Reproductive urologist James F. Smith, MD, MS, discusses the wide range of causes for male fertility problems, from structural abnormalities, such as varicocele, to lifestyle factors, such as tobacco use, to hormonal issues, which can arise from use of common medications and supplements. He walks through his diagnostic process – covering questions to ask, tests to order, and how to interpret results – as well as his medical and surgical approaches to treatment.
mm. Um With with that in mind the topics that you'll see as we go through and I serve as an advisor for fellow health. Um many of the patients who come into my practice and who you refer over. Um we'll have a chief complaint like this. They'll will say I've been able as a couple. We've been unable to get pregnant for extended period of time. Um from a an insurance standpoint, from a strict definition standpoint, the infertility would be defined as one year of unprotected intercourse. From my perspective, if a couple is curious if you have a 28-35 38 year old couple who are interested in understanding their reproductive health, I think they could be checked out for a semen analysis and some blood work and a chat with me or chat with you all. And I think the insurance barriers are sometimes not appropriate. The basic fertility evaluation as you see a patient like this would be taking a comprehensive history doing a physical exam and that's changed a bit in covid at least is and I'm trying to figure out exactly how to do that best. I actually I do many of the consultations and have a nurse practitioner who's my hands essentially. I'll often get a scrotal ultrasound which will help me getting a couple of semen analyses. There's a lot of variability from one semen analysis to the next. So it's it's helpful to get a couple. And then standard endocrine testing would be though these six that I've listed here. If you had to choose to, I choose FSH and testosterone, the others are important. But if if you had to be just parsimonious with the ones that you choose, I choose FSH in testosterone. When you think about the fertility problems you can see. And this this ties into many of the endocrine issues as well. Um And the diagnosis of these problems depends on interpretation of these hormones. But problems can be their pre testicular and central problems either with the hypothalamus or pituitary gland or inhibition of those brain centers. Um It can also be a testicular problem. And so this can be uh genetic conditions like climb filters, it can be toxic exposures to the testicle and then there can be obstructive causes whether it's a vasectomy or hernia repair or something else that's led to obstruction. And then there are many cases where we don't we don't know exactly what costs the problem when when you're looking at a patient's history, the and at least grouping them. I I find this this rubric, this the schema of pre testicular testicular and post testicular to be helpful. Both from medical and surgical standpoint. And and thinking about, you know, whether it's Coleman's or sickle cell or beta thalassemia. Where you get your getting iron deposition, just iron overload, you're getting iron deposition in the pituitary the testes. Um Pituitary tumors, testicular causes basically malignancy of any sort can can depress sperm quality. The treatments for uh for cancer um illnesses. Covid, well it doesn't look like covid actually directly directly infects the testicle. That illness itself can cause a lot of negative inflammatory change in the testicle and and can hurt semen, analysis parameters, mumps, and then genetic conditions like climb filters or varicose seal, um post testicular causes. So statistic fibrosis patients can are typically do not have sperm in the ejaculate, um Missing the vast difference having having court injury, just being unable to ejaculate. And then some of these surgical conditions, whether it's pituitary surgery or uh torgyan surgery testicle perhaps has been damaged from lack of blood flow and then problems with the duct work in the case of vasectomy or hernia. Um And then some of the retro peritoneal surgery, like for colon cancer patients, um or artistic metastatic testicular cancer patients can can have problems in this this area. I I added this bullet point at the bottom of this slide because really talking to your patients about the techniques of how they're doing this, you know, figure does the does the patient is that your male patient know when they should be timing sex. Um And you know, figuring this out is pretty helpful for many couples. Most lubricants can hurt sperm even if they don't necessarily say that they can. Coconut oil is one of my favorites. It's a solid at room temperature and it's a body temperature. It's a liquid. So that's a safe lubricant to use. And also letting couples know that when everything is normal, about 85 of them will get pregnant in a year when they're able to time sex with with population. And that that means about every other day leading up to population. And so then as you're taking your history, thinking about the kinds of kinds of things that we can reverse. So whether it's a patient taking testosterone or antibiotics or patients with IBD or taking Propecia for the hair potentially can can affect fertility, um, finasteride at the prostate dose. The five mg a day does definitely hurts, permit the one mg a day dose. It's more unclear. Um and different, different habits from high amounts of alcohol, tobacco poor diets, obesity, anabolic steroids, marijuana use. These are some of the things that can impact fertility and, and likewise many of these exposures from patients who are working in the fields and Salinas or other parts of Central Valley lead exposures. At a patient earlier today who was a law enforcement officer and had been working, he worked with lead all the time as part of his firearms work and that, that maybe that was probably his biggest cause of fertility problems. So as you take this history from this patient realize they've been timing intercourse for a year. No prior pregnancies, no toxic exposures reports normal sexual function and his partner is young, healthy, no no prior pregnancies. He tells you that he's been on Propecia, finasteride uh, for a while and when you do an exam, she has no gynecomastia, his normal body weight, his penis is circumcised, there's no hip asparagus, the mucus is at the tip. But you see that there is a discrepancy in the size of the testicles and normal testicles around 20 ml. You see that the rights of roughly normal size And typically around 18-2018 is about the bottom end of normals. When I'm denoting something like 16, I'm saying that there's there's a decrease in size here. Um, normal ductile structures, epidemics and vase and he's got a large visible varicose seal. So for this patient, these are the potentially modifiable factors. And when you're doing your exam, it's important to know that a large portion of the bulk of the testes is made up of cells that are making sperm. So when the testicles are smaller, that's often suggesting that it could be a sperm sperm production issue. And when you think about making changes and seeing improvement, it's about a three-month cycle. So it takes about 50-60 days for sperm to be made within the testis and then another couple of weeks for that sperm to make it out of the testicle, down the epidemics and then out the vast difference and eventually to be ejaculated. So roughly if you make a change, I would expect to see a difference three months three months later. So on the exam you're looking for vast difference. You're feeling for enlarged veins, varicose seal. Um Looking at the tip of the penis is the dissipation of significant hypoxia, radius, size, consistency of the testes and as far as the varicose seal goes, this is a very common problem and um it's graded as a 12 or a three. Grade three is the obvious one. That patient will tell you that he has. A grade two is one that it feels larger when a patient is standing in front of you. When he val salvias, you'll feel it bulge under your finger. And a grade one is one that you really don't feel or see anything. But when he bears down you'll feel that bulge underneath your fingertips. So as as you continue with the investigations for this patient, you get his affiliation testosterone. A testosterone more than about 300 is within the normal range. FSH ranges roughly from about 1-8. And so he also falls in the normal range. And the The most important numbers will talk about one of the next slides is this total mode account number. And so a 10 millions. The number to remember. But the way that you calculate the total number of moving sperm is you take volume of two times the concentration of 15 times .35. And so when he has this analysis done, you see that his total mode account is in the low range, but not really really low range. Um Specifically when you look at the semen analysis the World Health Organization in 2000 and 10, this is the mostly labs will will have this particular guideline, but it's more than about 1.5 mL of semen uh concentration greater than 15 million puts a man in the fifth percentile, so it's still pretty low but that would put it in the strictly the normal range and greater than 40% would be the fifth percentile and greater than 4%. Kruger strict would be normal for um uh semen analysis practically speaking medical options. Okay. Happened practically speaking when I look at sorry the semen analysis, the looking at this total mode account is really helpful and I I use this number line all the time for explaining this to patients. But generally if your total mode account is more than 40 that's often a time where if you get the timing of sex right, changing lubricants, making sure everything's ok from a female partner. Most of the time patients are going to be able to conceive spontaneously When it's in this range between five million and 40 million. This is a range where a couple could consider intruder insemination or they could consider in vitro. Um I'm always looking for anything that I can do to push the numbers to the right. So for this particular patient they can stop for an asteroid and wait three months. We could fix the varicose seal. Wait three months. We could talk in more detail about lifestyle, diet modification, antioxidants and again wait three months do I? You I now do in vitro fertilization. Now. Often realistically what I do is fix all three. I'll have them stop an asteroid. I'll fix the varicose seal and I'll emphasize the importance of healthy, healthy diet and lifestyle. Um Some couples to speed things up, we'll jump into I Ui IVF for this kind of patient. I would I deferred and they're both younger and healthier intra uterine insemination essentially is giving ovulation induction medications um and performing ultrasound to measure follicular size once the follicles are big enough stimulating with HCG and patient produces a semen sample and then with a thin catheter that crosses the cervix, putting the sperm inside the uterus and then getting a pregnancy test a few weeks later. Um you have to have at least five million moving sperm. So for a patient with really low sperm numbers is that previous slide showed. It's just it's not gonna work, it's relatively inexpensive from a success standpoint. Even for this couple, it's probably no better than about maybe 20 chance of getting pregnant. So couples are often surprised to know that that's that's relative low. And even just timing sex when everything looks normal is maybe 15%. So this gives a bit of a boost. But it's still in the low range lower than people are expecting for in vitro fertilization patients are women are usually use an injection medication stimulating the ovaries and at the end of a few weeks of doing this trans vaginally extracting eggs and then either just incubating sperm and egg together or directly injecting a sperm into an egg. As I show in the picture at the bottom of the slide. Um Once the egg is fertilized and become an embryo that grows in an incubator for several days. And then typically at either the third day or the fifth day. Those embryos are transferred back to a patient and then a pregnancy test a few weeks later. So here fried. Yeah if you need very very few sperm Um and the cost is very high. Not covered terribly well by insurance but the success rates are often quite a bit better. And on average I'll say that it's about 50 pregnancy rate. I mean there's a lot of variability based on the clinical situation but it's it is much better pregnancy rate As far as fixing varicoceles. Um I'll commonly fix this for pain. So patients have symptomatic varicose, seal this uh is a great way of fixing that problem. About 80 of the time. I'll see resolution of that kind of pain. Um For really small varicose feels like the ones that you see on ultrasound. That's one I'll often get a referral for that and that's rarely something that's benefited by varicose. It'll be this like only diagnosed on ultrasound and something you don't really see clinically. That is probably something else like pelvic floor pain or something else. Prostatitis, perhaps orc itis. Um I'll fix varicoceles for low sperm counts really just like this patient. And essentially the procedure has a pretty good chance of improving sperm quality. Um again, as from ultrasound standpoint, the way that stenographer would determine the patient has a varicose seal would be a vein greater than three million liter of mm. And these are always done supine. So one of the things that it's a potential problem with an ultrasound is that patients aren't standing up when they likely are going to be getting bigger and typically we'll see reversal of flow surgically. What I'm doing is making a small incision lifting up this chromatic chord separating the veins from all the important things that you need to stay and I tie and I cut the veins. Um So moving on to another type of case. And so this is a patient who came into my clinic with anosmia. And this particular patient I knew had Coleman's syndrome And had low testosterone. His partner was 37 regular cycles and had a large uterine fibroid. And so collaborating with my colleagues to take in Gynecologic colleagues to take care of the fibroid patient was on Androgel and on exam patient was well, had a big big thick beard. Um An exam pretty much normal until the genital exam where test scores were very small, bilaterally had had normal epidemic mus no hernia, no varicose seal. And so just like with any any patient getting, getting labs and the semen analysis in this patient patients very suppressed, has low FSH, very low localizing harm. But a normal testosterone essentially consistent with with taking that that Androgel semen analysis shows jesus sperm so you repeated a couple of times and when you get the semen analysis is important to make sure that the lab is actually centrifuging the sample. So it is amazing how often labs do not centrifuges sample and it's equally amazing how often you'll find some sperm and it changes things dramatically. If there is even 100 sperm, we can do IBF dixie, if there are zero sperm, then it's a surgical procedure as well. We'll talk about, So I commonly draw sketch out a picture like this when I'm talking to patients or when we're doing zoom video visits, I'm showing this kind of slide. But essentially the connection between the brain and the testicles, the brain is the central processing unit. Or I'll say that's the kind of the thermostat of the, the brain with respect to sperm production and testosterone production. And essentially, if sperm production is low, then uh FSH will will rise to try to stimulate sperm production. Likewise, if testosterone production is low legitimizing hormone will rise when we see patterns, like in this, this vignette, in this patient where FSH and LH are both low. That either suggests that patients taking a high amount taking testosterone that's leading to suppression of gestational age or it indicates that there's a central problem and in a case like comments that the latter is true. The problem is primarily here in the pituitary um to get a more complicated view essentially have generates that's released in a pulse style fashion. Um and this is this is stimulating the pituitary to release lutin. Izing hormone telling leading cells within the testis to produce testosterone and this high levels of intra testicular testosterone are really critical for sperm production. So just taking testosterone and having it floating in your bloodstream doesn't lead to high enough intra testicular testosterone. It's usually about a 10 fold higher concentration relative to two serum levels within fat cells of a person's body aroma taste. We'll convert testosterone to estradiol and both testosterone and estradiol will suppress um uh generation suppress the anterior pituitary. So for patients who are very overweight, this can be a mechanism by which their hip again attal and also have fertility problems. Um I'm often checking prolactin just to make sure that we don't have a proactive noma. And when when you see a significantly elevated prolactin that's getting a pituitary MRI is very helpful. Um checking FSH is very useful in these situations as well. I'll often get an inhibit B And so when cells within the testis, the Seattle cells are producing sperm, well, they'll generally you'll generally see lots of in him and be and so it's in him and he goes up FSH will will come come down. So in this particular patient, essentially this is treated hip again at a tropic hypogonadism. Where testosterone would have been low if it weren't for the Androgel. FSH, low LH low prolactin is would be normal and hip and d would generally be in the load into normal range. So for patient like this, the kinds of options at one consider would be clementine and so for some some patients, uh so this selective estrogen receptor modulator, what it's doing is it's blocking some of the negative feedback coming into the pituitary and hypothalamus. So taking Clomid can be very helpful for some patients where they're kind of their their hip again at all. Um And you can see the pituitary at sending out low levels of FSH and LH for commons patients. I've actually not found this to work very well. I try it for maybe a month, but I just haven't found it to help me too much. HCG is essentially mimicking legitimizing hormone and I'll usually do this first and I'll just keep going up on the dose until I get Testosterone levels up into the 3-500 range. And only then we'll add Manipur. Manipur is a mixture of FSH and LH, ideally I do this one to start with. But the problem is is it's multi thousands of dollars and most patients don't have insurance coverage for this and HCG while expensive, like in the hundreds of dollars a month range. Um it's not as expensive. So I'll usually start with HCG get testosterone up and then for a shorter period of time at at many pure if these don't work, um sperm retrieval is possible. We'll talk about in the next couple of slides. So this patient try try this approach. You do it again, you get semen analysis again and you find that it's just still you're not you're not seeing any sperm. So what what could a person do? So the current technique that I do for patients who have non obstructive jesus for mia and it's different when you have a blockage. It's simpler to get sperm out. But essentially these are patients I see at our reproductive center and under sedation, essentially I numb the testicles and giver said, make an incision down the midline of the scrotum, deliver the testes, open the testes up and under a microscope and operating microscope. I'm looking for dilated tubules that I can be really selective about taking out these seminar for his tubules. And you could take out lots of the testes. But I'm trying to be as selective as I can. So I'm not damaging the testicle. The procedure takes a couple of hours and then the lab goes through this test this tissue. They're opening up the seminar first tubules and under 400 x magnification. Looking for any sperm that could be used for IVF. Yeah. Okay. So transitioning to another, another common patient. So, this young man comes into your clinic, I can imagine this being a type of patient you you'd see probably even more frequently than than I do, but it's in good health reports, no medical problems, no surgical history. And the only thing that comes up is really muscular. He tells you that he's a bodybuilder, but he denies taking any medications. Um he's interested in fertility. And so you get these typical labs get testosterone FSH, LH and you see that his LH and FSH are really low. This testosterone is quite elevated and get the semen analysis and you see that he's as a sperm IQ. Well, so you you ask him again and say, well, you know, is are there any medications or supplements you have to be taking? And he tells you, well, actually, when I'm at the gym, there's this guy who's got this cream and I take this cream and I've got these special supplements and I I take them and they're really helping me out a lot. So you continue to talk to him about the potential danger for this. This medication and specifically high levels of testosterone lead to suppression of FSH and LH and that that's likely the cause of his, his jesus for mia. So our options for this kind of patient would be stopped his testosterone and wait. Or to start something like Clomid and typically I'll give 25 mg that's half a pill every day. Um You could give HCG or for a patient who had very high levels of estrogen, I'll probably not this patient, you could you could give Arimidex. And so for this, this patient we really have a hyper gunbattle syndrome and his tea is high with with suppressed FSH and LH. Normal proactive heaven be. And it's really, it's your history. That's history exam that are helping you figure out what's going on for this gentleman. Um So in in our next patient, you see a 30 year old patient who presents with fatigue and low Libido and again, desired design. Fertility patients had a vasectomy. Um in in the past, patient has rounded out and then mildly obese phallus is normal. Testicles are a little bit small, a little bit, a little bit soft and the epidemic is full and that generally goes along with having the vasectomy rectal exam is, is pretty much normal. So for this patient, the uh I apologize to go back, let's strike the vasectomy out of this. This patient's, this patient's history. Um, so this this patient presents with uh actually Olivo astana sperm kind of a low normal range of total mode account patients hip again, addle astronaut is quite high and your FSH and LH are kind of in the lower range, sort of surprisingly surprisingly low. Um, you would expect them to be higher and LH particularly higher given the low level of testosterone. So in this, in this type of patient, this is the sort of patients where diet, lifestyle overall health is really important to talk to them about. From medication standpoint, the sorts of medications you can consider would be Clomid. The challenge with Clomid for this patient though is that would boost FSH and LH. It would boost testosterone and would likely boost extra dial even even higher. If we were to give Arimidex or an Astros, all that would be decreasing his extra dial and then increasing FSH and LH boosting testosterone. So for him that would likely be a better option giving testosterone specifically. Not the best option for a patient considering fertility. Um and because again, I'd be suppressing has sperm production. You could give HCG a little more cumbersome and expensive than an option like Arimidex. Okay, so our next patient is a 35 year old patient who had, who has won three year old daughter, conceived easily their their spouse. They've been trying to conceive for the last couple of years and the patient reports that had some testicular pain. I'm not sure if one or both sides had fever a few years ago and was diagnosed with hepatitis treated with antibiotics and everything cleared up. Partners, young, healthy and one pregnancy, 11 delivery. Um, other than was reported above. No other medical problems, no medications. And on exam, you see normal sized testicle and while epidemics was normal, that was there, you also detects some fullness on both sides. And again, that suggests that there may be some type of of obstruction for for this patient. So we get our standard labs, we see our testosterone is normal. Our FSH is normal or legitimizing hormones normal. The patient is a sperm bank. So in this, this type of scenario, you're you're thinking that this is likely to be an obstructive type of problem that uh, and so that your your key differential diagnosis here is this this an obstructive type of zero sperm count or a non obstructive jesus for mia. And this this is a this is really is the best time for doing a testicular biopsy. So if you were to see a patient like this, this would be the kind of patient that you would want to send over for further evaluation. It's possible to do techniques like a vast epidemics, bypass and reconstruct this patient to do a sperm retrieval and gets from out of the testicle. And do IVF or the couple could consider using donor sperm along with intra uterine insemination. Or they could they could adopt. So as a small open window biopsy was the standard technique for many years. The way that I tend to do this is through a fine needle aspiration approach where I do this in the clinic and essentially I'm just using a needle to go into multiple spots. Typically half a dozen spots. It's testicle and it takes general least a week to two weeks of from business days standpoint before the results will come back. And these results are really helpful for a patient like this to confirm what's going on the patterns that you'd see. So if the report was coming back to you it can either be just normal sperm into genesis lots of sperm. And then I'm thinking okay this is clearly obstruction. A low sperm production that essentially the pathologist is seeing sperm inside the tubules. But it's very difficult to find those firms maturation arrest where sperm production is happening but it's getting stuck part of the way. And then this condition called police only where there really isn't isn't much action happening structurally. I think it'd be really unlikely you'd ever see these slides unless you happen to be studying for your O. G. Y. N. Or urology boards. But within a normal biopsy you see lots and lots of uh biotic and my topic figures there's lots of action happening within the testis. And you can see when you look closely on these kinds of side you can see sperm in the middle. For patients who have maturation arrest it looks it looks often quite quite differently. You'll see sperm stem cells around the basement membrane of a seminar for custodial but you're not seeing cells inside the loom in. Um It is still possible though to find sperm with with surgery in these kind of patients because there can be a heterogeneous distribution of sperm production for patients who have certainly sell only you really see Sir totally cells and nothing else going on. So for for a patient like this essentially the options that I discussed with them would be do you want to just have sex at home and get pregnant and then in that case a reconstructive process is probably a better approach. Um how how old is the patient? As patients get older? I'm generally leaning more toward in vitro fertilization approach. Usually reconstruction is a is a less expensive surgery, surgical cost versus doing in vitro fertilization. However, for this kind of reconstruction, it can take many months up to six months or a year, sometimes to see sperm coming back. So that could be a long time to wait for many patients. The kinds of techniques from a sperm retrieval standpoint are often straightforward. So let's say I've done the biopsy, it shows this is obstructive visas for mia. I would be looking either to get sperm out of the epidermis or out of the testicle. And so the kinds of techniques that I do something called a pizza or per cutaneous epidermal sperm aspiration, a taesa or a testicular sperm aspiration where I'm putting sperm getting sperm directly out of the testicle with a needle, a micro surgical epidermal sperm aspiration where I make an incision, see the tubules and then aspirate the sperm directly. Um and what it looks like from a surgical standpoint. When I'm doing a mesa, essentially small uh small incision and I can aspirate this cloudy fluid out of the epidemic mus. For patients who need a vast of as connection of the pregnancy rates are very high. When patients sees a reproductive microsurgeon, essentially, I'm removing scar tissue and reconnecting these tubes. This is the kind of situation for patients as head of vasectomy and they choose to have uh surgery to restore fertility for for patients who like this one for this case, essentially, I have to do a bypass. I go in the operating room, I deliver the testes, I'm able to to see the area of scar tissue from their infection and I can reroute the vast difference above that area of obstruction and asked the most them. And while this is offers them really their only opportunity for getting pregnant at home, the success rate is lower this this connection is really, really delicate and it has a tendency to discard down over over time. Okay, so shifting to a patient who is probably, I would imagine commonly seen in many of your practices, but patient reports to you directions are strong but has had slowly decreasing interest in sex over the last couple of years, mild hypertension, otherwise otherwise doing pretty well. Um, from a body habit of standpoint, slender, no acute distress and exam is really relatively unremarkable. Um, get labs for him. Get a P. S. A. Is normal Madhukar, it's normal testosterone is on the low side. So what are some of the options that we have for a patient like this? And I we can, I know we can dive in this and the questions and I'll leave plenty of time for questions here in just a few minutes. But the kinds of approaches that one could consider for a patient like this would be topical treatments like testimony or Androgel and applying medications every day, giving injections, testosterone recipient eight giving injection often I'll start with every two week injections and then pellet forms of testosterone. And so this is called testable and this is something that doing the clinic. Um, this would be something I imagine if you saw these patients regularly, I could teach you how to do this approach. Main main problems with doing the test appel is just the uh logistics of getting everything set up. But technically it's it's a pretty straightforward approach. The nice part about the test apple is that it lasts often around four months or so. And so patients they have to come into the clinic which is a down side of it. But they don't have to think about it. They don't have to post themselves with a needle. Um Let's see. Good things about the cream. It's pretty easy to do. It's easy to prescribe downside. You've got to do it every single day. Um is probably the most expensive of these. A person had to pay out of their own pocket. It can rub off on partners. And so that is sometimes a consideration. It's not always absorbed well across the skin. But for some people this this works fantastic. The injections. For many men, this works well. Other patients, they don't like how it goes up and they have a very high peak and they'll get down quite low and they don't like that. You can decrease the dose and shorten the interval and so instead of, say 200 mg every two weeks, you can do 100 mg every week and that will sometimes work well. Um And let's see test people. Usually what I do is I'll start with the testosterone pellets, I'll check testosterone about a week after the putting in the pellets and then again about three months later. And and just see how a certain number of pellets translated to both to a peak, how they felt and then how that how that that patient metabolized that testosterone over time.
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