In recent years, advances in molecular biology have provided us with a more thorough understanding of the erectile process as well as a more comprehensive view of the pathophysiology of erectile dysfunction (ED) and other erectile disorders. This shift in focus has dramatically changed and broadened the management options for ED. That said, prior research for the treatment of ED, with its focus on the local tissues of the penis and peripheral neurophysiology, led to the creation of highly effective treatments such as sildenafil and penile injections.
The current growing interest in the role of the central nervous system (CNS) in ED, however, has paved the way for the development of medications that directly affect the central mechanisms that pertain to erectile function. Primary among these treatment options is apomorphine, which has over a century of history in the management and treatment of diseases such as Parkinson’s, and has been assessed as a potentially potent treatment for ED since the mid-1980s. The idea behind apomorphine treatment is that, instead of acting strictly on penile tissue like sildenafil does, apomorphine would directly affect the brain and associated neurological processes in the treatment of erectile dysfunction. Apomorphine is currently under review by the Food and Drug Administration (FDA).
In 1998, a consensus group known as the Working Group for the Study on Central Mechanisms in Erections was formed in response to the development and potential availability of apomorphine as a treatment for ED. Their stated purpose was to examine the relationship between erectile processes and the brain and spinal cord. Recently, this consensus group met to review and discuss the information currently available about this neurophysiological relationship and consider where research may go in the future, and came up with the following conclusions:
The CNS has complete control over the penis, whether sexually aroused or at rest, and its ability to achieve and maintain erections. According to William D. Steers, erectile problems can come from any sort of disturbance in the nerve pathways connecting the penis and CNS. As a result, male arousal responses are a reflection of the relationship between the penile autonomic nervous system and the CNS. The parasympathetic system tends to excite erectile function, while the sympathetic nervous system can act as an inhibitor.
When arousal occurs, excitatory signals are sent from the brain and generally triggered by visual perception or thoughts regarding an appealing partner, or by physical stimulation of the penis. Regardless of the source, however, these signals will secrete proerectile neurotransmitters such as nitric oxide and acetylcholine in the excitatory nerves within the penis and act as signals for the penile arteries to relax and fill with blood, thus becoming an erection. Sildenafil, a drug used to treat ED, works directly on penile tissue to keep the muscles of the penile arteries relaxed and blood vessels engorged to maintain a state of erection.
Male arousal response is a product of the work done by several regions of the brains, from hindbrain centers that regulate basic bodily functions such as breathing, to parts of the cerebral cortex which control the capacity for intellectual thought. In short, research has shown that no single area of the brain is in charge of erectile function, but it is instead distributed throughout multiple areas of the brain and spinal cord. As a result, if one of these areas is damaged, the ability to have and maintain erections is often still intact.
Because the sympathetic nervous system inhibits erections, when this system is inactive, the ability to achieve erection is enhanced. One prominent example of this is nocturnal erections that generally occur in rapid eye movement (REM) sleep, which is the stage of the human sleep cycle that facilitates dreaming. According to one theory, sympathetic neurons in the an area of the brainstem called the locus coeruleus are at rest, which facilitates proerectile neural pathways and, in a sense, acts as a “recharging” mechanism for the penis due to the increase in both blood flow and oxygen intake for the penile tissue. According to several studies, women experience a similar state of genital arousal when undergoing REM sleep.
According to observations of World War II soldiers who had suffered spinal cord injuries at a time when it was thought that men with such injuries would suffer permanent, complete ED, the spinal cord seems to be able to generate “reflexive” erections entirely on its own. Further studies have shown that, while many men who have severely or completely injured spinal cords may not have control over other bodily functions, achieving erections and engaging in intercourse with a partner were often unaffected.
These studies, as well as animal studies as far back as the late nineteenth century, have indicated the existence of an erection-generating center located in the spinal cord near the sacrum, between the S3 and T12 vertebrae. Upon physical stimulation of the penis, the pudendal nerve would send signals to this sacral center of the CNS. The incoming sensory data would then activate connectors called interneurons to stimulate adjacent parasympathetic neurons, which would ultimately send signals from the sacral spine to blood vessels in the penis. As long as this neural connection is uninterrupted, erection can be achieved.
Studies of both men and animals with damaged spinal cords have also indicated that when the brain’s connection to this erection-controlling center in the sacral spinal cord is disconnected, erections occur more frequently and require less stimulation in order to occur than before injury. Rat studies by Benjamin D. Sachs of the Working Group has resulted in the theory that disconnecting the brain from the spinal cord lessens inhibitory control over erections, and this theory was further proven another member of the Working Group, physiologist McKenna.
In 1990, McKenna, along with his colleague, Lesley Marson, were able to locate and identify a cluster of neurons in an area of the hindbrain called the paragigantocellular nucleus (PGN), which oversees erections caused by the spinal cord. According to the research done by Larson and McKenna, PGN neurons will send most of their axons to the neurons in the sacral area of the spinal cord that controls erection generation. Once there, the neurons from the PGN secrete serotonin, which will inhibit erection by opposing the effects of proerectile neurotransmitters in the area. This is especially important to note for people taking drugs that increase the body’s serotonin levels. A prime example of this would be selective serotonin reuptake inhibitors (SSRIs) which are often used to treat mental health disorders such as depression, and have a common side effect of . This tends to present itself in the form of blocked or delayed ejaculation in men and difficulty in achieving orgasm and reduced arousal in women.
In short, Larson and McKenna’s research helps to explain how this common side effect of SSRIs and other serotonin-supplementing drugs can occur: increased serotonin levels caused by sending neurons from the hindbrain to the CNS increases the body’s ability to inhibit and control such functions as erection and ejaculation. Conversely, the results from other, more recent studies have indicated that this inhibitory effect caused by serotonin can aid patients suffering from dysfunctions such as excessive or inappropriate urges of a sexual nature, or premature ejaculation.
Research also seems to show that inhibiting sex-related behaviors can act as a protective mechanism for human beings, though it is not clear why this is the case, considering the vital role that sex plays in the survival of the species. Another Working Group member, John Bancroft, postulates that, in men, this inhibitory behavior is adaptive and acts as a preventive measure against the risks posed by excessive or high-risk behaviors of a sexual nature, and might also prevent men from having multiple ejaculations when engaging in sex, as this can lower sperm count and reduce fertility rates. While these inhibitory controls have benefits, too much inhibition of the CNS by neurotransmitters such as serotonin can lead to undesired erectile dysfunction.
Current study is focused on the role that the medial preoptic area (MPOA), a cluster of neurons in the hypothalamus, plays in regulating sex-related behavior in humans. Working Group member Francois Guiliano and his colleagues have recently found that electrical stimulation of this part of the hypothalamus in rats can cause erections to develop. This MPOA may do this by utilizing stimuli from multiple parts of the brain and redirect them to follow certain patterns of behavior pertaining to sex. Another part of the hypothalamus called the paraventricular nucleus (PVN) is another processing area that functions similarly to the MPOA, organizing data from various parts of the brain and spinal cord.
Dopamine is another neurotransmitter that affects erections, and, unlike serotonin, enhances them rather than inhibits their development. Apomorphine, for example, mimics dopamine and binds to specific receptors found in the PVN and MPOA, thereby encouraging neural pathways that enable erections. The PVN will also release another neurotransmitter that is noted for its potent proerectile effects in men, oxytocin. Oxytocin is also important for the execution of many other functions in humans, such as stimulating the childbirth process or the releasing of milk when breastfeeding.
According to research by Working Group member Rosen, higher brain functions, such as learning and memory, may also be vital to the controlling of erections in men. His work indicates that healthy men can be taught to achieve erection immediately and on demand in response to mental imagery, and even cues that are not inherently sexual.
As research has continued, many similarities and differences have been found between men and women regarding the role the CNS plays in a multitude of functions relating to sex and arousal, although the current research on men is more thorough than what is currently available about the same in women. By developing a more thorough understanding of the relationship the brain and spinal cord have with these functions, it is hoped that more effective and precise treatments for such dysfunction in both sexes can be developed.