Aimee Rogers, MD
■ Stanley Zaslau, MD, MBA, FACS
■ Introduction
■ Penile erection is the result of increased penile inflow of blood and reduced outflow.
• Arterial inflow of blood to the penis is coupled with vasodilation of the cavernosal and helicine arteries.
• This results in blood filling the sinusoidal spaces of the corpora cavernosa.
• This leads to expansion of the lacunar spaces and tunica albuginea.
■ Neural control of erection involves a shift from sympathetic tone to parasympathetic tone.
■ The neural circuitry for erection is based in the spinal cord.
■ Role of Spinal Cord and Neural Innervation of the Penis
■ The penis receives autonomic innervation from the sympathetic and parasympathetic nervous systems.
■ Both systems contain nuclei located in the spinal cord.
■ The parasympathetic nervous system is excitatory for erectile function.
• Preganglionic parasympathetic neurons arise from the sacral spinal cord segments S2—S4.
• The major segment contributing to erectile function is S3.
■ The sympathetic nervous system is inhibitory to erectile function.
• However, because of its vasoconstrictive properties, some fibers have a role in pelvic vasoconstriction, which may increase blood flow to the penis to promote erection.
• The nuclei for the sympathetic nervous system are located in the intermediolateral cell column and the dorsal gray horn at the thoracolumbar cord.
• Preganglionic sympathetic fibers arise from T11—L2 segments of the spinal cord.
• The dorsal nerve of the penis contains the sensory afferents from the penis.
■ Most penile erections occur as a result of the complex interplay of the peripheral and central nervous systems in an intact spinal cord, as described above. However, penile erections can also occur as a result of local stimulation.
■ Hormonal Control of Sexuality
■ There are a wide variety of hormones that play a role in control and potentiation of sexuality.
■ Much of the knowledge of these hormones has been achieved through the study of animal models.
■ Table 1.1 lists these important hormones that control sexuality. The role of each of these hormones and their contribution to sexuality will be described in detail following the table.
Serotonin
■ There are a large number of serotonin (5-HT) positive neurons in the central nervous system.
■ 5-HT is felt to have an overall inhibitory effect on male sexual functions.
• Johnson and colleagues found that stimulation of the 5-HT nuclei of the spinal cord diminishes the responsiveness of the dorsal nerve of the penis.1
Table 1.1 Important Hormones in the Control of Sexuality
Serotonin Norepinephrine Dopamine Nitric oxide Oxytocin
Adrenocorticotropic hormone Melanocyte-stimulating hormone
■ Several 5-HT receptors have been identified and have been divided into classes.
• The 5-HT1A receptor is thought to facilitate sexual behavior.
• The 5-HT1B receptor is thought to inhibit ejaculatory behavior.
■ In a rat study by Ahlenius and colleagues, the increased ejaculatory latency produced by 5-HTP was blocked by treatment with isamoltane, a 5-HT1B receptor antagonist.2
■ This group also studied the selective serotonin reuptake inhibitor citalopram and found that it did not affect the male rat ejaculatory behavior.
Norepinephrine
■ There is anatomical suggestion of the importance of adrenergic control in the physiology of erection.
• Yaici and associates have shown that sympathetic and parasympathetic preganglionic neurons that innervate the penis are adjacent to the neural endpoints for the alpha 2 a and c adrenoreceptor subtypes.3
• Kaplan and colleagues have shown that epinephrine can inhibit erectile activity through its actions on alpha 1 adrenoreceptors.4
■ The location of adrenergic control of sexual behavior may be central as well as peripheral.
• Morales and associates have shown that yohimbine, a centrally acting alpha 2 antagonist, can stimulate sexual motivation in male rats.5
• However, Ernst and associates, through systematic review and meta-analysis of randomized clinical trials, have shown limited clinical efficacy of yohimbine versus placebo in human subjects.6
Dopamine
■ Dopamine’s prosexual effect was noticed through the observation that Parkinson’s patients treated with dopamine agonists had increased sexual activity.
• Uitti and colleagues identified 13 parkinsonian patients who experienced hypersexuality as a consequence of anti-parkinsonian therapy.7 The majority of patients were men and had a relatively early onset of Parkinson’s symptoms. There was no relation between functional Parkinson’s improvement and increased sexuality.
• In rats, apomorphine is a proerectogenic agent. However, in humans, it appears to have a facilitatory effect. Thus, its likelihood of improving erectile function is minimal.
■ Dopamine may exert its possible role in erectile function through several structures, such as:
• The nucleus accumbens
■ May or may not have a significant role in dopamine’s function of sexuality. Results with study of rats have been contradictory to date.
• The medial preoptic area
■ This area appears to have prosexual effects.
• The paraventricular nucleus of the hypothalamus
■ According to a study by Melis and colleagues, this area can respond to injection doses of apomorphine and induce erections in rats.8
■ In this study, both penile erection and yawning behavior were noted.
• This secondary effect of apomorphine has limited this agent’s potential efficacy in the treatment of human erectile dysfunction.
• The spinal cord
■ Guliano and associates have shown spinal cord involvement with dopamine as an erectogenic agent with intrathecal injection via catheter.9
■ These results suggest that there may be a dopamine spinal component in the control of penile erection.
Nitric Oxide
■ Nitric oxide (NO) plays an important role in erectile function, both centrally and locally at the level of the penis.
■ In the central nervous system, particularly in the paraventricular nucleus, NO serves as a positive mediator of erectile function.
■ An increase in the production of NO in the hypothalamus is related to the positive effect of erections associated with administration of apomorphine.
■ At the level of the corpora cavernosa, nitric oxide facilitates relaxation of the smooth muscle of the cavernosal arterioles. This action promotes the filling with blood of these arterioles, which raises the pressure within the corpora cavernosa. This leads to closure of the emissary veins, further promoting the process of erection.
Oxytocin
■ Oxytocin may play an inhibitory role in erectile function.
• Melis and colleagues have shown that penile erections induced by NO delivery in the paraventricular nucleus can be blocked by an oxytocin antagonist.10
• On the other hand, Melis and colleagues have shown that oxytocin can induce penile erections in rats when injected bilaterally into the CA1 field of the hippocampus. However, the physiological importance of this strong cerebral role for oxytocin may be relative, as similar effects have not been demonstrated when oxytocin is administered peripherally.
Adrenocorticotropin (ACTH)
■ Adrenocorticotropin (ACTH) has been shown to produce sexual excitation in several animal species.
■ This peptide is derived from proopiomelanocortin and is expressed in the pituitary, hypothalamus, and brainstem.
■ Serra and associates have shown that intracerebral injection of ACTH can induce penile erection and yawning behavior in rats.11
• This group administered ACTH 1-24 (3—5 micro- grams/rat) and identified a behavioral syndrome characterized by recurrent episodes of penile erection and yawning in the rats.
• On the other hand, in rats that underwent hypophy- sectomy, the ACTH1-24-induced yawning and penile erection was prevented.
• These results suggest that the pituitary has a “trophic” action, not only on peripheral target organs but also on structures in the brain that control specific behavioral responses.
Melanocyte-Stimulating Hormone (MSH)
■ Melanocyte-stimulating hormone (MSH), like ACTH, has been shown to produce sexual excitation in monkeys, rabbits, and rats.
■ This peptide is derived from proopiomelanocortin and is expressed in the pituitary, hypothalamus, and brainstem.
■ As with ACTH (as demonstrated by the work of Serra and associates), intracerebral injection of MSH not only induces penile erection in rats but also stimulates yawning behavior.
■ Wessels and colleagues studied an MSH analog compound known as Melanotan II, which underwent preliminary clinical trials as a potential agent for the treatment of erectile dysfunction.12
• In this study, 10 subjects were enrolled in a doubleblind, placebo-controlled crossover study.
• Melanotan II (0.025 mg/kg) and vehicle were each administered twice by subcutaneous injection; realtime RigiScan monitoring and a visual analog were used to quantify the erections during a 6-hour period.
• Melanotan II initiated subjectively reported erections in 12 of 19 injections versus only 1 of 21 doses of placebo. Nausea and stretching/yawning occurred more frequently with Melanotan II, and 4 of 19 injections were associated with severe nausea.
• This agent has not been approved by the FDA for the treatment of erectile dysfunction because of the severe nausea in 20% of patients as well as the lack of demonstrated efficacy of this agent.
Androgen Control of Sexuality
■ Studies of patients who have undergone castration suggest that a decrease in male sexuality will occur.
■ This is seen in patients who undergo radical orchiectomy for the treatment of hormone refractory prostate cancer.
■ The resultant loss of testosterone after castration suggests the importance of androgens on sexual drive, motivation, and erectile function.
• However, there are some caveats to consider.
■ There is no clearcut correlation between serum testosterone levels and erectile function. While castration results in impaired erectile function in most men, there are some men who are able to maintain erectile function despite castrate levels of testosterone.
■ On the other hand, not all men who have low levels of testosterone will have an improvement of their erectile function when they receive testosterone supplementation.
■ Androgens bind to a variety of sites within the brain, including the medial preoptic area, the amygdala, and the hypothalamus. It is also likely the androgens can interfere with other hormonal functions to impair sexuality. Androgens can impair the serotonin system, which may impair sexual function and behavior.
■ Conclusions
■ Penile erection results from activation of autonomic nervous system with involvement of the sympathetic and parasympathetic systems.
■ Multiple aminergic agents such as serotonin, norepinephrine, dopamine, nitric oxide, oxytocin, ACTH, and MSH play important roles in sexual dysfunction. As such, each of these compounds may play a role in male and female sexual dysfunction. Details regarding the pathophysiology of sexual dysfunction and treatment will be discussed in subsequent chapters.
■ Physiology of Ejaculation
■ Orgasm and ejaculation complete the sexual response cycle.
■ Ejaculation is a reflex involving multiple receptors and pathways.
■ Ejaculation is controlled by a variety of hormonal forces, such as:
• Serotonin
• Dopamine
• Cholinergic
• Adrenergic
• Oxytocin
• GABA
■ There are three basic mechanisms involved in normal antegrade ejaculation, as described in Table 1.2.
■ Emission is the first mechanism of normal ejaculation.
• Emission occurs due to sympathetic spinal cord reflex initiated by genital stimulation.
• Contraction of the accessory sexual organs (seminal vesicles) occurs, leading to distension of the prostatic urethra.
• This mechanism has considerable voluntary control initially, but with an increase in sensation, a point of inevitability of ejaculation is reached.
Table 1.2 Key Features of the Three Mechanisms of Normal Ejaculation
Emission
• Sympathetic spinal cord reflex
• Initiated by erotic stimuli
• Significant voluntary control
• Contraction of seminal vesicles and accessory sexual glands
Ejection
• Sympathetic spinal cord reflex
• Some voluntary control
• Pelvic floor muscle contractions
• External urethral sphincter relaxation
Orgasm
• Pressure builds up in posterior urethra
• Involuntary control
• Urethra contraction dispels ejaculate in antegrade manner
■ Ejection is the second mechanism of normal ejaculation.
• Ejection also involves significant sympathetic neural control.
• Voluntary control in this phase is more limited.
• The following physiological responses occur:
■ Closure of the bladder neck to prevent retrograde flow of ejaculate.
■ Contraction of the pelvic floor musculature (is- chiocavernosus and bulbocavernosus muscles).
■ Relaxation of the urethral sphincter.
■ Orgasm is the final mechanism of normal antegrade ejaculation.
• Pudendal nerve stimulation occurs due to increased pressure in the posterior urethra. This pressure is ultimately released with contraction of the urethral bulb and accessory sexual organs.
■ The ejaculate can be divided into several components, as shown in Table 1.3. The secretions that comprise the ejaculate come from:
• The seminal vesicles (approximately 50—80% of the ejaculate volume)
• Prostate gland (15—30% of the ejaculate volume)
• Bulbourethral (Cowper) glands (less than 1% of the ejaculate volume)
• Spermatozoa (less than 0.1% of the ejaculate volume)
■ Hormonal Control of Ejaculation
■ There are multiple neurochemical factors that may play a role in stimulating or inhibiting ejaculation. While dopamine and serotonin likely play dominant roles, the contributions of GABA and the cholinergic and adrenergic nervous systems have associated roles, as described as follows.
Table 1.3 Normal Contributions to Ejaculate Volume
Seminal vesicles 50-80%
Prostate gland secretions 15-30%
Bulbourethral (Cowper) gland secretions 3-5%
Spermatozoa < 1%
Dopamine
■ We have discussed previously the important role of dopamine in facilitating sexual behavior in rats. The works of Uitti and colleagues and Melis and colleagues demonstrate this rather well. It is also felt that the relative concentrations, or balance, between dopamine and serotonin further contribute to sexuality.
■ On the receptor level, there are two families of dopamine receptors, known as D1 and D2.
• The D2 family is important in drug therapy and there may be a modulatory effect by the D1 receptor on the D2 receptors. It is believed that dopamine via the D2 receptors promotes ejaculation. Serotonin, on the other hand, appears to inhibit ejaculation.
■ It has been shown that altering this balance with selective serotonin reuptake inhibitors (SSRI) may prolong ejaculation.
• This has lead to these agents being used in the treatment of premature ejaculation.
■ Further studies by Hull and associates have suggested a possible sexual response regulatory role of dopamine.13
• This is suggested by the observation that dopamine is released in the medial preoptic area of male rats in the presence of a hormonally active female rat. This causes ejaculation in the male rat.
Serotonin
■ As mentioned previously, serotonin has an inhibitory effect on ejaculation.
■ Serotonin is a vasoconstrictor, is identified in the blood and is predominantly located in the enterocromuffin cells of the gastrointestinal tract.
■ Several 5-HT receptors have been identified and have been divided into classes.
• The 5-HT1A receptor is thought to facilitate sexual behavior and can decrease ejaculatory latency time.
• The 5-HT1B receptor is thought to inhibit ejaculatory behavior.
■ This has been shown by Ahlenius and col- legues. In their study utilizing rats, the increased ejaculatory latency produced by 5-HTP was blocked by treatment with isamoltane, a 5-HT1B receptor antagonist.
■ The brain serotonin system has an inhibitory role in sexuality and ejaculation in rats.
• This compound is released from the hypothalamus in male rats at the time of ejaculation.
• This inhibition of ejaculation also inhibits copulatory behavior as demonstrated by Lorrain and colleagues.14
Gamma-Aminobutyric Acid (GABA)
■ Gamma-aminobutyric acid (GABA) may play an inhibitory role in sexual functioning.
■ There are two types of GABA receptors:
• GABA-A
• GABA-B
■ Approximately 30—40% of neurons in the brain use GABA as their primary neurotransmitter.
■ Both receptor types appear to have an inhibitory response to sexual behavior.
■ Benzodiazepines, as a class, enhance GABA activity.
■ Qureshi and colleagues have shown that GABA inhibits sexual behavior in female rats.15
• They showed that postejaculatory suppression of sexual receptivity in female rats was partially reversed by intracerebroventricular injection of the GABA antagonist bicuculline and the behavior of receptive rats was inhibited by intracerebroventricular injection of the GABA agonist muscimol.
• Further, they showed that increasing the concentration of GABA in the cerebrospinal fluid by injection of the GABA transaminase inhibitor gamma-vinyl GABA caused an increase of the concentration of GABA in the cerebrospinal fluid and inhibited the display of sexual receptivity.
Cholinergic Nervous System
■ Cholinergic receptors are divided into two classes:
• Nicotinic
• Muscarinic
■ The nicotinic receptor is located predominantly at the neuromuscular junction.
■ When nicotinic receptor blockers are administered, an elevation of levels of serotonin in the brain is observed. Thus, administration of cholinergic blockers such as atropine will elevate serotonin levels and inhibit sexual behavior.
• Bitran and colleagues have shown that microinjection of the cholinergic blocker scopolamine into the ventricles of the rat brain prolongs sexual behavior and increases the time to ejaculation in those rats.16
Adrenergic Nervous System
■ Adrenergic control of erection and ejaculation occurs peripherally and centrally.
■ In the central nervous system, there are alpha-receptors in the brain, while there are beta 1— and beta 2—receptors in the cortex and cerebellum.
■ There is likely an important balance between adrenergic and cholinergic control of sexual function.
• This balance likely explains the condition of priapism, which is a prolonged erection unrelated to sexual stimulation. This condition results from prolonged alpha-adrenergic blockade.
■ Seagraves and associates have shown than prazosin results in competitive antagonism of postsynaptic alpha 1—adrenergic receptors in tissues that sustain high levels of alpha-adrenergic sympathetic tone, leading to priapism.17
Nitric Oxide
■ Nitric oxide (NO) is an important messenger in the brain.
■ NO regulates emotional and sexual behavior.
• Lorrain and associates have shown that nitric oxide facilitates copulatory behavior in rats by increasing dopamine release.18
■ In their study, local administration of the NO precursor L-arginine to rats also increased dopamine release in the medial preoptic area.
■ Males received either NO synthesis inhibitor, nitro-L-arginine methyl ester (L-NAME, 400 ^M), or its inactive isomer, D-NAME (400 ^M), in the medial preoptic area via a microdialysis probe for 3 hours prior to the introduction of a female.
■ Following D-NAME administration, dopamine increased during copulation, while L-NAME prevented this increase.
■ Therefore, NO may promote dopamine release in the medial preoptic area of male rats, thereby facilitating copulation.
■ Conclusions
■ Evidence concerning pharmacological effects on human sexuality suggests that dopaminergic receptor activation may be associated with penile erection.
■ Erection also appears to involve inhibition of alpha- adrenergic influences and beta-adrenergic stimulation plus the release of a noncholinergic vasodilator substance, possibly vasoactive intestinal peptide.
■ Ejaculation appears to be mediated primarily by alpha- adrenergic fibers. Serotonergic neurotransmission may inhibit the ejaculatory reflex.
■ An understanding of the neurobiological substrate of human sexuality may assist clinicians in choosing psychotropic agents with minimal adverse effects on sexual behavior and may also contribute to the development of pharmacological interventions for sexual difficulties.
■ References
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