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Anabolic Steroids
Androgen Replacement
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Ramasamy R, Dupree JM, Kovac JR, Lipshultz LI. Risks of testosterone therapy in elderly men. F1000Res 2014;3:11. Risks of testosterone therapy in elderly men - F1000Research
Testosterone supplementation therapy (TST) is a widely used treatment for men with late onset hypogonadism. The benefits seen with TST, such as improved libido and energy level, beneficial effects on bone density have been well documented. Although hypogonadism remains an independent risk factor for mortality, recent studies have examined the association between testosterone therapy and cardiovascular risk.
Vigen et al. examined the association between testosterone supplementation and cardiovascular morbidity in men older than 60 years. They performed a retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011.
The absolute rate of atherosclerotic events (myocardial infarction, stroke and mortality) was 19.9% in men who did not receive testosterone vs 25.7% in the men who were treated with testosterone. Men on testosterone supplementation were reported to have higher risk of adverse events than men not on testosterone, despite being younger and having less comorbidity.
One of the most important messages to glean from the study is that hypogonadism could be an adverse prognostic factor for cardiovascular and cerebrovascular morbidity and mortality. This message is also found in other studies about hypogonadism, including a large study on male veterans that showed that hypogonadism could be an important risk factor for increased mortality. Further, in men with hypertension3, low testosterone levels were shown to be associated with increased risk of major cardiovascular adverse events.
In the Vigen et al. study men who received testosterone had lower pre-therapy testosterone levels, suggesting that they were even more hypogonadal than men who did not start testosterone therapy. In addition, it is unclear how much testosterone the men in the treatment arm actually received. Based on prescription refills, most men were on testosterone therapy for less than one year, and their mean post-treatment testosterone level was 332 ng/dL.
With serum testosterone less than 300 ng/dL defined as biochemical hypogonadism by the Endocrine Society, we are concerned that a significant proportion of men could have remained hypogonadal, in spite of testosterone treatment.
Additionally, the reasons for starting testosterone therapy cannot be determined from this retrospective analysis. Because of the uncertain reasons for starting therapy in some hypogonadal men and not in others, and because of the variability in the amount of total testosterone that the patients actually received, there may be confounding factors that could also explain the higher risk of adverse events in men treated with testosterone. It is unclear whether the minimal exposure to testosterone in this elderly population (as evidenced by the post-treatment levels and duration of treatment) was responsible for such a dramatic difference in mortality and morbidity.
The association between testosterone therapy and mortality has remained controversial with studies demonstrating conflicting results. Until larger randomized studies demonstrate clear causation, physicians prescribing testosterone therapy to elderly men with co-morbidities should use it prudently with close follow-up.
Testosterone supplementation therapy (TST) is a widely used treatment for men with late onset hypogonadism. The benefits seen with TST, such as improved libido and energy level, beneficial effects on bone density have been well documented. Although hypogonadism remains an independent risk factor for mortality, recent studies have examined the association between testosterone therapy and cardiovascular risk.
Vigen et al. examined the association between testosterone supplementation and cardiovascular morbidity in men older than 60 years. They performed a retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011.
The absolute rate of atherosclerotic events (myocardial infarction, stroke and mortality) was 19.9% in men who did not receive testosterone vs 25.7% in the men who were treated with testosterone. Men on testosterone supplementation were reported to have higher risk of adverse events than men not on testosterone, despite being younger and having less comorbidity.
One of the most important messages to glean from the study is that hypogonadism could be an adverse prognostic factor for cardiovascular and cerebrovascular morbidity and mortality. This message is also found in other studies about hypogonadism, including a large study on male veterans that showed that hypogonadism could be an important risk factor for increased mortality. Further, in men with hypertension3, low testosterone levels were shown to be associated with increased risk of major cardiovascular adverse events.
In the Vigen et al. study men who received testosterone had lower pre-therapy testosterone levels, suggesting that they were even more hypogonadal than men who did not start testosterone therapy. In addition, it is unclear how much testosterone the men in the treatment arm actually received. Based on prescription refills, most men were on testosterone therapy for less than one year, and their mean post-treatment testosterone level was 332 ng/dL.
With serum testosterone less than 300 ng/dL defined as biochemical hypogonadism by the Endocrine Society, we are concerned that a significant proportion of men could have remained hypogonadal, in spite of testosterone treatment.
Additionally, the reasons for starting testosterone therapy cannot be determined from this retrospective analysis. Because of the uncertain reasons for starting therapy in some hypogonadal men and not in others, and because of the variability in the amount of total testosterone that the patients actually received, there may be confounding factors that could also explain the higher risk of adverse events in men treated with testosterone. It is unclear whether the minimal exposure to testosterone in this elderly population (as evidenced by the post-treatment levels and duration of treatment) was responsible for such a dramatic difference in mortality and morbidity.
The association between testosterone therapy and mortality has remained controversial with studies demonstrating conflicting results. Until larger randomized studies demonstrate clear causation, physicians prescribing testosterone therapy to elderly men with co-morbidities should use it prudently with close follow-up.
Pandit RS, Glueck CJ. Testosterone, anastrozole, factor V Leiden heterozygosity and osteonecrosis of the jaws. Blood Coagul Fibrinolysis 2014;25(3):286-8. Testosterone, anastrozole, factor V Leiden heterozygosity an... : Blood Coagulation & Fibrinolysis
Our specific aim is to describe the development of thrombotic osteonecrosis of the jaws after testosterone-anastrozole therapy in a 55-year-old white man subsequently found to have previously undiagnosed factor V Leiden heterozygosity.
Before the diagnosis of V Leiden heterozygosity, he was given testosterone gel, 50 mg/day, and on testosterone, serum testosterone (963 ng/dl) and estradiol were high (50 pg/ml). Anastrozole was started, and testosterone was continued. Six months later, osteonecrosis of the jaws was diagnosed.
Exogenous testosterone is aromatized to estradiol and estradiol-induced thrombophilia, when superimposed on underlying familial thrombophilia, as in this case, may lead to thrombosis and osteonecrosis.
We recommend that before giving testosterone, at a minimum, screening for the factor V Leiden and G20210A mutations, and factor VIII and XI activity be carried out, to avoid unanticipated thrombosis.
Our specific aim is to describe the development of thrombotic osteonecrosis of the jaws after testosterone-anastrozole therapy in a 55-year-old white man subsequently found to have previously undiagnosed factor V Leiden heterozygosity.
Before the diagnosis of V Leiden heterozygosity, he was given testosterone gel, 50 mg/day, and on testosterone, serum testosterone (963 ng/dl) and estradiol were high (50 pg/ml). Anastrozole was started, and testosterone was continued. Six months later, osteonecrosis of the jaws was diagnosed.
Exogenous testosterone is aromatized to estradiol and estradiol-induced thrombophilia, when superimposed on underlying familial thrombophilia, as in this case, may lead to thrombosis and osteonecrosis.
We recommend that before giving testosterone, at a minimum, screening for the factor V Leiden and G20210A mutations, and factor VIII and XI activity be carried out, to avoid unanticipated thrombosis.
Shortridge EF, Polzer P, Donga P, et al. Experiences and treatment patterns of hypogonadal men in a U.S. health system. Int J Clin Pract. Experiences and treatment patterns of hypogonadal men in a U.S. health system - Shortridge - 2014 - International Journal of Clinical Practice - Wiley Online Library
OBJECTIVE: To examine self-reported experiences with hypogonadism (HG) and patterns of testosterone replacement therapy (TRT) in men seeking care in a U.S. healthcare system.
METHODS: Men >/= 18 years old with HG were identified from the 2008-2010 Reliant electronic medical records database. Surveys, including validated instruments for measuring symptoms of HG, were collected and evaluated for demographic and behavioural data.
RESULTS: Surveys were mailed to 133 men with HG in 2012. Of the 107 surveys returned, 95 were included in the final analysis. Most respondents were Caucasian (90.5%). Men reported developing symptoms of HG, as well as being diagnosed, at a median age of 50 years.
The most common symptoms reported as reasons for seeking treatment were erectile dysfunction (66.3%), fatigue (59.0%) and decreased sex drive (57.9%).
These continued to be the most bothersome symptoms at the time of the survey regardless of whether the patient received treatment, although men who were currently taking TRT reported less severe symptoms. Approximately 88% of men reported taking TRT at some point, with 61.9% on therapy at the time of the survey.
CONCLUSIONS: This study examined men's experiences with HG, including symptoms, quality of life, and treatments.
Some symptoms continued despite treatment, and therapy was discontinued at a high rate, which men generally attributed to cost and perceptions of efficacy.
In light of this lack of adherence, patients may benefit from appropriate expectation setting regarding reasonable timelines for symptom improvement, the strengths and challenges of various TRT formulations, the importance of adherence and the benefits and risks of TRT.
OBJECTIVE: To examine self-reported experiences with hypogonadism (HG) and patterns of testosterone replacement therapy (TRT) in men seeking care in a U.S. healthcare system.
METHODS: Men >/= 18 years old with HG were identified from the 2008-2010 Reliant electronic medical records database. Surveys, including validated instruments for measuring symptoms of HG, were collected and evaluated for demographic and behavioural data.
RESULTS: Surveys were mailed to 133 men with HG in 2012. Of the 107 surveys returned, 95 were included in the final analysis. Most respondents were Caucasian (90.5%). Men reported developing symptoms of HG, as well as being diagnosed, at a median age of 50 years.
The most common symptoms reported as reasons for seeking treatment were erectile dysfunction (66.3%), fatigue (59.0%) and decreased sex drive (57.9%).
These continued to be the most bothersome symptoms at the time of the survey regardless of whether the patient received treatment, although men who were currently taking TRT reported less severe symptoms. Approximately 88% of men reported taking TRT at some point, with 61.9% on therapy at the time of the survey.
CONCLUSIONS: This study examined men's experiences with HG, including symptoms, quality of life, and treatments.
Some symptoms continued despite treatment, and therapy was discontinued at a high rate, which men generally attributed to cost and perceptions of efficacy.
In light of this lack of adherence, patients may benefit from appropriate expectation setting regarding reasonable timelines for symptom improvement, the strengths and challenges of various TRT formulations, the importance of adherence and the benefits and risks of TRT.
[Research Study] Exogenous Testosterone and Venous Thrombosis in Patients with Underlying Clotting Abnormalities
http://e-mercy.com/images/cholester...1/Private testosterone screening protocol.pdf
1. Purpose: Our aim is to conduct a study of patients who are treated with exogenous testosterone and subsequently develop venous thrombosis like central retinal vein occlusion, deep vein thrombosis, pulmonary embolism etc.
We will be prospectively studying two groups of patients and in both groups, will measure major components of thrombophilia and hypofibrinolysis (T-H) as well as total and free testosterone (T) and estradiol (E2).
a. Men already taking testosterone supplementation without previous thrombotic events.
b. Men about to begin testosterone supplementation
2. Significance in relationship to human health: Patients who have some underlying clotting abnormalities are at significant risk for venous thrombosis when given androgel/Testosterone.
Checking total and free T and E2 levels in these patients and their relationships in developing venous clots will help us in better understanding of the pathophysiology of the thrombotic events.
If these patients are treated with exogenous testosterone, their risk of developing complications from venous thrombosis becomes even higher. They might develop central retinal vein occlusion, deep vein thrombosis, pulmonary embolism and osteonecrosis of hip and jaws. Central retinal vein occlusion is an important cause of vision loss and is the second most common retinal vascular disorder in the United States. Avascular necrosis of the femoral head is also a debilitating disease that usually leads to osteoarthritis of the hip joint in relatively young adults (mean age at presentation: 38 y). The disease prevalence is unknown, but estimates indicate that 10,000-20,000 new cases are diagnosed in the United States per year.
Similarly, osteonecrosis of jaw (ONJ) has been reported as a rare complication of bone disorders and phosphorus exposure since the 1830s. Osteonecrosis of bone has been associated with a wide variety of factors, including advanced age, arthritis, chronic inactivity, corticosteroids, estrogen, female sex, hemodialysis, thrombophilic disorders, hyperlipidemia, hypertension, infection, and many other disorders. Intravascular coagulation appears to be the central underlying event, however, the exact pathoetiology is not completely understood.
We hypothesize that giving exogenous testosterone to patients with underlying clotting abnormality increases their chances of getting venous thrombosis by the conversion of testosterone to estradiol in the body.
http://e-mercy.com/images/cholester...1/Private testosterone screening protocol.pdf
1. Purpose: Our aim is to conduct a study of patients who are treated with exogenous testosterone and subsequently develop venous thrombosis like central retinal vein occlusion, deep vein thrombosis, pulmonary embolism etc.
We will be prospectively studying two groups of patients and in both groups, will measure major components of thrombophilia and hypofibrinolysis (T-H) as well as total and free testosterone (T) and estradiol (E2).
a. Men already taking testosterone supplementation without previous thrombotic events.
b. Men about to begin testosterone supplementation
2. Significance in relationship to human health: Patients who have some underlying clotting abnormalities are at significant risk for venous thrombosis when given androgel/Testosterone.
Checking total and free T and E2 levels in these patients and their relationships in developing venous clots will help us in better understanding of the pathophysiology of the thrombotic events.
If these patients are treated with exogenous testosterone, their risk of developing complications from venous thrombosis becomes even higher. They might develop central retinal vein occlusion, deep vein thrombosis, pulmonary embolism and osteonecrosis of hip and jaws. Central retinal vein occlusion is an important cause of vision loss and is the second most common retinal vascular disorder in the United States. Avascular necrosis of the femoral head is also a debilitating disease that usually leads to osteoarthritis of the hip joint in relatively young adults (mean age at presentation: 38 y). The disease prevalence is unknown, but estimates indicate that 10,000-20,000 new cases are diagnosed in the United States per year.
Similarly, osteonecrosis of jaw (ONJ) has been reported as a rare complication of bone disorders and phosphorus exposure since the 1830s. Osteonecrosis of bone has been associated with a wide variety of factors, including advanced age, arthritis, chronic inactivity, corticosteroids, estrogen, female sex, hemodialysis, thrombophilic disorders, hyperlipidemia, hypertension, infection, and many other disorders. Intravascular coagulation appears to be the central underlying event, however, the exact pathoetiology is not completely understood.
We hypothesize that giving exogenous testosterone to patients with underlying clotting abnormality increases their chances of getting venous thrombosis by the conversion of testosterone to estradiol in the body.
Kaufman JM. Mortality associated to late-onset hypogonadism: reasons not to treat with testosterone? J Clin Endocrinol Metab 2014;99(4):1161-3. http://press.endocrine.org/doi/full/10.1210/jc.2014-1103
Shores MM, Matsumoto AM. Testosterone, aging and survival: biomarker or deficiency. Curr Opin Endocrinol Diabetes Obes. Testosterone, aging and survival: biomarker or deficiency : Current Opinion in Endocrinology, Diabetes and Obesity
PURPOSE OF REVIEW: The purpose of this study is to review recent studies that examined the association of endogenous and exogenous testosterone and mortality in older men.
RECENT FINDINGS: Over the past several years, there has been a steep rise in testosterone prescriptions. The increased use of testosterone occurred in the context of several studies that reported an association between low serum testosterone and increased cardiovascular events and mortality. In contrast, recent studies have reported an association between testosterone treatment and adverse events. A testosterone treatment trial of mobility-impaired elderly men with prevalent cardiovascular disease was stopped due to increased cardiovascular events in the T-treated men and a meta-analysis reported increased cardiovascular events in T-treated men. In two recent large observational studies, testosterone treatment was associated with an increased risk for serious adverse cardiovascular events.
SUMMARY: Low testosterone is associated with mortality in multiple cohort studies; however, it is unclear if this is a causal association or due to low testosterone being a biomarker of poor health. Given recent reports of adverse outcomes associated with testosterone treatment, a conservative use of testosterone is warranted in men with cardiovascular disease who may be at greater risk for adverse outcomes.
PURPOSE OF REVIEW: The purpose of this study is to review recent studies that examined the association of endogenous and exogenous testosterone and mortality in older men.
RECENT FINDINGS: Over the past several years, there has been a steep rise in testosterone prescriptions. The increased use of testosterone occurred in the context of several studies that reported an association between low serum testosterone and increased cardiovascular events and mortality. In contrast, recent studies have reported an association between testosterone treatment and adverse events. A testosterone treatment trial of mobility-impaired elderly men with prevalent cardiovascular disease was stopped due to increased cardiovascular events in the T-treated men and a meta-analysis reported increased cardiovascular events in T-treated men. In two recent large observational studies, testosterone treatment was associated with an increased risk for serious adverse cardiovascular events.
SUMMARY: Low testosterone is associated with mortality in multiple cohort studies; however, it is unclear if this is a causal association or due to low testosterone being a biomarker of poor health. Given recent reports of adverse outcomes associated with testosterone treatment, a conservative use of testosterone is warranted in men with cardiovascular disease who may be at greater risk for adverse outcomes.
Schooling CM. Testosterone and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. Testosterone and cardiovascular disease : Current Opinion in Endocrinology, Diabetes and Obesity
PURPOSE OF REVIEW: Use of testosterone among men is increasing rapidly. Low serum testosterone is positively associated with cardiovascular disease and its risk factors. No large randomized controlled trial (RCT) has assessed the effects of testosterone on cardiovascular outcomes. Here recent evidence accumulating from other sources - pharmacoepidemiology, Mendelian randomization studies and meta-analysis of small RCTs - is reviewed to inform current testosterone usage.
RECENT FINDINGS: In a large, well conducted pharmacoepidemiology study specifically testosterone prescription was associated with myocardial infarction. Two Mendelian randomization studies did not corroborate beneficial effects of higher endogenous testosterone on cardiovascular risk factors, but suggested higher endogenous testosterone raised LDL cholesterol and lowered HDL cholesterol. A comprehensive meta-analysis of RCTs summarizing 27 trials including 2994 men found increased risk of cardiovascular-related events on testosterone (odds ratio 1.54, 95% confidence interval 1.09-2.18).
SUMMARY: Contrary to expectations from observational studies, current indications suggest testosterone causes ischemic cardiovascular disease with corresponding implications for practice. A large RCT would undoubtedly settle the issue definitively. Given mounting evidence of harm and the urgency of the situation assembling all the evidence from completed RCTs of testosterone or androgen deprivation therapy and use of Mendelian randomization might generate a definitive answer most quickly.
PURPOSE OF REVIEW: Use of testosterone among men is increasing rapidly. Low serum testosterone is positively associated with cardiovascular disease and its risk factors. No large randomized controlled trial (RCT) has assessed the effects of testosterone on cardiovascular outcomes. Here recent evidence accumulating from other sources - pharmacoepidemiology, Mendelian randomization studies and meta-analysis of small RCTs - is reviewed to inform current testosterone usage.
RECENT FINDINGS: In a large, well conducted pharmacoepidemiology study specifically testosterone prescription was associated with myocardial infarction. Two Mendelian randomization studies did not corroborate beneficial effects of higher endogenous testosterone on cardiovascular risk factors, but suggested higher endogenous testosterone raised LDL cholesterol and lowered HDL cholesterol. A comprehensive meta-analysis of RCTs summarizing 27 trials including 2994 men found increased risk of cardiovascular-related events on testosterone (odds ratio 1.54, 95% confidence interval 1.09-2.18).
SUMMARY: Contrary to expectations from observational studies, current indications suggest testosterone causes ischemic cardiovascular disease with corresponding implications for practice. A large RCT would undoubtedly settle the issue definitively. Given mounting evidence of harm and the urgency of the situation assembling all the evidence from completed RCTs of testosterone or androgen deprivation therapy and use of Mendelian randomization might generate a definitive answer most quickly.
April 10, 2014
Twenty-Five Medical Societies Join Androgen Study Group To Petition JAMA to Retract Misleading Testosterone Study http://androgenstudygroup.org/press-releases/92-2014-04-10 (April 10, 2014)
Unprecedented action taken to combat “false information” that has “harmed public health, distorted medical science, and violated the trust between medical journals and the consumer.” Failure to retract amounts to “medical literature malpractice.”
Boston, MA, April 8, 2014 – In an unprecedented action, twenty-five international medical societies have petitioned the Journal of the American Medical Association to retract the article that precipitated recent concerns regarding cardiovascular risks with testosterone therapy, citing “gross data mismanagement” rendering the study “no longer credible.” Twenty-two societies have added their names since the original petition was submitted to JAMA two weeks ago. The article by Rebecca Vigen and colleagues from the University of Colorado, published in the November 13, 2013 issue of JAMA, is entitled “Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels.” The results were widely reported as new evidence that testosterone therapy is associated with cardiovascular risks, resulting in a Food and Drug Administration safety bulletin issued January 31, 2014.
The 25 medical societies represent US and international groups dedicated to education and research in endocrinology, men’s health, andrology, and sexual medicine. These medical societies join more than 160 of the world’s leading figures in urology, endocrinology, and andrology from 32 countries, from every continent except Antarctica. Individual signers include 8 emeritus professors, 9 journal editors, and 67 full professors.
Societies recommending retraction are:
American Society for Men’s Health
Brazilian Society of Endocrinology and Metabolism
Canadian Men's Sexual Health Council
Canadian Society for the Study of Men’s Health
European Society for the Study of the Aging Male
European Society for Sexual Medicine
Indonesian Andrologist Association
International Society for Men’s Health
International Society for Sexual Medicine
International Society for the Study of the Aging Male Italian Society of Andrology
Italian Society of Andrology and Sexual Medicine
Japan ASEAN Council for Men’s Health
Aging Korean Society for Sexual Medicine and Andrology
Latin American Society for Sexual Medicine
Malaysian Men’s Health Initiative
Malaysian Society of Andrology and the Study of the Aging Male
Mens Health Initiative of British Columbia (Canada)
Middle East Society for Sexual Medicine
Russian Society for Men’s Health
South Asian Society for Sexual Medicine
Sexual Medicine Society of North America
The Society for Men's Health,
Singapore Society for the Study of Androgen Deficiency
Society for the Study of Andrology and Sexology, Singapore
“This is the first time in history a worldwide community of distinguished researchers, scholars, and clinicians has united to demand removal of a study from the literature,” stated Abraham Morgentaler, Chairman of the Androgen Study Group, which submitted the petition to JAMA. “This unprecedented action is a complete repudiation of the false information published by JAMA that has harmed public health, distorted medical science, and violated the trust between medical journals and the consumer. Although science must always be open to new information and ideas, the wholly unreliable data in this study by Vigen et al categorizes these results as misinformation. JAMA has been complicit in creating a media frenzy regarding false risks, and is directly responsible for the new wave of medical malpractice cases against physicians. For the good of consumers, physicians, and science, JAMA should retract the article before it causes even greater harm, accompanied by a letter explaining how its editorial process failed and steps taken to correct it.”
This article has already undergone two published corrections, and new revelations raise additional concerns. A first revision was published online November 12, 2013, six days following initial publication, due to the misleading presentation of results as raw data instead of complex, statistically derived estimates. JAMA’s decision to wait two months, until January 15, 2014, before disclosing this was a revised version was an ethical breach. A second correction published March 5, 2014, revealed major errors presented in the article’s text and figure. Specifically, in response to a letter questioning a group of 1132 men, the authors re-examined the data for this group and discovered the correct number of individuals should only have been 128, an 89% error rate, involving more than 1,000 individuals. The value for a second group was increased by more than 900 individuals. Astonishingly, this group included 100 women, meaning nearly 10% were the wrong gender for the study. New information raises additional questions and uncertainties regarding Figure 2 in the text, the key to their results.
“People find it hard to believe that JAMA would publish a study in which the percentages of men who suffered an adverse event was lower by half in men who received testosterone than untreated men, yet results were reported as if the opposite were true, thanks to absurdly complicated statistical manipulations of the data,” stated Andre Guay, MD, Clinical Professor of Endocrinology at Tufts Medical School. “Now we find out this is the gang that can’t shoot straight. In my 40 years in medicine I’ve never before seen a paper that says, ‘Here are our data, give or take a thousand individuals.’ There is nothing believable in this study.” The percentage of men who suffered an adverse event (heart attack, stroke, or death) based on reported numbers was 10.1% (123 events in 1223 men) in the testosterone group and 21.2% (1587 events in 7486 men) in the untreated group. Those percentages do not appear in the text of the study.
“This article has caused enormous damage,” stated Mohit Khera, MD, Associate Professor of Urology at Baylor Medical College. “This article created an unfounded negative perception of testosterone therapy. Physicians discontinued treatment for men who were benefitting from treatment. It harmed physician-patient relations, as patients ask why their physicians placed their health at risk. And a new field of medical malpractice has sprung up overnight, with plaintiff attorneys in the US advertising nationwide for patients who suffered a stroke or heart attack after receiving testosterone. And it’s all based on pure nonsense.”
“JAMA has violated the public trust,” concluded Dr. Morgentaler. “Its peer-review process failed. It recklessly promulgated false information that created the perception of medical risks. It withheld news that the study had been corrected, for two months, until interest had waned. It undermined the academic process by allowing the authors to avoid answering questions posed in letters. The lead author didn’t even sign the response to letters. It now stands by a highly statistical study after which it has been revealed that the statistics cannot be trusted. JAMA has left itself vulnerable to criticism that it promotes sensationalism to boost revenues, or is biased against the use of testosterone therapy in men. JAMA’s continued support of this discredited study, defying the worldwide community of experts, represents medical literature malpractice. ”
Twenty-Five Medical Societies Join Androgen Study Group To Petition JAMA to Retract Misleading Testosterone Study http://androgenstudygroup.org/press-releases/92-2014-04-10 (April 10, 2014)
Unprecedented action taken to combat “false information” that has “harmed public health, distorted medical science, and violated the trust between medical journals and the consumer.” Failure to retract amounts to “medical literature malpractice.”
Boston, MA, April 8, 2014 – In an unprecedented action, twenty-five international medical societies have petitioned the Journal of the American Medical Association to retract the article that precipitated recent concerns regarding cardiovascular risks with testosterone therapy, citing “gross data mismanagement” rendering the study “no longer credible.” Twenty-two societies have added their names since the original petition was submitted to JAMA two weeks ago. The article by Rebecca Vigen and colleagues from the University of Colorado, published in the November 13, 2013 issue of JAMA, is entitled “Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels.” The results were widely reported as new evidence that testosterone therapy is associated with cardiovascular risks, resulting in a Food and Drug Administration safety bulletin issued January 31, 2014.
The 25 medical societies represent US and international groups dedicated to education and research in endocrinology, men’s health, andrology, and sexual medicine. These medical societies join more than 160 of the world’s leading figures in urology, endocrinology, and andrology from 32 countries, from every continent except Antarctica. Individual signers include 8 emeritus professors, 9 journal editors, and 67 full professors.
Societies recommending retraction are:
American Society for Men’s Health
Brazilian Society of Endocrinology and Metabolism
Canadian Men's Sexual Health Council
Canadian Society for the Study of Men’s Health
European Society for the Study of the Aging Male
European Society for Sexual Medicine
Indonesian Andrologist Association
International Society for Men’s Health
International Society for Sexual Medicine
International Society for the Study of the Aging Male Italian Society of Andrology
Italian Society of Andrology and Sexual Medicine
Japan ASEAN Council for Men’s Health
Aging Korean Society for Sexual Medicine and Andrology
Latin American Society for Sexual Medicine
Malaysian Men’s Health Initiative
Malaysian Society of Andrology and the Study of the Aging Male
Mens Health Initiative of British Columbia (Canada)
Middle East Society for Sexual Medicine
Russian Society for Men’s Health
South Asian Society for Sexual Medicine
Sexual Medicine Society of North America
The Society for Men's Health,
Singapore Society for the Study of Androgen Deficiency
Society for the Study of Andrology and Sexology, Singapore
“This is the first time in history a worldwide community of distinguished researchers, scholars, and clinicians has united to demand removal of a study from the literature,” stated Abraham Morgentaler, Chairman of the Androgen Study Group, which submitted the petition to JAMA. “This unprecedented action is a complete repudiation of the false information published by JAMA that has harmed public health, distorted medical science, and violated the trust between medical journals and the consumer. Although science must always be open to new information and ideas, the wholly unreliable data in this study by Vigen et al categorizes these results as misinformation. JAMA has been complicit in creating a media frenzy regarding false risks, and is directly responsible for the new wave of medical malpractice cases against physicians. For the good of consumers, physicians, and science, JAMA should retract the article before it causes even greater harm, accompanied by a letter explaining how its editorial process failed and steps taken to correct it.”
This article has already undergone two published corrections, and new revelations raise additional concerns. A first revision was published online November 12, 2013, six days following initial publication, due to the misleading presentation of results as raw data instead of complex, statistically derived estimates. JAMA’s decision to wait two months, until January 15, 2014, before disclosing this was a revised version was an ethical breach. A second correction published March 5, 2014, revealed major errors presented in the article’s text and figure. Specifically, in response to a letter questioning a group of 1132 men, the authors re-examined the data for this group and discovered the correct number of individuals should only have been 128, an 89% error rate, involving more than 1,000 individuals. The value for a second group was increased by more than 900 individuals. Astonishingly, this group included 100 women, meaning nearly 10% were the wrong gender for the study. New information raises additional questions and uncertainties regarding Figure 2 in the text, the key to their results.
“People find it hard to believe that JAMA would publish a study in which the percentages of men who suffered an adverse event was lower by half in men who received testosterone than untreated men, yet results were reported as if the opposite were true, thanks to absurdly complicated statistical manipulations of the data,” stated Andre Guay, MD, Clinical Professor of Endocrinology at Tufts Medical School. “Now we find out this is the gang that can’t shoot straight. In my 40 years in medicine I’ve never before seen a paper that says, ‘Here are our data, give or take a thousand individuals.’ There is nothing believable in this study.” The percentage of men who suffered an adverse event (heart attack, stroke, or death) based on reported numbers was 10.1% (123 events in 1223 men) in the testosterone group and 21.2% (1587 events in 7486 men) in the untreated group. Those percentages do not appear in the text of the study.
“This article has caused enormous damage,” stated Mohit Khera, MD, Associate Professor of Urology at Baylor Medical College. “This article created an unfounded negative perception of testosterone therapy. Physicians discontinued treatment for men who were benefitting from treatment. It harmed physician-patient relations, as patients ask why their physicians placed their health at risk. And a new field of medical malpractice has sprung up overnight, with plaintiff attorneys in the US advertising nationwide for patients who suffered a stroke or heart attack after receiving testosterone. And it’s all based on pure nonsense.”
“JAMA has violated the public trust,” concluded Dr. Morgentaler. “Its peer-review process failed. It recklessly promulgated false information that created the perception of medical risks. It withheld news that the study had been corrected, for two months, until interest had waned. It undermined the academic process by allowing the authors to avoid answering questions posed in letters. The lead author didn’t even sign the response to letters. It now stands by a highly statistical study after which it has been revealed that the statistics cannot be trusted. JAMA has left itself vulnerable to criticism that it promotes sensationalism to boost revenues, or is biased against the use of testosterone therapy in men. JAMA’s continued support of this discredited study, defying the worldwide community of experts, represents medical literature malpractice. ”
Testosterone, The Biggest Men's Health Craze Since Viagra, May Be Risky.
Testosterone, The Biggest Men's Health Craze Since Viagra, May Be Risky : Shots - Health News : NPR
Men seek it out to combat low energy and decreased sex drive.
Prescription testosterone has become so popular that so-called "low T" clinics are becoming common sights in cities and suburbs.
The number of testosterone prescriptions written in the U.S. more than tripled in the past decade.
But researchers suspect that much of the testosterone dispensed at low-T clinics isn't tracked, since it's often bought with cash.
This unfettered flow of testosterone — officially a controlled substance — has raised concerns among doctors who specialize in hormonal problems.
Testosterone, The Biggest Men's Health Craze Since Viagra, May Be Risky : Shots - Health News : NPR
Men seek it out to combat low energy and decreased sex drive.
Prescription testosterone has become so popular that so-called "low T" clinics are becoming common sights in cities and suburbs.
The number of testosterone prescriptions written in the U.S. more than tripled in the past decade.
But researchers suspect that much of the testosterone dispensed at low-T clinics isn't tracked, since it's often bought with cash.
This unfettered flow of testosterone — officially a controlled substance — has raised concerns among doctors who specialize in hormonal problems.
Morgentaler A. Testosterone, Cardiovascular Risk, and Hormonophobia. The Journal of Sexual Medicine. Testosterone, Cardiovascular Risk, and Hormonophobia - Morgentaler - 2014 - The Journal of Sexual Medicine - Wiley Online Library
Introduction A public outcry against testosterone (T) therapy has suddenly occurred based on two reports suggesting treatment was associated with increased cardiovascular (CV) risks.
Aim To analyze scientific and social bases for concerns regarding T therapy.
Methods Analysis of recent articles regarding CV risks with T and comparison with events surrounding publication of results of the Women's Health Initiative in 2002.
Results In the first study, the percentage of individuals with an adverse event was lower by half in men who received T compared with untreated men (10.1% vs. 21.2%). However, an opposite conclusion was reached via complex statistics.
The second study reported minor increased rate of nonfatal myocardial infarction (MI) up to 90 days after receiving a T prescription compared with the prior 12 months. However, there was no control group, so it is unknown whether this MI rate was increased, reduced, or unchanged compared with untreated men.
Neither study provided substantive evidence of risk, yet these were lauded as proof of dangers, despite a substantial literature to the contrary.
Similar events followed the publication of the Women's Health Initiative in 2002 when a media frenzy over increased risks with female hormone replacement therapy obscured the fact that the reported excess risk was clinically meaningless, at two events per 1,000?person-years. Stakeholders driving concerns regarding hormone risks are unlikely to be clinicians with real-world patient experience.
Conclusions The use of weak studies as proof of danger indicates that cultural (i.e., nonscientific) forces are at play. Negative media stories touting T's risks appear fueled by antipharma sentiment, anger against aggressive marketing, and antisexuality.
This stance is best described as “hormonophobia.” As history shows, evidence alone may be insufficient to alter a public narrative. The true outrage is that social forces and hysteria have combined to deprive men of a useful treatment without regard for medical science.
Introduction A public outcry against testosterone (T) therapy has suddenly occurred based on two reports suggesting treatment was associated with increased cardiovascular (CV) risks.
Aim To analyze scientific and social bases for concerns regarding T therapy.
Methods Analysis of recent articles regarding CV risks with T and comparison with events surrounding publication of results of the Women's Health Initiative in 2002.
Results In the first study, the percentage of individuals with an adverse event was lower by half in men who received T compared with untreated men (10.1% vs. 21.2%). However, an opposite conclusion was reached via complex statistics.
The second study reported minor increased rate of nonfatal myocardial infarction (MI) up to 90 days after receiving a T prescription compared with the prior 12 months. However, there was no control group, so it is unknown whether this MI rate was increased, reduced, or unchanged compared with untreated men.
Neither study provided substantive evidence of risk, yet these were lauded as proof of dangers, despite a substantial literature to the contrary.
Similar events followed the publication of the Women's Health Initiative in 2002 when a media frenzy over increased risks with female hormone replacement therapy obscured the fact that the reported excess risk was clinically meaningless, at two events per 1,000?person-years. Stakeholders driving concerns regarding hormone risks are unlikely to be clinicians with real-world patient experience.
Conclusions The use of weak studies as proof of danger indicates that cultural (i.e., nonscientific) forces are at play. Negative media stories touting T's risks appear fueled by antipharma sentiment, anger against aggressive marketing, and antisexuality.
This stance is best described as “hormonophobia.” As history shows, evidence alone may be insufficient to alter a public narrative. The true outrage is that social forces and hysteria have combined to deprive men of a useful treatment without regard for medical science.
Morgentaler A, Khera M, Maggi M, Zitzmann M. Commentary: Who Is a Candidate for Testosterone Therapy? A Synthesis of International Expert Opinions. The Journal of Sexual Medicine. Commentary: Who Is a Candidate for Testosterone Therapy? A Synthesis of International Expert Opinions - Morgentaler - 2014 - The Journal of Sexual Medicine - Wiley Online Library
Introduction Despite increasing use of testosterone therapy (TTh) for men with testosterone deficiency (TD), there remains uncertainty determining who is a candidate for treatment.
Aim The aim if this study was to report the opinions of international experts on TTh, as initially presented at the meeting of the World Meeting on Sexual Medicine in Chicago, United States in August 2012.
Methods Expert responses to questions regarding the diagnosis of TD based on their own clinical and research experience.
Results All experts emphasized the primacy of symptoms for the diagnosis of TD. Total testosterone (T) thresholds used to identify TD ranged from 350?ng/dL to 400?ng/dL (12–14?nmol/L); however, experts emphasized the diagnostic limitations of this test. Free T was obtained by all, with some valuing this test more than total T for clinical decision making.
Only one expert routinely used a screening questionnaire.
None used age-adjusted values.
Bioavailable T and the free androgen index were not used.
Luteinizing hormone (LH) and sex hormone-binding globulin levels were routinely obtained at evaluation.
Additional supportive evidence for TD diagnosis included small testicular volume, high androgen receptor CAG repeats, elevated LH, and presence of diabetes or metabolic syndrome.
Two T tests were generally obtained but not always required.
Some experts did not require morning testing in men 50 years and older. All monitored prostate-specific antigen and hematocrit after initiation of TTh.
All but one expert would consider a trial of TTh to a symptomatic man with total T within the normal range.
Recent studies suggesting increased cardiovascular risk with T therapy were not found to be credible.
Conclusions Determining who is a candidate for TTh requires clinical assessment based on symptoms and signs, with confirmatory laboratory evaluation. These expert opinions differed from some published guidelines by the emphasis on symptoms as paramount, recognition of the limitations of total T as a diagnostic test, and the potential utility of a therapeutic trial in symptomatic cases with normal total T concentrations.
Introduction Despite increasing use of testosterone therapy (TTh) for men with testosterone deficiency (TD), there remains uncertainty determining who is a candidate for treatment.
Aim The aim if this study was to report the opinions of international experts on TTh, as initially presented at the meeting of the World Meeting on Sexual Medicine in Chicago, United States in August 2012.
Methods Expert responses to questions regarding the diagnosis of TD based on their own clinical and research experience.
Results All experts emphasized the primacy of symptoms for the diagnosis of TD. Total testosterone (T) thresholds used to identify TD ranged from 350?ng/dL to 400?ng/dL (12–14?nmol/L); however, experts emphasized the diagnostic limitations of this test. Free T was obtained by all, with some valuing this test more than total T for clinical decision making.
Only one expert routinely used a screening questionnaire.
None used age-adjusted values.
Bioavailable T and the free androgen index were not used.
Luteinizing hormone (LH) and sex hormone-binding globulin levels were routinely obtained at evaluation.
Additional supportive evidence for TD diagnosis included small testicular volume, high androgen receptor CAG repeats, elevated LH, and presence of diabetes or metabolic syndrome.
Two T tests were generally obtained but not always required.
Some experts did not require morning testing in men 50 years and older. All monitored prostate-specific antigen and hematocrit after initiation of TTh.
All but one expert would consider a trial of TTh to a symptomatic man with total T within the normal range.
Recent studies suggesting increased cardiovascular risk with T therapy were not found to be credible.
Conclusions Determining who is a candidate for TTh requires clinical assessment based on symptoms and signs, with confirmatory laboratory evaluation. These expert opinions differed from some published guidelines by the emphasis on symptoms as paramount, recognition of the limitations of total T as a diagnostic test, and the potential utility of a therapeutic trial in symptomatic cases with normal total T concentrations.
The Putative Mechanisms Underlying Testosterone and Cardiovascular Risk
Maganty A, Kovac JR, Ramasamy R. The putative mechanisms underlying testosterone and cardiovascular risk. F1000Res 2014;3:87. The putative mechanisms underlying testosterone and cardiovascular risk - F1000Research
The use of testosterone supplementation therapy (TST) is increasing primarily in men with symptomatic hypogonadism. While TST has been shown to have numerous benefits, as its use increases, the role on cardiovascular health must be explored.
Previous evidence showed no adverse cardiovascular risks associated with TST use; however, more recent studies suggest that there may be an associated risk. The exact mechanism by which TST may contribute to cardiovascular risk has not been elucidated.
Numerous mechanisms have been proposed which include testosterone's effect on thromboxane A2 receptors, vascular adhesion molecule 1 receptors, erythropoiesis, and obstructive sleep apnea, all of which can ultimately lead to atherogenesis and increased cardiovascular risk.
Proposed Schematic by Which TST May Contribute To Cardiovascular Risk
TST increases TXA2 receptor expression, VCAM1 expression, erythropoiesis, and worsens sleep disorder breathing, all of which ultimately contribute to atherogenesis and worsening of cardiovascular health.
VCAM1 - vascular cell adhesion molecule.
Maganty A, Kovac JR, Ramasamy R. The putative mechanisms underlying testosterone and cardiovascular risk. F1000Res 2014;3:87. The putative mechanisms underlying testosterone and cardiovascular risk - F1000Research
The use of testosterone supplementation therapy (TST) is increasing primarily in men with symptomatic hypogonadism. While TST has been shown to have numerous benefits, as its use increases, the role on cardiovascular health must be explored.
Previous evidence showed no adverse cardiovascular risks associated with TST use; however, more recent studies suggest that there may be an associated risk. The exact mechanism by which TST may contribute to cardiovascular risk has not been elucidated.
Numerous mechanisms have been proposed which include testosterone's effect on thromboxane A2 receptors, vascular adhesion molecule 1 receptors, erythropoiesis, and obstructive sleep apnea, all of which can ultimately lead to atherogenesis and increased cardiovascular risk.
Proposed Schematic by Which TST May Contribute To Cardiovascular Risk
TST increases TXA2 receptor expression, VCAM1 expression, erythropoiesis, and worsens sleep disorder breathing, all of which ultimately contribute to atherogenesis and worsening of cardiovascular health.
VCAM1 - vascular cell adhesion molecule.
Attachments
I have come to the conclusion that TRT is like any other drug on the market,it depends on what condition you are in as to what side effects you will get.An otherwise healthy male with low testerone will benefit greatly from replacement doses.I started using steroids in the 80's and used them for 4 or 5 years at higher doses than replacement.I used them again when i my early 60's at high doses 600mg of test weekly plus other compounds and i am very healthy now only needing thyroid medication.I have very good blood pressure according to my endo whos treating my thyroid. I always cycled my steroids 8 weeks on and at least 8 weeks off and my testosterone always recovered.my last blood work a couple years ago my TT was 502. I dont drink much at all and i dont do any recreational drugs at all,dont smoke and never have.Healthy men shouldnt have any problems with replacement doses of test and in most cases will help them.....
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Results Question Heart Risks of Testosterone Tx
Results Question Heart Risks of Testosterone Tx
A new analysis countered recent studies linking the use of testosterone therapy with increased risks of myocardial infarction (MI) and stroke.
Among roughly 20,000 patients treated with testosterone over a 6-year period, the rate of new MIs was 30 per 100,000 and the rate of new strokes was 10 per 100,000.
Results Question Heart Risks of Testosterone Tx
A new analysis countered recent studies linking the use of testosterone therapy with increased risks of myocardial infarction (MI) and stroke.
Among roughly 20,000 patients treated with testosterone over a 6-year period, the rate of new MIs was 30 per 100,000 and the rate of new strokes was 10 per 100,000.
Cecchin E, De Mattia E, Mazzon G, Cauci S, Trombetta C, Toffoli G. A pharmacogenetic survey of androgen receptor (CAG)n and (GGN)n polymorphisms in patients experiencing long term side effects after finasteride discontinuation. Int J Biol Markers. http://www.biological-markers.com/a...ng-term-side-effects-after-finasteride-discon
Finasteride is a steroid 5-alpha-reductase inhibitor, approved for the treatment of androgenetic alopecia (AGA) and benign prostate hyperplasia. In some patients, the treatment is associated with adverse side effects that could become persistent after therapy discontinuation, resulting in the so-called post-finasteride syndrome (PFS).
A pharmacogenetic component in the response to finasteride treatment was previously demonstrated. Two polymorphisms (CAG) rs4045402 and (GGN) rs3138869 in the gene encoding for the androgen receptor (AR) have been hypothesized to play a role in finasteride sensitivity.
We aimed to compare the rs4045402 and rs3138869 polymorphisms prevalence in a group of 69 selected subjects (AGA+PFS) that used finasteride to treat alopecia and developed persistent side effects, with that in a group of 91 untreated subjects with AGA (AGA), and a group of 76 untreated subjects without AGA (NO-AGA).
The rs4045402 and rs3138869 polymorphisms extreme-lengths alleles were more frequent among AGA+PFS (odds ratio, 5.88; 95% CI, 1.87-18.52) and AGA subjects (odds ratio, 3.55; 95% CI, 1.13-11.21) than among NO-AGA subjects, probably reflecting the genetic predisposing factors for AGA development.
In conclusion, we described a predictive effect of the less common repeats' length CAG-rs4045402 and GGN-rs3138869 on AGA development. Prospective trials are required to confirm our findings also in other ethnicities, and to highlight possible further pharmacogenetic predictive markers of susceptibility to adverse effects.
Finasteride is a steroid 5-alpha-reductase inhibitor, approved for the treatment of androgenetic alopecia (AGA) and benign prostate hyperplasia. In some patients, the treatment is associated with adverse side effects that could become persistent after therapy discontinuation, resulting in the so-called post-finasteride syndrome (PFS).
A pharmacogenetic component in the response to finasteride treatment was previously demonstrated. Two polymorphisms (CAG) rs4045402 and (GGN) rs3138869 in the gene encoding for the androgen receptor (AR) have been hypothesized to play a role in finasteride sensitivity.
We aimed to compare the rs4045402 and rs3138869 polymorphisms prevalence in a group of 69 selected subjects (AGA+PFS) that used finasteride to treat alopecia and developed persistent side effects, with that in a group of 91 untreated subjects with AGA (AGA), and a group of 76 untreated subjects without AGA (NO-AGA).
The rs4045402 and rs3138869 polymorphisms extreme-lengths alleles were more frequent among AGA+PFS (odds ratio, 5.88; 95% CI, 1.87-18.52) and AGA subjects (odds ratio, 3.55; 95% CI, 1.13-11.21) than among NO-AGA subjects, probably reflecting the genetic predisposing factors for AGA development.
In conclusion, we described a predictive effect of the less common repeats' length CAG-rs4045402 and GGN-rs3138869 on AGA development. Prospective trials are required to confirm our findings also in other ethnicities, and to highlight possible further pharmacogenetic predictive markers of susceptibility to adverse effects.
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