Why All Those Testosterone Ads Constitute Disease Mongering
http://www.forbes.com/sites/arlenew...itute-disease-mongering/?ss=pharma-healthcare
http://www.forbes.com/sites/arlenew...itute-disease-mongering/?ss=pharma-healthcare
MESO-Rx
Anabolic Steroids
Androgen Replacement
- Thread starter Michael Scally MD
- Start date
Perls T, Handelsman DJ. Disease Mongering of Age-Associated Declines in Testosterone and Growth Hormone Levels. Journal of the American Geriatrics Society. http://onlinelibrary.wiley.com/doi/10.1111/jgs.13391/full
A combination of direct-to-consumer product advertising (DTCPA) and lax consensus guidelines for testosterone prescribing have, over the past decade, led to 10- and 40-fold increases in testosterone prescriptions in the United States and Canada, respectively, with Internet pharmacies playing a major role in the latter's increase.[1] U.S. pharmaceutical sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales.[1, 2] On September 17, 2014, the U.S. Food and Drug Administration (FDA) convened a meeting to address concerns that many men are receiving testosterone who should not and because of reports of adverse cardiovascular events in men using testosterone.[3] We join others who characterize the mass marketing of testosterone coupled with the permissive prescribing of testosterone for common, nonspecific, aging-related symptoms as disease mongering of declines in testosterone with advancing age.[4, 5] Disease mongering is defined as “the selling of sickness that widens the boundaries of illness and grows the markets for those who sell and deliver treatments.”[6] The prescribing of growth hormone for “antiaging” or “age management” is another example of disease mongering.
A combination of direct-to-consumer product advertising (DTCPA) and lax consensus guidelines for testosterone prescribing have, over the past decade, led to 10- and 40-fold increases in testosterone prescriptions in the United States and Canada, respectively, with Internet pharmacies playing a major role in the latter's increase.[1] U.S. pharmaceutical sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales.[1, 2] On September 17, 2014, the U.S. Food and Drug Administration (FDA) convened a meeting to address concerns that many men are receiving testosterone who should not and because of reports of adverse cardiovascular events in men using testosterone.[3] We join others who characterize the mass marketing of testosterone coupled with the permissive prescribing of testosterone for common, nonspecific, aging-related symptoms as disease mongering of declines in testosterone with advancing age.[4, 5] Disease mongering is defined as “the selling of sickness that widens the boundaries of illness and grows the markets for those who sell and deliver treatments.”[6] The prescribing of growth hormone for “antiaging” or “age management” is another example of disease mongering.
What about all the ads for drugs treating arthritis another age related disease,should we just live with the pain because its part of getting older.......
What's Next For The Thousands Of Angry Men Suing Over Testosterone?
http://www.forbes.com/sites/arlenew...ousands-of-angry-men-suing-over-testosterone/
More than 1,340 angry men who tried testosterone supplementation to treat their “Low T”—and who believe they were harmed as a result—have joined a collection of lawsuits pending in the U.S. District Court in the Northern District of Illinois against seven companies involved in the marketing of the hormone. Now what?
A hint of what’s to come could emerge April 21, when the court overseeing the cases is scheduled to hold a conference on the progress of discovery efforts. All of the men involved in the suits believe they suffered heart attacks, strokes, or other health problems after taking testosterone, and as of now, the first case is scheduled to go to trial in the fall of 2016.
http://www.forbes.com/sites/arlenew...ousands-of-angry-men-suing-over-testosterone/
More than 1,340 angry men who tried testosterone supplementation to treat their “Low T”—and who believe they were harmed as a result—have joined a collection of lawsuits pending in the U.S. District Court in the Northern District of Illinois against seven companies involved in the marketing of the hormone. Now what?
A hint of what’s to come could emerge April 21, when the court overseeing the cases is scheduled to hold a conference on the progress of discovery efforts. All of the men involved in the suits believe they suffered heart attacks, strokes, or other health problems after taking testosterone, and as of now, the first case is scheduled to go to trial in the fall of 2016.
Testosterone Medications Need New Label Information
http://jama.jamanetwork.com/article.aspx?articleid=2214064
Men should not use prescription testosterone products to counteract the effects of aging, the US Food and Drug Administration (FDA) said March 3 in a safety announcement. In addition, the agency concluded that testosterone use might be linked to an increased cardiovascular risk. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm
“The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone,” the agency noted. “Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.” Such medical conditions include damage from chemotherapy or infection and disorders of the testicles, pituitary gland, or brain.
The FDA told manufacturers of these products to make 2 label changes: clarify the approved uses and add information about a possible increased risk of heart attacks and strokes. The agency is also requiring them to conduct a well-designed clinical trial, either collaboratively or individually, to see whether testosterone users have an increased heart attack or stroke risk.
Public Citizen, an advocacy organization in Washington, DC, had petitioned the FDA in February 2014 for a black box warning about cardiovascular risk on testosterone products. http://www.citizen.org/documents/21841.pdf
However, the agency rejected the petition for “insufficient evidence” last July—the day after Canadian health officials warned about cardiovascular risk linked to testosterone products. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/40587a-eng.php#you-vous
“Had the FDA made this announcement last summer when the Canadian government acted, it would have reduced the number of US prescriptions for and damage from testosterone,” Sidney Wolfe, MD, founder and senior advisor for Public Citizen’s Health Research Group, said in a statement. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=5430
http://jama.jamanetwork.com/article.aspx?articleid=2214064
Men should not use prescription testosterone products to counteract the effects of aging, the US Food and Drug Administration (FDA) said March 3 in a safety announcement. In addition, the agency concluded that testosterone use might be linked to an increased cardiovascular risk. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm
“The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone,” the agency noted. “Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.” Such medical conditions include damage from chemotherapy or infection and disorders of the testicles, pituitary gland, or brain.
The FDA told manufacturers of these products to make 2 label changes: clarify the approved uses and add information about a possible increased risk of heart attacks and strokes. The agency is also requiring them to conduct a well-designed clinical trial, either collaboratively or individually, to see whether testosterone users have an increased heart attack or stroke risk.
Public Citizen, an advocacy organization in Washington, DC, had petitioned the FDA in February 2014 for a black box warning about cardiovascular risk on testosterone products. http://www.citizen.org/documents/21841.pdf
However, the agency rejected the petition for “insufficient evidence” last July—the day after Canadian health officials warned about cardiovascular risk linked to testosterone products. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/40587a-eng.php#you-vous
“Had the FDA made this announcement last summer when the Canadian government acted, it would have reduced the number of US prescriptions for and damage from testosterone,” Sidney Wolfe, MD, founder and senior advisor for Public Citizen’s Health Research Group, said in a statement. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=5430
Testosterone Therapy: The New Drug Seekers
Kleier JA. Testosterone therapy: the new drug seekers. Urol Nurs. 2014;34(4):162-3. http://www.medscape.com/viewarticle/831646
As testosterone therapy (TT) has moved from being available only in injection form to more convenient topical solution gels and implantable pellets, drug manufacturers have turned to direct-to-consumer advertisement to promote its use.
Likely, we have all seen these advertisements that ask men if they have experienced low libido, fatigue, irritability, or weight gain and muscle loss – symptoms associated with low testosterone (or low-T).
At the same time, they show a middle-aged, physically fit, attractive man participating in a sports activity or in close, intimate proximity with a potential sexual partner.
The attention of viewers is so drawn to the on-screen activities that they hardly attend as the announcer rattles off the list of precautions and possible adverse effects of the medication.
The intent of the advertizing is for the aging, grumpy, tired, overweight male whose sexual appetite and ability has waned to be convinced that TT will restore his manhood, improve his physique, lead to social and sexual encounters, and make him attractive and happy, the proverbial fountain of youth.
These advertisements are effective. Over the past approximately 14 years, the number of men in the United States (U.S.) using TT has nearly quadrupled.
With the increase in demand has come evidence that many men start TT without clear medical need, receiving TT based on non-specific symptoms and without adequate testing of testosterone levels or with testosterone levels within normal range (Layton et al., 2014. http://press.endocrine.org/doi/full/10.1210/jc.2013-3570).
Testosterone therapy, which was once reserved as a treatment for people suffering from hormonal deficiencies, has now become more of a lifestyle product.
Kleier JA. Testosterone therapy: the new drug seekers. Urol Nurs. 2014;34(4):162-3. http://www.medscape.com/viewarticle/831646
As testosterone therapy (TT) has moved from being available only in injection form to more convenient topical solution gels and implantable pellets, drug manufacturers have turned to direct-to-consumer advertisement to promote its use.
Likely, we have all seen these advertisements that ask men if they have experienced low libido, fatigue, irritability, or weight gain and muscle loss – symptoms associated with low testosterone (or low-T).
At the same time, they show a middle-aged, physically fit, attractive man participating in a sports activity or in close, intimate proximity with a potential sexual partner.
The attention of viewers is so drawn to the on-screen activities that they hardly attend as the announcer rattles off the list of precautions and possible adverse effects of the medication.
The intent of the advertizing is for the aging, grumpy, tired, overweight male whose sexual appetite and ability has waned to be convinced that TT will restore his manhood, improve his physique, lead to social and sexual encounters, and make him attractive and happy, the proverbial fountain of youth.
These advertisements are effective. Over the past approximately 14 years, the number of men in the United States (U.S.) using TT has nearly quadrupled.
With the increase in demand has come evidence that many men start TT without clear medical need, receiving TT based on non-specific symptoms and without adequate testing of testosterone levels or with testosterone levels within normal range (Layton et al., 2014. http://press.endocrine.org/doi/full/10.1210/jc.2013-3570).
Testosterone therapy, which was once reserved as a treatment for people suffering from hormonal deficiencies, has now become more of a lifestyle product.
Malik RD, Wang CE, Lapin B, Lakeman JC, Helfand BT. Characteristics of Men Undergoing Testosterone Replacement Therapy and Adherence to Follow-up Recommendations in Metropolitan Multicenter Health Care System. Urology. http://www.goldjournal.net/article/S0090-4295(15)00106-5/abstract
OBJECTIVE: To identify the frequencies of treatment and recommended laboratory follow-up for men with low serum testosterone levels.
METHODS: The Electronic Data Warehouse was queried to identify men of ages 18-85 years, who obtained a testing for serum total testosterone level from 2009 to 2012. The frequency of testosterone replacement therapy (TRT), patient demographics, and clinical characteristics were collected. The frequency of follow-up with serum total testosterone and complete blood count levels was documented.
RESULTS: Among 9176 men who underwent testing for low testosterone levels, 3320 (36%) of them were hypogonadal with a mean serum total testosterone level of 194.3 +/- 64.9 ng/dL.
Of them, 17.7% men were treated with TRTs. The treatment frequency significantly increased from 8.3% in 2009 to 24% in 2012. A total of 4.8% of men of reproductive ages (age, 18-35 years) were placed on TRTs.
Within 180 days of initial testing, only 40% of treated men received follow-up with liver function tests and/or complete blood count, and only 49% had a follow-up serum testosterone level.
CONCLUSION: Although the frequency of TRT is increasing, only a small percentage of hypogonadal men are actively undergoing treatment.
A significant proportion of men of reproductive age are being treated with significant impacts on potential fertility. Less than half of the patients treated are being monitored appropriately after testosterone replacement.
This highlights the importance of further education for providers prescribing testosterone replacement.
OBJECTIVE: To identify the frequencies of treatment and recommended laboratory follow-up for men with low serum testosterone levels.
METHODS: The Electronic Data Warehouse was queried to identify men of ages 18-85 years, who obtained a testing for serum total testosterone level from 2009 to 2012. The frequency of testosterone replacement therapy (TRT), patient demographics, and clinical characteristics were collected. The frequency of follow-up with serum total testosterone and complete blood count levels was documented.
RESULTS: Among 9176 men who underwent testing for low testosterone levels, 3320 (36%) of them were hypogonadal with a mean serum total testosterone level of 194.3 +/- 64.9 ng/dL.
Of them, 17.7% men were treated with TRTs. The treatment frequency significantly increased from 8.3% in 2009 to 24% in 2012. A total of 4.8% of men of reproductive ages (age, 18-35 years) were placed on TRTs.
Within 180 days of initial testing, only 40% of treated men received follow-up with liver function tests and/or complete blood count, and only 49% had a follow-up serum testosterone level.
CONCLUSION: Although the frequency of TRT is increasing, only a small percentage of hypogonadal men are actively undergoing treatment.
A significant proportion of men of reproductive age are being treated with significant impacts on potential fertility. Less than half of the patients treated are being monitored appropriately after testosterone replacement.
This highlights the importance of further education for providers prescribing testosterone replacement.
Warburton D, Hobaugh C, Wang G, Lin H, Wang R. Testosterone replacement therapy and the risk of prostate cancer. Asian J Androl. http://www.ajandrology.com/preprintarticle.asp?id=150841
Understanding the role of testosterone replacement therapy (TRT) in the development and progression of prostate cancer is an important concept in treating patients with symptoms of hypogonadism.
This article revealed a small number of mostly retrospective, observational studies describing the use of TRT in the general population, in men with prostatic intraepithelial neoplasia (PIN), in men with a history of treated prostate cancer, and in men on active surveillance for prostate cancer.
The current literature does not report a statistically significant increase in the development or progression of prostate cancer in men receiving testosterone replacement for symptomatic hypogonadism, and the prostate saturation theory provides a model explaining the basis for these results.
The use of TRT in men with a history of prostate cancer is considered experimental, but future results from randomized controlled trials could lead to a change in our current treatment approach.
Understanding the role of testosterone replacement therapy (TRT) in the development and progression of prostate cancer is an important concept in treating patients with symptoms of hypogonadism.
This article revealed a small number of mostly retrospective, observational studies describing the use of TRT in the general population, in men with prostatic intraepithelial neoplasia (PIN), in men with a history of treated prostate cancer, and in men on active surveillance for prostate cancer.
The current literature does not report a statistically significant increase in the development or progression of prostate cancer in men receiving testosterone replacement for symptomatic hypogonadism, and the prostate saturation theory provides a model explaining the basis for these results.
The use of TRT in men with a history of prostate cancer is considered experimental, but future results from randomized controlled trials could lead to a change in our current treatment approach.
Jia H, Sullivan CT, McCoy SC, Yarrow JF, Morrow M, et al. Review of health risks of low testosterone and testosterone administration. World J Clin Cases. 2015;3(4):338-44. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391003/
Hypogonadism is prevalent in older men and testosterone replacement therapy (TRT) for older hypogonadal men is a promising therapy.
However, a number of important clinical concerns over TRT safety remain unsolved due to a lack of large-scale randomized clinical trials directly comparing the health risks of untreated hypogonadism vs long-term use of TRT.
Meta-analyses of clinical trials of TRT as of 2010 have identified three major adverse events resulting from TRT:
polycythemia,
an increase in prostate-related events, and
a slight reduction in serum high-density lipoprotein cholesterol.
There are other purported health risks but their incidence can be neither confirmed nor denied based on the small number of subjects that have been studied to date. Furthermore, subsequent literature is equivocal with regard to the safety and utility of TRT and this topic has been subject to contentious debate.
Since January 2014, the United States Food and Drug Administration has released two official announcements regarding the safety of TRT and clinical monitoring the risks in TRT users. Additionally, the health risks related to the clinical presentation of low or declining testosterone levels not been resolved in the current literature.
Because TRT is prescribed in the context of putative risks resulting from reduced testosterone levels, we reviewed the epidemiology and reported risks of low testosterone levels.
We also highlight the current information about TRT utilization, the risks most often claimed to be associated with TRT, and current or emerging alternatives to TRT.
Hypogonadism is prevalent in older men and testosterone replacement therapy (TRT) for older hypogonadal men is a promising therapy.
However, a number of important clinical concerns over TRT safety remain unsolved due to a lack of large-scale randomized clinical trials directly comparing the health risks of untreated hypogonadism vs long-term use of TRT.
Meta-analyses of clinical trials of TRT as of 2010 have identified three major adverse events resulting from TRT:
polycythemia,
an increase in prostate-related events, and
a slight reduction in serum high-density lipoprotein cholesterol.
There are other purported health risks but their incidence can be neither confirmed nor denied based on the small number of subjects that have been studied to date. Furthermore, subsequent literature is equivocal with regard to the safety and utility of TRT and this topic has been subject to contentious debate.
Since January 2014, the United States Food and Drug Administration has released two official announcements regarding the safety of TRT and clinical monitoring the risks in TRT users. Additionally, the health risks related to the clinical presentation of low or declining testosterone levels not been resolved in the current literature.
Because TRT is prescribed in the context of putative risks resulting from reduced testosterone levels, we reviewed the epidemiology and reported risks of low testosterone levels.
We also highlight the current information about TRT utilization, the risks most often claimed to be associated with TRT, and current or emerging alternatives to TRT.
Gomella LG. The testosterone storm. Can J Urol. 215;22(2):7677. http://www.canjurol.com/article.php?ID=2875
The concept of the thyroid storm is well known in medicine. Today we are dealing with what might be called a “testosterone storm” surrounding the scientific and public health debate over the use of testosterone replacement therapy. Last year, after a September 2014 FDA Advisory Committee meeting, manufacturers were required to include a label addition about a “possible” increased risk of heart attacks and strokes in patients taking testosterone. A large-scale study to assess cardiovascular risk was also recommended. The uncertainty of whether or not testosterone supplementation increases cardiovascular risks is the primary driver of the conflict.
There have been major improvements in the safety, quality, and ease of administration of testosterone replacements over the last few years. With these new routes of administration such as transdermal, subcutaneous and transmucosal, there has been an increase in interest in this aspect of men’s health with growth in both marketing and prescribing of testosterone supplements.
The 2014 meeting also included a rejection of a petition by Public Citizen to add a black box warning to testosterone supplements. In a published analysis prior to the meeting the FDA identified only 4 studies suggesting increased risk. In contrast, a systematic analysis of the literature identified over 80 studies demonstrating contradictory evidence. These note that low testosterone levels are associated with all-cause and cardiovascular mortality, and trials in men with angina showing improved exercise capability with testosterone supplementation. Testosterone therapy can improve metabolic syndrome (reduce fat and waist circumference, improve insulin resistance). Unfortunately, media focused attention on very few flawed studies and turned attention away from the positive accumulating evidence.
Could potentially flawed data have fueled the debate? Dr. Abe Morgentaler, Associate Clinical Professor, Urology, Harvard Medical School and more than 150 academic and clinical leaders questioned the veracity of one of the major studies that prompted the FDA action and called for its retraction on the basis of the data being “no longer credible”.1 The paper contained methodologic flaws and the inclusion of females in the analysis. In the publication erratum the rates of adverse cardiac events were actually reduced by half in the testosterone treated group. This was followed by 29 medical societies from around the world joining the petition for retraction.
While there is universal agreement that testosterone is generally safe and beneficial when used in young, hypogonadal men another controversy is the suggestion of an increase in the inappropriate use of testosterone supplements. There is the impression that testosterone can serve as a fountain of youth for the aging male. While prescription testosterone supplements are approved for hypogonadal conditions, marketing pieces are also seen by men who may not have low levels of testosterone. Advertisements promote the use of testosterone supplementation for low energy, decreased sex drive and poor performance. Many men receiving supplemental testosterone today may not meet the clinical guidelines for treatment. Of concern is that many men being prescribed testosterone have never had a serum blood test before the testosterone was prescribed. Much like pre-certification for high end cancer medications, perhaps it should be mandated that a proper determination of testosterone has been performed in order for any replacement to be administered. This is reasonable as no data exists to show additional testosterone in a man with normal levels yields any health benefits.
The concept of testosterone replacement and prostate cancer is yet another area of disagreement. Some advocate that men who have been successfully treated for localized prostate cancer who are free of disease and hypogonadal should be replaced. Every testosterone label has prostate cancer (known or suspected) as a contraindication sending a powerful message to the clinician. This is an area where there is more literature supporting this approach than showing harm.
While the FDA has focused on the potential adverse cardiovascular effects of testosterone a recent European study has suggested that there is no risk. A study of over 25,000 male Medicare beneficiaries who received testosterone therapy for up to 8 years had no demonstrable cardiovascular risk. Another recent meta-analysis of 75 studies has shown no increased risk, and a reduced risk among some men.
Until the FDA’s requested long term studies of testosterone supplementation are available, these numerous controversies are unlikely to abate. Prescribers are now obligated to inform patients of the cardiovascular risks of testosterone supplementation while these stormy disagreements continue.
Leonard G. Gomella, MD Thomas Jefferson University Philadelphia, PA
1. Vigen R, O’Donnell CI, Barón AE et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310(17):1829-1836 Erratum: JAMA 2014;311(9):967.
The concept of the thyroid storm is well known in medicine. Today we are dealing with what might be called a “testosterone storm” surrounding the scientific and public health debate over the use of testosterone replacement therapy. Last year, after a September 2014 FDA Advisory Committee meeting, manufacturers were required to include a label addition about a “possible” increased risk of heart attacks and strokes in patients taking testosterone. A large-scale study to assess cardiovascular risk was also recommended. The uncertainty of whether or not testosterone supplementation increases cardiovascular risks is the primary driver of the conflict.
There have been major improvements in the safety, quality, and ease of administration of testosterone replacements over the last few years. With these new routes of administration such as transdermal, subcutaneous and transmucosal, there has been an increase in interest in this aspect of men’s health with growth in both marketing and prescribing of testosterone supplements.
The 2014 meeting also included a rejection of a petition by Public Citizen to add a black box warning to testosterone supplements. In a published analysis prior to the meeting the FDA identified only 4 studies suggesting increased risk. In contrast, a systematic analysis of the literature identified over 80 studies demonstrating contradictory evidence. These note that low testosterone levels are associated with all-cause and cardiovascular mortality, and trials in men with angina showing improved exercise capability with testosterone supplementation. Testosterone therapy can improve metabolic syndrome (reduce fat and waist circumference, improve insulin resistance). Unfortunately, media focused attention on very few flawed studies and turned attention away from the positive accumulating evidence.
Could potentially flawed data have fueled the debate? Dr. Abe Morgentaler, Associate Clinical Professor, Urology, Harvard Medical School and more than 150 academic and clinical leaders questioned the veracity of one of the major studies that prompted the FDA action and called for its retraction on the basis of the data being “no longer credible”.1 The paper contained methodologic flaws and the inclusion of females in the analysis. In the publication erratum the rates of adverse cardiac events were actually reduced by half in the testosterone treated group. This was followed by 29 medical societies from around the world joining the petition for retraction.
While there is universal agreement that testosterone is generally safe and beneficial when used in young, hypogonadal men another controversy is the suggestion of an increase in the inappropriate use of testosterone supplements. There is the impression that testosterone can serve as a fountain of youth for the aging male. While prescription testosterone supplements are approved for hypogonadal conditions, marketing pieces are also seen by men who may not have low levels of testosterone. Advertisements promote the use of testosterone supplementation for low energy, decreased sex drive and poor performance. Many men receiving supplemental testosterone today may not meet the clinical guidelines for treatment. Of concern is that many men being prescribed testosterone have never had a serum blood test before the testosterone was prescribed. Much like pre-certification for high end cancer medications, perhaps it should be mandated that a proper determination of testosterone has been performed in order for any replacement to be administered. This is reasonable as no data exists to show additional testosterone in a man with normal levels yields any health benefits.
The concept of testosterone replacement and prostate cancer is yet another area of disagreement. Some advocate that men who have been successfully treated for localized prostate cancer who are free of disease and hypogonadal should be replaced. Every testosterone label has prostate cancer (known or suspected) as a contraindication sending a powerful message to the clinician. This is an area where there is more literature supporting this approach than showing harm.
While the FDA has focused on the potential adverse cardiovascular effects of testosterone a recent European study has suggested that there is no risk. A study of over 25,000 male Medicare beneficiaries who received testosterone therapy for up to 8 years had no demonstrable cardiovascular risk. Another recent meta-analysis of 75 studies has shown no increased risk, and a reduced risk among some men.
Until the FDA’s requested long term studies of testosterone supplementation are available, these numerous controversies are unlikely to abate. Prescribers are now obligated to inform patients of the cardiovascular risks of testosterone supplementation while these stormy disagreements continue.
Leonard G. Gomella, MD Thomas Jefferson University Philadelphia, PA
1. Vigen R, O’Donnell CI, Barón AE et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310(17):1829-1836 Erratum: JAMA 2014;311(9):967.
Borst SE, Yarrow JF. Injection of Testosterone May be Safer and More effective than Transdermal Administration for combating Loss of Muscle and Bone in Older Men. Am J Physiol Endocrinol Metab. http://ajpendo.physiology.org/content/early/2015/04/16/ajpendo.00111.2015
The value of testosterone replacement therapy (TRT) for older men is currently a topic of intense debate. While US testosterone prescriptions have tripled in the last decade (7), debate continues over the risks and benefits of TRT. TRT is currently prescribed for older men with either low serum testosterone (T) or low T plus accompanying symptoms of hypogonadism. Serum T </= 300 ng/dL is considered to be low and T </= 250 is frank hypogonadism.
Treatment for men who have low T without accompanying symptoms remains somewhat controversial. TRT produces benefits including increased muscle mass and strength, decreased fat mass, increased and bone mineral density.
TRT also produces known risks including development of polycythemia, decrease in HDL, breast tenderness and enlargement, prostate enlargement, and increases in serum PSA and prostate-related events.
Importantly, TRT does not increase the risk of prostate cancer. Several recent reports have also indicated that TRT may produce cardiovascular (CV) risks, while others report no risk or even benefit.
To address the potential CV risks of TRT, we have recently reported via meta-analysis that oral TRT increases CV risk and suggested that the CV risk profile for i.m. TRT may be better than that for oral or transdermal TRT.
Herein, we review the literature which indicates that i.m. TRT produces greater musculoskeletal and may be safer that either oral or transdermal preparations. We also review the literature discussing the use of 5alpha-reductase inhibitors as a promising means of improving the safety profile of TRT.
The value of testosterone replacement therapy (TRT) for older men is currently a topic of intense debate. While US testosterone prescriptions have tripled in the last decade (7), debate continues over the risks and benefits of TRT. TRT is currently prescribed for older men with either low serum testosterone (T) or low T plus accompanying symptoms of hypogonadism. Serum T </= 300 ng/dL is considered to be low and T </= 250 is frank hypogonadism.
Treatment for men who have low T without accompanying symptoms remains somewhat controversial. TRT produces benefits including increased muscle mass and strength, decreased fat mass, increased and bone mineral density.
TRT also produces known risks including development of polycythemia, decrease in HDL, breast tenderness and enlargement, prostate enlargement, and increases in serum PSA and prostate-related events.
Importantly, TRT does not increase the risk of prostate cancer. Several recent reports have also indicated that TRT may produce cardiovascular (CV) risks, while others report no risk or even benefit.
To address the potential CV risks of TRT, we have recently reported via meta-analysis that oral TRT increases CV risk and suggested that the CV risk profile for i.m. TRT may be better than that for oral or transdermal TRT.
Herein, we review the literature which indicates that i.m. TRT produces greater musculoskeletal and may be safer that either oral or transdermal preparations. We also review the literature discussing the use of 5alpha-reductase inhibitors as a promising means of improving the safety profile of TRT.
Sonmez A, Haymana C, Aydogdu A, Tapan S, Basaran Y, et al. Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. Endocr J. https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ15-0125/_article
Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear.
We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects.
A total of 60 patients with CHH (mean age 21.82+/-2.22 years) and 70 healthy control subjects (mean age 21.32+/-1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT.
The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls.
After 5.56+/-2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant.
The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT.
Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear.
We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects.
A total of 60 patients with CHH (mean age 21.82+/-2.22 years) and 70 healthy control subjects (mean age 21.32+/-1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT.
The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls.
After 5.56+/-2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant.
The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT.
Layton J, Meier CR, Sharpless JL, Stürmer T, Jick SS, Brookhart M. Comparative Safety of Testosterone Dosage Forms. JAMA Intern Med. Published online May 11, 2015.
Importance - Increases in testosterone use and mixed reports of adverse events have raised concerns about the cardiovascular safety of testosterone. Testosterone is available in several delivery mechanisms with varying pharmacokinetics; injections cause spikes in testosterone levels, and transdermal patches and gels cause more subtle but sustained increases. The comparative cardiovascular safety of gels, injections, and patches has not been studied.
Objective - To determine the comparative cardiovascular safety of testosterone injections, patches, and gels.
Design, Setting, and Participants - A retrospective cohort study was conducted using administrative claims from a commercially insured (January 1, 2000, to December 31, 2012) and Medicare (January 1, 2007, to December 31, 2010) population in the United States and general practitioner records from the United Kingdom (January 1, 2000, to June 30, 2012). Participants included 13 men (aged ≥18 years) who initiated use of testosterone patches, gels, or 14 injections following 180 days with no testosterone use. Our analysis was conducted from December 11, 2013, to November 12, 2014.
Exposures - New initiation of a testosterone dosage form, with use monitored for up to 1 year.
Main Outcomes and Measures - Inpatient or outpatient medical records, diagnoses, or claims for cardiovascular and cerebrovascular events including myocardial infarction (MI), unstable angina, stroke, and composite acute event (MI, unstable angina, or stroke); venous thromboembolism (VTE); mortality; and all-cause hospitalization.
Results - We identified 544 115 testosterone initiators between the 3 data sets: 37.4% injection, 6.9% patch, and 55.8% gel. The majority of men in the Medicare cohort were injection initiators (51.2%), most in the US commercially insured population were gel initiators (56.5%), and the UK database included equal proportions of injections and gel users (approximately 41%).
With analysis conducted using hazard ratios and 95% CIs, compared with men using gels, injection initiators had higher hazards of cardiovascular events (ie, MI, unstable angina, and stroke) (1.26; 1.18-1.35), hospitalization (1.16; 1.13-1.19), and death (1.34; 1.15-1.56) but not VTE (0.92; 0.76-1.11).
Compared with gels, patches did not confer increased hazards of cardiovascular events (1.10; 0.94-1.29), hospitalization (1.04; 1.00-1.08), death (1.02; 0.77-1.33), or VTE (1.08; 0.79-1.47).
Conclusions and Relevance - Testosterone injections were associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with gels. Patches and gels had similar risk profiles. However, this study did not assess whether patients met criteria for use of testosterone and did not assess the safety of testosterone among users compared with nonusers of the drug.
Importance - Increases in testosterone use and mixed reports of adverse events have raised concerns about the cardiovascular safety of testosterone. Testosterone is available in several delivery mechanisms with varying pharmacokinetics; injections cause spikes in testosterone levels, and transdermal patches and gels cause more subtle but sustained increases. The comparative cardiovascular safety of gels, injections, and patches has not been studied.
Objective - To determine the comparative cardiovascular safety of testosterone injections, patches, and gels.
Design, Setting, and Participants - A retrospective cohort study was conducted using administrative claims from a commercially insured (January 1, 2000, to December 31, 2012) and Medicare (January 1, 2007, to December 31, 2010) population in the United States and general practitioner records from the United Kingdom (January 1, 2000, to June 30, 2012). Participants included 13 men (aged ≥18 years) who initiated use of testosterone patches, gels, or 14 injections following 180 days with no testosterone use. Our analysis was conducted from December 11, 2013, to November 12, 2014.
Exposures - New initiation of a testosterone dosage form, with use monitored for up to 1 year.
Main Outcomes and Measures - Inpatient or outpatient medical records, diagnoses, or claims for cardiovascular and cerebrovascular events including myocardial infarction (MI), unstable angina, stroke, and composite acute event (MI, unstable angina, or stroke); venous thromboembolism (VTE); mortality; and all-cause hospitalization.
Results - We identified 544 115 testosterone initiators between the 3 data sets: 37.4% injection, 6.9% patch, and 55.8% gel. The majority of men in the Medicare cohort were injection initiators (51.2%), most in the US commercially insured population were gel initiators (56.5%), and the UK database included equal proportions of injections and gel users (approximately 41%).
With analysis conducted using hazard ratios and 95% CIs, compared with men using gels, injection initiators had higher hazards of cardiovascular events (ie, MI, unstable angina, and stroke) (1.26; 1.18-1.35), hospitalization (1.16; 1.13-1.19), and death (1.34; 1.15-1.56) but not VTE (0.92; 0.76-1.11).
Compared with gels, patches did not confer increased hazards of cardiovascular events (1.10; 0.94-1.29), hospitalization (1.04; 1.00-1.08), death (1.02; 0.77-1.33), or VTE (1.08; 0.79-1.47).
Conclusions and Relevance - Testosterone injections were associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with gels. Patches and gels had similar risk profiles. However, this study did not assess whether patients met criteria for use of testosterone and did not assess the safety of testosterone among users compared with nonusers of the drug.
Wierman ME. Risks of Different Testosterone Preparations: Too Much, Too Little, Just Right. JAMA Intern Med. Published online May 11, 2015. http://archinte.jamanetwork.com/article.aspx?articleID=2293076
There is a developing story that the increased use of testosterone therapy without a diagnosis of hypogonadism is associated with an elevated cardiovascular risk for some patients. In this issue of JAMA Internal Medicine, Layton and coauthors1 deepen our knowledge with their analysis of 3 large databases (Truven MarketScan and Medicare cohorts from the United States and the Clinical Practice Research Datalink cohort from the United Kingdom) to ask whether they could detect a difference in cardiovascular or cerebrovascular events and mortality in patients newly prescribed testosterone therapy in the form of injectable testosterone compared with testosterone gels or patches.
The strengths of the study include the large number of men in the data sets given testosterone therapy (>430 000), patient diversity, and difference in provider prescribing habits with stricter use of testosterone therapy in the United Kingdom compared with the United States. Layton et al1 examined cardiovascular event risk within the first year after testosterone prescription because a prior clinical trial2 and several large epidemiologic studies3,4 suggest the association is observed within this time frame. This new large data analysis demonstrated that prescription of injectable depo-testosterone was associated with a higher overall cardiovascular risk, including myocardial infarction, unstable angina, and stroke (hazard ratio
, 1.26; 95% CI, 1.18-1.35), hospitalization (HR, 1.16; 95% CI, 1.13-1.19), and death (HR, 1.34; 95% CI, 1.15-1.56) compared with testosterone gel or patch formulations. The outcomes of the analysis support the hypothesis that intermittent pharmacologic levels of testosterone, which are inevitable with an injectable depo-testosterone administration every 2 to 3 weeks, result in an association with an increase in the combined outcome of cardiovascular and cerebrovascular morbidity and death. The absolute risk between testosterone therapy groups was small in this epidemiologic analysis, but the risk does raise concern considering the marked increase in testosterone prescriptions both in the United States and internationally5 and prior associations in large data sets of increased risks in men receiving vs those not receiving treatment.3,4 In addition, Layton and colleagues1 did not include a comparison group of men not receiving testosterone, so overall risks and benefits of the therapy cannot be compared between the groups.
Layton et al1 acknowledge the limitations of the study, including lack of information concerning the indication for treatment and only partial data concerning testosterone levels before initiating or during therapy. However, their findings are consistent with those of other large epidemiologic studies3,4 and the recent alarming US Food and Drug Administration report that more than 25% of testosterone prescriptions in the United States are written without determination of a level and that more than 30% of patients receiving testosterone therapy do not have follow-up laboratory testing.5 Taken together, these reports suggest that testosterone therapy is often being prescribed off label as an anabolic steroid and not for a diagnosis of hypogonadism, which requires signs and symptoms together with a testosterone level below the reference range.6 The results from the analysis by Layton and coworkers1 are consistent with most, but not all, recent epidemiologic data sets6; together, these studies can inform both patients and health care professionals. It is somewhat reassuring that, more recently, there was an increase in testosterone gel and patch prescriptions over injectable prescriptions since those transdermal formulations have been noted to carry a smaller risk of pharmacologic dosing unless at dosages prescribed above the label indications.
The other important outcome in the data set was the lack of evidence for a signal of an increased association of venous thromboembolism with testosterone therapy (hazard ratio, 0.92; 95% CI, 0.76-1.11). The prior studies showing an increased risk of venous thromboembolism with testosterone use, which influenced the US Food and Drug Administration to add a comment to the prescribing label, most likely reflect either patients given pharmacologic testosterone, which is converted by aromatase into high levels of estrogens, or those rare patients with underlying genetic hypercoagulable risk.
As with all epidemiologic studies, the results reported by Layton and colleagues1 show associations, not necessarily causal relationships. There were limited data on whether testosterone therapy was prescribed for hypogonadism, whether the testosterone levels were low on initiation of therapy or at follow-up, or whether men who received injectable formulations were somehow at higher cardiovascular risk than those given gels or patches.
The new data provided by Layton et al1 support the Endocrine Society guidelines,6 which recommend testosterone therapy for the treatment of hypogonadism rather than just for specific symptoms alone or for a testosterone laboratory-determined cutoff level. Careful evaluation of each patient for an underlying cause that may be reversible is needed, as well as treatment with physiologic testosterone replacement strategies with close monitoring and follow-up to evaluate risk and benefit. The results of the Layton et al1 study can reassure physicians who rationally provide treatment for men with true hypogonadism with approaches that result in physiologic levels of testosterone, which is a safe and effective therapy. Finally, the study raises the issue of whether injectable depo-testosterone or other formulations that consistently result in levels outside the physiologic range should be restricted or at least more carefully monitored for cardiovascular risk.
Abundant epidemiologic data suggest that both very low and high testosterone levels are associated with increased cardiovascular risk. Thus, as with Goldilocks and her porridge, too much is bad, too little is bad, and just right is needed when it comes to testosterone treatment strategies in men with hypogonadism.
There is a developing story that the increased use of testosterone therapy without a diagnosis of hypogonadism is associated with an elevated cardiovascular risk for some patients. In this issue of JAMA Internal Medicine, Layton and coauthors1 deepen our knowledge with their analysis of 3 large databases (Truven MarketScan and Medicare cohorts from the United States and the Clinical Practice Research Datalink cohort from the United Kingdom) to ask whether they could detect a difference in cardiovascular or cerebrovascular events and mortality in patients newly prescribed testosterone therapy in the form of injectable testosterone compared with testosterone gels or patches.
The strengths of the study include the large number of men in the data sets given testosterone therapy (>430 000), patient diversity, and difference in provider prescribing habits with stricter use of testosterone therapy in the United Kingdom compared with the United States. Layton et al1 examined cardiovascular event risk within the first year after testosterone prescription because a prior clinical trial2 and several large epidemiologic studies3,4 suggest the association is observed within this time frame. This new large data analysis demonstrated that prescription of injectable depo-testosterone was associated with a higher overall cardiovascular risk, including myocardial infarction, unstable angina, and stroke (hazard ratio
, 1.26; 95% CI, 1.18-1.35), hospitalization (HR, 1.16; 95% CI, 1.13-1.19), and death (HR, 1.34; 95% CI, 1.15-1.56) compared with testosterone gel or patch formulations. The outcomes of the analysis support the hypothesis that intermittent pharmacologic levels of testosterone, which are inevitable with an injectable depo-testosterone administration every 2 to 3 weeks, result in an association with an increase in the combined outcome of cardiovascular and cerebrovascular morbidity and death. The absolute risk between testosterone therapy groups was small in this epidemiologic analysis, but the risk does raise concern considering the marked increase in testosterone prescriptions both in the United States and internationally5 and prior associations in large data sets of increased risks in men receiving vs those not receiving treatment.3,4 In addition, Layton and colleagues1 did not include a comparison group of men not receiving testosterone, so overall risks and benefits of the therapy cannot be compared between the groups.
Layton et al1 acknowledge the limitations of the study, including lack of information concerning the indication for treatment and only partial data concerning testosterone levels before initiating or during therapy. However, their findings are consistent with those of other large epidemiologic studies3,4 and the recent alarming US Food and Drug Administration report that more than 25% of testosterone prescriptions in the United States are written without determination of a level and that more than 30% of patients receiving testosterone therapy do not have follow-up laboratory testing.5 Taken together, these reports suggest that testosterone therapy is often being prescribed off label as an anabolic steroid and not for a diagnosis of hypogonadism, which requires signs and symptoms together with a testosterone level below the reference range.6 The results from the analysis by Layton and coworkers1 are consistent with most, but not all, recent epidemiologic data sets6; together, these studies can inform both patients and health care professionals. It is somewhat reassuring that, more recently, there was an increase in testosterone gel and patch prescriptions over injectable prescriptions since those transdermal formulations have been noted to carry a smaller risk of pharmacologic dosing unless at dosages prescribed above the label indications.
The other important outcome in the data set was the lack of evidence for a signal of an increased association of venous thromboembolism with testosterone therapy (hazard ratio, 0.92; 95% CI, 0.76-1.11). The prior studies showing an increased risk of venous thromboembolism with testosterone use, which influenced the US Food and Drug Administration to add a comment to the prescribing label, most likely reflect either patients given pharmacologic testosterone, which is converted by aromatase into high levels of estrogens, or those rare patients with underlying genetic hypercoagulable risk.
As with all epidemiologic studies, the results reported by Layton and colleagues1 show associations, not necessarily causal relationships. There were limited data on whether testosterone therapy was prescribed for hypogonadism, whether the testosterone levels were low on initiation of therapy or at follow-up, or whether men who received injectable formulations were somehow at higher cardiovascular risk than those given gels or patches.
The new data provided by Layton et al1 support the Endocrine Society guidelines,6 which recommend testosterone therapy for the treatment of hypogonadism rather than just for specific symptoms alone or for a testosterone laboratory-determined cutoff level. Careful evaluation of each patient for an underlying cause that may be reversible is needed, as well as treatment with physiologic testosterone replacement strategies with close monitoring and follow-up to evaluate risk and benefit. The results of the Layton et al1 study can reassure physicians who rationally provide treatment for men with true hypogonadism with approaches that result in physiologic levels of testosterone, which is a safe and effective therapy. Finally, the study raises the issue of whether injectable depo-testosterone or other formulations that consistently result in levels outside the physiologic range should be restricted or at least more carefully monitored for cardiovascular risk.
Abundant epidemiologic data suggest that both very low and high testosterone levels are associated with increased cardiovascular risk. Thus, as with Goldilocks and her porridge, too much is bad, too little is bad, and just right is needed when it comes to testosterone treatment strategies in men with hypogonadism.
Has T administration once every 2-3 weeks ever been optimal? I'd like to see outcomes with smaller weekly or 2x weekly dosages.
Should Family Physicians Screen for Testosterone Deficiency in Men?
No: Screening May Be Harmful, and Benefits Are Unproven.
[For Full-Text Email mscally@alum.mit.edu (Include Title)]
Testosterone testing leads to testosterone treatment, which is inappropriate for the vast majority of patients. Testosterone treatment should be reserved for patients who are truly hypogonadal (e.g., those with uncorrected cryptorchidism or Klinefelter syndrome). There is no point in screening men for a disease state for which the treatment has unproven benefits and proven risks. Although testosterone labeling is likely to change, the promotion of testosterone testing and treatment in normal men may continue. Family physicians should just say no.
Fugh-Berman A. Should Family Physicians Screen for Testosterone Deficiency in Men? No: Screening May Be Harmful, and Benefits Are Unproven. Am Fam Physician. 2015;91(4):226-8. http://www.aafp.org/afp/2015/0215/p226.html
Should Family Physicians Screen for Testosterone Deficiency in Men?
Yes: Screening for Testosterone Deficiency Is Worthwhile for Most Older Men.
[For Full-Text Email mscally@alum.mit.edu (Include Title)]
Although screening targets asymptomatic men, testosterone deficiency is unique because symptoms are not always well defined. This warrants casting a wider net to identify a treatable condition. Symptoms such as depression, fatigue, and inability to perform vigorous activity are related to low testosterone levels, whereas there is an inverse relationship between the number of sexual symptoms and testosterone levels.
Heidelbaugh JJ. Should Family Physicians Screen for Testosterone Deficiency in Men? Yes: Screening for Testosterone Deficiency Is Worthwhile for Most Older Men. Am Fam Physician. 2015;91(4):220-1. http://www.aafp.org/afp/2015/0215/p220.html
No: Screening May Be Harmful, and Benefits Are Unproven.
[For Full-Text Email mscally@alum.mit.edu (Include Title)]
Testosterone testing leads to testosterone treatment, which is inappropriate for the vast majority of patients. Testosterone treatment should be reserved for patients who are truly hypogonadal (e.g., those with uncorrected cryptorchidism or Klinefelter syndrome). There is no point in screening men for a disease state for which the treatment has unproven benefits and proven risks. Although testosterone labeling is likely to change, the promotion of testosterone testing and treatment in normal men may continue. Family physicians should just say no.
Fugh-Berman A. Should Family Physicians Screen for Testosterone Deficiency in Men? No: Screening May Be Harmful, and Benefits Are Unproven. Am Fam Physician. 2015;91(4):226-8. http://www.aafp.org/afp/2015/0215/p226.html
Should Family Physicians Screen for Testosterone Deficiency in Men?
Yes: Screening for Testosterone Deficiency Is Worthwhile for Most Older Men.
[For Full-Text Email mscally@alum.mit.edu (Include Title)]
Although screening targets asymptomatic men, testosterone deficiency is unique because symptoms are not always well defined. This warrants casting a wider net to identify a treatable condition. Symptoms such as depression, fatigue, and inability to perform vigorous activity are related to low testosterone levels, whereas there is an inverse relationship between the number of sexual symptoms and testosterone levels.
Heidelbaugh JJ. Should Family Physicians Screen for Testosterone Deficiency in Men? Yes: Screening for Testosterone Deficiency Is Worthwhile for Most Older Men. Am Fam Physician. 2015;91(4):220-1. http://www.aafp.org/afp/2015/0215/p220.html
MACHO MAN: ACUTE MYOCARDIAL INFARCTION IN A MALE BODY BUILDER RECEIVING TESTOSTERONE INJECTIONS [#408]
[This is a case of uniformed ignorant physicians presenting a case that isn’t! Shame? None!]
Anand Kumthekar, MBBS1, Raphael Hulkower, MD1, James Tauras, MD2
1. Jacobi Medical Center-Albert Einstein College of Medicine, 2. Monterfiore Medical Center - Albert Einstein College of Medicine
Objective: Testosterone therapy has shown to improve intermediate outcomes and cardiac risk factors but recent studies show an increased risk of cardiovascular events in patients receiving testosterone. The following case highlights this growing concern.
Case Presentation: 51-year old male bodybuilder with no known past medical history presented with a sudden onset of substernal chest pain with dyspnea, diaphoresis, nausea and vomiting. He had a similar episode three weeks back and a cardiac catheterization showed 20% occlusion of one artery.
He was prescribed aspirin along with testosterone injections which he has been taking for the past 10 years. He denied any toxic habits or family history of heart disease.
Physical exam was unremarkable aside from his muscular physique. EKG showed inferior lead ST elevations with reciprocal depressions in the anterior leads. Laboratory tests showed elevated CPK and negative troponin-T.
He underwent an emergent cardiac catheterization showing 100% mid right coronary artery lesion. He received one bare metal stent with significant improvement in his symptoms and EKG post procedure.
Laboratory work revealed HbA1c of 5.2% ,HDL 18 mg/ dl,LDL 328 mg/dl and Testosterone 1430 ng/dL. LH and FSH were undetectable. Echocardiogram was normal.
Discussion: In the last few years attention has been placed on the effects of testosterone therapy on cardiovascular outcomes and mortality. A retrospective study in JAMA found that men taking testosterone replacement therapy had a higher risk of death, myocardial infarction or stroke. Another study found that older and young men with preexisting heart disease had increased risk for non-fatal myocardial infarction after starting testosterone therapy.
Exogenous testosterone use was associated with increased risk of cardiovascular events, especially in studies not funded by pharmaceuticals. These findings are significant because previous trials have shown that testosterone therapy improves many intermediate outcomes and cardiac risk factors.
Furthermore, previous meta-analysis found that testosterone therapy increases hematocrit and reduces HDL, but did not find a significant association with cardiovascular risk. In light of these findings, consumer advocacy groups petitioned the FDA to add black box warnings to testosterone formulations.
Also, the endocrine society recommends that middle-aged and older men who are taking or considering testosterone therapy be advised of the potential risk of cardiovascular events.
Conclusion: Testosterone replacement therapy might be associated with increased cardiovascular risk and prospective, randomized controlled trials are needed to determine the risks and benefits of testosterone therapy.
[This is a case of uniformed ignorant physicians presenting a case that isn’t! Shame? None!]
Anand Kumthekar, MBBS1, Raphael Hulkower, MD1, James Tauras, MD2
1. Jacobi Medical Center-Albert Einstein College of Medicine, 2. Monterfiore Medical Center - Albert Einstein College of Medicine
Objective: Testosterone therapy has shown to improve intermediate outcomes and cardiac risk factors but recent studies show an increased risk of cardiovascular events in patients receiving testosterone. The following case highlights this growing concern.
Case Presentation: 51-year old male bodybuilder with no known past medical history presented with a sudden onset of substernal chest pain with dyspnea, diaphoresis, nausea and vomiting. He had a similar episode three weeks back and a cardiac catheterization showed 20% occlusion of one artery.
He was prescribed aspirin along with testosterone injections which he has been taking for the past 10 years. He denied any toxic habits or family history of heart disease.
Physical exam was unremarkable aside from his muscular physique. EKG showed inferior lead ST elevations with reciprocal depressions in the anterior leads. Laboratory tests showed elevated CPK and negative troponin-T.
He underwent an emergent cardiac catheterization showing 100% mid right coronary artery lesion. He received one bare metal stent with significant improvement in his symptoms and EKG post procedure.
Laboratory work revealed HbA1c of 5.2% ,HDL 18 mg/ dl,LDL 328 mg/dl and Testosterone 1430 ng/dL. LH and FSH were undetectable. Echocardiogram was normal.
Discussion: In the last few years attention has been placed on the effects of testosterone therapy on cardiovascular outcomes and mortality. A retrospective study in JAMA found that men taking testosterone replacement therapy had a higher risk of death, myocardial infarction or stroke. Another study found that older and young men with preexisting heart disease had increased risk for non-fatal myocardial infarction after starting testosterone therapy.
Exogenous testosterone use was associated with increased risk of cardiovascular events, especially in studies not funded by pharmaceuticals. These findings are significant because previous trials have shown that testosterone therapy improves many intermediate outcomes and cardiac risk factors.
Furthermore, previous meta-analysis found that testosterone therapy increases hematocrit and reduces HDL, but did not find a significant association with cardiovascular risk. In light of these findings, consumer advocacy groups petitioned the FDA to add black box warnings to testosterone formulations.
Also, the endocrine society recommends that middle-aged and older men who are taking or considering testosterone therapy be advised of the potential risk of cardiovascular events.
Conclusion: Testosterone replacement therapy might be associated with increased cardiovascular risk and prospective, randomized controlled trials are needed to determine the risks and benefits of testosterone therapy.
ESTABLISHED RISK FACTORS AND NOT TESTOSTERONE THERAPY IN ITSELF IS ASSOCIATED WITH INCREASED MYOCARDIAL INFARCTION IN HEALTHY YOUNGER MEN: THE LOW T EXPERIENCE [Abstract #914]
Kelly Cook, PA-C, MPAS, William Reilly, MD, Robert Tan, MD, MBA Low T Center
Objective: Of those that had MI at the Low T Centers, we wanted to assess if there were risk factors that resulted in MI. The community based specialized centers treats younger, relatively healthier men have strict protocols requiring regular 1-2 week monitoring in the office for efficacy and safety.
Methods: We conducted a retrospective analysis of patients that had MI pre and post testosterone therapy. IRB approval was obtained. Data was extracted from our electronic health record (Advance MD) of the multi site Low T Centers across the United States.
Altogether 40 Centers were examined. Prior to extraction of data; we held 3 nationwide conference calls with providers to ensure that all ICD-9 were updated, with particular attention to MI and strokes. We also interviewed patients & families of patients that had MI. Data was entered into Excel and comparative statistics was performed using Graph Pad®.
Case Presentation: 39,937 patients were seen between years July 2009- July 2014 and approximately 50% met criteria for treatment. 80.8% of patients are below 55 years.
Of the treated patients, there were 6 cases of MI (36-53 years); and rate of new MI was 30 per 100,000. Our MI rates are very low in comparison to a managed care (Kaiser Permanente) rate, which were 208 per 100,000.
Of the 9 patients, all had risk factors except one. The prevalence of risk factors in those that had MI was compared with those with that did not have MI. We found for higher rates of smoking (44% vs. 3.5%, p=0.0001); hypertension (44% vs. 15%, p=0.0001); DM (22% vs. 4%, p=0.0001).
Conclusion: Our study showed that carefully monitored testosterone treated younger patients was safe and did not cause MI. Established risk factors such as smoking, hypertension and diabetes are associated with higher rates of MI in our testosterone treated patients. Testosterone therapy is not causal of MI.
Kelly Cook, PA-C, MPAS, William Reilly, MD, Robert Tan, MD, MBA Low T Center
Objective: Of those that had MI at the Low T Centers, we wanted to assess if there were risk factors that resulted in MI. The community based specialized centers treats younger, relatively healthier men have strict protocols requiring regular 1-2 week monitoring in the office for efficacy and safety.
Methods: We conducted a retrospective analysis of patients that had MI pre and post testosterone therapy. IRB approval was obtained. Data was extracted from our electronic health record (Advance MD) of the multi site Low T Centers across the United States.
Altogether 40 Centers were examined. Prior to extraction of data; we held 3 nationwide conference calls with providers to ensure that all ICD-9 were updated, with particular attention to MI and strokes. We also interviewed patients & families of patients that had MI. Data was entered into Excel and comparative statistics was performed using Graph Pad®.
Case Presentation: 39,937 patients were seen between years July 2009- July 2014 and approximately 50% met criteria for treatment. 80.8% of patients are below 55 years.
Of the treated patients, there were 6 cases of MI (36-53 years); and rate of new MI was 30 per 100,000. Our MI rates are very low in comparison to a managed care (Kaiser Permanente) rate, which were 208 per 100,000.
Of the 9 patients, all had risk factors except one. The prevalence of risk factors in those that had MI was compared with those with that did not have MI. We found for higher rates of smoking (44% vs. 3.5%, p=0.0001); hypertension (44% vs. 15%, p=0.0001); DM (22% vs. 4%, p=0.0001).
Conclusion: Our study showed that carefully monitored testosterone treated younger patients was safe and did not cause MI. Established risk factors such as smoking, hypertension and diabetes are associated with higher rates of MI in our testosterone treated patients. Testosterone therapy is not causal of MI.
ASSOCIATION BETWEEN TESTOSTERONE THERAPY AND THROMBOTIC EVENTS IN ELDERLY MEN
http://www.aua2015.org/abstracts/abstractprint.cfm?id=PD37-01
Ranjith Ramasamy, Jason Scovell, Michael Mederos, Renzhong Ran, Lakshay Jain, Dolores Lamb, Larry Lipshultz, Houston, TX
Introduction and Objectives - The association between testosterone therapy (TT) and thrombotic risk in elderly men remains controversial.
We evaluated the prevalence of thrombotic events and all-cause mortality in men older than 65 years with hypogonadism treated with testosterone therapy.
We compared men treated with testosterone to an age and comorbidity matched cohort of hypogonadal men not treated with TT.
Methods - After IRB approval, we retrospectively reviewed the charts of 217 hypogonadal men (2 AM T < 300ng/dl associated with symptoms) older than 65 years. Of the 217 men, 153 men received TT (injections n=53; gel n=47; pellets n=53). We compared men who received TT to 64 hypogonadal men who did not receive TT.
We evaluated all-cause mortality (social security death index), prevalence of myocardial infarction (MI), transient ischemic attack (TIA), cerebrovascular accident (CVA, or ‘stroke’), and pulmonary embolism (PE). All events were verified by contacting patients.
We excluded men who had thrombotic events prior to initiation of testosterone therapy. We also excluded men who were previously on androgen deprivation therapy and men who had used TT prior to age of 65.
Results - Median age and Charlson Comorbidity Index of men on TT (74y; 5.1) was similar to hypogonadal men not on TT (73y, p=0.48; 5.3, p=0.36). The median follow-up in men on TT was 3.8 years and 3.5 years in men not on TT.
No man who received TST died, whereas 5 hypogonadal men who did not receive TST died (p=0.007).
There were 4 thrombotic events (1 MI, 2 CVA/TIA, 1 PE) in men who received TST compared to 1 event (CVA/TIA) among men who did not receive TST (p = 0.8). All the events (except one death which took place at 6 months of follow-up) occurred 2 years or more after follow-up.
Strengths of the study include long follow-up (>3 years), availability of serum testosterone levels before and after therapy and of a control group (hypogonadal men not treated with TST) for comparison. In addition, we performed a power analysis (80% power), and confirmed that the sample size studied was adequate. Limitations included retrospective study design, a small sample size and lack of information on cause of death.
Conclusions - Consistent with the majority of the studies in the literature, there was increased all-cause mortality in hypogonadal men not treated with testosterone compared to men who received testosterone therapy. There was no difference in prevalence of MI, TIA/CVA, or PE between patients who were treated with testosterone and hypogonadal men not treated with testosterone.
http://www.aua2015.org/abstracts/abstractprint.cfm?id=PD37-01
Ranjith Ramasamy, Jason Scovell, Michael Mederos, Renzhong Ran, Lakshay Jain, Dolores Lamb, Larry Lipshultz, Houston, TX
Introduction and Objectives - The association between testosterone therapy (TT) and thrombotic risk in elderly men remains controversial.
We evaluated the prevalence of thrombotic events and all-cause mortality in men older than 65 years with hypogonadism treated with testosterone therapy.
We compared men treated with testosterone to an age and comorbidity matched cohort of hypogonadal men not treated with TT.
Methods - After IRB approval, we retrospectively reviewed the charts of 217 hypogonadal men (2 AM T < 300ng/dl associated with symptoms) older than 65 years. Of the 217 men, 153 men received TT (injections n=53; gel n=47; pellets n=53). We compared men who received TT to 64 hypogonadal men who did not receive TT.
We evaluated all-cause mortality (social security death index), prevalence of myocardial infarction (MI), transient ischemic attack (TIA), cerebrovascular accident (CVA, or ‘stroke’), and pulmonary embolism (PE). All events were verified by contacting patients.
We excluded men who had thrombotic events prior to initiation of testosterone therapy. We also excluded men who were previously on androgen deprivation therapy and men who had used TT prior to age of 65.
Results - Median age and Charlson Comorbidity Index of men on TT (74y; 5.1) was similar to hypogonadal men not on TT (73y, p=0.48; 5.3, p=0.36). The median follow-up in men on TT was 3.8 years and 3.5 years in men not on TT.
No man who received TST died, whereas 5 hypogonadal men who did not receive TST died (p=0.007).
There were 4 thrombotic events (1 MI, 2 CVA/TIA, 1 PE) in men who received TST compared to 1 event (CVA/TIA) among men who did not receive TST (p = 0.8). All the events (except one death which took place at 6 months of follow-up) occurred 2 years or more after follow-up.
Strengths of the study include long follow-up (>3 years), availability of serum testosterone levels before and after therapy and of a control group (hypogonadal men not treated with TST) for comparison. In addition, we performed a power analysis (80% power), and confirmed that the sample size studied was adequate. Limitations included retrospective study design, a small sample size and lack of information on cause of death.
Conclusions - Consistent with the majority of the studies in the literature, there was increased all-cause mortality in hypogonadal men not treated with testosterone compared to men who received testosterone therapy. There was no difference in prevalence of MI, TIA/CVA, or PE between patients who were treated with testosterone and hypogonadal men not treated with testosterone.
Long-term TRT study refutes concerns about prostate safety
http://urologytimes.modernmedicine....futes-concerns-about-prostate-safety?page=0,1
Abdulmaged M. Traish, MBA, PhD, professor of urology and biochemistry at Boston University School of Medicine, was a co-author of the paper. Speaking to Urology Times, he said, “Androgen deprivation therapy has been used in the management of prostate cancer for more than 7 decades based on the concept that testosterone causes prostate cancer development and progression. During that time, there is no evidence that quality of life or survival has improved with ADT,” Dr. Traish said.
“Now it is time to have a paradigm shift in our view of the relationship between testosterone and prostate cancer. Clearly, there is no credible scientific or clinical evidence that links testosterone to development or progression of prostate cancer. The time has come to train the new generation of clinicians and scientists in the light of the new paradigm and leave the old myth behind.”
“The incidence of prostate cancer in our population was calculated as 27.7 per 10,000 patient years, which is far below the incidence reported in large screening studies,” he said, citing the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial and the European Randomized Study of Screening for Prostate Cancer.
Incidence of Prostate Cancer and Effects on Prostate-Related Parameters under Long-Term Therapy with Testosterone Undecanoate Injections (TU) In Hypogonadal Men For Up To 84 Months: Real-Life Experience from an Observational Registry Study
http://www.aua2015.org/abstracts/abstractprint.cfm?id=PD45-04
Authors: Ahmad Haider, Karim Sultan Haider, Bremerhaven, Germany, Gheorghe Doros, Abdulmaged Traish, Boston, MA
Introduction and Objectives - There are still concerns regarding prostate safety of testosterone replacement therapy (TRT). We investigated how long-term TRT with TU affected prostate-related parameters.
Methods - Prospective, longitudinal, registry study of 347 patients (mean age 57.32 ± 7.12 years, min.: 32, max.: 69), with testosterone (T) levels ≤ 350 ng/dL (12.1 nmol/L) received TU 1000 mg injections at baseline, after 6 weeks and then every 12 weeks for up to 84 months (7 years).
Prostate volume and residual voiding volume were measured by ultrasound at every or every other visit. IPSS was filled in at every visit and blood samples taken to measure PSA. Because prostatic diseases are closely associated with obesity, we also assessed anthropometric parameters and C-reactive protein (CRP).
Results - Registry participants contributed 1,806 person-years (21,678 person-months). Total T increased from 9.84 ± 1.28 nmol/L to trough levels of approximately 16 to 17 nmol/L for the total observation period.
Prostate volume increased from 28.98 ± 10.4 to 30.87 ± 12.06 ml (p<0.0001 vs baseline) by 2.46 ml.
PSA increased from 1.73 ± 0.94 to 1.79 ± 0.93 ng/ml (p=0.0151 vs baseline).
6/347 patients were diagnosed with prostate cancer following elevated PSA (> 4 ng/mL). Tumour stage was pT2a in four and pT1b in two men, Gleason score 3+3 in five and 3+2 in one patient, resp. They all underwent radical prostatectomy. The proportion was 1.7% with an incidence of 27.7 per 10,000 patient-years.
The International Prostate Symptom Score (IPSS) decreased from 6.35 ± 4.05 to 2.21 ± 1.04 (p<0.0001) by 4.92 score points.
The residual voiding volume decreased progressively from 46.82 ± 22.71 to 15.22 ± 5.4 ml (p<0.0001).
Within the observation time, BMI dropped progressively from 33.18 ± 5.35 kg/m2 to 28.42 ± 2.95 kg/m2, with waist circumference declining from 105.77 ± 8.6 cm to 97.74 ± 7.05 cm.
CRP decreased from 5.42 ± 7.12 to 0.51 ± 0.92 mg/dl (p<0.0001). The high baseline level of CRP results from the fact that 75 patients had inflammatory bowel diseases and/or psoriasis.
Conclusions - The incidence of prostate cancer did not suggest an increased risk of prostate cancer in hypogonadal men on long-term TRT.
Long-term treatment with TU did not negatively affect voiding function as measured by IPSS, or residual voiding volume.
Part of these effects may be a result of parallel reduction in body weight and abdominal fat, as well as inflammation.
http://urologytimes.modernmedicine....futes-concerns-about-prostate-safety?page=0,1
Abdulmaged M. Traish, MBA, PhD, professor of urology and biochemistry at Boston University School of Medicine, was a co-author of the paper. Speaking to Urology Times, he said, “Androgen deprivation therapy has been used in the management of prostate cancer for more than 7 decades based on the concept that testosterone causes prostate cancer development and progression. During that time, there is no evidence that quality of life or survival has improved with ADT,” Dr. Traish said.
“Now it is time to have a paradigm shift in our view of the relationship between testosterone and prostate cancer. Clearly, there is no credible scientific or clinical evidence that links testosterone to development or progression of prostate cancer. The time has come to train the new generation of clinicians and scientists in the light of the new paradigm and leave the old myth behind.”
“The incidence of prostate cancer in our population was calculated as 27.7 per 10,000 patient years, which is far below the incidence reported in large screening studies,” he said, citing the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial and the European Randomized Study of Screening for Prostate Cancer.
Incidence of Prostate Cancer and Effects on Prostate-Related Parameters under Long-Term Therapy with Testosterone Undecanoate Injections (TU) In Hypogonadal Men For Up To 84 Months: Real-Life Experience from an Observational Registry Study
http://www.aua2015.org/abstracts/abstractprint.cfm?id=PD45-04
Authors: Ahmad Haider, Karim Sultan Haider, Bremerhaven, Germany, Gheorghe Doros, Abdulmaged Traish, Boston, MA
Introduction and Objectives - There are still concerns regarding prostate safety of testosterone replacement therapy (TRT). We investigated how long-term TRT with TU affected prostate-related parameters.
Methods - Prospective, longitudinal, registry study of 347 patients (mean age 57.32 ± 7.12 years, min.: 32, max.: 69), with testosterone (T) levels ≤ 350 ng/dL (12.1 nmol/L) received TU 1000 mg injections at baseline, after 6 weeks and then every 12 weeks for up to 84 months (7 years).
Prostate volume and residual voiding volume were measured by ultrasound at every or every other visit. IPSS was filled in at every visit and blood samples taken to measure PSA. Because prostatic diseases are closely associated with obesity, we also assessed anthropometric parameters and C-reactive protein (CRP).
Results - Registry participants contributed 1,806 person-years (21,678 person-months). Total T increased from 9.84 ± 1.28 nmol/L to trough levels of approximately 16 to 17 nmol/L for the total observation period.
Prostate volume increased from 28.98 ± 10.4 to 30.87 ± 12.06 ml (p<0.0001 vs baseline) by 2.46 ml.
PSA increased from 1.73 ± 0.94 to 1.79 ± 0.93 ng/ml (p=0.0151 vs baseline).
6/347 patients were diagnosed with prostate cancer following elevated PSA (> 4 ng/mL). Tumour stage was pT2a in four and pT1b in two men, Gleason score 3+3 in five and 3+2 in one patient, resp. They all underwent radical prostatectomy. The proportion was 1.7% with an incidence of 27.7 per 10,000 patient-years.
The International Prostate Symptom Score (IPSS) decreased from 6.35 ± 4.05 to 2.21 ± 1.04 (p<0.0001) by 4.92 score points.
The residual voiding volume decreased progressively from 46.82 ± 22.71 to 15.22 ± 5.4 ml (p<0.0001).
Within the observation time, BMI dropped progressively from 33.18 ± 5.35 kg/m2 to 28.42 ± 2.95 kg/m2, with waist circumference declining from 105.77 ± 8.6 cm to 97.74 ± 7.05 cm.
CRP decreased from 5.42 ± 7.12 to 0.51 ± 0.92 mg/dl (p<0.0001). The high baseline level of CRP results from the fact that 75 patients had inflammatory bowel diseases and/or psoriasis.
Conclusions - The incidence of prostate cancer did not suggest an increased risk of prostate cancer in hypogonadal men on long-term TRT.
Long-term treatment with TU did not negatively affect voiding function as measured by IPSS, or residual voiding volume.
Part of these effects may be a result of parallel reduction in body weight and abdominal fat, as well as inflammation.
Similar threads
