Narrative Review

Pathogenesis, Diagnosis, and Treatment of Sleep-Related Painful Erection

Yutao Wang; Jianzhong Zhang; Hongjun Li

Disclosures

Transl Androl Urol. 2021;10(12):4422-4430. 

In This Article

Underlying Pathological Mechanism of Sleep Related Painful Erection

Twenty-one sleep related painful erection reference were taken into this section (Table S1). To better understand abnormal penile erection, it is necessary to first consider normal physiologic erection. Penile physiologic erection is caused by relaxation of the smooth muscles of the penile artery and cavernous body activated by the parasympathetic nerve pathway and accompanied by inhibition of the spinal reflex caused by sympathetic nerve excitement.[3,4] Penile erection results from interactions of the central nervous system and local factors and is regulated by psychological and hormonal factors.[5] Nitric oxide (a neurotransmitter and molecular signal sensor) and other mediators released by nerves or endothelium play essential roles.[4,6]

Penile erection can be classified as reflex erection caused by mechanical stimulation,[6] psychogenic erection caused by psychological stimulation,[7] nocturnal spontaneously erection, and persistent abnormal erection. NPT is an everyday physiological occurrence which is not caused by sexual stimulation and can physiologically spontaneously occur during REM sleep.[8] Men achieve erections three to five times during eight hours of sleep, and each erection may last for at least 30 minutes, regardless of age.[9] The detail classification of penile erection is shown in Figure 1.

Figure 1.

Classification of penile erections.

We summarized the pathogenesis of SRPEs and proposed the pathogenesis concept of "O-PAINT" where "O" represents Obstructive Sleep Apnea (OSA) Syndrome, "P" represents Psychological and spiritual factors, "A" is for Androgen Elevation, "I" is for Compartment Syndrome caused by ischemia, "N" is for Neuroendocrine regulation, and "T" is for Threshold of pain in the REM phase.

OSA Syndrome

Researchers[10–13] have found patients with OSA have different levels of SRPE, which has become the core concept of SRPE widely accepted by scholars. OSA is characterized by frequent episodes of partial or complete collapse of the upper airway during sleep, followed by hypoxia and activation of sympathetic nerves. The apnea event is terminated by awakening, followed by an increase in pulse and blood pressure.[14] Hypoxia causes an increase in blood flow to tissues and organs, especially to the cavernous body of the penis, which becomes the physiological mechanism for erections. Continuous positive airway pressure may treat apnea and reduce symptoms, and the mechanism may be mediated by intermittent changes of the autonomic system and blood-gas exchange related to OSAS, interfering with the autonomic nervous system and eventually causing SRPE.[10]

Abnormal Androgen Elevation

Testosterone plays a crucial role in developing and maintaining male sexual characteristics and is an essential participant in nocturnal physiological erections. Changes in testosterone at night are related to sleep, with the level of testosterone during sleep being higher than during wakefulness.[15] Testosterone regulates the release of nitric oxide from the nitrergic nerve fibers in the cavernous nerve and other non-nitrergic processes in the cavernous body and central nervous system.[16] In contrast, the erectile response to sexual stimulation while awake is independent of the testosterone system.[17] Buvat et al. showed that androgens regulate the expression levels of nitric oxide synthase and phosphodiesterase 5 (PDE-5) by regulating the NO-cGMP erection signal pathway.[18] Therefore, high nocturnal serum testosterone levels are needed for penile erection and may mediate or encourage SRPE via positive regulation of NO.

Nerve and Neuroendocrine Disorder

In REM sleep, 5-hydroxytryptamine (5-HT) levels are low at the central nerve-neural junction. Selective serotonin reuptake inhibitors (SSRIs) are used to inhibit the REM stage in SRPE patients and improve their symptoms. In addition, SSRIs increase the content of 5-HT in peripheral hematomas. 5-HT inhibits NO synthase, reduces NO synthesis, reduces the content of second messenger cGMP, and reduces the activation level of the G protein pathway, resulting in contraction of vascular smooth muscle (Figure 2A).[19,20] 5-HT also directly acts on the 5-HT2A receptors of vascular smooth muscle cells to contract vascular smooth muscle (Figure 2B). Therefore, 5-HT neurotransmitter disorders play an important role in the pathogenesis of SRPE.[21]

Figure 2.

Center and periphery regulation mechanism of 5-HT in sleep related painful erection. SSRIs, Selective serotonin reuptake inhibitors; 5-HT, 5-hydroxytryptamine.

Szücs et al. found the posterior cerebral artery of an SRPE patient was compressed on the lateral basilar border of the hypothalamus corresponding to the anatomical position of the preoptic area of the hypothalamus through a cranial MRI examination.[22] Central neurotransmitters and neuropeptides act on multiple brain regions to promote the secretion of neurotransmitters to cause or inhibit penile erection.[23] One study found that REM-initiating neurons (cholinergic and gamma-aminobutyric neurons) were significantly active during REM, while REM-off neurons (adrenergic and serotonin neurons) which were active during REM, remained silent. Recent studies found that SRPE patients with an abnormal REM stage often complain of gastrointestinal symptoms and nerve-ending abnormalities (small fiber neuropathy). For these reasons, it can be speculated that during REM sleep in patients with SRPE, cholinergic neurons produce more acetylcholine and cause a penile erection. Therefore, neuroendocrine regulation disorder is also a pathogenesis of SRPE.

Psychological and Spiritual Abnormalities

A study found that the function and anatomy of the penis have no apparent effect on SRPE, and in the reported cases, neurological and neurophysiological examinations were found to be normal.[12] Some researchers speculate that SRPE is psychogenic in nature, as repeated awakening and insomnia are related to lack of sleep and anxiety.[24] Others speculate that almost all extragonadal endocrine diseases may affect sexual function. Endocrine diseases may be caused by mental and physical involvement, and hormones directly or indirectly regulate the process of erection.[25] Meanwhile, mental disorders such as nighttime awakening, anxiety, and irritability often coexist with SRPE, with a high incidence. Psychological is a symptom or manifestation of SRPE, and may also be a trigger or aggravating factor, resulting in a vicious cycle. Therefore, since mental health has significant adverse effects on SRPE patients, special attention must be paid to patients' mental and psychological changes in SRPE diagnosis and treatment, so the improvement of psychological and spiritual status should also become a target of our treatment.[13]

Reduced Pain Threshold in the REM Phase

During sleep in healthy adults, non-rapid eye movement (NREM) and REM sleep switch at 90–110-minute intervals. In the first third of the night, light sleep alternates with slow-wave sleep but as sleep progresses, slow-wave sleep decreases, and REM sleep increases. In the final third of the night, light sleep almost entirely alternates with REM sleep.[26] During autonomic nerve function and penile erection, rhythmic changes can be observed in the over-frequency range of 1 to 2 hours.[27] During REM sleep and wakefulness, there are many neuronal networks in the ventricular septum, and these neurons coordinate with erection-related activities.[28] The relationship between pain and sleep is mutual, as pain may interrupt or disrupt sleep, while poor sleep quality increases pain perception, and the reduction in sleep time and the specific loss of REM sleep can produce hyperalgesia the following morning. Medications and conditions that reduce sleep and REM sleep time may also increase pain.[29] Dai et al. observed that postoperative pain after male circumcision is very common, especially in the SRE stage,[30] and interrupted REM sleep relieved SRE-related incision pain. A study of migraines during sleep found that the decrease in pain threshold was related to increased sleep pressure, and lack of adequate rest may be a factor inducing hyperalgesia.[31]

Compartment Syndrome Caused by Ischemia

When the urinary bladder is overfilled at night, the erectile center is stimulated, causing a continuous erection. The inflammation caused by overfilling of the bladder hinders deep venous return, causing continuous erection and pain. Prostatitis, urethritis, and thrombophlebitis can also cause such consequences, and the obstruction of deep venous return leads to penile compartment syndrome, characterized by constant high pressure in a fixed space which impedes microvascular circulation. The pathophysiological feature of penile compartment syndrome is continuous cavernous smooth muscle relaxation and contraction failure accompanied by increased hypoxia in the cavernous body, increased pCO2, and acidosis.[32] Symptoms include evident stiffness of the cavernous body, disordered venous blood outflow, and persistent painful erection, which may cause the trabeculae of the cavernous body of the penis to be exposed to ischemic blood when persistent.

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