University of Groningen Pathologic erections Vreugdenhil, Sanne

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University of Groningen

Pathologic erections

Vreugdenhil, Sanne

DOI:

10.33612/diss.95437816

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Publication date: 2019

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Vreugdenhil, S. (2019). Pathologic erections: historical, pathophysiological and clinical aspects. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.95437816

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534099-L-bw-Vreugdenhil 534099-L-bw-Vreugdenhil 534099-L-bw-Vreugdenhil 534099-L-bw-Vreugdenhil Processed on: 15-8-2019 Processed on: 15-8-2019 Processed on: 15-8-2019

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39

Sleep-related painful erections –

A meta-analysis on the pathophysiology

and risks and benefits of medical treatments

CHAPTER 4

Sanne Vreugdenhil MD1_{, Alida Cornelia Weidenaar MD, PhD}1_,

Igle Jan de Jong MD, PhD1_{, Mels Frank van Driel MD, PhD}1 1_{Department of Urology, University Medical Center Groningen,}

University of Groningen, Groningen, the Netherlands. Institution at which work was performed: Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

J Sex Med. 2018 Jan;15(1):5-19 https://doi.org/10.1016/j.jsxm.2017.11.006

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40

Chapter 4

Abstract

Background Patients with sleep-related painful erections (SRPEs) suffer from frequent awakenings due to deep penile pain during nocturnal erections. This results in severe sleep deprivation. Aim. We reviewed the current literature on SRPEs and discuss the theories on the pathophysiology and risks and benefits of medical treatments.

Methods PubMed was searched using the terms ‘sleep-related painful erections’, ‘nocturnal priapism’, `treatment’ and ’sleep-related erections’.

Outcome Variables included patient demographics, medical history, diagnostics, hypotheses on pathophysiologic explanation, treatment modalities and their effect on SRPE on the short- and long term.

Results Our search yielded in total 66 cases with SRPE that were analysed, including our mono-institutional series of 24 patients. Until now, the phenomenon of SRPEs has not been well understood. Theories about the pathophysiology concerned increased serum testosterone levels, altered autonomic function, compression of the lateral preoptic area, co- existent obstructive sleep apnoea syndrome, the existence of a `compartment syndrome’ and psychosomatic factors. Except for polysomnographic findings, that showed sleep fragmentation and reduced sleep efficiency in all patients, other diagnostic results varied widely. Multiple agents have been tried. Baclofen and, to lesser degree, clonazepam showed noticeable results, most likely due to their influence on the GABA-ergic system and thereby suppression of glutamate release. In addition, baclofen relaxes the ischiocavernous and bulbospongious muscles, both involved in penile erection.

Clinical implications By providing a critical analysis and complete overview on the limited literature about this overlooked and undermanaged condition, this review contributes to a better understanding of the pathophysiology and does provide directions for future research on the treatment of SRPE.

Strengths & limitations As the literature on SRPEs includes only case-reports and small case- series the level of evidence of treatment advices limited.

Conclusion The pathophysiology of SRPEs is not yet clarified. Further diagnostic evaluation, including electromyography of the ischiocavernous- and bulbospongious muscle to elucidate the pathophysiology, is recommended. Prospective controlled investigations are warranted to assess the efficacy and safety of long-term use of baclofen and come to an evidence-based treatment advice.

Keywords: (3-10 words) Sleep-related painful erection, parasomnia, humans, GABA, baclofen, nocturnal erection, priapism, treatment

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41 SRPE-A meta-analysis on the pathophysiology and risks and benefits of medical treatments

Introduction

The International Classifi cation of Sleep Disorders of the American Academy of Sleep Medicine defi nes sleep-related painful erections (SRPEs) as `penile pain that occurs during erections, typically during rapid eye movement (REM) sleep episodes`.(1) Patients with SRPEs report frequent awakenings related to this deep penile pain. The awakenings and REM sleep fragmentation may result in anxiety, tension, irritability and daytime fatigue. Typically, patients report no pain during erections related to sexual activity. The majority present with chronic complaints deriving from sleep deprivation and have a mean patient-doctor delay between onset and diagnosis of several years. Common urological disorders as Peyronie’s disease and phimosis may be present but their clinical presentation is clearly diff erent and they do not explain SRPEs.(2)

SRPEs belong to the so-called parasomnias, which can be defi ned as undesirable physical phenomena, events (movements, behaviours) or experiences (emotions, perceptions, dreams) that occur during falling asleep, being asleep or while waking up.(3)

Diagnostics and management options for SRPEs are not clearly defi ned. The aim of this study was to review the current literature regarding the hypotheses that concern the pathophysiology and to discuss diagnostics and risks and benefi ts of medical treatment options.

Methods

A systematic search was conducted to identify all literature on SRPE. We searched the electronic database PubMed using the terms ‘sleep-related painful erections’, ‘nocturnal priapism’, ‘treatment’, and ’sleep-related erection’. Complementary, we manually scanned the reference list of all articles and followed-up those assumed relevant. The search covered articles published from 1972 to August 2016. No language restrictions or methodology fi lters were implemented to maximize the sensitivity of searches. Results were described in a descriptive manner. Study reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).(4)

Selection of studies and quality assessment

1291 articles were screened on title and abstract through database searching, of which 82 full texts were assessed for eligibility. No restrictions on level of evidence were applied. Since the search only yielded retrospective and descriptively evaluated case-reports and small case-series no checklists could be used to assess the methodological quality of the studies. [Figure 1]

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42 1291 records screened through database searching 82 full texts assessed for eligibility 20 studies included

single case reports

(n=12) two-case series (n=4) three-case series (n=1) four-case series (n=1) >5 -case series (n=2) 62 full texts

excluded 1209 records

excluded

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of literature reviewing process.

Results

Our search yielded 19 articles including 44 cases with SRPEs, which were reported in a mono- institutional case series of 17 patients,(5) 12 single case reports,(6-17) four two-case series,(2,18-20) one three-case series,(21) and one four-case series.(22) One 2-case report written in Korean language was excluded. Data were supplemented by our recent mono- institutional series of 24 patients.(23) (Table 1) In the latter, two patients were overlapping with the four-case series described by Van Driel et al. in 2007.(22) Since the included studies were confined to retrospectively described case studies, the risk of bias is assumed to be high and the level of evidence not higher than IV to V (Table 1).

Theories about the pathophysiology concerned increased serum testosterone levels,(23) altered autonomic function,(24) compression of the lateral preoptic area,(10)] co-existent obstructive sleep apnoea syndrome,(2,17,17) the existence of a `compartment syndrome’(23) and psychosomatic factors.(18,21)

Several diagnostics were performed in cases described in literature, including laboratory testing for endocrinological and metabolic abnormalities, penile duplex/Doppler ultrasound, ultrasound of the kidneys/pelvic area, polysomnography (PSG) with or without simultaneous nocturnal penile

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43 tumescence and rigidity (NPT-R) measurement, electromyography (EMG) of the ischiocavernous – and bulbospongious muscles and magnetic resonance imaging (MRI) of the brain and/or spine. Diagnostic fi ndings are shortly summarized in Table 1.

Multiple agents have been investigated to manage SRPEs, including antidepressants, antipsychotics, anti-epileptics, benzodiazepines, anti-androgens, beta-blockers, phosphodiesterase type 5 (PDE5) inhibitors, muscle relaxants, anticholinergics, beta- mimetics and cardiac glycosides. Results of the diff erent pharmacologic treatment options for the management of SRPEs are summarized in Table 2.

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44

Table 1. O

ver

view of all SRPE c

ases r ep or ted in lit er atur e fr om 1972 t o 2017 (n=66) (k ey w or ds: sleep -relat ed painful er ections , nocturnal priapism, REM sleep , sleep -relat ed er ections): N= n umber of c

ases described in the ar

ticle . F or e ver y ar e list ed: c

ase special char

act eristics , c omorbidities , diagnostics as w as described in the ar ticle (N=normal), treatment effor ts and their effic ac y (- = no effect, + = transient or par tial effect during X w eeks , ++ = full remission af ter X w eeks of follo w -up , ? = no information) r epor

ted side effects

. In the last c

olumn pr

esumptions r

egar

ding the pathophysiology stat

ed in the ar ticle ar e list ed . A ut ho r N Ag e (y ea rs ) D et ai ls C omo rb id iti es D iagn os tic s Tr ea tm en t Do se (mg ) Effe ct (w eek s) Si de ef fe ct H yp ot he sis o n pat hop hys io logy Jova nov ic 1972 2 57 45 ad 1+ 2: + h ypop ot enc y ad 2 : S R PE s o cc ur re d p ar al lel to d is sa tis fa ct io n a nd str es s w ith in (s ex ua l) r el at io ns hi p ad 1 : v ar ic es , g as trit is , sl ee pd is or de r, a nx ie ty ad 2 : t ub er cu lo si s ? ad 1 : n o t re at m en t ad 2 : ps yc ho the ra py dna dna dna ++ NA NA - psyc hos om at ic Fi sh er e t al 1972 1 ? ? ? ? ph en el zi ne 75 + los s of s ex dr ive ? M at te w s e t al 1987 1 63 SR PE a cc om pa ni ed w ith fe el ings o f t ens ion pe rine um gl au com a - P SG : i ns om ni a M AO I ( not spe ci fie d) pr opa nol ol ? 10 - + 12 - - - St ei ger e t al 1989 1 31 SR PE a cc om pa ni ed w ith l os s of se x dr iv e - - PSG : t ot al sl ee p tim e↓ a w ak eni ngs ↑ - NP T-R : s hor t a nd i nc omp le te S RE s di az ep am cl oz ap in e ami trip ty lin e tri m ip ra m in e bi pe ride ne 5 25 50 100 4 - ++ 36 - - - - - - - - - i m pa ire d ne ur ot ra ns m is si on Fe rin i -St ra mb i e t al 1996 6* 1= 44 2= 63 3= 35 4= 53 5= 36 6= 59 - - - - ad 6: m yo ca rd ia l in fa rc tio n - l ab (h /m ): ad 1 -6 : N - do ppl er : ad 1 -6 : N - PSG : a d 1 -6: sl ee p ef fici en cy ↓ R EM -s le ep fr ag m R EM -s leep % ↓ w ak e t im e↑ - bu lbo -c av er no us r ef le x t es t: ad 1 -6: N ad 1 ,3 : a m itr ip ty lin e? ad 2: p ro pr an ol ol ad 4, 6: lo ra ze pa m ? ad 5: pa ro xe tine ? 20 ? 20 - + 5 - + 12 - - - - - be ta -a dr en er gi c h yp er ac tiv ity C al vet 1999 3 1= 48 2= 69 3= 31 ad 1+ 2: SR PE s oc cu rr ed /d is ap pe ar ed p ar al le l to d is sa tis fa ct io n a nd str es s w ith in (s ex ua l) r el at io ns hi p ad 1, 2, 3: a nxi et y ad 2 : pr em at ur e ej ac ul at io n a d 3: c on ge ni ta l pe ni le cu rva tur e - do ppl er : a d 1, 2: hyp er tro phy m . IC+ BS - PSG : a d 1 -3: a w ak eni ngs ↑ s ta ge sh ift s↑ s ta ge 1 sl ee p% ↑ - NP T-R : a d 1 : dur at ion S R E↑ ad 2, 3: fr eq ue nc y SR E↑ un st ab le /in co m pl et e/ flu ct ua ting S R E ad 1: bet a-bl oc ke r ad 1 : d ia ze pa m ? ad 1 : T CA (n ot sp eci fied ?) ? ad 1 : c ar ba m az ep in e? ad 1 : f luvo xa m ine ? ? ? ? ? ? - - - - - - - - - - - p syc hos om at ic a nd/ or i m pa ire d n eur ol ogi c c ont rol m m . I C e n B S

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45 M en en de z 1999 1 34 H IV -in fe ct ed NA (du e t o i m pa ire d ge ne ra l c ond iti on) pa rox et ine 20 + ? - Sz ücs e t al 2002 1 65 Ex tra ma rit al se xu al ac tiv ity de pr es si on - l ab (n .d .) : N - M R I s pi ne : N - M R I b rai n: lef t c er eb ral ar te ry c om pr es se s LP OA - P SG + pha llog ra ph y: di sr upt ed sl ee p, aw ake ni ng fr om R EM sl ee p due to e re ct io n la st in g 3 -8 m in. m et opr ol ol cl oz ap in e cl on az ep am cl om ip ra m in e ? ? ? ? - - - + ? - - - - - ne ur ov as cul ar c om pr es si on L PO A R our ke 2002 2 1= 41 2= 35 - ad 2 : m eg al ope ni s w ith im pa ire d sex ual func tion - l ab (m ): ad 1, 2: N ad 1 : a lpha - a dr en er gi c a gon is t ad 1 : di gox ine ad 1 ,2 : b ac lof en ad 2 : Gn R H a gon is t ? ? 40 + ? + ? ++ 20& 48 ++ di st ur ba nc e of sl eep cy cl e ‘t ro ub le so m e’ ? m ild d iz zin es s im po te nc e - Ru iz -C as ta ne 2002 2 1= 55 2= 60 ad 1 : is ch ae mic ca rdi opa thy hyp er te ns ion - l ab (s T) : a d 1: N - NP T-R : ad 1 : SR E 7x 70% rig id ity ad 2: ri gi di ty ↑ ad 1 : l or az ep am ad 1, 2: c yp ro te rona et at e ad 2 : t er bu ta lin e ad 2 : d ia ze pa m 1 50 5 10 + -/+ - + + - Loss of li bi do - - - m ec ha ni sm is pr oba bl y ce nt ral Y am aguc hi 2004 1 66 - O be si ty OS AS PLM S - l ab (n .d .): N - P SG : A H I↑ sl ee p ef fici en cy ↓ R EM -s leep % ↑ - NP T-R : N cl om ip ra m in e 25 ++ ? - - ne ur ov as cul ar c om pr es si on L PO A K ar se nt y 2005 1 45 - ope ra tion for inc om pl et e s pi na l co rd le si on a s a re sul t of a thor ac al epe nd ym om a T h6 -Th7 NA ami trip ty lin e 125 + 3 da yti me sl ee pi ne ss a nd conc ent ra tion di ff ic ul tie s - r el at io n w ith p ria pi sm ? - da m age to LP O A - i nc omp le te s pi na l c or d l es ion? Tab el 1 : Con tinu ed (1) Table 1. contin ued

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46 V an Dr ie l 2007 4 1= 47 † 2= 48 † 3= 34 4= 66 ad 1 : m ild d epr es si on due to SR PE ad 2: a nxi et y d ue to S R PE ad 3 : i nc re as ed p el vi c f lo or m us cl e t on e ad 4 : S R PE s a cc om pa ni ed w ith u rina ry ur ge nc y ad 2 : HNP L 5-S1 & ce re be lla r c ys t - l ab (s T): a d 1, 2: N - d opp le r: ad 1: N - NP T-R : ad 1, 3, 4: sus ta in ed er ec tile a ct iv ity ↑ ad 2: N a d 3, 4: du rat io n↑ - E M G m .IC +B S: a d 1: N ad 1 : n itr az ep am ad 1 : te rb ut ali ne ad 1 : b ic al uta mid e ad 1 : c ar ba m az ep in e ad 1 : a mit rip ty lin e ad 1 : b ac lof en ad 2 : m id azo lam ad 3 : i m ip ra m in e ad 3, 4: c lo na ze pa m ad 4 : c yp ro ter on ac et ad 4 : a m itr ip ty lin e 5 5 50 100 100 30 15 25 1 50 25 - - - - + ++ 24 ++ 16 - ++ 20& 36 - - - - - - loss o f in itia tiv e - - - dizz in es s - - - β -a dr ene rgi c hy pe ra ct ivi ty - da m age to LP O A - i nc omp le te s pi na l c or d l es ion - l oc al d is tu rb an ce s o f ne ur ot ra ns m is si on o r e ndo th el ia l f un ct ion - i m pa ire d n eur ol ogi c c ont rol mm. IC e n B S Fe rr é 2010 2 1= 63 2= 58 ad 1 ,2 : S R PE s d is ap pea re d pa ra lle l to C PA P tre at me nt ad 1 : hy pe rte ns ion ad 1 ,2 : OS A S ad 2 : a nxi et y ad 2 : mil d B PH + po st voi da l re si du - l ab (h /m) : a d1 : N - u ltr as ou nd ur ina ry sy st em : ad 1, 2: N - M R I br ai n: ad 1 : h ypox ic le si on s f ron ta l r egi on ad 2: se mi -ov al ic c en tre a nd righ t m es enc epha lo n - PSG : a d 1, 2: AHI ↑ ad. 1: fi na st eri de ad. 1: a te no lo l + br om az epa m ? ? - + 8 - - - - r el at io n w ith O SA S: a lte ra tio ns in a ut onom ous s ys te m s a nd bl ood g as p ar am et er s. C hi ne r 2010 1 50 - de af -m ut e an xie ty - PSG : s ev er e R EM -sl ee p fr ag me nt ati on - NP T-R : 9x SR E ci ni ta pr id e 1 + 24 - d os e w as ti trat ed up t o 3m g in thr ee dos es - β -a dr ene rgi c hype ra ct iv ity ? K uha di ya 2014 1 77 - es se nti al tr emo r - l ab (n .d .)+ ur in e sc re en in g: N cl on az ep am 1 ++ 48 - - β -a dr ene rgi c hype ra ct iv ity u nl ike ly M el la do 2014 1 59 SR PE s + b ur ni ng a nd ti ngl ing se ns at io ns in pe ni s a nd pe rin ea l ar ea - PSG : R EM sl ee p fr ag me nt at io n ga ba pe nt in e co mb in ed w ith cl on az ep am 300 1 ++ ? - - D e Fr ei ta s G . S ua re s 2014 1 35 - re ac tiv e ar th rit is (tr an sie nt) - P C R c hl am ydi a. he rpe s s im pl ex : N - l ab (h /m) : N - CT : N - M R I s pi ne : se ro ne ga tive spon di loa rthr opa thy ba cl of en c om bi ne d w ith c lo na ze pa m 10 0.5 ++ 8 - - i m pa ire d n eur ol ogi c c on tro l o f mm. IC a nd B S - i sc he m ia ? Table 1. contin ued

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47 A bouda ₂₀₁₆ 1 61 - S R PE s i nc re as ed d ur ing C PA P t reat m en t - Ex tra m ar ital se xu al ac tiv iti es - A ss oci at ed ra di at in g p ai n t o s cr ot um a nd pe lv ic fl oo r, w ith re lie f o f p elv ic te ns io n by w al ki ng a nd fl at us - N o a bn or m al iti es o n M R I OS AS , dy sli pi da emia hype rte ns ion , pr os ta te hy pe rpl as ia - u ltr as ou nd: N - PSG : AHI ↑ + s ev er e de sa tur at ion - vi de o s ur ve ill an ce d ur in g PSG : 4x S R E of w hi ch 2 x p ai nf ul pa rox et ine fin as te rid e pr opa nol ol 20 5 40 + 12 - - - - n o re la tion w ith O SA S - ne ur ov as cul ar c om pr es si on LP OA? V re ugde nhi l 2017 †† 24 53 (38-7 4) ** - 1 2/ 24 su ffe re d fro m r adi at in g p ai n t ot a dj ac ent a re as . - 5 ou t of th es e 1 2 a ls o s uf fe re d fro m L U TS . - 2/ 24 pa tie nt s e xp er ie nc ed a ss oc ia tio n w ith st re ss a nd /o r ma rit al is su es . C V D 6 x D M II 3x Pu lm on ar y d is ea se 3x OSAS 1 x A bdom in al sur ge ry 6x Scrot al sur ge ry 3x Spi ne sur ge ry 2x LU TS 5 x Pr em at ur e ej ac ul at io n1x M oo d di so rde r 2 x (o f w hi ch o ne co mb in ed w ith anxi et y di sor de r) C hr on ic fa tigu e synd rom e 1x - l ab ( sT , 22 x) : N - d opp le r ( 8x ): 3 x: re stf lo w ↑ 5 x: N - NP R (15x ): 7x: S R E d ur at io n + fr eque nc y↑ 7 x: N 1 x: fa ile d ba cl of en 14x cypr ot er on ac et aa t 7 x ami trip ty lin e 5 x tada la fil 4 x pelv ic p hys io the ra py 5x no tr ea tm en t 4 x 10-80 10-50 20-30 5 NA NA ++ (3 x) + ( 10x ) - ( 1x) - ( 7x) + ( 2x) - ( 3x) ++ ( 2x) - ( 1x) ? ( 1x) ++ ( 3x) - ( 2x) ++ ( 1x) + ( 1x) - ( 1x) ? ( 1x) dr ow si ne ss, he ad ac he , m ya lg ia , i ns om ni a im pai red E E dr ow si ne ss , m ood di sor de rs no si de e ff ec ts NA NA - p elv ic flo or mu sc le hype rton ia - i sc he m ia Table 1. contin ued

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48

Table 2. P

harmac

olo

gic options for the management of SRPEs

. Mechanism of action, dose applic

ation, effic ac y (- = no effect, + = tr ansient/par tially effectiv e, ++ = full permanent r emission of sympt oms , ? = no information av ailable), pot ential/r epor

ted side effects and specific

ations if applic able . Tr ea tm en t M ec ha ni sm M ed ic at io n Do se (mg ) Ef fica cy C as es + re f Effe ct Si de ef fe ct s C om me nts An ti-de pr ess an ts ; MA O Is, TCA s, S SRI s (ph en el zin e, a m itr ip ty lin e, cl om ip ra m in e, i m ip ra m in e, tri m ip ra m in e, p ar ox et in e, flu vo xa m in e) R EM s leep supp re ss ion; I nh ibi ts de gr ada tion o r s yna pt ic r eup ta ke of se rot oni n a nd nor adr ena lin; an tic ho lin er gi c, an tih is ta min er gic e n se dat iv e. fe nel zi ne ami trip ty lin e cl om ip ra m in e im ip ra m in e tri m ip ra m in e pa rox et ine flu voxa m ine 45-75 20-12 5 25 25 100 20 - 2 ca ses 5,6 8c as es 4, 7, 11, 21, 22 2 ca ses 9, 10 1 ca se 21 1 ca se 7 3 ca ses 4, 8, 16 1 ca se 20 2/ 2 + 4/ 8 + , 4/ 8 -1/ 2 + +, 1/ 2 + 1/ 1 - 1/ 1 - 3/ 3 + 1/ 1 - Sl ee pi ne ss , i m pa ire d conc ent ra tion , l os s o f s ex d rive , lo ss in iti at iv e, M AO Is ha ve pot en tia lly f at al si de ef fec ts M ost ly a pp lie d in lo w d os e; li ttl e ef fe ct o n RE M sl ee p c an b e e xp ec te d An ti-ps yc ho tic s (c lo zap ine ) D ib en zo dia ze pi ne de riv at iv e w ith pa ra sy m pa tic ol yt ic a ct io n; i nh ib its gl ut am ate . B lo ck s m an y ne ur otr an smit te rs . cl oz ap in e 25 2 ca ses 7, 9 1 /2 + +, 1/ 2 - Sl ee pi ne ss , d iz zi ne ss a nd co ns tip at io n. Po te nt ia lly f at al si de e ff ec t ( m ye los upp re ss io n) An ti-ep ile pt ic s (c ar ba m az epi ne , pr ega bal ine , ga ba pe nt ine ) Inhi bi ts th e conv er si on of g lut am at e; se da tive a nd a nt ic hol in er gi c. ca rb am az ep in e pr eg aba line ga ba pe nt in e 100 - 300 1 ca se 21 1 ca se 22 ca se 14 1/ 1 - 1/ 1 - 1/ 1 + + N one m ent ion ed . P ot ent ia l s id e ef fe ct s i nc lud e l eukop en ia , di zz in es s, dr ow si ne ss , na us ea , he ad ac he . The se a nt i-e pi le pt ic s ca n al so b e us ed as n eur opa thi c pa ink ill er s G ab ape nt ine w as us ed co m bi ne d w ith cl on az ep am B en za m id es (c in ita pr id e) St ro ng c ho line rgi c ac tion ; bl oc ks pr es yna pt ic r ec ept or s for s er ot oni n an d t he re by ra is es s er oto ni n re le as e; in cr ea se d se ro to ni ne rg ic a ct iv ity , al so d is cr et e a nt id op am in er gi c ci ni ta pr id e 1 1 ca se 12 1/ 1 + N one m ent ion ed . P ot ent ia l s id e ef fe ct s i nc lud e dr ow si ne ss , di ar rhe a, i nv ol unt ar y m us cul ar m ov em ent s of t he he ad, n ec k and t ongue . Th is dr ug is m ai nl y us ed in S pa in an d M exi co, n ot a pp rov ed in t he N et he rla nd s B en zo di az ep in es (sh ort -, m edi um - en l on g ac ting) R EM sl ee p s uppr es si on, m us cl e re la xa nt. cl on az ep am mi da zo la m lo ra ze pa m ni tra ze pa m br om az ep am di az ep am 1 15 - 5 - 5 6 ca ses 9, 13 -1 5, 21 1 ca se 21 2 ca ses 4,1 9 1 ca se 21 1 ca se 2 3 ca ses 7, 19, 20 5/ 6 + +, 1/ 6 ? 1/ 1 - 2/ 2 - 1/ 1 - 1/ 1 + 2/ 3 -, 1/ 3 + D iz zi ne ss , sl ee pi ne ss , a nx ie ty , na us ea . P hy si ca l de pe nd enc e i n long -te rm u se a nd w ith dr aw al sym pt om s i f s to ppe d a br upt ly . C lo na ze pa m w as us ed c om bi ne d w ith anot he r m edi ca tio n tw ic e ( ba cl of en , ga ba pe nt in e) . B ro m az ep am w as us ed in co m bi na tio n w ith a be ta -b lo ck er An ti-and rog ens (c yp ro te ro na ce ta te , bi ca lu ta m id e) B loc ki ng t he a nd rog en r ec ept or f or DHT a nd t es to st er on e. Al so a nti -gona dot rop ic . cypr ot er ona ce t at e bi ca lu ta m id e 10-50 50-10 0 10 cas es 19, 21 ,22 1 ca se 21 1/ 10+ +, 9/ 10 - - Los s of s ex d rive , di m ini she d qu al ity o f e ro tic er ec tio ns , os te opo ro si s It is a dv is ab le to d et er m in e s er um te st os te ron e le ve ls be for e u si ng a nt i-andr oge ns

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49 Be ta -b loc ke rs (p rop an ol ol , m et op rol ol , at en ol ol ) Ef fe ct is po ss ibl e ba se d on (te m por ar y) re st or at ion o f aut onom ic dys re gul at ion . I t a ls o low er s s er um te st os te ron e le ve ls . pr opr ano lol m et opr ol ol at enol ol 10-20 - - 3 ca ses 4, 6, 16 2 ca ses 9, 22 1 ca se 2 2/ 3 + , 1/ 2/ 2 - 1/ 1 + A m ongs t o th er thi ngs : s le ep di st ur ba nc es , br ad yc ar di a, R ayna uds ’ s ynd rom e, exha us tio n, e re ct ile d ys func tion A te nol ol w as u se d c om bi ne d w ith br om az ep am PD E5 -in hi bi to rs (ta dal af il) Enha nc es P D E5 func tion ing a nd in cr eas es c G M P l ev el s, of w hi ch th er e mi gh t p re su ma bl y b e a d ef ic it in th e s m oo th m us cl e ce lls o f t he pa tie nt s co rp or a ca ver no sa. ta da la fil 5 4 ca ses 22 2/ 4 + +, 2/ 4 - W el l t ol er at ed in thi s l ow dos e. Po ss ib le s id e ef fe ct s i nc lu de he ad ac he , f lu sh in g, n as al obs tru ct ion , r hi ni tis , di zz ine ss M os tly s uc ce ss ful te st ed in pa tie nt s w ith re cu rr en t p ria pi sm . M us cl er el ax an ts (bac lo fe n) GAB A -a go ni st, in hi bi ts e re ct io n an d e ja cu la tio n, re la xa tio n of m m . IC & BS . ba cl of en 10-75 17 cas es 15, 18, 21, 22 7/ 17 ++ 9/ 17 + 1/ 17 - D row si ne ss , di zz ine ss , he ad ac he , n au se a, h yp ot en si on H ig h r el ap se rat es af te r di sc on tinua tion Pa ra sy mp ati co liti cs (bi pi ri de en) A nt ic ho lin er gic ; in hi biti ng pa ra sym pa th ic , pr o-er ec til e a ct io n. bi pi rid ee n 4 1 ca se 7 1/ 1 - Po ss ib le s id e ef fe ct s i nc lu de dr yn es s o f m uc ou s m em br ane s, im pa ire d a cc om m oda tion , m ydr ia si s, ur ina ry re te nt io n, hypoh id ros is , c on st ip at ion , ta ch yc ar di a, n au se a 5-al pha -r ed uc ta se in hi bi to r (fi na ste rid e) C onve rs ion o f t es to st er one in n on -pot ent D H T fin as te rid e 5 1 ca se 16 1/ 1 - N one m ent io ne d. P os si bl e s id e ef fe ct s i nc lu de : e re ct ile dys func tion , l os s of se xd rive , gyna ec om as tia Be ta -mi me tic s (te rb ut ali ne ) β-2 s el ect iv e sy m pa tico -m ime tic s w ith a ls o α-adr ene rg ic pr ope rti es . te rb ut al in e 5 2 ca se s 19 ,21 1/ 1 - Po ss ib le si de e ff ec ts in cl ud e: he ad ac he , b lus hi ng di apho re si s, ta ch yca rd ia, qu ive ring, h ot flus he s, na us ea O nl y i nv es tig at ed in tr ea tm en t o f pr ia pi sm, d ata is li mit ed C ar di ac g lyc os ide s (di gox ine ) Inhi bi ts sod ium /p ot as si um /A TP -a se in s m oo th m us cl e, le ad ing tot smo oth mu sc le c ell c on tra cti on . di go xi ne 0. 25 -0. 50 1 ca se 18 1/ 1 + Pa tie nt e xp er ie nc ed b ot he rs om e si de e ff ec t ( no t d ef in ed ). Po ss ib le s id e ef fe ct s i nc lu de di zz in es s, v is ua l d is tu rb an ce s, ar itmia s, E C G d is tu rb an ce s B ec au se o f t he s m al l t he ra pe ut ic in de x a nd p ot en tia lly fa ta l s id e ef fe ct s, r ou tine us e of thi s dr ug i s di sc ou rag ed Table 2. contin ued

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50

Discussion

Sleep-related erections (SREs) have been observed in boys and men of all ages and were even described in an unborn.(25) SREs are perceived to represent an intrinsic protective mechanism to secure the morphodynamic integrity of the corpora cavernosa (CC).(26)

The SRPE population showed heterogeneity with respect to age and medical history. The mean (±SD) age of men suffering from SPRE is 52(±11.79). Some authors assume a possible relation between SRPE and certain comorbidities, but overall SRPE appeared neither to be related to comorbidities, nor associated with other sexual problems. Reports with regard to the influence of alcohol and food on SRPEs are inconsistent. No other risk factor can be identified. Several studies sought to understand the aetiology and pathophysiology of SRPEs, which are thought to embody an abnormal extension of SREs.

Neurophysiology of the sleep-related erection

The brainstem contains all structures necessary for the generation of REM sleep. Schmidt and co-workers separated the cerebral cortex from the brainstem by performing a series of transections at the level of the rostral mesencephalon and investigated its effect on REM sleep episodes and associated SREs.(27) In rats with only their brainstem left in situ REM sleep episodes remained intact, while SREs disappeared. This implicates that the cerebral cortex plays an essential role in generating SREs. Subsequently, the same researchers inflicted neurotoxic lesions to various cortical areas to localize the areas involved in controlling SREs. The preoptic area, known to be involved in both slow wave sleep generation and reproductive mechanisms, was their primary region of interest.(28-31) Bilateral lesions of the medial pre-optic area (MPOA) did not have any effect on SREs, whereas lesions of the lateral pre-optic area (LPOA) eliminated SREs while wake-state erections remained intact.(32) These results indicated an important role of the LPOA regarding the generation of SREs.(33) SREs are believed to be (mainly) regulated by dopaminergic systems and systems controlling gamma aminobutyric acid (GABA). In the mammalian brain GABA and glutamate are by far the most common neurotransmitters with GABA acting as a major inhibitor on erection whereas glutamate acts pro-erectile.(34)] Artificially induced SREs in rats using dopamine reuptake inhibitors and/or cocaine could be suppressed using GABA-like agents. (35,36)

Hypotheses regarding the pathophysiology of SRPEs

Increased serum testosterone levels

Androgens exert their influence on central as well as on target organ level. In the central nerve system androgens are mainly involved in sex drive and copulatory behaviour. In the CC androgens are essential for maintaining the endothelial nitric oxide (eNO) production.(37,38) Age, sleep pattern, testosterone secretion and SREs are closely related.(26,39) SREs are already present in infant boys, but eventually become more prolonged and rigid during puberty.(40) Frequency and rigidity of SREs increase after testosterone supplementation in hypogonadal men.(41-44) Additionally, there is an elevation of serum testosterone levels during the non-REM to REM sleep transition, parallel to the development of an SRE.(25,45,46) In older men the circadian rhythm of serum testosterone levels is different from that of younger ones and their testosterone peak levels

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51 in response to gonadotropin stimulation are lower. Moreover, SREs show decreased duration and frequency with increasing age and sleep patterns get more unstable and interrupted.(26,47,48) However, the hypothesis of increased serum testosterone levels contributing to prolonged, more rigid and eventually painful SREs, could not be confi rmed. From the 31 patients in whom serum testosterone levels were measured (between 9-10am), none had levels above the upper limit adjusted for age.(2,5,16,20,22) The treatment with anti-androgens proved to be ineff ective.(23) Additionally, in larger series of patients with variable serum testosterone levels no cases of painful nocturnal erections were reported in patients with increased levels of serum testosterone (>199 ng/dl).(49,50)

Altered autonomic function

The autonomic nerve system plays an important role in the regulation of penile erection. Contraction of trabecular smooth muscle by norepinephrine is dependent on expression of post-junctional alpha 1 and alpha 2 adrenergic receptors.(51) Alpha adrenergic receptor antagonists, administered systematically, facilitate penile erection and in some cases produce prolonged erection or priapism. (52-58) Ferini-Strambi et al. hypothesized that SRPEs are associated with alternated autonomic functions.(24) Compared to controls they found reduced cardiac vagal activity during sleep and a trend towards faster heart frequency accelerations related to spontaneous movements in their 18 patients with SRPE. This would implicate nocturnal beta-adrenergic hyperactivity and it might explain why some SRPE patients experienced a temporary positive eff ect of beta-blockers. However, cardiac vagal activity in SRPE patients has never been further investigated and the positive eff ect of beta- blockers could not be confi rmed in other SRPE studies.(2,7,17,21,23,59) Moreover, in our recent study several patients developed SRPEs while using beta-blockers for cardiovascular problems.(23)

Compression of the LPOA

In an attempt to fi nd a central explanation for SRPEs, Szucs et al. performed MRI of the brain in one patient with SRPEs and found that the left posterior cerebral artery compressed the laterobasal border of the hypothalamus.(10) This site corresponds to the anatomic location of the LPOA. In light of the aforementioned relationship between SRE and the LPOA, this could be a plausible hypothesis. However, visualization of this area by MRI was described in four other patients with SRPE and no such abnormalities were described.(2,12,17,23) More adequate imaging, such as the new 7-T-MRI, may be obligate to visualize subtle vascular or neuronal changes within the hypothalamus, as was stated by Abouda et al.(17) Further investigations are warranted to elucidate its possible contribution.

SRPEs and the Obstructive Sleep Apnoea Syndrome (OSAS)

Ferré et al. assumed a relationship between SRPEs and the Obstructive Sleep Apnoea Syndrome (OSAS).(2) Intermittent alterations of the autonomic system and the exchange of blood gas related to OSAS are thought to interfere with the neural network regulating the SREs. This would create a misbalance between parasympathetic and sympathetic systems, provoking SRPEs. They described two SRPE patients also suff ering from OSAS, who were treated with Continuous

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52

Positive Airway Pressure (CPAP). In both of them the SRPEs disappeared simultaneously with the improvement of their apnoea. In a more recent study, however, the beneficial effect of CPAP treatment on SRPEs could not be confirmed.(17) Of all reported SRPE cases, our own recent study included, only five had associated OSAS,(2,11,17,23) which makes a relationship between SRPEs and OSAS less likely.

A compartment syndrome

Most patients with SRPEs describe a deep penile pain, sometimes radiating to the groins, the abdomen, the (hemi) scrotum and/or the perineal area. During the last phase of a `normal` penile erection a compartment syndrome arises, created by repetitive contractions of the ischiocavernous- and bulbospongious muscles compressing the proximal portions of the CC and corpus spongiosum.(60) A compartment syndrome is characterized by the presence of a persisting high pressure within a fixed space, impeding the micro vascular circulation within the compartment concerned.(61,62) When this penile compartment syndrome persists the tissue of the CC may be exposed to ischemic blood. Basically, pain during SRPEs might be caused by ischemia, as it does in recurrent intermittent priapism (RIP). RIP is a form of low- flow priapism and usually evolves from a non-resolving morning erection (a morning erection represents the last SRE). Occasionally the self-limiting form develops into prolonged ischemic priapism. The pathophysiology of RIP is thought to be explained by reduced availability of endothelial nitric oxide (eNO) in the CC. This may result in down-regulation of the cyclic guanine monophosphate (cGMP)-specific enzyme PDE5 and RhoA/Rho-kinase, which primarily mediate degradation of cGMP.(63-65) Subsequently, an increase of the local intracavernous cGMP concentration occurs and thus prevents the penis from detumescence. Despite of the similarities, there are a few important differences between RIP and SRPEs. Firstly, an SRPE is of short duration and ceases quickly after the patient wakes up. None of the described SRPE patients suffered from haematological disease, whereas sickle cell disease is the most common cause of RIP. Moreover, during nocturnal erection in RIP patients the CC alone are involved, whereas in SRPE patients it involves a complete erection in which also the spongiosum is taking part. The latter was already described by Hinman in the early 20th century.(66)

An increased tone of the pelvic floor muscles, including the ischiocavernous- and bulbospongious muscle, can theoretically contribute to the development of a penile compartment syndrome. Moreover, the hypertonia by itself might as well be an explanation for the pain experienced during SRPEs. It also elucidates the radiating character of the pain to adjacent areas, such as the lower abdomen, groins, scrotum and perineum described by 15 patients in four different studies. (7,15,17,23) Moreover, Calvet found bulbospongious hypertrophy on penile Doppler ultrasound in two of their patients.(21) Van Driel and co- workers described hypertonic pelvic floor muscles at rectal examination that was confirmed by biofeedback measurements performed by the pelvic floor physiotherapist in one of their patients (22) and the patient described by Abouda et al. specifically mentioned pelvic floor tension due to the erection which was relieved by walking and flatus.(17)

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53 The fact that erections related to sexual activity are not impaired in SRPE patients might plead against this hypothesis, because it seems inevitable that in case of pelvic fl oor muscle hypertonia the patient should also experience pain during erotic erections. However, if the sexual stimulus continues, erotic erections mostly end up in an orgasm after a defi ned period of time. Obviously, the ischiocavernous- and bulbospongious muscles will then relax, as they do in SRPE patients who wake up and apply their manoeuvres to make the erection disappear. EMG of the pelvic fl oor muscles was performed only in one patient and showed no abnormalities.(22) A more standard implementation of an EMG of the pelvic fl oor muscles in SRPE patients may help to assess their pathophysiologic contribution and indicate to what extent pelvic fl oor physiotherapy could be eff ective.

Psychosomatics

In the seventies of the last century Jovanovic already emphasized the role of psychosomatic factors.(18,21) SRPEs disappeared simultaneously to the improvement of marital issues and anxiety symptoms. Calvet assumed anxiety and stress to be the cause of the painful erections, instead of the consequence of the associated sleep defi cit.(21) They designated the presence of anxiety symptoms in SRPE cases that were earlier described in literature in order to emphasize this hypothesis.(7,8,67) However, from all SRPE cases described so far, it is in our opinion impossible to draw fi rm conclusions regarding the relationship with stress-, mood- or anxiety symptoms and SRPEs. There are about as much men with pre-existent anxiety symptoms and marital issues as men that develop anxiety due to the progressive sleep deprivation and in our recent study only one out of 24 SRPE patients reported associated marital issues.(23) In the end, the impact of psychosomatic factors on SRPEs can neither be entirely excluded, nor can it fully explain the development of SRPEs.

Evaluation and management

Laboratory test results including hormonal-metabolic assessment and/or general blood counts (n=42), pelvic ultrasound (n=3), penile duplex/Doppler ultrasound (n=18) and EMG of the ischiocavernous-and bulbospongious muscles (n=1) did not show abnormalities in any of the patients. Description of NPT-R observations (n=26) varied from short, partial and/or incomplete erections (n=3) to prolonged, more frequent periods of nocturnal erection with increased rigidity and increased total tumescence time (n=14). Completely normal NPT-R results were also described (n=9). Due to this wide variety, NPT-R results cannot directly be interpreted as a representation of the extent and seriousness of the SRPE, but are of added value to monitor disease progression and/ or evaluate treatment effi cacy in the patient concerned. PSG showed (REM) sleep fragmentation and reduced sleep effi ciency in all patients (n=16). Therefore it is useful to objectively render the infl uence of the SRPEs on the patients sleep pattern and –quality and assess treatment effi cacy. Gas analysis of intracavernous blood aspirated during an SRPE would be convenient to assess the presence of ischemia during an SRPE. However, due to the invasive character it is not reasonable to implement this procedure as a standard diagnostic in this self-limiting disorder.

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54

Based on the processes involved in nocturnal erections one can speculate about the efficacy of certain drugs on the SRPEs (Table 2). Pharmacological interference might be achieved by hormonal inhibition of nocturnal erections, improvement of sleep architecture, REM-sleep suppression, analgesia and/or relaxation of pelvic floor muscles.

Muscle relaxants – baclofen (Lioresal®)

Baclofen is a skeletal muscle relaxant, which acts on spinal and supraspinal sites. It is a potent GABA-β receptor agonist, inhibiting the release of glutamate and aspartate.(68) In 2004, Andersen and Tufic already described the inhibitory effect of the GABA-ergic system on the frequency of SREs.(36) The beneficial effect of baclofen on SRPES can be explained by the suppression of glutamate release as well as the relaxation of the ischiocavernous and bulbospongious muscles, both involved in penile erection.

Common side effects are most often a consequence of the CNS depressant effect. Over 10 per cent of patients report sedation, drowsiness, dizziness, nausea, headache or hypotension. In literature, baclofen has been applied in 17 SRPE patients described in three different case series and in one case-report. (16,19,22,23) Six out of 17 patients reported a full and permanent remission of symptoms after follow-up periods varying from 8 weeks to 8 years. Another ten reported a partial relief and only one experienced no effect at all. On the long term (≥ six months) five out of the 17 patients were still using baclofen and reported full remission, without experiencing too many side effects. However, most patients discontinued the use of baclofen (n=11) because of debilitating side effects (n=3) or for unknown reasons (n=8). Only three of the 11 patients still reported partial or full relief of symptoms after discontinuation. The remainder suffered from a full relapse. In three patients there was no information about the long-term result. The feasibility and applicability of baclofen especially on the long term deserves further investigation.

Antidepressants - phenelzine (Nardil®), amitriptyline (Sarotex®), clomipramine (Anafranil®), imipramine (Tofranil®), trimipramine (Surmontil®), paroxetine (Seroxat®), fluvoxamine (Fevarin®) Antidepressants can be roughly distinguished into Mono-Amine-Oxidase inhibitors (MAOIs), Tricyclic Antidepressants (TCAs) and Specific Serotonin Reuptake Inhibitors (SSRIs). All of them have an inhibitory effect on the downregulation or synaptic reuptake of serotonin and/or noradrenalin, resulting in an anticholinergic, antihistaminic and sedative effect.(68)Increased availability of serotonin and noradrenalin appears to be associated with suppression of REM sleep, which is assumed to be the common mechanism of action of these drugs on SRPEs. The anticholinergic properties also ensure blockade of the peripheral autonomous nerve system. (5,15)

Amitriptyline (TCA) is the most used antidepressant in the SRPE cases described in the literature (n=8) and proved to be effective on the short-term in four. The other four did not notice any improvement. Other antidepressants were experimentally applied in nine different SRPE patients, with TCAs in four cases (clomipramine, imipramine, trimiparine, fluvoxamine), SSRIs in three (paroxetine and fluvoxamine) and a MAOI (phenelzine) in two. The effect of these drugs showed

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55 variable results. Imipramine, trimipramine en fl uvoxamine were applied in single cases without any noticeable eff ect. Phenelzine (n=2), paroxetine (n=2) and clomipramine (n=2) showed transient effi cacy in almost all subjects. Only one patient treated with clomipramine 25mg experienced a permanent benefi cial eff ect.(11) Long-term applicability was either not possible due to debilitating side eff ects (n=5) or not described. In particular MAOIs might have potential fatal side eff ects related to bone marrow suppression.

Benzodiazepines – clonazepam (Rivotril®), midazolam (Dormicum®), lorazepam (Temesta®), nitrazepam (Mogadon®), bromazepam (Lexotanil®), diazepam (Stesolid®)

In addition to the suppression of REM sleep, these drugs generally cause muscle relaxation by enhancing the eff ect of the neurotransmitter GABA as well as reducing the excitatory glutamate transmission. Clonazepam has already proven its effi cacy for the treatment of other REM sleep related parasomnias.(69,70) We found six SRPE patients who had been treated with clonazepam. (10,14-16,22) In fi ve of them clonazepam proved to be eff ective on the short-term (<1 year), in the other one the eff ect was not described. However, this positive result could not fully be attributed to the use of clonazepam alone since in two successfully treated patients clonazepam was administered together with respectively gabapentin(15) and baclofen(16).

Benzodiazepines interfere with cognitive and motor performances, as they lead to central nervous system depression. This, in addition to the fact that long-term use may result in tolerance, physical dependence and withdrawal symptoms if stopped abruptly, provides a limited long-term applicability of benzodiazepines in the treatment of SRPEs.

Anti-psychotics – clozapine (Leponex)

Clozapine was merely used in two cases of SRPE with inconsistent result.(8,10) The precise mode of action is not clear. It is a dibenzodiazepine derivate with anticholinergic eff ects and an inhibitory eff ect on glutamate. Moreover, it blocks neurotransmitters including noradrenalin and, to a lesser extent, dopamine.(68) The anticholinergic properties inhibit the peripheral autonomous nerve system that, amongst other things, mediates erection.(8) However, clozapine has potentially dangerous and even fatal side eff ects as agranulocytosis and myocarditis. The strong sedative eff ect often leads to drowsiness and daytime fatigue. Moreover, clozapine can cause priapism, most likely by α-adrenergic blockade in the CC.(71) This makes clozapine a less favourable drug for patients with SRPEs.

Anti-epileptic drugs – carbamazepine (Tegretol®), pregabalin (Lyrica®), gabapentin (Neurontin®) The possible mode of action of anti-epileptic drugs on SRPEs is based on the inhibition of glutamate conversion as well as sedative and anticholinergic eff ects. However, the three cases in the literature showed disappointing results.(15,22,23) In one case gabapentin was used in combination with clonazepam, so that the eff ect of the anti-epileptic itself was hard to diff erentiate.(15) Given the limited effi cacy described in only a very small number of patients the use of antiepileptic drugs should not be considered as standard therapy for SRPEs.

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Anti-androgens – cyproterone acetate (Androcur®), bicalutamide (Casodex®)

Anti-androgens are androgen receptor antagonists that competitively bind to particular receptors, thereby inhibiting the influence of both endogenous and exogenous androgens. As androgens appear to play an important role in the regulation of SREs, anti-androgens were presumed to be an effective treatment by creating a hypogonadal state. Anti- androgens were successfully used to prevent RIP.(72-75) The flip side of this coin was the concomitant negative impact on erotic erections, loss of sex drive and erectile dysfunction. No effectiveness can be demonstrated in SRPE patients. Cyproteronacetate was used in ten patients; nine of them reported no improvement of symptoms.(20,22,23) The only patient who reported improvement used cyproteronacetate combined with baclofen 20mg. Bicalutamide was used in only one patient without success. (22) Besides the disappointing results eight of these nine patients reported the aforementioned debilitating sexual side effects. Therefore, anti-androgens should not be implemented as a standard treatment of SRPE.

Beta-blockers – propranolol (Inderal®), metoprolol (Selokeen®), atenolol (Tenormin®)

Beta-blockers were thought to have a positive influence on the aforementioned described adrenergic hyperactivity observed in some SRPE patients during sleep.(24) Additionally, beta-blockers lower serum testosterone levels by a direct effect on the Leydig cells.(76) In literature, five cases of SRPE patients treated with a beta-blocker were described; three used propranolol, one metoprolol and the other one atenolol.(2,7,10,17,24) A temporary positive effect was reported in two patients who used propranolol for 5 and 12 weeks respectively and in one who used atenolol combined with bromazepam for 8 weeks. In the latter the combined treatment makes it hard to assess the effect of the beta-blocker alone. The two patients using respectively metoprolol and propranolol did not notice any positive effect, so beta-blockers do not appear to be suitable for long-term treatment of SPRE.

Phosphodiesterase type 5 (PDE5) inhibitors – Tadalafil (Cialis®), Sildenafil (Viagra®)

The cGMP-specific PDE5 enzyme is responsible for the degradation of cGMP. PDE5 inhibitors ensure reversible inhibition of the enzyme. Thereby they provide an increase of the local intracavernous cGMP concentration and thus serve to prevent the penis from detumescence. For this reason, they are used by patients with erectile dysfunction. However, the drugs may have a paradoxical effect, when used in the long-term in low doses.(64,77-83) These cause an elevated basal level of penile cGMP, which consequently results in restoration of PDE5 expression and activity. According to the European guidelines on priapism 25 mg sildenafil daily or 5 mg tadalafil daily or three times a week, may alleviate and prevent intermittent priapism.(84) The application of tadalafil might also be interesting for SRPE patients, given the hypothesis that the pathophysiologic mechanism of SRPEs possibly corresponds to that of intermittent priapism.

In low doses side effects are confined, but can include headache, syncope, flushing and nasal congestion, all due to the vasodilating properties of PDE5 inhibitors. Unfortunately, for most patients in Europe PDE5 inhibitors are not covered by medical insurances.

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57 Nevertheless it is too early to give a substantiated advice about the use of PDE5 inhibitors in SRPE patients, while they were applied in only four patients.(23) One of them reported full and permanent relief of symptoms, one experienced partial remission and in two tadalafi l was not benefi cial at all. None of them experienced side eff ects.

The remainder drugs, including cardiac glycosides, parasympaticolytics, 5-alpha reductase inhibitors, benzamides and beta-mimetics, were sporadically used without any benefi cial eff ect in any of the cases described in literature.

Conclusions

SRPE is an unusual and poorly recognized phenomenon. There are a few plausible explanations about the underlying pathophysiology, but none of these has yet been substantiated. In our opinion, hypertonia of the pelvic fl oor muscles might be the most conceivable one. A combination of diagnostics including gas measurement of blood aspirated from the CC during an SRPE, NPT-R measurement with simultaneous PSG and EMG of the pelvic fl oor muscles and functional brain MRI would be helpful to further determine the origin of SRPE and thereby optimize treatment advice. Unfortunately, performing all of these diagnostics together in every patient has not been feasible due to their invasive and burdensome character and costs.

The literature on the treatment of SRPE is largely based on case-reports and small case-series rather than randomized controlled trials. Current data suggest promising effi cacy of baclofen and, to a lesser degree, clonazepam. These drugs showed noticeable results in multiple cases, most likely on account of their infl uence on the GABA-ergic system and consequently the suppression of glutamate release, which contributes to relaxation of the pelvic fl oor muscles. Prospective controlled investigations are needed to assess the effi cacy and safety of long-term use of baclofen and come to an evidence-based treatment advice.

Acknowledgements

None

Disclosure statement

Financial disclosure: none

Confl icts of interest: Sanne Vreugdenhil, Alida Weidenaar and Igle Jan de Jong: no confl icts of interest. Mels van Driel: speaker for GSK and Lilly

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58

References

American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.

Ferre A, Vila J, Jurado MJ, Arcalis N, Camps J, Cambrodi R, et al. Sleep-related painful erections associated with obstructive sleep apnea syndrome. Arch Sex Behav 2012;41(4):1059-63.

Howell MJ. Parasomnias: an updated review. Neurotherapeutics 2012 Oct;9(4):753-75.

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015 Jan 1;4:1 doi: 10.1186/2046-4053-4-1.

Ferini-Strambi L, Oldani A, Zucconi M, Castronovo V, Montorsi F, Rigatti P, et al. Sleep- related painful erections: clinical and polysomnographic features. J Sleep Res 1996;5(3):195- 7.

Fisher C, Gorss J, Zuch J. Cycle of penile erection synchronous with dreaming (Rem) Sleep. Preliminary report. Arch Gen Psychiatry 1965;12:29-45.

Matthews BJ, Crutchfield MB. Painful nocturnal penile erections associated with rapid eye movement sleep. Sleep 1987;10(2):184-7.

Steiger A, Benkert O. Examination and treatment of sleep-related painful erections - a case report. Arch Sex Behav 1989;18(3):263-7.

Menendez Lopez V, Mora Rufete A, Prieto Chaparro L, Galan Llopis JA, Fernandez Puentes C, Garcia Lopez F. Painful erections related to sleeping. Actas Urol Esp 1999;23(6):539-41.

Szucs A, Janszky J, Barsi P, Erdei E, Clemens Z, Migleczi G, et al. Sleep-related painful erection is associated with neurovascular compression of basal forebrain. J Neurol 2002;249(4):486-7.

Yamaguchi,Yuji, Ohki,Kaoru. First case report of sleep-related painful erection in Japan. Sleep and Biological Rhythms 2004;2:159-61.

Karsenty G, Werth E, Knapp PA, Curt A, Schurch B, Bassetti CL. Sleep-related painful erections. Nat Clin Pract Urol 2005;2(5):256-60.

Chiner E, Sancho-Chust JN, Llombart M, Camarasa A, Senent C, Mediero G, et al. Sleep- related painful erection in a 50-year-old man successfully treated with cinitapride. J Sex Med 2010;7(11):3789-92. Kuhadiya ND, Desai A, Reisner M. Sleep-related painful erections in an elderly man successfully treated using clonazepam. J Am Geriatr Soc 2014 Feb;62(2):407-8.

Mellado M. A case of sleep-related painful erections with chronic daytime genital discomfort. Urologia 2015;82(3):184-6.

De Freitas G. Soares, D, Luis Rhoden E. A 35-year old man presenting sleep-related painful erections (Erpes): A case report and review of literature. Advances in Sexual Medicine 2014;4(1):6-10.

Abouda M, Jomni T, Yangui F, Charfi MR, Arnulf I. Sleep-related painful erections in a patient with obstructive sleep apnea syndrome. Arch Sex Behav 2016;45(1):241-5.

Jovanovic U. Sexuelle Reaktionen und Schläfperiodik bei Menschen. Stuttgart: Enke verlag; 1972. p. 157-93. Rourke KF, Fischler AH, Jordan GH. Treatment of recurrent idiopathic priapism with oral baclofen. J Urol 2002;168(6): 2552-3.

Ruiz-Castane E, Briceno OM, Rodriguez-Villalba R. Sleep-related painful erections. BJU Int 2002;90:1-2. Calvet U. Painful nocturnal erection. Sleep Med Rev 1999;3(1):47-57.

van Driel MF, Beck JJ, Elzevier HW, van der Hoeven JH, Nijman JM. The treatment of sleep-related painful erections. J Sex Med 2008;5(4):909-18.

Vreugdenhil S, Weidenaar ACW, De Jong IJ, Van Driel MF. Sleep-related painful erections - a case-series of 24 patients regarding diagnostics and treatment options. Sex Med. 2017; In press : e1-e7 https://doi. org/10.1016/j.esxm.2017.09.001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chapter 4

(22)

59 Ferini-Strambi L, Montorsi F, Zucconi M, Oldani A, Smirne S, Rigatti P. Cardiac autonomic nervous activity in sleep-related painful erections. Sleep 1996;19(2):136-8.

Giuliano F, Rampin O. Neural control of erection. Physiol Behav 2004;83(2):189-201.

Montorsi F, Oettel M. Testosterone and sleep-related erections: an overview. J Sex Med 2005;2(6):771-84. Schmidt MH, Sakai K, Valatx JL, Jouvet M. The eff ects of spinal or mesencephalic transections on sleep-related erections and ex-copula penile refl exes in the rat. Sleep 1999 Jun 15;22(4):409-18.

Siegel J, Wang RY. Electroencephalographic, behavioral, and single-unit eff ects produced by stimulation of forebrain inhibitory structures in cats. Exp Neurol 1974;42(1):28- 50.

Ogawa Y, Kawamura H. Increase of multiple unit activity during slow wave sleep in the cat preoptic area. Brain Res Bull 1988;20(6):897-902.

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(12):4705-21.

Sachs B, Meisel R. The physiology of male sexual behavior. In: Knobil E, Neill J, editors. The Physiology of Reproduction New York: Raven; 1988. p. 1393-485.

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(17):6640-7.

Schmidt MH, Schmidt HS. Sleep-related erections: neural mechanisms and clinical signifi cance. Curr Neurol Neurosci Rep 2004;4(2):170-8.

Curtis DR, Johnston GA. Amino acid transmitters in the mammalian central nervous system. Ergeb Physiol 1974;69(0):97-188.

Gulia KK, Mallick HN, Kumar VM. Sleep-related penile erections do not occur in rats during carbachol-induced rapid eye movement sleep. Behav Brain Res 2004;154(2):585-7.

Andersen ML, Tufi k S. Inhibitory eff ect of GABAergic drugs in cocaine-induced genital refl exes in paradoxical sleep-deprived male rats. Pharmacol Biochem Behav 2004;78(2):301- 7.

Bhasin S, Taylor WE, Singh R, Artaza J, Sinha-Hikim I, Jasuja R, et al. The mechanisms of androgen eff ects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci 2003;58(12):M1103-10.

Traish A, Kim N. The physiological role of androgens in penile erection: regulation of corpus cavernosum structure and function. J Sex Med 2005;2(6):759-70.

Luboshitzky R, Shen-Orr Z, Herer P. Middle-aged men secrete less testosterone at night than young healthy men. J Clin Endocrinol Metab 2003;88(7):3160-6.

Karacan I, Hursch CJ, Williams RL, Littell RC. Some characteristics of nocturnal penile tumescence during puberty. Pediatr Res 1972;6(6):529-37.

Aversa A, Isidori AM, Greco EA, Giannetta E, Gianfrilli D, Spera E, et al. Hormonal supplementation and erectile dysfunction. Eur Urol 2004;45(5):535-8.

Cunningham GR, Hirshkowitz M, Korenman SG, Karacan I. Testosterone replacement therapy and sleep-related erections in hypogonadal men. J Clin Endocrinol Metab 1990;70(3):792-7.

Davidson JM, Camargo CA, Smith ER. Eff ects of androgen on sexual behavior in hypogonadal men. J Clin Endocrinol Metab 1979;48(6):955-8.

Salmimies P, Kockott G, Pirke KM, Vogt HJ, Schill WB. Eff ects of testosterone replacement on sexual behavior in hypogonadal men. Arch Sex Behav 198;11(4):345-53.

Hirshkowitz M, Schmidt MH. Sleep-related erections: clinical perspectives and neural mechanisms. Sleep Med Rev 2005;9(4):311-29. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45