Testosterone and Prostate Cancer: Testing & Treatment Modalities

[Dr. Jose Silva]
You mentioned bone health. We as urologists, we treat prostate cancer and we start patients on Lupron or other anti-hormonal treatment. We mention the consequences, but not going into details or follow-up in terms of what's going on with the patient's body. Let's talk about what testosterone means in the body and why we need it.

[Dr. Rodrigo Valderrábano]
Sure. Testosterone is the male-type hormone. It is secreted in men mostly from the testicles. It's controlled by the pituitary gland, so we have hormones that go from the brain and tell the testicles what to do and then testosterone and estrogen get sensed in the brain. That's how we maintain our balance. Testosterone has a huge role in development obviously of a male phenotype, so male characteristics, but in adulthood, it is very important to maintain sexual function. It's important to maintain energy and vitality and also proper muscular strength and muscular mass.

[Dr. Jose Silva]
The relationship between bone and testosterone, what is it?

[Dr. Rodrigo Valderrábano]
That's an interesting and maybe a more loaded question than you thought. Testosterone interacts with bone in many different ways. Testosterone gets converted into estrogen and estrogen maintains bone. That's why women after menopause will lose bone mass. Actually, many people thought that estrogen was for women and testosterone was for men. Actually, it's also estrogen for men that controls bone density, but all of the majority of estrogen in men is derived from testosterone. Anything that affects testosterone will, in effect, then move on to estrogen and then to bone.

In the setting of prostate cancer, it's incredible to me that we don't pay attention to this as much as we should. When women get treated with anti-hormonal agents for breast cancer, it's a huge deal. It's really come more into the forefront of therapy, especially now that our treatments are getting better and now we worry about long-term effects of our medications. Definitely, testosterone is indirectly the main driver of bone health in men. Obviously, if you have low testosterone and you have low muscle mass and strength, that also will by virtue of decreased loading on bone and decreased torsion and tension on bone, you will also start losing bone over time.

[Dr. Jose Silva]
You mentioned low testosterone. You as an endocrinologist, what are the parameters to say that the patient has low testosterone? Based on symptoms or a combination of both? Because I know it's always changing. Or people have their own information, their own opinion on what exactly is low testosterone.

[Dr. Rodrigo Valderrábano]
Yes, this is exactly why I had to give that disclaimer because you can get into trouble with all these. I think it's important to recognize a couple of things. Number one, the radioactive immunoassays, the regular tests that are used for testosterone are pretty bad in terms of that they're not very precise. That's one thing. If you got a blood test done on separate assays, if you've got five blood tests and got them done at the same time but on different assays, you might get different numbers.

Another thing that's really important, testosterone naturally goes down during the day. We did a study when I was at Stanford in Palo Alto where we looked at people that had gotten their testosterone level at the VA and outside. The take-home message is even just an hour later, testosterone could be lowered by like 100 points, so it could make a real difference. We try to use good tests. We try to standardize it, do it early in the morning, 8:00 to 10:00 in the morning. Then, don't just think about the number. There's a lot of other things that can affect testosterone like sex hormone-binding globulin. Exercise and stress can move it around and then it bounces back naturally. We really want more than one test to determine whether testosterone is really low. Current guidelines agree that around 300 or maybe under 275 total testosterone is considered low. In terms of free testosterone, which we look at as well, if you directly measure free testosterone, you can use those numbers too, but I like to think about the number 75 micrograms. That's because in our group when we looked at young men who didn't have diseases, everyone was 75 or up for free testosterone.

When you see low testosterone, you start thinking about it, and then you have to have symptoms. That's really the thing. You need to have especially sexual symptoms, so you asked, are people having morning or nighttime erections. You ask about libido, sexual desire. The caveat is that there are many things that go into sexual desire: state of mind, whether you've slept or not. All of these things are also important. You really need the low number and you need symptoms to really determine whether someone's hypogonadal.

It gets dicey because people that have obstructive sleep apnea or people that are obese can have lower numbers for their testosterone, but it doesn't mean that they are hypogonadal. It's just that their comorbidities are bringing testosterone down. There ideally, you would have someone lose weight and testosterone would bounce back up, whereas for someone that has an organic disease due to pituitary problems or testicular problems, you really do need to think about giving testosterone.

[Dr. Jose Silva]
Then that patient that you just mentioned, sometimes I see that they have elevated estrogen. Is it something that you should start those patients on aromatase inhibitors to boost their testosterone or it depends just on the symptoms?

[Dr. Rodrigo Valderrábano]
Like I was mentioning before, most of the estrogen in the body comes from testosterone in men. The more fat mass you have, the more aromatase you have, and so you have higher levels of estrogen. There you would want to treat the root cause. You would want to try and get someone to lose weight and that could go away. There are no FDA-approved indications for the use of aromatase inhibitors for men that have high estradiol levels. There are some case reports that it can help, certainly, but you have to be careful about how you do it. You could also affect bone density by giving aromatase inhibitors. That's the big thing in women with breast cancer, that you can lose 10 to 15% of your bone mass in a year. Very, very high levels of bone loss, so because of my focus on bone, I'm less keen on using aromatase inhibitors. We always want to at least try to get the person to lose some weight beforehand. Improving sleep apnea may help with testosterone levels as well. At the very least it's a good idea.

[Dr. Jose Silva]
Because those patients, they always say, "Well, I don't have the energy to lose weight. I need something now." Then, they want the testosterone. I say that in my clinic I see both. I have the patient that just continues doing nothing. He says that testosterone doesn't work, but the other one that really motivates himself and starts losing weight and at some point, like you said, maybe they don't need the testosterone anymore. I think the few cases of patients that once I start testosterone they don't need any more are the ones that lose a lot of weight.

[Dr. Rodrigo Valderrábano]
Yes, that definitely does help. Testosterone is an anabolic hormone, if they don't also increase their physical activity, they're going to actually gain weight with the testosterone but you're right, there's a subset of people that have terrible symptoms and you give them testosterone and they do really well. I've had patients like that as well in my clinic. That's why you have to personalize what you do.

For these people that have obesity and sleep apnea, you could also consider using clomiphene. Clomiphene is a serum, a selective estrogen receptor modulator that is used in fertility. Essentially what it does is it helps increase cycling of our pituitary hormones, on our gonadotropins and some people do really, really well on the clomiphene. It's an off-label use, but there are studies that have taken it out to two to three years and it's very safe. Without the risk factors that we deal with when we treat with testosterone. Honestly, there's less bother in the prescription and it's not a controlled substance and some people do excellent on it.

[Dr. Jose Silva]
Yes, recently, I think there's a shortage of clomiphene, clomid, and it is been a challenge for patients to continue their treatments, but we're using compounding pharmacies and definitely that has helped but the regular pharmacies, for some reason they don't have it at least in the Orlando area. Rodrigo, in terms of treatment options for testosterone, I find myself always giving injections at the end of the day because that's mostly what the insurance covers. What's your preference?

[Dr. Rodrigo Valderrábano]
Yes actually, the injections are totally reasonable, but my preference is actually the gels.

[Dr. Jose Silva]
They're more natural. They do what the body is supposed to do. They boost in the morning, but they don't at night.

[Dr. Rodrigo Valderrábano]
Yes, that's right. I do it because you get less pituitary suppression. If somebody's on injections for a long time, they can have androgen withdrawal when you try to wean them off. With the gels, you get an even level of testosterone. You don't get these peaks and valleys. Most people do well on it.

The thing to consider with the gels is that if you have small kids or if you have a female spouse, it can get dicey if they get the gel on them. It really dries within 15 minutes but there is some trace gel there for several hours after. If you have small kids and they're jumping on you and they get some of it on them, things can get hairy, literally.

The injections are very good too. Generally, my second go-to are usually the injections, but what I find is sometimes at the tail end, so if you're doing for example, 200 milligrams every two weeks at the tail end, some people are running out and then they feel really fatigued at the tail end, but what you can do then is instead of doing 200 every two weeks, you could do 100 every week and that's good. Some other forms, there's patches as well. I've seen that work for some people, but they do cause a lot of dermatitis and the patch falls off and then that's the problem, but that's available.

[Dr. Jose Silva]
Yes. Especially patients that sweat a lot. It falls. Yes. They're going to the gym, yes.

[Dr. Rodrigo Valderrábano]
Definitely in the Orlando area it's a bigger problem than in the Boston area, but those are good. You have the-- I don't know if you implant the pellets? Some people really like those.

[Dr. Jose Silva]
No, I'm not doing that in the clinic. I started doing it, but it was a mess trying to get the insurance to cover it. It took too many resources from the office so I just stopped doing it.

[Dr. Rodrigo Valderrábano]
People like it while it's on, and then they can get some scar tissue. I've never seen someone that really stays on it for years and years. They'll use it for a while and then they'll stop. Then, there's a pill now that's a testosterone undecanoate pill. That one, it's hard to cover because it's newer and more expensive. That also in the clinical trials, it did increase blood pressure a little bit. I sometimes hesitate to use those in people that have high blood pressure.

[Dr. Jose Silva]
There's also, I think it's new: the intranasal one, have you seen that one? They use it four or five times, I think it's three or four times a day. I usually use the intranasal chart. Supposedly in terms of the axis, it doesn't have any major side effects. That's how they sell it because it is short-acting, but I think I tried twice for patients and the insurance didn't cover it.

[Dr. Rodrigo Valderrábano]
Yes, I haven't been able to access that myself either. I'm not as familiar with the data on those, so I can't comment on the effectiveness of it, but I know it is out there.