IMAGINE a pill that you could pop before sex to ensure an orgasm on time, every time. Since Viagra brought erection on demand, the next big thing in sexual medicine is ejaculation and its accompanying sexual high. For the millions of men and their partners who suffer the let-down of premature ejaculation, it could spell the end of frustration and relationship misery. And for some paralysed men, it could mean the difference between having children and remaining childless.
No such pill exists yet. But in August it came a step closer when Lique Coolen and William Truitt of the University of Cincinnati College of Medicine discovered a long-sought-after cluster of cells in the spinal cord of male rats that are crucial for ejaculation (Science, vol 297 p 1566). It was the first time anyone had identified an “ejaculation generator” in the spine, although the existence of one has long been suspected. And although the researchers have not yet found a human equivalent, finding such cells in rats means that there is at last something to work with. Coolen’s team is already looking at the neurotransmitters, or signalling chemicals, these cells use to communicate, in the hope of modulating the reflex – delaying it in men with premature ejaculation, for instance. And they are busy tracing the cells’ connections in the brain to find out how they contribute to the intense sensations of orgasm.
It was observing patients with spinal cord injuries that first started speculation about the existence of an ejaculation generator in the spine. Some men with spinal injuries can have an erection and ejaculate in response to genital stimulation even if they feel nothing and have no control of the muscles below the injury. Their reflexes are preserved as long as the lesion is high enough, roughly above the level of the navel, to leave the nerves that flow out of the spinal cord toward the genitals intact. That means the brain alone cannot be triggering and coordinating ejaculation. There must be something else in the spine.
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The cells the Cincinnati researchers identified, called lumbar spinothalamic (LSt) cells, are buried deep in the centre of the spinal cord in the rat’s lower back. In 2001 they reported that the LSt cells were activated after ejaculation but not after other kinds of sexual activity. Clearly the cells were somehow involved in ejaculation. But were they the elusive ejaculation generator?
To find out, Coolen’s team decided to see how male rats got along without their LSt cells. The cells are easy to distinguish from their neighbours by the unique pattern of neurotransmitters and receptors associated with them. By targeting a toxin at one of these, a surface receptor for a peptide called neurokinin-1, Truitt and Coolen killed off the LSt cells. After giving the rats 10 days to recover, they put them in cages with sexually receptive females and settled down to watch.
Normally, says Coolen, it’s hard to miss a male rat ejaculating. “They basically throw out their front paws and stand on their hind paws for a little while, they vocalise, and then they take a five minute break,” she says. The rats with destroyed LSt cells did everything else that was expected of them, including mounting and penetrating the females with fully erect penises, but they couldn’t finish the job. There was no paw-waving and no semen deposited in the females’ vaginas.
Ejaculation takes place in two phases. In the first, emission, a complex series of muscle spasms moves sperm from the seminal vesicles, where it is stored after being manufactured by the testes, via the ejaculatory duct into the urethra. Along the way it mixes with fluids secreted by glands, including the prostate, to produce semen. In the second phase another train of rhythmic contractions expels the semen – an event that usually but not always coincides with orgasm.
Both phases rely on signals from the autonomic nervous system, which controls involuntary actions such as breathing. One part of the system coordinates the muscle spasms of emission, while another regulates erections, the activity of the prostate gland and closure of the urinary sphincter, which allows the semen to be expelled. Conducting this autonomic orchestra, Coolen is now convinced, are the LSt cells.
By labelling the cells with a tracer for galanin, a peptide found in the cells in high concentrations, she has traced their thread-like projections to the neurons that coordinate the muscle spasms of emission, as well as the ones that regulate prostate activity. She has also found that the LSt cells receive inputs from nerves in the penis and the brain.
Coolen believes the LSt cells act as a kind of interface, processing stimuli related to sexual activity – including sensory cues from the genitalia and erotic thoughts from the brain – and sending out signals that control the muscular spasms and glandular secretions of phase 1 of ejaculation. At some point the cells also trigger phase 2. While nobody knows precisely what that trigger is, other than a general accumulation of sexual activity, the point at which the switch is thrown is probably recognisable to any man who has ever enjoyed sex. “Some people refer to this as the point of no return,” says Coolen.
In premature ejaculation, the point of no return arrives too soon. It is the most common sexual problem in men, though accurate figures are difficult to come by. Premature ejaculation has long been regarded as psychological, and men who go to their doctor tend to be referred for psychotherapy or behavioural therapy. There are ejaculation-inhibiting creams on the market but they are little more than anaesthetics to dull the sensitivity of the penis.
A few researchers, however, have long seen premature ejaculation as a physical condition. In the early 1990s, neuropsychiatrist Marcel Waldinger of the Leyenburg Hospital in The Hague, the Netherlands, noticed that patients prescribed antidepressant drugs called SSRIs (selective serotonin reuptake inhibitors) would sometimes complain that it took them too long to reach orgasm. SSRIs, of which there are five including Prozac, prevent nerve endings re-absorbing the neurotransmitter serotonin after it has been released. That means it lingers longer at its receptors. Controlled studies in men with premature ejaculation seemed to confirm Waldinger’s finding. “The effect on ejaculation occurred after six hours,” says Waldinger, who now regularly prescribes SSRIs to premature ejaculators. “By using SSRIs, the troubles of most of these men disappeared within two weeks.”
The SSRI effect makes sense. Before Coolen’s team discovered the spinal ejaculation generator, animal studies had shown that the brain is involved in the ejaculatory reflex, exerting both excitatory and inhibitory control. Excitation is provided by the hypothalamus, while inhibitory control is provided by a group of cells in the brain stem called the nucleus paragigantocellularis (PGi). Crucially, the most abundant neurotransmitter in the PGi is serotonin, so the SSRIs might be strengthening inhibition. But they only work for a minority of men and can have unpleasant side effects.
The discovery of the spinal ejaculation generator could therefore be a big breakthrough in male sexual medicine. It suggests the potential for a selective drug that works by tinkering with the neurotransmitters that act on LSt cells, or their target cells in the autonomic nervous system. It’s early days, says Coolen, but they have already identified a potential drug target. The neurokinin-1 receptors on the surface of LSt cells appear to bind to the peptide substance P, better known for its involvement in pain response. But in the LSt cells it could turn out to have an entirely different function – one central to ejaculation.
Unlike premature ejaculators, what some spinal cord injury patients need is a means of lowering their response threshold to sexual stimulation. Depending on the level of the injury, a man’s ejaculatory reflex might remain intact, but he can’t ejaculate because the signals that lead to arousal don’t get through. There are various treatments available for those men who might have been considered infertile in the past even though they produce healthy sperm. Stimulation of the penis with a mechanical vibrator can do the trick, but some men need a more invasive technique. In Europe, injecting the drug physostigmine into the penis has been shown to work. In the US, the preferred alternative is electroejaculation, in which a rectal probe produces an alternating current that stimulates the autonomic nervous system, leading to erection and ejaculation.
“The electroejaculation probe was developed to collect sperm from livestock,” explains Steven Stiens of the University of Washington in Seattle, an expert in rehabilitation after spinal cord injury (SCI), sex counsellor and paraplegic himself. “It’s been adapted for people with SCI mainly because we don’t have any sensation and we’re desperate to have kids.”
It is successful in nine out of ten patients. But next to the rectal probe, a cold shower looks like a potent aphrodisiac. After treatment, an assistant has to “milk” the patient’s penis to squeeze the accumulated semen into a container. In people who have some residual feeling, the rectal probe can be extremely painful – like a powerful electric shock. Even the vibrator, generally regarded as a pleasant experience, can cause pain because the spasticity or tightness of muscles that accompanies paralysis makes expulsion through the urinary sphincter difficult.
If a drug existed that acted on the ejaculation generator and lowered its threshold, says Stiens, masturbation or sexual activity with a partner could be enough to produce the goods.
And there might be another therapeutic spin-off. Stiens says inducing ejaculation in patients with spasticity sometimes causes their cramped muscles to relax. “The ejaculation centre fires with such intensity that something happens to the spinal cord. We don’t understand it, but the spasticity goes away for hours, even days.” Now that Coolen’s group has identified the ejaculation centre in rats, Stiens hopes it will be possible to trace the connections responsible for this relaxation, and perhaps to design drugs to enhance it.
Coolen also has preliminary data suggesting that the LSt cells contribute to another poorly understood element of male sexuality, orgasm. Travelling up the spinal cord and pushing through the brain stem, the cells form synapses with neurons in an area at the top of the brain stem called the ventral tegmental area, which is important for reinforcing rewarding behaviours, notably drug-seeking. Brain imaging studies have already implicated this area in orgasm. In unpublished research presented at a meeting of the US Society for Neuroscience in November, neuroanatomist Gert Holstege of the University of Groningen in the Netherlands used positron emission tomography to scan the brains of 11 healthy men as they were brought to orgasm by their female partners. They found that the ventral tegmental area lit up just as the men reached orgasm, but not before.
The ejaculation generator clearly is not the only trigger for male orgasm. In some patients whose spinal cord has been severed, genital stimulation can still trigger orgasm. And remarkably, Stiens estimates that around a quarter of his patients can achieve orgasm after stimulation of the lowest part of their body where sensation remains – typically, in a paraplegic, the chest or abdomen. Exactly what’s going on remains a mystery.
For now, though, Coolen has another puzzle to solve. Although female rats also have LSt cells, she has no idea what they do. “In males these cells become activated during sexual behaviour, specifically with ejaculation,” she says. “In females we have never, ever seen an activated cell.” Women, it seems, will have to wait longer than men for the pill that ensures an orgasm every time.
