Written by Dan Gwartney, M.D.
21 May 2014
[h=1]Testosterone Replacement Scare: False Alarm?[/h]
Public access to accurate and unbiased information is essential. While conspiracy theorists wish to believe that a shadow government of Illuminati controls our very thoughts, often the misinformation campaigns are more benign. Newspaper publishers and broadcast news channel executives direct what news the public is exposed to and how it is presented; Jon Stewart had a nice comical rant about this on “The Daily Show” some years ago. If this influence skews the presentation of the facts to confirm one side’s opinion rather than reality, that is called media bias.
The government does control a great deal of the scientific information and clinical guidelines through its control of research funds, FDA approval process, and all the backroom “nudge & wink” shenanigans. For some, this works to their benefit— for example, LDL cholesterol-lowering or erectile dysfunction drugs; others are impeded, e.g., weight-loss drug developers and female libido support. Perhaps the most egregious insult has been to testosterone.
The history of testosterone and [COLOR=#6F0303 !important]anabolic-androgenic steroids (AAS) dates back to the 1930s; unfortunately, so does the history of abusive or dangerous experimentation with these drugs. The parent compound for AAS is testosterone; its role in men’s health, not just quality of life, is difficult to dispute. Several studies have shown that men suffering from hypogonadism (low testosterone) experience greater rates of depression, erectile dysfunction, the metabolic syndrome, and premature death— all conditions that have great impact on individual well-being and national health care expense.[SUP]1[/SUP] Yet, confirmed or suspected benefits of testosterone or other AAS do not appear in headlines or on primetime news. Instead, what makes news is the association with individual tragedy (e.g., adolescent suicide), seemingly forced affiliation with crime or high-risk behavior, or violations by sports celebrities.[SUP]2,3[/SUP][/COLOR]
An example of varying media presentations of testosterone was the coverage given to the halting of a testosterone trial involving elderly men whose health was sufficiently compromised to limit their ability to walk or climb stairs. A brief review of the study and comparison of the words of the authors versus those of the media will demonstrate how facts, or the lack thereof, can alter public perception. The New England Journal of Medicine— one of the most highly recognized and influential medical journals— published a report of the early termination of a testosterone trial involving hypogonadal men over 65 who had limited mobility (unable to walk two city blocks or climb 10 stairs).[SUP]4[/SUP] The purpose of the trial was to determine whether such men could benefit from the strengthening effects of testosterone— increasing mobility, improving quality-of-life and health.
As expected, compared to the control group with testosterone concentrations ranging from 100-350 ng/ml, men who were being treated for six months with testosterone gel to maintain testosterone in the 500-1,000 ng/ml range became stronger and more capable of performing physical tests. However, during the course of the study, a number of men suffered from problems that required medical attention. Appropriately, the investigators unblinded (decoded) the groups— discovering more problems in subjects from the testosterone-treated group. They submitted data to the safety committee— who combined certain events, and decided that the testosterone-treated group was suffering serious cardiovascular events more frequently than the control group. At that time, the study was terminated.
Terminating a study is a fairly rare event. Months, even years of preparation go into a human clinical trial; these types of studies are also very expensive, costing in excess of $1,000,000— likely several times that number. Yet, it was appropriate to stop the study to evaluate this unexpected and unexplained trend.
Confusing Study Results
The authors, including some of the most prolific researchers in the field of testosterone, were perplexed. To begin with, the randomization process that is designed to prevent the groups from being different from each other failed to account for some relevant factors. All subjects demonstrated serious health impairments including advanced age, hypertension, diabetes, hyperlipidemia (high cholesterol or triglycerides), and obesity. Further, subjects were very limited in how much activity they could tolerate, being unable to climb a flight of stairs or walk two city blocks. With an average age of 74, both the testosterone and control groups consisted of unhealthy, older men. However, subjects who were treated with testosterone gel, and suffering a greater rate of infirmity, demonstrated certain conditions that placed them at a greater risk of cardiovascular injury.
Hyperlipidemia is a medical term that refers to dangerously high concentrations of cholesterol, bad cholesterol, or triglycerides (blood fats). The disorder is treated with drugs that have become household names, such as Lipitor. People with hyperlipidemia have a greater risk of developing atherosclerosis, a narrowing of arteries— blood vessels providing oxygen to working tissues.[SUP]5[/SUP] If blood flow is severely restricted, even blocked in extreme cases, then tissue oxygenated by that artery experiences pain and it can lead to tissue death. In the heart, this is a heart attack; for the brain, it is a major cause of stroke. The testosterone-treated group had a significantly higher prevalence of hyperlipidemia (diagnosed or treated), compared to the control group before treatment.
Another difference between groups was the prevalence of hypertension (high blood pressure); hypertension was more common in testosterone-treated subjects prior to treatment.[SUP]4,5[/SUP] The imbalance of two major risk factors in fragile older men makes it difficult to determine if testosterone caused, contributed to, or was even involved in the health problems noted.
Not discussed in the study or accompanying editorial was another discrepant factor between the two groups— race.[SUP]4[/SUP] The testosterone-treated group contained a higher percentage of African-American subjects (14 versus 4 percent). Black males have a higher rate of cardiovascular-related injury, and when experienced, suffer greater damage.[SUP]6[/SUP]
Additionally, when an adverse event is associated with a particular treatment (e.g., stomach upset with aspirin overuse), it generally is seen consistently in those who are affected. However, the spectrum of illness/injury varied considerably in the testosterone-treated group, challenging the researchers to find a common injury instigated by testosterone.[SUP]4[/SUP] Terminated studies often do not accurately agree with completed studies. In fact, these findings disagree with the majority of studies involving testosterone use in hypogonadal men— many studies included more subjects, were of longer duration, and/or used a similar or greater testosterone target range.[SUP]7-12[/SUP]
Professionals must acknowledge and respect the safety committee’s decision to end this study prematurely, and commend the authors for acknowledging at several points that there is no clearly evident cause noted for this outcome discrepancy between the groups— that the results may be a consequence of the randomization process of clustering men with hyperlipidemia and hypertension in the testosterone-treated group; or the findings may be a statistical matter of chance.[SUP]4[/SUP]
The following collection of quotes from the article demonstrates the authors’ unwillingness to comment on the differences noted between the groups:
“… trials that have been stopped early tend to overestimate treatment differences.”
“Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than are those who do not have limitations in mobility.”
“Meta-analysis of previous trials of testosterone therapy have not shown significant increases in cardiovascular risk…”
“Some epidemiologic studies have shown that low testosterone levels are an independent risk factor for death from cardiovascular causes and from all causes.”
“The lack of consistent pattern and small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone.”[SUP]4[/SUP]
The authors conclude by stating that the emergence of adverse events should be interpreted with caution, and that any association may not be relevant to other populations (healthy men or younger adults), or with other dosing regimens.
Media Polarizes the Report
Of course, the media polarized on the report, suggesting more concrete evidence of harm caused by testosterone. Despite the rational reporting and a concise editorial appearing in the same issue of The New England Journal of Medicine, testosterone-replacement advocates immediately criticized the report; many media outlets provided the usual alarming narrative.[SUP]4,13[/SUP]
The Life Extension Foundation, anti-aging advocates, wrote a scathing report on the study that unfairly criticized the authors and “conventional doctors” in regard to their knowledge about testosterone use in aging men.[SUP]14[/SUP] A fair argument was raised that high-dose [COLOR=#6F0303 !important]topical testosterone can lead to supraphysiologic increases in estrogenic (female sex hormone) concentrations in men, and the dose applied was higher than standard practice. The study did not report baseline estrogen concentrations (estradiol and estrone), nor did it track estrogen concentrations during treatment or as a variable in men suffering side effects. Anti-aging practitioners generally follow estradiol levels during testosterone therapy and provide aromatase inhibitors (e.g., Arimidex) to prevent spikes in the female sex hormones. Elevated estrogen increases the risk of vascular disease or premature death in men.[SUP]15,16[/SUP] The Life Extension critique noted that the testosterone-treated group was at greater risk due to the above-stated facts, but the verbiage was suggestive that the differences were by design. To give the study authors professional credit, randomization was likely programmed to match for age and body mass index. It is a challenge to account for every possible contributing factor when randomizing.[/COLOR]
Certain media seized the raw results of the report titled “Adverse effects with testosterone administration” to support the perception that testosterone is far too dangerous to justify its use or availability to the medical community and society. In fairness, objective reports like “Testosterone supplement may have cardiovascular risks for older men” appeared in venerable newspapers such The Washington Post.[SUP]17[/SUP] Others were more biased, as demonstrated by The Boston Globe’s abridged story titled, “Cardiac problems halt testosterone gel study.”[SUP]18[/SUP] Working from the same source, a reprint of The New York Times story, the editors of The Boston Globe failed to mention the significant positive effects on strength and mobility, and cut out the comments of Dr. Peter Snyder— who headed a $45,000,000 study that investigated benefits of testosterone in men over 65, including possible cardiovascular benefits— both afforded full paragraphs in The New York Times version of the article.[SUP]19[/SUP]
The New England Journal of Medicine report is not a study per se, nor was the original intent to assess cardiovascular events in testosterone-treated older men with mobility issues. It is an alert to practitioners and researchers involved in testosterone replacement that in an at-risk group, these observations were made. Clinicians and researchers, as well as those using testosterone recreationally, need to be fully aware of both the risks and benefits of drug therapy in order to protect patient/public safety, and make informed decisions about the value of drug use in specific populations or individuals.
A similar scare regarding [COLOR=#6F0303 !important]hormone replacement therapy (HRT) in women occurred several years ago, causing post-menopausal women to stop or avoid estrogen/progesterone replacement. One feature that was found to affect a woman’s risk was the age at which HRT was initiated.[SUP]20,21[/SUP] Women who began estrogen replacement as menopause began did not have elevated cardiovascular risk, as opposed to those who did not begin until their 60s and later to treat osteoporosis. Apparently, if the body is allowed to enter physiologic “old age,” it does not tolerate or respond to endocrine signals in the same manner.[/COLOR]
So when bloggers, talk show hosts, and newspapers ring the alarms over this report, don’t treat it as a false alarm, but a fire drill. It is important to stay alert and informed.
A lack of professional training and willful risk-taking make AAS misuse/abuse by athletes and recreational lifters dangerous. The irresponsible use of AAS holds significant potential for peril in healthy young men; as the subjects become frailer, this risk multiplies. If those who direct or self-direct AAS use are aware of the potential risk, screening and monitoring can be more effective. Also, future research can be more appropriately directed.
Nonetheless, in order to best serve the needs of society, it is important that news and science not manipulate the presentation of risk versus benefits. The fact that such research is only now being conducted is a sad commentary, and direct consequence of the 40-plus-year stigmatization of performance-enhancing drugs.
References:
1. Giltay EJ, Tishova YA, et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med, 2010 Jul;7(7):2572-82.
2. Klötz F, Garle M, et al. Criminality among individuals testing positive for the presence of anabolic androgenic steroids. Arch Gen Psychiatry, 2006 Nov;63(11):1274-9.
3. Geiger K. Clemens pleads not guilty. Los Angeles Times, 2010 Aug 31.http://articles.latimes.com/2010/aug/31/sports/la-sp-roger-clemens-20100831, accessed September 10, 2010.
4. Basaria S, Coviello AD, et al. Adverse events associated with testosterone administration. N Engl J Med, 2010 Jul 8;363(2):109-22.
5. Munro JM, Cotran RS. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest, 1988 Mar;58(3):249-61.
6. Mensah GA, Mokdad AH, et al. State of disparities in cardiovascular health in the United States.Circulation, 2005 Mar 15;111(10):1233-41.
21 May 2014
[h=1]Testosterone Replacement Scare: False Alarm?[/h]
Public access to accurate and unbiased information is essential. While conspiracy theorists wish to believe that a shadow government of Illuminati controls our very thoughts, often the misinformation campaigns are more benign. Newspaper publishers and broadcast news channel executives direct what news the public is exposed to and how it is presented; Jon Stewart had a nice comical rant about this on “The Daily Show” some years ago. If this influence skews the presentation of the facts to confirm one side’s opinion rather than reality, that is called media bias.
The government does control a great deal of the scientific information and clinical guidelines through its control of research funds, FDA approval process, and all the backroom “nudge & wink” shenanigans. For some, this works to their benefit— for example, LDL cholesterol-lowering or erectile dysfunction drugs; others are impeded, e.g., weight-loss drug developers and female libido support. Perhaps the most egregious insult has been to testosterone.
The history of testosterone and [COLOR=#6F0303 !important]anabolic-androgenic steroids (AAS) dates back to the 1930s; unfortunately, so does the history of abusive or dangerous experimentation with these drugs. The parent compound for AAS is testosterone; its role in men’s health, not just quality of life, is difficult to dispute. Several studies have shown that men suffering from hypogonadism (low testosterone) experience greater rates of depression, erectile dysfunction, the metabolic syndrome, and premature death— all conditions that have great impact on individual well-being and national health care expense.[SUP]1[/SUP] Yet, confirmed or suspected benefits of testosterone or other AAS do not appear in headlines or on primetime news. Instead, what makes news is the association with individual tragedy (e.g., adolescent suicide), seemingly forced affiliation with crime or high-risk behavior, or violations by sports celebrities.[SUP]2,3[/SUP][/COLOR]
An example of varying media presentations of testosterone was the coverage given to the halting of a testosterone trial involving elderly men whose health was sufficiently compromised to limit their ability to walk or climb stairs. A brief review of the study and comparison of the words of the authors versus those of the media will demonstrate how facts, or the lack thereof, can alter public perception. The New England Journal of Medicine— one of the most highly recognized and influential medical journals— published a report of the early termination of a testosterone trial involving hypogonadal men over 65 who had limited mobility (unable to walk two city blocks or climb 10 stairs).[SUP]4[/SUP] The purpose of the trial was to determine whether such men could benefit from the strengthening effects of testosterone— increasing mobility, improving quality-of-life and health.
As expected, compared to the control group with testosterone concentrations ranging from 100-350 ng/ml, men who were being treated for six months with testosterone gel to maintain testosterone in the 500-1,000 ng/ml range became stronger and more capable of performing physical tests. However, during the course of the study, a number of men suffered from problems that required medical attention. Appropriately, the investigators unblinded (decoded) the groups— discovering more problems in subjects from the testosterone-treated group. They submitted data to the safety committee— who combined certain events, and decided that the testosterone-treated group was suffering serious cardiovascular events more frequently than the control group. At that time, the study was terminated.
Terminating a study is a fairly rare event. Months, even years of preparation go into a human clinical trial; these types of studies are also very expensive, costing in excess of $1,000,000— likely several times that number. Yet, it was appropriate to stop the study to evaluate this unexpected and unexplained trend.
Confusing Study Results
The authors, including some of the most prolific researchers in the field of testosterone, were perplexed. To begin with, the randomization process that is designed to prevent the groups from being different from each other failed to account for some relevant factors. All subjects demonstrated serious health impairments including advanced age, hypertension, diabetes, hyperlipidemia (high cholesterol or triglycerides), and obesity. Further, subjects were very limited in how much activity they could tolerate, being unable to climb a flight of stairs or walk two city blocks. With an average age of 74, both the testosterone and control groups consisted of unhealthy, older men. However, subjects who were treated with testosterone gel, and suffering a greater rate of infirmity, demonstrated certain conditions that placed them at a greater risk of cardiovascular injury.
Hyperlipidemia is a medical term that refers to dangerously high concentrations of cholesterol, bad cholesterol, or triglycerides (blood fats). The disorder is treated with drugs that have become household names, such as Lipitor. People with hyperlipidemia have a greater risk of developing atherosclerosis, a narrowing of arteries— blood vessels providing oxygen to working tissues.[SUP]5[/SUP] If blood flow is severely restricted, even blocked in extreme cases, then tissue oxygenated by that artery experiences pain and it can lead to tissue death. In the heart, this is a heart attack; for the brain, it is a major cause of stroke. The testosterone-treated group had a significantly higher prevalence of hyperlipidemia (diagnosed or treated), compared to the control group before treatment.
Another difference between groups was the prevalence of hypertension (high blood pressure); hypertension was more common in testosterone-treated subjects prior to treatment.[SUP]4,5[/SUP] The imbalance of two major risk factors in fragile older men makes it difficult to determine if testosterone caused, contributed to, or was even involved in the health problems noted.
Not discussed in the study or accompanying editorial was another discrepant factor between the two groups— race.[SUP]4[/SUP] The testosterone-treated group contained a higher percentage of African-American subjects (14 versus 4 percent). Black males have a higher rate of cardiovascular-related injury, and when experienced, suffer greater damage.[SUP]6[/SUP]
Additionally, when an adverse event is associated with a particular treatment (e.g., stomach upset with aspirin overuse), it generally is seen consistently in those who are affected. However, the spectrum of illness/injury varied considerably in the testosterone-treated group, challenging the researchers to find a common injury instigated by testosterone.[SUP]4[/SUP] Terminated studies often do not accurately agree with completed studies. In fact, these findings disagree with the majority of studies involving testosterone use in hypogonadal men— many studies included more subjects, were of longer duration, and/or used a similar or greater testosterone target range.[SUP]7-12[/SUP]
Professionals must acknowledge and respect the safety committee’s decision to end this study prematurely, and commend the authors for acknowledging at several points that there is no clearly evident cause noted for this outcome discrepancy between the groups— that the results may be a consequence of the randomization process of clustering men with hyperlipidemia and hypertension in the testosterone-treated group; or the findings may be a statistical matter of chance.[SUP]4[/SUP]
The following collection of quotes from the article demonstrates the authors’ unwillingness to comment on the differences noted between the groups:
“… trials that have been stopped early tend to overestimate treatment differences.”
“Frail elderly men with limitations in mobility are more likely to have clinical and subclinical cardiovascular disease than are those who do not have limitations in mobility.”
“Meta-analysis of previous trials of testosterone therapy have not shown significant increases in cardiovascular risk…”
“Some epidemiologic studies have shown that low testosterone levels are an independent risk factor for death from cardiovascular causes and from all causes.”
“The lack of consistent pattern and small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone.”[SUP]4[/SUP]
The authors conclude by stating that the emergence of adverse events should be interpreted with caution, and that any association may not be relevant to other populations (healthy men or younger adults), or with other dosing regimens.
Media Polarizes the Report
Of course, the media polarized on the report, suggesting more concrete evidence of harm caused by testosterone. Despite the rational reporting and a concise editorial appearing in the same issue of The New England Journal of Medicine, testosterone-replacement advocates immediately criticized the report; many media outlets provided the usual alarming narrative.[SUP]4,13[/SUP]
The Life Extension Foundation, anti-aging advocates, wrote a scathing report on the study that unfairly criticized the authors and “conventional doctors” in regard to their knowledge about testosterone use in aging men.[SUP]14[/SUP] A fair argument was raised that high-dose [COLOR=#6F0303 !important]topical testosterone can lead to supraphysiologic increases in estrogenic (female sex hormone) concentrations in men, and the dose applied was higher than standard practice. The study did not report baseline estrogen concentrations (estradiol and estrone), nor did it track estrogen concentrations during treatment or as a variable in men suffering side effects. Anti-aging practitioners generally follow estradiol levels during testosterone therapy and provide aromatase inhibitors (e.g., Arimidex) to prevent spikes in the female sex hormones. Elevated estrogen increases the risk of vascular disease or premature death in men.[SUP]15,16[/SUP] The Life Extension critique noted that the testosterone-treated group was at greater risk due to the above-stated facts, but the verbiage was suggestive that the differences were by design. To give the study authors professional credit, randomization was likely programmed to match for age and body mass index. It is a challenge to account for every possible contributing factor when randomizing.[/COLOR]
Certain media seized the raw results of the report titled “Adverse effects with testosterone administration” to support the perception that testosterone is far too dangerous to justify its use or availability to the medical community and society. In fairness, objective reports like “Testosterone supplement may have cardiovascular risks for older men” appeared in venerable newspapers such The Washington Post.[SUP]17[/SUP] Others were more biased, as demonstrated by The Boston Globe’s abridged story titled, “Cardiac problems halt testosterone gel study.”[SUP]18[/SUP] Working from the same source, a reprint of The New York Times story, the editors of The Boston Globe failed to mention the significant positive effects on strength and mobility, and cut out the comments of Dr. Peter Snyder— who headed a $45,000,000 study that investigated benefits of testosterone in men over 65, including possible cardiovascular benefits— both afforded full paragraphs in The New York Times version of the article.[SUP]19[/SUP]
The New England Journal of Medicine report is not a study per se, nor was the original intent to assess cardiovascular events in testosterone-treated older men with mobility issues. It is an alert to practitioners and researchers involved in testosterone replacement that in an at-risk group, these observations were made. Clinicians and researchers, as well as those using testosterone recreationally, need to be fully aware of both the risks and benefits of drug therapy in order to protect patient/public safety, and make informed decisions about the value of drug use in specific populations or individuals.
A similar scare regarding [COLOR=#6F0303 !important]hormone replacement therapy (HRT) in women occurred several years ago, causing post-menopausal women to stop or avoid estrogen/progesterone replacement. One feature that was found to affect a woman’s risk was the age at which HRT was initiated.[SUP]20,21[/SUP] Women who began estrogen replacement as menopause began did not have elevated cardiovascular risk, as opposed to those who did not begin until their 60s and later to treat osteoporosis. Apparently, if the body is allowed to enter physiologic “old age,” it does not tolerate or respond to endocrine signals in the same manner.[/COLOR]
So when bloggers, talk show hosts, and newspapers ring the alarms over this report, don’t treat it as a false alarm, but a fire drill. It is important to stay alert and informed.
A lack of professional training and willful risk-taking make AAS misuse/abuse by athletes and recreational lifters dangerous. The irresponsible use of AAS holds significant potential for peril in healthy young men; as the subjects become frailer, this risk multiplies. If those who direct or self-direct AAS use are aware of the potential risk, screening and monitoring can be more effective. Also, future research can be more appropriately directed.
Nonetheless, in order to best serve the needs of society, it is important that news and science not manipulate the presentation of risk versus benefits. The fact that such research is only now being conducted is a sad commentary, and direct consequence of the 40-plus-year stigmatization of performance-enhancing drugs.
References:
1. Giltay EJ, Tishova YA, et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med, 2010 Jul;7(7):2572-82.
2. Klötz F, Garle M, et al. Criminality among individuals testing positive for the presence of anabolic androgenic steroids. Arch Gen Psychiatry, 2006 Nov;63(11):1274-9.
3. Geiger K. Clemens pleads not guilty. Los Angeles Times, 2010 Aug 31.http://articles.latimes.com/2010/aug/31/sports/la-sp-roger-clemens-20100831, accessed September 10, 2010.
4. Basaria S, Coviello AD, et al. Adverse events associated with testosterone administration. N Engl J Med, 2010 Jul 8;363(2):109-22.
5. Munro JM, Cotran RS. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest, 1988 Mar;58(3):249-61.
6. Mensah GA, Mokdad AH, et al. State of disparities in cardiovascular health in the United States.Circulation, 2005 Mar 15;111(10):1233-41.
