Boston University Medical Campus.
by Irwin Goldstein, MD.
The management of erectile dysfunction (ED) has changed dramatically in recent years, as advances in molecular biology have given us a better understanding of the erectile process as well as the pathophysiology of erectile disorders. Until relatively recently, however, most research in ED focused on peripheral neurophysiology and on the local tissues of the penis, leading to the development of highly effective treatments such as penile injections and sildenafil. There has, however, been growing interest in the role of the central nervous system (CNS) in the control of erectile function, and researchers have begun to develop medications that target these central mechanisms. The first of these agents is apomorphine, a drug that has been used for over a century for the treatment of Parkinson’s disease and other disorders. Researchers began evaluating apomorphine as a potential treatment for ED in the mid 1980s, and it is currently under review by the Food and Drug Administration. Unlike sildenafil, which acts only on tissues in the penis, apomorphine acts directly on the brain.
In response to the development and impending availability of apomorphine as a centrally acting agent for ED, a consensus group known as the Working Group for the Study of Central Mechanisms in Erectile Dysfunction was formed in 1998 to examine how the brain and spinal cord control penile erections. Members of this group include Irwin Goldstein, Boston University, John Bancroft of Indiana University, François Giuliano of the Faculté de Médecine, Université Paris-Sud, Jeremy P. W. Heaton of Queen’s Universiry, Ontario, Ronald W. Lewis of the Medical College of Georgia, Tom F. Lue of the University of California, San Francisco, Kevin E. McKenna of Northwestern University, Harin Padma-Nathan of the University of Southern California, San Francisco, Raymond Rosen of the Robert Wood Johnson Medical School, Benjamin D. Sachs of the University of Connecticut, R. Taylor Segraves of Case Western Reserve University, and William D. Steers of the University of Virginia. The group met recently to discuss and review what is presently known about these mechanisms and to consider future areas of research. The following are some of our findings and conclusions.
An erection is a carefully orchestrated series of events controlled by the CNS. We now know that the penis is under the complete control of the CNS, both during sexual arousal and at rest. As our Working Group colleague William D. Steers has noted, any disturbance in the network of nerve pathways that connects the penis and the CNS can lead to problems with erections.
The male sexual response reflects a dynamic balance between exciting and inhibiting forces of the autonomic nervous system within the penis and throughout the CNS. The sympathetic component tends to inhibit erections, whereas the parasympathetic system is one of several excitatory pathways. During arousal, excitatory signals can originate in the brain, either by the sight or thought of an appealing sexual partner or by physical genital stimulation. Regardless of the source of these signals, the excitatory nerves in the penis respond by releasing proerectile neurotransmitters such as nitric oxide and acetylcholine. These chemical messengers signal the smooth muscles of the penile arteries to relax and fill with blood, resulting in an erection. The drug sildenafil works directly on the tissue in the penis to keep muscles relaxed and the vessels engorged.
Many regions in the brain contribute to male sexual response, ranging from centers in the hindbrain that also regulate basic body functions such as breathing, to areas in the cerebral cortex, the organ that controls higher thought and intellect. Research demonstrates that no single area of the brain controls sexual function. Rather, control is distributed throughout multiple areas of the brain and spinal cord. Should injury or disease destroy one or more of these regions, the ability to have erections often remains intact.
Switching off the activity of the sympathetic nervous system enhances erections. Nocturnal erections are a good example of this. Nocturnal erections occur primarily during rapid eye movement (REM) sleep, the stage in which dreaming occurs. During REM sleep, sympathetic neurons are turned off in the locus coeruleus, a specific area of the brain stem. According to one theory, when the sympathetic nervous system is at rest, proerectile pathways predominate and allow nocturnal erections to occur. We often refer to these events as a “battery-recharging” mechanism for the penis, because they increase blood flow to the penis and thus bring oxygen to reenergize it. Studies show that women also experience episodes of nocturnal arousal when the sympathetic nervous system is a rest. Approximately four or five times a night, or during each period of REM, women experience labial, vaginal, and clitoral engorgement.
Some erections may be generated entirely by the spinal cord. Evidence for these “reflexive” –type of erections comes from observations on World War II soldiers with spinal cord injuries. Prior to these observations, it was generally believed that men with spinal cord injuries had permanent and complete ED. We now know that this view is mistaken. Studies in men with severe or complete spinal cord injury have demonstrated that many men were able to achieve erections and engage in vaginal penetration even though their injuries left them unable to control other bodily functions. These observations, as well as information from studies in laboratory animals as far back as the 1890s, led to the discovery of an erection-generating center located in the sacral segments of the spinal cord (between the S3 and T12 vertebrae). Researchers found that physical stimulation of the penis sends sensory signals via the pudendal nerve to this erection center. Incoming signals activate connector nerve cells (interneurons) to stimulate nearby parasympathetic neurons. These neurons then transmit erection-inducing signals from the sacral spine to the penile blood vessels. As long as this reflex arc remains intact, an erection is possible.
Observations of men and laboratory animals with spinal cord damage indicate that when the brain is disconnected from the erection-generating center in the spinal cord, erections generally occur more often and with less tactile stimulation than before the injury. Studies in rats by Group member Benjamin D. Sachs led to the theory that disconnecting the brain from the body, removed some inhibitory control over erections. This proved to be the case, as demonstrated by physiologist Kevin E. McKenna, also a member of our Working Group. In 1990, McKenna and his colleague Lesley Marson identified the area of the brain that controls spinal-mediated erections. This cluster of neurons in the hindbrain (an evolutionary ancient part of the brain that controls blood pressure and heart rate) is called the paragigantocellular nucleus (PGN). The investigators found that the PGN neurons send most of their axons down to the erection-generating neurons in the lower spinal cord. There the PGN neurons release the neurotransmitter serotonin, which inhibits erections by opposing the effects of proerectile neurotransmitters.
This discovery may have important implications for people who take drugs that enhance levels of serotonin, such as the selective serotonin reuptake inhibitors (SSRIs) that are used to treat depression and other mental health disorders. These drugs often cause sexual dysfunction as a side effect, most commonly delayed or blocked ejaculation in men and a reduced sexual desire and difficulty reaching orgasm in women. The work by McKenna and Marson helps explain how this common and troublesome SSRI side effect may occur. By increasing levels of serotonin in the CNS, the SSRIs may tighten the brain’s built-in controls on erection, ejaculation, and other sexual functions. Interestingly, however, some recent studies also suggest that the inhibiting effects of the SSRIs may actually be helpful for some patients with other types of sexual dysfunction, such as premature ejaculation or inappropriate or excessive sexual urges.
Inhibitory control over sexual behavior may be a protective mechanism for humans. Considering the importance of sex to the preservation of the species, it is not clear why these elaborate inhibitory controls have evolved. One theory by Group member John Bancroft suggests that for most men this central inhibition is adaptive and helps keep them out of trouble resulting from excessive sexual activity or high-risk sexual behavior. These internal controls may also prevent men from experiencing repeated ejaculations during sexual encounters, which could lower sperm counts and thus reduce fertility. Despite these potential benefits, Bancroft believes that too much central inhibition, such as from high levels of serotonin, could result in unwanted sexual dysfunction.
The hypothalamus plays an important role in regulating sexual behavior. This region of the brain links the nervous and endocrine systems and is involved in certain basic behaviors such as eating and aggression. A cluster of neurons in the hypothalamus called the medial preoptic area (MPOA) appears to play a critical role in sexual function and is being intensively studied at the moment. Group member François Guiliano and his colleagues have recently shown that electrical or chemical stimulation of the MPOA causes erections in rats. The MPOA appears to integrate stimuli from many areas of the brain, helping to organize and direct the complex patterns of sexual behavior. The hypothalamus also contains the paraventricular nucleus. Like the MPOA, the paraventricular nucleus acts as a processing center that sends and receives messages from different parts of the brain and spinal cord. The erection-enhancing effects of apomorphine occur when it mimics the actions of the neurotransmitter dopamine and binds to specific receptors in the paraventricular nucleus and the MPOA, thereby turning on proerectile pathways.
During sexual arousal, the paraventricular nucleus also releases oxytocin, the hormone that stimulates uterine contractions during labor, as well as the release of milk during breast-feeding. We now know that oxytocin is also an important neurotransmitter in men, with powerful proerectile effects, as it activates excitatory nerve pathways from the spinal erection-generating center to the penis.
In addition to the above discoveries and advances, we are also exploring how higher brain functions such as memory and learning help to control erections. Group member Raymond Rosen has recently shown that healthy men can be taught to have erections on demand in response to mental imagery or nonsexual cues.
We have also become aware of the many similarities and differences between the sexes regarding CNS control of arousal, orgasm, and various sexual functions, although this area of research in women lags far behind that in men. We hope that a further understanding of the role of the brain and spinal cord in controlling sexuality will lead to the development of more effective treatments for both male and female sexual dysfunction.