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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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-(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 11th_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

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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

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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

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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

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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 11th

edition – Physiology of erections).

200 100 0 Intracorporeal pressure (cm H 2 O) 25 0

Pudendal arterial flow (mL/min)

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)

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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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