The Road to Sildenafil – A history of artifical erections

The inability to achieve erection has been a source of consternation for men for, well, a really long time. But the recent history of treatments for impotence, wait, I mean Erectile Dysfunction, oh no, now they’re calling it Male Sexual Dysfunction, represents a medical revolution. In the last 100 or so years, we’ve gone from nonspecific and largely ineffective treatments, to progressively more successful treatment, finally resulting in a highly specific and effective pharmaceutical solution to the problem. The goal of this post is to share a history of this unique field of medical endeavor, the medical and biological insights we’ve gained, and the rather interesting characters involved along the way.

Erectile dysfunction is reported in about one out of five of all men and increases with age. It is therefore a serious problem for millions of American men (and their spouses a fair amount of the time), and hundreds of millions worldwide.

Our story starts with one of the earliest “medical” treatments for male impotence. Starting in the late 1800s, sheep testis extract was injected as a source of testosterone (although they didn’t know it at the time). This was the standard of care until testosterone was purified in the 1940s. However, testosterone as a treatment for impotence was pretty poor. The inability to obtain an erection has little to do with levels of androgens, and in studies at the time testosterone fared no better than placebo.

Thus, this was the treatment that failed for Geddings Osbon in 1960, leading to the next great leap forward in treatment of male erectile dysfunction. Osbon, a successful owner of a tire-retreading business, did what doctors dread their patient will do. He went home and looked around his shop and home and tried to come up with a solution to his medical problem. Usually, this results in disaster, and many doctors have hilarious stories of the attempts of such patients to cure less mechanical disorders with household materials. However, in this case, Osbon invented a device which he called the “YED” or “youth equivalence device” that is still today one of the most effective solutions to erectile disfunction. It’s also known as the penis-pump.

I’m afraid the rest must continue below the fold. I think it’s safe for work, but you never know…the description of probably the most infamous urology lecture of all time might be a bit much.

The device, which now goes under the moniker Erecaid, looks something like this.

It works, because of the nature of how the penis becomes erect. The penis is like a sponge that is being compressed. The sponge in this case is the corpus cavernosum and spongiosum, and the compression is coming from the smooth muscle of the arteries feeding the sponge which prevent blood from flowing in.

With relaxation of the smooth muscle surrounding these arteries, blood can then flow into the cavernosum and spongiosum, and the spongy organs then expand and become rigid. Note also the “I-beam” like structure. The erect penis is incredibly resistant to pressure, and can apparently withstand pressures up to 6000 torr.

The penis pump, by creating negative pressure around the penis, causes blood to flow into the cavernosum and spongiosum resulting in an erection. Blood is then prevented from flowing back out by placing an elastic ring or band around the base of the penis. This treatment is effective more than 90% of the time, and works no matter what the cause of erectile dysfunction with some rare complications related to using excess pressure (cysts or blisters) or accidentally getting the scrotum or testes in the vacuum chamber. Osbon cornered the market, and made a huge difference in many men’s lives.

The next major innovation, was implantable inflatable devices or bendable metal implants that allowed the patients to physically inflate the penis to create an erection. They look something like this.

This was, as you can imagine, a far more invasive treatment, but still had a high rate of patient satisfaction (amazingly).

But what was still missing was a medical treatment for erectile dysfunction. The discovery of the first such treatment was an accidental observation. Patients being given a drug paparevine during surgery to lower blood pressure were observed to get spontaneous erections. The obvious thing to do, for surgeons anyway, was to then see what happened when papaverine was injected directly into the penis. The results were revolutionary. But not appreciated until what was likely the most outrageous scientific presentation of all time. A British physiologist named Giles Brindley decided to present the results of his study of intra-cavernosal papaverine injections to the 1983 Urodynamics society in Las Vegas.
His method of communication of this discovery has since become infamous. A witness of this extraordinary presentation, Laurence Klotz, communicated his experience in the journal BJU International:

The lecture, which had an innocuous title along the lines of ‘Vaso-active therapy for erectile dysfunction’ was scheduled as an evening lecture of the Urodynamics Society in the hotel in which I was staying.

This was an evening programme, between the daytime sessions and an evening reception. It was relatively poorly attended, perhaps 80 people in all. Most attendees came with their partners, clearly on the way to the reception. I was sitting in the third row, and in front of me were about seven middle-aged male urologists, and their partners in ‘full evening regalia’.

Professor Brindley, still in his blue track suit, was introduced as a psychiatrist with broad research interests. He began his lecture without aplomb. He had, he indicated, hypothesized that injection with vasoactive agents into the corporal bodies of the penis might induce an erection. Lacking ready access to an appropriate animal model, and cognisant of the long medical tradition of using oneself as a research subject, he began a series of experiments on self-injection of his penis with various vasoactive agents, including papaverine, phentolamine, and several others. (While this is now commonplace, at the time it was unheard of). His slide-based talk consisted of a large series of photographs of his penis in various states of tumescence after injection with a variety of doses of phentolamine and papaverine. After viewing about 30 of these slides, there was no doubt in my mind that, at least in Professor Brindley’s case, the therapy was effective. Of course, one could not exclude the possibility that erotic stimulation had played a role in acquiring these erections, and Professor Brindley acknowledged this.

The Professor wanted to make his case in the most convincing style possible. He indicated that, in his view, no normal person would find the experience of giving a lecture to a large audience to be erotically stimulating or erection-inducing. He had, he said, therefore injected himself with papaverine in his hotel room before coming to give the lecture, and deliberately wore loose clothes (hence the track-suit) to make it possible to exhibit the results. He stepped around the podium, and pulled his loose pants tight up around his genitalia in an attempt to demonstrate his erection.

At this point, I, and I believe everyone else in the room, was agog. I could scarcely believe what was occurring on stage. But Prof. Brindley was not satisfied. He looked down sceptically at his pants and shook his head with dismay. ‘Unfortunately, this doesn’t display the results clearly enough’. He then summarily dropped his trousers and shorts, revealing a long, thin, clearly erect penis. There was not a sound in the room. Everyone had stopped breathing.

But the mere public showing of his erection from the podium was not sufficient. He paused, and seemed to ponder his next move. The sense of drama in the room was palpable. He then said, with gravity, ‘I’d like to give some of the audience the opportunity to confirm the degree of tumescence’. With his pants at his knees, he waddled down the stairs, approaching (to their horror) the urologists and their partners in the front row. As he approached them, erection waggling before him, four or five of the women in the front rows threw their arms up in the air, seemingly in unison, and screamed loudly. The scientific merits of the presentation had been overwhelmed, for them, by the novel and unusual mode of demonstrating the results.

The screams seemed to shock Professor Brindley, who rapidly pulled up his trousers, returned to the podium, and terminated the lecture. The crowd dispersed in a state of flabbergasted disarray. I imagine that the urologists who attended with their partners had a lot of explaining to do. The rest is history. Prof Brindley’s single-author paper reporting these results was published about 6 months later

Professor Brindley’s presentation was, however, enormously effective in convincing the urologists in attendance of the success of the treatment. Injection of papaverine was revolutionary, and helped scientists discover new insights into the molecular physiology of erection as well as providing a highly efficacious, if somewhat scary, treatment for erectile dysfunction. A papaverine-induced erection would typically last 1-2 hours and the treatment could be safely used once a day, about 3 times a week. The main complication was priapism.

But that’s not the end of the story of course. The last great revolution in treating erectile dysfunction was removing the frightening prospect of using a needle to generate a medical erection.
Everyone knows about the little blue pill, and Viagra (Sildenafil), is of course one of the most widely-recognized brands in the world. However, it’s discovery was equally unanticipated.

Smooth muscle is largely responsible for maintaining blood pressure by contracting or relaxing your blood vessels, thus increasing or decreasing blood pressure.
i-2928b758e3e6b25069f7067abb91fb0a-SMC Relaxation.jpg
Pfizer was investigating a drug named “UK-92480” that they had discovered by rational drug design. It caused smooth muscle relaxation through inhibition of the phosphodiesterase (specifically PDE5), which is responsible for hydrolysis of cyclic GMP. It was hoped that inhibition of PDE5 would cause smooth muscle relaxation via the pathway above, and lower blood pressure in patients. Unfortunately, results were modest. An interesting side-effect of the drug was noticed by male patients however, and the drug was surprisingly popular among the study participants despite the poor control of blood-pressure. Pfizer, not being idiots, realized they had hit gold. Finally, a treatment for erectile dysfunction in pill form had arrived.

Viagra is not 100% effective though, and some of the old-line treatments that work in patients that tend to be resistant (like diabetics with hypertension) are still in use. Further, it is completely ineffective in women. The reason is captured in the highly scientific chart below:
i-08855add6bdcfad00932a14d749ad9c3-Male vs Femal Sexuality.jpg
I shamelessly replicated this after seeing a similar one in a lecture last Friday (it was sex day – a series of lectures on taking sexual histories, sexual dysfunction, and treatments). Men are pretty simple when it comes to creating sexual desire. Even if the problem is lack of interest or desire, if you give a man an erection, he wants to stick it somewhere. I realize this is simplistic, but for the most part, bypassing desire and going straight to arousal solves the problem in us.

Women, however, are not primed for sex by mere engorgement of their sex organs. As a result, a simple pill treatment for lack of female desire has not been forthcoming. Although, I hear, a trial is underway to study the “love-patch” which contains – guess what? Testosterone!

We’ve come full circle – starting with testosterone as the treatment for female sexual dysfunction. The patch is probably ineffective or it likely would have been approved more rapidly. But maybe, after 100 years, we’ll eventually figure out the female counterpart to Viagra.

I’d like to thank Dr. Ray Costabile for providing the inspiration for this post in the excellent lecture he gave us medical students this last Friday. His lecture was a large part of the source material, and his advice on sources for this post was invaluable.