Journal Maturitas publishes position statement on testosterone replacement therapy in the aging male‏

Journal Maturitas today announced the publication of a position statement by the European Menopause and Andropause Society (EMAS) covering testosterone replacement therapy in the aging male.

19 nov 2015--Late-onset hypogonadism (LOH) represents a common clinical entity in older men. It is characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate because of the uncertainties regarding risk of cardiovascular disease and prostate cancer. The position statement provides a practical guide to the use of testosterone replacement in older men.
The overall conclusion is that a general policy around offering TRT to all aging men with low testosterone concentrations is not recommended. It is always advisable to encourage older men with LOH to undertake lifestyle modifications, including weight loss, increasing exercise, stopping smoking and reducing alcohol intake before considering starting TRT. The assessment procedure should include individual evaluation of co-morbidities and careful risk versus benefit estimation; TRT should be very carefully weighed up in testosterone deficient older men with or without pre-existing heart disease, until evidence from large randomized prospective trials regarding cardiovascular safety becomes available.
Older men should be able to discuss testosterone replacement therapy with their health professional so that shared and informed decisions can be made.

More information: Manuel Neves-e-Castro et al. EMAS position statement: The ten point guide to the integral management of menopausal health, Maturitas (2015). DOI: 10.1016/j.maturitas.2015.02.003


Provided by Elsevier

New recommendations addresses the diagnosis and management of testosterone deficiency

An expert panel convened by the International Society for Sexual Medicine has developed a detailed "Process of Care" for the diagnosis and management of testosterone deficiency in men.

18 july 2015--After an extensive literature review and in-depth consultations, the panel of 18 experts from a wide range of medical disciplines recommended that testosterone deficiency be defined as a clinical and biochemical syndrome characterized by both a deficiency of testosterone or testosterone action, and relevant symptoms. The panel stressed that the condition may affect multiple organ systems as well as sexual function. They also noted that the prevalence of symptomatic testosterone deficiency in men is within the range of 2% to 6%, and it is often associated with obesity and type 2 diabetes, but not necessarily with aging.

The Process of Care provides information on who should be tested for testosterone deficiency, which tests to perform, and which lifestyle modifications or drug interventions are appropriate for different types of patients. It also provides recommendations on when and how to monitor patients after initiating treatment.

The expert panel noted that decisions regarding the appropriate use of testosterone replacement therapy have been complicated by well-publicized controversies about a possible relationship between testosterone replacement therapy and risk of developing prostate cancer and heart disease. The panel found that there were no large-scale, long-term, controlled studies that supported such concerns and that the balance of available evidence is strongly against there being any such relationship in men who are appropriately treated.

"The Process of Care characterizes testosterone deficiency and provides easy-to-follow, evidence-based guidance on its investigation and management, in both general and special populations, such as those with cardiovascular and prostate disease. It highlights the importance of identifying men with testosterone deficiency who want to maintain their fertility, which is likely to be compromised by testosterone replacement therapy, and who need a different approach to treatment," said Dr. John Dean, lead author of the Process of Care, which is published in The Journal of Sexual Medicine. "Very importantly, it should help doctors to make a consistent and reliable diagnosis of a much-neglected problem that may confer a significant health burden on the individual, and to identify the 'worried well' who may request testosterone replacement therapy but do not need it."

More information: DOI: 10.1111/jsm.12952 

Provided by Wiley

Testosterone therapy might increase heart attack risk

Researchers say risk doubles after treatment starts for men under 65 with heart problems and all men over 65.

30 jan 2014—Testosterone therapy—widely advertised as a way to help men improve a low sex drive and reclaim diminished energy—might raise the risk of heart attack, according to new research.

The increased risk was found in men younger than 65 with a history of heart disease, and in older men even if they didn't have a history of the disease. In both groups, heart attack risk doubled in the 90 days after the men began testosterone therapy, said researcher William Finkle, CEO of Consolidated Research, in Los Angeles.

"It was more or less the same increase in risk," Finkle said.

Testosterone therapy typically is given in gel, patch or injection form, and is widely promoted in television advertisements about "low T." Although the treatment risk to men over 65 has been documented in previous research, Finkle said, the new study is believed to be the first to look at men under 65.

The study, published online Jan. 29 in the journal PLoS One, was conducted by a research team that included experts from Consolidated Research, the U.S. National Cancer Institute and the University of California, Los Angeles.

It was triggered by a 2010 report in the New England Journal of Medicine, Finkle said. In that study, a clinical trial of testosterone gel in men over 65 was halted early after an increase in heart attacks and other heart problems occurred in the group using the testosterone supplements.

Finkle's team used data from Truven Health Analytics, which gathers nationwide information on patient care. The researchers looked at the medical records of nearly 56,000 men who had been prescribed testosterone therapy—more than 48,000 of whom were under age 65.

"We identified the [timing of the] first prescription and followed them for 90 days," Finkle said. The risk for heart attack doubled in that 90-day period for men over 65 and those under 65 with a history of heart disease, the researchers found.

When they continued to follow the men for another 90 days, the researchers said, the risk declined to the level it was at the study's start for men who did not refill their initial prescription.

Even though the two-fold increase in risk in younger men was seen only in those with a history of heart disease, Finkle said he's uncertain of the therapy's safety in younger, healthy men.

"We don't have enough evidence to say testosterone supplements in men under age 65 without heart disease are safe," he said.

Although the researchers found an association between testosterone therapy and increased risk of heart attack, the study did not prove a cause-and-effect relationship.

The study authors also did not examine the explanation for the link, but Finkle said it could be tied to the effect of testosterone in blood.

"The theory is that testosterone most likely promotes clotting," he said. In older men who tend to have thinner vessels, that clotting could cause problems, he said.

The supplements might also increase men's circulating estrogen, the researchers said. Estrogen therapy has been linked to an increase in heart troubles in both men and women.

AbbVie and Actavis, the makers of testosterone therapies, did not respond to requests for comment on the study.

But one expert not involved in the research expressed skepticism, citing flaws in the study design.

"Based on the best available data, testosterone replacement still appears to be safe ... for properly selected patients," said Dr. Ryan Terlecki, director of the Men's Health Clinic at the Wake Forest Baptist Medical Center.

Among the flaws in the study, Terlecki said, was the use of information obtained from medical claims data, which makes it uncertain which men actually used the testosterone.

"This is important since compliance can be poor, especially with topical formulations," he said. Terlecki reported that he previously worked as a consultant for Auxilium, which makes testosterone therapy.

The researchers did not have information on why the testosterone therapy was prescribed, so it could have been prescribed inappropriately, Terlecki said. He also cited other data that has linked low testosterone—not testosterone therapy—to an increased risk of heart disease.

Men who are discussing testosterone therapy with their doctors "should add the risk of heart attack to the discussion of the risks and benefits of testosterone," Finkle said.

Terlecki said men who have a lack of energy should first see their doctor and ask about screening for depression and other conditions—such as thyroid disease or B12 deficiency—that could also be the cause.

Testosterone therapy is marketed so successfully that the independent medicine website Drugs.com reported that sales of Androgel exceeded sales of Viagra in 2013, according to UCLA researchers.

More information: To learn more about low testosterone, visit the Urology Care Foundation.

Testosterone therapy following angiography associated with increased risk of adverse outcome

Among a group of men who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of death, heart attack, or ischemic stroke, according to a study in the November 6 issue of JAMA.

06 nov 2013--"Rates of testosterone therapy prescription have increased markedly in the United States over the past decade. Annual prescriptions for testosterone increased by more than 5-fold from 2000 to 2011, reaching 5.3 million prescriptions and a market of $1.6 billion in 2011. Professional society guidelines recommend testosterone therapy for patients with symptomatic testosterone deficiency. In addition to improving sexual function and bone mineral density and increasing free-fat mass and strength, treatment with testosterone has been shown to improve lipid profiles and insulin resistance and increase the time to ST depression [a finding on an electrocardiogram suggesting benefit] during stress testing," according to background information in the article. However, a recent randomized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety.

Rebecca Vigen, M.D., M.S.C.S., of the University of Texas at Southwestern Medical Center, Dallas and colleagues evaluated the association between the use of testosterone therapy and all-cause mortality, myocardial infarction (MI; heart attack), and stroke among male veterans and whether this association was modified by underlying coronary artery disease (CAD). The study included 8,709 men with low testosterone levels.

The researchers found that the proportion of patients experiencing events 3 years after coronary angiography was 19.9 percent in the no testosterone therapy group (average age, 64 years) and 25.7 percent in the testosterone therapy group (average age, 61 years), for an absolute risk difference of 5.8 percent. Even accounting for other factors that could explain the differences, use of testosterone therapy was associated with adverse outcomes and was consistent among patients with and without CAD. The increased risk of adverse outcomes associated with testosterone therapy use was not related to differences in risk factor control or rates of secondary prevention medication use because patients in both groups had similar blood pressure, low-density lipoprotein levels, and use of secondary prevention medications.

"These findings raise concerns about the potential safety of testosterone therapy," the authors write. "Future studies including randomized controlled trials are needed to properly characterize the potential risks of testosterone therapy in men with comorbidities."

"Perhaps the most important question is the generalizability of the results of this study to the broader population of men taking testosterone: men of this age group who are taking testosterone for 'low T syndrome' or for antiaging purposes and younger men taking it for physical enhancement," writes Anne R. Cappola, M.D., Sc.M., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, in an accompanying editorial.

"Are the benefits—real or perceived—for these groups of men worth any increase in risk? These populations represent a sizable group of testosterone users, and there is only anecdotal evidence that testosterone is safe for these men."

"In light of the high volume of prescriptions and aggressive marketing by testosterone manufacturers, prescribers and patients should be wary. There is mounting evidence of a signal of cardiovascular risk, to which the stud

More information: DOI: 10.1001/jama.2013.280386
DOI: 10.1001/jama.2013.280387

Provided by The JAMA Network Journals

Testosterone Gel Increases Risk Of Heart Attacks And High Blood Pressure In Older Men - Treatment Phase Of Clinical Trial Stopped

According to a trial in older men using testosterone gel treatment, published in the New England Journal of Medicine, using testosterone gel results in a higher risk of adverse cardiovascular events, such as heart attacks and high blood pressure (hypertension) compared to a placebo.

The trial was stopped because of these adverse events. The study was supported by a grant to Shalender Bhasin, M.D., at Boston Medical Center from the National Institute on Aging (NIA), part of the National Institutes of Health.

Decreased muscle strength may contribute to difficulties in mobility, such as in walking or climbing stairs, which can limit older persons' independence. Testosterone treatment has been shown to improve muscle strength in some older men, but it is not yet known whether it would reduce mobility limitations in older men with low testosterone levels. The TOM (Testosterone in Older Men) Trial was designed to address this question. It was a randomized, double-blind, placebo-controlled clinical trial of the effects of six months of testosterone gel treatment on strength and ability to walk and climb stairs in 209 older men with low testosterone levels and mobility limitations. The testosterone gel used in this study was administered to the skin daily. The 209 men in the trial had an average age of 74 and high rates of chronic diseases such as diabetes and cardiovascular disease.

The treatment phase of the trial was stopped on Dec. 31, 2009, following a review by the study's Data and Safety Monitoring Board (DSMB). The DSMB is an independent panel of medical and statistical experts set up from the start of the trial to check regularly for the occurrence of adverse health events in participants and to detect any possible risks from treatment. In December 2009, the board found that 23 of the 106 men who had received testosterone experienced adverse cardiovascular-related events during the study, compared to five of the 103 men who received placebo. The cardiovascular-related events included heart attack, heart rhythm disturbances and elevated blood pressure, and one death from a suspected heart attack. The DSMB weighed the severity of the adverse events in relation to the potential benefits and recommended that participants stop taking study medications and that enrollment be stopped.

As soon as the DSMB made its recommendation, the treatment phase of the trial was halted. All participants were promptly notified and asked to meet with study physicians to discuss any questions they might have. The men who experienced cardiovascular events were treated by their personal physicians for their specific conditions. No new participants will be enrolled in the study. The study team will continue to monitor the health of all participants for at least another year after stopping testosterone use to further evaluate effects of the treatment.

The report in the New England Journal of Medicine provides detailed data about the outcomes and adverse events in participants. The authors note that physicians and patients, especially older men, should consider this study's findings on adverse effects along with other information on the risks and benefits of testosterone therapy. They also note that further research is needed to clarify the safety issues raised by this trial.

The authors caution that the ability to draw broader conclusions about the safety of testosterone therapy based on these findings is constrained by several factors, including this study's small size and the fact that the study's population was older and had higher rates of chronic diseases and mobility limitation than individuals in most other studies.

In addition, the trial's eligibility criteria excluded men with severely low testosterone levels, limiting the ability to make inferences about safety in this population. The authors also note that the testosterone doses and serum levels in this trial may be higher than those usually used in clinical practice and in some previous clinical trials. NIA is funding six other trials studying the effects of testosterone. All of the principal investigators of those trials and their DSMBs and Safety Officers have been informed of the findings in the TOM Trial. After reviewing these findings, and other evidence relating to safety of testosterone treatment, the DSMBs and Safety Officers recommended continuation of the trials, with provision of additional information to participants and additional safety precautions. NIA has reviewed these recommendations and concurs with them.

"Adverse Events Associated with Testosterone Administration"
Shehzad Basaria, M.D., Andrea D. Coviello, M.D., Thomas G. Travison, Ph.D., Thomas W. Storer, Ph.D., Wildon R. Farwell, M.D., M.P.H., Alan M. Jette, Ph.D., Richard Eder, B.A., Sharon Tennstedt, Ph.D., Jagadish Ulloor, Ph.D., Anqi Zhang, Ph.D., Karen Choong, M.D., Kishore M. Lakshman, M.D., Norman A. Mazer, M.D., Ph.D., Renee Miciek, M.S., Joanne Krasnoff, Ph.D., Ayan Elmi, B.A., Philip E. Knapp, M.D., Brad Brooks, B.S., Erica Appleman, M.A., Sheetal Aggarwal, B.S., C.C.R.P., Geeta Bhasin, B.A., Leif Hede-Brierley, Ashmeet Bhatia, M.B., B.S., Lauren Collins, R.N.P., Nathan LeBrasseur, Ph.D., Louis D. Fiore, M.D., and Shalender Bhasin, M.D.
New England Journal of Medicine10.1056/NEJMoa1000485

Source: National Institute on Aging

Testosterone Replacement For Men With Low Testosterone Improves Liver Function, Metabolic Syndrome

15 june 2009--In middle-aged and older men with low testosterone levels, long-term testosterone replacement therapy greatly improves their fatty liver disease and their risk factors for cardiovascular disease and diabetes, a new study found. The results were presented at The Endocrine Society's 91st Annual Meeting in Washington, D.C.

Testosterone deficiency, which becomes more common with age, is linked not only to decreased libido but also to a number of medical problems. These include the metabolic syndrome a cluster of metabolic risk factors that increase the chances of developing heart disease, stroke and type 2 diabetes. Nonalcoholic fatty liver disease, also called a fatty liver, commonly co-occurs with the metabolic syndrome and may aggravate the metabolic problems. To receive a diagnosis of the metabolic syndrome, patients must have three of the following five risk factors: abdominal obesity (a large waist line), low HDL ("good") cholesterol, high triglycerides (fats in the blood), high blood pressure and high blood sugar.

"Physicians often are reluctant to prescribe testosterone for conditions not related to sexual function," said the study's co-author, Farid Saad, PhD, of Berlin-headquartered Bayer Schering Pharma. "However, our study shows that testosterone has a much wider therapeutic role than just for improving sexual desire and erectile function."

The study included 122 testosterone-deficient men, ages 36 to 69 years (mean age: 59.5). Results showed that restoring testosterone to normal levels led to major and progressive improvements in many features of the metabolic syndrome over the 2 years of treatment. Specifically, the men's weight, waist line and body mass index (a measure of body fat) continued to decline over the full study period. The other metabolic risk factors also significantly improved during the first year of testosterone treatment. Of the 47 men who met the criteria for a diagnosis of the metabolic syndrome at the beginning of the study, 36 (77 percent) no longer had the diagnosis after 2 years of treatment, the authors reported.

Furthermore, liver function significantly improved during the first 12 to 18 months of therapy and stabilized for the remainder of the study period. Treatment also greatly decreased blood levels of C-reactive protein, a measure of inflammation that is linked to increased risk of cardiovascular disease.

"We conclude that testosterone therapy in men with testosterone deficiency can largely improve or even remedy the metabolic syndrome, which will most likely decrease their risk of diabetes and cardiovascular disease," Saad said.

Study participants received treatment in Bremerhaven, Germany. Treatment used a slow-release, injectable form of the male hormone (testosterone undecanoate) that is not yet available in the United States.

Saad is an employee of Bayer Schering, which makes a brand of testosterone undecanoate.

Source: Endocrine Society

Testosterone replacement and prostate cancer: Is therapy safe?

For men with low testosterone, taking supplements can mean greater libido, energy and muscle. It also goes against decades of medical thinking.

05 april 2009--Manny Hamelburg, 68, a retired businessman, had fought prostate cancer for years. First, he tried radiation, then a drug with side effects that nearly killed him, and finally Lupron, a drug that blocks production of testosterone, the hormone that can fuel prostate cancer.

The cancer disappeared. But life was miserable.

Without normal levels of testosterone, Hamelburg says, he had no energy, and "zero libido for seven years. I was like a eunuch. I was chemically castrated. Sex was just hugs."

So three years ago, with his cancer undetectable and his oncologist and urologist cautiously on board, the Holbrook, Mass., man made a decision that many doctors consider anathema: He took testosterone supplements.

"The cancer hasn't come back," Hamelburg says, "but my libido has, my sense of being alive. It's like a fog cleared. It's being aware of things, being more vibrant."

For decades, the idea of giving testosterone to a man who had had prostate cancer was forbidden -- "verboten" in the words of Hamelburg's urologist, Dr. Abraham Morgentaler of Beth Israel Deaconess Medical Center. "It would have been considered heresy, or malpractice," Morgentaler says.

That thinking is changing, due in part to Morgentaler and his new book, "Testosterone for Life."

Morgentaler argues that although depriving tumors of testosterone does make them shrink, other evidence is beginning to suggest that it may be safe to give testosterone to men who have been successfully treated for prostate cancer and who appear to be cancer free.

One revolutionary aspect of Morgentaler's theory is the observation that prostate cancer is often found in men with low testosterone levels, not high ones, underscoring the idea that taking it may not be an added risk. It's not surprising that Morgentaler -- who has received honorariums and research funding from companies selling testosterone-related products -- has generated such controversy with his ideas.

"To say that testosterone replacement therapy is safe because we have no evidence it's harmful is making an assertion on faith, not facts," said Dr. Ian Thompson, chairman of the department of urology at the University of Texas Health Science Center at San Antonio, echoing the view of other doctors who disagree with Morgentaler.

But amid often-confusing testosterone research results, there are hints that Morgentaler and like-minded physicians may be on to something. In the test tube, prostate cancer cells have been shown to grow faster when testosterone is added, but only up to a point. Then the growth plateaus, even if more testosterone is added.

In 2006, Morgentaler co-wrote a study on 345 men with low testosterone. The study -- published in the journal Urology and not industry funded -- showed prostate cancer risk was higher in men with the lowest testosterone, a finding supported by a handful of other small-scale studies using human subjects.

That was contrary to findings suggested by the Physicians' Health Study in 1996, a discrepancy doctors cannot fully explain. And in February, an analysis of data from 18 studies around the world involving nearly 4,000 men with prostate cancer, and more than 6,000 without, showed no correlation between high testosterone levels and cancer risk. The study was published in the Journal of the National Cancer Institute.

Understanding the pros and cons of testosterone replacement is not easy.

An estimated 2 million to 6 million American men have low testosterone, and the benefits of replacement therapy can be huge: revival of sagging libido, better mood, more energy, more muscle, better bone density, more red blood cells.

But there are also risks, in large part because many seemingly healthy men have undetected prostate cancer, which could be stimulated by taking testosterone. Studies suggest that prostate cancer is lurking in as many as 25% or more of men 50 and older. Only when a man has a "clean" biopsy -- an invasive procedure in which snippets of the prostate are surgically removed and tested -- can a doctor confidently say the man doesn't have cancer.

As an extra measure of safety, Morgentaler says, he biopsies men older than 50 before he prescribes testosterone for them. But most doctors don't, says Dr. Marc Garnick, a cancer specialist at Beth Israel Deaconess Medical Center and editor in chief of Harvard Medical School's publication "Perspectives on Prostate Disease."

Even with apparently healthy men, "Nobody has proven that it is completely safe" to give testosterone," says Dr. Philip Kantoff, head of the Prostate Cancer Program at the Dana-Farber Cancer Institute.

So, what's a guy to do?

The traditional recommendations are to steer clear of testosterone supplementation if you have prostate or breast cancer; or if you meet one of several criteria: your physician can feel a nodule on the prostate during a digital rectal exam, your PSA (a marker of potential cancer) score is higher than 3 nanograms per deciliter, your hematocrit (the proportion of blood volume occupied by red blood cells) is greater than 50%, or you have untreated sleep apnea, severe urinary tract symptoms or heart failure. These standards are set by the Endocrine Society, a professional group of doctors who study and treat patients with hormones.

And if you have had prostate cancer that appears to be gone? Proceed with caution.

"Most physicians consider testosterone replacement therapy contraindicated for men with a history of prostate cancer," says Dr. Matthew Smith, director of genitourinary medical oncology at Massachusetts General Hospital Cancer Center.

But if you do wish to explore testosterone supplements, it's smart, given the controversy, to get a second opinion. Grill your doctors on how serious your prostate cancer was to start with -- that is, how high your PSA was, and how many gland segments contained cancer.

Also, keep being monitored for cancer recurrence.

Hamelburg is glad he eventually opted for testosterone. "My body was my enemy," he says. "Now, I just feel like a man again."