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Testosterone Risks

I have had a great experience with HRT (TRT) overall.  It has been a life changer - positively of course - and helped me in my relationship with my wife, my career and I am convinced my general health and personal psychology.  That said, I had absolutely no idea what I was doing when I got on testosterone and no doctor ever told me about any of the risks associated with it.  I personally was blindsided by an issue, for example, that I will discuss below. 

Why do physicians not give full disclosure?  Well, many of them simply know very little about testosterone therapy and are on end the early stages of the learning curve.  Still others feel financially and time constraned.  Finally, it is clear to anyone following the industry that there are many out there who just want to grab your money before they tell you about any potential issues.  Many of you have seen very aggressive advertisements from testosterone manufacturers and HRT clinics for example.

NOTE:  HRT has its risks, but it also has incredible potential rewards.  I cover those in my page called The Benefits of Testosterone.

So "eyes wide open" as I always say and please scan through the STEP 10 of my Examining Your Testosterone Program, which includes these Ten Significant Risks of Testosterone Therapy and then discuss with a (hopefully knowledgeable) physician:

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1. What if Have to Go Off of HRT?  I was stunned one day by my HRT clinic.  They were the ones that started me on testosterone cypionate and cypionate powerfully changed my life for the better:  it vanquished my dysthymia (mild depression) and gave me morning erections for the first time in my life. My libido went through the roof; my boss commented how much easier I was to work with; and my erectile strength improved, etc.

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However, everything came crashing down when my HRT clinic told me that I had a PSA read of 6.3 - my baseline was 1.4 or 1.5 - and that I had to immediately quit testosterone until I got urological clearance. I was horrified.  Not only might I have prostate cancer, but, even if I didn't, I had to have a prostate biopsy and no T for an indefinite period of time.  One month after quitting HRT, my testosterone was 111 ng/dl!  That was probably about an eighth of my average testosterone over the last year.  I was miserable when my testosterone was in the low 300's and I could not bear the thought of living with levels in the 100's and 200's for months and months.. 

The story has a happy ending.  I was able to go back on HRT - they found inflammation and no cancer during the biopsy - and all seems to be well as my PSA has since dropped down to 1.9.  But it was a very sobering experience and very stressful.  (You can read about the details in my page on High PSA But No Cancer.)

On the Peak Testosterone Forum, this is not a very common issue, but it certainly can happen. Furthermore, considering that prostatitis can raise PSA very significantly, the percentage of men on TRT facing the issue over many decades can probably be significantly magnified. In addition, there are other issues that I have seen take men off of HRT: high, persistent hematocrit / hemoglobin and high blood pressure. Some men cannot get these in line even if they donate blood and thus are forced off of HRT due to stroke/heart attack risk concerns.  Still other men find that testosterone raises their blood pressure and/or pulse.  So discuss these kind of risks with your physician before you go on HRT and find out how he or she handles it.

2. What If I Feel Nothing?  Being forced off of testosterone therapy (#1) is not all that common.  However, I quite often get asked the following question:  "when will I feel something?"  A significant percentage of men have one of two scenarios happen:

a) After three months, they notice little change from HRT, i.e. no real benefit.

b) They had some improvements for a few days or weeks, and then the honeymoon phase was over and they have felt nothing for several months.

Sometimes these can occur because of a lousy protocol.  However, that is certainly not always the case.  There are many other reasons that HRT can have little effect, but I would guess the most common is that more than one issue is going on.  If a man has gut issues, sleep disorder, high prolactin, insulin resistance, hypothyroidism, etc., these can override any benefit that a man might get from increasing testosterone.

Other reasons are low SHBG, which makes HRT much more difficult to dial in.  In addition, some men just don't need high levels of HRT.  We had one younger man on the Forum who really struggled with HRT and then just decided to go off of it.  He felt fantastic almost immediately! 

3. Possible Decrease in HDL?  There are a few studies that show that testosterone can lower HDL.  On the other hand, there are more studies that show no change, except perhaps at supraphysiological levels, i.e. > 1200 ng/dl.  Testosterone improves many cardiovascular parameters, so some say this concern can be dismissed.  I think a more prudent approach is to take an HDL read before and after HRT and see if it is an issue for you individually.  It probably won't be, but you never know until you check.  You can use my page Testosterone Labs for inexpensive self-testing if you need to.

4. Partial Shutdown of Various Hormones. Exogenous (outside-the-body) testosterone therapy will partially turn off signaling at the hypothalamus.  And this, in turn, turns off (partially) the signaling that goes to the pituitary. Theoretically, only the testosterone cascade should be affected by this.  For example, we do indeed see the sister pathway shutting down fertility in men.

But can this shutdown affect other hormones, such as DHEA, progesterone and cortisol?  These should not be affected, but some men have reported decreases in these hormones.  Furthermore, one of the most well-known HRT physicians out there has reported that DHEA often shuts down and thus prescribes the same for most of his men on testosterone. 

I know that I have been on cypionate for a couple of years and my DHEA was quite low - basically at the bottom of the scale.  I can also tell you that I feel very good, though, and I would never have known it if I hadn't taken the measurement simply out of curiosity.  But on the Peak Testosterone Forum we have seen men experience nice improvements in libido and/or morning erections using DHEA, so this could definitely be an issue.  Low cortisol can also be a very negative issue, leading to tremendous fatigue.

5. Can I Get My Old Testosterone Level Back?  Let's say one has to go off of HRT.  We all assume that, after a few months of pain and suffering during the rebound period, we will get our old baseline testosterone levels back, right?  For example, I was always in the lower 300's before I went on HRT.  So, if I quit HRT for some reason, I would expect to go below 300 for several months and then come back to the lower 300's at my old baseline level.  Unfortunately, this appears not to be a given.  Some men, especially older, never bounce all the way back apparently.

NOTE:  This probably can be avoided by simultaneously going on HCG, which keeps the testes active and restores volume.   However, if the pituitary is more the problem, then this may not be particularly helpful.

6.  Existing Hypertension.  I do not have a study to prove this, but I have spoken to a doctor and, separately, an HRT clinic that stated that some men with hypertension will actually experience a rise in blood pressure after receiving testosterone therapy. In fact, the doctor was quite upset, because she had heard that some of the HRT clinics were not monitoring blood pressure and that taking vitals is an obvious and necessary protocol during any medical exam.  And she had a point:  perhaps some clinics will get themselves into trouble by ignoring this easy step.  The bottom line:  if you have high blood pressure, this is something to discuss with your doctor if you are considering going on HRT and something to be monitored during your therapy.  And, by the way, I have seen this many times on Peak Testosterone Forum.

7. Blood Clots. This great interview of Dr. Glueck reveals a potential issue with HRT: blood clots. As testosterone increases, estradiol increases and many men are put on an aromatase inhibitor (or sometimes a SERM), all of which can increase the risk for a DVT / clot. Dr. Glueck states that as many as 1-2% of men may be at risk. Now I have not heard of clotting being a big issue, but I know that my clinic is considering raising their estradiol thresholds from 20-30 pg/ml to 25-35 pg/ml for just this reason. The key takeaway from this is that Dr. Glueck recommends that a man have four tests before undergoing HRT:

  • Factor V Leiden
  • Prothrombin gene
  • Factor VIII
  • Factor XI
  • 7.  Pain.  This is not common, but occasionally HRT can cause pain, especially if done poorly. In my link on Testosterone Therapy and Pain, I discuss nipple, joint and other issues that occasionally crop up. (I suspect these are usually caused by estradiol mismanagement however.)

    8. Cardiovascular Disease Risk?  A couple of years ago, testosterone manufacturers were on the ropes:  two negative studies had come out showing that testosterone therapy could increase cardiovascular disease. These studies were widely criticized, but class action lawsuits began forming against the pertinent pharmaceutical companies.  Interestingly, the FDA published a refutation of these studies and, in the meantime, two positive testosterone therapy-related studies came out. Plus, the research shows that testosterone improves many CVD parameters as well, such as insulin resistance, inflammation, hardening of arteries, etc. Of course, discuss this issue with your physician, as it is his or her job to stay abreast of the latest research.  And keep in mind that, if you have a clotting disorder, you are likely in a special category.  There is also another potential concern with injections, something I discuss in #9 below.

    9. Injection Risk.  The most common form of HRT on the Peak Testosterone Forum is testosterone cypionate and enanthate injections.  Of course, I doubt that is the norm in the U.S. and it definitely is not in many other countries.  But it bears pointing out that a recent study showed that injections were more risky for cardiovascular issues than topical (transdermal) HRT.  My guess is that this is due to the fact that most injections done by endocrinologists and PCPs (from what I have seen) are on a two week schedule and massive doses of testosterone are given.  These huge doses also shoot up estradiol levels, and estradiol is a well-known clotting risk factor for both men and women.  I discuss this in a separate section below.

    10. Feeling Worse on TRT.  Some men just never feel good on TRT.  And, oddly enough, when they go off of testosterone therapy, they feel much better and are glad they got off of it.  Now one could argue that this is because they had a lousy protocol.  On my page Feeling Worse on Testosterone Therapy, I discuss some examples where, in my opinion, it likely was not the protocol that was the root cause of the problem: these guys probably should have never been on testosterone in the first place.

    11. Oxytocin. Oxytocin is a "good" hormone and a must-read page for any guy is my page on Sex and Oxytocin. But oxytocin's importance goes way beyond the fact that it is released upon orgasm and can even be used to heat up your woman. Researcher Paul Zaks has made huge discoveries about this hormone and found that it, quite literally, is "The Moral Molecule". Oxytocin allows us to trust others, empathize, be generous and give to charitable causes. I highly encourage you to Watch This Video to see a nice summary of his research in this area.

    What he points out is that testosterone tends to lower oxytocin and thus this could be theoretically be socially undesireable.  However, as I point out in my page on Testosterone and Empathy, the evidence shows that men with normal testosterone and DHT levels also have perfectly normal empathy levels.  However, going too high with either of these could potentially be an issue.  This is important, because topicals often raise DHT to supraphyiological and some men go too high with testosterone as well.

    12Existing Kidney Disease.  One potential contraindication that does not seem to be well known is the fact that may experts think it is unwise to give HRT to men with significant kidney disease. Basically, testosterone could aggravate the kidneys in this case and potentially cause issues for men with existing renal issues. Basically, testosterone stimulates the kidneys and could cause issues for men with existing renal issues.  This likely explains one of the reasons behind #4 as well.

    13. Negative Psychological Effects and Even a "Freak  Out". Testosterone really affects the male brain.  Generally, the changes are very good as mood and libido are lifted and depression, anxiety and mental fog are decreased.  However, sometimes the changes are overwhelming and can induce very disturbing emotions and psychological states.  Some men actually get more depressed and find that their mood is negatively impacted.  This may be from high estradiol - many doctors mistakenly do not manage or monitor this ultracritical hormone that rises with HRT - or from the above shutdown process.  But this is not always the case. 

    I also want to mention that every once in awhile a man will have a really "bad trip" from HRT.  It's not common, but it does happen.  Look at what this poster wrote after receiving testosterone pellets:

    "On the day 5 after insertion in the evening I suddenly felt an agitated state of mind, and tension. It almost feel like I have intoxication and high blood pressure. I woke up at night with heart palpitations, uneasy feeling in heck/head, and feeling of being depersonalized, as if things were happening not in this reality. I never felt anything like that before. It was scary/horrifying. This night I slept maybe 3 hours total. In the morning I started to feel that it is getting worse. In fact, symptoms resembled heart attack. So I went to GP, she measured blood pressure – 122/74, normal. Pulse rate was elevated to about 100. So it appeared to be an anxiety/panic attack."

    "I called the urologist and asked him what is happening. His reaction was – it cannot be Testopel. He said it has been less than 10 days, you cannot even feel the effect of it yet. But I insisted on checking levels of testosterone and estrogen. The test came back as testosterone – 500, estrogen – 39. Urologist said, T level is good, and E is in the range. So everything is going like it should. But I have experienced during these days series of mood swings, where I go from super-focused, clear-minded to crying spells for no reason, feeling sad and extremely down. Mind fog, depersonalization/derealization also visited me a few times. Also, my sleep pattern changed drastically. I could sleep 4 hours a night, wake up at 5 am, and not be tired all day. " [3]

    Now the above is an extreme case, but a significant percentage of men feel worse psychologically post-testosterone therapy, even when on a decent protocol.  Some feel more depressed or have increased anxiety. 

    12. Topical Cardiovascular Risk. I've never tabulated it, but my guess is that most men coming to the Peak Testosterone Forum have either tried or are currently using one of the topicals, i.e. testosterone therapy applied to the skin such as Androgel, Testim, Fortesta or Axiron. With Abbott Labs behind Androgel, the word has made it out to PCP's, urologists and endocrinologists. Many doctors who would not have been comfortable with HRT even five to ten years ago are now prescribing these products much more consistently.

    What is ironic is that it is these very products whose safety is now somewhat in question. Yes, they broke the market wide open and may bring more scrutiny to HRT than even issues like prostate cancer have. [1] The study basically looked at 203 "community dwelling" men, meaning seniors in a community center of course, and these men had very high rates of high blood pressure and cardiovascular and respiratory disease. 

    Now one would expect that giving these men testosterone would be of huge benefit, because testosterone's sweet spot is heart disease and, to a lesser but still significant extent, blood pressure.  As I discuss in in my link on Testosterone and Heart Disease, low testosterone is a risk factor for arteriosclerosis, increased cardiac mortality and high blood pressure. Furthermore, testosterone replacement therapy in such men has done quite well in the studies and has helped correct all of the above.

    However, what occurred in this study took the researchers totally by surprise: 23 of the men on testosterone had cardiac events compared to only 6 in the control group. Admittedly, the study was small in size, but this was an alarming increase by almost any standard, especially when one would expect the exact opposite result! And a question apparently plagued one of the leading labs: where was the missing testosterone?

    ZRT labs, who apparently has built an extensive database of testosterone measurements and usage for a wide variety of products, came to an alarming conclusion: capillary testosterone in the extremities is 30-50 times higher in the capillary and small vessels of the extremities than that seen in healthy young men or men on testosterone via injections or pellets. [2] For reasons not yet understood, the topical application of testosterone allows testosterone to "pool" in the small vessels. Thus, plasma levels can appear to be reasonable, the testosterone in end point extemities is "through the roof" and estradiol as well. ZRT labs believes these ultrahigh estradiol levels could be responsible for the adverse events.

    A 2015 study showed that topicals, interestingly enough, were more safe than injections.  However, my guess is that this is due to the fact that a big percentage of doctors use a massive every two or three week cypionate or enanthate protocol that really spikes estradiol, and Med School 101 covers the fact that estradiol increases clotting risk all things being equal.  But the bottom line is that ZRT Labs concerns may not have played out.

    UPDATE: A recent study actually topicals to be more safe than injections. This is an involved issue but somewhat exonerated these concerns about topicals. See my chapter below on the subject.

    REFERENCES::

    1)  N Engl J Med, 2010 Jul 8, 363(2):109-22. "Adverse events associated with testosterone administration"

    2) http://www.zrtlab.com/blog/entry/testosterone-elixir-or-dangerous-drug  

    3) http://peaktestosterone.com/forum/index.php?topic=1250.msg11895#msg11895

     

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