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The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME, to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.

Melanie Cole: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to listen as we examine male infertility. Joining me is Dr. Kevin Campbell. He's an assistant professor at the University of Florida Department of Urology.

Dr. Campbell, it's a pleasure to have you join us today. So tell us a little bit about what you're seeing in the trends and how common infertility in males really is.

Dr. Kevin Campbell: Hi, Melanie. First of all, I wanted to thank you for having me on the podcast. I'm really excited to have the opportunity to be here as well as to discuss a portion of healthcare that I'm really passionate about, and that being men's health and fertility. So getting into a little bit of background on male fertility and the trends, evaluation of fertility in men, it's often a multi-step process for clinicians and patients alike. And infertility can affect approximately 15% of couples who are attempting to conceive.

And when we look at the male factor and how that attributes to these statistics, approximately 50% of infertile relationships have a factor coming from or stemming from the man. Thirty percent of couples have a significant male factor alone and then another 20 combined with male and female factors.

And you may ask, "Well, how do we define infertility?" And I would say infertility is really considered to exist after 12 months of attempted conception without contraception. And so this consideration is in the setting that pregnancy rates by intercourse in couples are approximately 20% to 25% per month and 90% at a year.

So a male who comes in for an infertility workup should be evaluated with the goal of identifying reversible conditions, which can improve a man's fertility as well as irreversible conditions that can relegate candidates to assisted reproductive techniques or identify non-treatable genetic causes. So those was patients with irreversible conditions not amenable to reproductive therapies can also be appropriately counseled.

So currently, it's estimated that approximately 7.3 million couples seek infertility care annually in the United States. So it's certainly on the rise. And although the use of assisted reproductive technology has steadily increased and currently contributes to about 1.4%, 1.5% of all births in the US, the number of male reproductive procedures performed is on the decline. So that's something that we're really looking at in the field of men's health and men's fertility.

Melanie Cole: Well, thank you for that. So tell us a little bit about the evaluation and the initial steps in the workup of male infertility. What tests do you typically run? Who runs them? Tell us a little bit about how that works.

Dr. Kevin Campbell: Certainly, I'd be happy to. So the initial steps in the workup and evaluation of male fertility can really be broken up into a three-part approach. And this is often geared at trying to find the main cause, which can be from a production of too few sperm to fertilize an egg, making sperm that aren't shaped properly or don't move the way that they should or even having a blockage in the reproductive tract that keeps the sperm from getting out.

So the first of these approaches as with many aspects of medicine is a comprehensive history and physical. The evaluation of the history really is structured to uncover all potential causes, including congenital, medical, surgical, environmental, genetic, and even psychosocial etiologies that can be contributing to a couple's inability to achieve a pregnancy.

And really the workup requires assessment of each partner with an appreciation by the physician of the sensitive and anxiety-provoking nature of the process, because you're really delving into the more personal aspects of a patient's healthcare. The interview and the history revolves around relevant, past medical and surgical histories, even those from childhood. So reports of genitourinary anomalies, reconstructive surgery and so forth can really prove important.

So in utero childhood exposures to chemotherapies, radiations, hormones can result in defects in sperm production, and even cryptorchidism and delay in its treatment can be associated with testicular failure, surgery for testicular torsion or pediatric hernia repair can similarly affect future paternity.

So during this workup, we discuss a couple of sexual behavior as commonly there's misconceptions regarding the optimum timing and frequency of intercourse. Often it's not appreciated that semen parameters peak after two to four days of abstinence, but waiting longer than this can actually result in poor sperm quality. So to optimize fertilization rates, intercourse should be performed every other day, beginning about five days expected before ovulation and up to five days afterwards.

So once we get a good history, we then move on to the physical exam, which can give us key information about the patient's overall wellbeing. So this involves the general appearance of the patient and their body habitus and progresses to a genital exam in which the testicles are examined for size, consistency, and location. So depending on the testicular size, their consistency, this can indicate impaired spermatogenesis as normal sperm-producing seminiferous tubules that make up the testicle make up about 85% of that volume.

So also if you have high-riding testicles or their location's in close proximity to the thighs, this can produce insufficient temperatures, which normally is around two degrees Fahrenheit or less between the body and scrotal contents. And that can decrease the amount of sperm production that we normally see. So that's the first part of the workup.

The second part is really looking at the hormonal evaluation of the patient. This tests the hypothalamic-pituitary-testicular axis. So endocrine causes of male fertility are present in less than 3% of cases, but they can be really devastating if they're missed. So the initial hormone assessment should include an evaluation of the FSH, which is the serum follicle-stimulating hormone, which causes your testicles to secrete and produce sperm and testosterone, which is drawn in the morning because testosterone has a well-described diurnal variation throughout the day. Then a more comprehensive evaluation includes the luteinizing hormone, prolactin, estradiol, free testosterone, and even the sex hormone binding globulin. And these can be obtained when abnormalities are present in the initial evaluation.

So lastly, the third part of this in the male workup for fertility is the semen analysis. It's the cornerstone laboratory evaluation in the male undergoing an infertility workup and it really can't be understated. So at minimum, we have two to three semen analyses that should be obtained, and these should be maintained with a similar duration of abstinence for consistency.

The ideal abstinence period is two to four days as we previously said. And shorter periods can affect concentration, whereas longer periods may actually affect the motility of the sperm. And we often evaluate the semen for several key parameters, including the volume of the ejaculate, the concentration of the sperm, motility and morphology among others. And these are based on reference ranges that are set out by the World Health Organization as recently as 2010.

Melanie Cole: Well then, Dr. Campbell, explore for us the medical therapies that could be offered to men to optimize fertility. Please speak about kind of the order that you would do this non-surgical first and then the surgical options that might be available.

Dr. Kevin Campbell: Certainly. There exists a diverse variety of medical options that can be used to augment or induce male fertility. And these agents have to really be selected with the patient's medical history, goals of care and etiology of infertility in mind. So one of these is the anti-estrogen group of medications. Anti-estrogen therapy has been popular due to its safety, its low cost and ease of administration. These are agents like clomiphene or Tamoxifen, which are estrogen receptor modulators, and they have a predominant antagonist activity that blocks negative feedback exerted by estrogens on the hypothalamus and the anterior pituitary. So this results in increased pituitary gonadotropin production, which is the LH and FSH that can both stimulate testicular production of testosterone and spermatogenesis.

Next, we have the gonadotropins, which in many cases of hypogonadotropic hypogonadal men, spermatogenesis can be restored with this hypogonadal gonadotropin therapy. Men can be addressed with agents such as luteinizing hormone or follicle-stimulating hormone. And this acts on the pituitary axis to increase the sperm production in a natural fashion.

So let's say we start with hCG, which is a luteinizing hormone analog. We will often combine this with clomiphene and, after six months of hCG therapy and clomiphene, if no sperms detected, then we'll supplement treatment with FSH and this regimen can take anywhere from six months to two years to achieve its maximum effect on sperm production. And so then we see the sperm count start to rise during that time.

Additionally, there's aromatase inhibitors, which decrease the conversion of androgens to estrogens and that increases serum androgen levels. So the mechanism of increasing testosterone is likely by decreasing that feedback inhibition on the pituitary and hypothalamus. And this affects greater gonadotropin release. So administration of aromatase inhibitors, such as anastrozole restores the testosterone to estrogen ratio to normal, and this has been suggested to significantly increase and improve semen parameters in oligospermic men, including sperm concentration and motility.

Now, if the man has a prolactin-secreting pituitary macro or microadenoma that's been identified, then medical treatment with a dopamine agonist is indicated. So this would be something like cabergoline, which would be taken twice weekly. That's the preferred agent because it's got a high efficacy in normalizing prolactin levels, and then shrinking the prolactin-secreting tumor and reversal of infertility with dopamine agonist therapy occurs in 53% of cases.

And lastly, we also have antioxidant therapy, which infertile men have higher levels of seminal-reactive oxygen species than fertile men in their semen. And high levels of these reactive oxygen species are associated with sperm dysfunction, sperm DNA damage, and reduced male reproductive potential. So this observation has led clinicians to treat infertile men with antioxidant supplements, which can be taken orally or on a daily basis.

Melanie Cole: That was very comprehensive, Dr. Campbell. So for other providers, one underappreciated psychosocial aspect is that both members of the couple need to be involved in the assessment and discussion of the results. Tell us a little bit about the importance of this.

Dr. Kevin Campbell: Certainly. I'd be happy to. So, this is really a dive into a patient's most intimate and oftentimes private aspects of their life. And when we get to see a patient for their fertility issues, it's really a privilege because we're trying to help them conceive and bear a child. And so this isn't an effort that's often undertaken just by one individual. It's the couple. And so if we're able to see the male and the female together and start the work up together, we often have better results because of the communication as well as the followup and achieving a patient's goals.

Also, this conversation that we have can be very important because not all men and women together and couples will be able to have a biologic child without the assistance of assisted reproductive therapy. So goals of care can be important if we're talking about doing something like in vitro fertilization, intrauterine inception, or trying to undergo certain procedures to assist with sperm retrievals. So I really encourage all patients to be evaluated on a couple basis.

Melanie Cole: As we wrap up, Dr. Campbell, what's exciting in your field? Tell us about some recent advances in assisted reproductive technology or techniques in IVF. And what would you like to summarize for other providers and other urologists and healthcare providers? What would you like them to know about treating male infertility and when you feel it's important that they refer to the specialists at UF Health Shands Hospital?

Dr. Kevin Campbell: Certainly. So some of the most exciting options in the treatment of male fertility that I've been part of and able to take part in are largely diagnostic or aimed at those improving sperm production, improving sperm delivery or providing sperm for assisted reproductive therapies. And this would be things such as in-office testicular aspirations, which can be largely diagnostic, but they can be performed in post-vasectomy patients or on those on testosterone therapy to confirm sperm production. And so that can help differentiate between either an obstructive or nonobstructive cause of fertility and also gear us towards our next step, which may be a testicular biopsy to obtain tissue in order for a patient to undergo IVF or a reversible cause of fertility, such as epididymal obstruction, in which case we can do what's called an epididymovasostomy and bypass that obstruction.

So additionally, we're starting to see a lot of improvement in patients following varicocele repairs. Now, varicocele are varicose veins in the scrotum and the most common procedure performed to improve sperm production is a varicocele repair. Common approaches can be inguinal or subinguinal, and so it's like a hernia repair as far as that approach. And we use a microscope to identify these varicose veins and ligate them in an ambulatory surgery setting.

So looking at the data and meta-analysis looking at randomized trials, almost 30 of them shows that the overall pregnancy rate after a varicocele repair was 39%. And this is fantastic looking at men who 80% of which have shown improvements in their sperm concentration and then 72% of which had improvements in sperm motility. And additionally, we see increases in serum testosterone afterwards.

So techniques to provide sperm for assisted reproductive therapy are certainly in the forefront of our goals of care, because we're excited to be able to offer this to patients over at the University of Florida. And so it's not just all men and women going to assisted reproductive therapies or IVF, but oftentimes we can restore that fertility potential that a couple may have thought that they didn't have to begin with.

Melanie Cole: What great information. And it's such an interesting and ongoing topic. Dr. Campbell, thank you so much for joining us today. To refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters for more information and to get connected with one of our providers.

That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.