinicians must monitor for urogenital dysfunction by asking appropriate questions in the clinic and providing prompt treatment. Bladder storage symptoms, such as urinary frequency and urgency, are more common than voiding problems, such as difficulty initiating urination and poor stream. Anticholinergic medications may help with storage symptoms; α1 antagonists may be tried for voiding dysfunction. Nonpharmacologic interventions may also be beneficial. Sexual dysfunction may occur in individuals with PD, including decreased libido as well as impaired orgasm, erection, and ejaculation. Phosphodiesterase-5 inhibitors are first line treatments for ED. Other treatments, such as levodopa, apomorphine, and STN-DBS, have shown promise in addressing both urinary and sexual dysfunction.