BackTable / Urology / Podcast / Transcript #124

Podcast Transcript: Testosterone & Hypogonadism: A Clinical Perspective

with Dr. Mohit Khera

In this episode of BackTable Urology, Dr. Jose Silva interviews Dr. Mohit Khera, professor of Urology at Baylor College of Medicine, about hypogonadism and testosterone replacement therapy. You can read the full transcript below and listen to this episode here on BackTable.com.

(1) Hypogonadism Signs & Symptoms

(2) Testosterone in the Body: Impacting Factors

(3) Lab Workup for Low Testosterone

(4) Free Testosterone: Calculations, Modifications & Implications

(5) Managing Estrogen: A Balancing Act

(6) Testosterone Treatment & Fertility Concerns

(7) Methods of Testosterone Treatment: Injections & Oral Pills

(8) Combating Infertility: What are the Options?

(9) Testosterone & Prostate Cancer Patients

(10) Testosterone Treatment in Females

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[Dr. Jose Silva]
Hello, everyone. Welcome back to the Backtable Urology podcast: your source for all things urology. You can find all previous episodes of our podcast on iTunes, Spotify, and at backtable.com.
Jose Silva, as your host this week, I'm happy to introduce our guest, Dr. Mohit Khera. He received his medical degree from the University of Texas Medical School at San Antonio, and then completed a urology residency in the Scott Department of Urology at Baylor College of Medicine. After completing his urology residency, he went on to complete a one-year fellowship in male reproductive medicine and surgery, also at Baylor. Currently, he's a professor in the Scott Department of Urology at Baylor College of Medicine, and he holds the F. Brantley Scott Chair in Urology. Dr. Khera specializes in male and female sexual dysfunction, men's health, and hormone replacement therapy. Dr. Khera also serves as the director of the Laboratory of Andrology Research, the medical director of the Baylor Executive Health Program, and the medical director of the Scott Department of Urology. He has also served as president of the Sexual Medicine Society of North America. Mo, welcome to the Backtable.

[Dr. Mohit Khera]
Jose, thank you so much for the invitation.

[Dr. Jose Silva]
Now you have a lot of hats in the department, right?

[Dr. Mohit Khera]
I think I have quite a few.

(1) Hypogonadism Signs & Symptoms

[Dr. Jose Silva]
Today, we're going to talk mainly about testosterone: low testosterone, hypogonadism, the pathophysiology of those patients, and what to look for when we're seeing those patients in the office. Mo, can you define hypogonadism?

[Dr. Mohit Khera]
Yes. Hypogonadism essentially means a man having a low serum testosterone value. The number you want to remember that we use is 300 nanograms per deciliter. I have a little problem using that number. I think that it's not really fair that we pick one number for everyone in the world, and if you're below that number, you feel bad and above that number, you feel good, but the number we use is 300. We were involved in some international guidelines that pushed that number to 350 and we can get into that. If a man has a low testosterone and he has signs and symptoms of low testosterone, then that patient suffers from hypogonadism.

[Dr. Jose Silva]
Not just only the patient with testosterone less than 300, do you need the symptoms also?

[Dr. Mohit Khera]
You bring up a very good point. Listen, so I have many patients that come in, and let's talk about the symptoms: low energy, low libido, erectile dysfunction, decreased muscle mass, increased fat deposition, some depression, and poor sleep. These are very common symptoms in men who have low testosterone. The most sensitive specific symptoms are the sexual symptoms, meaning libido and erectile dysfunction. If a man comes in with a testosterone level of 450 and he has every sign and symptom of low testosterone, you cannot treat him, because he doesn't have the testosterone value. Conversely, if he comes in with a level of 250 and says, "I feel great," I wouldn't treat him either. He really has to have both signs and symptoms and a low serum testosterone value.

[Dr. Jose Silva]
You mentioned that patient with increased adipose tissue. I have seen in my practice that sometimes some people are used to low testosterone and they don't know it versus the patient that has that decrease in the past six months and they will see it. Are you seeing those patients that have just constant low T and they just ride life, because that's what they know?

[Dr. Mohit Khera]
Yes. If you think about the symptoms I mentioned, low energy, low libido, ED, increased fat, decreased muscle, many men say, "I'm just getting older, right? This is just part of aging”. The reality is they don't realize that they suffer from a condition that can be treated and help to reverse many of these signs and symptoms. You're absolutely right. I think many people just accept it without getting tested to see if there's a potential treatment option.

[Dr. Jose Silva]
I'm sure you see it in your office also. Sometimes the wife is actually the one bringing the husband in saying, "Hey, I have seen it," and the husband either doesn't want to talk about it or, like you mentioned, they think that it's normal with age. Most of the time I think they're just embarrassed.

[Dr. Mohit Khera]
Yes. I talk about this, many times I call it suffering in silence. I know we're talking about testosterone, but when you talk about ED, erectile dysfunction, Peyronie's, low testosterone, many men are truly embarrassed to talk about sexual dysfunction and their symptoms. We know that the majority of men do suffer, and will suffer in silence. They think there's no treatment option or that their primary care doctor won't take them seriously. I'll tell you, my wife is a family practitioner. I said to her, do you screen for ED and low testosterone? She says, "To be honest with you, I have to go through diabetes, hypertension, sleep apnea. My patients are very sick. It's hard to get through everything in a short period of time." I think a lot of physicians don't go through when it gets to sexual dysfunction, don't get to sexual dysfunction on the chain.

[Dr. Jose Silva]
Just like you mentioned, I always ask the patient, "Hey, are you having low libido?" Because like you mentioned, most of the patients are just suffering in silence and they come because of BPH, even a kidney stone. When you start asking the patient, “hey, yes, I think”, or sometimes even in the office, they can see an ad for testosterone and they can see the symptoms, they can read it and say, "Hey, doctor, I think I have low testosterone."

[Dr. Mohit Khera]
Many times patients are almost relieved that you asked them. If you just say, "Mr. Smith, do you suffer from rectal dysfunction?" They will say, "Actually, I do." It's almost like, there’s finally someone asking me. "Tell me about your libido," which is not commonly asked. Now, conversely, many patients do come in specifically for those symptoms. They say, "Look, I got ED," or, "I have low libido." I would tell you that many men just suffer from silence when they really don't have to.

(2) Testosterone in the Body: Impacting Factors

[Dr. Jose Silva]
Going back to those symptoms or prior to that, in terms of the testosterone pathway, can you just give us a review of how testosterone works in the body?

[Dr. Mohit Khera]
Yes. Remember that testosterone comes from cholesterol. That's the basic building block for testosterone. Remember that the majority of testosterone in men comes from the testicles. Roughly 90% will come from the testicles. Roughly 10% will come from the adrenal glands. As men get older, there is a slight decline in testosterone production from the testicles. Then testosterone, remember, is broken down into two very important things. 0.3% of testosterone is broken down into estradiol. That's why you can get gynecomastia. Then 6% to 8% is broken down into dihydrotestosterone, which has been implicated for BPH and hair loss. It's very important to know the breakdown, because many times, patients will get anastrozole when they get testosterone. They'll give them finasteride. They'll give them medications to block the conversion. That is the essential pathway for testosterone.

Remember that testosterone, when I first started my practice, I thought that there was this thing called andropause, meaning that if you get older, men's testosterone goes down, because they're just getting older and they're going to suffer from low testosterone. Now, we know that's not true. Andropause is really not a true entity. Men who are very healthy do not see a significant decline in their total testosterone levels as they get older. It is the acquisition of comorbid conditions, diabetes, metabolic syndrome, obesity, and obesity is one of the notorious, that drops their testosterone as they age. Getting these comorbid conditions drops it. It's not aging in itself. Now aging does do one thing that's important, and we'll get into this, is that aging does increase SHBG. As the SHBG goes up, your free testosterone will go down as you get older, but we don't see significant declines in total testosterone in healthy men.

[Dr. Jose Silva]
So, do you see patients that are completely healthy that have low testosterone?

[Dr. Mohit Khera]
I do, but remember, there are many other factors that can drop their T, right? For example, stress and sleep. If you sleep deprived someone, five nights in a row, you can see a 15% decline right off the bat in their serum testosterone levels. That's important. There are many things that can drop their T: injury, traumatic brain injury. There's a lot of things you can see in healthy people that can still go down, but the majority, over 65%, of hypogonadism fell into three buckets. There was a wonderful study by Dr. Corona, came out of Italy. If it was secondary hypogonadism, it was obesity, metabolic syndrome, or diabetes, that’s 65% right there.

[Dr. Jose Silva]
You mentioned sleep deprivation. What about patients, and I always find these patients very hard to treat, patients that work at night?

[Dr. Mohit Khera]
Yes, it's difficult. It's very difficult, because the shift workers tend to have lower serum testosterone values, because of this fragmented sleep, but it's a risk factor. Now, it's not the whole thing. Sleep is just, I tell the patient, it's a pie. Sleep is a part of the pie, it's not everything. The four pillars I tell everyone they have to focus on are diet, exercise, sleep, and stress reduction. Again, it's diet, exercise, sleep, and stress reduction. I don't have a pill on the planet stronger than diet, exercise, sleep, and stress reduction. That can help with many things. Just forget testosterone. Diabetes, hypertension, joint pain, depression. I can go on and on. I tell patients, 50% of this is you helping me with diet, exercise, sleep, and stress reduction. I'll manage the hormones. Together, this team approach is very effective. Just giving someone testosterone and they keep not exercising, eating terribly, smoking, doesn't help as much.

[Dr. Jose Silva]
That's a fair point, a good point, actually. I always tell a patient, "Hey, you need to do it yourself also. This will help you." For example, the patient tells me, "I don't even have energy to do exercise." This might give you some, but you need to start doing it. You cannot expect everything to be done from testosterone.

[Dr. Mohit Khera]
Yes. What I've been focusing on and paying a lot of attention to lately is weight loss. Weight loss has this very strong bi-directional relationship with testosterone. There was a great study called the European Male Aging Study. What they showed was that if you lost 10% of your body weight, you can see almost 100 nanograms per deciliter increase in serum testosterone. If you lose 15% of your body weight, you can get almost 250 nanograms per deciliter increase in your serum testosterone. The converse is true. If you gain weight, you'll see a decline as well in testosterone. The best studies are with the bariatric surgery literature. When patients do bariatric surgery, they typically can see almost 250-300 nanogram per deciliter increase in their serum testosterone. I do feel that patients who lose weight not only benefit from an increase in natural testosterone, weight loss actually helps with a lot of the symptoms that we see with hypogonadism, meaning energy. Energy being the most. You tell someone to lose 15, 20, 30 pounds, their energy level goes up. They sleep better. We focus really heavily on weight loss.

(3) Lab Workup for Low Testosterone

[Dr. Jose Silva]
You have that patient tell you, "Dr. Khera, I have symptoms of low T." What's the next step? What labs do you order?

[Dr. Mohit Khera]
Sure. Typically we'll check a testosterone, and I do check a free testosterone initially. The guidelines will say, just check a total testosterone. If the total testosterone is low, then you're supposed to repeat the total testosterone and check other labs, meaning LH, FSH, prolactin. I'm at an academic institution, so I do like to check other parameters like estradiol and DHT. Those are my go-to. Then how do you know if it's really due to low testosterone? Maybe he has hypothyroid. Maybe there's other things going on. I do check TSH, and we do use peptides a lot, so I'll check an IGF-1 to check the growth hormone level as well. Then I always check vitamin D and a B12 just to make sure that they're in check as well. Those are my go-to labs when I know that someone is hypogonadal. I will check a PSA and a hematocrit, because if I'm going to start them on testosterone, I gotta make sure the PSA's okay. I want to make sure they don't have a baseline elevation of erythrocytosis before I start them on it. Because again, erythrocytosis can be an issue.

[Dr. Jose Silva]
You mentioned vitamin D and I, we always talk, I'm in Florida, a lot of sun. We always were taught in medical school that vitamin D, sun exposure. I see a lot of workers that, they're always outside and I see a lot of patients with low vitamin D. Do you replace them, if you see a patient with a vitamin D?

[Dr. Mohit Khera]
Yes, I do. I think that there's several reasons. It helps with immunity. It helps with the testosterone production, endogenous testosterone production as well. If the levels are low, but sometimes people just don't absorb, you'll start at 1,000 units a day, 2,000, you have to go to 5,000, 10,000. Then eventually, you just may use the prescription version, which is 50,000 once a week just to get the levels up. I do think it's important. I do like vitamin B12. I think it can be helpful as well when people are talking about fatigue. Those are the ones I check, but I still go back to, I say, "Look, if you're really tired, the number one cause of fatigue is not low testosterone." The number one reason for fatigue is poor sleep. It's not the amount of hours that you're sleeping. It's how efficient you're sleeping as well. For example, Jose, if you went to bed last night and you slept eight hours, but you were only 30% efficient and I went to bed last night and I only slept five hours, but I was 80% efficient. I will feel better, the efficiency. It's really important that people get sleep. It's not just the amount of hours they're sleeping there. Sleep is very important. Number one, I say, I can give you all the testosterone you want, but if you don't sleep, you will be tired. There's nothing I can do about it. You have to sleep. If you want to sleep better, control your sugars, don't eat three hours before you go to bed, work out for me, manage your stress. It all comes together. Each one of those four pillars play off each other.

[Dr. Jose Silva]
You mentioned sleep, and that can be a separate podcast on its own, because not everybody is the same. Some people, for example, for me, I wake up every day at six, but if I wake up at seven, I'll feel much better. Even if I sleep less, for some reason, that extra hour, because of the line of work that we do, I have to wake up earlier.

[Dr. Mohit Khera]
There's been some interesting studies looking at that. There was a really interesting study looking at testosterone production and that if you deprive patients of sleep for the first half of the night versus the second half of the night, and if you deprive them, say, from 10:00 to 2:00, but then let them sleep from 2:00 to 6:00, they don't see a significant decline in their testosterone values. If you let them sleep from 10:00 to 2:00 and you deprive them from 2:00 to 6:00, they could see. I think there may be some data to suggest that the second half of the night may be more important than the first half of the night.

[Dr. Jose Silva]
Probably. The thing is that the way we live doesn't change.

[Dr. Mohit Khera]
Yes, that's true.

(4) Free Testosterone: Calculations, Modifications & Implications

[Dr. Jose Silva]
The kids go to school at 8:00, so the entire society will have to change for one to be better, if that's the case. You mentioned total T, that's in the guidelines, but what about free T? Patients that have normal low total testosterone, but symptomatic and low free testosterone?

[Dr. Mohit Khera]
Yes. All the body really cares about is your free testosterone, right? That is the most sensitive indicator of symptoms. What happens invariably is that there are patients who have a normal testosterone, let's say it's 400, but they have a very elevated SHBG, the free testosterone will be low. In that patient, I would definitely treat them. The guidelines will say if someone is borderline, they still have symptoms, then you may want to consider getting a free T. I think free T is very important. We check it on all patients. If someone is symptomatic, they have a normal testosterone, but the free T is low, we will treat them.

Now, there are many ways to get the free T. I prefer to calculate my own free T, and you can use these calculators that are online, they're called free testosterone calculators. Essentially all you do is you put in a total testosterone, you put in SHBG, and you hit calculate, and it will give you a free testosterone value. I think the free T is a great indicator of symptoms and it should be checked in patients, particularly if they have normal testosterone values, but they're still symptomatic. I just want to make one other comment, because I said this at the beginning, it makes no sense to have one number for all of us. I have patients that walk in at 250, and they feel great. I can have patients walk in at 400, and they have every sign and symptom of low testosterone.

Many years ago, and we're still doing this, every time someone comes in for hypogonadism, we collect their blood, and I have a lab, and we send the blood to the lab, and we look for something called CAG repeats. CAG repeats is the sensitivity of the androgen receptor. It makes sense, we showed this earlier on, those patients with very sensitive androgen receptors don't require as much testosterone to get symptomatic improvement. Those patients with insensitive androgen receptors, longer CAG repeats, do require more testosterone. That makes sense. All of us are very different. We can't expect everyone to have symptomatic improvement at the same level. That's why when we treat patients, I try to put them in the upper quartile of normal. Still in the normal range, but the upper quartile, because sometimes a patient comes in, you start at 250, and they say, "Oh, he's at 350, he's normal, so must be something else." No. Raise that patient up to the upper quartile, and you may be able to salvage some of these patients that you thought were failures to testosterone.

[Dr. Jose Silva]
What about the patient with total testosterone in 400, low free T? Also, you will go up to the 800 to 750, 800s?

[Dr. Mohit Khera]
I look at the free T, I look at the range. The range, it depends on what you're using. Five to 25, so you can go up to 20. You can use 20 as your gauge. Sometimes you may have to get super physiologic on the total T to get the free T into a good range. I don't want to say that someone is a failure to testosterone unless I've given them a chance. Now, let's say I did get the total testosterone or the free testosterone into the upper quartile of normal. Look, those symptoms I explained to you could happen from a lot of things. Depression can cause it. there's a lot of things that can cause, but you want to at least check off that you've optimized the T. He still has symptoms, now go look for other causes.

[Dr. Jose Silva]
Yes, like you mentioned, the symptoms, I see the opposite. Patients with depression, for example, they've been treated with medications and what they had was low T all along. When you start treating them with testosterone, they feel great, "Doctor, thank you," and those patients do really well.

[Dr. Mohit Khera]
Yes, that's a really important point. Many years ago, I ran this registry called the TRiUS registry, it was a testosterone registry. It had 100 sites over the country, 850 patients. We found that those patients with low testosterone, 93% of them had some degree of depression. That's a lot, whether it be mild, moderate, or severe. When we treated these patients, the severe depression was reduced by eightfold, 17% down to 3% or 2.5%, so it was a big reduction. I am not advocating that we use testosterone to treat men for major depressive disorder, but what I do advocate when I give this talk to family practitioners or to psychiatrists is that when you have patients with depression, you should at least check the testosterone level, right? Because it can, maybe in some ways, be synergistic with the SSRI in treating these men for depression.

[Dr. Jose Silva]
You mentioned, SSRIs will then give you other sexual side effects which can perpetuate the symptoms, like you mentioned, the suffering in silence.

[Dr. Mohit Khera]
Yes, but you know what's interesting? In the study with the TRiUS study? Even patients who are on an SSRI, when we use the PHQ-9 questionnaire, which is a depression questionnaire, those patients who are on SSRIs, many of them saw significant improvement in depression scores just by adding the testosterone. I do think there may be a role with testosterone and depression.

(5) Managing Estrogen: A Balancing Act

[Dr. Jose Silva]
The other thing I want to ask in terms of estrogen, patients that have hyperestrogen in the body, in the blood. Will you start them on an anastrozole or any other aromatase inhibitor?

[Dr. Mohit Khera]
I think that's a really good question because if you go to a lot of these testosterone clinics, a lot of the people that prescribe, what they'll do is they'll start patients on testosterone and an aromatase inhibitor immediately. That never made sense to me, because you don't know what their estrogen is. What you should do is manage the estrogen. My sweet spot is typically 30 to 50. I like to keep it in that range. If a patient has an estrogen level of 40, why would you start them on an aromatase inhibitor, right? It doesn't make any sense.

First, check the estrogen, decide if it's elevated. If it's elevated, you can consider giving them an aromatase inhibitor, but just give them enough to drop them into the normal range. Don't shut them down to zero. Because when I was a fellow in 2006, we actually gave men aromatase inhibitors: one milligram a day. We thought, "Look, men, why do they need estrogen? Just give them testosterone and they don't need estrogen." We found out many years later that men need estrogen. Estrogen is actually critical for sexual function and libido. A wonderful study out of the New England Journal of Medicine by Dr. Finkelstein showed that he felt that estrogen was the main part of the benefit that patients are experiencing, not the testosterone. I think that you should check the estrogen. If it's elevated, use small doses. I typically will use half a milligram, maybe even 0.25 milligram, once a week, and then recheck. If I need to go 0.25 twice a week, but don't shut that estrogen down.

[Dr. Jose Silva]
A patient that has, for example, estrogen in the 200s and then low testosterone, will you do anastrozole first, see if the testosterone goes up on its own with the medication, or would you treat testosterone as well?

[Dr. Mohit Khera]
The problem is anastrozole as monotherapy is not a very good therapy. Now, we're going to probably talk about this, but there are several ways to raise endogenous testosterone. If we talk about medications, there's only three. There's anastrozole, there's HCG, and there's clomiphene citrate. Just three medications. If a patient has an elevated LH and FSH before you start treating them, then clomid and HCG are less effective, because the way clomid and HCG work is they raise the LH, but now it's already elevated. You have a patient with testis failure. The best example is a patient with Klinefelter's. They have elevated LH and FSH. In these patients, anastrozole tends to work better, because what you're trying to do is not make the patient produce more testosterone, you're trying to block the conversion from testosterone to estrogen to keep more testosterone around. Now, you got to go be careful. Long-term usage of anastrozole, say for greater than two years, can lead to some risk for osteoporosis, osteopenia, because you're shutting down their estrogen completely. I typically reserve anastrozole for patients who have elevated LH and FSH initially as monotherapy, but it's not a great monotherapy for low T.

(6) Testosterone Treatment & Fertility Concerns

[Dr. Jose Silva]
You mentioned the patient that is looking for endogenous testosterone instead of exogenous. What patient will fall into this category? Other than a patient wanting to preserve fertility, right?

[Dr. Mohit Khera]
That's the biggest one. Jose, I know you've seen this. I can't tell you how many patients have come in and they have been on testosterone, they've been getting injections, and they were never told it could cause infertility. Then now they say, now I want to have a child. I tell them that we can reverse it. That paper came out of our institution. We showed that you can reverse it, but it can take three to seven months, and not everyone was reversed, although the majority were. Our protocol for this is basically tapering testosterone. You don't want to stop it cold turkey, because they feel lousy. We taper it every two weeks, all the way down to zero, and then we give them HCG, 3,000 units, three times a week, to try to bring back their endogenous testosterone. If they're trying to have children, then I will also give them Gonal-F at the same time. Gonal-F is expensive, so if they can't afford the Gonal-F, then I'll give them clomid. Clomid or Gonal-F with the HCG. That tends to work quite well, and typically these patients will recover anywhere from three to seven months of the spermatogenesis. I've found that if you don't taper the testosterone over time, they tend to relapse sometimes, because they just feel so lousy, they want to get back on the T.

[Dr. Jose Silva]
Patients, for example, that were doing testosterone in the past and already have a physical exam, atrophic testicle, will that work? Your therapy will work on them or that patient most likely is already beyond salvage?

[Dr. Mohit Khera]
Yes, so remember, the only way these therapies work is if your testicles work, right? All they are trying to do is either rev up the production from the testicle or stop the breakdown of testosterone that the testicle's producing. If the testicles cannot produce, they can't produce. I tell patients, the older you are, the greater the apoptosis of the Leydig cells within the testicle, and you have less Leydig cells. The older you are, the less likely you are to respond to any of these types of medications. At some point, you're just going to have to switch over to testosterone if you want to have this as your form of therapy.

[Dr. Jose Silva]
A patient that has never been treated with testosterone, has low T symptoms, wants to preserve fertility, what are the options?

[Dr. Mohit Khera]
I will tell them that I think patients respond best to HCG. I think that patients respond second best to clomid. Clomid is sometimes hard to get, so we now use N-clomid, which is a compounded off-label. Then the third option is anastrozole. Why? But most patients like clomid, because it's a pill, it's not an injection, and it's cheap. The problem with clomid is the following: the way clomid works is it blocks estrogen receptors centrally in the brain. When it blocks the estrogen receptor, then that blocks the negative feedback and you increase LH and FSH. That's great, but what happens is many men will have a good testosterone level, but they'll say, "I have no desire for sex. My libido's low." Remember what I said earlier is that men need estrogen. He has the estrogen, but he can't see it in the brain because all the receptors are blocked, right? We call this a discrepancy effect. You can take that same patient who has an 800 testosterone on clomid, put him on exogenous testosterone injections, put him back at 800, and now he'll say, "I feel it. My libido's better. Sexual function's better." We see that quite a bit. You don't get that with HCG, because HCG bypasses the brain, and HCG is just simply an LH analog, goes directly to the testicles, stimulates the Leydig cells to produce more testosterone. That's why patients tend to feel more symptomatic improvement on HCG. Again, it's expensive, it's an injection, and has to be done several times a week.

[Dr. Jose Silva]
You mentioned, so first choice, HCG, and then clomid, if they don't want to inject themselves.

[Dr. Mohit Khera]
Exactly. Now remember, there are other options, not medical options, but lifestyle. I told you about weight loss. There has been a big movement in the United States for using semaglutide for weight loss. I don't know if you've seen that, so I'm sure you have. These patients come in and their endogenous testosterone does go up quite a bit after they've lost significant amounts of weight. That's weight loss. We do know that improving sleep, there's some studies looking at CPAP machines and improving sleep apnea, which can potentially improve serum testosterone values. Exercise has been shown, but the most profound, even varicocele repair now. I don't advocate fixing varicoceles for testosterone, I want to be very clear, but they have been shown to increase the endogenous testosterone by about 100 nanograms per deciliter in several studies. If someone did have a varicocele repair and they did fix their sleep apnea and they did lose some weight, now you start adding it all up. Now you have a person who has a normal serum testosterone. That will be helpful. The only problem is that most of my patients say, "I don't want to do the work, just give me the pill." It's like, just give me the pill. I say, "Fine, I get it," but you could do the work and it would make a difference.

(7) Methods of Testosterone Treatment: Injections & Oral Pills

[Dr. Jose Silva]
You mentioned the pill in terms of clomid; some patients like it, because it'd be a pill versus an injection. Now in the market, there's a few oral pills out there, right?

[Dr. Mohit Khera]
Right.

[Dr. Jose Silva]
What's the difference between a couple of years ago that we didn't have that many in the market recently? Now, we have three in the market.

[Dr. Mohit Khera]
You have to remember, there's a long history behind this. The testosterone was invented in the 1930s, and it was also- Ruscica invented the oral testosterone formulation in the 1930s. The problem was if you give someone oral testosterone, it gets degraded very quickly by the liver, and it's gone. What they did in the '30s was they methylated it. They put a methyl component on the testosterone so it would stay around. The problem with that is that when the testosterone went through the liver, it caused liver toxicity, hepatotoxicity, even liver cancer implicated as well. For decades, all providers thought that if I give oral testosterone, I'm going to cause liver damage and liver cancer. There was a fear.

In the 1970s, there came out a medication called Andriol, which was the first testosterone undecanoate. Why was this different? It wasn't methylated, it's called undecanoate, and it actually bypassed the liver and it goes through the lymphatics, right? It actually was very popular, but the only issue with undecanoate was that it had to be taken three to four times a day, had to be taken with a fatty meal, and so that can be cumbersome, right? But you finally have an oral that has no liver toxicity whatsoever. What's so interesting is that Andriol medication made it throughout the world. It was available in China, it's available in Canada, it's available in Europe, you can go to Australia, but it never got FDA approved in the United States. Never got approved.

In 2019, the US, we got our first oral testosterone undecanoate. Clarus came out with theirs in 2019. Then in 2022, which was three years later, in the same year, we got two new testosterone products. Now Kyzatrex is the newest testosterone product. It's by Marius Pharmaceuticals. There's been some changes in some of the older oral products. Now Tolmar purchased their product from Jitenzo, and Halozyme now has the Tolando product as well. We have three orals. What's nice about these new orals is that they are only twice a day. That's a big plus, right? You don't have to take them with a fatty meal. You can just take it with a meal, which is really nice as well. With a meal, twice a day, and Americans like pills. We're used to taking pills. They have pill boxes, they're used to taking a morning and evening dose. This seems to be very easy to just add this to their regimen of taking pills as well. The levels on the orals are very good, and there's no hepatotoxicity, so we don't have to worry about any liver damage again with this.

Now what's interesting, in 2015, the FDA did require that all testosterone products do hypertensive testing. There is a slight increased risk in hypertension. You just monitor the blood pressure, but the hypertension risk is pretty low. You'll see about maybe a five millimeter increase in mercury of the systolic. What's really nice about the orals is that they have one of the lowest rates of erythrocytosis. Think about this. When the hematocrit gets a little high, above 54, there's a theoretical increased cardiovascular risk. If you have someone on an injectable, their risk of erythrocytosis can be as high as 67%, in one of the studies that we published. One trick that you can do is get them off the injectable, and I used to switch them to a gel, because the rate of erythrocytosis was about 12%, pretty low. The orals are even lower, it's about 5%. If someone is suffering from erythrocytosis, elevated red blood cell count, just switch them from the injectable down to the oral, and you'll drop that erythrocytosis significantly.

[Dr. Jose Silva]
The reason for that is the spike?

[Dr. Mohit Khera]
That's part of it. Actually, you're right. I think that we're not getting those high sustained spikes because remember, on the injectables, I like giving injectable testosterone, I do sub-Q. Once we started giving sub-Q twice a week instead of once a week, the erythrocytosis rate went down. You take the same dose, 100 milligrams a week, but if you give 50 milligrams on Sunday, 50 milligrams on Thursday, the erythrocytosis rate goes down. You don't see a crash towards the end of the week. We tend to like to split our doses. Because remember, so testosterone peaks in 24 hours. Most patients, when do they want the testosterone? They want it Monday morning, and they want it on Friday for the weekend, right? That's why we give it Sunday, Thursday.

[Dr. Jose Silva]
Sometimes patients don't want to get injections. How do you tell them, hey- and sometimes the primary was done once every two weeks. How do you change that to, hey, we're going to- instead of once every two weeks, we're going to do twice a week?

[Dr. Mohit Khera]
Yes, a couple of ways you can do it. One, if they want to do it twice a week, we have to let them know first, it's sub-Q. Sub-Q goes a long way, right? Because people think, I say, you don't have to use a big needle, and you don't have to stick the needle in your muscle. Oh, okay. That's very good. What I found is that the 25-gauge needle, five-eighths inch, one CC syringe, is perfect to draw up the solution and it's small enough not to cause pain. You can inject with the same one. Sometimes people say, I'd like to draw up with an 18-gauge needle and inject with a 27-gauge. That's fine too. Because remember, we're only injecting small amounts. It's only 0.25 CCs. 0.25 CCs, so it's a very small amount. Typically, patients say, "Oh, you're telling me that it's not a big needle, I can do it sub-Q, I can do it twice a week." That tends to catch their interest. Particularly, think about this. Let's say they have erythrocytosis, and they have to donate blood every two months. They'd much rather inject twice a week than donate blood every two months. That may be another way to convince them to use it.

[Dr. Jose Silva]
Yes, because you have to donate blood, and then you have to also get blood drawn out for the labs.

[Dr. Mohit Khera]
Yes.

[Dr. Jose Silva]
For follow-up on the testosterone.

[Dr. Mohit Khera]
I think it's a big hassle, so either switch the formulation. One other thing, because we just brought this up. If you do have somebody that does develop erythrocytosis, their red blood cell count goes up, we typically ask them to donate when the hematocrit is at 51. I don't want to wait until 54, so I have them donate at 51. I like to drop it down below 48. They typically donate one pint once a week. They split it by a week. I don't want them to get hypotensive. We just wait a week and donate the next pint. On these patients, I hope the take-home message everyone gets is, make sure you screen the patient for sleep apnea. Because many of them have occult sleep apnea. That's why they're getting erythrocytosis. Patients with O-sleep apnea are much more sensitive to testosterone in terms of developing erythrocytosis, and they're typically hypoxic at night. Get a sleep study on these patients that have to keep donating.

[Dr. Jose Silva]
It seems now I need a sleep specialist next to the office, because with testosterone, and also patients with nocturia.

[Dr. Mohit Khera]
Yes, that's true, too. Great treatment for nocturia is to treat sleep apnea. You know that. It's a great treatment.

[Dr. Jose Silva]
It doesn't have to be the classic patient with obesity. I've seen a lot of patients with sleep apnea. Skinny guys, have upper respiratory symptoms, and whatever. I do see a lot of patients with sleep apnea.

[Dr. Mohit Khera]
Yes, very important.

[Dr. Jose Silva]
In terms of the pills, in terms of preservation of fertility, is that something that happens with pills or not really?

(8) Combating Infertility: What are the Options?

[Dr. Mohit Khera]
I always thought that it does. I'm trying to conduct a study now looking at that. Let's be clear. Exogenous testosterone has been related to infertility. If someone on this podcast is trying to conceive and have a child, you would want to stay away from exogenous testosterone. Several years ago, the nasal formulation, the testo, in a trial that came out of the University of Miami, showed that maybe it doesn't decrease sperm production if you take it. I don't want everyone to think, "Oh, I'm going to do the nasal and everything will be fine." It may not decrease sperm production as much as other formulations, and so it's an option. I do think that there is a potential that the orals may not decrease sperm production either. That's currently something I'm working on right now, just to look and see if it has an effect. I think we may be surprised. One other thing that you may see in the community is that some patients will get HCG with testosterone, because remember, HCG may help preserve testicular function while you're getting the exogenous testosterone and not take that much of a hit on decreasing your sperm count. Remember, many men just take it to preserve testicular volume. They don't want atrophy. That may be another reason why they take the HCG.

[Dr. Jose Silva]
You mentioned that the patient that is taking the testos, for example, are your theories behind lower spikes compared to the injections?

[Dr. Mohit Khera]
Yes, in the testo, the way it works is that the spikes are rapid. If you look at the testo spike, it's like literally an hour, it's up and down. When I first initially looked at that, I thought, "Wow, how can patients feel good when there is barely any testosterone in the body?" It's just these rapid spikes and it comes right back down and they're getting symptomatic improvement. Later I learned that what happens is when that testosterone binds to the androgen receptor, its activity goes on for hours. It can go on for much longer than what you see is in the blood. I don't have to have that serum blood level elevated in order to get the benefits of the androgen receptor and the androgen binding, right? Patients do see improvement, but I think that rapid in and out of the bloodstream does help protect the pituitary from getting suppressed. I do think there is a potential that the orals may offer the same thing.

[Dr. Jose Silva]
I think with the testo, I think it's like three times a day.

[Dr. Mohit Khera]
Yes, two. We got to get to the ATI, you're exactly right.

[Dr. Jose Silva]
Going back to that patient that goes to the office with symptoms, is there a patient that is not a candidate for testosterone replacement?

[Dr. Mohit Khera]
I think the biggest one is infertility. If someone says to me that I am planning on having children in the future, I really try, obviously try to avoid getting it to them. I really try to avoid giving it to young patients, because I think about it. If you're 25 years old and I'm going to suppress your access today, what's the end game? I'm going to treat you for life on testosterone? When there are many ways I can raise your natural endogenous testosterone. There are many times where I can give a patient clomid, a young man, clomid. Remember, the way it works is it increases LH and FSH, and then you can stop the clomid after several months, say three to six months, and some of these men will continue to produce testosterone. I really don't want to, we use the word hook, them on testosterone at such a young age. Now look, it's reversible, that's true, but there's no guarantee that I can get you back to the level you started with. Some would say, "Well, Dr. Khera, you can reverse it and I'll go back, I can start making testosterone or you can reverse it and I can start making sperm again." That is true. I can reverse it and you can start making sperm again, but there's no guarantee that I can get you to the level you started with. If you started with 120 million per ML and you are now at 20 million per ML, that is true. I did reverse it, but you're far less fertile than you started with.

[Dr. Jose Silva]
I'm sure you see this patient. For example, a patient that is 25, you mentioned 25-year-old, is healthy, goes to the gym every day, eats right, minimal body fat index, and they still have low T, and say, "Doctor, I'm doing everything right." What are the options for that patient? Is it just either clomid, HCG, or testosterone?

[Dr. Mohit Khera]
First you want to find out why someone's so young and healthy, it always doesn't make sense, but there's a large portion of these young patients that's idiopathic, cause unknown, it is. Again, we can give them HCG, clomid, are my two go-to, but one comment: In 2015, the FDA changed the indication for testosterone therapy. If you open the package insert for any testosterone product, you will read that it's indicated for primary hypogonadism, and they list all of the things like testis tumor, testis failure. Secondary hypogonadism, they list pituitary tumor, injuries to the pituitary. Nowhere in the indication of the package insert does it say ED, or low libido. It doesn't say that. It has conditions, right? This is an important statistic, only 15% of the patients we treat have a true medical condition. 85% don't have a medical condition like a testis tumor. In 2015, we used to call this, well, they're idiopathic, and that's right, but the reality is that the majority of men we treat have an unknown cause, right? An unknown cause. Now, I think that diabetes, metabolic syndrome, and obesity should be considered causes. They're not identified as causes, but I do think they're considered causes. Just realize that the majority of patients are treated off-label. Why is that important? Because many insurance companies love it, because they don't have to pay for the drug if you're treating them off-label. They say, "I'm sorry, we're not paying for it," and that's why the compounding pharmacies got very busy, because compounders are very cheap.

[Dr. Jose Silva]
They're cheap, and also it takes time away from the office. I'm sure you're in your office, there's people, it just takes time, a lot of time getting the insurance to try to cover some of the injections, pills, or whatever, and the patient just waits a couple of months until they can get some treatment. Sometimes after three, four months, the insurance just keeps saying, "Yes, we need more information." At the end of the day, yes, it's easier just to send the patient to a compounding pharmacy.

[Dr. Mohit Khera]
You can just pay cash. If the drug has a reasonable price, and you can just pay cash and not have to deal with insurance, that's also very helpful. It's just, that depends on what you have.

[Dr. Jose Silva]
Sometimes, even with the insurance, the copay might be still very high. Even if they approve it.

(9) Testosterone & Prostate Cancer Patients

[Dr. Mohit Khera]
I agree. Jose, one more thing we didn't mention, but I got to go mention this. In June, last month, a large trial came out called the Traverse Trial, and I was involved in this trial. We started this trial in May of 2018, and we finished in June of 2023. It was a long, five-year trial. This trial, primary endpoint, was looking at MACE. Actually, we started in 2017, I apologize, so it was five years, but it was looking at MACE, and it showed no increase in cardiovascular risk. I think that's really important, because many times I get clinicians that come to me and say, "I heard testosterone causes a heart attack," based on all the hype that they heard in 2015. The Traverse Trial finally puts that to rest. I think that's very important to realize that. It was a large study, a little over 5,000 patients, but finally, we have a large randomized placebo-controlled trial looking at testosterone and MACE. Many other studies are going to come out of this, so you should know, looking at prostate cancer risk, sexual function. Looking at anemia, bone fractures, diabetes. Very exciting. These studies are going to come out shortly.

[Dr. Jose Silva]
That's extremely good because we definitely need that advertisement or that positive feedback in terms of the research, because like you mentioned, after the cardiovascular events came out in 2015, a lot of the primary physicians, which are usually the gatekeepers of these patients the patients come scared to the office, because the primary say, "Hey, you shouldn't be on testosterone. You're going to have a heart attack." Sometimes it's difficult for us or it takes time for us to convince, "Hey, you should be fine."

[Dr. Mohit Khera]
Yes, I think it's the largest study we've ever had on testosterone, a randomized placebo-controlled trial. It's a big, big effort, and it's just a great study, and I think, again, more to come on that. I think more to come also on prostate cancer. We didn't talk about that, but that was the main concern when I started my residency, and now that's put to rest. The AUA guidelines in 2018 state that men should be aware that there's no increased risk of prostate cancer giving testosterone, but they still say it is controversial or risk unknown if he has a history of prostate cancer, meaning radical prostatectomy or radiation. I do think that most urologists are getting more and more comfortable treating men with a history of prostate cancer. I think that the one they have more difficulty with is obviously sometimes active surveillance.

[Dr. Jose Silva]
Yes, I do have a patient that, on active surveillance, a 3.3, 5% core, but yes, I do have patients that are in remission, that have radiation after, and I feel completely safe after radical prostatectomy and a PSA with zero, but definitely those patients with radiation are a little bit more challenged. That PSA never goes down to zero, but the patients need it and its quality of life. If they have depressed moods, they have low energy, low libido, they don't want to do anything. I don't think that's living either.

[Dr. Mohit Khera]
Yes. The hardest patients to treat are really the ones with radiation, with the radiation and androgen deprivation therapy. Let's say someone had high grade, high Gleason score, got androgen deprivation therapy. There's this concept called the androgen saturation model. Essentially what it means is that when your levels of testosterone are low, your PSA correlates with changes in testosterone. We think the saturation point is around 250. If a man comes in with a testosterone of 110 after radiation, and I start him on testosterone, his PSA will go up. If you believe in the saturation model, once it gets to about 250 or above, it'll plateau. That first PSA, when they come back in six weeks, everyone's freaking out. They're like, "Oh, my God, this is about chemical recurrence." Tell patients, it's going to go up, then we'll recheck it again. After we check it again, it tends to find its own plateau. Now that's, again, what we do in our practice. I typically have patients who have radiation. In this case, I'll wait 18 months before I treat them, and I will biopsy them. I'll biopsy them if they want to be treated. The radiated patient with androgen deprivation therapy is, I think, one of the hardest patients to treat with testosterone, and it involves a lot of counseling and making sure that they're really informed on the risks and benefits.

[Dr. Jose Silva]
In those patients, do you, let's say, you do the biopsy, there's no cancer, treat them as the same as a patient, cancer-naïve, in terms of treatment options, or do you go specific for something different?

[Dr. Mohit Khera]
Two different things I would do is I wouldn't give them a long-acting. I wouldn't give them Testopel, because I can't take it out of the body. I don't want their PSA to go up, they get concerned. I use a short-acting, and I think that's very important. The only other difference is that I would monitor their PSAs a little bit more often, just to show them that there is no concern, no increase. Instead of doing it every six months, I may do it every three months of the first year, showing that there's no issues, then start spacing it out. I definitely would not use a long-acting in this patient.

[Dr. Jose Silva]
You mentioned the pellets, and we didn't mention the pellets before. You mentioned Testopel, but I know there's a lot of offices out there using different kinds of pellets that are compounding, and they usually don't even care about your testosterone. Can you talk a little bit about that?

[Dr. Mohit Khera]
Yes. We typically use the Testopel, which is commercially available, but some patients don't have coverage, and some states will only allow six pellets, which doesn't really do much. In those states or if a patient doesn't have coverage, we offer a compounded version of the pellets. The difference between the Testopel. Testopel comes at 75 milligrams per, basically, pellet, but the compounded ones we use are 100 milligrams per pellet. I'll use 12 Testopels or nine compounded, which is essentially 900 milligrams either way. I think we looked at this and we did some studies. We don't see a significant difference in levels. Patients tend to respond to testosterone, whether it's compounded or it's a pellet. You just gotta make sure that you're getting your compounded pellet from a reliable source, right? That's very important. There are many compounders now that are FDA certified, so you know they're getting very high quality. If you are using compounded pellets, make sure you check the testosterone levels frequently at the beginning to make sure these patients are responding, because not all compounders are the same.

[Dr. Jose Silva]
You mentioned the labs also, and you mentioned that you wanted the patients to be in the upper quarter. How often do you repeat the labs?

[Dr. Mohit Khera]
Typically, it depends on what type of formulation they're on. If they're on a gel, it's typically about two weeks. Typically on an injectable, I may have them come back in four weeks. Now, it's not that it has to be exactly two weeks. It can be any time two weeks or after. Let's say he says, "I'm going on vacation. I can't come back for a month." No problem. I just want some time where they can get to their new baseline level.

Now, there's a controversy here. There are many different ways to check the testosterone level, and I'll use the example with the injectable. A lot of endocrinologists like to check the mid of the week. If he's getting one injection in a week or one injection every two weeks, they'll check it at the halfway mark. I prefer to check it at the trough. I tell them, the day before you come in, I'd like you to check your blood so I can see how low you are, because I'm not so concerned sometimes about how high the levels get, because he can get erythrocytosis, but if the trough is low, let's say the trough is 110. Clearly that's not going to work. I try to make sure that my trough is in a reasonable range. If my trough is at 300 or 400, I know the peak can't be that high anyway. That's really important to me to check it at the trough.

[Dr. Jose Silva]
Then once you establish that the patient is on the ideal medication or dose, will you go every six months?

[Dr. Mohit Khera]
Exactly right, every six months. The guidelines say you can check every year. I think that's a bit long. what if they get erythrocytosis or what if something happens or the level's not, so I think every six months, if I can just check the blood to make sure they're fine, I think it goes a long way.

[Dr. Jose Silva]
Are you checking liver enzymes all the time, every six months?

[Dr. Mohit Khera]
You don't need to. It's not indicated. In fact, even with the oral testosterone, you don't have to check the liver enzymes. That was only with the methylated. I think the take-home is that the stigma that oral causes hepatotoxicity is not true. You don't need to check the LFTs.

[Dr. Jose Silva]
You're doing hemoglobin, hematocrit, testosterone, free testosterone, estradiol?

[Dr. Mohit Khera]
No, that's exactly it. My workup on a repeat visit is T3TE, H&H, and a PSA. Those are the five that I get on every single patient when they come for follow-up. Yes, I think it's- that's just the standard. Now a lot of women also take this too. Testosterone is extremely effective in women and women also use pellets, but it's off-label in women. A lot of the women also will use injections, the compound injections as well.

[Dr. Jose Silva]
Do you treat them the same? Twice a week at a lower dose?

[Dr. Mohit Khera]
Yes, so the dose for a woman, again this is off-label, is one-tenth what we use in a man, one-tenth. I've found that when it comes to libido, testosterone is extremely effective in women. A lot of the women don't mind injecting Sub-Q once a week. Some use a cream, some use a pellet. It just varies, whatever they want, but those are the three most common ones that we use. We'll compound a cream, we'll compound a testosterone formulation, or we'll use a pellet. Again, all off-label, but very effective.

(10) Testosterone Treatment in Females

[Dr. Jose Silva]
Are you seeing more female patients in your practice for testosterone?

[Dr. Mohit Khera]
Yes, what happens is I'm starting to see them as a couple. The patient will come in and say, "You know what? I'm doing great, but now I have no one to have sex with. We haven't had sex in 10 years, and you got me these great erections, this great libido, but I'm stuck." Many, many years ago, I went out to California, I did some extensive time with Irwin Goldstein, who I think is the godfather of female sexual dysfunction. He's amazing. Took some courses at ISSWSH, which is a phenomenal society that teaches about female sexual dysfunction. We've been treating women, I've been treating them now for 16 years, because it's a couples disease. There's no point in raising the libido in one partner and not the other, because that is a setup for a conflict. If you're going to keep both libidos low, that's fine. Leave them both low. That's okay. If you want them both high, but you don't want one high and one low. I think by treating one patient and not asking about the couple, you're missing the boat.

[Dr. Jose Silva]
Well, Dr. Khera, anything else you want to add? I think we covered a lot of things today.

[Dr. Mohit Khera]
No, this was really good. I really appreciate the opportunity and thank you for having me on the show.

Podcast Contributors

Dr. Mohit Khera

Dr. Mohit Khera is a professor of urology at Baylor College of Medicine in Houston, Texas.

Dr. Jose Silva

Dr. Jose Silva is a board certified urologist practicing in Central Florida.

Cite This Podcast

BackTable, LLC (Producer). (2023, October 4). Ep. 124 – Testosterone & Hypogonadism: A Clinical Perspective [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.