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Melanie Cole: Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're discussing hypogonadism and the management of testosterone therapy. Joining me is Dr. Kevin Campbell. He's an assistant professor in the Department of Urology at the University of Florida College of Medicine.

Dr. Campbell, it's a pleasure to have you join us again today. Can you tell us a little bit about hypogonadism and how prevalent it is?

Dr. Kevin Campbell: Sure. Well, thanks Melanie. I first want to thank you for having me on the podcast. Again, I'm glad to have the opportunity to be here and discuss this aspect of men's health that I really find interesting and important in today's medical world. So a little bit of background on male hypogonadism, which is also to say low testosterone.

So the prevalence of hypogonadism or low testosterone, you can describe them interchangeably in the American male population, it really ranges widely. There are some reports that have it as low as 2% and some that have it as high as almost 77%, depending on what you read. So expectedly, you have testosterone testing and prescriptions nearly tripling in the recent years.

And you can also look back from a really historical perspective and see that this has been going on for a long time. So even Aristotle was right about castration and the effects of the lack of testosterone in the 4th century, BC, and then all the way up to the early 1900s, even have vocalists who were being castrated to avoid the masculinizing effects of puberty and they were called castrato.

So we first testosterone being synthesized in 1935 and those folks even won a Nobel Prize for it. So if we fast forward to today, we see testosterone therapy is a common therapy in the aging male, who is known to be hypogonadal

Melanie Cole: Well, so then let's talk about some of the complications of it. And you mentioned some things from long ago. Do we know what causes it?

Dr. Kevin Campbell: So we know that it's a natural phenomenon as the body in the male gets older, you produce less testosterone. There's also a lot of comorbidities like obesity., Hyperlipidemia, these things can cause decreases in testosterone production. And also you have decreases in the available testosterone because there's other proteins in your body that can bind to your testosterone and make it less available.

And so if we were to really look at what a normal testosterone range is, it's going to vary from reference range to reference range or whichever lab you look at. But in general, it's between 300 and 800 or even 300 and 1000 nanograms per deciliter. And that's just if you took a hundred people off the street and you measured their levels and they weren't having any signs or symptoms, or you wouldn't say that they were hypogonadal.

Now, there's other levels and other periphery values that can influence that decision to go on testosterone therapy, such as the free testosterone, as well as some other hormones like a sex hormone binding globulin. But the testosterone itself, if you look at it, about half of it is bound to a protein called albumin. The other half or just under it is bound to that SHBG which we just talked about. And then another 2% is free.

So you can hear someone talk about bioavailable testosterone, and that's that free testosterone, and also the loosely bound testosterone. However, when we look at diagnosis, the total testosterone is the most important. So because these values can really vary widely, depending on what time of day you take it, you know, if a person has a viral illness, if you've have a high cortisol response, like you just get sick or you haven't gotten much sleep, it can really change.

So going back to your point, your environment is certainly something that can affect your testosterone production. It can be genetics. There's a whole lot of things. So we really have to take that into consideration. And so we recommend getting two measurements or two blood values on separate occasions. Both in the early morning fashion when your testosterone generally is at its highest, so low value is truly indicative of a deficiency. And then also we have to pair that with your symptoms and your signs. So all those together lead to a diagnosis of hypogonadism or low testosterone that we see in today's population.

Melanie Cole: Well, thank you for that. And as we're talking about diagnostic criteria and that evaluation, as you say morning and evening, tell us a little bit about those symptoms, if you would expand. Why is somebody going to be telling this to a urologist, if a male is seeing their urologist or is this something a primary care provider would notice? Tell us a little bit why and expand on that evaluation for us.

Dr. Kevin Campbell: Now, certainly a primary care physician or urologist, or really any provider who's taking care of a patient should have this in the back of their mindset. So signs and symptoms of low testosterone can include a combination of physical, cognitive or even sexual symptoms. Those being reduced energy, decreased sex drive, decrease in erections, diminished work performance, increased fatigue, the inability to maintain lean muscle mass or an increase in fat content. Additionally, low testosterone can also manifest in depressive symptoms or persistent mental fog. So that's why you have to kind of keep a keen eye because these are very generalizable symptoms.

But who should be tested? Well, I really go by the AUA guidelines. I'll reference them probably throughout the talk here as we get more in depth here. But they recommend screening people with unexplained anemia, bone density loss, diabetes, if you have a history of chemotherapy or radiation to the genitals, those with HIV or AIDS, chronic narcotic use or opioid use, which is very important in today's culture, male infertility, pituitary dysfunction, and chronic steroid use. So these are the patients who in addition to the previously described symptomatic patients should be screened in the absence of symptoms.

Melanie Cole: Does it often go undiagnosed for a while, doctor?

Dr. Kevin Campbell: Yes, it can go undiagnosed for a long time. In fact, the average person may see anywhere between three to seven physicians before they're diagnosed with hypogonadism because the symptoms will lead you down other workup paths, those for depression, for low blood sugar, lots of different things can be thought to be coincidental with low testosterone. So that's why we really do a workup looking for the signs and symptoms and serum levels too.

So once you have the signs, it's really important to do blood work. We measure morning testosterone as we talked about. And if that's low, then we repeat the testosterone to get a second value and also some other labs including what's called a luteinizing hormone and a hermatocrit.

So luteinizing hormone is a gonadotropin, which is a signal to the testes from the pituitary in the brain. And that can be suppressed by another hormone called prolactin. So we get this hormone as well in the blood value. And if you have a testosterone out of range, this will confirm the deficiency and leads us into discussion for the aspects of treatment.

So you can do also additional testing that can be considered in select circumstances. So we do a DEXA scan, which can be performed to evaluate bone strength in patients who have a history of unlikely bone fractures, such as those with low volume trauma. If you have an elevated gonadotropin level, so like the luteinizing hormone I talked about, that with a low testosterone can be suggestive of a genetic cause of hypogonadism and warrants a karyotype or genetic workup. And also patients over the age of 40 should obtain a PSA prior to starting therapy, because we're also screening for prostate cancer in those patients.

And lastly, as with any good medical workup, a physical exam is included to evaluate for general body habitus, BMI, body hair patterns, and a genital exam, including testicular evaluation.

Melanie Cole: So then speak to us about management, risks and benefits. You mentioned testosterone therapy. Tell us about the standard treatment options and what UF Health Shands Hospital is doing differently. Tell us a little bit for other providers about this type of treatment and how it's working for you.

Dr. Kevin Campbell: Sure. I'd be happy to. So with medical options or medication options, there's tons of them out there. There's about 1,001 different formulations of testosterone nowadays. There's testosterone gels. There's creams. There's patches. Oral formulations for daily use and all these maintain a more even serum level. These are good for those patients who wish to avoid needles and want to maintain a daily administration regimen. They also have to consider taking into the risk of transference of these topicals for people you come into contact with such as children and loved ones.

Additionally, there's oral formulations, such as pills that had previously fallen out of favor because their compounds were alkylated and they put stress on the liver whenever you're taking these on a daily fashion. But they do have newer formulations that are absorbed into the lymphatics, which avoid this concern and make these oral pills a good option or alternative.

There's also a weekly or biweekly injections. These can be performed and are titrated up in order to maintain a trough above the symptomatic level, without an exceptionally high peak and injections can be performed either intramuscularly to directly get the medication into the bloodstream or even subcutaneously. There are even auto-injectors which disperse the medication over the course of about a 10-second period with little or no discomfort to the patient.

There's also longer-acting formulations. They're present in the form of testosterone pellets, which are roughly the size of a grain of rice and are implanted under the skin of the buttock and dissolve over the time, giving an even serum level for several months before having to go back in and have a second pellet placement. And there's a longer acting testosterone injection that can be performed in the office, which needs to be repeated every 10 months.

So these are all formulations of exogenous testosterone replacement. But in consideration of patients who mainly do not want to go on exogenous testosterone or who want to maintain fertility potential, then stimulation of a patient's own hypothalamic-pituitary-testicular axis can be performed to increase production of testosterone from a patient's own Leydig cells in the testicle. This also supports a Sertoli cell function, which are responsible for sperm production in the testicle as well. And we have a couple of options.

First, there's clomiphene. This is commonly used to inhibit the negative feedback of estrogen on the brain. And this in turn can lead to an increase in those gonadotropins, which leads to an increase in testicular testosterone production. This is a medication that's commonly used in the male infertility world to assist with sperm production. And if you want to look further, that clomiphene molecule can be broken down into two different isomers or two different components, zuclomiphene and enclomiphene. And enclomiphene has been manufactured to be a standalone pill. And it's got fewer estrogenic side effects, which has been shown in studies to have similar raises in testosterone to the 1% testosterone gels that are out there and also maintains a patient's sperm production. So this is a very favorable alternative to exogenous testosterone.

There's also recent and ongoing studies, which is focused on the use of intra-nasal testosterone gel. And the dose isn't as high as the other formulations, and it's roughly 11 milligrams and it's taken over three times daily. So that level of testosterone doesn't meet the threshold for suppression of that HBG access. And it hasn't been shown to significantly lower gonadotropins and thus sperm production. So this is also good for maintaining sperm production while also fighting those hypogonadal symptoms.

Let's talk a little bit about supplemental roles. So there's supplemental regimens to these other testosterone therapies in the form of hCG and anastrazole. And hCG is also a gonadotropin as we talked about. It's called human chorionic gonadotropin. It's an analog of luteinizing hormone, which is that same hormone that promotes the production of intratesticular testosterone. And so all men who are looking to have children or are children-bearing age and haven't made up their mind, if they want to maintain their fertility, should consider also being on an hCG supplementation regimen in addition to their testosterone. And this is in the form of a subcutaneous injection one to three times weekly.

And lastly, I want to talk about the body's conversion to estrogen. So your body's naturally going to try and convert your testosterone to estrogen with an enzyme called aromatase. It's found in your liver and your fat tissue all throughout the body. And so in an effort to maintain higher levels of testosterone, this enzyme can be blocked and it's done by an aromatase inhibitor, such as aanastrazole, and this is weekly pill.

So during routine serum hormone evaluation and medical checkups, estrogen levels can dictate the need for increasing or decreasing estrogen blockade. So these are some of the things that we will consider whenever we're talking to someone about their testosterone management and what they're looking to achieve and what sort of side effect profile we should talk about.

Melanie Cole: That's so interesting. Dr. Campbell. Wow. So many available therapies in your armamentarium. As you wrap up for us, what would you like other physicians to know about hypogonadism in males and the management with testosterone therapy and some of these other therapies that you've mentioned here today?

Dr. Kevin Campbell: So there's a couple of things that go with testosterone management that I think are important for all providers. And that's knowing the side effect profiles, and also some of the things to monitor. So, in all patients who are on an exogenous testosterone regimen, you got to make sure that you're looking at their hermatocrit or their blood density since testosterone can cause an increase in the production of red blood cells. If that density gets too high, side effects can include fatigue, sluggishness, headaches, and more seriously blood clots can also be possible. So if a patient's coming to you and saying that, you know, "I've still got more fatigue and sluggishness," despite having appropriate serum levels of testosterone, it could be indicative that they have too high of a hermatocrit and they need to undergo a therapeutic phlebotomy to attain a lower hermatocrit

Also, prostate cancer. So it should be pointed out to patients with testosterone deficiency and a history of prostate cancer should be informed that according to those American Urological Association guidelines we talked about, there's an absence of evidence linking testosterone therapy to the development of prostate cancer. And so that's very important because there's a lot of controversy surrounding testosterone therapy and prostate cancer. And so now What that means is that the decision to initiate testosterone therapy in men with previously treated prostate cancer orwhere those who are on active surveillance should discuss the risk and benefits of testosterone therapy prior to starting that therapy.

So if you have undergone a radical prostatectomy or you have a patient who has, and you have a subsequent undetectable PSA on followup, those patients can be considered for therapy as the studies, though limited, have not demonstrated a significant increase in prostate cancer recurrence.

Additionally, if a patient's prostate cancer was treated with radiation, studies have shown that these patients do not experience increased risks of recurrences or progression of that prostate cancer once starting testosterone therapy. So similar results have also been shown in men who initiated that testosterone therapy while on active surveillance for low-risk prostate cancer. Now, this is different from those patients with metastatic prostate cancer, who are being treated with androgen deprivation therapy, who should not be considered for testosterone therapy

Lastly, I'd also like to talk about cardiovascular disease. So there's conflicting information out there regarding the use of testosterone therapy in the setting of cardiovascular disease. And it should be noted that low testosterone is an independent risk factor for cardiovascular disease, not high testosterone.

So our literature has consistently shown that low testosterone levels are associated with an increased incidence of major cardiac events, such as myocardial infarctions, strokes, possible cardiovascular-related mortality as well. And it's because of this, that testosterone deficient patients should also be assessed for modifiable risk factors like smoking, high blood pressure, diabetes, dyslipidemia, for instance.

So now, in these patients who have had a recent cardiovascular event, such as a heart attack or a stroke, testosterone therapy should be withheld for at least three to six months before resuming therapy with close monitoring. And we previously talked about blood clots. Patients should be notified that there's no definitive evidence linking testosterone therapy to a higher incidence of these venous thromboembolic events, which are blood clots.

The FDA requires pharmaceutical companies to add a warning label of concern about possible association between testosterone therapy and these events. And the AUA or those American Urological Association guidelines note that in testosterone deficiency, this decision was based on anecdotal cases and not peer reviewed literature. So since this warning came out in 2014 by the FDA, close followup observational studies have not shown an association between testosterone therapy and an increased risk in these events. So these are some things that I think should be known for anyone who's talking about testosterone therapy, that being prostate cancer or cardiovascular disease.

And also briefly we touched on fertility, which should also enter the discussion whenever we're talking about initiating exogenous testosterone or not, because elevated testosterone levels or exogenous testosterone levels can shut down a person's own production of testosterone and thus sperm production, so we have to really keep these in mind whenever we're talking to a patient about what their goals are.

Melanie Cole: What an informative episode, Dr. Campbell. And what a great guest you are. Thank you so much for such an educational episode today.

To refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. 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.