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A Critical Review of the PLOS Study

A Critical Review of the PLOS Study: Increased Risk of Myocardial Infarction Following Initiation of Testosterone Therapy in Men

The information contained on this blog is for educational purposes only. Titles and institutional affiliation for individuals who contribute to this blog are for identification purposes only. The opinions expressed are solely those of the blog post author and do not represent the views of any organization that the post author is affiliated with or with the opinions of any other author who publishes on this blog.

Neal Rouzier, MDNEAL ROUZIER, M.D.

It was bound to happen sooner or later. I recently saw an ad on television soliciting patients by a law firm. “If you have been taking testosterone and recently suffered a heart attack, then you may be entitled to a large compensation from the pharmaceutical company that caused your heart attack. A recent study showed that testosterone therapy can cause heart attacks. Contact the experts in pharmaceutical claims to get you the compensation that you deserve.” Perfect!

Oddly enough only a few of my patients have contacted me out of the large population of men that I treat with testosterone, and I have heard from no one that stopped their testosterone. Patients seem to somehow understand that the recent media hype is just that, hype. On the other hand I have received emails (again) from several hundred physicians asking my take on the latest study and what advice I have for them. My advice is the same that I gave in November for the last negative article on testosterone: one (or two) negative observational studies of questionable power do not negate many other prior RCT’s that show benefit and lack of harm. Over 50 years of well designed controlled trials, as well as laboratory research, should not be ignored based on several observational studies of questionable design. All be it, clinical decision making should be the summation of all available data and not reflexive rejection of all past studies based on one recent observation. Had this study, or review, occurred 40 years ago it probably would be very much ignored today due to the succeeding 40 years of data after the study that supports safety and efficacy of testosterone administration. However since it is of recent publication, it catches the public eye as well as all the naysayer physicians (and legal zealots) that will jump on the bandwagon to condemn all the physicians (and patients) that take or prescribe testosterone. (Sounds just like the WHI all over again). The true challenge that we will face is to convince our peers that an MI that occurs in a man that has been on testosterone for years is probably not due to testosterone but rather the natural course of the disease. Nevertheless, there have now been several recent negative reviews (I have difficulty referring to them as studies) that should be addressed and not completely ignored. Forty years of positive studies of women’s hormones were suddenly challenged by the WHI and HERS trials that proved undiscovered harm of cardiac events in some older women (30 per 10,000) with pre-established heart disease. These recent reviews certainly require careful scrutiny but also concern if there is truly an early iatrogenic, thrombotic effect of testosterone that to date has not been evident. I therefore do not change my therapy based on several studies of weak data that is the opposite of the plethora of data showing safety and benefit. Rather, I base my therapy on a composite of many studies over several decades of research. As stated recently in Family Practice News, February 15, 2014: “The FDA has not concluded that approved testosterone formulations increase cardiovascular risk. Final recommendations are pending.” Hopefully the FDA will access all prior studies in addition to the recent study before coming to any conclusion.

A Review of the Recent Study

The gist of the PLOS study was that researchers encountered an unexpected increased incidence of MI shortly after initiating testosterone therapy. The risk was seen in older men, both with and without a prior history of heart disease, and in younger men with prior CVD. This same phenomenon was also observed in older women that started HRT in both the HERS and WHI trials, whereas we had 40 years of prior study demonstrating a protective effect of estrogen on CVD. Is there a pro-thrombotic effect of testosterone in men similar to the pro-thrombotic effect of menopausal hormones in older women many years out from menopause? Several recent studies seem to suggest this and therefore this phenomenon should not be ignored. There was also a similar pro-thrombotic effect in younger men with pre-existing CVD, whereas there was no pro-thrombotic effect seen in younger men who were healthy. This begs the question as to whether there is a pro-thrombotic effect of testosterone on diseased arteries similar to the pro-thrombotic effect that estrogen has on diseased vessels in women that start estrogen for the first time and are beyond the 10 year protective window since menopause as seen in the WHI. Oddly enough, and similar to that seen in the WHI study, after 3 months of TT the incidence of MI seemed to resolve once the men (and women) with the diseased vessels get weeded out. We then experience a protective effect on the vasculature due to the many positive effects demonstrated on lipids, lipoproteins, inflammatory cytokines, endothelium, visceral fat, and BMI. So far this phenomenon in men seems to be identical to that in women in the HERS and WHI trials with older men (and women) suffering an MI (plaque rupture) after initiation of HRT. However now we see an early and unexpected inflammatory effect seen in men with significant pre-existing disease that occurred late in the course of their vascular disease process causing rupture in plaque, destabilization and thrombosis. This effect in men, similar to women, shows that heart disease ≠ heart disease. One type of heart disease is slow deposition of plaque over years (protection against which has been clearly demonstrated for both estrogen and testosterone in multiple studies). A completely different type of heart disease that involves plaque rupture occurs only in mature plaque with a necrotic core that ruptures due to some inflammatory factor (as in matrix metalloproteinase or MMP-9) and occurs in older women with pre-established severely diseased vessels. As in the HERS and WHI, younger women that did not have diseased vessels did not suffer plaque destabilization and rupture as did older women, and these women derived CVD protection by prevention of plaque build-up. In other words, it requires healthy vessels to achieve benefit (prevention of plaque build-up) whereas diseased vessels may thrombose secondary to some undiscovered inflammatory effect similar to that caused by increased MMP from first pass effect of oral estrogen that ruptures plaque in severely diseased coronary arteries. If this truly is the same process, let us not repeat history and ignore these observed pro-thrombotic effects of HRT which can lead to an increase in CAD (plaque rupture but not plaque deposition) and CVD in women, just as we observed in the WHI and HERS trials. As we learned from the WHI, early administration of estrogen is protective and should be started early, long before some vessel becomes seriously diseased. On the other hand we really need to further investigate any possible thrombotic effect on diseased vessels so that we can avoid an increase in MI, just as we witnessed in the WHI and HERS studies. In women, avoiding first pass effect of oral estrogen by using transdermal estrogen eliminated that plaque rupture from oral estrogen as there is not any pro-thrombotic effect from transdermal estrogen as it does not raise MMP.

I have read many different posts from physicians, all criticizing the study design and rejecting the outcomes. In fact I don’t think that I have read one physician rebuttal that did not reject the design and/or findings of this study. And I agree that we should not extrapolate a poorly designed and weak study to include all men on testosterone, i.e. don’t repeat the WHI fiasco. However, rather than rejecting and ignoring this study for its flaws, perhaps we should carefully reconsider our denigration of this study, and other recent studies, so that we don’t make the same mistakes that we did by rejecting the WHI and HERS analysis. As of right now, my take on this study is that there truly might be an early pro-thrombotic effect from testosterone administration as evidenced by 3 most recent studies demonstrating such risk. There is a pattern here that should not be ignored, yet should be further studied and evaluated. This would then allow us to be most cautious in our prescribing to older men with pre-established CVD so that we don’t cause any increase in morbidity or mortality. On the other hand, we should still continue to prescribe testosterone to all younger men (and healthy older men) just as we have been doing in order to prevent the plaque from forming in the first place. Prevention of ASVD thereby would prevent any future plaque rupture as there would not be any plaque present to rupture. However, once an older man develops this unstable vulnerable plaque, it could rupture upon starting testosterone for the first time. I will still continue to do what I have been doing by prescribing testosterone to most men, but I might be more cautious in prescribing testosterone for the first time to older men that have pre-existing disease or significant risk factors for such. In women the solution is simple by avoiding oral HRT that can cause plaque rupture through first pass effect that increases MMP that is responsible for the plaque rupture. Transdermal estrogen is the simple solution/prevention in older women that have diseased vessels as later studies demonstrate excellent safety of transdermal estrogen. Therefore we avoid oral estrogen in any women that may be at risk. The answer, however, is not as easy in men as we don’t know/understand the mechanism that is responsible for the plaque rupture and I’m not sure what the solution will be. However, according to the most recent study, if you believe it, there is no risk in younger men and TRT may certainly be of benefit, according to the last 50 years of studies. And the apparent risk was seen only in the first 90 days which should provide confidence in continuing TT in current users. We should use our medical literature to guide our therapy and learn to decipher and analyze these studies, keeping in mind that one or two studies do not negate 4 decades of study and our course of therapy should be based on the summation of all the data and studies, not on just one or two contradictory studies to dictate our therapy. Years of studies prove the effect of testosterone in preventing plaque deposition which should be our goal. Preventing the plaque from forming in the first place would thereby render any future pro-thrombotic effect of testosterone improbable. However lack of that beneficial effect of testosterone in protecting the vasculature, i.e. not utilizing testosterone for its anti-atherogenic effect, may eventually lead to this pro-thrombotic effect on already established mature plaque as seen in older women in the HERS and WHI trials. Knowledge of all the studies on women’s hormones, as presented in Parts III & IV of the WorldLink Medical courses, is tantamount to understanding the mechanism by which testosterone may do the same.

In addition to the PLOS study which demonstrated harm in the first 90 days of initiation of therapy, which is the most recent published and criticized study, there was also a recent separate retrospective analysis of 8,000 men that also showed an increase in MI and CVA within the first year of therapy. In contrast to the PLOS study, this study is more similar to the WHI and HERS trials that demonstrated harm within the first year of initiating therapy. This early pro-thrombotic effect of testosterone then diminishes with time, resulting in less relative risk as time progresses which can also provide security to practitioners in not needing to terminate long-term administration. Again, as per recent FDA recommendations, men should continue their current course of treatment until final analysis is made by the FDA.

What My Study Indicates

Some others have posted criticism as to the type of study (pick and choose from a data bank without any control or randomization). Picking from a data bank sure can be fraught with error, slanted, and biased which detracts from the credibility of the study as opposed to having a randomized, controlled trial. Others have presented excellent rebuttals and criticisms. I have a very geriatric practice in Palm Springs and have an excellent patient population that provides a similar age range as did the article by Finkle et. al. In my population of older men that I have placed on testosterone, I have not encountered one patient that developed an MI while on testosterone or upon initiating it in over 15 years. It is true that some have moved or been lost in follow up, however during this time of initiation the patients are seen on a monthly basis and not one patient reported to us on follow up that an MI occurred. I had taken over a practice of 5,000 established patients. Out of this population, I have treated approximately 2,000 men and with an average age of 60-70 (that certainly would have included by chance many men with pre-existing heart disease). I feel confident that the population that I have scanned is quite similar to the one published in PLOS. When I took over my current practice, I solicited all male patients with the intent of initiating testosterone for purely preventive medicine reasons and cardiovascular protection, compatible with so much of the literature in the past 15 years. I thought that I was providing an excellent preventive service and treatment that which most physicians were unaware. The current search of my patient population also included new patients that were of varying age groups, some of which included older men similar to the age range of my pre-existing patient population. Just from natural selection, I would have imagined that at least one man would have ruptured plaque and had an MI, yet I did not find that in my records. More importantly, however, not one patient had suffered an MI after initiation of testosterone in my 15 years of treating men. The PLOS study demonstrated that in older men, as well as in younger men with pre-existing CVD, the risk of MI following initiation of TT is substantially increased. In my cohort of approximately 2,000 patients, which I feel is an excellent older cohort of men to search and evaluate, I did not find one patient that experienced an MI, either immediately after initiation of TT or thereafter. My patient population was quite small (2,000) in comparison to the large number (55,000) studied in the PLOS. Nevertheless I did not encounter any adverse event in the last 15 years. Of course my study is not a study, rather it is an anecdotal observation of “my” patient population which I feel is fairly well representative of an older population that might be prone to plaque rupture, but they didn’t! My study shows no increased risk of MI and prolonged safety of therapy. However it is an observation, not a RCT, and that’s all that should be surmised from my study population. Maybe it was the clean desert air that was protective and not the testosterone? Perhaps my caring staff was the protective effect? Regardless of whatever association I might claim, it does not prove that anything that I did, including administering testosterone, resulted in any protection or benefit and any claim by me is only speculation.

The same critique of my study applies to the PLOS: small sample, subject to selection bias, so on and so forth. Everyone in every post has their own take or criticism of the PLOS article by which they reject the results or conclusions (and extrapolations) of the study. Nevertheless, three recent studies have raised some concerns about possible adverse cardiovascular outcomes from TT, especially myocardial infarction, and we should not ignore this. A meta-analysis of smaller studies also suggests an increase in cardiovascular risk. The recent VA study also reported an excess of events, however an identical study in a similar VA cohort 2 years ago did not. We should keep in mind though that these are observational studies in design, and other recent more powerful controlled trials did not show cardiovascular harm which has supported the long term safety seen in 40 years of study. I cannot emphasize the importance of realizing that one or two negative studies, that are weak studies in contrast to RCT’s, do not negate all of the past 40 years of positive studies that demonstrated the opposite of this study and that are RCT’s with more power and predictive value. A recent statement from the AACE is right on when they suggest that physicians and patients not jump to conclusions and stop the testosterone prescription, rather patients should continue taking testosterone until further evaluation and review by the FDA is complete. The PLOS study creates more questions than answers, but we should not change 40 years of practice and positive studies based on several observational studies. However we should not ignore them either.

The Issue and Concern of Recent Studies

The issue and concern with several of the recent studies, though, is the increase in events that appear very soon within 3 months of initiation of TT. This is similar to the harm seen in the first year of initiation of HRT in older women with pre-existing CVD. For decades the medical literature supported a protective effect of estrogen against cardiovascular disease. The medical establishment was shaken when 2 studies (HERS & WHI) demonstrated increased cardiovascular harm in older women with pre-existing disease that was felt to be due to plaque rupture from the enzymatic degradation of the inner necrotic core by MMP production through first pass liver effect that occurred within the first year of initiating HRT. Utilizing transdermal estrogen, and avoiding the first pass effect of oral HRT, has resulted in no further risk (plaque rupture) by HRT in older women that initiate HRT more than 10 years after menopause which is the time frame for them to develop mature vulnerable plaque that can rupture by enzymatic degradation by MMP-9. The current studies on TT have the same pattern of risk enhancement soon after initiation of therapy which is consistent with an effect of the drug on thrombosis. This underscores the concerns of initiating TT in men with pre-established disease as evidenced in these recent studies, and particularly in older men as well as younger men with more extensive coronary vascular disease. On a good note, and similar to the results seen in the HERS and WHI trials, this early pro-thrombotic risk diminishes with time such that after 90 days of therapy the risk decreases and TT (and HRT) become protective. This appears to be same with TT and it makes no sense to stop TT if there is a long-term protective effect once men pass that 3 month window of harm. This bodes well for both patients and practitioners in that once they have been on the therapy for 90 days, any risk subsides and therapy thereafter does not appear to be harmful. As the result, stopping TT does not appear to be indicated in men once they have been on TT for a period of time, and TT is protective once the patient is past that critical window of plaque rupture, and this applies to both men and women.

On the other hand, a plethora of data and studies supports that low endogenous levels of testosterone may be positively associated with cardiovascular disease. Many RCT’s have demonstrated the protective effect of testosterone replacement, both on symptomatic improvement as well as CVD progression. I refer you to my prior post from November 2013 where I listed many of those trials providing evidence and confidence for those of us that continue to prescribe TT for health and wellness. However I urge caution in prescribing TT to any man with pre-existing CVD or to one that may have the undiagnosed disease with many risk factors. On the other hand it does not make sense to prematurely stop TT once a patient has passed the critical window of plaque rupture which seems to be 90 days, as per the recent studies. Utilize extreme caution when initiating TT and perhaps do further work up and evaluation to discover any undiagnosed CVD and thereby use caution in initiating therapy as well as thoroughly discussing the issues and concerns with the patient. Given the popularity of TT, the current study emphasizes the urgency for further study of this early pro-thrombotic effect and the need for addressing the potential risk of TT in men with pre-existing CVD.

Lastly, and beyond the scope of this review, I found the comments from the many posts amazing, entertaining, fascinating, and troubling as to the proposed mechanism of harm of testosterone. These will be addressed in a separate post but briefly mentioned here. Similar points/concerns/causes for the increase in risk of CAD were also addressed by the authors of the PLOS study. However, most physicians do not understand the effects of testosterone on erythrocytosis or aromatization into estrogen, both of which are incorrectly claimed to result in thrombosis and clotting. Testosterone does not cause polycythemia, RBC clumping, hyperviscosity, or platelet aggregation as they surmised. Polycythemia (PV or polycythemia vera) does cause the foregoing, however testosterone does not cause polycythemia, rather testosterone produces physiologic erythrocytosis via increase in erythropoietin produced in the kidneys. Unfortunately everyone mistakenly makes claim that testosterone causes PV but it does not. See the this article on polycythemia vera and my article on polycythemia vs. erythrocytosis. If erythrocytosis truly caused thrombosis and “RBC clumping”, then we would witness a later and persistent effect on clotting as erythrocytosis (increase in RBC’s) occurs after several months of therapy and not much during the first three months of therapy which is the time frame of harm in the recent study. Therefore if erythrocytosis were the culprit, then we would continue to see the thrombosis escalate as time progresses but we don’t, either in this study or other long-term studies. The effect on thrombosis should escalate as the erythrocytosis progresses but it doesn’t. More importantly, if erythrocytosis truly caused clotting and RBC clumping, then everyone that lived at altitude (above 5,000 feet) would experience an increase in CAD, CVD, and RBC clumping and clotting. If this did occur, then everyone would run to the beach and not live at altitude. In addition, every patient with COPD with physiologically high RBC counts due to hypoxemia (which I see in the ER daily) would have significant increases in MI and CVA yet we don’t see that either. If we phlebotomized every COPD patient with erythrocytosis, they would all die from hypoxia. Physiologic erythrocytosis is never harmful, only beneficial, otherwise we would phlebotomize everyone that lives at altitude but we don’t. Testosterone causes the same physiologic effect as living at altitude and the effect is only on RBS’s, not platelets. Polycythemia is different and PV is not physiologic erythrocytosis. Polycythemia vera is an increase in multiple (poly) cells including white cells, red cells, and platelets with the resultant splenomegaly, not seen with testosterone use. It is the platelet count of over a million that causes clotting, not high RBC’s. Unfortunately we monitor phlebotomy by hemoglobin counts, and not by platelet counts, which makes us intuitively think that it is the RBC that is the important factor to lower whereas it is the high platelet count that is the culprit and not the high hemoglobin. Just because we monitor RBC counts and adjust phlebotomy based on H & H does not mean or prove that high hemoglobin causes any morbidity or mortality, as does PV. Phlebotomizing lowers platelets and that is the beneficial effect in protecting against thrombosis. The meta-analysis from the NEJM demonstrated that in over 40 years of studies on testosterone therapy, not one study showed any thromboembolic event to date. Polycythemia is a blood cell dyscrasia that causes increased clotting, DVT’s, cancer, myelofibrosis, myelodysplasia, and progression to leukemia. Does any study show that testosterone causes any of this? Absolutely not and therefore testosterone does not cause polycythemia, or an increase in WBC’s or platelets or splenomegaly, in spite of the literature incorrectly stating testosterone causes PV. Multiple published papers mistakenly claim that testosterone causes polycythemia whereas testosterone only causes erythrocytosis and patients should receive the same therapy as those with erythrocytosis that live at altitude-nothing. I recently treated a prominent physician who was overly phlebotomized by a prominent clinic which resulted in extreme fatigue, with a serum iron level of 5 and a ferritin level of 2! IV iron (Venofer) completely resolved the year long fatigue and the physician swore never to phlebotomize again. I’m still searching for that study that demonstrates high H & H with normal platelet count causes harm. Erythrocytosis is not PV and testosterone does not cause PV, regardless of the incorrect claims. My hemoglobin has been above 19 since I was 20 because I have worked and trained at a ski resort since I was 20. My platelet and white counts are normal. I once saw a Sherpa that had a hemoglobin of 23 as he frequently traveled between 20,000 to 30,000 feet. Phlebotomizing patients with PV saves lives as evidenced in the attached article. No study has ever shown benefit to phlebotomizing anyone with physiologic erythrocytosis and normal platelet counts.

Estrogen in Men

Last year I presented this lecture at AMMG on estrogen in men. It is commonly accepted that estrogen should be lowered in men due to the cardiovascular complications of high estrogen in men. Nothing could be further from the truth. You may view the lecture at WLM.com. Understanding that observation does not prove causation is paramount to understanding that estrogen does not cause harm in men. Every interventional trial (except for high dose DES) where estrogen has been administered to men has prevented heart disease, both for oral as well as transdermal estradiol. Every long-term study whereby estrogen is elevated through aromatization of testosterone into estrogen has resulted in cardiovascular benefit. Every study where estrogen is blocked or lowered has resulted in harm. Lowering estrogen in men has shown to increase the risk of cardiovascular disease, DM, lipid abnormalities, memory loss, Alzheimer’s disease, bone loss and osteoporosis, and loss of libido and EF. Raising estrogen in men, either via testosterone administration or estrogen administration, has shown protection against the foregoing. I was once tickled by an attendee’s comments that we only want to lower estrogen a little bit. Translation: you only want to increase the risk of CAD, CVD, osteoporosis, DM, and ED a little bit? The estradiol level of a young is 75-90 pg/ml. Should we start blocking estrogen in young men? View the lecture on the harm of using aromatase inhibitors in men.

The authors of the PLOS study site the same observational studies, as does Life Extension and everyone else, where high estrogen levels in men are associated with increase in CVD. (Remember association does not prove causation). However, it is the increase in visceral fat that increases the production of estrone, and concomitantly estradiol, which only proves an association and not causation. In order to prove causation, one must intervene and administer estrogen. The results of the interventional, randomized trials prove the opposite of the observation that high estrogen is harmful. It is the increase in visceral fat, insulin resistance, inflammatory cytokines, and lipid abnormalities that cause the increase CVD risk, not the claimed estrogen elevation. And how do we then prove that? The answer is simply to intervene and administer estrogen in an interventional trial and observe if the increase in estrogen proves causative or protective. Every study (except the high dose DES) proves a protective effect of raising estrogen, and that applies to both oral and transdermal estrogen. It has been shown that the cardioprotective effects of testosterone are related to aromatization to estrogen. Block the testosterone and the cardioprotective effect of estrogen persists. Raise testosterone and block estrogen and the cardioprotective effect will thereby be eliminated as well as all the beneficial effects on lipids and lipoproteins. Every study whereby estrogen is raised by testosterone administration has resulted in long-term cardiovascular protection. The randomized trials whereby estrogen was administered to men resulted in cardiovascular protection. (View the lecture on line). The randomized trials whereby aromatization is blocked by anastrozole result in loss of CVD protection when estrogen is lowered. So then why is everyone promoting blocking estrogen when studies show harm to lowering estrogen and other studies show benefit when we intervene and raise estrogen? The reason is simply because they don’t understand the literature, the difference between observational vs. randomized trials, or the concept that observation does not prove causation, and the fact that multiple RCT’s prove estrogen’s cardiovascular protective effects, and that observing high baseline levels of estradiol in obese men with heart disease does not prove anything.

Do Not Extrapolate Effects of Oral Estrogen

Finally one should not extrapolate the first pass effect of oral estrogen on clotting factors to be the same as raising estrogen via aromatization from testosterone or by transdermal administration. The effect on clotting and clotting factors from oral estrogen is through the first pass liver effect. Transdermal estrogen has never been shown to have the thrombotic effects of oral estrogen, and neither has testosterone. The PLOS authors do make this mistake as testosterone, with the aromatization into estrogen, has never been shown to raise clotting factors, lower clotting inhibitors, or increase clotting as does oral estrogen, yet these authors make claim that raising estrogen via aromatization is the mechanism for the increase in thrombosis. Their extrapolation to testosterone causing the harm of oral estrogen and polycythemia is without any basis in fact.

Although many articles have many postulated theories as to the cause of this newly discovered plaque rupture in recently treated men, we do not understand the mechanism as of yet. Perhaps some form of testosterone has a similar effect in raising matrix metalloproteinase as seen with oral estrogen thereby causing plaque rupture? Until that research is conclusive, speculation should be careful and cautious. In the interim we must be careful in administering testosterone to older men that may have significant cardiovascular disease. However don’t throw out 40 years of studies that demonstrate long-term cardiovascular protection by testosterone therapy. Treatment should be prevention in the first place by early administration of testosterone and continued indefinitely as per 40 years of study, and then we would never have to worry about that plaque rupture in the first place. Evidence, not conjecture, should guide clinical practice and policies. And don’t extrapolate evidence or conjecture.

– Neal

Related Resource:

The Institute for Continuing Healthcare Education
A Panel Discussion on the Importance of Early Diagnosis for Myeloproliferative Neoplasms

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