Sexual Concerns in Men after Transplantation

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Sexual Concerns in Men after Transplantation

Monday, May 2, 2022

Presenter: John Mulhall MD, MSc, FECSM, FACS, FRCSI, Director, Male Sexual and Reproductive Health Program, Memorial Sloan Kettering Cancer Center

Presentation is 36 minutes long with 20 minutes of Q & A.

Summary:  Stem cell transplant recipients have an increased risk of developing sexual problems and infertility after transplant.  In men, erectile dysfunction and low testosterone are the most common sexual problems reported, and both are very treatable.

Highlights: 

• In 80-85% of men with erectile dysfunction, the cause is a physical health problem which may, or may not, be related to transplant.
• Chemotherapy and chronic use of steroids can cause a low testosterone level. If left untreated, low testosterone can increase the risk of losing bone density, diabetes, heart attack and stroke.
• Chemotherapy can increase the risk of infertility after transplant. Sperm-banking before transplant should be considered by those who wish to preserve their fertility.

Key Points:

(02:11): Endocrine problems, some antidepressants and psychological concerns can cause low sex drive.  

(03:37): Delayed orgasm can be caused by certain antidepressants, low testosterone, chemotherapy that causes loss of penile sensation and psychological stressors.

(08:13): Twice as many male cancer survivors report difficulty achieving an orgasm and/or erectile problems than the general population.

(16:51): Oral drugs, vacuum devices, penis injections, Muse, penile implants and vascular surgery are other treatment options for erectile dysfunction.  

(19:25): Medication can help men achieve an erection, but don’t address other problems the contribute to sexual difficulties

(20:31): Men who do not have the stamina to briskly walk up and down two flights of stairs don’t have enough exercise reserve to participate in sex.

(21:48) Vacuum devices help some men with erectile dysfunction, but since the penis does not look or feel normal when using a vacuum device, patients often stop using it. 

(22:31): The urethral suppository, MUSE, helps approximately 50% of men with erectile dysfunction, 50% of the time.

(23:55): Penile injections for are a good option for more than 90% of men who do not respond to erectile dysfunction pills, but 50-60% of men stop doing the injections, within the first five yeas after starting, for a variety of reasons.

(26:59): Over the counter supplements are not FDC approved and could cause dangerous drug interactions.

Transcript of Presentation:

(00:01): [Steve Bauer]    Introduction. Hello. My name is Steve Bauer. Welcome to the workshop: Sexual Concerns in Men after Transplantation. It's my pleasure to introduce today's speaker, Dr. John Mulhall.

Dr. John Mulhall is the Director of the Male Sexual and Reproductive Medicine Program at Memorial Sloan Kettering Cancer Center in New York City. He also serves on the board of directors of the Sexual Medicine Society of North America and is a past president. He is currently the Editor-in-Chief of the Journal of Sexual Medicine and has published extensively on sexual health and fertility preservation after cancer therapy. Please join me in welcoming Dr. Mulhall.

(00:48): [Dr. John Mulhall] Overview of Talk. Thank you, Steve. Thanks to BMT for having me do this. Thank you for joining me in the middle of your day. I'm a urologist who specializes in sexual and reproductive medicine. I've been doing this for 26 years. I've been at Memorial Sloan Kettering for 19 years, so pretty much 100% of the patients I see have sexual complaints or fertility problems. And of course, being at a cancer center, I'm very experienced treating patients after transplantation of various types.

(01:25): These are my disclosures that I wanted to show you, I have no industry conflicts in this space, especially in the testosterone space where there are potentially a lot of conflicts.

(01:40): So, male sexual dysfunction covers a broad array of problems from erectile problems, low sex drive, failure to ejaculate, premature ejaculation, low testosterone, orgasm problems including failure to achieve orgasm, painful orgasm. Sexual incompetence, which is not a problem so much after transplant, but certainly a problem in patients who have radical pelvic surgery, so radical prostatectomy, or radical cystectomy patients. And then penile length alterations and penile deformity.

(02:11): Endocrine problems can cause low sex drive.  To start, I'm talking a little bit about low sex drive. Our focus today is going to be on low testosterone and erectile dysfunction. So, we will just do a little bit of a preamble with low sex drive and a couple of other problems. There aren't that many causes of low sex drive. Technically, there are three causes: there are endocrine or hormonal problems, which include low testosterone; high prolactin, a hormone from the brain, hyperprolactinemia, is associated with low sex drive; and then underactive thyroid.

(02:47): Some antidepressants can cause low sex drive. The use of antidepressant medications is complicated by the fact that people use antidepressant medications when they're depressed, and if you're depressed, very likely you're going to have low sex drive. But there are classes of antidepressants that are associated with low sex drive, and they are classically SSRIs or SNRIs. And there are a couple of very penis-friendly or sex-friendly antidepressants, including Buspirone, and Wellbutrin.

(03:18): Psychological difficulties are the most common cause of low sex drive. Psychological causes throughout the country are probably the most common cause of low sex drive, and anything under that umbrella term that is a distressing event or occurrence in someone's life can distract you from sex and is a cause of low sex drive.

(03:37): Use of certain antidepressants classified as SSRIs can cause delayed orgasm. Delayed orgasm or at its very terminal stage anorgasmia is a complete failure to achieve an orgasm, and we really only has four major causes: the use of SSRI medications - and remember ,these medications, particularly the first generation of these medications like Prozac, Zoloft, Paxil, are those classic drugs which are used for premature ejaculation treatment, are so effective at delaying orgasm that they may in fact in some men cause a delay in orgasm.

(04:06): Low testosterone can affect ability to achieve orgasm.  Low testosterone, again, not even very low testosterone, testosterone in the low normal range has been associated with difficulty with achieving an orgasm.

(04:15): Chemotherapy that causes neuropathy and loss of penile sensation can make it difficult to achieve orgasm. Penile sensation loss as you can imagine, if for some reason you have sensation loss in your penis, your penis is no longer sensitive, then it may be more difficult for you to achieve an orgasm. Throughout the world, the most common cause of that will be diabetes, of course, diabetics are at risk for neuropathy. But at a cancer center, a very common cause of this is the use of chemotherapy that causes neuropathy, and we see this all the time in my practice.

(04:43): Delayed orgasm often has a psychological cause. And just as with low sex drive, again, a very common cause of delayed orgasm is psychological causes. And again, there's lots of different reasons under there, whether it's interpersonal conflict or life stressors, forced relationships after being widowed, forced relationships after being divorced, or conflict relationships.

(05:05): From a fertility standpoint, any chemotherapy technically puts a man at risk for at least temporary fertility problems. It takes about 74 days for a sperm to be formed, and when you're exposed to chemotherapy, there is DNA damage to the sperm, and you should not attempt to get anyone pregnant for the first 12 months, at least, after the completion of chemotherapy or testes cure, or pelvic radiation.

(05:34): Sperm banking before chemotherapy is an option to preserve fertility after transplant. We always recommend people undergoing chemotherapy who are interested in having a family to bank sperm before the commencement of chemotherapy. If you had chemotherapy and you're wondering about your future fertility stats, I would wait at least one if not two years after completion of your chemo. And typically somewhere between two and five years after transplant, the optimum recovery of sperms to the semen will occur.

You may have perfectly normal semen, but there may be no sperm inside it. So you may look at your semen, it may look the exact same as it always has all your life, but there might be no sperm in there. Only 5% of semen is actually sperm, so you wouldn't be able to tell from just looking at the semen whether there's a problem or not. That would require a semen analysis.

(06:23): Many cancer surgeries can interfere with blood supply to the penis. So, how does cancer cause sexual problems? Well, on the far left-hand side surgery, of course, prostate cancer, bladder cancer, rectal cancer, those operations which are not really relevant to you today, but they interfere with the nerve supply and blood supply to the penis.

(06:39): Cancer treatment can harm erectile tissue. Chemotherapy, hormone therapy, radiation, they can have a negative impact upon erectile tissue. And I'll talk about erectile tissue in a little bit but suffice it to say that your penis is very much like your biceps, it's only muscle. If you put your hand around your penis, most of what's inside your hand is a muscle, and that muscle needs to be exercised. Radiation can cause damage to that muscle, and low testosterone can cause damage to the muscle, especially if the testosterone levels are very low.

(07:10): The distress of being diagnosed with cancer can be a psychological cause of sexual problems. Now, again, you've heard me say that several times already, psychological causes or factors is an umbrella term, and there are many different things that are under there. In fact, even just the distress of being diagnosed with cancer can cause sexual problems. This is very common for us to see men who've literally had no treatment for their cancer, but they've literally just been diagnosed and that alone can tip them over into a state of sexual dysfunction.

(07:36): A Scandinavian study of childhood cancer survivors found that 57% of women and 35% of men reported sexual dysfunction as adults. The next slide is looking at some of the literature on the transplant population. The literature is not fantastic, I have to tell you, but I'll talk you through this. This is from a Swedish group, one of these Swedish registries, probably the best registries in the world are in Scandinavia. They keep track of everyone from the time they're born to the time that they die. This is over two and a half thousand men and women survivors of childhood cancer. Sexual function was compared to the general population sample. Sexual dysfunction was reported by 57% of women, and 35% of male survivors, so it's a very prevalent, very common problem.

(08:13): Twice as many male cancer survivors report difficulty achieving an orgasm and/or erectile problems than the general population. Among the men, the most common dysfunctions were decreased satisfaction with sex life. So, men complaining about a significant reduction in their sex life satisfaction, reduction in sexual interest, and then of course erectile dysfunction. Erectile dysfunction just so you know, the definition is the consistent inability to obtain and/or maintain an erection sufficient for satisfactory sexual relations. Compared with the general population, the cancer survivors, the male survivors, had an increased likelihood of difficulty achieving an orgasm, a twofold risk, and erectile problems for a twofold risk, also. More intensive cancer treatment regimens, emotional distress, and body image disturbance were associated with sexual dysfunction in survivors, men, and women.

(08:58): In one small study, chronic graft-versus-host disease (GVHD) was associated with an increased risk of developing erectile dysfunction. This is an observational single-center study with only 105 subjects so this will be classified as a very small study. Testicular function and sexuality were evaluated to hormone testing and a sex questionnaire. A higher occurrence of low testosterone was seen in men one in five. Impaired sperm production, this is very common in men that get chemotherapy, especially temporary sperm production problems, and erectile dysfunction in this study occurred in the majority of men within the population. Chronic graft-versus-host disease was associated with increased risk of developing ED. Of course, these patients are sick, and any sickness is going to put your sex life towards the bottom of the list of things that are important in one's life.

(09:44): Multiple studies have found that sexual dysfunction negatively impacts quality of life. This is called a systematic review, so basically they took a number of studies and they looked at them together as a unit. Fourteen studies were included. What they show is heterogeneity in how sexual function is measured. So, from one study to the next, how one author or investigator defines sexual dysfunction might be different from another investigator. The common theme that emerged from most of these studies is that sexual dysfunction negatively impacts upon quality of life. And this is very, very common for any medical condition, not just cancer, not just transplant, but any medical condition that causes sexual dysfunction impairs quality of life. The most common sexual problems reported were erectile dysfunction for men, and lack of desire in women. And in the majority of studies, improvement in physical and psychological symptoms and sexual function led to improvement in quality of life over time.

(10:37): Doctors get very little training in sexual medicine and rarely ask patients about their sexual health. Let's talk about erectile dysfunction. This is an important slide. This asks men and women over the course of the last 12 months when you come out of seeing your family doctor, how often were you asked about any sexual difficulties you had? The far right-hand side is North America, USA, and Canada. And you can see that really throughout the world with rare exception it's uncommon that people get asked in regular family practice about their sex life. In fact, when I used to speak on female sexual dysfunction, I used to ask the women in the audience, put your hand up if your gynecologist has asked you about your sex life in the last 12 months, and very rarely would someone's hands go up. And the reasons for this are really, there are a multitude of reasons, but most physicians don't get trained in sexual medicine. The average medical student gets two hours of education in sexual medicine during medical school.

(11:33): Patients often don’t initiate a discussion with their doctor about sexual problems because they believe the doctor will be embarrassed. One of the barriers to discussing ED for the patient, of course, there is embarrassment, shame, ignorance about normal function, cultural and religious beliefs that precludes a patient talking to a doctor, and just general discomfort. Physicians, likewise, discomfort of physicians. When patients are surveyed about why they didn't bring up their sex life to the doctor, two thirds of those patients will say, because I got the impression that the doctor would be embarrassed if I discussed this.

(12:05): Physicians lack of knowledge, I've already talked about the very little education that physicians get. Personal bias and time in modern clinical practice. There's a lot to get through when talking to patients and one's sex life is low on the totem pole for most physicians. It would be important for you, if your sex life is important for you, to bring this up to your doctor. So, whether that doctor is comfortable speaking to you about it or not, they should know or should have resources for you to follow-up on if they're not the person to speak to you.

(12:41): Anything that impacts the brain including stress, a tumor or stroke, can interfere with sexual function. I put this up very simply to support the concept that the brain is incredibly important for sexual function. First of all, orgasm occurs in the brain, but even for erectile function, there are centers in the brain that are essentially the spark plug for starting the erectile machinery to function. So, anything that impacts upon the brain, whether it's stress, whether it's a tumor, whether it's a stroke, can interfere with sexual function.

(13:12): During an erection, the penis fills with blood which is released when an orgasm occurs.  This is a diagrammatic representation of down here, the flaccid state in the penis, and then the erect state. And I want you to think of this Swiss cheese structure of the erectile tissue. And these spaces they're called lacuna. These lacunae are contracted under adrenaline during the day. We walk around with the high levels of adrenaline in our penis, that's what keeps the muscle contracted and our penis flaccid.

(13:39) When we are aroused, chemicals, particularly nitric oxide, are secreted into the penis and they cause this muscle to undergo relaxation. And these tiny little Swiss cheese spaces become broad and large, and they fill up with blood, and that is essentially what erection is.

(13:58) I want you to think of your penis like a bicycle tire. There are two arteries you can see: the cavernosal artery in the middle of the erection chamber, and that brings in blood. And that blood fills up the erection chamber, but the blood has to be trapped inside the penis. So, there is a valve mechanism, and the health of the muscle and the penis controls the valve. So, blood flows in, oxygenated red blood, and it gets trapped in there until we have an orgasm. And then the muscle contracts again, and blood leaves the penis. And that's essentially all an erection is. It's a hydraulic event that is best thought of just like a bicycle tire.

(14:39): In 80-85% of men with erectile dysfunction, the cause is a physical health problem which may, or may not, be related to transplant. If you were to look at the general population of men who had physically-based ED, that's generally estimated to be 80 to 85% of all men. 80 to 85% of all men have physically-based ED. That's not to say that they don't have a secondary psychological component. As a man, we're only as good as our last erection. If our last erection is not good, then the next erection's going to be a problem, we have anticipatory anxiety.

But if you just look at men, these are the major causes. If you've had a transplant, and you've had erection problems, you might actually have another cause besides your transplant of having erection problems, such as vascular diseases, high blood pressure, high cholesterol, coronary artery disease, cigarette smoking, diabetes, as you can see is a very strong cause. Certain medications are associated with erection problems, pelvic surgery, neurological, and hormonal problems.

(15:38): The most common causes of erection problems are vascular problems and diabetes. So, if you look at the very top of that pie graph, you'll see that 70% of men have either vascular causes or diabetes and that they are, by far and away, the most common causes of erection problems in the world. If you look at conditions that cause, even in a transplant patient, I know you've had chemo, I know you haven't been feeling well, but a man who comes in who's had a transplant who has erection problems might actually have underlying diabetes, or maybe his vascular diseases have caused a problem. As you can see listed here, these are the fold likelihood of men having erection problems. And as you can see, diabetics have, like, terrible risk of developing erection problems.

(16:18): Lifestyle modifications, medication adjustments, or resolving interpersonal conflicts are the first step in treating erectile dysfunction. This is a process of care model. It's a very useful model to think about how we would, as physicians, treat men with erection problems. The first would be lifestyle modifications. Stopping cigarette smoking, looking after sugar, looking after blood pressure, looking after cholesterol, looking after stress levels. Medication adjustments. If a man went on a medication and had temporally related erection problems then maybe we would try to change that medication. If there's obvious interpersonal conflict, try to have that addressed at the same time.

(16:51): Oral drugs, vacuum devices, penis injections, Muse, penile implants and vascular surgery are treatment options for erectile dysfunction. There are at least three lines of increasingly serious treatment for erectile problems. From a treatment standpoint, then oral agents, the Viagra drugs known as PDE5 inhibitors are, of course, the first-line treatment as are vacuum devices. Second-line treatment penis injections, that's called intracavernosal injections, and then the urethral Alprostadil called Muse which I'll talk about in a few minutes. Third-line therapy is penile implants and vascular surgery. These are typically reserved for very special populations, especially men who've tried the first and second-line therapies and either failed or found them unpalatable.

(17:26): Oral drugs for erectile dysfunction include Viagra, Levitra, Cialis and Stendra. So, this is the Viagra group. Viagra was introduced in March 1998. It was tried for many years before then as a medication for angina. It wasn't a very good antigen agent, but the men in the trials were not giving their Viagra back because they were all getting erections again. And that's how the story started.

(17:47): You should not be using nitroglycerin. The interaction between Viagra drugs and nitroglycerin is potentially lethal, massive drop in blood pressure. You should be able to walk up and down two flights of stairs without chest pain. If you can't do that, you do not have enough exercise reserve to participate in sexual relations. It's not even for Viagra, it's just for resumption of sex, you have to have some kind of exercise reserve.

(18:14): Dosing and timing of Viagra, Levitra, Cialis and Stendra. We start all of our patients at maximum dose pills, whether it's Viagra, Levitra, Cialis. We reduce the dose then for good response or for side effects. You take maximum dose and you get a phenomenal erection. Then we'll probably drop you to half maximum dose to see how you do to be cost-efficient. If you look at the patient instructions, mostly physicians will never give patients instructions about how to use the pill, but if you're using Viagra, Levitra, or Stendra, it's pretty straightforward. You take two hours before a meal, you have an eight-hour window of opportunity, and sexual stimulation is required for penis and brain. You can't go sit in the corner with the New York Times and get an erection. You need to be sexually aroused for these pills to work.

(19:00): For Cialis, Cialis kicks in usually within two, definitely four hours, but Cialis is unique in the sense that it lasts. One dose, maximum dose, lasts for at least 24 hours. So, for couples who have frequent or unpredictable relations, these are the patients in my practice who use Cialis, where most of the people are going to be happy with Viagra.

(19:25): Medication can help men achieve an erection, but don’t treat other problems contributing to sexual difficulties. We always follow up with our patients because patients drop out. The estimates are that one third of men will drop out from using Viagra pills after one prescription and 50% by six months. Even though the pills are giving men erection, they're not treating all of the problems that they're having sexually in the bedroom.

(19:44) Side effects of drugs used to treat erectile dysfunction. Side effects are classic: 15% of men get headache, 10% get facials flushing, 7% get GI side effects, predominantly heart burn; 4% get nasal congestion. And 2% get visual disturbance, which is blurred vision, double vision, and this loss of color vision - what's called the blue haze - because these drugs are PDE5 inhibitors, but they cross-react with PDE6, which is Retinal enzyme, the end enzyme in the eye.

Long-acting PDE5 inhibitors, like Cialis, are sometimes associated with muscle aches, which for most men are not particularly bothersome, but for occasional men, they're very bothersome. And then there is an increased incidence of tinnitus in men who use these pills also, most of which is reversible.

(20:31): Men who do not have the stamina to briskly walk up and down two flights of stairs don’t have enough exercise reserve to participate in sex. So, the high-risk groups are those men who have inadequate exercise reserve, they cannot exercise, they don't have enough exercise reserve to participate in sexual relations. And that's why we ask the question, Mr. Jones, can you walk up and down two flights of stairs briskly without chest pain?

(20:50) Men with retinal diseases, pulmonary hypertension or those with retinal disease may not be a good candidate for erectile dysfunction drugs.  Retinal diseases, such as Retinitis pigmentosa, or macular degeneration, we would always ask the ophthalmologist to give us approval to use these drugs. Certain HIV medications cause such a massive increase in the dose of Viagra drugs in the blood that they are associated with problems. And then pulmonary hypertension medications may be a problem.

(21:16): How vacuum devices to treat erectile dysfunction work. This is a diagrammatic representation of a vacuum device, a cylinder that's placed over the penis. Usually, we encourage men to trim their hair off of the base of the penis. We encourage them to put K-Y Jelly around the base of the penis to act as a seal. And then either using, you can see on the left-hand side, the manual pump or battery-operated, the penis becomes erect inside the chamber, and then these little rings that you see here, these little black rings are placed around the cylinder, and they're slid down over the base of the penis to act as an artificial valve.

(21:48) Since the penis does not look or feel normal when using a vacuum device, patients often stop using it.  Now, the compliance with this, the use for the long-term is fairly low, and it's fairly low because the penis doesn't look normal, nor does it feel normal. The penis is usually not completely rigid, and for most men, the kind of tightness to the ring that's required to act as the artificial valve may be quite uncomfortable. But it is a good strategy, and it has very, very few side effects, and it's very easy to use. If you are on anticoagulants, if you're on warfarin, or you are on some other anticoagulants like Pradaxa or something like that or Eliquis, then we would encourage you not to use the vacuum device because of the concerns of getting a penile hematoma.

(22:31): The urethral suppository, MUSE, works in approximately 50% of men, 50% of the time. This is the urethral suppository, MUSE, medicated urethral suppository for erection, introduced in 1997, about the size of Uncle Ben's grain of rice. And it's put into the urethra, and it gets absorbed through the urethra, into the erection chamber. It works in about 50% of men. The problem is it works in those men about 50% of the time. You have to stand; you have to apply the suppository after urinating. The urine lubricates and speeds up the dissolution, the dissolving of the suppository. And you have to massage the penis for 10 to 20 minutes or so. So, it's not the most spontaneous treatment, but there are some people, for example, who don't respond to Viagra, and don't want to try penis injections, and this is an option.

(23:21): This tends to be expensive if it's not covered by insurance. As with all medications for erections, the only real risk is the risk of priapism. You see priapism [long-lasting painful erection], call your doctor. The chances of priapism occurring with a pill in my practice - so I've been using PDE5 inhibitors now for 24 years - never, not once have I had a case of priapism with a pill. And MUSE is associated with priapism, and particularly at the maximum dose, although it's very uncommon.

(23:55): Penile injections for are a good option for more than 90% of men who do not respond to erectile dysfunction pills. And this is a gold standard medication, as unappetizing as it may appear here, if you have tried a pill and it's not working, this is an excellent strategy for you. By the way, it's important to know that 15% of men who have psychologically-based erection problems, whose erection machinery is perfectly normal, 15% do not respond to pills. And so injection therapy might be used temporarily in those men.

(24:23): But injection therapy is very easy. A man injects his penis five to 10 minutes before sexual intercourse. 90%+ of men will get an erection good enough for intercourse. The average man gets an erection in five to 10 minutes, and it's lasting 30 to 40 minutes.

 It's a two-visit training session to teach you how to inject yourself, and then how to figure out a good starting dose because Priapism prolongs erection. Erections lasting longer than four hours is a real entity with injection therapy, but an hour program, for example, with good training and monitoring, the chances of Priapism happening is about 0.2%.

(25:03): Penile injections may not be a good treatment option for men on certain antidepressants, those with manual dexterity or vision problems, men on blood thinners or those with penile curvature. Contraindications. Antidepressant medications that are known monoamine oxidase inhibitors, MAOIs, they are not very frequently used in depression but they're making a comeback actually in that field. That's something that we're always inquiring about. If you can't see your penis, if you have manual dexterity problems, if you're visually impaired, and there are problems for putting a needle in any part of your body, especially the penis, because we want you injecting in a particular place, at a particular angle, on a particular depth with the needle. People are on blood thinners, and people of penile curvature, they're not absolute contraindications but there are precautions, and they make us think more carefully about whether that patient is a good candidate for injection therapy or not.

(25:46): The advantages of penis injections are they're highly effective. I've already told you probably 90 plus percent of men will get a good erection. It mimics the natural physiology of erection, penis looks normal, it feels normal. There's no effect on penile sensation or fertility. It's got a high level of discretion, and some level of spontaneity. Obviously, you have to take a break and say, I need to inject my penis. It's not a great strategy for men who are starting a new relationship and they're out on dates with partners, et cetera, et cetera. So, it's always a good idea to perhaps explore the concept of disclosure if you're going to use injections in a new relationship.

(26:21): For a variety of reasons, 50%-60% of men stop doing penile injections after a few years. On a disadvantage standpoint, they have poor long-term tolerability. So, the dropout rate is probably 50 to 60% over the first five years, people get tired of injecting, et cetera, or they're needle-phobic. It does require training, and it does require follow-up. And there are insurance issues where the medication itself is not covered.

Saying that, the medication we use is called Trimix, T-R-I-M-X. It's a mixture of three generic drugs that have been around since 1985, and they're all generic and dirt cheap. The bottle is about $75, and that bottle should last most men three to six months.

(26:59): Use of over-the-counter supplements, which are not approved by the FDA to treat erectile dysfunction, can be ineffective and risky. What about over-the-counter supplements? You see ads on TV all the time about over-the-counter supplements. Now, I think you're all aware, I think the American consumer is much more savvy now than a decade ago. You're all aware that these products that you see advertised on TV, or you go to GNC, or a vitamin shop, there's no regulatory agency approval. So, they're not actually approved by the FDA for these indications. There's a 30% placebo response rate in ED drug trials, so 30% of men, you give them an aspirin, they're going to say they're better, after taking an aspirin for example.

(27:38): Some of these over-the-counter supplements contain testosterone, and some actually contain traces of drugs like Viagra or Cialis. And of course, it's not a victimless crime. By that, by that I mean that if you are a patient who must not use Viagra medications because, let's say, you're using nitroglycerin or certain pulmonary hypertension medications, and you go to GNC and you buy some of these products and they are laced with Viagra, theoretically, you're putting your life at risk.

(28:07): Low testosterone can be caused by chemotherapy, chronic use of steroids and other factors. So, let's switch over and talk about low testosterone. There are many causes of low testosterone. The ones that are most germane to you are going to be exposure to chemotherapy or testicular radiation. But there are many causes, including HIV Aids, chronic narcotic use, chronic steroid use, et cetera.

(28:27) The symptoms of low testosterone are the same as symptoms of other problems. The best way to determine if testosterone is low is a simple blood test. The signs and symptoms are pretty straightforward. The problem with the signs and symptoms of low testosterone is that they're also the signs and symptoms of chronic stress, chronic fatigue, or poor sleep for a patient, for example, who has sleep apnea. Low sex life, low energy afternoon fatigue, depression irritability, loss of muscle, decreased endurance, weight gain, bone density loss, decreased productivity at work, these are the classic symptoms of low testosterone. And probably the most important thing in a testosterone is getting a blood test to check the testosterone level. The problem is, I don't know what your testosterone level was. If you walk in at 55 years of age, I don't know what your testosterone level was when you were 20, which is really the most important number. Where did that man start off in the prime of his testosterone manhood?

(29:18): Chemotherapy causes low testosterone. And that's why many patients during chemotherapy, and some in the long-term, are left with many of these symptoms. If you are going to get a testosterone level check, it should be in the early morning while there is a circadian rhythm with highs in the morning and lows in the afternoon. While that circadian rhythm is blunted in older men, we always check testosterone levels in an early morning fashion and have a look at what is the most accurate testosterone level.

(29:51): A low testosterone level has been linked to health problems like loss of bone density, diabetes heart attack and stroke. What are the risks of low testosterone? There is accumulating evidence that major adverse cardiac events, heart attacks, and strokes, cardiovascular events are associated with low testosterone levels, particularly testosterone levels that are very low. So, low is below 300. Below 200, that's when you start getting into the risk of cardiac events, that's when you get into the risk of developing diabetes, that's when you get into the risk of developing osteoporosis.

(30:17): Our phrase in our practice is bone, sugar, heart. Low testosterone we don't give it to you because we want you to look like Arnold Schwarzenegger did as a young man, we give it to you to prevent cardiovascular events, to prevent bone density loss, and to prevent diabetes. There are no benefits of having a low testosterone.

(30:35): There is no evidence to show that your testosterone level in any way predicts the chances of you getting prostate cancer. In fact, the accumulating evidence now is that low testosterone is associated with higher stage higher-grade prostate cancer, not the other way around.

(30:55): The risks of testosterone therapy. If I give you testosterone therapy in any of its formats, well, there is usually, particularly if you're using intramuscular testosterone, an increase in the hemoglobin, especially in patients who have sleep apnea. Sleep apnea raises hemoglobin, and when sleep apnea patients go on testosterone, their hemoglobin can go dangerously high. Breast engagement called gynecomastia is very rare.

(31:52) Testosterone therapy does not increase the risk of prostate cancer. And then I've already alluded to the concept of prostate cancer. I'm a urologist, this is what I do for a living. I'm the chairperson for the American Neurological Association of the Testosterone Guidelines Committee, and I will tell you definitively there is no, zero, zilch evidence to suggest that prostate cancer risk is increased by me giving you testosterone therapy. The benefits improve physical symptoms, cognitive symptoms, reduce heart attack risk perhaps, improve surgery control and reduction in the risk of having osteoporosis.

(31:57): Studies are mixed on whether testosterone therapy affects the risk of heart attack or stroke. If your testosterone level gets very low, below 200, besides bone, sugar, heart, there is very good evidence in the Veteran's Administration studies that there's an increased risk of death among those men. Low testosterone, I'm supposed to tell you, is a risk factor for heart attacks and strokes. That's the guidelines from the American Neurological Association. We don't know just yet whether testosterone therapy is good or bad. There's just not enough evidence yet, but most of the literature in that regard shows that at least testosterone therapy is neutral to a heart attack. And increasingly the more modern literature is showing that testosterone therapy is protective against heart attacks.

(32:42): This is that data. If you just look at large observational studies, evaluating T [testosterone] therapy and risk of major adverse cardiovascular events, has reported conflicting data. But if you look at the very bottom, the neutral effect on MACE [major adverse cardiovascular events], and then the decrease in cardiac adverse events, the number of papers is accumulating.

(33:04): A variety of therapies including gels, creams, patches, pills and others can be used to increase testosterone. There are gels, creams, patches, pills, nasal sprays, shots, subcutaneous injections, subcutaneous pellets, there's an absolute host of therapies that are out there that can be used. And much of it depends on what's covered by your insurance company, and what your preference is. I will tell you that if you come in contact with young children on a regular basis, under 12 years of age, before puberty on a regular basis, we will discourage you from using gels because the gels can be transferred from your skin or your hands onto your grandchildren, for example, or your children.

(33:44): Testosterone therapy can compromise fertility. Testosterone insufficiency patients interested in fertility should have a reproductive health evaluation before testosterone therapy and should avoid testosterone therapy. Testosterone therapy, TTH, turns off our fertility hormones as men. And so you can go from having normal sperm concentration, going on testosterone and having no sperm. That's not semen, perfectly normal semen volume, but no sperm inside your semen. So, testosterone, in many regards, is, let's say, a mediocre contraceptive.

(24:18) If you had low testosterone, and fertility was important to you, there are three classes of drugs that we can use, clomiphene, HCG - human chorionic gonadotropin, and aromatase inhibitors.

(34:30): This is our checklist, what does the patient want, the preferences for shots, or the preferences for gels. What's the cost? We always check hemoglobin, hematocrit level of baseline, what's the PSA level, the prostate cancer blood test. What's the risk of transference, what's the interest in fertility., And some other factors that are important in us deciding, in a shared decision fashion, with the patient, which option -pills, gels, patches, shots are best for him.

(35:00): Summary of main points of the presentation. So take-home messages. Transplant patients are at high risk for sexual dysfunction, for a variety of reasons. Dysfunctions and quality of life may improve over time. There's very little research in this specific population. Erectile dysfunction and low testosterone are by far the common sexual problems for men. Both conditions are eminently treatable. And see a clinician with expertise.

(35:26): Bring it up to your physician., If your physician says, this is not my area of expertise, see if he or she can refer you to a sexual medicine physician. They're nearly always urologists and there are plenty of us around. So with that, I'm going to stop, and I'm happy to take any questions from you.

Question and Answer Session

(35:45): [Steve Bauer]  Thank you Dr. Mulhall, for this excellent presentation. We'll now take questions. Our first question is please address the matter of men's fertility. Has there been any success for fertility after pediatric transplant? I do not mean adoption; I mean genetic children.

(36:15): [Dr. John Mulhall] Yeah. That's an excellent question. So, it used to be thought that if you gave chemotherapy to a male before puberty, that the testicles were somewhat quiescent and were protected from chemotherapy. When I was in residency in the mid-nineties, that was the standard philosophy. That is now known not to be true. Let me explain that to you.

(36:39): So, chemotherapy damages the stem cells in the testis. And if you eradicate enough stem cells, then you won't have new stem cells developed, and you won't be able to make sperm. So, we now know that when young boys, 6, 7, 8, 9, 10, get exposed to chemotherapy, that they, too, are at risk of long-term fertility problems. Now, this is dependent on many factors, but among the most important are what kind of chemotherapy agents? The worst ones will be alkylating agents, cyclophosphamide and drugs like that.

(37:19): But some regimens, for example, ABVD, is associated with very good sperm recovery. The sperm recovery after chemotherapy can take anywhere from one to five years, and that depends a little bit on the regimen that's used, and how the dosing and how long that regimen, how many cycles, et cetera. So, nowadays what we do even in pre-pubertal boys is we'll do sperm extraction. So, an eight-year-old is not going to be able to acquire any sperm in his ejaculate because when he's ejaculating because he's pre-pubertal. And so we do sperm extraction from the testicle in those young boys, and we store that tissue. We store that tissue in the hope that in the future, we will have technology that can take that tissue, those cells, and we can either transform those cells into real sperm or put those cells back into the testicle, or some part of the body and they will start maturing and growing sperm again.

(38:18): So, this is a very, very hot area of research. It's been going on for a decade. We know that we can do exactly as I've told you in other animals, rabbits, and rats, and in some monkeys. We know that for sure, but we've not been able to grow immature sperm out to fully functional sperm in humans as of yet. I am very confident that at some point in time in the future we will.

(38:44): So, if you are on the phone and you have a child who needs to have a transplant for some reason, it would be not unreasonable for you to speak to your cancer doctor and say, is there any chance we could just extract some testicle tissue? It takes 15, 20 minutes in the operating room, and store that for potential future use. That's an excellent question.

(39:07): [Steve Bauer] Okay. Thank you. My next question is, are sexual function problems permanent? Are you ever able to get back to normal sexual activity like pre-transplant?

(39:18): [Dr. John Mulhall] Yeah. That's an excellent question. So, what literature exists, as I said to you, it's not fantastic. The literature suggests that there is improvement over time in the first few years after transplant is completed. It all depends on what the cause of the erection problems are. So if there's a physical change in the machinery, which is not the most common cause in transplant patients, but if there is, then you're probably not curable. You might be eminently treatable. The men who are curable are men who have predominantly psychologically-based sexual problems. And that would require, probably, some testing or at least speaking to an expert to try to find what the cause was. If you had predominantly psychologically based sexual dysfunction, then technically you are curable. You might need to do treatment for a period of time for confidence restoration, but you are technically curable, absolutely.

(40:13): [Steve Bauer] Thank you. The next question is, does exercise help your sex drive?

(40:20): [Dr. John Mulhall] So, I think that exercise is good for stress. So we can reduce our stress level by exercising. And if you have a large contribution of stress towards your sexual dysfunction, one of which is low sex drive, then yes, absolutely. Exercise can help blood vessels. So the lining of our blood vessels is called endothelium, and endothelium is activated by blood flow. And if you get your blood flowing quickly through your blood vessels, including through your penis, then the endothelium is healthier and the endothelium may contribute to your erectile function for example. But from a sex drive standpoint, if your sex drive is reduced because of high stress, then doing something meditative, exercise will be one of those things, yoga, meditation, for example, they all improve your sex drive for sure.

(41:19): [Steve Bauer] Okay. I take Viagra, and I'm able to achieve and maintain an erection that cannot achieve orgasm. Is this a common problem with transplant patients?

(41:32): [Dr. John Mulhall] So it's a common problem, period. If I could direct you back to the slide that I had for delayed orgasm, we talked about things like penile sensation loss. So if you had chemotherapy and you've got a neuropathy in your penis and sensation loss, it'll be difficult for you to get enough stimulation through to the brain centers that coordinate orgasm. If your testosterone levels low from chemotherapy, even temporarily, it may be difficult for you to achieve an orgasm. If you are on an SSRI or related meds, then maybe for chronic pain, for example, any of those classes of medications can interfere with your orgasm. But if you look at the entire country, this is not just transplant patients, but the entire country. Probably one of the most common causes of delayed orgasm is psychologically based.

(42:19): Now, these men come in and they'll frequently say to me, I can never have an orgasm with my partner, or it takes me 45 minutes doctor. And when we talk about when they're on their own, with self-stimulation, 'oh no, I routinely have an orgasm, that takes me five or 10 minutes'. If that's the case, then those men have one of two problems: they either have a sensation problem in their penis, neuropathy, which they can overcome with vigorous self-stimulation, or it's a psychological phenomenon.

(42:48): That's a good question to think about if you are a doctor. Can the patient have an orgasm on their own without their partner? Yes. Psychological or neuropathy in the penis. But if they have problems on their own or with a partner, then it might be something else like an SSRI medication, like neuropathy, or like low testosterone.

(43:09): [Steve Bauer] Thank you. Next question is, how about vitamins, do they help?

(43:17): [Dr. John Mulhall] So, the bottom line is that there's no evidence to show that vitamins help. But I have to tell you the amount of study that's been put into vitamins, studies that have been done in a really correct way, is almost zero. So, it's hard to say there's no benefit, there's no literature to suggest that is a benefit. Remember I told you, this is a 30% placebo response rate. So in the Pfizer trials, when we're developing Viagra, 25 to 35% of patients using the placebo had improved erectile function. And that's a testament to the fact that every man with physically based ED has at least some secondary psychological sexual dysfunction on top of their physical cause. So the bottom line is that we don't use vitamins, that if you have a normal, healthy diet and your vitamin levels are normal, there's probably little benefit to your general health for taking vitamins, and certainly not for your sexual health.

(44:20): [Steve Bauer] Okay. Thank you. Next question. As a 25-year-old who's anxious to have sex, and a year post transplant, who do you suggest I talked to about this?

(44:34): [Dr. John Mulhall] So I think the first thing to do will be to see a urologist who specializes in sexual medicine. And if they felt you would benefit from speaking to a psychologist, then that's what I would do. When I speak to patients, I can usually very quickly discern if the patient has pure physical, or I say predominantly physical, versus predominantly psychological. So, for example, men who've got psychological erection problems will frequently wake up in the middle of an eye with excellent erections because the machinery's good, but when they're with their partner on their own, they don't do well at all. Or they might do well with one partner and not with another, right, that intermittency of function. So, there are features in a man's history with erectile dysfunction that can guide somebody, like me, to determine whether it's physically based or psychologically debate. And if I thought it was important, you could do an ultrasound and measure blood flow to define for sure if there was a physical problem or not. So, I would start with the urologist first. There are many patients to all they really need is a little confidence restoration. They use Viagra for a period of months and they get their confidence level back and they don't have to even see a psychologist if they can't get off the medication. Or if they prefer to see a psychologist, then we will refer them to a psychologist for sure.

(45:59): [Steve Bauer] Thank you. Next question. I am 30 years old, day 150 after transplant, erections and orgasms are fine, but semen volume has been dropping since transplant and is now zero., Is semen expected to return in the future?

(46:18): [Dr. John Mulhall] So, the first thing you need to do is get a testosterone level. So, our semen is a testosterone-dependent fluid. If you have low testosterone, you'll make less semen, and if your testosterone is very low, you might not make any semen at all. Now, there are other causes of no semen. There are classes of medications, for example, which cause the bladder neck, which usually contracts during orgasm, causes the bladder neck to relax. And they would be the classic prostate symptom drugs like Uroxatral and Flomax that cause relaxation of the bladder neck. But I think the first thing to do to get a testosterone level check and see if your T-level is low or not. It's not uncommon for me to see men who've got low testosterone and the only symptom is their semen volume.

(47:12): [Steve Bauer] All right, next question. Thank you for answering the question about preserving fertility for extracting tissue for prepubertal boys. However, if this was not done, is there anything at all that can be done? Do you recommend IVSI, the attempt to extract sperm, which may be hidden in the testis, but does not appear in the ejaculate, or is this just an invasive procedure which has no success in this population?

(47:45): [Dr. John Mulhall] So, we have huge experience in what's called Testis Sperm Extraction, TSE, in the post-chemotherapy population. And if I'm to be honest with you, when men have no sperm in their semen, so you're going to do it as semen specimen, a semen analysis, the lab will take it and they will centrifuge it, and they'll look to see if at the bottom of the specimen, are there any sperm. If there's zero sperm in there, you have somewhere between a 30 and 40% chance of us finding sperm if we go into your testicle and do TSE.

(48:17): So, it's not a hundred percent, but it's not zero. And that will be the clinical care pathway, the flow that we would do. Do a good semen analysis. If there's no sperm, that's called azoospermia. If there's no sperm, then TSE for sure, absolutely. And we would always wait till at least 12 months after that, and if you weren't in a huge rush, I would try and encourage you to wait two to three years because the evidence suggests that maximum recovery is at two to three years.

(48:47): [Steve Bauer] All right. I have noticed less morning erections since transplant. Is it normal due to aging, hormonal, due to meds, and long-term Prednisone use, I'm 32?

(49:01): [Dr. John Mulhall] Yeah. That's an excellent question. Thank you so much for these questions, they're really very, very insightful questions. So, nocturnal erections are complicated., We get three to six erections every night as a male after puberty, and they occur during REM sleep, rapid eye movement sleep. The first problem is, if you're not getting rapid eye movement sleep, then you can't get nocturnal erection. There are many causes of sleep disruption in patients, whether they're cancer or not, whether they're transplant or not. So, if you're not in REM sleep, you might just have no nighttime erection, number one.

(49:39): Number two, if your testosterone level is low enough, your nocturnal erection is testosterone independent. So if you have very poor testosterone levels, you may, in fact, not have a nocturnal erection. So again, this is an excellent time, we're going to see a urologist who specializes in sexual medicine. Get a testosterone level check, get a good history, get a physical examination. And we should be able to tell with those tests, whether you have good nocturnal erections or not, and you're just not waking up with them, whether you've low testosterone, whether you have a sleep problem, et cetera, et cetera.

(50:16): [Steve Bauer] Thank you for that. Next question is I'm a 71-year-old male. I was administering a gel testosterone, but I think my breasts were enlarging., You mentioned this in your presentation, but can you elaborate?

(50:31): [Dr. John Mulhall] Yeah. So, testosterone in the male body gets converted to estrogen. That's done through an enzyme called aromatase. Different men have different levels and different activity levels of aromatase in our system. It's usually held in fat, so heavier men, men with more fat tissue are going to typically have more aromatase than skinnier men. So, depending on your aromatase levels and activity, you may take a lot of the testosterone that you were taking from the outside gel, and you may convert it to estrogen. If your estrogen level is high chronically, this doesn't happen over a few weeks, but if for months and months and months, you may end up getting breast tissue. That's called gynecomastia. The problem is if you develop gynecomastia and you stop your testosterone, and your testosterone level drops, and your estrogen level drops, the gynecomastia may not reverse.

(51:35): [Dr. John Mulhall] Whenever we are putting men on testosterone, first of all, we always check an estrogen level before they go on any form testosterone therapy, and we monitor that very carefully when men are on testosterone. The three things we measure very carefully when men are using testosterone are, besides testosterone levels which are critically important, we measure hemoglobin, so men don't get a high hemoglobin level. That's called Polycythemia. And they don't get a high estrogen level. And if they're above 40 years of age, then we would also measure a PSA, the prostate specific antigen, the test that aid in the diagnosis of prostate cancer. So yes, high estrogen levels can be associated with testosterone treatment, especially if you have very high testosterone levels, or you have high aromatase activity in your body.

(52:29): [Steve Bauer] Thank you. My semen has been really watery since transplant., is it because the lack of viable sperm or other cause?

(52:41): [Dr. John Mulhall] Yeah, good question. So, only 5% of semen is sperm. So, if you had no sperm in your semen, you would not see an iota of difference in the consistency or volume of semen. The average semen volume is one and a half to 5cc probably. 5cc, by the way, is a teaspoon, that's the average volume of our ejaculate. So, it's impossible to tell by looking at your semen if there's sperm or there's not. When there's a consistency change, the first thing we think of is your testosterone level.

(53:14): So, the first thing to do there will be to get a testosterone level check. And while we're on that, I told you before, get a blood test. Make sure you do it before 10 o'clock in the morning. It's not mandatory that you fast., Some physicians like you to fast. It's not mandatory, but it's best done before 10 o'clock in the morning. That will be a good reason, consistency of semen changes, will be a good reason to get some hormone testing done.

(53:43): [Steve Bauer] Okay. I am a 76-year-old who has had prostate cancer removed at age 63., I had some function with dialysis until my transplant, which was nine months ago., Is there any hope for me?

(54:01): [Dr. John Mulhall] So, what I'm deducing from that is that the pills have stopped working. So if you're early after transplant you might have temporary problems, and that might recover. It sounds as if you are many years after your prostatectomy and these pills, Viagra were working. So, there is a chance they will work again. But again, remember in the transplant population, psychological factors and low testosterone.

(54:31): So, this is a common theme you're hearing me talk about all the time. When a transplant patient comes in, we routinely measure testosterone levels because we frequently see transplant patients with sexual problems having low testosterone. And that might be the cause. When you have very low testosterone levels so remember I said let's say 300 - 800 is considered normal. When new levels are very low, 200 and below, it is difficult for those patients to respond well to Viagra, Levitra, and Cialis, and Stendra those PDE5 inhibitors. That might be an indication that your key levels are low.

(55:09): [Steve Bauer] All right. We're about out of time, so this next question will have to be our last question. I take Viagra and I'm able to achieve and maintain an erection but cannot achieve orgasm. Is this a common problem with transplant patients?

(55:25): [Dr. John Mulhall] Yeah. So, that goes back to the whole concept of delayed orgasm. So, the use of SSLI medications, penile sensation loss, low testosterone, and psychological causes. So, go see somebody who specializes in sexual medicine. What we would do if you came to see us is we would measure your penile sensation. We would get a blood test, and we'll see if you're using antidepressant medication.

(55:47): In sexual medicine, psychological causes or diagnoses of exclusion, we have to make sure that the physical causes of that problem are ruled out. So, we've got a blood test, do penile sensation test, look at your meds. And if they were all normal, then I would look at you, and I would say Mr. Jones, this is a psychologically mediated phenomenon.

(56:15): [Steve Bauer]    Closing. Thank you very much. On behalf of BMT InfoNet, and our partners, I'd like to thank you, Dr. Mulhall, for your very helpful remarks. And thank you, the audience for your excellent questions. Please let BMT InfoNet know if we can help you in any way, enjoy the rest of the symposium.