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PDE5 is a dimeric enzyme that is composed of two identical 100 kD proteins. There are four known isoforms of PDE5 ( PDE5A 1-4 ) ACC . No : NM _ 03343I : these isoforms are products of a single gene and are formed by alternative splicing of mRNA . The enzymatic characteris- tics of the PDE5A1-3 appear to be quite similar although there may be some selectivity in their tissue distributions ; PDE5A3 is largely expressed in smooth muscle. The enzymatic properties of PDE5A4 have not been character- ized . Each of the monomers in PDE5 is a chimeric protein that contains two major functional domains that are approximately equal in size , i . e ., a catalytic domain ( C domain ) located in the more C-terminal portion of the protein and a regulatory domain ( R domain ) located in the more N-terminal portion. The single catalytic site located in the C domain is the target for sildenafil. The R domain of PDE5 contains allosteric cGMP-binding sites that contribute importantly to regulation of enzyme functions and to potency of these PDE5 inhibitors . However , the allosteric cGMP-binding sites in PDE5 are evolutionarily and biochemically distinct from that of the catalytic site . These sites are highly specific for cGMP : and do not interact with sildenafil. The catalytic site binds cGMP in a shallow pocket along the sur- face of the enzyme . When cGMP occupies this site , the cyclic phosphate bond of cGMP is brought into proximity with the catalytic machinery of the enzyme , which involves an array of amino acids and divalent cations including Zn2 +. This arrangement provides for the rapid hydrolysis of the cyclic phosphate bond of cGMP to form 5 ‘ -GMP , which has low affinity for the enzyme and rapidly dissociates from PDE5 . 5 ‘ -GMP is inactive in the cellular cGMP-signaling pathway . Other cellular phosphohydrolases do not hydrolyze the novel cyclic phosphate bond of eGMP or cAMP . Because the structure of sildenafil resembles that of eGMP , it can occupy the PDE5 catalytic site , thus blocking access to eGMP . In addition , sildenafil is stable and is not inactivated by the catalytic machinery ; nor is it metabolized significantly in the smooth muscle cell . For these reasons , occupation of the PDE5 catalytic site by sildenafil competitively inhibits eGMP breakdown since eGMP cannot gain access to the catalytic machinery . In the face of ongoing synthesis of eGMP in any tissue containing PDE5 , this will cause eGMP to accumulate and to increase cGMP signaling through PKG . In the penile corpora cavernosa , this contributes to improved erectile function . Although the C domain of PDE5 is the direct target of PDE5 inhibitors, functions of the R domain enhance the PDE5 inhibitor actions on the enzyme . Allosteric cGMP-binding is provided by sites in the R domain ; whether one or two eGMP molecules are bound per subunit is still unclear . In addition , there is a single consensus phosphorylation site for PKG or PKA near the N-terminus . Phosphorylation of this site activates PDE5 catalytic function and thereby provides for negative feedback regulation of cGMP levels. Phosphorylation of this serine is tightly controlled by cGMP levels since occupation of the PDE5 allosteric cGMP-binding sites is required for phosphorylation to occur , and the site is preferentially phosphorylated by PKG compared to PKA . Therefore , it is likely that the site is only phosphorylated when cGMP is elevated in the cell . When cGMP binds to the allosteric sites , cGMP is not degraded as it is in the catalytic site , but PDE5 enzyme functions are altered . Cyclic GMP binding to the allosteric sites in the R domain pro- duces a conformational change that exposes the serine allowing it to be rapid- ly phosphorylated , thereby increasing PDE5 catalytic activity. Cyclic GMP occupation of the allosteric sites also increases the affinity of the catalytic site for cGMP , thereby further activating PDE5 catalytic site func- tions. However , in the presence of a PDE5 inhibitor and ongoing syn- thesis of cGMP , cellular cGMP is elevated , which fosters increased binding of cGMP to the allosteric sites and phosphorylation of the serine by activated PKG ; as a result , the affinity with which PDE5 inhibitors bind at the catalytic site is increased . Therefore , due to its molecular mechanism , the potency of sildenafil is actually greater than would occur in the absence of the R domain . This property of the enzyme translates into greater clinical efficacy and poten- cy of sildenafil and other PDE5 inhibitors . Following ingestion of a PDE5 inhibitor tablet , any elevation of cGMP in smooth muscle cells should increase the avidity with which the PDE5 catalytic site binds that inhibitor . That is , the PDE5 inhibitor , by fostering increased binding of cGMP to PDE5 allosteric sites , stimulates its own efficacy and potency.

Viagra is a recent invention , but sex is not . And for as long as humans have engaged in sexual activity , there has been impotence . The word impotence first appeared in the fifteenth century , but today it has been abandoned in politically correct circles in favor of the term erectile dysfunction , or more colloquially , ED . Incredibly , it took a panel of experts to meet and decide on the name change . In 1993 , at the Consensus Meeting of the National Institutes of Health , participants agreed that the failure of the penis to achieve and sustain adequate rigidity for sexual intercourse was equivalent to other types of organ failures , such as hepatic dys- function for liver disease . Moreover , the experts recognized that the word impotence had negative connotations that should not be invoked just because a man ‘ s penis did not work properly . To be impotent , after all , means that someone lacks power , force , or effec- tiveness . Since we would not attribute such qualities to someone whose liver did not work well , the meeting attendees agreed that the term impotence should not be applied to men with erectile dysfunction . Nevertheless , unlike men with liver disease , kidney disease , or rhythm disturbances of the heart , men with erectile dysfunction do in fact feel impotent , in the full sense of the word . For this reason , I continue to use the word interchangeably with erectile dysfunc- tion . Depression , embarrassment , a diminished sense of masculin- ity-these are some of the feelings men experience when erectile dysfunction occurs . Women are often surprised at the depth of despair men exhibit when the erection fails . Of course , it can be disappointing at the moment for both partners . But when it first happens to a couple , many women describe an ” oh , well ” attitude about it , with the expectation that there will be other opportunities later . Only rarely do men have such a response . Typically , they expe- rience a frenzy of anxiety and despair when they go soft during a sexual encounter . The experience is mocked in the first of the Austin Powers movies , when the comic sleuth Austin temporarily loses his ” mojo .” The cocky , sexually aggressive aspect of his per- sona disappears until he gets it back . On a much more serious note , many a young man fantasizes about being a great lover-a Casanova or Don Juan-but if his penis will not cooperate enough even to get started , then what hope of sexual greatness can he entertain ? A torrent of questions rushes in on him when he expe- riences erectile dysfunction for the first time : ” What is happening ?” ” Why ?” ” Why now ?” ” Does this mean that my penis is broken for good ?” ” Will I never be able to have sex again ?” ” Will she laugh at me ?” ” Will she leave me ?” ” Will she tell everyone and shame me ?” Since a normal erection occurs as if by magic , the failure of the penis to respond appropriately in a sexual situation can be an unpleasant mystery for the affected man . An erection is one of the few things in life that is not improved by greater determination and willpower . A woman may roll over and say nonchalantly , ” Let ‘ s just sleep on it , and I bet things will be great in the morning .” The man will probably not sleep a wink .

This is a book about real people . The men and women who pass through my office share intimate details of their lives that would otherwise never see the light of day were it not for this book . Nat- urally , names and details have been changed in order to preserve privacy , and in many stories I have combined features from two or more patients . Each story is unique , yet there are themes familiar to every reader because of the commonality of human experience . Men want to feel powerful and capable and accepted , to be able to relate to their partners in a way that affirms these qualities . Women want to feel attractive to their partners and emotionally connected . When sex goes awry , particularly because of erection problems , not only do relationships come crashing down , but men and women lose their grip on these most fundamental human needs : secure identity and intimate connection . To be sure , the power of Viagra lies in its ability to correct a man ‘ s erection problems . Whether this fix rights the ship depends on the individuals involved and what they bring of themselves on board . So often , as the stories that follow show , men and women are at cross-purposes within their relationships and lack a shared language for understanding each other . As we are continually reminded by advertisements and testimonials in the media , Viagra can help correct the erection problem . But if a man is worried only about his lost machismo while his partner is concerned about a lack of emotional intimacy , then the reappearance of a firm penis is not likely to provide them with a happily-ever-after . Both will fall vic- tim to the Viagra Myth . To dispel this myth and help readers distinguish between fact and fiction , this book seeks to answer some of the questions most frequently raised by my patients and their partners , such as the following :

1. When is Viagra the ” perfect ” cure ?
2. When is Viagra not a cure but an obstacle to a relationship ?
3. How does a man determine whether his partner loves him or Viagra ?
4. What does a woman experience when she ‘ s with a man who can function sexually only with Viagra ?
5. If a man can function only with Viagra , does he continue to think of himself as impotent or does he feel inauthentic ?
6. Does Viagra make a man more virile , more attractive , and a better lover ?
7. What happens when a man doesn ‘ t tell his partner he ‘ s taking Viagra ? Will she know ? Is it the same as lying ?
8. What ‘ s the relationship between an erection and desire ?
9. Can Viagra work after prostate cancer surgery ?
10. If Viagra doesn ‘ t work for a man , will he ever be able to have sex again ?
11. Can a couple have sex without an erection ?
12. Does Viagra make sex less spontaneous and more predictable ?

I have written this book in the hope of provoking a more thoughtful and frank discussion about sexuality than currently exists . On a practical level , I hope that men and women can use these stories as starting points to improve the dialogue they have with each other in their relationships and ultimately to create a more fully satisfying life for themselves . I also hope this book will lead to the more realistic application of Viagra and other sexual therapies for the benefit of all men , women , and their relationships .

As someone who treats men with Viagra nearly every day , I can tes- tify to the remarkable effects of this medication . For many men and their partners , Viagra has unquestionably brought about significant improvements in their lives , and to a degree that was not previ- ously possible with other treatments . And yet there is clearly much
more to the story of human sexuality and relationships than the Viagra Myth would have us believe . The Viagra Myth has less to do with the effectiveness of the medication than with our cultural propensity to look for the easy fix . This myth suggests that a pill that improves blood flow to the penis can solve personal relation- ship issues , no matter how complex . I started wondering about the disconnect between the Viagra Myth and reality soon after I had started prescribing the medica- tion . John , a fifty-five-year-old man married for over twenty years , saw me three months after I had prescribed Viagra as treatment for his erectile dysfunction , with which he had suffered for over two years . ” So , John , how ‘ s the Viagra working out for you ?” I asked . ” Well , it works , Doc . But I don ‘ t take it anymore .” ” Why not ?” ” To tell you the truth , my wife and I decided to separate . All this time , I ‘ d thought that if I could have sex with her again , every- thing would work out fine . But it turns out that our problems are bigger than the sex thing . So we ‘ re splitting up .” Viagra had done wonders for John ‘ s erection problem but noth- ing toward solving his relationship problem . Then there was Chester , who at seventy-one years old had initially complained that his erections were only semifirm . Sex with his wife had become awkward and unsatisfying , and he asked specifically for a prescription for Viagra . It seemed a reasonable request , and his physical exam revealed no health risks , so I pre- scribed the medication . When Chester returned to the office sev- eral months later , he reported on various other medical issues but never mentioned how he was doing sexually , even though that had been the main concern for him at his last visit . ” Did you ever try the Viagra ?” I asked . Chester gave me a big smile , and there was a gleam in his eye . ” Oh , the Viagra ! Well , it definitely makes me harder !” he chuck- led . ” But I don ‘ t need it . The wife and I are okay with how things are going without it . I don ‘ t want to spoil her , you know !” John and Chester are just two examples of the many men for whom Viagra works in a physical sense as it is supposed to , but the medication failed to meet their expectations in other ways . Even when Viagra works , men like John and Chester often do not want to take it , and their reasons vary . Although I saw these men in my practice every day and intently followed their stories , I was still sur- prised to learn that the refill rate for Viagra prescriptions is less than 50 percent . What happened to the old crude joke that all a man needs in order to be happy is a hard penis and a place to put it ? Could our perception of Viagra and our sense of masculine sexual- ity be so out of kilter with reality ? Surprisingly the answer is yes . The Viagra Myth , which promotes the notion of the hard penis as the salvation of sexual relationships , is so pervasive that even professionals in the field bought into it . After reflecting on cases like those of John and Chester and their partners , I began to see an enormous gulf between appearances and reality when sexual relationships are in question . Many of my male patients , together with many of their part- ners , came to realize that finally achieving a great erection did not solve their relationship problems . In fact , it frequently made them worse . As with John and his wife , sometimes when the erection issue is solved , couples are forced to deal with more profound trou- bles in the relationship . As I listened to my patients , I came to see that our culture had taken Viagra and created a legend out of it that went far beyond its actual pharmacological properties . People had come to expect that taking a little blue pill could solve their personal and relationship problems , no matter how complex those difficulties were . I heard variations on this theme almost daily . Men or their partners requested prescriptions for Viagra for all sorts of problems , some- times with the barest of sexual symptoms : a lack of desire , struggles in existing relationships , fear of intimacy , or a desire to be a sexual superstud , for example . The range of issues for which men could envision successful treatment only with Viagra was astounding to me . This aura surrounding a medication that enhances blood flow to the penis is clearly a reflection of who we are and our desire for the easy , quick fix . I have called this exaggerated sense of Viagra as a wonder drug for various complex issues the Viagra Myth . Yes , the drug is enormously powerful , and it can be a lifesaver for many men , but it has also turned a bright spotlight on previ- ously hidden areas of sexuality and relationships . In particular , it forces couples to decide what is real in their relationships and what is not . I have come to see Viagra as providing a window into the psyche of men , and perhaps indirectly into the psyche of women as well , since women are not immune from unduly high expectations regarding the benefits of Viagra and its potential to provide sexual healing . The lessons I have teamed by listening to my patients and their partners form the basis of this book , and in the pages that follow I share the stories of those who have taught me so much about sex and sexuality and , by extension , about personal growth and humanity . The lessons to be learned are startling , profound , and often inspiring . What does it mean for a man to lose his sense of mas- culinity and self-esteem ? How does this loss manifest itself in the relationship between him and his partner ? How do couples survive when a man loses the ability to function sexually ? What is it like when his sexual powers return ? What is it like for a woman to have her partner restored to his ” youthful vigor ” after a prolonged period of inactivity ?

In 1998 , Viagra was first introduced to the world , and it is fair to say that the world has not been the same since . The impact of this medication has been enormous , not just in the narrow area of treat- ing erectile dysfunction ( ED ) for which it was approved , but also in the way we think of sex and sexuality , and even in the realm of relationships between men and women . Millions of men in the United States have tried Pfizer ‘ s wonder drug , sildenafil , better known as Viagra , and there are thus millions of women who have also seen its effects on their husbands , boyfriends , and lovers . Many other millions of men and women wonder about whether Viagra can offer a solution for their own sexual and emotional problems or for the problems of their part- ners . We human beings are sexual animals , after all . And unfortu- nately , our sex lives are not always the way we want them to be . So it ‘ s no surprise that when sex goes sour , relationships suffer in other ways as well . As a practicing urologist in Boston on the faculty of Harvard Medical School , I have treated many men with sexual problems and many couples who have sexual issues in their relationships . I knew about the development of Viagra before it was introduced to the public and was involved in its clinical application as soon as the Food and Drug Administration approved the new drug . I had anticipated using Viagra primarily for older patients with well- established erectile dysfunction , but it didn ‘ t take long before I real- ized that I had completely underestimated the huge extent of public interest in trying this new medication . For example , shortly after Viagra became available , an orthopedic surgeon came up to me in the surgeons ‘ lounge as I was having a cup of coffee between operations . ” Tell me ,” he said , ” what should I know about prescribing Viagra ? I have a patient who I think should try it .” Now I have great respect for my orthopedic colleagues , but I have yet to meet one who would take on the treatment of a problem outside his area of expertise in bones and cartilage . It was quite clear that this surgeon ‘ s patient was none other than himself ! Everyone wants to know about Viagra , and many are interested in trying it , whether or not they think they have an erection prob- lem . When I lecture to students at Harvard Medical School about sexuality , there are always a good number of Viagra questions , such as , ” What happens when a young , healthy man with normal sexual function takes Viagra ?” Or ” Can a woman tell during sex that her partner has taken Viagra ?” Or ” Is it true that Viagra increases a man ‘ s sex drive ?” No one ever falls asleep in those classes ! Viagra quickly tapped into a set of wishful fantasies that mir- rored our culture ‘ s hunger for certainty and the quick fix . Supported by stories that described elderly men restored to such sexual vital- ity by Viagra that they abandoned their wives in favor of younger women , a conventional wisdom arose that Viagra was a fountain of youth , a sure cure , the real deal . Baby boomers could now look for- ward to fabulous sex well into their nineties . Men shared Viagra stories with each other at cocktail parties or around the office water cooler . ” All I can say is ‘ Wow !”‘ says one man , and other men listen- ing in wonder how their lives might be different if they also took the magic blue pill . Women too have been targeted to confirm Viagra ‘ s ability to create satisfaction and serenity within a relationship where frustra- tion and friction had once been the rule . One of the most success- ful early Pfizer ads showed a series of couples happily dancing together after Viagra apparently cured the loss of rhythm in their relationship .

Former senator and presidential candidate Bob Dole appeared in Pfizer ads soon after Viagra ‘ s introduction and instantly turned into household words the terms Viagra and ED . Viagra jokes became a staple of comedy acts on late-night television ( Have you heard the one about the man who swallowed Viagra , but it stuck in his throat ? He wound up with a very stiff neck !), thus ensuring its place in our cultural lexicon . Viagra tapped into both our fantasies and our embarrassment about sexuality in a way that no other drug had ever done . When , for example , was the last time you heard a joke about a new cholesterol-lowering medication ? Skillful marketing contributed to our perception of Viagra as the pill that put the ” man ” in ” manly .” Star professional athletes- vigorous men such as baseball ‘ s Most Valuable Player Rafael Palmeiro of the Texas Rangers and NASCAR driver Mark Martin-endorse the medication in widely seen advertisements . Other kinds of athletes use Viagra as well . Hugh Hefner , the aging head of the Playboy empire who is known for his bevy of beautiful blondes , gives Viagra credit for maintaining his pleasure quotient . Rumor has it that he provides bowls of Viagra tablets at his famous parties . Magical Viagra . A wonder drug . Or so we have come to believe . But does the reality live up to the myth ? Is it really that good ? Can it truly solve erection problems ? What about relation- ship issues ? What does Viagra do for a man who has lost his sexual desire or for a man who is simply nervous about having sex with a new partner ? What ‘ s the real story ?