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BackTable / Urology / Article
Optimizing Testosterone Treatment: Clinician Perspectives & Therapeutic Innovations
Olivia Reid • Jan 3, 2024 • 79 hits
Urologists Mohit Khera and Jose Silva highlight the critical nuances in testosterone therapy. They stress the importance of managing estrogen levels alongside testosterone administration, advocating for targeted use of aromatase inhibitors to maintain optimal ranges without complete suppression of estrogen. Dr. Khera details considerations for patients seeking fertility preservation, explaining protocols to transition from testosterone therapy to endogenous testosterone, combining HCG and medications like clomid.
Additionally, the intricacies of oral testosterone formulations are explored, giving rise to pills that can be taken one to two times daily with limited risk of liver toxicity and erythrocytosis, increasing both safety and convenience of testosterone treatment. Dr. Khera and Dr. Silva emphasize the significance of patient education and tailored approaches in testosterone therapy.
This article features excerpts from the BackTable Urology Podcast. We’ve provided the highlight reel in this article, and you can listen to the full podcast below.
The BackTable Urology Brief
• It is important to evaluate estrogen levels when beginning testosterone treatment prior to starting an aromatase inhibitor, due to the role that estrogen plays in male sexual function and bone health.
• There are several options for minimizing a patient’s risk of infertility when undergoing testosterone treatment, including the use of HCG and clomid, as both work to preserve fertility while allowing for symptomatic relief.
• New oral testosterone formulations like Kyzatrex (Marius), Jatenzo (Tolmar), and Tlando (Halozyme) allow for an enhanced efficacy and safety profile, with minimal hepatotoxicity concerns compared to older formulations.
Table of Contents
(1) Testosterone Treatment: Managing Estrogen Levels With Aromatase Inhibitors
(2) Testosterone Treatment & Fertility Considerations
(3) Advancements in Oral Testosterone Formulations
Testosterone Treatment: Managing Estrogen Levels With Aromatase Inhibitors
When patients are undergoing testosterone treatment, it is crucial to measure estrogen levels prior to initiating an aromatase inhibitor. Dr. Khera advocates for a targeted approach to maintaining estrogen within the optimal range of 30 to 50. There is often a misconception in which patients are immediately started on aromatase inhibitors alongside their testosterone treatment regime, yet it is important to look at the whole picture, allowing for personalized management of hormones based on individual levels. With this, Dr. Khera suggests low doses, between 0.25 and 0.5 milligrams weekly, of aromatase inhibitors if necessary to regulate elevated estrogen levels.
This is due to the pivotal role that estrogen plays in male sexual function and libido, according to Dr. Finkelstein's study in the New England Journal of Medicine. Furthermore, both LH and FSH levels need to be checked before deciding on hormonal therapy, as there are different treatment approaches should these levels be elevated. The conservative use of aromatase inhibitors decreases the potential risks of osteopenia and osteoporosis that can result from estrogen suppression.
[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.
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Testosterone Treatment & Fertility Considerations
Preserving fertility when undergoing testosterone treatment is often a major concern for many male patients. One of the ways in which infertility can be reversed following treatment involves tapering the testosterone regimen gradually to minimize withdrawal symptoms while simultaneously using HCG with Gonal-F or clomid to restore endogenous testosterone. This allows for chances of conception to increase, following a three to seven month period of spermatogenesis recovery post-tapering. The success of HCG and clomid is dependent upon the presence of functional testicles, meaning that the treatment efficacy is often impacted in older patients who have diminished Leydig cell function. Additionally, there are limitations with clomid in regards to the male libido and estrogen receptor blockage in the brain.
With this, Dr. Khera suggests that lifestyle changes like weight loss, improved sleep quality, and increased exercise should be investigated prior to the aforementioned therapeutic options. Due to the concern of infertility while managing symptoms of low testosterone, there are emerging treatments like nasal testosterone formulations which may be able to limit the impacts of the testosterone on sperm production. Overall, patient-centered approaches in testosterone treatment should be the focus because of the lifelong treatment implications of varying the hormone’s levels.
[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.
Advancements in Oral Testosterone Formulations
The formulations for testosterone have evolved over the years, working to decrease the risks associated with oral treatments and increase the efficacy simultaneously. The first oral testosterone treatment involved methylated oral testosterone which was found to be very dangerous due to its association with liver toxicity. This evolved in the 1970s to Andriol, an oral testosterone undecanoate, which decreased the risk of harmful side effects by bypassing liver metabolism yet still required patients to consume a large, fatty meal prior to taking the medication and take the pill three to four times each day.
There was a delay in FDA approval in the United States for the aforementioned medication, ultimately giving rise to newer formulations such as Kyzatrex (Marius), Jatenzo (Tolmar), and Tlando (Halozyme) in the late 2010s; each of which offered ease of administration, reduced hepatotoxicity concerns, and lower rates of erythrocytosis. Additionally, the newer medications align with patients' preferences for pill-based regimens and minimize some of the side effects related to the spikes in testosterone levels from injectable treatment methods.
[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.
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.
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