Sleep-related erections: Clinical perspectives and neural mechanisms

Sleep Medicine Reviews (2005) 9, 311–329

www.elsevier.com/locate/smrv

CLINICAL REVIEW

Sleep-related erections: Clinical perspectives and neural mechanisms Max Hirshkowitza,b,*, Markus H. Schmidtc a

Department of Psychiatry, Baylor College of Medicine, Houston Veterans Affairs Medical Center Sleep Center, Houston, TX, USA b Department of Medicine, Baylor College of Medicine, Houston Veterans Affairs Medical Center Sleep Center, Houston, TX, USA c Ohio Sleep Medicine and Neuroscience Institute, 4975 Bradenton Ave., Dublin, OH 43017, USA

KEYWORDS Sleep-related erections; Nocturnal penile tumescence; Erectile dysfunction; Mechanisms of erection

Summary Involuntary sleep-related erections (SREs) occur naturally during REM sleep in sexually potent men and other mammals. The regularity of their pattern and non-volitional nature made SREs useful clinically for differentiating psychogenic and organic erectile dysfunction (ED) in candidates for surgical intervention. Normative data available for different age groups added to the attractiveness of SRE measurement for clinical decision-making. Clinical SRE testing is less commonly applied today with the advent of minimally invasive medical therapies for ED. Nonetheless, as an objective measure of erectile function, SRE recording for research provides a precise technique for examining the mechanisms of erection and is still conducted to resolve legal disputes. SRE alterations provoked hormonally and pharmacologically are discussed. Different SRE patterns are associated with comorbid factors and some of these are illustrated, described, or both. Recording techniques developed for rats have proved extremely valuable for furthering our understanding of brain centers mediating erectile response. Data from lesion and stimulation studies are examined in the present review, moving us a step closer to understanding the underpinnings of erectile function. Published by Elsevier Ltd.

Background Sleep-related erections (SREs) are naturally occurring, involuntary episodes of penile erections that occur cyclically during sleep in all sexually potent

* Corresponding author. Present address: VAMC Sleep Center 111i, 2002 Holcombe Blvd, Houston, TX 77030, USA. Tel.: C1 713 794 7562; fax: C1 713 794 7558. E-mail address: [email protected] (M. Hirshkowitz).

1087-0792/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.smrv.2005.03.001

men in close temporal relationship with rapid eye movement (REM) sleep. In a healthy young adult male, the erection begins near the onset of REM sleep, increases quickly to full tumescence, persists throughout the REM sleep episode, and then ends in rapid detumescence with the termination of REM sleep. SREs are also widely known as nocturnal penile tumescence (NPT), a term coined by Ismet Karacan who pioneered research in this area. Karacan’s original work was part of his dissertation at Downstate Medical Center in Brooklyn, NY in the mid 1960s. Notwithstanding the ongoing sexual revolution of the time, his advisors suggested that

312 the phrase ‘penile erections in sleep’ was too explicit. Thus, the phenomenon was enshrouded in less obvious terms. However, ‘NPT’ became a widely accepted acronym and is still used in many circles. The term sleep-related erection (SRE) was adopted by the International Classification of Sleep Disorders1 in the interest of linguistic accuracy. SRE testing has long been part of sleep disorders medicine and is the polysomnographic technique used to diagnose the ICSD parasomnia ‘impaired sleep-related penile erections’. Thus, impaired SREs are considered a parasomnia, even though they do not disrupt sleep, produce daytime sleepiness, or represent an ‘undesirable physical phenomena that occur predominantly during sleep’.1 In fact, impaired SREs are the lack of a desirable phenomenon. Unfortunately, the newest addition of the ICSD (yet to be released) has entirely removed SRE from the classification system. Why then are SREs commonly included in core sleep medicine? First, the close concordance between SREs and REM sleep was discovered at a time when sleep research was largely fueled by interest in REM-related phenomena. Second, SRE testing to differentially diagnosis impotence provided an opportunity for sleep studies to serve as an applied medical technology. Finally, studying the REM–SRE relationship has enhanced our understanding of both the sleep process and the mechanism of erection. Long before SREs were described in the scientific literature, it was common knowledge that men could have erections, and even nocturnal emissions, during sleep. Many, including the religious community, viewed these nocturnal erections and emissions, to represent ‘unhealthy’ thoughts or dreams. Consequently, devices were designed to prevent such erections, including ‘spermatorhea rings’. Old catalogs depict devices ranging from frightening looking, teeth-encased, penis rings to circumferential, expansion-triggered, electrical switches that triggered bells or buzzers. Given what we now know about the frequency and magnitude of SREs one can only imagine what pain and suffering users must have endured. One dramatic anecdotal account concerned a man with a recurrent nightmare in which a bear attacked him and clawed off his genitals (Dement, personal communication). The nightmares were distressing and reportedly the origin was not known. However, it was later discovered through abreactive therapy that the individual, as a child, had been fitted with a teeth-encased style ring that ultimately required removal by an emergency response team. To our knowledge, SREs first appeared in the medical literature in 1944.2 These authors

M. Hirshkowitz, M.H. Schmidt demonstrated sleep erectile activity occurring cyclically approximately every 80 min and lasting 20 min each in duration. The pattern was virtually identical to that described for REM sleep almost a decade later.3 Aserinsky was aware of this SRE literature and speculated in his dissertation that the erection cycle might be related to REM sleep. Finally, more than a decade later, the REM–SRE relationship (80–90% coincidence rate in young adults) was firmly established4,5 dispelling the incorrect notion that nocturnal erections were somehow produced by the need to urinate. The REM–SRE coupling seemed an opportunity to validate Freud’s postulated underlying psychosexual nature of dreaming. Fisher6 published a case series in which sudden SRE increases correlated with overtly erotic dream content. By contrast, Karacan4 did not find sexual dream content to be associated with SREs. Considering that men nightly have multiple erections during REM sleep and that dreams seldom contain erotic content, SREs cannot be explained as resulting from dream content. Nonetheless, SREs rapidly became established as an important physiological correlate of REM sleep. Because studies describing REM sleep correlates were in vogue, SRE monitoring was in the mainstream of sleep medicine. SRE work came to a crossroad in 1970 when Karacan and colleagues7 suggested SRE testing could be used to differentiate impotence as either psychogenic or organic in origin. Little was known at that time about erectile dysfunction. Following conceptualizations of Masters and Johnson,8 it was widely believed that most male impotence was psychogenic, even in older age groups. Furthermore, diagnosis relied mainly on self-report. Research regarding biological markers was popular at the time and medical sexology needed an objective diagnostic technique because surgical interventions (prosthetic implants) were rapidly evolving. In response to these developments, SRE research activity increased in two directions. One direction was the continued exploration related to the psychophysiological study of sleep. The other direction concerned advancing and validating the technology of SRE testing for urological diagnostic purposes. Occasionally, these goals overlapped. One important step for advancing SRE testing as a diagnostic technique was to establish normative values. Karacan and coworkers began with descriptive SRE studies in different age groups and later SRE trends across the life-span were compiled. 9 SRE consistency became immediately apparent. Boys and men in all age groups reliably had penile erections during REM sleep episodes.

Sleep related erections SRE occurrence was not just statistical; SREs were a robust phenomenon occurring in nearly every REM episode of every subject tested. Subsequent work has replicated these findings.10,11 Although SREs decline somewhat in later life Reynolds and colleagues,10 estimate that it accounts for only 15% of the variance. Nonetheless, it is clear that SREs are ubiquitous in healthy, sexually potent men, of all ages.

SREs and the diagnosis of erectile dysfunction Overview Erectile dysfunction has a variety of definitions. In general, erectile dysfunction means that a man is unable to attain a rigid erection satisfactory to achieve penetration and maintain that erection for sufficient duration to engage in intercourse. This clinical definition, however, provides no clue to etiology. Therapeutic interventions historically were limited. Some treatment options were invasive (i.e. surgery) and were specifically targeted for ‘organic’ dysfunction. In contrast, other treatments involved psychotherapy or counseling and were designed to treat psychological or marital issues.12 The choice between therapies largely became dependent on whether etiology was deemed organic or psychogenic. Although these definitions of erectile dysfunction originated from the need to guide patients into one of two therapeutic arms of intervention, the psychogenic–organic dichotomy is certainly an oversimplification. Until recently, etiologies of ‘organic’ erectile dysfunction have centered almost exclusively on the end organ or its immediate neurovascular supply. Recent advances in central nervous system (CNS) erectile control suggest, however, that the higher central mechanisms of penile erection differ depending on the context or situation in which the erection is generated (see below). These data affirm what should be intuitively obvious, that ‘psychogenic’ impotence also has its roots in ‘organic’ CNS pathophysiology. Moreover, critics of the psychogenic–organic dichotomy feel that it has hindered research into understanding central or psychogenic etiological processes. For the interest of simplification and the vast published data using the psychogenic–organic terminology, we will review this work using this long-held classification and then reassess these definitions in

313 light of new data on higher central erectile mechanisms. SRE studies have great intuitive appeal for several reasons. First, they are a natural biological process that recurs in a predictable manner. Second, they can be measured non-invasively. Third, and most importantly, SREs are involuntary. To appreciate the importance of SREs, consider the following scenario. If a man can attain a good, firm erection of reasonable duration in response to visual sexual stimulation or sexual fantasy, such is taken as evidence that erectile physiology is intact. Thus, it might be concluded that if complaints of erectile dysfunction exist they are largely psychiatric, psychological, behavioral, or situational. However, if visual sexual stimulation or fantasy fails to elicit a full erection in a clinical setting, etiology is not known because the failure can relate either to situational inhibitory factors or organic impotence. Similarly, a full, firm erection that persists throughout REM sleep is taken as evidence of intact erectile capacity, at least from the spinal cord to the end organ. In such cases, if pelvic steal syndrome, peripheral neuropathy, or acute androgen deficiency were ruled out, psychogenic erectile dysfunction would be diagnosed. By contrast, because SREs are non-volitional and automatically occur in response to REM sleep, failure to obtain full erections during sustained REM sleep is taken to indicate erectile pathophysiology.13 Fig. 1 shows a normal and abnormal SRE profile from two different men, both complaining of erectile dysfunction. Validation work has followed two main approaches. The first was to demonstrate that behavioral, psychological, and psychiatric disorders did not alter the SRE pattern. The second was to examine SREs in patients with conditions presumed or known to carry organic risk factors that might adversely affect erectile physiology.

Behavioral, psychological, and psychiatric influences SREs appear to be insulated from most psychological factors. Pre-sleep sexual activity or arousal does not alter SRE patterns. Conversely, sexual abstinence in healthy volunteer subjects is not associated with SRE alterations. Viewing a dysphoric film or a sexually arousing film before bed does not affect subsequent erections during sleep.4,7,14,15 However, SRE isolation from psychological factors is not complete. SREs are adversely affected in patients with Major Depressive Disorders.16 It should be noted that although total tumescence

314

M. Hirshkowitz, M.H. Schmidt A 0 Awake Stage 0 REM Sleep Sleep Stage 1 Sleep Stage 2 Sleep Stage 3 Sleep Stage 4 40 30 PCI/TIP (millimeters) 20 10

1

2

3

Hours of Record 4 5 6

7

8

9

1

2

3

Hours of Record 4 5 6

7

8

9

10

40 PCI/BASE 30 (millimeters) 20 10

B Awake Stage 0 0 REM Sleep Sleep Stage 1 Sleep Stage 2 Sleep Stage 3 Sleep Stage 4

10

40 30 PCI/TIP (millimeters) 20 10 40 PCI/BASE 30 (millimeters) 20 10

Figure 1 Normal and abnormal SRE patterns. Panel A illustrates a normal SRE pattern for a 56-year-old man with psychogenic erectile dysfunction. Rigidity measured during the first SRE episode was 880 g. Panel B shows the sleep and erection pattern for a 64-year man with organic erectile dysfunction and comorbid diabetes. Although SREs were well coordinated with REM sleep, circumference increase and maximum rigidity were below normal. Furthermore, SREs did not persist throughout the REM sleep episode and rigidity measured during the patient’s best erection was 220 g (Adapted from Ref. 123).

time is decreased in milder forms of depression or anxiety, such patients still exhibit robust erections in REM sleep with total tumescence time still exceeding total REM sleep time. It is unclear whether SRE alteration in patients with depression represents psychiatric influence on SREs, depression-related alterations in sleep, or is a demonstration that Major Depressive Disorders have other associated organic CNS features. Nonetheless, the work concerning SREs and depression underscore the fact that ‘organic’ does not necessarily mean ‘non-reversible’. It also suggests that ‘organic’ dysfunction is not isolated to the end organ and demonstrates the need to understand central etiologies of erectile failure. Furthermore, any disorder that alters the basic sleep pattern, particularly REM sleep, may also alter the SRE pattern. Indeed, REM sleep is often fragmented in

depressed patients, and it remains to be determined if fluctuations in SRE in such patients simply reflects the instability of the pro-erectile stimulus, i.e. REM sleep.

SREs and comorbid factors Erectile physiology may be influenced by vascular, neurological, and endocrine disorders. Thus, serious conditions adversely affecting these systems may compromise SREs, especially in individuals complaining of erectile failure.112 SREs have been examined in a wide range of conditions. Some of the earliest and most extensive work was performed on men with diabetes.17,117,18 Patients with diabetes, particularly in its more advanced forms, are widely afflicted with erectile problems. Diabetes adversely affects neurological, vascular,

Sleep related erections

315

and endocrinological systems. SRE studies confirm decreased, and in many cases, absent SREs in diabetic patients. When such patients are compared with potent subjects, SREs occur less frequently, have smaller maximum circumference increases (often less than 15 mm), have shorter duration, and are less rigid (often less than 500 g buckling force). Fig. 2 shows differences in SRE penile circumference increases in different age groups of patients with and without diabetes. SREs also are adversely affected in men with cardiovascular disease. Patients with hypertension and complaints of erectile dysfunction were compared to patients with hypertension without complaints of erectile dysfunction, and normotensive controls. 19,20 Significantly less total tumescence time was found in hypertensive men with erectile problems than in the men in the other groups. Men with erectile dysfunction who

Maximum Increase (mm)

Number of Episodes

Nondiabetic

Diabetic

4 3 2 1 0 <45

45-54

55-64

<45

45-54

55-64

>64

20 15 10 5 0 >64

TTT (minutes)

100 75 50 25 0 <45

45-54

55-64

>64

Age Group (Years)

Figure 2 SREs in men with diabetes. Frequency, magnitude, and duration of SREs for men with erectile dysfunction, with and without comorbid diabetes. Mean values across two nights for measures made at the penile base are illustrated for different age groups. The number of episodes, the maximum circumference increase, and the total tumescence time (TTT) (Adapted from Ref. 115).

smoke cigarettes also have been studied.21 Heavy smokers (O40 cigarettes per day) have less penile rigidity, lower total tumescence time, and more rapid detumescence during sleep compared to non-smokers. Similar SRE decrements are found in patients with chronic obstructive pulmonary disease (COPD).22 It is well known that patients with compounded cardiovascular risk factors have increased risk for erectile dysfunction120 and SREs appear to be no exception. For example, men complaining of erectile dysfunction who have diabetes, hypertension, and/or obesity have lower maximum SRE rigidities than patient with erectile complaints who do not have these comorbid factors.122 Fig. 3 shows age-related and arterial risk factor group differences in men with erectile dysfunction. Rosen and Weiner, 23 however, emphasize that design and methodological problems have hampered conclusiveness regarding the adverse effects of cardiovascular disease on SRE. Although more research is needed, the overall data suggest a trend toward reduced SREs in patients with cardiovascular disease. Endocrine studies demonstrate mild, but consistent, SRE decrements in men with subnormal testosterone.24–26 Fig. 4 shows how SRE declines in frequency, magnitude, duration, and rigidity associated with cessation of androgen replacement in hypogonadal patients with erectile dysfunction. Diminished total tumescence time in sleep also has been demonstrated in patients with end-stage renal disease relative to controls.27 SREs decrements are found in men with kidney failure, regardless of whether or not they undergo dialysis. However, the greatest SRE declines are found in dialysis patients on their pre-dialysis nights. Patients on dialysis also had shorter durations of the maximum circumference increase during SREs. Finally, no differences in SREs are found between control subjects and patients who have undergone successful renal transplant. Alcoholism appears to adversely affect SREs.28 Alcoholic men have fewer SREs and lower maximum SRE duration compared to non-alcoholic controls. These differences remain even though REM sleep parameters do not differ between groups.

Methodology Given the temporal relationship of erections with REM sleep, clinical sleep laboratory practice has involved polysomnographic recording montages that permit scoring of sleep stages, incorporating

316

M. Hirshkowitz, M.H. Schmidt

Rigidity (g)

Nondiabetic

Normotensive

Diabetic

800

800

600

600

400

400

200

200

0

0

Hypertensive

M <45

45-54

55-64

Rigidity (g)

Nonobese

<45

>64 Obese

55-64

Nonsmoker

800

800

600

600

400

400

200

45-54

M >64 Smoker

200 M

0 <45

45-54

55-64

M 0

>64

<45

Age Group (Years)

45-54 55-64 >64 Age Group (Years)

Figure 3 SREs in men with arterial risk factors as a function of age. Maximum rigidity during SREs in 911 men with erectile dysfunction. Rigidities are shown in different age groups for men with and without the arterial risk factors diabetes, hypertension, obesity, and cigarette smoking. Differences between patients with and without the comorbid risk factor within each age group are shown with a star where statistically significant (p!0.05) and with an M where marginally significant (0.05!p!0.10) (Adapted from Ref. 122).

40 Maximum Increase (mm)

Number of Episodes

6

4

2

0

20 10 0

1-4 Days

1-4 Days

7-8 Weeks

50

7-8 Weeks

1200

40

900 Rigidity (g)

TTT (Percent of SPT)

30

30 20

600 300

10 0

0 1-4 Days

7-8 Weeks

1-4 Days

7-8 Weeks

Figure 4 SREs in hypogonadal men during withdrawal from androgen replacement therapy. Frequency, magnitude, duration, and rigidity of SREs 1–4 days and 7–8 weeks after cessation of testosterone administration in hypogonadal men. Individual data from six hypogonadal men are illustrated for the number of episodes, the maximum circumference increase, and total tumescence time (TTT) as a percentage sleep period time (SPT) recorded from the penile base. Mean reductions are statistically reliable (p!0.05) for all four measures (Adapted from Ref. 25).

Sleep related erections the electroencephalogram (EEG), electro-oculogram (EOG), and submentalis electromyogram (EMG).13 The recording of erections involves monitoring circumference changes using strain gauges placed at both the penile base and coronal sulcus. In addition to continuous circumference monitoring, patients are awakened at a time of maximal circumference increase in order to quantify rigidity using a buckling force device. This device is pressed against the tip of the penis and, while applying an axial force, the pressure in grams force is recorded when the penis first begins to bend or ‘buckle’. At the time of a buckling force measurement, the penis is usually photographed to document potential deformities, and both patient and technician estimate the erection’s percent of fullness to document any discrepancies between the patient’s and technician’s perception of the degree of erection attained. A scoring system defines phases of SRE episodes, criteria for maximum and partial erection, schema for tabulating fluctuations and pulsations, and procedures for incorporating measures of rigidity (for details, see Ref. 13). Since SREs may be disrupted in patients who have concomitant sleep-disordered breathing or periodic limb movement disorder,29,18 respiration and leg movement channels have been added to standard recording montages. Sleep laboratory SRE studies, however, are expensive. Consequently, a wide assortment of alternative techniques emerged. Stamp bands that break, rings that expand, and devices that snap were developed as methods to detect SREs.30 These devices work on the principle that when worn around the penis, a full erection will break, stretch, or unsnap the apparatus. However, movements can also break stamp rings, expand rings, and snap gauges thereby producing unreliable results.31 Moreover, some men may have full rigidity with only small increases in circumference that fail to trigger these recording devices, causing the false assumption that SREs are diminished or absent even though full erections may consistently have been attained. Similarly, failure of a device to detect SREs can result from poor disrupted sleep, or even lack of REM sleep, secondary to a primary sleep disorder or anxiety rather than organic erectile dysfunction. More importantly, however, these devices provide no data concerning frequency, magnitude, duration, or rigidity of erections. More sophisticated SRE home-monitoring systems also evolved.32,33 These systems record penile circumference continuously throughout the night. One system even tests circumferential

317 compressibility to estimate rigidity. However, these devices do not assess sleep state; therefore, they are susceptible to false-positive results (a finding of reduced SREs secondary to disturbed REM sleep rather than due to organic erectile dysfunction). In addition, they rely on the patient’s ability to properly place and use the device. Laboratory SRE testing offers greater certainty but at a price. Laboratory testing is the preferred technique for scientific investigation because it offers experimental control, and it is preferred in litigation because false-positive and false-negative results can be avoided. Clinically, portable monitors are considered generally reliable for supporting true negative SRE tests (finding of satisfactory SREs in a psychogenic case). REM sleep’s importance in SRE testing is not widely appreciated outside the sleep community. Therefore, for pragmatic reasons (convenience and economy), non-polysomnographic SRE techniques became clinically popular for pre-surgical erectile dysfunction screening. However, it may be argued that if a patient is to undergo an invasive procedure that will destroy remaining erectile function, and since a primary sleep disorder such as sleep-disordered breathing can adversely affect SREs by disrupting REM sleep, then such a patient population would be ideal for a comprehensive polysomnographic SRE evaluation (see Ref. 34). Ironically, SRE testing for differential diagnosis of impotence has, to some extent, come ‘full circle’. Fifty years ago, few and mainly noninvasive treatments were available for erectile dysfunction; therefore, understanding etiology was somewhat academic. As understanding of penile physiology advanced, the prevalence of organic etiologies was appreciated, surgical interventions were developed, and greater therapeutic successes were achieved. Natural erectile physiology is destroyed by implanting a penile prosthesis; therefore, it became important to have objective markers for organic, presumably non-reversible, erectile failure. SRE testing was well suited to this need. In the past three decades, medical, social, and lifestyle changes have increased the public demand for erectile dysfunction treatment, resulting in less invasive medical therapies, including oral medication. These more benign therapies can be tested with ‘treatment challenge’ making differential diagnosis somewhat less essential. The result has been a decline in the use of SRE testing for clinical purposes. By contrast, SRE testing remains the ‘gold standard’ in scientific erectile function outcome research.

318

M. Hirshkowitz, M.H. Schmidt

Practice points: 1 Recent guidelines regarding clinical indications for formal SRE evaluation in combination with polysomnography were recently published.34 The previous lack of such guidelines is responsible, at least in part, for the decline in SRE testing in the sleep laboratory over the past decade. Urologists continue to use home monitoring devices to evaluate erectile function in sleep in spite of their known limitations. Proposed guidelines for clinical utilization of formal SRE evaluation are listed below (from Ref. 34). 1. Patients who fail medical therapy. A new class of medications commonly utilized for erectile dysfunction is the phosphodiesterase inhibitors such as sildenifil. Although 20–30% of impotent patients who try sildenifil are not responsive to this medication, a lack of response does not imply organic erectile dysfunction since the proerectile benefits of these medications requires sexual arousal or excitation. Additionally, patients with underlying cardiac conditions taking vasoactive substances may not be candidates for phosphodiesterase inhibitors. The cost effectiveness of SRE evaluation with polysomnography would be greatly enhanced if generally limited to such non-responders or those with contraindications to current medical therapy. 2. Patients not responsive to psychosexual therapy. Erectile function can be adversely affected by numerous psychological influences, including depression, performance anxiety, lack of sexual desire or intramarital conflicts. Although psychosexual counseling may be beneficial in such circumstances, formal SRE evaluation should be considered in patients not responding to psychotherapy, particularly prior to longterm counseling which is costly and potentially psychologically harmful if the patient is later discovered to suffer from an organic erectile failure. 3. Presurgical work-up prior to prosthetic implantation. Placement of a prosthetic implant for erectile dysfunction

irreversibly destroys the erectile tissue. As a result, a potential psychogenic impotence must be eliminated prior to surgery. The necessity of a prosthetic implant should be questioned in an individual with normal REM-related erections. 4. Patients with apparent abnormal findings using home erection screening devices. Home screening devices, such as the RigiScan, do not evaluate the presence of the pro-erectile stimulus REM sleep. The absence of erections during sleep using a home screening device cannot be regarded as proof that REM-related erections are impaired without objective data regarding REM sleep. REM sleep architecture can be markedly diminished or fragmented secondary to numerous disease states or concurrent medications. 5. Patients with erectile dysfunction and occult sleep disorders. Obstructive sleep apnea (OSA) and periodic limb movement disorder (PLMD) can fragment sleep architecture and may adversely affect the quality of erections in sleep. OSA in particular has numerous long-term cardiovascular consequences such as hypertension, which is a risk factor for erectile dysfunction. Formal SRE testing with polysomnography should be considered in patients with erectile dysfunction and suspected occult sleep disorders to simultaneously evaluate erectile capability and the underlying sleep disorder. 6. Medico-legal cases requiring objective evaluation of erectile function. Formal SRE evaluation with polysomnography has several distinct advantages for evaluating erectile function in medico-legal cases. First, it monitors both the quality of penile erections and the pro-erectile stimulus REM sleep. Second, it minimizes psychological influences or secondary gain; yet it objectively evaluates the integrity of virtually the entire neuraxis from brain to end-organ level with respect to erectile function. Finally, SRE testing requires attended monitoring in the sleep laboratory and thus minimizes technical difficulties or intentional deception such as gauge tampering from the patient.

Sleep related erections

319

SREs and the psychophysiological study of sleep

The mechanism by which androgens augment SREs remains to be elucidated.

Neuroendocrine influences

Sleep disordered breathing

Testosterone involvement in SREs has long been suspected.35,36 In animal studies, destruction of the androgen-sensitive medial preoptic area leads to cessation of male mating behavior.37,38 In humans, clinical studies shed some light on testosterone’s role underlying SREs. A sequential case series found 6 of 172 men with erectile dysfunction were androgen deficient;24 furthermore, all 6 clearly had diminished SREs. Loss of libido and erectile dysfunction are associated with hypogonadism and both are restored with androgen replacement therapy.39 Various studies have shown that SRE frequency, magnitude, duration, and rigidity can show improvement when hypogonadal men have androgen replacement therapy.25,40 There are several reports concerning anti-androgen drug effects on libido, erectile function, and SREs. Wincze and colleagues 41 administered medroxyprogesterone acetate (MPA) to three pedophilic sex offenders and found diminished maximal SRE circumference (up to 75% in one subject). Acutely reducing testosterone with a luteinizinghormone releasing-hormone agonist (leuprolide acetate) in normal young adult men diminishes SREs without affecting REM sleep or libido.26 By contrast, selective dihydrotestosterone (but not testosterone) reduction with a 5-alpha-reductase inhibitor (finasteride) does not decrease SREs.111 SREs increase at puberty onset in boys, 9 suggesting that sleep-related tumescence may be potentiated by increased circulating testosterone. Indeed, peak testosterone levels occur near the transitions from NREM to REM sleep42 close to SRE episode onset. Whether testosterone-induced erectile changes primarily involve central or peripheral mechanisms is unknown. However, androgen increases sexual fantasies while antiandrogen medications decrease them; suggesting a possible direct central physiological mechanism underlying the relationship between testosterone and SREs. Although SREs are androgen ‘sensitive’, they are not androgen ‘dependent’. Androgen deficiency may adversely affect SREs in the adult, but such erections usually persist and, even in hypogonadal men, generally remain within the normal range.25 Moreover, approximately half of all total sleep time in infants involves REM sleep, and SREs are a consistent finding during REM sleep in infants in the face of undetectable testosterone levels.

In one of the earliest sleep apnea clinical series, Guilleminault and colleagues43 mention a high prevalence of erectile complaints in men with sleep apnea. These authors also reported that some men indicated the sexual problems resolved after sleep-disordered breathing was treated. Overall, it is now well documented that erectile problems are common in men with sleep apnea.29, 18 The mechanism of erectile dysfunction in sleepdisordered breathing remains to be clarified. The dovetailing of apnea-related impotence and endocrine function (or dysfunction) emerged accidentally during an obesity study at A.J. Block’s laboratory.44 Obesity was highly correlated with sleep apnea in all subjects except one patient who was a hypogonadal man. This generated interest in the relationship between sleep apnea and androgens. Testosterone administration in several case reports, however, was found to exacerbate sleep apnea.45,46 Follow-up systematic studies revealed that androgen-related worsening of sleep-related breathing occurs mainly in patients with a predisposition to apnea, i.e. elevated baseline apnea indices.47 Santamaria and colleagues48 report decreased androgen in men with sleep apnea and Grunstein and associates49 found endocrine normalization with continuous positive airway pressure therapy. Whether SRE decrements in patients with sleep-disordered breathing are secondary to endocrinological dysfunction or are a consequence of recurrent episodic hypoxia (and its associated altered physiology) remains unknown.

Clinical pharmacology Several classes of drugs can adversely affect erectile function and SREs.50 Some drugs act directly on SREs while others act indirectly by altering REM sleep. As previously mentioned, antiandrogens decrease SREs without necessarily affecting REM sleep. Some antihypertensives can adversely affect erectile function and lower testosterone. Furthermore, the beta-blocker propanolol can decrease SREs in some men.51 Cimetidine, atropine, digoxin, and cancer chemotherapy agents may cause iatrogenic impotence. In a randomized, placebo-controlled study, disulfiram decreased the frequency and duration of SREs in chronic, sober alcoholics.119 Tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin

320 reuptake inhibitors all potentially suppress REM sleep and are known to adversely affect sexual function in some individuals. Antidepressants used as anticataplectic agents in narcolepsy are thought to iatrogenically produce erectile failure, possibly via an anticholinergic mechanism.52 By contrast, the atypical antidepressant trazodone increases SRE duration in young normal males by prolonging the detumescence phase of the erection.53 Antidepressants that do not reduce REM sleep include nefazodone,54 bupropion,55 and trimipramine.56 These medications also appear less likely to impair sexual functioning than the tricyclic and selective serotonin reuptake inhibitor antidepressants. Finally, Yohimbine, a drug that reportedly enhances sexual performance, did not alter SREs in a placebocontrolled trial.118

SRE neurophysiology The neural control of SREs remains largely a mystery, even though our understanding of the executive mechanisms generating other tonic and phasic REM-related phenomena have been relatively well elucidated. This lack of understanding of SRE control is largely because an animal model for the study of SRE neurophysiology had not been available. Indeed, until recently it was unknown if erections during REM sleep actually occurred in non-humans. Although several early anecdotal accounts report erections during sleep in some non-human animals,57 these reports relied entirely on visual observation and did not clarify if erections in non-humans are simply random events during sleep or if they are consistently associated with a specific sleep state. A technique for chronic penile erection monitoring in freely moving rats has now been developed,58,59 involving pressure monitoring within the erectile tissues with simultaneous electromyography of the ischiocavernosus (IC) and bulbospongiosus (BS) muscles which lie at the base of the penis. This technique of erection monitoring not only quantitatively and qualitatively records penile erections in freely behaving rats,58 but also demonstrated for the first time that rodents exhibit REM-related erections,60 thus establishing an animal model for SRE research. Several fundamental concepts, as well as the first working neural model, regarding SRE neurophysiology have now been developed using this animal model.61 As will be addressed, REM-related erections rely on the coordinated control of neural structures spanning virtually all levels of

M. Hirshkowitz, M.H. Schmidt the neuraxis from forebrain to spinal cord. To begin to comprehend this compartmentalized control, our discussion will begin with the spinal cord.

Spinal control Spinal erectile mechanisms are by far the best understood of the central nervous system’s control of penile erection. The spinal cord contains all of the neural elements necessary to generate both erection and ejaculation even in the absence of any supraspinal neural connections. Indeed, reflexive erections induced by genital stimulation are facilitated following spinal transection 62 or spinal block63 above the midthoracic level. Such reflexive penile erections also are easily elicited in humans with spinal cord injury, even though the individual is unable to ‘perceive’ these erections. At the level of the spinal cord, the generation of penile erections involves the complex interplay and coordination between parasympathetic, somatic motor and sympathetic arms of the nervous system. The parasympathetic nervous system plays a proerectile role in generating the relaxation of the supplying arteries and smooth muscles within the erectile tissues,64 allowing blood to enter and engorge the spongy cavernous sinuses. The release of both acetylcholine and nitric oxide are thought to play an essential role in this local vasodilitory process. The parasympathetic preganglionic neurons are located in the sacral parasympathetic nucleus of S2 to S4 spinal cord segments (Fig. 5). Penile rigidity is augmented from a somatic motor component by bursts of the IC and BS muscles which surround and insert onto the proximal corpora cavernosa and corpus spongiosum, respectively.65 By compressing the proximal portion of Spinal Generator T11-L2

Glans

IML Sympathetic (-)

SPN

S2-S4

Parasympatheti c (+) Onuf’s Nucleus

CCP Body of CSP

SomaticMotor (+)

BS Muscles IC Muscles

Figure 5 Schematic diagram of the spinal control of penile erections. Sympathetic and parasympathetic ganglia and somatic sensory afferents from the penis and surrounding skin are not depicted in the figure. See text for details. BS, bulbospongiosus muscles; CCP, proximal corpus cavernosa; CSP, proximal corpus spongiosum; IC, ischiocavernosus muscles; IML, intermediolateral cell column; SPN, sacral parasympathetic nucleus.

Sleep related erections the erectile tissues once they are filled with blood, the IC and BS muscles generate large suprasystolic intracavernous and intraspongious pressure peaks several times in excess of the systemic circulation, thus enhancing penile rigidity for vaginal penetration. As shown in Fig. 5, the motoneurons innervating the IC and BS muscles are located in Onuf’s nucleus in the ventral horn of S2 to S4 spinal cord segments.64 Following tumescence, a penile erection has thus been divided into two distinct phases. These include the parasympathetically driven ‘vascular-subsystolic’ phase and the somatic motor ‘muscular-suprasystolic’ phase generated by contractions of the IC and BS muscles (see recording of penile erections in Fig. 7).66,58 Although blood flow is essential in maintaining the vascular-subsystolic phase, blood flow into the erectile tissues momentarily ceases during the muscular-suprasystolic phase as the pressure within the erectile tissues exceeds the systolic arterial filling pressure.67,68 The sympathetic nervous system plays an important role in ejaculation, detumescence and the maintenance of the flaccid state.64 The sympathetic preganglionic neurons are found in the intermediolateral cell columns of T11 to L2 spinal cord segments (Fig. 5). The release of norepinephrine from sympathetic postganglionic fibers causes vasoconstriction of the supplying arteries and contraction of smooth muscles in the erectile tissues, and thus plays an important role in both detumsecence and the tonic inhibition of erectile activity. The sympathetic nervous system also may play an important role in inhibiting erections during SWS sleep and, in pathological conditions, during REM sleep. Skin sympathetic activation can be measured by skin conductance responses. Electrodermal activity was originally described as especially active during slow wave sleep (occurring in so-called ‘storms’). This type of electrodermal activity occurs when SREs are absent,69 demonstrating a reciprocal activation pattern between electrodermal activity during SWS and absent SREs and then a reduction of electrodermal activity during REM sleep and the occurrence of SREs. Ware and coworkers121 also found that 36% of men with erectile dysfunction and diminished SREs had more electrodermal activity in REM than in NREM sleep. Although the spinal cord is sufficient to generate reflexive erectile activity, it is not sufficient to generate REM-related erections in the absence of supraspinal connections. Midthoracic spinal cord transections in the rat,70 or following paraplegia in man,71 results in an elimination of REM-related

321 erectile activity. Reflex-induced erections, in contrast, are markedly facilitated in such a condition,70 demonstrating that the spinal erection generator is not only intact, but becomes facilitated following spinal cord transection. These data clearly indicate that the integrity of REM-related erections is dependent on preservation of intact connections from brain to the spinal erection generator.

Supraspinal control of the spinal erection generator The supraspinal control of spinal autonomic structures governing erections during REM sleep remains unclear. It has been hypothesized that, relative to SWS, there is a general decrease in sympathetic tone and an increase in parasympathetic drive, leading to the generation of REM-related erections.72 However, the role of the autonomic nervous system in REM-related erectile control is complicated by the great variability in activity in these two autonomic divisions during REM sleep both within and among species.73 Moreover, numerous phasic alterations in autonomic activity typically occur during REM sleep resulting in variable responses (parasympathetic vs sympathetic) depending on the effector organ involved.73 The well-known observation that spinal transection above the midthoracic level facilitates reflexive erections has led to the long held theory that the spinal generator controlling erections is under a tonic descending inhibition from the brain, and the removal of this inhibition (disinhibition) likely plays an important role in generating penile erections. More recent evidence suggests that erectile activity involves coordination between descending disinhibition and direct excitation. Disinhibition of the spinal generator may be mediated by two principle means: (1) decreased excitation (or even inhibition) of sympathetic preganglionic neurons or (2) activation of parasympathetic preganglionic neurons. This disinhibition would have a pro-erectile effect leading to decreased sympathetic activity with a corresponding increase in parasympathetic tone. Direct excitation of the spinal generator, on the other hand, may involve descending systems that directly stimulate parasympathetic preganglionic neurons governing erectile control. A major inhibitory source of the spinal generator is located in the medullary nucleus paragigantocellularis (nPGi).74,75 As shown schematically in Fig. 6, the nPGi contains serotonergic (5-HT) neurons that project to spinal sympathetic preganglionic neurons.76–78 It is hypothesized that these serotonergic inputs excite thoracolumbar sympathetic

322

M. Hirshkowitz, M.H. Schmidt

Hypothalamus cc

LV

GP ic

aca

LPOA MPOA

AV

Rt

PVN

ic

f 3V

ot

4V

Pons scp

LC

DR

? PB LDT py

5

ml

Medulla 5

nPGi 7 py

5-HT (-)

OXY (+)

Spinal Generator Figure 6 Supraspinal control of the spinal erection generator and sleep-related erectile mechanisms. Serotonergic (5-HT) neurons in the medullary nucleus paragigantocellularis (nPGi) send direct projections to spinal autonomic structures innervating the penis and appear to play a major role in the tonic descending inhibition of penile erections. Oxytocinergic (OXY) neurons in the paraventricular nucleus (PVN) of the hypothalamus, on the other hand, may play a pro-erectile role through their direct or indirect activation of parasympathetic preganglionic neurons in the sacral spinal cord destined to the penis. The lateral preoptic area (LPOA) likely modulates spinal erectile mechanisms during REM sleep through its relay connections with the nPGi and PVN. The executive mechanisms generating REM sleep are located in the mesopontine tegmentum (see rostral pons in figure). The ascending and descending systems from pontine REM executive structures controlling REM-related erections remains to be determined. 3V, 3rd ventricle; 4V, 4th ventricle; 5, spinal trigeminal nucleus; 7, facial nucleus; aca, anterior commissure, anterior part; AV, anteroventral nucleus; cc, corpus callosum; DR, dorsal raphe ´ nucleus; f, fornix; GP, globus

preganglionic neurons destined to the penis. The sympathoexcitatory role of the nPGi may be the primary source of the tonic descending inhibition of penile erections. 5-HT neurons in the brainstem are well documented to exhibit a tonic firing activity during wakefulness, a decreased activity during SWS, but cease firing entirely during REM sleep.79,80 It has been hypothesized that the removal of this descending inhibition during REM sleep may play an important role in the generation of REM-related erections.61 Direct experimental evidence of 5-HT neuronal activity within the nPGi during REM sleep, however, currently is lacking. Recent investigations suggest that the hypothalamic paraventricular nucleus (PVN) may be the major source of direct descending excitation of the spinal erection generator (Fig. 6).81,82 Oxytocinergic (OXY) neurons within the PVN send long descending projections to parasympathetic preganglionic neurons and surrounding autonomic structures in the sacral spinal cord that govern erectile activity.83,84 The pro-erectile role of the PVN is hypothesized to be mediated through the release of OXY, stimulating parasympathetic preganglionic neurons either directly or indirectly and thus increasing parasympathetic drive to the penis. These two descending systems, one inhibitory (serotonergic nPGi) and the other excitatory (oxytocinergic PVN), have been hypothesized to comprise a final common path from brain to spinal cord in the control of the spinal erection generator through either inhibition or excitation, respectively.61 The role of other descending systems in the control of spinal erectile mechanisms, such as those using dopamine or norepinephrine as neurotransmitters, require further exploration.82 Recent data also suggest that the higher central mechanisms of penile erections may vary depending on the context in which the erection is generated,85,86 and this context-specific erectile control may be relayed to the spinal generator by modulating or tapping into such a final common path.61 For example, the olfactory bulbs,87 amygdala88 and bed nucleus of the stria terminalis (BNST)89 play an essential role in erections generated from olfactory cues. The medial preoptic area (MPOA), in contrast, may play an important role in erections generated specifically during copulatory behavior.86 The stimulation of the hippocampus can generate penile erections90 and the hippocampus and cortex may be 3 pallidus; ic, internal capsule; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; LV, lateral ventricle; ml, medial lemniscus; MPOA, medial preoptic area; ot, optic tract; PB, parabrachial nucleus; py, pyramidal tracts; Rt, reticular nucleus; scp, superior cerebellar peduncle.

Sleep related erections more involved in erections generated from memory or fantasy. These neural structures implicated in context-specific erectile control do not send projections to the spinal cord, requiring relay structures such as the nPGi or PVN. As will be discussed below, erections generated during sleep also appear to utilize specific higher central mechanisms that differ from erections generated in other contexts. These unique REM-related erectile mechanisms may transmit information to the spinal cord through relay structures such as those described in the above final common path.

Sleep-related erectile mechanisms The brainstem contains all of the executive structures necessary to generate REM sleep since REM persists even following the removal of all neural elements rostral to the pons, as in the pontine cat preparation.91 Indeed, the executive mechanisms of REM sleep, as well as the subsystems that generate its tonic and phasic events, are now established to be located in the mesopontine tegmentum and rostral medulla (see Fig. 6).92,93 An essential question is whether the brainstem also is sufficient for the generation of REM-related erections, as it is sufficient for the generation of all other REM-related phenomena. Using the new animal model for SRE research, a recent study suggests that the forebrain plays an essential role in SRE neurophysiology.70 Sleep-wake states and penile erections were recorded before and after transection of the rostral mesencephalon in the rat. In this cerveau isole preparation, REM sleep persisted in all rats caudal to the transection as seen by the ultradian appearance of rapid eye movements with muscle atonia. REM-related erections, however, were virtually eliminated. These data suggest that although the brainstem is sufficient to generate REM sleep, it is not sufficient for the generation of REM-related erections. Structures rostral to the transection, as in the forebrain, appear to be essential in REM-related erectile mechanisms. Numerous forebrain structures have been implicated in erectile mechanisms and, therefore, are potential candidates in SRE neurophysiology. As noted above, these include the amygdala, BNST, MPOA, PVN, hippocampus and even the cortex. The forebrain source of SRE control, in contrast, had until recently remained a matter of speculation. The preoptic area is a basal forebrain region that has been implicated in numerous physiological functions, including sleep generation, reproductive mechanisms and thermoregulation, suggesting that

323 it may be a primary candidate in SRE control. The MPOA, for example, appears essential in copulatory mechanisms since its lesioning eliminates copulatory behavior in every species examined to date.94 Moreover, chemical stimulation of the MPOA generates penile erections in rats.95 The MPOA also contains androgen-dependent neurons important for reproductive control,96 and SREs appear to be androgen sensitive as noted earlier.26 The lateral preoptic area (LPOA) has been described as a ‘sleep center’ since cytotoxic or electrolytic lesions of this region leads to a longlasting insomnia.97,98 Stimulation of this basal forebrain region generates cortical slow waves in cats99,100 and induces SWS.101 The ventrolateral preoptic nucleus (VLPO) appears to contain the highest concentration of SWS generating neurons. The VLPO is comprised of GABAergic neurons that express the immediate early gene c-fos after long bouts of sleep,102 suggesting an active role in sleep generation. Moreover, single unit recording studies demonstrate an increased number of SWS-on neurons as the recording electrode approaches the VLPO.103 The VLPO has been hypothesized to generate SWS through its inhibitory connections with major systems involved in maintaining wakefulness.104 In addition to SWS-on neurons, the LPOA also contains a group of neurons that exhibit a specific unit firing activity during REM sleep.105 These REMon neurons are inactive during both SWS and wakefulness. The role of these REM-on neurons in the LPOA, as well as their relationship with REMrelated erections, has remained unknown. Schmidt et al.106 performed neurotoxic lesions using ibotenic acid of the MPOA, LPOA or both in three groups of rats to determine the potential contributions of these structures in both SRE control and sleep generation. Continuous recordings of body temperature, sleep–wake states and penile erections were performed before and up to 3 weeks after cytotoxic lesions. Bilateral lesions of the MPOA had no effect on penile erections or sleep–wake architecture. In contrast, bilateral cytotoxic lesions involving the LPOA severely disrupted REM-related erectile activity (see Fig. 7), as seen by the significant decrease in the number of erections per hour of REM sleep, the total number of REM-related erections, and the percent of REM sleep episodes exhibiting an erectile event. Although these more lateral lesions also resulted in a long-lasting insomnia, REM sleep architecture was not significantly affected after lesion in this study, suggesting that the disruption of REM-related erections was not secondary to a disruption of REM sleep architecture. These data not only confirm

324

M. Hirshkowitz, M.H. Schmidt

the importance of the forebrain in SRE mechanisms as was originally suggested from the brainstem transection experiments,70 but further localizes this control to the LPOA. The above experiment also demonstrated that waking-state erections remained intact following LPOA lesions even though REM-related erections were severely disrupted (Fig. 7). These data give further credence to the hypothesis that higher central erectile mechanisms differ depending on the context in which they are generated. The LPOA, therefore, appears to play a specific role in REMrelated erectile generation. How does the LPOA modulate spinal erectile mechanisms? The LPOA, like other structures involved in the higher central control of penile erections, does not project to the spinal cord, Control

suggesting that it must modulate the spinal erection generator by interacting with secondary or relay structures. The microiontophoretic application of the anterograde tracer phaseolus vulgaris leukoaglutinin (PHAL) into the region of the LPOA in which bilateral lesions eliminate REM-related erections demonstrates a strong projection to both the hypothalamic PVN and medullary nPGi (unpublished observations). Such projections from the LPOA to the nPGi107 and to the PVN108 have been reported by others. The LPOA, therefore, may modulate spinal erectile mechanisms during REM sleep through its connections with both excitatory and inhibitory arms of this potential final common path from brain to spinal cord (Fig. 6). As noted above, the mesopontine tegmentum and rostral medulla contain the executive Wake

Post-Lesion

Neck EMG EEG

CSP Pressure

BS EMG 200 150 100 50 0

Neck EMG

SWS

EEG

CSP Pressure

BS EMG 200 150 100 50 0

Neck EMG

PS

EEG

CSP Pressure

BS EMG 200 150 100 50 0

3 sec.

Figure 7 An example of a polygraphic recording of wakefulness, SWS, and REM sleep (also known as paradoxical sleep, PS) before (control) and circa day 10 after bilateral cytotoxic lesions of the lateral preoptic area (LPOA) in a rat. All erectile events were associated with an increase in baseline corpus spongiosum of the penis (CSP) pressure from 10– 15 mm Hg to a tumescence pressure of approximately 70 mm Hg. In addition, bursts of the bulbospongiosus muscles (BS EMG) were associated with dramatic suprasystolic pressure peaks that saturated the polygraph pens at 220 mm Hg during erectile events. Following lesions of the LPOA, penile erections persisted during wakefulness but were virtually eliminated during REM sleep (Reprinted with permission from Ref. 106).

Sleep related erections mechanisms generating REM sleep, as well as the subsystems controlling its tonic and phasic events.80,93 Although the brainstem is not sufficient for the generation of REM-related erections as demonstrated following mesencephalic transection, numerous questions regarding the brainstem control of REM-related erections remain to be elucidated. For example, what are the ascending mechanisms from brainstem (REM sleep) executive structures to the LPOA that modulate or trigger this forebrain structure to generate REM-related erections? Secondly, what is the role of REM executive structures in the direct descending control of the spinal erection generator? As described earlier, 5-HT neurons in the medullary nPGi are believed to play a major role in the tonic descending inhibition of the spinal generator, and 5-HT neurons are well known to become silent during REM sleep. Although brainstem mechanisms remain to be explored, the brainstem likely plays an important role in generating penile erections during REM sleep through both ascending and descending systems (Fig. 6). Several clinical observations also remain to be explained from a neurophysiological perspective. For example, REM sleep deprivation is followed not only by a REM rebound, but also an SRE rebound in that SREs begin to intrude into other stages of sleep in humans.4,116 The role of REM generating structures in the contribution to this SRE rebound is only a matter of speculation. In addition, two laboratories have independently reported hemispheric electroencephalographic asymmetries during SREs.109,110 Greater right than left temporal lobe EEG activation reportedly occurs during maximal phase of SRE episodes. By contrast, symmetrical EEG activity was found for parietal lobe sites. The involvement of other forebrain structures, such as the amygdala and even cortex, in SRE neurophysiology remains to be clarified.

Summary Erections occur during REM sleep in all normal healthy males from infancy to old age. The historical background of SRE testing, its role in the psychophysiological study of sleep, and the neural mechanisms of SREs were reviewed. New advancements in erectile neurophysiology suggest that the higher central mechanisms of erections differ depending on the context in which they occur. For example, erections generated during sleep, or those generated from sensory input such as olfactory cues, tactile stimulation,

325 or visual input, or erections generated from memory or fantasy, or even during copulation, all may involve specialized higher central structures, leading to the theory of context-specific erectile failure. Advocates of this conceptual framework of erectile dysfunction suggest that the psychogenic– organic terminology often used to describe etiologies of impotence is an oversimplification because ‘psychogenic’ erectile failure may have its roots in CNS ‘organic’ pathophysiology. Unfortunately, standardized techniques for evaluating contextual effects are not available. Sleep erection consistency, reproducibility, and their involuntary nature makes SRE testing a valuable technique for objectively assessing erectile capability. Intact REM-related erections suggest that the spinal cord, peripheral nerves, erectile tissues and immediate vascular supply at the end organ level are intact. By contrast, absence of REMrelated erections strongly suggests abnormal erectile pathophysiology. SRE testing reached peak popularity when the prosthetic implantation was the main intervention for erectile dysfunction. However, as treatments became medical, less invasive, and reversible, empiric treatment trials largely replaced involved or expensive diagnostic procedures. Furthermore, home-testing systems, notwithstanding their limitations, steadily supplanted laboratory testing. The decline in SRE testing reflects treatment driven changes in care delivery. SRE testing, though no longer routinely used clinically, remains the most objective and reliable technique for indexing erectile capacity. As such, it continues as the preferred method in research and legal arenas where the rules of evidence are strict and accuracy is vital.

Practice points: 2 1. SREs are involuntary and REM sleep related. 2. SREs do not occur because dreaming is sexual in nature or because there is a need to urinate. 3. SRE testing is an objective technique to diagnose erectile dysfunction. 4. Many medications, especially those with anticholinergic or antiandrogenic properties and most classes of antidepressants, can adversely affect SREs either by directly influencing erectile physiology or indirectly by decreasing the pro-erectile stimulus REM sleep.

326

Research agenda 1. The specific SRE pattern associated with erectile dysfunction arising from different etiologies needs further definition and description. 2. Although adverse drug effects on sexual function are well described, SRE alteration from drugs needs to be studied with randomized controlled trials. 3. The role of forebrain structures, such as amygdala and cortex, in SRE activity needs further clarification. 4. The ascending mechanisms from brainstem (REM sleep) executive structures to the LPOA and other forebrain structures to generate SREs need to be determined.

References 1. ICSD—International Classification of Sleep Disorders: Diagnostic and coding manual. Diagnostic Classification Steering Committee, Thorpy MH, Chairman, Rochester, Minnesota: American Sleep Disorders Association; 1990. *2. Ohlmeyer P, Brilmayer H, Hullstrung H. Periodische vorgange im schaf pflug. Arch Ges Physiol 1944;248:559–60. 3. Aserinsky E. Ocular motility during sleep and its application to the study of the rest-activity cycles and dreaming. PhD dissertation, University of Chicago; 1953. 4. Karacan I. The effect of exciting presleep events on dream reporting and penile erections during sleep. Unpublished doctoral dissertation, Department of Psychiatry, Downstate Medical Center Library, New York University, Brooklyn, NY; 1965. *5. Fisher C, Gross J, Zuch J. Cycle of penile erection synchronous with dreaming (REM) sleep: preliminary report. Arch Gen Psychiatry 1965;12:29–45. 6. Fisher C. Dreaming and sexuality. In: Loewenstein RM, Newman LM, Schur M, Solnit AJ, editors. In: Psychoanalysis—a general psychology. New York: International Universities Press; 1966. p. 537–69. 7. Karacan I, Williams RL, Salis PJ. The effect of sexual intercourse on sleep patterns and nocturnal penile erections. Psychophysiology 1970;7:338. 8. Masters WH, Johnson VE. Human sexual inadequacy. Boston: Little Brown; 1970. *9. Karacan I, Williams RL, Thornby JI, et al. Sleep-related penile tumescence as a function of age. Am J Psychiatry 1975;132:932. 10. Reynolds CF, Thase ME, Jennings JR, et al. Nocturnal penile tumescence in healthy 20- to 59-year olds: a revisit. Sleep 1989;12:368.

* The most important references are denoted by an asterisk.

M. Hirshkowitz, M.H. Schmidt *11. Ware JC, Hirshkowitz M. Characteristics of penile erections during sleep recorded from normal subjects. J Clin Neurophysiol 1992;9:78. 12. Scott FB, Byrd GJ, Karacan I, et al. Erectile impotence treated with an implantable, inflatable prosthesis: five years of clinical experience. JAMA 1979;241:2609–12. 13. Ware JC, Hirshkowitz M. Monitoring penile erections during sleep. In: Kryger MH, Roth T, Dement WC, editors. In: Principles and practice of sleep medicine. Philadelphia: W.B. Saunders; 1994. p. 967–77. 14. Karacan I, Ware JC, Salis PJ, et al. Sexual arousal and activity: effect on subsequent nocturnal penile tumescence patterns. Sleep Res 1979;8:61. 15. Ware JC, Hirshkowitz M, Thornby J, et al. Sleep-related erections: effects of presleep sexual arousal. J Psychosom Res 1997;42:547–53. 16. Thase ME, Reynolds CF, Glanz LM, et al. Nocturnal penile tumescence in depressed men. Am J Psychiatry 1987;144: 89. 17. Karacan I. Clinical value of nocturnal erection in the prognosis and diagnosis of impotence. Med Aspects Hum Sexuality 1970;4:27. 18. Hirshkowitz M, Karacan I, Arcasoy MO, et al. Prevalence of sleep apnea in men with erectile dysfunction. Urology 1990;36:232. 19. Karacan I, Salis PJ, Hirshkowitz M, et al. Erectile dysfunction in hypertensive men: sleep-related erections, penile blood flow, and musculovascular events. J Urol 1989;142: 56–61. 20. Hirshkowitz M, Karacan I, Arcasoy MO, et al. The prevalence of periodic limb movements during sleep in men with erectile dysfunction. Biol Psychiatry 1989;26:541. 21. Hirshkowitz M, Cunningham GR, Gokcebay N, Hamilton CR, Karacan I. Effects of testosterone on sleep architecture and sleep apnea in hypogonadal men. In: Smirne S, Franceschi M, Ferini-Strambi L, Zucconi M, editors. In: Sleep, hormones and immunological system. Milano: Masson; 1992. p. 141–7. 22. Fletcher EC, Martin RJ. Sexual dysfunction and erectile impotence in chronic obstructive pulmonary disease. Chest 1982;81:413. 23. Rosen RC, Weiner DN. Cardiovascular disease and sleeprelated erections. J Psychosom Res 1997;42:517–30. 24. Cunningham GR, Karacan I, Ware JC, et al. The relationships between serum testosterone and prolactin levels and nocturnal penile tumescence (NPT) in impotent men. J Androl 1982;3:241. *25. Cunningham GR, Hirshkowitz M, Korenman SG, et al. Testosterone replacement and sleep-related erections in hypogonadal men. J Clin Endocrinol Metab 1990;70:792. 26. Hirshkowitz M, Moore CA, O’Connor S, et al. Androgen and sleep-related erections. J Psychosom Res 1997;42:541–6. 27. Karacan I, Dervent A, Cunningham G, et al. Assessment of nocturnal penile tumescence as an objective method for evaluating sexual functioning in ESRD patients. Dial Transplant 1978;7:872–6. 890. 28. Snyder S, Karacan I. Effects of chronic alcoholism on nocturnal penile tumescence. Psychosom Med 1981;43: 423–9. *29. Schmidt HS, Wise HA. Significance of impaired penile tumescence and associated polysomnographic abnormalities in the impotent patient. J Urol 1981;126:348–52. 30. Barry JM, Blank B, Boileau M. Nocturnal penile tumescence monitoring with stamps. Urology 1980;15:171. 31. Allen R, Brendler CB. Snap-gauge compared to a full nocturnal penile tumescence study for evaluation of patients with erectile impotence. J Urol 1990;143:51.

Sleep related erections 32. Kenepp D, Gonick P. Home monitoring of penile tumescence for erectile dysfunction. Initial experience. Urology 1979;14:261. 33. Bradley WE. New techniques in evaluation of impotence. Urology 1987;29:383. *34. Schmidt MH, Schmidt HS. Sleep-related erections: neural mechanisms and clinical significance. Curr Neurol Neurosci Rep 2004;4:170–8. 35. Bagatell CJ, Heiman JR, Rivier JE, et al. Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 1994;78:711. 36. Morali G, Larsson K, Beyer C. Inhibition of testosteroneinduced sexual behavior in the castrated male rat by aromatase blockers. Horm Behav 1978;9:203. 37. MacLean PD, Denniston RH, Dua S. Further studies on cerebral representation of penile erection: caudal thalamus, midbrain, and pons. J Neurophysiol 1963;26:274. 38. Slimp JC, Hart BL, Goy RW. Heterosexual, autosexual and social behavior of adult male rhesus monkeys with medial preoptic–anterior hypothalamic lesions. Brain Res 1978; 142:105. 39. Davidson JM, Camargo CA, Smith ER. Effects of androgen on sexual behavior in hypogonadal men. J Clin Endocrinol Metab 1979;48:955. 40. O’Carroll R, Shapiro C, Bancroft J. Androgens, behaviour and nocturnal erection in hypogonadal men: the effects of varying the replacement dose. Clin Endocrinol 1985;23: 527. 41. Wincze JP, Bansal S, Malamud M. Effects of medroxyprogesterone on subjective arousal, arousal to erotic stimulation, and nocturnal penile tumescence in male sex offenders. Arch Sex Behav 1986;15:293. 42. Roffwarg HP, Sachar EJ, Halpern F, Hellman L. Plasma testosterone and sleep: relationship to sleep stage variables. Psychosom Med 1982;44:73. 43. Guilleminault C, Eldridge FL, Tilkian A, et al. Sleep apnea syndrome due to upper airway obstruction: a review of 25 cases. Arch Intern Med 1977;137:296–300. 44. Harman E, Wynne JW, Block AJ, et al. Sleep disordered breathing and oxygen desaturation in obese patients. Chest 1981;79:256. 45. Camargo CA. Obstructive sleep apnea and testosterone. N Engl J Med 1983;309:314. 46. Sandblom RE, Matsumoto AM, Schoene RB, et al. Obstructive sleep apnea syndrome induced by testosterone administration. N Engl J Med 1983;308:508. 47. Schneider BK, Pickett CK, Zwillich CW, et al. Influence of testosterone on breathing during sleep. J Appl Physiol 1986;61:618–23. 48. Santamaria JD, Prior JC, Fleetham JA. Reversible reproductive dysfunction in men with obstructive sleep apnoea. Clin Endocrinol (Oxf) 1988;28:461–70. 49. Grunstein RR, Lawrence S, Handelsman DJ, et al. Endocrine dysfunction in obstructive sleep apnea-changes with nasal CPAP. Sleep Res 1987;16:340. 50. Segraves RT, Schoenberg HW, Segraves KAB. Evaluation of the etiology of erectile failure. In: Segraves RT, Schoenberg HW, editors. In: Diagnosis and treatment of erectile disturbances: a guide for clinicians. New York: Plenum Press; 1985. p. 165–95. 51. Rosen RC, Kostis JB, Jekelis AW. Beta-blockers effects on sexual function in normal males. Arch Sex Behav 1988;17: 241–55. 52. Karacan I, Gokcebay N, Hirshkowitz M, et al. Sexual dysfunction in men with narcolepsy. Loss Grief Care 1992; 5:81.

327 53. Saenz de Tejada I, Ware JC, Blanco R, et al. Pathophysiology of prolonged penile erection associated with trazodone use. J Urol 1991;145:60–4. 54. Ware JC, Rose FV, McBrayer R. The acute effects of nefazodone, trazodone and buspirone on sleep and sleeprelated penile tumescence in normal subjects. Sleep 1994; 6:544–50. 55. Nofzinger EA, Reynolds 3rd CF, Thase ME, et al. REM sleep enhancement by bupropion in depressed men. Am J Psychiatry 1995;152:274–6. 56. Ware JC, Brown FW, Moorad PJ, et al. Effects on sleep: a double-blind study comparing trimipramine to imipramine in depressed insomniac patients. Sleep 1989;12:537–49. 57. Pearson OP. Reproduction in the shrew (blarina brevicaudasay). Am J Anat 1944;75:39–93. *58. Schmidt MH, Valatx JL, Sakai K, Debilly G, Jouvet M. Corpus spongiosum penis pressure and perineal muscle activity during reflexive erections in the rat. Am J Physiol 1995; 269:R904–R13. 59. Giuliano F, Bernabe J, Rampin O, Courtois F, Benoit G, Rousseau JP. Telemetric monitoring of intracavernous pressure in freely moving rats during copulation. J Urol 1994;152:1271–4. 60. Schmidt MH, Valatx JL, Schmidt HS, Wauquier A, Jouvet M. Experimental evidence of penile erections during paradoxical sleep in the rat. NeuroReport 1994;5:561–4. 61. Schmidt MH. Sleep-related penile erections. In: Kryger MH, Roth T, Dement WC, editors. In: Principles and practice of sleep medicine. Philadelphia: W.B. Saunders; 2000. p. 305– 18. 62. Sachs BD, Garinello LD. Spinal pacemaker controlling sexual reflexes in male rats. Brain Res 1979;171:152–6. 63. Sachs BD, Bitran D. Spinal block reveals roles for brain and spinal cord in the mediation of reflexive penile erections in rats. Brain Res 1990;528:99–108. 64. Giuliano FA, Rampin O, Benoit G, Jardin A. Neural control of penile erection. Urol Clin N Am 1995;22:747–66. 65. Schmidt MH, Schmidt HS. The ischiocavernosus and bulbospongiosus muscles in mammalian penile rigidity. Sleep 1993;16:171–83. 66. Lavoisier P, Schmidt MH, Aloui R. Intracavernous pressure increases and perineal muscle contractions in response to pressure stimulation of the glans penis. Int J Impot Res 1992;4:157–64. 67. Beckett SD, Reynolds TM, Hudson RS, Holley RS. Serial angiography of the crus penis of the goat during erection. Biol Reprod 1972;7:365–9. 68. Hanyu S, Iwanaga T, Kano K, Sato S. Mechanism of penile erection in the dog. Urol Int 1987;42:401–12. 69. Ware JC, Karacan I, Mefferd RB, et al. Electrodermal activity during sleep: relation to other polysomnographic parameters. Sleep Res 1979;8:73. *70. Schmidt MH, Sakai K, Valatx JL, Jouvet M. The effects of spinal or mesencephalic transections on sleep-related erections and ex-copula penile reflexes in the rat. Sleep 1999;22:409–18. 71. Karacan I, Dimitrijevic M, Lauber A, Ware JC, Halstead L, Attia SAU, et al. Nocturnal penile tumescence (NPT) and sleep stages in patients with spinal cord injuries. Sleep Res 1977;6:52. 72. Hirshkowitz M, Moore CA. Sleep-related erectile activity. Neurol Clin 1996;14:721–37. 73. Parmeggiani PL. Autonomic nervous system in sleep. Exp Brain Res 1984;Suppl. 8:39–49. 74. Marson L, List MS, McKenna KE. Lesions of the nucleus paragigantocellularis alter ex copula penile reflexes. Brain Res 1992;592:187–92.

328 75. Yells DP, Hendricks SE, Prendergast MA. Lesions of the nucleus paragigantocellularis: effects on mating behavior in male rats. Brain Res 1992;596:73–9. 76. Marson L, McKenna KE. A role for 5-hydroxytryptamine in descending inhibition of spinal sexual reflexes. Exp Brain Res 1992;88:313–20. 77. Skagerberg G, Bjorklund A. Topographic principles in the spinal projections of serotonergic and non-serotonergic brainstem neurons in the rat. Neuroscience 1985;15: 445–80. 78. Loewy AD, McKellar S. Serotonergic projections from the ventral medulla to the intermediolateral cell column in the rat. Brain Res 1981;211:146–52. 79. Jacobs BL. Overview of the activity of brain monoaminergic neurons across the sleep–wake cycle. In: Wauquier A, Gaillard JM, Monti JM, Radulovacki M, editors. In: Neurotransmitters and neuromodulators. New York: Raven Press; 1985. p. 1–14. 80. Sakai K. Neurons responsible for paradoxical sleep. In: Wauquier A, Gaillard JM, Monti JM, Radulovacki M, editors. In: Sleep: neurotransmitters and neuromodulators. New York: Raven Press; 1985. p. 29–42. 81. Melis MR, Stancampiano R, Argiolas A. Penile erection and yawning induced by paraventricular NMDA injection in male rats are mediated by oxytocin. Pharmacol Biochem Behav 1994;48:203–7. 82. Giuliano F, Rampin O. Central neural regulation of penile erection. Neurosci Biobehav Rev 2000;24:517–33. 83. Luiten PGM, ter Horst GJ, Karst H, Steffens AB. The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord. Brain Res 1985;392: 374–8. 84. Tang Y, Rampin O, Calas A, Facchinetti P, Giuliano F. Oxytocinergic and serotonergic innervation of identified lumbosacral nuclei controlling penile erection in the male rat. Neuroscience 1998;82:241–54. 85. Sachs BD. Placing erection in context: the reflexogenic– psychogenic dichotomy reconsidered. Neurosci Biobehav Rev 1995;19:211–24. 86. Liu YC, Salamone JD, Sachs BD. Lesions in medial preoptic area and bed nucleus of stria terminalis: differential effects on copulatory behavior and noncontact erection in male rats. J Neurosci 1997;17:5245–53. 87. Fernandez-Fewell GD, Meredith M. Facilitation of mating behavior in male hamsters by LHRH and AcLHRH5-10: interaction with the vomeronasal system. Physiol Behav 1995;57:213–21. 88. Kondo Y. Lesions of the medial amygdala produce severe impairment of copulatory behavior in sexually inexperienced male rats. Physiol Behav 1992;51:939–43. 89. Valcourt RJ, Sachs BD. Penile reflexes and copulatory behavior in male rats following lesions in the bed nucleus of the stria terminalis. Brain Res Bull 1979;4:131–3. 90. Chen K-K, Chan JYH, Chang LS, Chen M-T, Chan SHH. Elicitation of penile erection following activation of the hippocampal formation in the rat. Neurosci Lett 1992;141: 218–22. *91. Jouvet M. Neurophysiology of the states of sleep. Physiol Rev 1967;47:117–77. 92. Sakai K. Anatomical and physiological basis of paradoxical sleep. In: McGinty DJ, Drucker-Colin R, Morrison A, Parmeggiani, editors. In: Brain mechanisms of sleep. New York: Raven Press; 1985. p. 111–37. 93. Jones BE. Paradoxical sleep and its chemical/structural substrates in the brain. Neuroscience 1991;40:637–56.

M. Hirshkowitz, M.H. Schmidt 94. Sachs BD, Meisel RL. The physiology of male sexual behavior. In: Knobil E, Neill J, editors. The physiology of reproduction. New York: Raven Press; 1988. p. 1393–485. 95. Giuliano F, Rampin O, Brown K, Courtois F, Benoit G, Jardin A. Stimulation of the medial preoptic area of the hypothalamus in the rat elicits increases in intracavernous pressure. Neurosci Lett 1996;209:1–4. 96. Cherry JA, Tobet SA, DeVoogd TJ, Baum MJ. Effects of sex and androgen treatment on dendritic dimensions of neurons in the sexually dimorphic preoptic/anterior hypothalamic area of male and female ferrets. J Comp Neurol 1992;323: 577–85. 97. Szymusiak R, McGinty D. Sleep suppression following kainic acid-induced lesions of the basal forebrain. Exp Neurol 1986;94:598–614. 98. Sallanon M, Denoyer M, Kitahama K, Aubert C, Gay N, Jouvet M. Long lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat. Neuroscience 1989; 32:669–83. 99. Sterman MB, Clemente CD. Forebrain inhibitory mechanisms: cortical synchronization induced by basal forebrain stimulation. Exp Neurol 1962;6:91–102. 100. Siegel J, Wang RY. Electroencephalographic, behavioral, and single-unit effects produced by stimulation of forebrain inhibitory structures in cats. Exp Neurol 1974; 42:28–50. 101. Sterman MB, Clemente CD. Forebrain inhibitory mechanisms: sleep patterns induced by basal forebrain stimulation in the behaving cat. Exp Neurol 1962;6:103–17. 102. Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Activation of ventrolateral preoptic neurons during sleep. Science 1996;271:216–9. 103. Szymusiak R, Alam N, Steininger TL, McGinty D. Sleep– waking discharge patterns of ventrolateral preoptic/ anterior hypothamic neurons in rats. Brain Res 1998;803: 178–88. 104. Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 1998;18:4705–21. 105. Koyama Y, Hayaishi O. Firing of neurons in the preoptic/anterior hypothalamic areas in rat: its possible involvement in slow wave sleep and paradoxical sleep. Neurosci Res 1994;19:31–8. 106. Schmidt MH, Valatx JL, Sakai K, Fort P, Jouvet M. Role of the lateral preoptic area in sleep-related erectile mechanisms and sleep generation in the rat. J Neurosci 2000;20: 6640–7. 107. Murphy AZ, Rizvi TA, Ennis M, Shipley MT. The organization of the preoptic–medullary circuits in the male rat: evidence for interconnectivity of neural structures involved in reproductive behavior, antinociception and cardiovascular regulation. Neuroscience 1999;91:1103–16. 108. Sawchenko PE, Swanson LW. The organization of forebrain afferents to the paraventricular and supraoptic nuclei of the rat. J Comp Neurol 1983;218:121–44. 109. Hirshkowitz M, Karacan I, Thornby JI, et al. Nocturnal penile tumescence and EEG asymmetry. Res Commun Psychol Psychiatr Behav 1984;9:87. 110. Rosen RC, Goldstein L, Scoles V, et al. Psychophysiologic correlates of nocturnal penile tumescence in normal males. Psychosom Med 1986;48:423. 111. Cunningham GR, Hirshkowitz M. Inhibition of steroid 5alpha reductase with finasteride: sleep-related erections, potency and libido in healthy men. J Clin Endocrinol Metab 1995;1934–40.

Sleep related erections 112. Halstead LS, Dimitrijevic M, Karacan I, et al. Impotence in spinal cord injury: neurophysiological assessment of diminished tumescence and its relation to supraspinal influences. Curr Concepts Rehabil Med 1984;1:8. * 115. Hirshkowitz M, Karacan I, Rando KC, Williams RL, Howell JW. Diabetes, erectile dysfunction, and sleep-related erections. Sleep 1990;13:53–68. 116. Hirshkowitz M, Moore CA, Karacan I. Sleep-related erections during REM sleep rebound. Sleep Res 1992;21:319. 117. Karacan I, Salis PJ, Ware JC, et al. Nocturnal penile tumescence and diagnosis in diabetic impotence. Am J Psychiatry 1978;135:191–7. 118. Rowland DL, Kallan K, Slob AK. Yohimbine, erectile capacity, and sexual response in men. Arch Sex Behav 1997;26:49–62.

329 119. Snyder S, Karacan I, Salis PJ. Disulfiram and nocturnal penile tumescence in the chronic alcoholic. Biol Psychiatry 1881;16:399–406. 120. Virag R, Bouilly P, Frydman D. Is impotence an arterial disorder? Lancet 1985;1:181–4. 121. Ware JC, Karacan I, Salis PJ, Thornby J, Hirshkowitz M. Sleep-related electrodermal activity patterns in impotent patients. Sleep 1984;7:247–54. 122. Karacan I, Hirshkowitz M. Aging and sleep apnea in impotent men with arterial risk factors. In: Smirne S, Franceschi M, Ferini–Strambi L (eds). Sleep and Ageing. Milano: Masson, 1991, 135–48. 123. Hirshkowitz M, Moore CA. Techniques for the assessment of sleep-related erections. In: Chokroverty S (ed). Sleep Disorders Medicine (2nd ed) Boston, MA: ButterworthHeinemann, 1999, 263–74.