University of Groningen

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University of Groningen

Pathologic erections Vreugdenhil, Sanne

DOI:

10.33612/diss.95437816

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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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Pathologic erections

Sanne Vreugdenhil

Historical, pathophysiological and clinical aspects

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Financial support by P.W. Boerstichting Urologie, Ferring Farmaceuticals, Chipsoft, IPSEN Farmaceutica B.V. and Rijksuniversiteit Groningen for the publication of this thesis, is gratefully acknowledged.

Layout Bianca Pijl, www.pijlldesign.nl

Groningen, the Netherlands

Cover design (illustration) Bianca Pijl

Printed by Ipskamp Printing

Enschede, the Netherlands

ISBN 978-94-034-1903-9 (print)

978-94-034-1902-2 (digital)

All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior written permission of the author, or when appropriate, of the publishers of the publications included in this thesis.

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Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties

De openbare verdediging zal plaatsvinden op woensdag 25 september 2019 om 14.30 uur

door

Sanne Vreugdenhil geboren op 16 april 1991

te Kampen

Pathologic erections

Historical, pathophysiological and clinical aspects

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Promotoren Prof. dr. I.J. de Jong Copromotor Dr. M.F. van Driel

Beoordelingscommissie Prof. dr. E.J.H. Meuleman Prof. dr. M. Albersen Prof. dr. H.G.D. Leuvenink

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5 Paranimfen

Jossie Rotman Sterre T. Paijens

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6

Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Chapter 8

Chapter 9

Chapter 10

Table of contents

PART I GENERAL CONSIDERATIONS General introduction

1.1 Objectives of this thesis Physiology of erection 2.1 Contexts of penile erections 2.2 Tumescence

2.3 Flaccid state and detumescence 2.4 REM-sleep and related erections

2.5 Relation between testosterone and sleep-related painful erections PART II SLEEP-RELATED PAINFUL ERECTIONS

Sleep-related painful erections 3.1 Characteristics and epidemiology 3.2 Historical background

Sleep-related painful erections – A meta-analysis on the pathophysiology and risks and benefits of medical treatments. J Sex Med 2018

Sleep-related painful erections – A case series of 24 patients regarding diagnostics and treatment options. Sex Med 2017

PART III PRIAPISM

Priapism throughout the ages. Urology 2018

Priapism is an emergency. Ned Tijdschr Geneeskd 2018 Pseudo-aneurysms in high-flow priapism. Submitted

Ischemic priapism as a model to study metabolic activity in a closed system. Physiol Rep 2019

Fasciotomy of the corpora cavernosa in refractory ischemic priapism – an old method revived in a new era

11 13

17 19 20 22 24 24

31 33 33

39

63

87

107

117

125

135

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7 Chapter 11

PART IV GENERAL DISCUSSION

Summary

PART V APPENDICES

Dutch summary About the author Dankwoord List of publications

153

165

173

175

179

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PART I GENERAL CONSIDERATIONS

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General introduction

CHAPTER 1

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13 General introduction

Pathologic erections have fascinated mankind for ages. In Antiquity, the term “priapism” was already linked to a prolonged erection unrelated to sexual stimulation. The name originates from the Greek god Priapus, who was depicted with a disproportionately large erect penis and seen as the god of fertility.

Frank Hinman sr. (1880-1961), a famous American urologist who described the natural history of priapism, already distinguished “recurrent painful nocturnal erections” from “true priapism”.

(1) In his opinion, the fi rst included erections characterized by a relatively short duration (< 1 hour), frequent occurrence and tendency to recur, which strongly distinguished them from the latter being “an uncommon, remarkable condition of prolonged and persistent erection”. Hinman recognized that the “recurrent or nocturnal erections of transitory refl ex nature” could be painful and severely disturb the patients’ sleep, but he acknowledged that surgical treatment had never been proved necessary. In 1972 the German physiologist Jovanović rediscovered these nocturnal painful erections and called them: “erectio nocturna dolorosa”. (2)

When talking about erectile disorders, one often thinks about the disability to acquire or sustain an erection. This thesis, however, concentrates on the disorders including a failure of the detumescence mechanism, resulting in an unwanted persistent erection. Paradoxically, some of these disorders can secondarily lead to erectile dysfunction (ED).

Over the last fi ve decades, there have been appreciable advances in the understanding of the pathophysiology of priapism and sleep-related painful erections (SRPEs). However, the literature related to its pathophysiology and treatment is neither voluminous nor accurate, comprising case reports and small case series rather than controlled trials. As a result, the effi cacy and safety of diff erent treatments are not yet clarifi ed.

Life can be heavily disturbed by the consequences of priapism and SRPEs. For example, delayed or inadequate treatment of ischemic priapism can result in permanent ED, whereas untreated SRPEs lead to severe sleep deprivation and consequently daytime sleepiness, stress, anxiety and marital problems. Both conditions are rare and especially SRPEs are poorly recognized by physicians. As a result, the last patient group is frequently exposed to disappointing consultations and inadequate treatments.

1.1 Objectives of this thesis

Sexual medicine is a dynamic enterprise. New concepts as, for example, sleep-related painful erections (SRPEs) continue tot evolve. Similar to priapism, another form of pathological prolonged erection, the phenomenon of SRPEs is characterized by a very limited understanding of causes and mechanisms. Both priapism and SRPE are poorly recognized by medical professionals and they lack well-established guidelines. Reviews on these disorders are mostly based on individual case reports and small case series. Defi nitions and methodologies have been inconsistent, which means that data for best practices are lacking. The relevance of clinical research concerns mainly the signifi cant consequences that may result from improper diagnosis and/or inadequate

General introduction

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14 Chapter 1

treatment of both disorders. Especially priapism has a disproportionate representation in litigations for medical malpractice. Patients with SRPEs are suffering from severe sleepdeprivation after years of dissapointing consultations and non-succesfull experimental treatments.

Unfortunately, performing epidemiologal studies on these two disorders remains very problematical, due to their low incidence and/or acute character.

This thesis attempts to provide a comprehensive overview of the struggle to find adequate treatments. Basic as well as clinical research into priapism and SRPEs has only relatively recently been initiated. Though, by improving the understanding of the pathophysiology, clinicians may hopefully be provided with etiology-specific medical alternatives or alterations adressing timely detumescence in men with prolonged erections. Furthermore, a lot of questions remain to be answered, especially with regard of the timing of surgical treatments in patients with long-lasting priapism.

This thesis was written with the aim to further elucidate the underlying pathophysiology of pathological erections and, in particular, to provide adequate therapeutic options by extended reviews and clinical studies, including one case-report.

It is divided into two main sections, concerning: I. the sleep-related painful erections and II.

priapism.

The following issues/questions are described:

What is the physiology of a normal and healthy erection? (Chapter 2) PART I

What are the current insights on the pathophysiology, diagnostics and treatment of SRPE?

(Chapters 3+4)

Where are the the most important knowledge gaps concerning SRPE? (Chapters 3+4) Which symptomatological and diagnostic features are typically seen in our SRPE population? (Chapter 5)

Is baclofen an effective, tolerable and safe medical treatment for SRPE, and if so, which dose is preferable? (Chapter 5)

Is there a role for non-medical treatment in SRPE patietns? (Chapter 5)

How can we improve future SRPE research to find out more about the pathophysiology and ultimately reach evidence based treatment advises concerning SRPE (Chapter 5)

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15 PART II

How did the ideas about the pathophysiology and treatment of priapism evolve throughout the ages? (Chapter 6)

Can we improve current surgical modalities by reviving ancient surgical approaches (Chapter 6) What are the results of the applied golden standard of diagnostics and treatment on priapism patients in our hospital (Chapter 7)

How can medical professionals dealing with priapism prevent medicolegal litigations?

(Chapter 7)

Is there a need to treat high-fl ow priapism; what would be the right timing and how should it be performed (Chapter 8)

Which extended metabolic changes are seen in intracavernosal blood of patients witch ischemic priapism? (Chapter 9)

Is the intracavernous acidotic environment that exists during ischemic priapism of metabolic or respiratory origin? (Chapter 9)

How can the extreme metabolic values be explained and is the erectile tissue still capable of regaining contractility when all fuel resereves are exhausted? (Chapter 9)

Do these metabolic fi ndings off er any new treatment opportunitites for ischemic priapism?

(Chapter 9)

Is it safe and possible to perform a fasciotomy of the tunica albuginea and would it be an eff ective surgical treatment option for refractory ischemic priapism (Chapter 10)

Would Magnetic Resonance Imaging of the penis be a viable diagnostic to optimize treatment decision making in patients with refractory ischemic priapism? (Chapter 10)

References

Hinman F. Priapism: report of cases and a clinical study of the literature with reference to its pathogenesis and surgical treatment. Ann Surg 1914;60(6):689-716.

Jovanović U. Sexuelle Reaktionen und Schläfperiodik bei Menschen. Stuttgart: Enke verlag;1972.p.157-93.

General introduction

1 2

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17

Physiology of erection

CHAPTER 2

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19 Physiology of erection

To understand how pathologic forms of erection develop, it is indispensable to comprehend the mechanisms leading to a physiological erection. Normal erectile function is facilitated by a complex interaction of intact vascular, neurological, hormonal and psychological systems. (1) The initiation and maintenance of erections is primarily a vascular phenomenon, triggered by neural signals.

2.1 Contexts of penile erection

Penile erection can be initiated by various stimuli. The role of the central nervous system varies depending on the context in which the erection is generated. (2) Examples include tactile stimulation of the genital region and other forms e.g. visual, auditory or olfactory stimuli.

Additionally, memories and fantasies can contribute to the initiation of an erection, the so-called

“psychogenic erection” and there are “refl ex” or “touch-based” erections that can be induced via the spinal course only.

For the “psychogenic” erections, higher central control systems of the brain are required, especially the medial amygdala plays an important role. The diff erent brain centres involved in sexual function are demonstrated in Table 1. The most common context that involves no interaction includes the sleep-related erections (SREs). They arise shortly after the onset of Rapid Eye Movement (REM)- sleep and persist during the whole REM-sleep cycle. (6) In the scientifi c literature SRE is frequently referred to as “nocturnal penile tumescence periods”, which is a somewhat misleading term since they also may occur during daytime napping.

Table 1. Brain centers involved in sexual function (Adapted from Campbell-Walsh Urology 11t^h edition)

LEVEL REGION FUNCTION

Forebrain Medial amygdala Stria terminalis Pyriform cortex Hippocampus

Right insula + inferior frontal cortex

Controls sexual motivation Inhibits sexual drive Involved in penile erection

Increased activity during visually evoked sexual stimulation (sexual arousal)

Hypothalamus Medial preoptic area Lateral preoptic area Paraventricular nucleus

Recognizes a sexual partner, integrates hormonal and sensory cues

Controls nocturnal penile tumescence in rats Facilitates penile erection (via oxytocin neurons to lumbosacral spinal autonomic and somatic efferents)

Brainstem Nucleus paragigantocullularis A5-catecholaminergic cell group

Inhibits penile erection (via serotonin neurons to lumbosacral spinal neurons and interneurons) Major noradrenergic center

Midbrain Periaqueductal gray Relay center for sexually relevant stimuli

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2.2 Tumescence

The erectile process is mainly regulated by the relaxation and contraction of the smooth musculature (also called trabeculae) in the corpora cavernosa (CC), the corpus spongiosum (CS) and the walls of the supplying penile arteries (Figure 1). On molecular level this contraction and relaxation process is mainly regulated by the intracellular calcium concentration. A low cytosolic free calcium concentration favours smooth muscle relaxation. (4)

Figure 1. Penile vasculature: the internal pudendal artery is a branch of the internal iliac artery and the most important blood vessel supplying the penis. It splits in 3 branches: the dorsal, the central cavernous and the bulbourethral artery. The dorsal penile artery causes swelling and thrust of the glans penis during erection. The cavernous artery has the most important role in providing an erection by supplying the corpora cavernosa and the bulbourethral mainly causes tumescence of the spongious body around the urethra.

A parasympathetic pathway, arising from neurons in the intermediolateral cell columns of the 2nd, 3rd, and 4th sacral spinal cord segments, passing the pelvic nerves to the pelvic plexus, causes relaxation of 1) the smooth muscles that control the diameter of the arteries to the penis, causing increased blood flow towards it and 2) the relaxation of the smooth muscle cells of the trabeculae in the CC, allowing the increased blood flow to rapidly fill and expand the CC (Figure 2). (5) This relaxation is mainly facilitated by the synthesis of the neurotransmitter nitric oxide (NO). NO is catalysed by nitric oxide synthase (NOS), which is expressed in different isoforms in the terminals of the cavernous nerve (nNOS) and endothelial cells of the CC (eNOS) and is responsible for initiating and sustaining erection, respectively. (6,7) Via its receptor soluble guanylyl cyclase (sGC), NO stimulates the production of cyclic guanosine monophosphate (cGMP), a major second messenger involved in smooth muscle relaxation. Through the activation

Cavernosal artery Bulbourethral artery

Dorsal artery Glans penis

Corpus spongiosum Corpora cavernosa

Internal pudendal artery Bulbar vein

Bulbourethral vein Chapter 2

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21

pelvic nerve

<

autonomic nuclei systemic effects cortex thalamus

hypothalamus limbic system

<<

<

medulla oblongata

Th11-12

S2-4

penile dorsal nerve pudendal nerve

sympathetic chain ganglia

superior hypogastric plexus

pelvic plexus

cavernous nerve hypogastric nerve

of protein kinase G, it opens the potassium and closes the calcium infl ux channels. This results in a decrease of the cytosolic free calcium concentration, favouring smooth muscle relaxation. Due to relaxation of the supplying penile arteries and intracavernous smooth muscles, blood fl ow increases and sinusoids expand, compressing the subtunical venous plexuses against the non- resilient encapsulating tunica albuginea, which reduces venous outfl ow. (4) This tunica is then stretched to its full capacity, occluding the emissary veins lying between the inner circular- and outer longitudinal layers, decreasing venous outfl ow even more. Intracavernous pressure raises to around 100mmHg and the penis erects to its maximum.

Figure 2. Neural pathways controlling human penile erection

The role of the striated bulbospongiosus (BS) and ischiocavernosus (IC) muscles in erotic erection is somewhat debatable. These muscles can be contracted either voluntary or involuntary. Whereas Karacan registered increased activity of the striated pelviperineal muscles during sleep-related erection using surface electrodes to the perineal skin, Gerstenberg and co-workers performed electromyographic assessment of the IC and BS muscles during erotic erection and ejaculation in seven healthy subjects using needle electrodes and observed no maintained or burst activity in either the IC or the BS muscles during the tumescent phase and even at full erection. (8,9) From this observation Gerstenberg and his co-workers concluded that there is no essential requirement for

Physiology of erection

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22

involvement of the IC and BS muscles to initiate or maintain an erection. However, it appears that reflexive and/or voluntary contractions of the striated pelviperineal muscles, under the somatic control of the pudendal nerve, can intensify the erection and contribute to the achievement of maximum penile rigidity and circumference with intracavernous pressures reaching several hundreds of mmHg. (4)

2.3 Flaccid state and detumescence

Sympathetic stimulation causes constriction of the intracavernous- and arterial smooth muscles, serving to achieve detumescence and to maintain the flaccid state. This pathway originates from the 11th thoracic to the 2nd lumbar spinal segments and passes through the white rami to the sympathetic chain ganglia, of which some fibres travel through the lumbar splanchnic nerves to the pelvic plexus via the inferior mesenteric and superior hypogastric plexuses. (4) Tonic smooth muscle contraction is needed to keep the penis in flaccid position. On molecular level two major factors control this contraction: 1) the intracellular free calcium concentration and 2) Rho-kinase signalling. (10) Norepinephrine has generally been accepted as the principal neurotransmitter to maintain flaccidity. (11,12) It is released from α1- adrenergic nerve fibres that are present in the cavernous trabeculae and arteries. Adrenergic receptors in the penile vessels and CC are stimulated by norepinephrine, which causes Ca2+ entry through calcium channels and mediation of calcium sensitization mechanisms by protein kinase C, tyrosine kinases and Rho-kinase. (11) This induces contraction of the smooth muscles. Another potent endothelial mediator is endothelin-1. It induces slow, long-lasting contractions of the smooth muscles in the CC, the cavernous artery, deep dorsal vein, and penile circumflex veins. Moreover, endothelin-1 is thought to potentiate the constrictor effects of catecholamines in the cavernous trabecular smooth muscle cells. (13) Other endothelium-derived contracting factors are angiotensin II, prostaglandin F2α and thromboxane.

In summary, three factors facilitate the maintenance of the intracavernous smooth muscle in a semi-contracted (flaccid) state, including 1) intrinsic myogenic activity 2) adrenergic neurotransmission and 3) endothelium-derived contracting factors. (14)

Detumescence of the erect penis is initiated by cessation of NO release, the breakdown of cyclic nucleoids (2nd messengers) by phosphodiesterase type 5 and/or sympathetic discharge during ejaculation. (15) The latter consists of activation of the involuntary sympathetic hypogastric nerves.

(15) In healthy men, a precise temporal coordination between the smooth muscle contraction of the ejaculatory ducts and sphincter muscles exists, providing a forceful expulsion of semen after pressure has been built up behind the closed external sphincter. During the first emission phase, sympathetic stimulation from the autonomic nervous system via the hypogastric nerve causes the smooth muscles in the testicular capsules, seminal vesicles, prostate, the ducts of the epididymis and in the vas deferens to contract and to transfer semen into the prostatic urethra. (5,16) Once in the prostatic urethra, the semen is prevented from retrograde movement towards the bladder by contraction of the internal urethral sphincter. Simultaneously, the external urethral sphincter

Chapter 2

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23 relaxes and prostatic contractions begin, moving the semen towards the pendulous urethra.

(17) This is further promoted by a rhythmically and involuntary contractions of the pelviperineal striated muscles (the BS muscle in particular), controlled by the pudendal nerve. If this nerve is compromised, for example due to diabetic neuropathy, dribbling ejaculation may occur. (16,18) The abovementioned mechanism, that suggests a close correlation between smooth muscle contraction providing the “supply” of semen into the duct system and striated muscle contraction in combination with intermittent external urethral sphincter opening and closing that causes a forceful ejaculation of semen, has not yet been completely identifi ed. Gerstenberg and his co- workers, for example, observed that the fi rst BS muscle contraction is often not accompanied by semen expulsion. (9) They presumed a temporal delay between the fi lling of the upper part of the prostatic urethra and the initial contraction. During the next six to ten contractions, expulsion of semen was observed, after which several non-expulsive contractions followed. The latter is possibly a safety mechanism of the male reproductive system ensuring a complete delivery of all sperm to increase the chance on fertilisation. In addition, it has long been thought that the cascade of events leading to ejaculation was triggered by the distension of the prostatic urethra, but up till now there is no clinical evidence for this theory. (18)

Hemodynamically, detumescence starts with a short and transient increase of the intracavernous pressure, caused by the initiation of smooth muscle contraction against the closed venous system. (19) During the second phase the pressure in the CC slowly starts to decrease, indicating a slow reopening of the veins with resumption of arterial fl ow to the basal level. Detumescence ends with a fast intracavernous pressure decrease and fully restored venous outfl ow during the third phase (also demonstrated in Figure 3).

Figure 3. The upper graph shows the alterations of arterial blood fl ow in the internal pudendal artery. The lower shows alterations of the intracavernous pressure during the fi ve phases of erection (Campbell Urology 11^th edition – Physiology of erections).

200 100 Intracorporeal pressure (cm HO)2 0

25

Pudendal arterial flow (mL/min) 0

Pudendal nerve Cavernous nerve

6 7

5 3 4 3 2 1

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2.4 REM-sleep and related erections

SREs appear throughout human life. There are even observations of SREs in foetuses. (20) The current theory is that intermittent nocturnal “filling” of the CC, provides periods of better penile tissue oxygenation, preventing fibrosis of the spongy tissue in the CC. Fibrosis is most likely the (histo-)pathological base of veno-occlusive dysfunction, which is one of the most common causes of organic ED. So, SREs represent an intrinsic mechanism protecting the morphodynamic integrity of the CC. (21)

The structures involved in the generation of REM-sleep are localized in the brainstem. After removal of all neural elements rostrally from the pons, REM-sleep remains. Schmidt and coworkers investigated what happened with REM-sleep and SREs in rats after resection of the cerebral cortex. (22) With only the brainstem left in situ the REM sleep episodes remained intact, but the SREs disappeared. This means that the cerebral cortex plays an essential role in the generation of SREs. Subsequently the researchers inflicted neurotoxic lesions on different areas of the cortex to localize the sites that control SREs. (23) Bilateral lesions in the lateral pre-optic area (LPOA) eliminated SREs, while at least some types of waking-state erections remained intact. These findings indicated that the LPOA plays an important role in the generation of SREs and that this pathway differs from that of waking-state erections.

In general, the pre-optic area is involved in the generation of sleep, reproductive mechanisms and thermoregulation. The lateral part does not project directly on the spinal cord but modulates the spinal erectile areas via the paraventricular nucleus (PVN) located in the hypothalamus and the paragigantocellular nucleus (nGPi) in the brainstem.(22)

Apomorphine, a dopamine reuptake inhibitor, and cocaine can induce SREs in rats and these erections can be supressed by gamma aminobutyric acid (GABA)-like substances. (24) This indicates that SREs are partly regulated by dopaminergic and GABA-ergic systems. The brain, however, uses only very little dopamine, while GABA and glutamate are by far the most common neurotransmitters. GABA represents an inhibiting neurotransmitter that functionally binds to pharmacologically different α and β receptors. These are both activated by GABAα and GABAß agonists. The activation of the GABA-α-receptors in the paraventricular nucleus proved to counteract apomorphine induced erections. (24,25) One can conclude that a change in the regulation of GABA-ergic systems will result in inhibition of the genital reflexes.

2.5 Relation between testosterone and sleep-related erections

One of the first explanations of SREs was based on the fact that the noradrenergic neurons in the cerulean locus are counteracting the erection. (21) It was assumed that during REM- sleep these neurons are attenuated, causing testosterone-related excitatory actions to manifest as an SRE. Androgens indeed exert influence on end organ level (cavernous tissue and –vasculature) and in areas of the nervous system that mediate erections. Centrally, androgens are playing an important part in copulatory behaviour and sex drive. In the CC, androgens are essential for the NO production. (26,27)

Chapter 2

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25 All in all, one cannot deny that testosterone is important for SRE generation. This is evident from a number of observations. For example, SREs are already observed in boys since they are babies, but they become longer and more rigid when these boys enter puberty. (29) Moreover, from several studies in hypogonodal men it is known that SREs become longer and more frequent, rigid and intense after testosterone suppletion. (28-31) On top of that, serum testosterone levels rise during the NREM to REM-sleep transition, which is the moment an SRE starts. (3,32,33) Finally, in older males, the circadian rhythm of serum testosterone is diff erent compared to younger ones. The average 24-hour serum testosterone levels are lower and the peak values in response to gonadotropin stimulation are less high. As a result, SREs are less frequent and shorter in older males. Moreover, with increasing age, the sleep pattern becomes more unstable and contains frequent interruptions. (21,34,35)

In conclusion, one can state that age, sleep pattern, testosterone and its secretion pattern are strongly interrelated. (21,36)

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References

Cunningham GR, Rosen RC. Overview of male sexual dysfunction. 2014; available at: http://www.

uptodate.com/contents/overview-of-male-sexual-dysfunction

Sachs BD. Contextual approaches to the physiology and classification of erectile function, erectile dysfunction, and sexual arousal. Neurosci and Biobehav Rev 2000;24:541-60.

Hirshkowitz M, Schmidt MH. Sleep-related erections: clinical perspectives and neural mechanisms. Sleep Med Rev 2005;99(4):311-29.

Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. In: Campbell-Walsh Urology 11th edition;1(5):612-42e9.

Komisaruk BR, Beyer-Flores C, Whipple B. The science of orgasm. The Johns Hopkins University Press, Baltimore, USA. 2006; Ch3 (Bodily Changes at Orgasm):20-3.

Hurt KJ, Musicki B, Palese MA, et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA 2002;99:4061- 6.

Musicki B, Ross AE, Champion HC, et al. Posttranslational modification of constitutive nitric oxide synthase in the penis. J Androl 2009;30:352-62.

Karacan I, Hirshkowitz M, Salis PJ, Narter E, Safi MF. Penile blood flow and musculoascular events during sleep-related erections of middle-aged men. J Urol 1987;138:177-81.

Gerstenberg TC, Levin RJ, Wagner G. Erection and ejaculation in man. Assessment of the electromyographic activity of the bulbocavernosus and ischiocavernosus muscles. Br J Urol 1990;65:395-402.

Berridge MJ. Smooth muscle cell calcium activation mechanisms. J Pysiol 2008;586(21):5047-61.

Andersson KE. Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011;63:811–59.

Diederichs W, Stief CG, Lue TF, et al. Norepinephrine involvement in penile detumescence. J Urol 1990;143:1264–6.

Christ GJ, Lerner SE, Kim DC, et al. Endothelin-1 as a putative modulator of erectile dysfunction: I.

Characteristics of contraction of isolated corporal tissue strips. J Urol 1995;153:1998–2003.

Andersson KE, Wagner G. Physiology of penile erection. Physiol Rev 1995;75:191– 236.

Campbell, 11th edition, Vol I, Part V, Ch26, p620-1

Clement P, Giuliano F. Physiology and pharmacology of ejaculation. Basic & Clinical Pharmacology & Toxicology 2016;119:18-25.

Vale J. Ejaculatory dysfunction. Br J Urol 1999;83:557-63.

Levin RJ. The mechanisms of human ejaculation – a critical analysis. Sexual and Relationship Therapy 2005;20:123-31.

Bosch RJ, Benard F, Aboseif SR, et al. Penile detumescence: characterization of three phases. J Urol 1991;146:867–71.

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;26:771-84.

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

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 of Neurosci 2000,20(17):6640-7.

Andersen ML, Tufik S. Inhibitor effect of GABAergic drugs in cocaine-induced genital reflexes in paradoxical sleep-deprived male rats Pharmacol Biochem Behav 2004;78(2):301-7.

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.

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27 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):1103-10.

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.

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. Testosteronereplacement 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 Endorcinol Metab 1979; 48(6)955-8.

Salmimies P, Kockott G, Pirke KM, Vogt HJ, Schill WB. Eff ects of testosterone replacement on sexual behaviour in hypogonadal men. Arch Sex Behav 1982;11(4):345-53.

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

Glina S, Morales AM, Vardi Y, Perelman MA, Schultheiss D. Nocturnal erections, diff erential diagnosis of impotence, and diabetes. I Karacan, FB Scott, PJ Salis, SL Attia, JC Ware, A Altinel, and RL Williams. J Sex Med 2009;6(2):318-323.

Karacan I, Hursch CJ, Williams RL, Thornby JI. Some characteristics of nocturnal penile tumescence in young adults. Arch Gen Psychiatry 1972;26(4):351-6.

.Karacan I, Hursch CJ, Williams RL. Some characteristics of nocturnal penile tumescence in elderly males.

J Gerontol 1972;27(1):39-45.

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.

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PART II SLEEP-RELATED PAINFUL ERECTIONS

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Sleep-related painful erections

CHAPTER 3

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33 Sleep-related painful erections

3.1 Characteristics and epidemiology

The occurrence of sleep-related painful erections (SRPEs) is probably a rare phenomenon. It includes nocturnal episodes with rigid penile erection accompanied by an unpleasant oppressive, sometimes burning sensation or even excruciating pain inside the penis that awakens the person concerned. SRPEs typically occur during the cyclic rapid eye movement (REM) sleep, resulting in frequent sleep interruptions. This causes SRPE patients to suff er from severe sleep deprivation, increased daytime fatigue, stress and agitation. (1) The intensity of the pain and the duration of the associated sleep defi cit generally increases during the second part of the night, when the REM episodes are longer. (2) SRPEs have a major impact on the patients’ daily life. The prevalence of this condition was estimated to be 2% of all patients who see a doctor because of sexual problems. (1) Many patients, however, do not know where to fi nd the appropriate medical support. Feelings of embarrassment are often the reason that these men are reluctant to visit a physician. The average patient delay is around fi ve years with a range from one to twenty.

3.2 Historical background

The fact that nocturnal erections are not related to dream content and in no way health threatening was not understood for many ages to come. In 1920, however, the famous Viennese psychiatrist Wilhelm Stekel recognized the physiological character of SREs, which appeared to occur in healthy men of all ages. (3) He suggested that there was no physical explanation for ED if the patient observed normal morning erections, which in fact represented the last nocturnal erection.

This was confi rmed by the observation of nocturnal erections that “frequently awakened the infant” in completely undressed babies lying in a single large room during the late thirties of the 20th century. (4) It is interesting to realize that newborn babies spend about 16 hours each day sleeping, and about half of this is in REM sleep. So, one may expect long lasting SREs, particularly while after birth, a 3-month lasting period of relatively high testosterone levels begins, the so- called “mini- puberty.” (2)

The cyclic character of SREs was fi rst observed by Peter Ohlmeyer in 1944. (5) By using simple electromechanical transducers, a binary signal was observed, based on which the presence or absence of an erection could be determined. Ohlmeyer established a nocturnal erectile cycle with a mean duration of 85,4 minutes and an average active phase of 25,3 minutes. The post-war sequel of his research showed that this cycle was not only seen in night-time sleep, but also with similar periodicity during daytime napping. (6)

Approximately 10 years later SREs were associated with the REM-sleep cycle for the fi rst time by Aserinsky and Kleitman. (7) In 1965 this association was demonstrated experimentally and somewhat problematically by Charles Fisher and his co-workers. (8) The monitoring and registration of nocturnal erections appeared to be diffi cult due to local mechanical stimulation of the instruments on the glans penis. The contemporary used Rigiscan® measures rigidity at the top and base of the penis. Although this device has its limitations, the Rigiscan is considered to be the best diagnostic method for measuring night-time erections. (9) The nocturnal penile tumescence and rigidity (NPT-R) measurement should preferably be conducted during two consecutive

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nights and can be combined with polysomnography. A normal NPT-R result shows 4-6 episode of nocturnal erection that last 15-50 minutes. The NPT-R measurement is dependent on a number of patient-specific factors such as age, comorbidities (incl. diabetes, cardiovascular disease, obesity, chronic obstructive lung disease, abnormal serum testosterone levels, sleep disorders, depression), intoxications (alcohol, tobacco) and medication. (10) These factors especially have a negative influence on the “total tumescence time” (TTT) and to a lesser extent to rigidity and frequency of SREs. An overview of normative values of this measurement related to age based on information from four studies is shown in table 1. Figure 1 illustrates the typical aberrant aspect of the REM-sleep related erection pattern that can be seen in some of the SRPE patients, compared to a “healthy” pattern displayed in an NPT-R measurement.

Table 1. Normative data of total tumescence time (TTT) in minutes and SRE frequency per night for various age categories. The average values are composed out of 4 studies: Karaçan et al. (1976), Reynolds et al. (1989), Schiavi et al. (1990) and Hirshkowitz et al. (1992).

In conclusion

To date, statements regarding SRPE are mostly based on assumptions, treatment is still in the expert-based-opinion phase and long-term follow-up is lacking. There is no consensus on how to treat this debilitating problem, especially since the pathophysiological understanding and the natural course of this parasomnia have barely been elucidated. As a result, the average SRPE patient often has a history of multiple unsatisfactory consultations and non- or less effective experimental treatments. With, among other things, the aim to accommodate to the abovementioned shortcomings in SRPE research, this thesis was written.

Age category (years) Mean TTT in minutes (range) Mean SRE frequency per night (range)

20-29 151 (139-161) 4.3 (3.9-4.8)

30-39 123 (123-124) 3.6 (3.6-3.6)

40-49 124 (101-143) 3.6 (3.0-4.0)

50-59 122 (100-146) 3.3 (2.9-3.7)

60-69 100 (84-122) 3.1 (2.2-3.9)

Chapter 3

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35 Figure 1.

A: an example of a normal NPT-R pattern in a 58-year old (TTT=115 minutes and frequency of SREs= 5 per night).

B: an example of an aberrant NPT-R pattern in a 71-year old SRPE patient: frequent and prolonged nocturnal erections (TTT=275 minutes and frequency of SREs= 8 per night).

Normal Noctural Penile Tumescence and Rigidity Pattern

A

1

0 2 3 4 5 6 7 8 9 10

Time (hours) Base

Tip Rigidity (%)Teumescence (cm)

0 100

5 15

Rigidity (%)Teumescence (cm) 0 100

5 15

Abnormal Noctural Penile Tumescence and Rigidity Pattern

1

0 2 3 4 5 6 7 8 9 10

Time (hours) Base

Tip Rigidity (%)Teumescence (cm)

0 100

5 15

Rigidity (%)Teumescence (cm) 0 100

5 15

B

Sleep-related painful erections

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References

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.

Van Driel MF. Sleep-related erections throughout the ages. J Sex Med 2014;11(7):1867-75.

Stekel W. Impotence in the male – the psychic disorders of sexual function in the male. Chapter V Masturbation & potency p. 91-128. Vol 1. 1927 Authorized English version by Oswald H Bolz. Liveright publishing corporation New York

Halverson HM. Genital and sphincter behavior of the male infant. J Genet Psychol1940;56:95-136.

Ohlmeyer P. Brilmayer H, Hüllstrung H. Periodische Vorgänge im Schlaf. Pflüger’s Archiv für die gesamte Physiologie des Menschen und der Tiere. 1944;248(4- 6):559-60.

Ohlmeyer P. Brilmayer H. Periodische Vorgänge im Schlaf II. Pflüger’s Archiv für die gesamte Physiologie des Menschen und der Tiere. 1947;249(1):50-5.

Aserinsky E, Kleitman N. A motility cycle in sleeping infants as manifested by ocular and gross bodily activity. J Appl Physiol 1955;8(1):11-8.

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

Ghanem H, Shamloul R. An evidence-based perspective to commonly performed erectile dysfunction investigations. J Sex Med 2008;5(7):1582-9.

Hirshkowitz M, Schmidt MH. Sleep-related erections: clinical perspectives and neural mechanisms. Sleep Med Rev 2005;9(4):311-29.

Jovanovic U. Sexuelle Reaktionen und Schläfperiodik bei Menschen. Suttgart: Enke Verlag; 1972:157-93.

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4 5 6 7 8 9 10 11 Chapter 3

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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, PhD¹, Igle Jan de Jong MD, PhD¹, Mels Frank van Driel MD, PhD¹

1Department 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]