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Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're talking about testosterone and fertility. Joining me is Dr. Kevin Campbell. He's an Assistant Clinical Professor and an Associate Medical Director in the Department of Urology at the University of Florida College of Medicine. Dr. Campbell, it's such a pleasure to have you join us today. Let's just start with kind of how common and the prevalence is testosterone deficiency and disorders in men?

Kevin Campbell, MD: Absolutely. And Melanie, thanks for having me. It's a pleasure to be here today. So, testosterone and the implications of having high and low testosterone are really, really at the forefront of what I practice on a day-to-day in clinical medicine. And it's a topic that's near to my clinical interests and heart.

So if we're looking at the number of people who have testosterone deficiency or low testosterone, depending on what clinical picture you look at, you're going to be seeing somewhere from like 5% all the way up to 20%. So, it's not without a big presence in the general community. And you likely know somebody who either has low testosterone or testosterone deficiency or is being treated for testosterone deficiency and may not even know it.

Melanie Cole, MS: Well, since it's so common, speak a little bit about what would send a man to a physician, whether it's his primary care or urologist. Tell us some of the signs and symptoms that they might notice or that a partner might notice.

Kevin Campbell, MD: Absolutely. There's really two main drivers of men to the physician, especially for younger, healthier men usually, and that's fertility or sterility. Men are either trying to either get a vasectomy or worried about their reproductive healthcare or something's going wrong and they're worried about their testosterone. And a lot of the times, the signs and symptoms may be difficulty with pregnancy. It may be increased fatigue, it may be low sex drive, low muscle mass, decreased ability to achieve an erection. Now, they're starting to have all this adipose or fat tissue around their abdomen, and also sometimes orgasmic or other sexual disorders.

And the thing we worry about with these is we try to screen them early because sometimes they might be a sign or symptom of something greater like a pituitary pathology or an endocrine disorder or testosterone deficiency. So, we have to rule out some of the scary things to get down to it. And so, we're really trying to listen to what the patient's are saying when they're coming to us.

Melanie Cole, MS: And then how is diagnosis made?

Kevin Campbell, MD: So, diagnosis is made with signs and symptoms of low testosterone. A lot of those symptoms we talk about like fatigue, decreased energy, decreased muscle mass, poor bone health, sometimes easy fractures. So, those are the subjective aspects. And then, they have to have a low morning testosterone value. So, testosterone is highest in the morning. It peaks with a pulsatile release of GnRH in your pituitary, and hypothalamus to then make LH and FSH, and your LH goes to your testicles and tells them to make testosterone. And so, that's signals highest in the morning, and then starts to decrease throughout the day. So, we do try to get a morning testosterone before 10:00 AM. And depending on what reference range or what lab value you're using, you're going to have some degree of variation with that set number. So, many labs and FDA will say that's around 300 nanograms per deciliter. And a testosterone below that, along with the signs and symptoms, would give you reason to say somebody has testosterone deficiency. Now, if you look at the Endocrine Society guidelines, they actually take their testosterone number and use it as a statistical reference and take two standard deviations beyond what's normal. And so, their reference range is going to be around like 250 to 950 or so. So, you do see some change in the reference.

And then, even the Androgen Society and the Society of the Aging Male have used cutoffs as high as 350 in the past. And so, a lot of this is really geared at signs and symptoms because not everybody has the same need for a certain level of testosterone. Not everyone has the same androgen receptors, so we have to look at the objective and the subjective together.

Melanie Cole, MS: Well, thank you for that. So, Dr. Campbell, as we look at a quick overview of the history of AUA guidelines on male infertility, speak a little bit about the priority topics addressed in the guidelines as they are today and those statements.

Kevin Campbell, MD: This is a really timely question. I'm glad you brought this up. The first guidelines came out in 2020. And prior to that, we had a bunch of consensus statements and a lot of variations of different particular aspects of male infertility. But we didn't have any overarching or just larger guidelines that men could look at. And then, those were updated in 2024 to continue to stay relevant with just a couple of major changes.

But really, the guidelines start and the workup starts with an evaluation, a history and physical of both partners, both the male and the female partner. Because oftentimes, if we look at the breakdowns of what causes fertility, there's a 30% male factor alone, 20% combined factor, and a 50% female factor. So if you do some back of the envelope calculations and fudge the factors a little bit, you can say that the male aspect contributes to at least 50% of the infertility aspects for couples. And 15% of couples will have a degree of infertility. And it might be something as routine as a different type of lifestyle modification that a patient may employ that we find on the initial history and physical. There might be a medication that someone's taking, or it might be in the history that someone had some sort of chemotherapeutic or radiation that then may limit to what degree we can restore sperm production or lend us to recommend surgery over different stimulatory techniques.

So, the first and biggest part of the workup is going to be the history and discussing with the patient, and also finding their goals. We have some couples who come in who are very young, and they just starting to try their fertility journey and try to conceive, and so there's a little bit more leeway. We have some financial constraints as well sometimes, so we have to take that all into account. Whereas if we have a couple that might be a decade or two older than that, we're discussing potentially assisted reproductive therapies or ways to optimize the fertility outcomes when we don't have the same sort of flexibility that we may have with another couple.

So, a lot of the basic workup for fertility goes into what I call the big three, and that's going to be the history and physical and blood work. So, we can see how the hypothalamus And the testicles are talking to each other, and the pituitary, and how they all feed back. And then, also a semen analysis. And when we get those big three, we can make a recommendation of how to optimize fertility. No one test can really say someone is fertile or infertile, but we take all these things together to come up with our recommendations.

Melanie Cole, MS: That was very comprehensive. So, first-line management of testosterone disorders. Tell us a little bit about some of the therapies that are available right now.

Kevin Campbell, MD: Certainly, I think a lot of what goes into first-line therapy when people are thinking about testosterone deficiency is going to be giving somebody testosterone, and that is often the case. However, one of the first steps that we have to evaluate is why someone has low testosterone. Is it a issue with the testicles? Is it an issue with the pituitary? Is it an issue with the hypothalamus? Is it a systematic or global insult to a patient's physiology? Are they on some chemotherapeutic or some medication that causes them to have blunting of this HPG access or decreased testosterone? This bounces down even after starting some medications that men often will use. So, it's important that we do, again, this history and physical and do this workup.

The mainstay of treatment is often going to be replacement of testosterone or stimulatory therapy. If someone's trying to conceive, we don't want to give that person testosterone right off the bat because that can shut down their natural production of intratesticular testosterone as well as sperm production. So, many men who go on testosterone who are trying to conceive will drop their sperm counts to zero. Now, we know that testosterone is not a contraceptive and that people will get pregnant on testosterone, but it doesn't optimize someone's ability to get pregnant. So, we have to take that into account.

And there's different therapies depending on what hormones are elevated or normal that we can employ. So if someone's FSH and LH are, say, in the normal range, we might try and stimulate that with, say, a serum like clomophine or enclomiphene or tamoxifen, or even give someone FSH or hCG, which is an analog of LH to try and stimulate testosterone production in the testicles.

Now, if that's not an issue or we're looking at an androgen deficiency or a testosterone deficiency for the aging male, we are going to have a more robust discussion about the different types of formulations of testosterone. There's almost a million formulations of testosterone out there, and that has been a little bit facetious, but there are quite a few. Many of which are all different types of conjugated esters of testosterone, different lengths which may last a little bit longer in the body. We will oftentimes use an injection either intramuscular, subcutaneous that may last for a week or two weeks or even 48 hours in some of the shorter acting testosterones. And then, there's gels or creams that men will put either on their upper outer chest over the subclavians to absorb or the inner thigh or even on the forearms to absorb. And that would be on a daily application. So, a lot of what goes into our first-line therapy is tailoring it to the patient. I think it would be inappropriate for us to give an overall recommendation of what works for everybody. Because if we have the gardener who's going outside every morning and is going to be sweating and has to be up at, say, you know, 6:00 AM or when the sun's coming up, they're going to sweat off a lot of this testosterone gel, where we might have somebody who who has a fear of needles, and so they don't appreciate the idea of giving themselves injection or maybe a tremor. And once we've established a response to testosterone, we might move on to pellets or even an intranasal gel or many other applications as well. So, that's generally how we approach the first-line for testosterone management.

Melanie Cole, MS: Well, thank you for that, Dr. Campbell. So, speak a little bit with all of these available therapies and more tools in your toolbox all the time. What factors should other providers consider before recommending some of these therapies. Speak a little bit about any side effects, complications you discuss with the patients, patient preference and lifestyle preference. Speak about to other providers about what they should consider when they're looking at all of these different therapies.

Kevin Campbell, MD: Yeah. Thanks for bringing this up, Melanie. This is very important because I think one testosterone application for one person is not the same for the next. And so, when someone comes to see me, we're going to talk about the risk and benefits of testosterone And then, the modalities of treatment.

So, let's talk about the risks and benefits first. There's definitive evidence to say that testosterone, if it's low and we replace that, that can help with libido. It can help with sex drive, it can help with increasing muscle mass and decreasing visceral adipose tissue. It can help with bone density and prevent osteoporosis, and it can help with insulin sensitivity. There are sporadic reports of it helping also with mental cognition and brain fog. Those are a little bit less reported in large studies and having definitive evidence. But we do have a lot of anecdotal evidence there. And there are also risks involved. Testosterone is a molecule that's seen by the body, so it's we call bioidentical, so it's not as high-risk as other synthetic molecules, but it does have an effect on a body's physiology. It can go to your bone marrow and tell it to make more red blood cells. So if someone is undergoing testosterone therapy and not undergoing monitoring, they can get polycythemia, they can have increased hematocrit, they can put themselves at risk for blood clots, for their legs, for their hearts, and brains as well. So, there's a non insignificant risk for heart attack, stroke, DVTs if someone has polycythemia that's unchecked. Now, testosterone has been proven to cause these. But secondarily, if it's raising the hematocrit and that goes unchecked, it can lead to it. So, that's very important as a risk.

Another risk that is very popular is prostate health. So, there is a misconception that testosterone causes prostate cancer. Testosterone has never been known to cause prostate cancer since it's been first synthesized in 1935. So, what we worry about though is that if someone has prostate cancer and it goes to other parts of the body metastasizes, well, then one of the ways we know we can actually stop that spread or help kill the cancer is to starve it of testosterone. So, we do think of testosterone in that regards as being a Lack of testosterone as a treatment for some prostate cancers. So, it can help grow prostate cells. So if someone's hypogonadal, they have low testosterone, and they have potentially a smaller prostate or a prostate that's not fully saturated by their androgens because their testosterone's low. And now, you give someone testosterone, that prostate can respond in a more robust way than it has been. And so, some people will see urinary tract symptoms like an increased prostate size that can cause what we call LUTS, or increased urinary frequency, hesitancy, and growth of the prostate. And with that comes an elevation of PSA, because if you have more prostate tissue, you make more PSA.

Now, it does not, again, cause prostate cancer, but it is something we screen for in this population because we're already seeing them and we want to make sure that if we're growing the prostate, if there's any already present significant prostate cancer, that we can catch it early and treat it appropriately.

Some of the other effects that we see or side effects with testosterone therapy is how your body recycles testosterone. There's enzymes in your natural adipose tissue and fat, and your liver and brain called aromatase, which will take your testosterone and turn it into estrogen. And so, if that estrogen gets very high, that can also put you at risk for blood clots. And it can decrease sex drive, it can decrease erectile quality. And so, we have to take that into account and monitor estrogen and even put someone on an estrogen blocker if it gets too high. But we also don't want to go too low because then that can put someone at risk for osteoporosis.

Some other issues we see with testosterone management are increased acne, because there's increased oil production by the skin. Think of someone when they're going through puberty and they're getting these testosterone surges. The skin produces more oil and sebum, and that can cause blockages of all the hair follicles. Then, other times, we can even see some hair thinning. So if someone is prone to male pattern baldness, testosterone, if given in a higher state, it can lead to advanced hair loss. So, all these are things we're taking into effect.

Now, when someone goes on testosterone, they may have a job that may not allow them to have a daily application. Like, let's say someone's traveling a lot and it's harder to travel with hypodermic syringes or needles, then we may say, "Okay, a daily application with a gel or a cream will be best for you," versus if someone has maybe a deployment job or maybe a job that would say, "Let's go ahead and use a weekly syringe or even a biweekly injection of testosterone," then certainly they can use that. Some providers will also favor putting in pellets for patients. And these last for about three months before they dissolve. And so, some patients like the kind of the set it and forget it. So, all these are things that we consider.

Some of the newer testosterones are the oral formulations. In the 1980s, oral formulations were very popular too, but they were alkylated. And so, every time somebody would take testosterone, it was putting a little bit of pressure on the liver. And so, we quickly moved and pivoted from that application. But now, there are newer formulations. There's three of them that are out now. These types of testosterone undecanoate that get absorbed with the lymphatics in the gut. So, you take them once or twice a day and it brings your testosterone up. So if someone doesn't want to do a gel or a cream or an injection, we have different options now. So, the future is bright for testosterone management.

Melanie Cole, MS: Wow. It's such an exciting time in your field, Dr. Campbell. And you are such a wealth of knowledge. As we wrap up, I'd like you to speak a little bit about lifestyle factors, relationships between infertility and general health, and how you, as you summarize, with shared decision-making inform your patients of all of these different therapies and what goes into the treatment options available.

Kevin Campbell, MD: Yes. This is really important because when someone's coming in to be evaluated for either testosterone deficiency or fertility, it's not always the end all, be all of that particular person. This is oftentimes the peak of an iceberg where there's something underlying that we really need to evaluate and treat.

We know that men who have increased fertility issues have an increased morbidity and mortality. There's an increase by 1-3% higher mortality rate in the infertility population. And that might be because there's some overlying condition that we identify. Sometimes there's no overlying condition that's identifiable, and treatment does have a burden as well. So, we have to keep all those things in mind when evaluating patients for fertility.

Now, sometimes people will come in and they understand their fertility burden, but don't necessarily want treatment and just want answers. And so, really, the workup is going to be dependent on the back and forth with patient and provider. So, I would really harp on this patient and physician model where we really try to hear what the patient's saying and meet them where they're at. Because if we're telling somebody that has low libido and decreased erectile quality and decreased adipose or increased adipose tissue, decreased muscle mass, that they need to go on testosterone. But then, they say, "Hey, but I'm trying to also start a family," or "I want to get pregnant in a couple years," well, now we've just added a degree of complexity that we can't overlook. So, we have to keep all these things in mind when going forward with our patient care.

Melanie Cole, MS: Great information, Dr. Campbell. Thank you again for joining us and sharing your incredible expertise with other providers today. And to learn more, you can visit ufhealth.org/specialties/urology, or to learn more about this and other healthcare topics at UF Health Shands Hospital, you can always visit innovation.ufhealth.org. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.