71 - 76: Sexual Problems in Parkinson’s Disease

Parkinson’s disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in the substantia nigra. In addition to the movement disorder, patients with PD often show non-motor disorders. The non-motor problems of PD include neuropsychiatric disorders, sleep disorders, sensory symptoms, and autonomic disorders. Sexual dysfunction is one of the most common autonomic disorders [1]. Studies have shown that sexual dysfunction has great significance in relation to quality of life measures [2]. It is particularly important to note that, unlike motor disorder, sexual dysfunction is often not responsive to levodopa, suggesting that it occurs through a complex pathological mechanism; for this reason, add-on therapy is required to maximize patients’ quality of life. This chapter reviews sexual dysfunction in PD, with particular reference to neural control of the genital organs, symptoms, objective assessment, and treatment.

Sexual dysfunction is not uncommon in PD [2, 3]. Studies have shown that sexual dysfunction has great significance in relation to quality of life measures. However, the detailed mechanism of sexual dysfunction in PD has not been well explored.

The genital organs primarily share lumbosacral innervation with the lower urinary tract. Erection is a vascular event [4] occurring secondarily after dilatation of the cavernous helical artery and compression of the cavernous vein to the tunica albuginea [4]. Helical artery dilatation is brought about by activation of cholinergic and nitrergic nerves; this activation facilitates nitric oxide secretion from the vascular endothelium. Ejaculation is brought about by contraction of the vas deferens and the bladder neck, in order to prevent retrograde ejaculation, by activation of adrenergic nerves. Sexual intercourse in healthy men can be divided into 3 phases: (a) desire (libido), (b) excitement and erection, and (c) orgasm, seminal emission from the vas deferens, and ejaculation from the penis. Erection can be further classified into 3 types by the relevant stimulation: (1) psychogenic erection (by audiovisual stimulation), (2) reflexive erection (by somatosensory stimulation), and (3) nocturnal penile tumescence (NPT; associated with rapid eye movement sleep). ‘Morning erection’ is considered the last NPT in the night-time.

Among the 3 types of erection, reflexive erection requires an intact sacral cord, particularly the intermediolateral (IML) cell columns. Pathology studies have shown that involvement of the IML nucleus is common in MSA, whereas it is uncommon in PD. Therefore, reflexive erection can be affected in patients with MSA. In patients with a suprasacral spinal cord lesion, reflexive erection might be preserved, whereas psychogenic erection is severely disturbed because of a lesion in the spinal pathways to the sacral cord. Libido and erection are thought to be regulated by the hypothalamus; particularly the medial preoptic area (MPOA) and the paraventricular nucleus (PVN; fig. 1) [5]. Electrical or chemical stimulation in the MPOA/PVN evoked erection and mating behaviors in experimental animals; both were abolished by destruction of these areas. Somatosensory input from the genitalia ascends in the anterior spinal cord and project to the MPOA/PVN via the thalamic nuclei. Erotic visual input from the retina is thought to reach the MPOA via the mammillary body. Recent neuroimaging studies have shown that penile stimulation or watching pornography activate these areas in humans [6]. NPT [7] seems to be regulated by the hypothalamic lateral preoptic area [8]. The raphe nucleus and the locus ceruleus are candidate areas participating in the regulation of NPT. Oxytocinergic neurons in the hypothalamic PVN are thought to facilitate erection by projecting directly to the sacral cord, and by projecting to the midbrain periaqueductal gray and Barrington’s nucleus (identical to the PMC). Serum oxytocin concentration increases during masturbation in healthy men.

In experimental animals, dopamine is known to facilitate erection and mating behaviors. The MPOA/PVN receives projections from the nigral dopaminergic neurons [4, 5]. A microdialysis study showed that the dopamine concentration in the MPOA was increased by sexual stimulation. It is reported that dopamine D1/ D2 receptors in the hypothalamus participate in erection, whereas only D2 receptors participate in ejaculation. Pathology studies have shown that the hypothalamus is affected in PD [9]. Recently, a polymorphism in the dopamine D4 receptor gene has been shown to contribute to individual differences in human sexual behavior [10]. Prolactinergic neurons are thought to be inhibitory to sexual function. Serum prolactin levels increase after orgasm in healthy men. Prolactin-producing pituitary tumors often cause gynecomastia and erectile dysfunction in male patients. Hyperprolactinemia occurs after the use of sulpiride, metoclopramide, and chlorpromazine (all dopamine receptor antagonists). Therefore, dopaminergic neurons seem to facilitate oxytocinergic neurons, whereas they inhibit prolactinergic neurons. Some de novo PD patients have hyperprolactinemia [11], which may contribute to erectile dysfunction in those patients.

The reported prevalence of sexual symptoms in patients with PD ranges from 37 to 65% [12-14]. Only few previous studies have looked at sexual symptoms in PD and control subjects. Jacobs et al. [12] studied 121 men with PD (mean age 45 years) and 126 age-and sex-matched community derived 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 explored. Sakakibara et al. [2] analyzed sexual function of 84 PD patients (46 men, 38 women, age 35-70 years old) and 356 healthy control subjects (258 men, 98 women, age 30-70 years old) [2]. As compared with the control group, the frequency of dysfunction in PD patients was significantly higher for decrease in libido (84% men, 83% women), decrease in sexual intercourse (55% men, 88% women), decrease in orgasm (87% men), and decrease in erection (79%) and ejaculation (79%) in men. 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 [2]. 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 in libido and orgasm was more common in women (p < 0.01). In the PD group, there was no significant difference in sexual function items. Bronner et al. [14] 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 multiple system atrophy, 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® (Timm Medical Technologies, Eden Prairie, Minn., USA) is an objective measure for erectile dysfunction, which allows both tumescence and rigidity measurement; and it 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 rapid eye movement stages during sleep than did control animals.

It is possible that levodopa and other antiparkinson medication may affect sexual function in PD. However, it is not entirely clear to what extent levodopa ameliorates sexual dysfunction in PD. In contrast, subcutaneous apomorphine injection is used to ameliorate fluctuating symptoms in PD. It has also been used to treat erectile dysfunction in the general population [15] and in patients with PD [16], although the dose is different (general population, initial 2 mg and up to 3 mg [15]; PD, 4 mg [17]). Apomorphine is thought to stimulate dopamine D2 receptors, and activate oxytocinergic neurons in the PVN. Nausea is a common side effect of this drug. Cabergoline [18] and pergolide [19] are also reported to improve sexual dysfunction in PD. In contrast, pathological hypersexuality may occur together with [20] or without delirium [21], which is attributed to the dopamine dysregulation syndrome (impulse control disorder) in this disorder. DBS in the STN has produced either improved sexual well-being [22] or transient mania with hypersexuality [23] in patients with PD.

When dopaminergic drugs do not help, phosphodiesterase-5 inhibitors, e.g. sildenafil, valdenafil, etc., become the first-line treatment in PD [24, 25]. These drugs inhibit nitric oxide degradation and facilitate smooth muscle relaxation in the cavernous tissue. When treating PD patients with postural hypotension, these drugs should be prescribed with extreme caution [24, 25].

This article reviewed the current concepts of sexual dysfunction in PD. Central nervous system pathology is clearly associated with sexual dysfunction (decrease in libido and erection) in PD. Phosphodiesterase inhibitors are used to treat erection dysfunction. These treatments are beneficial in maximizing patients’ quality of life.