Dr. Gluck, a seasoned urologist from Boston with a career spanning four decades and inspired by his father’s innovative work in neonatology at Yale, delves into the physiology of erection and its advancements over the last 30 years. He elaborates on the cellular and biochemical mechanisms, acknowledging the knowledge gaps from the start of his residency. Dr. Gluck details the importance of testosterone in erectile function and discusses contemporary treatments such as tadalafil, L-arginine, PRP injections, shock wave therapy, and new approaches in prostate cancer management. His talk underscores the complexity and interconnectedness of urological health, specifically in erectile function and prostate well-being.
Thank you Dana and thank you to Neil and the whole world link crew for setting up such an amazing conference. It’s wonderful! I think it’s a privilege for me to be here so I thank you for being here as well.
I am a urologist in Boston Massachusetts, been there about 40 years. I’m still considered a newcomer, thank you. My patients would say, “Doc, why did you decide on urology”? And when people ask me this, which is kind of a hard question, I have to thank my father Lewis Gluck, who was a pioneer in the field of neonatology.
My father, amongst his many accomplishments, opened the first neonatal Intensive Care Unit at Yale University in 1960. Treating premature babies with ventilators and IV fluids was kind of a novel concept at that time. He saw that one of the biggest causes of death, blindness, and cerebral palsy, was premature birth resulting in respiratory distress syndrome. We now know that the fetal lungs don’t reach maturity until just before a baby’s ready to be born, but in those days before ultrasound, obstetricians did not have an accurate method to know exactly when a baby should be born.
My father was also a scientist and a very curious guy, and he wanted to find a way to prevent respiratory distress syndrome in infants born prematurely. Very much ahead of his time in wellness, this is infant wellness and fetal wellness, he saw at that time there was no accurate way to assess fetal lung maturity and he set up a lab to do some basic science research on phospholipids. And he began sampling amniotic fluid because that’s where he thought he might find surfactant when the fetus would first begin to manufacture it.
Surfactant, as you know, is composed of two phospholipids, lecithin and sphingomyelin and it’s critical to the proper functioning of the lungs because it breaks surface tension and it equalizes alveolar pressure. The fetus is breathing in and out this amniotic fluid and by taking serial samples of the amniotic fluid and analyzing it with liquid chromatography, my father actually discovered that a critical shift happened just before the end of pregnancy in the ratio of lecithin and sphingomyelin signaling that surfactant was being produced and he called this the LS ratio.
Suddenly, obstetricians had a tool to predict exactly when a baby should be born and hundreds of thousands of cases of respiratory distress syndrome were prevented. But why urology? Well, my two older brothers were born in the early 50s after which my father contracted a severe case of mumps orchitis. He told me that at the time his testicles swelled up to the size of cantaloupes and after that there were no more pregnancies, until 5 years later my mother happily and surprisingly found herself pregnant.
My father was a resident in pediatrics at Columbia University and my mother was ready to give birth on a winter day in February during a blizzard. The anesthesiologist at my birth happened to be Virginia Apgar who was working on a brand new test to assess the newborn. Unfortunately for me and for my mother the delivery was quite prolonged and extremely difficult and when I finally arrived I was very blue in color.
I looked pretty lifeless and half my face was paralyzed. On a score of 1 to 10 , Dr Apgar gave me a score of two. Virginia Apgar put her arm around my father and gently told him, “Lou, don’t expect too much out of this one.” I can’t repeat her actual words because they were a little politically incorrect but jump to two decades later, I’m in medical school. Inspired by my father who always thought that the field of neonatology should be under the purview of obstetricians and not pediatricians I decided to go into obstetrics. However, in medical school taking rotations in OBGYN, I was introduced to cystoscopy and urology and I decided that was going to be the field for me.
When I approached my father with my decision and told him I was going to be a urologist he just looked at me and his response was, “I guess Virginia Apgar was right after all”. Now that was his sense of humor too. I have no professional conflicts.
Today I want to talk to you about the physiology of erection. I want to talk to you about the cellular biology and the biochemistry of erection, exactly what we’ve learned in the past 30 years. Since I’ve been in my residency, this was one of the first topics I was asked to talk about when I was a resident and when I went to investigate it, I found out we know almost nothing about erectile physiology.
There were theories dating back to the 1800s which were totally wrong, but thankfully, a lot of research has been done and like the other lecturers who’ve done such a wonderful job yesterday and today in showing you how we’ve made advances in this kind of biochemistry, I’m going to kind of show you how this all applies to erectile physiology. And I also want you to know even though I’m talking about erections in men this also applies to women so this is for everybody.
We’re going to start off with a case study. One of my patients, a 63 year old man, 10 years status, post radical prostatectomy, and he had been unable to get an erection since his surgery. He’d been put on PDE five inhibitor’s in the past but had no results. He tried a vacuum erection device without success but he was unable to do penile self-injection due to a fear of needles and discomfort. Lately he’s been suffering from a lack of energy, moodiness, temperature swings, and fatigue. His wife has a strong libido and they previously had enjoyed a healthy sexual relationship but they had not been intimate since his surgery. They have a good marriage and his wife has so far been patient. He is afraid that his wife is on the verge of seeking a new relationship due to the lack of sexual intercourse.
His past medical history includes hypertension treated with metoprolol. He’s a non-smoker, a social drinker. On physical exam he was a well appearing male: BMI 25, heart regular rate and rhythm without murmur, pulses 4/4 all extremities, genitalia circumcised, phallus without plaque, testes descended normal volume, no masses. Rectal exam: prostate absent, sphincter tone 4/4, S2 and S3. Neuro exam: grossly intact, motor 4/4 on all extremities and sensation intact to light touch.
On his Labs the CBC and CMP were within normal limits, a PSA was undetectable, a testosterone 230, free testosterone 23.7, sex hormone binding globulin 32, and a vitamin D of 52. Treatment: we started po daily tadalafil 5 milligrams and L-Arginine 1 gram TID. We found an alternative to his metoprolol sanctioned by his primary care and changed him to losartin at my suggestion. We optimized testosterone starting with a T100 1cc to the scrotom and shaft of the penis on a daily basis. We switched him to an anti-inflammatory diet, added some antioxidant relief with glutathione, turmeric, Resveratrol, CoQ10 and then treated him with a PRP injection once and the next week started low intensity shock wave therapy twice weekly for 3 weeks.
At his one month follow-up, the patient reported having strong erections 4/4, sufficient for penetration. His libido has returned, he has more energy, he stopped having temperature swings, and he and his wife are now planning a one month cruise in East Asia and Australia as a second honeymoon. His ship has come in! So this is just one story out of many, many stories.
I’m not going to go through other case studies right now but let’s get right into talking about erectile dysfunction. This is a really common problem, it affects millions of men – 40% after age 40 and more than 70% after age 70. However, there is no expiration date for sex. Amongst the men in their 70s, 59% still reported having sex in the past year and even for those above 80, 40% of men still were having sex.
So what is our goal for treatment? It’s the goal of every man to have a nice rigid rock hard erection that he’s able to use in a functional way. We do this by increasing penal capacitance, increasing vascularity, increasing neuronal connections by optimizing testosterone, and improving cortical input. I look at those as the five pillars of erection which I discuss with men when we’re doing that.
If we want to understand the physiology of erection we have to look at anatomy and the penis and the clitoris because the clitoris is very, very similar. The penis is just a capacitor. It is an organ that’s made to fill up with a finite volume of blood in these very specialized chambers which are going to react under certain circumstances. These paired Chambers are called the corpora cavernosa, underneath is a corpus spongiosa which carries the urethra and that’s connected to the glands penis which does not get rigid but does engorge. Inside the corporate carinosa are these sinusoids which we’ll be talking a lot about because they’re lined with both smooth muscle cells and endothelial cells.
On top of the corpus cavernosum and underneath a sheath called Buck’s fascia runs the dorsal vein of the penis which is the place where the helisine veins flow. They drain the blood from the penis. Once the penis gets hard enough it will compress those veins and then they’ll stop draining blood. So in order to stop draining blood out of the penis and to reach a solid state, the penis has to become rigid enough to close off those veins that are going circumflex around the corporal bodies.
Inside the middle of the corpus cavernosum is the artery of the corpus cavernosum which has little branches which are coiled like springs called helicine arteries. And these things unfurl to supply blood to all the sinusoids. Also on top of the penis are paired cavernosal nerves which are going to be providing sensation to the penis. The dorsal nerves of the penis arise from branches as S2 and S3 and S4 also known as nervi arenes. They form the pudendal nerve and with the sympathetic chain they also form the pelvic nerve leading to a pelvic plexus, which under autonomic control gives off the cavernous nerve which supplies both corpus cavernosum. The sacral roots form a feedback loop giving rise to reflex erections from direct stimulation of the genitalia. This is mediated by connections in the spinal cord to the supraspinal centers in the brain including the pons and the cortex so both a reflex down below and supraspinal connections above.
Arousal occurs in the lymbic system of the medial temporal lobe and modulation of the arousal occurs in the thalamus and striatum of the brain. The physiology of orgasm happens in the brain. Neuroimaging studies during orgasm show a huge release of dopamine and this happens in different parts of the brain. It happens in the nucleus accumbens also known as the award center, the amygdala which is the emotional center, the hippocampus for memory, the cerebellum for coordinated muscle tension, and the hypothalamus with a release of oxytocin.
The Surge of dopamine stimulates the award center responsible for feeling of pleasure, desire and motivation. In this case dopamine acts like a learning chemical helping to take notice of rewards like sex and figure out how to get more of them. Oxytocin released by the pituitary gland also makes us feel close to others and promotes affection. Prolactin released during orgasm is responsible for the feeling of satisfaction. For patients complaining of difficulty achieving orgasm or experiencing a significant lack of intensity of orgasm, treatment can include oxytocin, Amal nitrate, or PRP and we’ll talk more about PRP later.
So erection really starts on a cellular level. The corpus cavernosum sinusoids are lined with smooth muscle cells and covered by endothelial cells. Let’s look at these cells to understand the physiology of cellular relaxation. First, from the inside out, smooth muscle relaxation occurs when overall intracellular calcium is decreased releasing actin and myosin. This happens by sequestering calcium in the sarcoplasmic reticulum and also by pumping calcium out of the muscle cell.
At the cell membrane this decrease in calcium happens under the influence of two protein kinases: protein kinase A and protein kinase G. So we have two separate pathways. Let’s take a first look at protein kinase G and the guanine cycle. Protein kinase G is activated by cyclic GMP and cyclic GMP is produced from GTP under the influence of an enzyme called guanylate cyclase. Nitric oxide induces guanylate cyclase to make this conversion. Nitric oxide itself is released by nitrergic nerves, from those end nerve endings in the corpus cavernosum which are the terminal branches of cavernosal nerves.
Stimuli, either through central or visual, olfactory or erotic thought, or locally through tactile response cause neural stimuli resulting in a release of nitric oxide.
So to summarize, our brain sends a signal down the nerve endings into the penis which release nitric oxide synthase, which create nitric oxide, which induces guanylate cyclase to convert GTP to GMP and then induces the protein kinase G to sequester calcium, thereby relaxing the smooth muscle. Simple, right?
A second pathway occurs by activation of protein kinase A under the influence of cyclic AMP. This is created by adenylate cyclase via G protein receptors. In this manner prostaglandin E1 can induce the activation of adenylate cyclase leading to erection.
Let’s talk a little bit about the degradation of cyclic GMP which is important to the class of drugs known as the PDE5 Inhibitors or phosphodiesterase 5 Inhibitors. Cyclic GMP is degraded by this enzyme PDE5 and can be inhibited by different medications including selenophile, et al.
In other words, more cyclic GMP means more sequestration of calcium and more smooth muscle relaxation promoting erection. Another source of nitric oxide actually comes from the endothelial cells and this happens when those cells start to get stretched out as the penis becomes tumescent and this is called sheer force. Under the influence of the sheer force the endothelial nitric oxide synthase will catalyze the formation of nitric oxide from L-arginine
The erection starts from neural impulses, is maintained by the increase in nitric oxide from these endothelial cells released by the stretching of the corpus cavernosum. L-arginine is an important building block of proteins. It is required to maintain the urea cycle in the active state, to detoxify ammonia. It also activates cellular mechanistic target of rapamycin (MTOR) which you heard about yesterday and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, and promoting spermatogenesis and sperm quality. It’s a busy molecule.
Much evidence shows that oral administration of arginine within the physiologic range can confer health benefits to both men and women by increasing nitric oxide synthesis and thus blood flow in the skeletal muscle and the corporate cavernosum. In the penis, L-arginine is converted by nitric oxide synphase into nitric oxide and L-citrulline. The L-citrulline is reduced back to L-arginine in a circular manner. In the liver, L-arginine is involved in the urea cycle and is cleaved by arginase into urea and L-ornithine.
Generally, arginase levels are significant in the liver and insignificant in the genital tissues. Arginase may be upregulated in certain disease states including aging, diabetes and atherosclerosis. This sets up a competition reducing the amount of L-arginine available. Conversion by nitric oxide synthase. These pathological changes would lead to dysfunctional sexual arousal responses in both men and women. Besides disease states, many medications can interfere with erectile function. This would include anti-depressants, specifically SSRIs, anti-hypertensive medications, especially beta blockers, also benzodiazapines, like diazapam and lorazapam and the five Alpha reductase Inhibitors, notably finasteride. What about Angiotensin? Angiotensin 2 is known to play a significant role in the pathogenesis of erectile dysfunction. Angiotensin 2, if it’s injected intracavernosal, will terminate a spontaneous erection. The intracavernosal injection of Losartin and Angiotensin blocker has the opposite effect. Changing patients on anti-hypertensives including ACE inhibitors, beta blockers and diuretics, to Losartin can help reverse erectile dysfunction. This was one of the elements of treatment of our case study at the beginning of the lecture. The patient began on metoprolol, he was changed to losartan. Also it should be noted that alpha blockers are no longer a contraindication to the use of pde5 Inhibitors. I personally have never seen a significant adverse reaction when using both of these medications.
In urology, it’s fairly common to have people both on an alpha 1 blocker for urinary symptoms as well as a pde5 inhibitor for erectile dysfunction. If you see that contraindication just ignore it. Other medications can interfere with erectile dysfunction. For example, opioids which reduce serum testosterone levels, and five Alpha reductase Inhibitors which reduce intracellular dihydrotestosterone. Finasteride can cross the blood brain barrier and inhibit the production of DHT throughout the central nervous system and thereby decrease libido. Finasteride has also been shown in an animal model to evoke stress in the endoplasmic reticulum under the influence of reactive oxygen species. Reactive oxygen species interfere with the folding process of polypeptides in the endoplasmic reticulum and cause damage to vascular endothelial cells leading to apoptosis and compromising nitric oxide release. Finasteride has also been shown to cause a permanent alteration in androgen receptor expression and nerve density in different portions of the dermal prepuse. This change can lead to decreased erections and decrease penile sensitivity as well as decrease libido, even after discontinuing Finasteride.
One effective treatment for erectile dysfunction in the post-Finasteride syndrome can just be testosterone replacement therapy. Chronic Finasteride use has also been shown to decrease overall serum testosterone. Androgen insufficiency disrupts cellular signaling pathways and produces pathologic alterations in penile tissues leading to erectile dysfunction. Studies of testosterone treatment of castrated animals, restored myelin sheath structure in the cavernosal nerves. We actually have studies with rats where substances have been given and causes nerves to regenerate.
What about testosterone? Testosterone is critical for the maturation and maintenance of terminal axon density and neuropeptide expression. Castration has also been shown to reduce the expression and activity of pde5 whereby Androgen supplementation causes upregulation in the expression and activity of pde5 suggesting a likely homeostatic mechanism between Androgen level and pde5 expression. This is why I put most men on a pde5 inhibitor as their first step in treating their erectile dysfunction to reestablish that homeostatic mechanism. Testosterone regulates cellular growth and differentiation. Androgen deprivation causes a significant reduction in the dracular smooth muscle content and a marked increase in connective tissue deposition. These structural alterations are also associated with loss of erectile function. After castration smooth muscle cells show a large number of cytoplasmic vacuoles and the structure of the tunica albegenia is thinner with few or elastic fibers and the collagen is more disorganized.
Finasteride may also result in increased fibrosis in decreased elastic fibers inside the corpus cavernosum. Inhibition of 5alpha reductase activity induces stromal remodeling and smooth muscle dedifferentiation in the prostate, suggesting that the corpus cavernosam androgens are critical for promoting and maintaining the normal formation of smooth muscle cells. Research has also shown that normalizing plasma testosterone in diabetic animal models will restore erectile response by balancing pde5 with endothelial and neural nitric oxide synthase.
Erectile function depends on a threshold dose of testosterone. In rats, erectile function is maintained by a wide range of systemic testosterone levels, as low as 10 to 12% of normal physiologic plasma concentration. Below these concentrations, erectile function is significantly attenuated and this attenuation correlates with the concentration of plasma testosterone. This research suggests that there is likely a threshold value for testosterone below which will impair erectile function.
Traditional therapy for erectile dysfunction includes the use of oral therapy. When I was a resident, the bark of the Yohimbine tree was used as an adjunct to erectile dysfunction as well as such other herbs as the panix ginseng, maca, ginko biloba, Mondia whitei, also known as white’s ginger, horny goatweed and tribulus terrestris. Most studies on these nutraceuticals have not shown any proven benefit.
Injection therapy for the penis was also discovered by accident in 1983 when during a vascular surgery, papaverine was accidentally injected into the corpus cavernosum resulting in an erection. Since then, papaverin phentolamine and prostaglandin E1 have become the mainstays of self-injection just prior to intercourse. The vacuum erection device was first described by a Dr John King in 1874 in the diatribe The American Physician Domestic Guide to Health, describing a 9-inch glass tube with a pump at the distal end which would draw the penis up into the vacuum chamber in order to increase the size of the male organ. The modern vacuum erection device works exactly the same way but is aided by the placement of a silicone constricting band or a tourniquet at the base of the penis in order to retain blood and preserve the erection. Unfortunately, it’s a cold erection and most men find this form of therapy unsatisfactory.
Increase nitric oxide as well as balance the homeostatic mechanism between testosterone and the five Alpha reductase, increased erections during REM sleep will exercise the cavernosal tissues and may naturally improve erectile function. The five Alpha reductase Inhibitors also work at the level of the vascular smooth muscle cell cytoplasm to inhibit the action of pde5 thereby inhibiting the conversion of cyclic GMP to its inactive form five Prime GMP. Cyclic GMP activates the protein kinase G to decrease intracellular calcium leading to smooth muscle relaxation.
Now injection of vasoactive substances. First papaverine. It’s an opium alkaloid. It is a potent inhibitor of phosphodiesterases leading to an increased activation of both protein kinase G and protein kinase A and subsequent smooth muscle relaxation.
Because it works on both pathways, Papaverine has the highest risk of causing a priapism. Phentolamine works by blocking Alpha receptors in the smooth muscle which cause relaxation by blocking the action of catacolamines. Prostaglandin E1 activates prostaglandin receptors in the corpus cavernosa tissues and subsequently increases cyclic adenosine monophosphate or cyclic am in the smooth muscle. Prostaglandin E1 has less risk of priapism and is sold commercially for self-injection. Oxytocin can act centrally by activating nitric oxide synthase in the paraventricular nucleus of the brain. Direct injection into the penis is not helpful. Intranasal administration has had inconclusive effects in human studies, but it may be useful in treating problems of libido and orgasm. And vasointestinal peptide increases Venus outflow resistance and can be used in conjunction with papaverine, phentolamine or both.
The mechanism of action of papaverine. Papaverine blocks cyclic and cyclic GMP phosphodiesterases to raise the concentration of cyclic AMP, cyclic GMP and this further allows dephosphorilation of the myosin by the myosin light chain kinase deactivation and that results in smooth muscle relaxation.
Prostaglandin E1 is also known as alprostadil. It is sold commercially. It’s useful for self-injection as it is a natural substance and has a lower risk of priapism. On the negative side it can be associated with localized pain. If patients are experiencing pain with prostaglandin injection I ask them to take an NSAID about 15 minutes prior to their injection and that usually solves the problem.
Anatomic studies show that nitric oxide synthase and VIP coexist in neural fibers in the corpus cavernosum allowing nitric oxide and VIP to act as neural comediators. In erection nitric oxide will lead to dilation of the cavernosal sinus and VIP will help constriction of the Venus outflow.
So what is the self-injection technique? I teach patients this in the office. We start with some prostaglandin E1 at a low dose somewhere between 10 and 40 micrograms depending on the need. If the prostaglandin E1 is ineffective we can advance to either a bi-mix which is papaverine and phentolamine or tri-mix which includes the prostaglandin E1.
When doing self-injection it’s important to pull the skin tight radially around the base of the penis so tight that the skin is smooth over the corpus cavernosum and then I instruct the patient to push the needle in at a 90° angle at either the 10 or the 2:00 position on the penis so that he avoids the urethra underneath and avoids the dorsal vein or the nerves on top and to make sure that that needle’s pushed in all the way to the hub and just inject. No need to pull back on the stopper, it should inject very easily.
If a patient gets an erection lasting longer than four hours this requires urgent medical assistance. The treatment would be phenylephrine 500 microgram per milliliter injected every 10 minutes until the priapism is reduced. You have to monitor blood pressure and you may need to aspirate blood from the corpus cavernosum in order to initiate that detumescence. I do keep a vial of phenylephrine in the office. Luckily I’ve never really had to use it.
Endothelial dysfunction and vascular erectile dysfunction, what about those? Endothelial cells lining the corpus cavernosum, they can be subject to oxidative stress which is directly toxic to the endothelium and this also interferes with nitric oxide signaling. Free radical damage impairs endothelial function as well as decreases nitric oxide availability, resulting in increased adhesion and aggregation of platelets and neutrophils and the release of vasoconstrictor substances. Let’s take a look at some of these substances and how they interact with the endothelial cells and how they inhibit the relaxation of smooth muscle leading to erectile dysfunction.
Arginase oxidative stress is associated with increased arginase activity and expression. Diabetes induced erectile dysfunction involves elevated arginase activity. Other studies suggest that arginase activity in the corpus cavernosum is increased by insulin resistance or hypoglycemia. What about TNF-Alpha? Endothelial dysfunction is a key event in the pathophysiology of erectile dysfunction as endothelium is impaired and the presence of increased oxidative stress and inflammatory condition.
Cytokine levels including TNF-Alpha are increased in response to inflammation and contribute to changes in vascular reactivity. TNF-Alpha is also associated with Rho-kinase signaling in endothelial cells The Rho-kinase Rock pathway inhibits myosin light chain phosphoralase which leads to smooth muscle cell and vascular contraction. Whoops, I have to go back one slide, thank you.
MAP kinases are mitogen activated protein kinases, a group of serine/threonine protein kinases which can play an active role in cellular processes such as proliferation, stress response apoptosis and immune defense. One of these MAP kinases is the extracellular signal related regulated kinases or ERK ½. Phosphorilation of endothelial nitric oxide synase is catalyzed by ERK which reduces enzyme activity in the cavernosal tissue. It has an inhibitory influence on endothelial nitric oxide synthesis. ERK can be triggered by cellular stresses such as oxidative stress and hypoglycemia. It has been demonstrated that ERK inhibition will decrease arginase activity and improve corpus cavanos relaxation and function.
Angiotensin 2. This rather complicated diagram shows the role that the Rho-kinase plays in the inhibition of myosin light chain phosphorate leading to smooth muscle cell contraction. What we do know is that by blocking Angiotensin 2 at the cellular level with drugs such as losartin we can decrease the adverse effects of angiotensin on erectile dysfunction. I’m not going to go through this so we don’t have enough time, but it is quite complicated and fascinating.
So in this diagram, we see in the endothelial cell represented at the top the enemies of nitric oxide synthase including TNF-alpha, ERK and other MAP kinases. Lowering the production of nitric oxide leads to decreased nitric oxide and inhibition of erection.
On the bottom is a diagram of the corpus carinos smooth muscle cell showing that Angiotensin 2 stimulates rho-kinase activity and a blockade of the myosin lightchain phosphorase. This results in cellular contraction and an increase in erectile dysfunction. TNF-Alpha causes damage to the elastic properties of the erectile tissue as well as reducing nitric oxide formation.
What are the next steps? When oral medication and self injection are unsuccessful we can use regenerative therapy including PRP, low intensity shock wave therapy, exosomes and stem cells. This meta-analysis shows the therapeutic effects of stem cell derived exosomes in erectile dysfunction in rat models. Exosomes may improve erectile function by activating the nitric oxide signaling pathway, improving endothelial damage and inhibiting the fibrosis and apoptosis of the corpus cavernosum. The authors report that stem cell derived exosomes in this study have a potential to afford a novel cell-free therapy for erectile dysfunction, but they caution that further studies in humans are needed. Both stem cells and exosomes may be effective therapies for endothelial and Vascular repair of erectile dysfunction but the FDA will not approve the use of these in humans.
So what can we use in order to improve both endothelial function and the architecture of the corpus cavernosum and improve the function of affected smooth muscle cells and in endothelial cells lining the sinusoids of the corpus cavernosum? PRP is a safe and effective form of penile rejuvenation.
As a treatment for erectile dysfunction, multiple studies have been done looking at PRP for use in erectile function. In this observational study 88.5% of patients reported improvement in their hardness and another 78% achieve successful intercourse with just one PRP injection. Using a concentration of a minimum five time platelet density in this meta analysis, authors identified only one randomized placebo-controlled trial that had been published to date regarding the use of PRP intracavernosal injection as monotherapy for erectile dysfunction. This study showed an impressive response in erections in a highly selected cohort of men. Follow-up was only six months. The authors also identify a working definition of PRP as a platelet concentration of more than 1 million platelets per microliter. This article examines the value of various activation methods. Should we or should we not activate PRP? Some clinicians advocate the use of calcium for Activation and release of growth factors. While this may result in a quicker release it does not appear to offer any benefit over simple injection into the tissue. Platelets are activated once they are removed from the bloodstream and then reinjected into tissue. It is the injection into the tissue which will cause the activation of the platelets and the platelets will remain active for a period of up to two months.
This is my method for PRP injection. There are lots of good methods, this is just what I do. I use a 30cc serum separator and I centrifuge at 1100 RPM for 15 minutes a single spin sample. From this tube I aspirate platelet, pour plasma from the top leaving 5 CC of the platelet rich plasma on the bottom which I mix by gently swirling the tube. I then aspirate four cc’s of this into a 5cc syringe and I fix a 27 gauge needle and then I take one more CC and a 3cc syringe and put on a 30 gauge needle. I put an anesthetic cream topically on the shaft and glans of the penis about 10 minutes prior to the injection. Prior to the injection I give four micrograms of prostaglandin E1 to induce tumescence into the corpus cavernosum. I find this very very useful because it eases the injection of the PRP and it also starts to activate the sinusoidal tissues so that they’re able to receive the platelets. With the penis now tumescent, I use the 5cc syringe injecting in four different spots: two in the proximal corpus cavernosum right and left, and two in the distal corpus cavernosum right and left. And then I take the final 3cc syringe and inject that into the gland’s penis, telling the patient that while those first injections were a little bit like bee stings, this last one’s going to be more like a hornet! I then inject 10 cc’s of the platelet rich plasma into the proximal corpus cavernosum and you can use either side for that so they get the benefit of the entire tube of serum. I’m going to skip Doppler ultrasound in the interest of time but there are small handheld doppler ultrasound that you can use and I just put in a word about Peak and end-diastolic velocity.
It’s not necessary to do this kind of a diagnostic test prior to treating somebody for erectile dysfunction but I just put it there for education. What about low intensity shock wave therapy this is another way to improve the architecture of the corpus cavernosum and stimulate more blood flow. It’s been around for more than a decade. How does this work? The shock wave energy is provided as a mechanical force externally on the tissue, causing compression tension and sheer forces. You remember that sheer force is one of the components of activation of endothelial cells? The shock waves proceed through the extracellular Matrix and plasma membrane into the cytocol. Mechanical transduction via cytoskeleton chemical signals cause activation of transcription factors and induction of gene expression leading to increased angiogenesis, tissue remodeling regeneration and healing. It also decreases apoptosis, necrosis and inflammation. If we look at cardiac muscle treated with shock wave therapy we can actually see a therapeutic range for regeneration of eschemic myocardium.
In a single blind randomized sham-controlled trial of low intensity shock wave therapy, Goldstein, a well-known urologist, showed that flaccid penile low intensity shock wave therapy appears to be safe and efficacious for treating erectile dysfunction based on statistical changes between the Sham and active treatments and primary outcome measures.
What about the differences between focus shock wave which penetrates more deeply into the tissues and radial shock wave therapy which is more superficial, penetrating into the first few centimeters of tissue. In this retrospective study there was no difference between the two modalities. This appears to be corroborated in several other studies and I would venture to say that either Shockwave modality could be chosen for use in patients. However there is a significant price difference between the radial shock wave machine and the focus shock wave machine. I don’t like to waste money so the optimum benefit for shock waves appears to be at an energy flux density of about .15 Millijoule per mm squared. In this therapeutic window we see the greatest amount of angiogenesis and healthy cell proliferation and beyond that we see cytotoxicity.
The effect of low intensity shock wave therapy appears to be it lasts somewhere between one and two years. It is repeatable and maintenance therapy may be beneficial. My method for low intensity shock wave therapy includes using a radial Shockwave machine. I happen to have a Zwave machine. 3,000 shocks total are given at 8 Hertz at an intensity of 80 to 100 Millijoule divided, 1,000 shock to the right 1,000 shock to the left corpus cavernosum and then 500 shocks on either side of the perineum to get the Crux of the penis. We give this treatment twice a week for three weeks for a total of six treatments.
So to summarize we increase arterial flow by increasing compliance using PRP and shock wave. We improve vascularity with low intensity shock waves. We decrease Venus outflow by complete filling of the corpus cavernosum. You can also do surgery to remove the veins around the penis and this was done for a time but it always fails after a few months to a year. We improve compliance by relaxing the smooth muscle, improving nitric oxide levels, improving tissue compliance, reducing fibrosis, and restoring elasticity to the tissue with the PRP and shock wave.
I’m just going to skip that so we have a few minutes to talk about prostate cancer and I think it’s really important as a urologist here at this conference to let you know that the things that you are doing are fine but I want to keep you out of trouble when men in your practice develop prostate cancer and what to do and what to look for and what you should be testing for. So you know what to do and when to refer.
Okay, prostate cancer is a very common cancer in men. It’s the second most common cause of cancer death in the United States. Diagnosis of prostate cancer includes drawing a yearly PSA and we can refine PSA diagnosis using either a 4K score, a newer test called ISO PSA which I think is only available at Cleveland Clinic. My recommendation for all men undergoing hormonal optimization are a yearly PSA and rectal exam. Monitor the PSA rise. It should be less than 75 per year. If the PSA is suspicious then draw a 4K score and if the 4K score is suspicious order an MRI of the prostate and refer to Urology for biopsy.
About MRI and PSMA pet scan for prostate cancer imaging. These are new and advanced tools PSMA stands for prostate specific membrane antigen. It is a membrane-like protein which is overexpressed on prostate cancer cells and the expression increases with tumor aggressiveness. Androgen independence metastatic disease and disease recurrence. It’s done by injecting a radioactive substance into the patient’s arm which will specifically bind to the p SMA and then a scan is taken inside a PET scan machine combined with an MRI or CT. The images can reveal extra prostatic disease especially in organs and lymph nodes which was not previously visible on conventional screening.
So what about genetic testing? It’s a new frontier for prostate cancer treatment – a simple and relatively inexpensive blood test, cheek swab or spit sample can provide enough information to screen patients who might be at greater risk for prostate cancer. These are patients who could be followed more closely with early PSA and digital rectal exam. If you’re in the habit of doing genetic testing it’s worthwhile. This is a partial list of genes which can raise the risk for prostate cancer notably BRCA1 and BRCA2 which lead to more cancer when mutated, or patients who have a family history of Lynch syndrome, they might you might look for changes in msh2, msh6, mlh1, and pms2, which can lead to colon cancer, pancreatic cancer, thyroid cancer, and prostate cancer. And there are other Gene groups listed on the slide. Individuals with metastatic castrate resistant prostate cancer and a genetic mutation are candidates for PARP inhibitors. For example, olaparib and rucaparib, that’s a new treatment for metastatic prostate cancer which is castrate resistant but you have to have a genetic issue.
One of the major deterrents for treatment of prostate cancer in the eyes of physician and government agencies has been the high risk of complications from the treatments that are offered. What do they offer? Surgery and radiation – or Androgen deprovation. And therefore the government and the medical societies are trying to identify prostate cancers which they don’t really want to call cancer. They’re early, they’re favorable, they’re moderately favorable, and they say well just don’t do anything, just observe these cancers. But what happens when we actually do that? It’s a role of the dice – those patients are at a risk.
Studies in Denmark and Sweden, they’ve followed them longitudinally on active surveillance for 20 and 30 years, show that within five years, greater than 60% of those men are going to have to go for treatment and at the time of treatment, 20% of those men already have metastatic disease so they miss the boat for their POS possible cure. So we do have other treatments, non-invasive therapies that are great treatments for prostate cancer and they’ve not even been considered in terms of whether or not you should do active surveillance for a patient.
Focal therapy has gotten a lot of attention in the recent decade. Scientists who tried to use MRI images to localize tumors within the prostate and just treat the tumor itself without harming the rest of the prostate. And while you can do focal therapy in some cases, in most of the cases you’re going to be missing a lot of the tumor because MRI actually misses about 20% of prostate cancer on imaging. If you look at images of prostate cancer and then try to theorize where you might put the therapy you’re going to see, if you can, on these slides that there’s lots of red area outside the light blue therapeutic window that are going to be missed in terms of treating a focal therapy prostate cancer.
So we do have a solution and that solution has been around since 1994. It has been well studied. It is used all over the world. England just bought 30 new machines for their National Health Service and it is called HIFU, but somehow in America we don’t believe in HIFU, we don’t believe HIFU works, but it does, I guarantee it!
In 2015 the FDA finally approved HIFU as a treatment for prostate diseases in America, but everybody knows it’s for prostate cancer.
HIFU works by focusing safe ultrasound sound waves. It’s the same energy that we use to image the fetus or image your kidney and when you focus that wave on the prostate it immediately destroys that tissue on contact. That results in a mechanical effect and also a coagulation necrosis that happens. The HIFU probe is placed in the rectum. The prostate sits right on the rectum, it is 3 mm away from the surface of the inside of the rectum, so it is very close but because the HIFU waves are focused only on the prostate and they’re not focused on the rectal wall it’s safe for the rectal wall. The energy is lined up in these little cones of energy. They’re stacked into plates and then into blocks and as I select the treatment area for treatment of the prostate, the entire area is treated by this robotic machine and completely destroyed. The whole procedure takes less than two hours. It is a one-time procedure, it is outpatient and the patients can go back to their regular activities the next day. The incidence of erectile dysfunction is extremely low, the incidence of incontinence is almost zero, it is about 1 to 2%. This is the machine – the patient lies comfortably on their right side. Anesthesia has full access to the patient during the procedure. There are no fluid shifts, there is no real pain happening during the procedure. They do very, very well.
This can show different types of treatments that we can set up a focal therapy, a Hemi oblation, or a total prostate. I don’t believe in the first, because we’re going to miss too much cancer, but if a patient has a tumor localized to either the right or the left side a Hemi ablation is a good idea because you can treat all the cancerous tissue and leave the normal prostate alone and then you can put that under surveillance and the patient has a low risk of forming more prostate cancer in the future. Although between surgery and hifu, there is in their lifetime a 25% recurrence of prostate cancer for radiation. That number goes up to 66% now if cancer is on both side of the prostate. You treat the whole gland with HIFU and that’s a total treatment. This is what it looks like when I set up the energy things. There the prostate is visualized live under ultrasound imaging and I can actually see the nerves of erection, the external urinary sphincter and the bladder neck all during the procedure, all live, so I can make sure that the patient stays safe and we avoid complications.
If a patient is in an MRI for something like a focal laser oblation or a TULSA which is a transurethral ultrasound procedure, anesthesia has to work in a radiology suite in an MRI machine unless they put that in the O um it’s not very safe and frankly these are experimental therapies they’re not well proven and their results to date are not very good.
I will take your questions. Thank you for your attention. A few questions, yes questions.
Any idea of tadalafil contraindicated in aortic Arch or aortic aneurysm patients who do not qualify for surgery? The only contraindication to the pde5 Inhibitors including tadalafil are the ingestion of nitrates or nitroglycerin, other than that no there’s no contraindication.
Does HIFU and laser light prostate volume reduction compared to traditional turp mechanical method cause more post-op pain and incontinence issues in recovery period?
Just the opposite happens. With HIFU there’s an initial period of a few days to a couple of weeks where the patient may have difficulty emptying their bladder all the way. I use a super pubic catheter during that time so that they won’t have any issue to empty their bladder. TURP doesn’t cause any pain and no pain medicines are prescribed after that and similar with high food there really isn’t any pain except for maybe a little discomfort um immediately after waking up they might notice from the rectum, but it’s very very minimal.
Could olfactory changes related to covid play a role in Ed PT listed below – swears this started after having covid in 2019 and it still has loss of smell and altered taste.
So the changes in Covid, I don’t think we understand everything that’s happening in the postcovid syndrome, but I can imagine that some reactive oxygen species are affecting our bodies after covid and that those changes in our cellular physiology are going to affect erectile function. Erectile dysfunction has been known as kind of the canary in the Coal mine because men who have that early on often will develop cardiac disease, vascular disease, and other chronic diseases later on. Clarification, so PRP injections last for approximately two months. No PRP injection therapeutic effect usually lasts somewhere between one and two years. The actual activation of the platelets and the work that the platelets are doing is going to be going on for a period of two months.
Can you please comment more on what steps we can take as providers to help decrease Venus leak outflow – when men have difficulty maintaining their erection?
Sure, the number one thing is to get the man as full as possible inside the sinusoids because that will naturally pinch off the circumflex veins that are draining the penis but the aid of a ring around the base of the penis is sometimes useful. They sell them their silicone rings and they come in different sizes so they can find one that’s comfortable for them.