Testosterone Deficiency & Replacement: Endogenous vs Exogenous Therapies

[Dr. Jose Silva]
Andrew, why is men's health important?

[Dr. Andrew Sun]
How much time do you have? The general idea is that men, well, we just don't take care of ourselves very well. We don't eat well, we don't exercise enough, and we definitely don't go see the doctor when we should have, right? It's only when things are really, really catastrophic that we do. The idea was, okay, well, most urologists face patients, men and women, 50s, 60s, when they get some issues. What about when they're 20 and 30 and 40? At that time, that's when they're getting a lot of the chronic conditions, diabetes, hypertension that are going to affect them when they're 50 and 60.

Convincing a 25 year old guy to come to the doctor is very, very difficult. The thing that appeals to these men, the way that you can get them into the healthcare setting to engage in some of their healthcare is likely through things that they care about, like sexual dysfunction, like male infertility and these kinds of things. I see it as, somebody has to be the gatekeeper of this disease process. I think that should be us as men's health urologists. I think, when the 35 year old guy comes in, and he has ED, "When's the last time you went to the doctor?"

In this age group, 20s, 30s, 40s, men care about their sexual health. This is a perfect way to get guys to understand what's going on with their health, because many of the things that are going to be the because of their heart disease when they're 50, it's also because of ED, right? Whether it's diabetes, high blood pressure or whatnot. Yes, I think it's a fun field. It's definitely growing, especially as the burden of chronic illness continues to rise. We enjoy it. Plus it's fun.

[Dr. Jose Silva]
Exactly. Definitely. Like you mentioned, we need to take care of ourselves since we start. At 25, usually when the patient, 40, 50, then probably it's too late. Definitely, being proactive is good for all of us. You already mentioned ED, Peyronie's. How much of your practice is testosterone replacement?

[Dr. Andrew Sun]
A fair chunk, because many of these other diagnoses, Peyronie's disease, erectile dysfunction, right? We screen all of these men for low T because many of them have it. Now, unfortunately, many men with ED think that testosterone is the cure for their erectile dysfunction, which we all know it's not. But it certainly plays a role. There's some evidence that hypogonadal men may have worse outcomes from Peyronie's disease as well. It definitely is a component. We screen all the men for it. Then, of course, there's many guys that come in because they've heard X, Y, and Z about testosterone, and they may be exhibiting some of the symptoms. Yes, it's a fair chunk, maybe 40% even.

[Dr. Jose Silva]
When you see that patient, let's say, that classic patient that does come with decreased libido, just loss of focus, tired all the time. Do you go straight into options? Do you go talk about what to expect? For example, a guy that has two jobs, wakes up at 5:00 in the morning, and expects to have had the same energy at 1:00 AM. Expectations are always very important. Go through that initial encounter with the patient.

[Dr. Andrew Sun]
Yes, I totally agree. I sort of tell the guys, "Look, you might have some of these symptoms. The difficult thing with testosterone is that the symptoms of low T can have so many explanations, right? You're tired, your libido is less, you don't feel like you're gaining as much in the gym. That could be low testosterone. That could be a hundred other things. The only thing we can do is, let's check the numbers. If the numbers and the symptoms go together, then we might have some of the treat. If your numbers are totally fine, 650 testosterone or something like that, then we might have to think about other things.

I also, of course, always start most of my discussions with lifestyle management, right? Sleeping, eating well, exercise, all this stuff. For sure, many of these men exhibit the symptoms, and so we check their labs, and we sort of go from there.

[Dr. Jose Silva]
What options do you offer the patient?

[Dr. Andrew Sun]
The way that I talk to the guys, there's definitely several different varieties of these low testosterone guys, right? All the way from the 32-year-old or 28-year-old guy that's heard too much stuff from his buddies at the gym, to the 75-year-old guy who is very hypogonadal. First we talk about, "Okay, these might be the symptoms of low testosterone. Let's check labs."

Sometimes they come in and they've already had a lab checked, like a total testosterone, but usually, that's all that's been checked. I tell them, "I don't just need to know your total testosterone. We want to check where that's coming from. Is it something in the brain? Is it something in the testicles? Is it production? What's your estradiol? What's your free testosterone?" We go into all of that because there's a whole slew of labs, FSH, LH, right, that we check.

[Dr. Jose Silva]
For that initial patient, you send everything? FSH, LH, everything?

[Dr. Andrew Sun]
I send everything because the reality is that, yes, you could just check a total testosterone and then if it's low, you check other things. In the real world, the patients don't want to come back four different times to get labs on labs on labs. They just want the answer, and so, yes, I check everything.

[Dr. Jose Silva]
That's definitely true. In terms of exogenous treatments, what is out there?

[Dr. Andrew Sun]
There's a long discussion. There are more ways of doing this than just about anything, except maybe how to open up a prostate. The way that I talk to patients is I tell them there's essentially four things to consider. There's cost, of course, there's a side effect profile, and then all the versions of testosterone are some sort of trade-off between how frequent you have to do it, and how invasive it is, right? The most invasive is the least frequent, that's pellets, and the least invasive, say orals, right, is twice a day. We go down the line that way.

Each of these have some different considerations to think about. I guess we'll start classically, the vast majority of people still take injections. Injections either of testosterone cypionate or testosterone enanthate. That is definitely the most popular. It's very cheap, it's generic, you can get it for $20, $30 a month, either compounded, or even from CVS with a GoodRx coupon.

Lots of varieties of protocols that people inject, anywhere from 400 milligrams once a month, which makes no biological sense, to the most common version that I see for most primary cares, which is 200 milligrams every two weeks, which still doesn't make a lot of biological sense because most of the testosterone is gone after about 10 days. Most commonly for us, we'd use testosterone cypionate weekly injections. Most of my patients, we start at 100 milligrams per week. There's IM versus sub-Q.

When testosterone was first developed, it was told to be injected IM. If you look at sub-Q administration, the pharmacokinetics are almost identical. There might be slight differences, but in my experience, not big enough to really matter. Plus, you really wonder, when people are taught to inject IM, how many of them are really getting it all the way into the muscle, and how many just end up sub-Q anyway?

Patients definitely find sub-Q injections much easier to do. We tell most of our patients, sub-Q, pinch a little bit of belly fat, most of us have a little bit, and just inject it there. The weekly injection tends to be easiest for people to remember. Sometimes people like to split those doses into twice a week, and I think that's perfectly fine, and actually probably has an even lower incidence of side effects.

Enanthate versus cypionate, cypionate is more commonly available. There may be a little bit less lower extremity edema and fluid retention with enanthate. If you have an elderly patient with some fluid retention or some heart issues, that kind of thing, you might preferentially go towards enanthate. Both of them are, we mostly tell our patients sub-Q, mostly once a week, starting at half a milliliter or 100 milligram, and then going up or down from there.

Some of the issues with any sort of depot-type shot is that you're going to get a very high peak in the beginning, and it's going to then taper off at the end. Part of why we don't like the every two-week administration, because usually they report that on day 12 or 13 or 14, they feel pretty bad again, One of the most common and annoying side effects of testosterone replacement is the erythrocytosis or polycythemia that occurs, which tends to be associated with the peak dose.

If you give a huge dose, like 400 milligrams once a month, you'll get huge peaks, and you'll get a lot of erythrocytosis, whereas if you give 50 milligrams twice a week, that rate will be significantly better. Those are definitely some of the considerations. Obviously, a lot of patients don't like needles and injections. They can be a little painful, and patients can sometimes have difficulty remembering exactly how much they were supposed to inject. There's definitely, I'm sure we've all experienced it, where you told them 0.5 milliliters, and they injected 5 milliliters or something like that. That's most common.

[Dr. Jose Silva]
You mentioned the 200 versus the 100. When I started doing testosterone with the patients I was doing the two weeks, so a patient that did have to inject herself only twice a month.

Definitely, when I started having those patients with erythrocytosis that I wanted to decrease or the patient, like you mentioned that, okay, by the 10th day, they already want more, then it was harder to go back to the 0.5 ml because they're already used to that high peak and the rush. Definitely, a couple of years ago, everybody starts in 100, and we go from there.

[Dr. Andrew Sun]
Yes, I think from a clinical practice standpoint, it is always much easier to start low and go up with testosterone than to start high and try to convince the patients to take less. That is an uphill battle.

[Dr. Jose Silva]
For patients that have needle phobia, they say, "There's no way I'm going to inject myself." What are the options?

[Dr. Andrew Sun]
Yes. A lot of interesting, cool, fancy options for those patients, which is a lot of people. We'll talk about Ziasted. Ziasted is a testosterone enanthate weekly EpiPen-style auto-injector. Very clever design. It's just testosterone enanthate, but it's in a spring-loaded EpiPen, 27-gauge needle, virtually painless, subcutaneous. They basically inject that once a week. It comes in a 50, a 75, and a 100 milligrams. If they're taking more than 100 milligrams a week, it's hard to use Ziast, because you can't really use a higher dose than that, right? As with most testosterone things, insurance is always an issue. We'll talk more about that later, I'm sure, but that is a nice option from a patient administration standpoint. Even more, sort of less invasive than that would be something like the gels, which were popular for a long time. Still popular amongst many primary care doctors and endocrinologists, perhaps. Most of us men's health urologists prescribe very little gels. I am not a big fan of the gels because my patients are generally not big fans of the gels. Absorption can vary drastically. 20% of men basically don't even absorb it.

It's hard to dose-titrate because, how do you really tell a patient, "Go to two and a half pumps," it's not really a thing, right? Transfers risk is real. Skin irritation is significant. The one thing that is nice about it is that it does mimic the natural circadian rhythm of testosterone, which is supposed to be secreted every day and not sort of constantly on board. The risk of erythrocytosis, and that kind of stuff is definitely less in gels than in injections.

[Dr. Jose Silva]
You mentioned the gels, but definitely, you mentioned, let's say the patient has two pumps. What's more? Three pumps. It becomes a mess. How much really a day is getting absorbed?

[Dr. Andrew Sun]
Who knows, right? There's diminishing returns. The pharmacokinetics are going to vary between patient to patient. It's very uncontrolled. But, hey, it was an attractive option that didn't require a needle, and that's what we had for a long time. We covered injections, we covered gels, Ziasted. On the other end of sort of the invasiveness and frequency scenario is pellets, whether it's the Testopel, or many versions of compounded pellets made by different compounding pharmacies, this is a very relatively quick office procedure.

You make a little incision usually in the buttocks, and put these slow-eluding pellets in. You only have to do this procedure every three to four months or so, sometimes longer depending on their absorption. It definitely gives them a steady, sort of hands-free version of testosterone, but in an extremely non-physiologic way, I guess you could argue, right? Because you're going to get a massive whopping dose in the beginning, which basically slowly tapers off over time.

That is very nice for many patients. A lot of patients just don't want to do something all the time. That is a sort of set it and forget it way. But because you're getting such a big dose up front, there can definitely be a high risk of polycythemia, erythrocytosis and other side effects and whatnot. Plus, once the pellets are in, you can't really like take them out, and you can't titrate them that carefully. You have to do it every three to four months. That can be challenging. Certain patients really enjoy that because they just don't want to deal with it at home. I think that's definitely still an attractive option.

[Dr. Jose Silva]
I don't know if it happens the same to you, but definitely, the patients that I see in the office with pellets most of the time were not administered by a urologist.

[Dr. Andrew Sun]
Correct. I would agree with that statement. Most of the time, it's not an official Testopel. The vast majority of this now is compounded pellets at independent hormone clinics. Let's put it that way.

[Dr. Jose Silva]
The problem with that, just like you mentioned before, now the patient is, before they had a testosterone in 400, they got pellets. Now six months after, the testosterone 100, and now they're in a bad position now.

[Dr. Andrew Sun]
Agreed. They definitely have the biggest swing between immediately after the insertion and before their next one. These can be significant, symptomatic, and lifestyle swings in different directions. Sometimes that just means they have to do it more often. Then, over time, many of these patients can form scar tissue tracks in the areas. There's only so much real estate. The trocar is not that small, really, especially if you're doing males, because you have quite a number of testosterone pellets usually that you have to place.
Sometimes people do it for a while, and it's an option. We definitely offer that in our clinic as well, because there will be patients that just want to come in. It is convenient because, ultimately, they have to come in and do labs anyway, either every three or every six months. They're like, "Well, that doesn't mean I have to do anything else." Yes, there's that. On the other side, so now to the least invasive options, you have Natesto, and then the new oral testosterones.

Natesto is an intranasal jelly. A lot of people think it's a nasal spray. It's not. It's like a castor oil that's placed in the nose three times a day. Some interesting things about Natesto is that the peak of testosterone is reached very quickly, less than an hour, and then it fades away very quickly. That's part of why you have to do it three times a day, but you definitely get the fastest sort of absorption.

The most interesting thing about Natesto is that the Natesto data shows that the FSH and LH levels do not get completely suppressed, compared to most versions of testosterone like injectable cypionate, where over time your FSH and LH will essentially go to zero, which means your internal production is shut down. Natesto seems to preserve pituitary secretion, and therefore it preserves fertility. The numbers still go down, but just not to zero.

For patients that are looking for a testosterone replacement option but still want to preserve their fertility, it is an option, although to be fair, if patients are actively still trying to have a kid, we usually will give them Clomid or something like that instead. Things with Natesto. The fertility aspect is very interesting. We think that it's because of the short on-off that that's the reason why they still preserve their spermatogenesis, because the pituitary essentially gets a break. It gets a period of time where the signal is still on, and that's enough time for the preservation of the HPG axis to be maintained. That's really cool.

I'll tell you an anecdote. A patient taught me this. He was a young guy, testosterone like 400 or so, wanted some extra energy and whatnot. We said, "Okay, let's try some Clomid." He takes the Clomid, and his testosterone is like 650, and he feels pretty good. Then he got Natesto, and he says, "Doc, I take the Natesto every morning before I work out, once a day. Not three times a day. I don't need it three times a day, but I take it almost as a pre-workout boost. Because within 30 minutes, boom, the testosterone goes up, feel great, get my workout in. Then I'm not worried that it's suppressing because I'm only doing it for a short amount of time."

I'm like, that's actually genius in some ways. Very off-label, but very interesting. Actually, I have several guys now that do that regimen. Many of these younger guys will take Natesto before sex, or before athletic activity. It's an interesting use of it.

[Dr. Jose Silva]
You need to ask to see what they do during the day, the rest of the day, because I don't think as a surgeon, we can do that and then just be without any energy during the day.

…

[Dr. Andrew Sun]
There's Aveed. We didn't talk about Aveed. That is a long-acting testosterone undecanoate depo injection. It works for about 10 weeks. It occupies a bit of an interesting space between pellets and injections, but that is something that's also available through UroGPO and can be administered out of the office, and there are sort of programs to help offices with that.