Androgen Replacement

Discussion in 'Men's Health Forum' started by Michael Scally MD, Sep 30, 2010.

  1. thrombus

    thrombus Member

    Agreed. Answers are rarely found in the first place searched.
     
  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust 2013;199(8):548-51. https://www.mja.com.au/journal/2013...ing-2000-2011-expanding-spectrum-prescription

    OBJECTIVE: To provide the first multinational survey of temporal trends in testosterone prescribing, given that anecdotal evidence indicates that it is increasing in some countries, including Australia.

    DESIGN: Sales data for all testosterone products were obtained for 41 countries for each year from 2000 to 2011. For each testosterone product type (injectable, implantable, oral, transdermal), units sold were converted into defined monthly doses per year, reflecting total testosterone prescribing per product.

    MAIN OUTCOME MEASURES: National testosterone prescribing rate overall and per product type on a per capita basis.

    RESULTS: For every region and 37 of 41 countries, there was a major and progressive increase in defined monthly doses per year per capita over the 11 years surveyed. In most countries, the increases were steeper for the last half of the survey period. The proportion of testosterone prescribing represented by transdermal testosterone products, a surrogate measure of prescribing for older men, increased even more than did the total usage of testosterone products.

    CONCLUSIONS: In the absence of any new indications, off-label testosterone prescribing has increased in most countries in 2000-2011, especially over the last half of the period. The increased testosterone prescribing appears to be primarily for older men and driven by clinical guidelines that endorse testosterone prescribing for age-related functional androgen deficiency (andropause). By eliminating the fundamental distinction between pathological and functional androgen deficiency, these guidelines tacitly promote increased testosterone prescribing, bypassing the requirement for high-quality clinical evidence of safety and efficacy and creating dramatic increases in prescription of testosterone products.
     
  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    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. JAMA Network | JAMA | Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels

    Importance Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown. 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.

    Objectives To assess the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease.

    Design, Setting, and Patients A retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011.

    Main Outcomes and Measures Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke.

    Results Of the 8709 men with a total testosterone level lower than 300 ng/dL, 1223 patients started testosterone therapy after a median of 531 days following coronary angiography. Of the 1710 outcome events, 748 men died, 443 had MIs, and 519 had strokes. Of 7486 patients not receiving testosterone therapy, 681 died, 420 had MIs, and 486 had strokes. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. The absolute rate of events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% (95% CI, ?1.4% to 13.1%) at 3 years after coronary angiography. In Cox proportional hazards models adjusting for the presence of coronary artery disease, testosterone therapy use as a time-varying covariate was associated with increased risk of adverse outcomes (hazard ratio, 1.29; 95% CI, 1.04 to 1.58). There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, P?=?.41).

    Conclusions and Relevance Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.
     
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Endocrine News - November 2013
    https://interactivepdf.uniflip.com/2/34023/316582/pub/

    • The number of men using testosterone replacement therapy has tripled over the past 10 years.
    • A recent study found that 25% of the men prescribed the drug never had their testosterone levels measured.
    • Controversy remains over the benefits vs. risks, particularly in older men.
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Selling That New-Man Feeling
    http://www.nytimes.com/2013/11/24/business/selling-that-new-man-feeling.html

    November 23, 2013
    By NATASHA SINGER

    One afternoon a few months ago, a 45-year-old sales representative named Mike called “The Dr. Harry Fisch Show,” a weekly men’s health program on the Howard Stern channel on Sirius XM Radio, where no male medical or sexual issue goes unexplored.

    “I feel like a 70-year-old man in a 45-year-old body,” Mike, from Vancouver, British Columbia, told Dr. Fisch on the live broadcast. “I want to feel good. I don’t want to feel tired all day.”

    A regular listener, Mike had heard Dr. Fisch, a Park Avenue urologist and fertility specialist, talk about a phenomenon called “low testosterone” or “low T.” Dr. Fisch likes to say that a man’s testosterone level is “the dipstick” of his health; he regularly appears on programs like “CBS This Morning” to talk about the malaise that may coincide with low testosterone. He is also the medical expert featured on IsItLowT.com, an informational website sponsored by AbbVie, the drug maker behind androgel, the best-selling prescription testosterone gel.

    Like many men who have seen that site or commercials or online quizzes about “low T,” Mike suspected that diminished testosterone was the cause of his lethargy. And he hoped, as the marketing campaigns seem to suggest, that taking a prescription testosterone drug would make him feel more energetic.

    “I took your advice and I went and got my testosterone checked,” Mike told Dr. Fisch. Mike’s own physician, he related, told him that his testosterone “was a little low” and prescribed a testosterone medication.

    Mike also said he had diabetes and high blood pressure and was 40 pounds overweight. Dr. Fisch explained that conditions like obesity might be accompanied by decreased testosterone and energy, and he urged Mike to exercise more and to lose weight. But if Mike had trouble overhauling his diet and exercise habits, Dr. Fisch said, taking testosterone might give him the boost he needed to do so.

    “If it gives you more energy to exercise,” Dr. Fisch said of the testosterone drug, “I’m all for it.”

    Recommendations like Dr. Fisch’s and the marketing of low T as a common medical condition helped propel sales of testosterone gels, patches, injections and tablets to about $2 billion in the United States last year, according to IMS Health, a health care information company. In 2002, sales were reported to be a mere $324 million; around that time, Solvay Pharmaceuticals, which was then marketing AndroGel, began using the term “low T,” replacing a previous euphemism for male aging, “andropause.” Today the low-T trend is global. From 2000 to 2011, there was “a major and progressive increase” in testosterone use in 37 countries, according to a recent study published in the Medical Journal of Australia.

    This marketing juggernaut is running into mounting opposition from some prominent medical researchers and industry experts. They contend that the pharmaceutical industry has vastly expanded the market for testosterone drugs to many men who may not need them and may be exposed to increased health risks by taking them. And drug makers have done so, these critics say, by exploiting loopholes in federal marketing regulations.

    Drug makers spent $107 million last year to advertise the top brand-name testosterone drugs in the United States, according to Kantar Media. That amount doesn’t include marketing known as unbranded campaigns, which raise awareness of low T itself. The Food and Drug Administration closely regulates advertisements for brand-name prescription drugs, but does not generally regulate unbranded campaigns. That two-track system, says John Mack, an analyst who runs a blog called Pharma Marketing, has enabled companies to position low T as a malady with such amorphous symptoms — listlessness, increased body fat and moodiness — that it can be seen to afflict nearly all men, at least once in a while. Drug makers also promote low-T screening quizzes directly to consumers, Mr. Mack says, in an effort to prompt men to seek testosterone prescriptions from their doctors.

    “You might not have the medical condition as described in the textbook,” Mr. Mack explains. “But you may have low T as defined by marketing quizzes, and you go to the doctor and ask for treatment.”

    David Freundel, a spokesman for AbbVie, declined requests to interview company executives. In a statement, Mr. Freundel wrote: “AndroGel is approved by the F.D.A. to treat adult men with low or no testosterone (hypogonadism) who have been diagnosed by a physician, and has more than 10 years of clinical, safety, published and post-marketing data.” He added that the company continues to finance research into the long-term effects of testosterone therapy and that its unbranded informational efforts, like the IsItLowT.com site, “follow F.D.A.’s guidance.”

    Nevertheless, some public health experts warn that the popularization of testosterone drugs is outpacing research into efficacy and possible harms. The drugs’ labels warn users about the potential for sleep apnea, congestive heart failure and low sperm counts; the topical gels warn that women and children exposed to the substances could develop male characteristics like chest hair. Others have raised concerns about the potential for prostate cancer and heart attacks.

    “The big thing is, we just don’t know the long-term risk of testosterone therapy at this time,” says Jacques G. Baillargeon, an epidemiologist at the University of Texas Medical Branch at Galveston who has studied testosterone-prescribing trends in the United States. “It’s particularly concerning when you see the dramatic increase happening at such a large scale so quickly.”

    Seeking a Fountain of Youth

    In a TV commercial promoting awareness of “low T,” the shadow of a middle-age man sits on a bench watching his friends play basketball in an indoor gym.

    “Feeling like a shadow of your former self? Don’t have the hops for hoops with your buddies?” says the voice-over for the spot, paid for by AbbVie and currently posted on the IsItLowT site. “You might have a treatable condition called low testosterone or low T.”

    A few seconds later, presumably after the man is treated with testosterone, the shadow evaporates and a man materializes in the flesh, besuited and smiling. Cue the voice-over: “Step out of the shadows.”

    Testosterone, which plays a central role in the development of the male sexual organs, as well as muscle and body hair, has long been a synonym for youthful vigor and virility. And the quest to stave off aging by manipulating the hormone is an old business.

    Toward the end of the 19th century, Charles-Édouard Brown-Séquard, a French physiologist, began injecting himself with “juice” extracted from crushed dog or guinea-pig testicles, asreported in The Lancet in 1889. Although he contended that the injections were rejuvenating, subsequent researchers came to believe that the placebo effect was at work.

    In the 1920s and ’30s, surgeons began transplanting monkey and goat testes into men, says Dr. John E. Morley, the director of endocrinology and geriatrics at the Saint Louis University School of Medicine. But that fad ended quickly after one well-known surgeon implanted goat testicles into his patients, where they apparently emitted a noxious odor.

    “This is the hilarious history of testosterone,” recounts Dr. Morley, who in the past received speaking fees or consulting fees from drug makers that marketed testosterone treatments or planned to do so. “It may not have gotten any better. But, gee whiz, it was crazy.”

    Researchers were eventually able to synthesize testosterone, and drug makers capitalized on the discovery by using it to develop medical treatments.

    The classic endocrine disorder for which testosterone drugs were originally developed and federally approved is called hypogonadism. That condition can be caused by problems like undescended testicles or a tumor in the pituitary gland, typically resulting in severe testosterone deficiency, along with poor libido, minimal muscles and scant body hair. “That is the real hypogonadal patient,” says Dr. Richard Quinton, an endocrinologist at Newcastle University in Britain, “not the overweight businessman whose erections aren’t as good as they used to be.”

    In fact, physicians weren’t precisely quantifying men’s testosterone levels until the 1960s, after the development of sensitive tests to determine the concentration of different hormones in blood samples. These enabled researchers to record men’s testosterone levels over time. Dr. Morley and others have reported that, after age 30, men’s testosterone levels typically decline by 1 percent a year. To the pharmaceutical industry, that decline was ripe for treatment.

    But the science here is complicated by the fact that weight gain and illness can be accompanied by decreased testosterone levels. In fact, some researchers argue that declining testosterone may not be attributable to aging in itself, but to the fact that older men tend to gain weight more and develop more diseases.

    “Which comes first, the hen or the egg?” says Dr. Farid Saad, the director of global medical affairs for andrology at Bayer HealthCare Pharmaceuticals in Berlin, which markets a testosterone injection called Nebido in 76 countries. “Changes in weight seem to be more important than aging itself.”

    Whatever the cause, an age-associated testosterone decline in men was good news for drug makers seeking to expand sales beyond uncommon endocrine disorders. Aging men could be a vast and perpetual audience.

    There was just one problem. The F.D.A. approved testosterone treatments like Androderm, a skin patch, in 1995, and the original AndroGel, in 2000, for men with classic testosterone deficiency, and the agency prohibits pharmaceutical companies from marketing branded drugs for uses that have not been federally approved as safe and effective.

    In 1997, for instance, the F.D.A. admonished Unimed Pharmaceuticals, the developer of AndroGel, saying that the company had violated federal regulations.

    Even before the gel went on sale, Unimed was preparing to market it for “andropause” — in other words, for symptoms of male aging, according to a continuing whistle-blower lawsuit asserting that Solvay, which acquired Unimed, promoted AndroGel for unapproved uses. (AbbVie, a spinoff of Abbott Laboratories — which acquired Solvay in 2010 — is not accused of any wrongdoing.) The F.D.A. cited Unimed for a news release promoting AndroGel for potential uses “such as the treatment of geriatric hypogonadism in elderly men.”

    Three years later, the agency issued another letter to Unimed, emphasizing that AndroGel was approved for “primary” testicular problems and secondary problems like pituitary or hypothalamus disorders.

    “Claims and representation that suggest that AndroGel is indicated for men with ‘age-associated’ hypogonadism or ‘andropause’ are misleading,” the F.D.A. letter said, according to the complaint.

    Tests That Anyone Can Fail

    Do you have a decrease in libido? Do you have a lack of energy? Are you sad and/or grumpy? Are you falling asleep after dinner? Have you noticed a recent deterioration in your ability to play sports?

    More than a decade ago, a Dutch pharmaceutical company, Organon BioSciences, asked Dr. Morley to devise a screening questionnaire covering symptoms common to older men with low testosterone. The way Dr. Morley recalls the drugmaker’s instructions, “they said, ‘Don’t make it too long and make it somewhat sexy.’ ”

    In return, he says, Organon gave $40,000 to his university for research into the effects of testosterone on muscle. Along the way, Dr. Morley’s quiz acquired an official name that emphasized its intended audience was older men: the Androgen Deficiency in Aging Males, or ADAM, test.

    That test has become standard fare on brand-name drug sites like androgel.com and on informational sites like AbbVie’s IsItLowT.com — where the ADAM test has been re-branded as the “ ‘Is It Low T?’ Quiz.” If the questions drive many men to identify themselves as low-T sufferers and visit their doctors seeking remedies, well, that is their purpose.

    The test has also become controversial. Most of the questions invoke symptoms that are so general that they could apply to many men who are clinically depressed or simply having a bad day — or even to women, says Dr. Adriane J. Fugh-Berman, an associate professor at Georgetown University Medical Center in Washington.

    “There are tests that everyone will fail — that is the idea,” says Dr. Fugh-Berman, who directs PharmedOut, a Georgetown project that educates doctors about drug marketing claims. “ ‘Do you feel tired after dinner?’ Depends how long after dinner. We all do eventually. It’s called sleep.”

    In 2010, the Endocrine Society, a professional medical association, issued guidelines on testosterone therapy advising doctors that there was little evidence to recommend self-reported quizzes.

    Dr. Morley recalls that he drafted the questionnaire in 20 minutes in the bathroom, scribbling the questions on toilet paper and giving them to his secretary the next day to type up. He agrees that it is hardly a perfect screening tool.

    “I have no trouble calling it a crappy questionnaire,” he says. “It is not ideal.”

    He says he believes that the test does catch a subset of the aging population, like older men with low bone-mineral density and decreasing strength, who might benefit from treatment; he prescribes testosterone injections for some of them.

    In his email, Mr. Freundel, the AbbVie spokesman, wrote that the ADAM test “is designed to help men assess their risk for low testosterone and determine whether they should speak to their doctor about low testosterone testing.”

    He added, “For men concerned about low testosterone, we encourage discussion between physicians and patients that leads to proper diagnosis based on symptoms, lab tests and a patient’s other health needs and underlying conditions.”

    But researchers like Dr. Lisa M. Schwartz and Dr. Steven Woloshin, professors at the Dartmouth Institute for Health Policy, say disease promotions and quizzes do more than just worry men into visiting their doctors. The implicit message is that taking testosterone will improve men’s energy and mood, the pair wrote in a recent article in JAMA Internal Medicine.

    The F.D.A. doesn’t regulate how doctors practice medicine, and physicians are free to prescribe drugs as they deem appropriate. Some doctors believe that testosterone can be a good treatment to increase energy. Nevertheless, the F.D.A. has not approved testosterone for such uses.

    “None of the testosterone products have indications for weight loss, increasing energy or improving mood,” said Andrea Fischer, a spokeswoman for the F.D.A.

    The agency prohibits drug makers from marketing unapproved uses for brand-name drugs — because these “off label” uses have not been federally vetted for safety and efficacy. But Ms. Fischer declined to discuss testosterone ads, saying the agency doesn’t comment on brand-name ad campaigns that had not been subject to regulatory action.

    Drug makers’ unbranded promotions talking up a disease or a condition are typically not subject to the same scrutiny. Ms. Fischer said that if the F.D.A. determined an unbranded “disease awareness” campaign to be false or misleading, the agency could refer the matter to the Federal Trade Commission for investigation. She declined to comment on whether the agency had done so regarding low T.

    ‘Enhancing Awareness’

    Earlier this year, Medical Marketing & Media, a trade magazine, named two AbbVie executives as “the all-star large pharma marketing team of the year” for promotions of AndroGel and unbranded efforts to advance low T.

    “It didn’t hurt that baby boomers have proven less than shy about availing themselves of any product that they believe will increase their quality of life,” an article in the magazine said. The article lauded AbbVie’s DriveForFive.com, an unbranded site that encourages men to have regular checkups and to ask their doctors about five tests, among them tests forcholesterol and blood pressure — and testosterone.

    Mr. Freundel of AbbVie described the effort as “a national disease-awareness initiative aimed at encouraging men to take a more proactive approach to their health.” The F.D.A., he added, encourages companies to develop such initiatives “because they serve an important role by enhancing awareness of health conditions.”

    Critics, however, see the site as another tactic to create testosterone takers out of generally healthy men, using the kind of unbranded campaign that federal regulators don’t typically police. Dr. Fugh-Berman of Georgetown refers to this kind of marketing as “disease mongering.”

    In contrast to the promotion of testosterone tests on DriveForFive.com, for instance, the Endocrine Society recommends against screening the general population. For one thing, men’s testosterone levels fluctuate so wildly — depending on time of day, sleep quality, whether they just ate, whether they are taking care of a newborn and even how their favorite sports team is faring — that a single low testosterone reading may not indicate a problem. For another thing, the society says that there is a lack of medical consensus on the extent to which testosterone deficiency “is an important health problem.”

    For men with serious symptoms, testosterone deficiency can be debilitating. A decade ago, Dr. Fisch, the talk-radio urologist, diagnosed testicular failure in a small-business owner from New Jersey. Now 52, the patient, who has been taking testosterone shots for eight years, said he felt that the medication had significantly increased his strength, energy and libido.

    “I’ve run half-marathons, which I could never run before,” said the business owner, who asked that his name be withheld. “I wonder what I could do if my hormone levels weren’t balanced, if they were what they were before the shots.”

    Yet some researchers warn that men whose problems are not caused by low testosterone are also taking the drugs, potentially putting them at unneeded risks for side effects.

    A recent study published in JAMA Internal Medicine reported that about a quarter of men had received testosterone prescriptions without having had blood tests to check their levels.

    “A lot of these men don’t have clear, unequivocal indications for this drug,” says Dr. Baillargeon of the University of Texas, the lead author of the study, “and yet you see the aggressive advertising on ESPN, on radio, on the Internet.”

    Dr. Saad of Bayer acknowledged that occasionally men who are not truly deficient may be treated with testosterone therapy. “This is something that worries us and we would not encourage,” he said.

    For his part, Dr. Fisch says many medicines follow a parabolic pattern of prescriptions — first used for limited purposes, then overprescribed, followed by a pullback to a more targeted group of patients. Testosterone drugs, he says, may go the same route.

    Still, Dr. Fisch, an occasional paid speaker on men’s health for AbbVie, says he remains bullish on low T. But he prefers his own euphemism for aging: “the male biological clock.”

    “This is a huge industry,” Dr. Fisch says, “and I expect it to grow even bigger.”
     
  7. MR10X

    MR10X Member

    I went for over a year without test due to ADT while treating Prostrate cancer and i can say its night and day difference on how i feel and the way my body reacts now that i started taking just 100mg of Test E a week now for the past 2 months. I dont care what anybody says testosterone has a lot more effects on your whole body than you realize other than just sex drive and energy...........
     
    Michael Scally MD likes this.
  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    What finally convinced your doctor to start TRT?
     
  9. MR10X

    MR10X Member

    I showed him some of the studies we discussed here and since mine was confined to my prostrate and my PSA test were so low ( 0.09 ) we decided to do a low dose since the highest my level got back to was 137 and i was having a lot of issues. We are going to retest my PSA and test levels in Jan and go from there.
     
    Michael Scally MD likes this.
  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Editorial Commentary: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, by Ravi Kacker, MD and Abraham Morgentaler, MD.
    Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, Editorial Commentary by Ravi Kacker, MD and Abraham Morgentaler, MD | Androgen Deficiency | UroToday


    BERKELEY, CA (UroToday.com) - Considerable concern has been expressed regarding the safety of testosterone (T) therapy since the recent publication in JAMA of a study alleging increased risk of death, and cardiovascular events in men who received testosterone. However, a careful reading of this study by Vigen, et al. reveals this concern is misplaced, and that the data appear to support the opposite conclusion.

    The authors retrospectively investigated rates of death, myocardial infarction (MI), and stroke in a large cohort of men in the VA hospital system who had undergone coronary angiography and had a documented serum T < 300ng/dl.[1] The authors reported that men who were treated with T therapy had a greater risk of events than untreated men.

    To anyone familiar with the testosterone field, this conclusion was surprising as it contradicts a rich literature spanning more than 20 years demonstrating a beneficial effect of T on cardiovascular function.[2] The discrepancy between the conclusion of this study and prior literature is explained by the highly statistical nature of the paper, and by a serious methodological error.

    The raw data was as follows. Among 1 223 men who received T therapy, there were 67 deaths, 23 MIs, and 33 strokes for an event rate of 10.1% (123 of 1 223 men). For 7 486 men who did not receive T therapy, there were 681 deaths, 420 MIs, and 486 strokes for a rate of 21.2% (1 587 of 7 486 men), or roughly twice the rate of events for men on T therapy. Despite this, the authors wrote, “The absolute rate of events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group” at 3y following angiography. This is mathematically impossible, and the authors have since been obligated to revise their article, replacing “absolute risk” with “Kaplan-Meier estimated cumulative percentages with events.” The significance of this change is that it accurately reflects the fact that the conclusion was based on statistical estimates rather than compelling raw data. By the end of the study, the estimated event rate was approximately 30% for the T-group, a threefold multiple of what actually occurred, greatly magnifying potential errors.

    The rationale for such a high degree of statistical manipulation becomes evident when one looks at the study design. All men began in the no-T group until some of them filled a prescription for testosterone, at which point they were assigned to the T group. However, men in this group also contributed survival data to the no-T group for the period prior to initiating T therapy. There was also a significant delay (mean 531d) in initiating treatment. An MI was attributed to the T group if a man filled his testosterone prescription the same day, but to the no-T group if he hadn’t yet filled it. Moreover, the two groups were dissimilar in important ways at baseline, with greater coronary artery disease burden in the no-T group, and lower serum T concentration in the T-group, each of which could influence outcomes. Clearly, a sophisticated statistical approach was necessary to accommodate these and other complex issues, causing the investigators to adjust for more than 50 variables. While understandable, this degree of complexity undermines the reliability of the results.

    However, our greatest concern is the incorrect exclusion of 1 132 men who were placed on T therapy after MI or stroke. For the purposes of the study, once the event occurred it was irrelevant what happened subsequently to these men. All these events should have been attributed to the no-T group, which would have increased events in that group by 71.8%. Corrected for that serious methodological error, it seems likely that the results of this study would be consistent with two previous reports showing a substantial reduction in mortality with T therapy.[3, 4]

    Shores, et al. also investigated the use of T therapy in a VA population of men with T< 300ng/dl. In that study, mortality in T-treated men was 10.3% compared with 20.7% in untreated men (P < 0.0001). Muraleedharan, et al. performed a similar investigation in diabetic men with T< 300ng/dl, and reported mortality of 8.4% in T-treated men and 19.2% in untreated men (P=0.002).

    Defining the cardiovascular risk of T therapy is important, and will ultimately require a large, prospective trial. In the meantime, we must make do with available data, indicating on the whole that men with T deficiency are at increased risk for diabetes, metabolic syndrome, cardiovascular disease, and mortality.[5, 6] The conclusions of Vigen et al notwithstanding, early retrospective results suggest that T therapy may actually reduce cardiovascular events and mortality.

    References:

    1. Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA : The journal of the American Medical Association. Nov 6 2013;310(17):1829-1836.

    2. Traish AM, Kypreos KE. Testosterone and cardiovascular disease: an old idea with modern clinical implications. Atherosclerosis. Feb 2011;214(2):244-248.

    3. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. Journal of Clinical Endocrinology and Metabolism. Jun 2012;97(6):2050-2058.

    4. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. European Journal of Endocrinology / European Federation of Endocrine Societies. 2013;169(6):725-733.

    5. Tajar A, Huhtaniemi IT, O'Neill TW, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). The Journal of Clinical Endocrinology and Metabolism. May 2012;97(5):1508-1516.

    6. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. Apr 2000;23(4):490-494.
     
  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Highlights
    testosterone Deficiency Syndrome is a recognized but controversial clinical entity.
    • The clinical diagnosis is clear only in cases of profound testosterone deficiency.
    • A great deal of emphasis is put on the biochemical evaluation of T serum levels.
    • Issues of biological and analytical variability need to be considered in the diagnosis.
    • In “borderline” situations, the clinical manifestations plus the laboratory diagnosis and a therapeutic trail of testosterone may be necessary.
    • Therapeutic options depend on issues of availability, efficacy, safety and cost.

    Morales A. Testosterone Deficiency Syndrome: An Overview with Emphasis on the Diagnostic Conundrum. Clin Biochem. Testosterone Deficiency Syndrome: An Overview with Emphasis on the Diagnostic Conundrum

    OBJECTIVES: To review the controversial issues of the Testosterone Deficiency Syndrome (TDS) with an emphasis on the concerns about the diagnosis.

    DESIGN AND METHODS: The relevant literature was reviewed with particular attention to matters related to the clinical manifestations of the syndrome, the need for biochemical assessment and questions of biological and analytical variation that have to be taken into account. Therapeutic options were also appraised.

    RESULTS: There are numerous difficulties with the clinical diagnosis of TDS due to the lack of specificity and subtlety of the manifestations when the degree of deficiency is not severe. Confirmation of the clinical impression requires laboratory evaluation but the choice of assays remains an unsettled issue although there is a general consensus that both free and bioavailable testosterone best reflect the degree of androgenicity. The laboratory diagnosis enjoys a great deal of credibility among clinicians but shortcomings in the interpretation of the assays need to be reiterated and the need for close collaboration between the clinician and the clinical biochemist is important for diagnostic accuracy. Even when the clinical picture is convincing, the laboratory may produce inconclusive results. The option of a therapeutic trial should be contemplated in this situation. Treatment options should be decided between the physician and the patient considering issues of availability, tolerance, efficacy and cost.

    CONCLUSIONS: TDS is a prevalent condition but a matter of persistent controversy due to the vagaries of the clinical and laboratory diagnosis. Symptomatic men with documented T deficiency deserve treatment to improve their quality of life.
     
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study) - Hackett - 2013 - International Journal of Clinical Practice - Wiley Online Library

    BACKGROUND: The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established. Current Endocrine Society and European Association of Urology guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes and in men suffering from erectile dysfunction. It is recognised that a range of physical symptoms appear as the testosterone level falls but few studies have addressed the threshold at which symptoms improve with physiological replacement. We report the first double-blind placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess the metabolic changes with testosterone replacement.

    METHODS: The type 2 diabetes registers of seven general practices were screened to establish the prevalence of low testosterone and the associations with diabetes control. Of 550 eligible patients approached, 488 men (mean age 62.6) consented to take part in screening with a morning testosterone level, assessed between 8 and 11 am. This identified 211 patients for a double-blind placebo-controlled study of long acting testosterone undecanoate (TU) 1000 mg lasting 30 weeks followed by 52 weeks of open label use.

    The population was divided into a SEVERE group with either total testosterone (TT) of 8 nmol/l or less or free testosterone (FT) 180 pmol/l or less or a MILD group with TT 8.1-12 nmol/l or FT 181-250 pmol/l.

    RESULTS: Men in the SEVERE group increased mean through TT from 7.73 nmol/l at baseline to 9.93 at 30 weeks and the MILD group from 10.47 to 11.94. The SEVERE group showed marked improvement in sexual function, but no significant improvement in metabolic parameters.

    The MILD group showed no improvement in sexual function, but significant improvement in weight, body mass index, waist circumference and Hospital Anxiety and Depression Scale.

    Improvement was seen in all parameters during 52 weeks open label treatment where trough TT levels approached 15 nmol/l. Baseline prostate-specific antigen (PSA) was lower in the SEVERE group and increased with TU for 30 weeks and then stabilised. There was no increase in PSA with treatment in the MILD group.

    CONCLUSIONS: Testosterone undecanoate significantly improves sexual parameters and Ageing Male Symptom Score, but not metabolic factors at 30 weeks in men with SEVERE testosterone deficiency syndrome (TDS).

    In men with MILD TDS, significant improvements in metabolic but not sexual parameters were seen, suggesting that there are threshold levels for response to testosterone replacement therapy and that trials of therapy need to achieve sustained therapeutic levels to be effective. PSA showed minor rises, but only for 30 weeks in the SEVERE group.
     
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Layton JB, Li D, Meier CR, et al. testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000-2011. The Journal of Clinical Endocrinology & Metabolism. An Error Occurred Setting Your User Cookie

    Context: New formulations, increased marketing, and wider recognition of declining testosterone levels in older age may have contributed to wider testosterone testing and supplementation in many countries.

    Objective: To describe testosterone testing and testosterone treatment in men in the United Kingdom (UK) and US.

    Design: Retrospective incident user cohort.

    Setting: Commercial and Medicare insurance claims from the US, and general practitioner healthcare records from the UK for the years 2000–2011.

    Participants: We identified 410,019 US men and 6,858 UK men who initiated a testosterone formulation, as well as 1,114,329 US men and 66,140 UK men UK with a new testosterone laboratory measurement.

    Main outcome measures: Initiation of any injected testosterone, implanted testosterone pellets, or prescribed transdermal or oral testosterone formulation.

    Results: Testosterone testing and supplementation have increased, pronouncedly in the US. Increased testing in the UK has identified more men with low levels, yet US testing has increased among men with normal levels. Men in the US tend to initiate at normal levels more often than in the UK, and many men initiate testosterone without recent testing. Gels have become the most common initial treatment in both countries.

    Conclusions: Testosterone testing and use has increased over the past decade, particularly in the US, with dramatic shifts from injections to gels. Substantial use is seen in men without recent testing and in US men with normal levels. Given widening use in spite of safety and efficacy questions, prescribers must consider the medical necessity of testosterone prior to initiation.
     
  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Taya M, Koh E, Izumi K, et al. Comparison of testosterone fractions between Framingham Heart Study participants and Japanese participants. International Journal of Urology. http://onlinelibrary.wiley.com/doi/10.1111/iju.12393/abstract

    Objectives To determine testosterone fractions in Japanese men and to compare these values with those of Framingham Heart Study participants.

    Methods We enrolled 498 healthy Japanese men. Total testosterone was assayed by liquid chromatography tandem mass spectrometry, sex hormone-binding globulin was assayed by immunoassay and free testosterone was calculated by a laboratory at the Boston Medical Center. Analog-based free testosterone and immunoassay-based total testosterone were determined by immunoassay. We compared mass spectrometry assay-based total testosterone and calculated free testosterone values in the Japanese participants with values in the American Framingham Heart Study third generation cohort.

    Results The mean serum mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone values were 439.4?±?167?ng/dL, 65.34?±?30.61?nmol/L, and 58.75?±?20.0?pg/mL, respectively. The correlation coefficients with age for mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone were 0.0010, 0.5041, and ?0.496, respectively. There were no age-related changes in mass spectrometry assay-based total testosterone values in healthy men (P?=?0.981), whereas sex hormone-binding globulin and calculated free testosterone levels showed similar age-related changes (P?<?0.0001). Serum analog-based free testosterone levels (8.24?±?2.9?pg/mL) showed age-related changes (P?<?0.0001) regardless of immunoassay-based total testosterone levels (P?=?0.828). Serum immunoassay-based total testosterone values (486.1?±?162.5?ng/dL) correlated with serum mass spectrometry assay-based total testosterone values (r?=?0.740, 95% confidence interval 0.6965–0.7781, P?<?0.0001). Similarly, analog-based free testosterone and calculated free testosterone values showed a highly significant correlation (r?=?0.706, 95% confidence interval 0.6587–0.7473, P?<?0.0001). The analog-based free testosterone values were approximately 10% of the calculated free testosterone values.

    Conclusions In contrast to the Framingham Heart Study cohort, total testosterone values in Japanese men are not associated with advancing age; thus, they cannot be used to diagnose late-onset hypogonadism in Japan. The analog-based free testosterone value can be considered instead as a suitable biochemical determinant for diagnosing late-onset hypogonadism syndrome.
     
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Yeap BB. Sex steroids and cardiovascular disease. Asian J Androl. Sex steroids and cardiovascular disease Yeap BB, - Asian J Androl

    As men grow older, testosterone (T) levels decline and the significance of this change is debated. The evidence supporting a causal role for lower circulating T, or its metabolites dihydrotestosterone (DHT) and estradiol, in the genesis of atherosclerosis and cardiovascular disease (CVD) in men is limited. Observational studies associate low baseline T levels with carotid atherosclerosis, aortic and peripheral vascular disease, and with the incidence of cardiovascular events and mortality. Studies using mass spectrometry suggest that when total T is assayed optimally, calculation of free T might not necessarily improve risk stratification. There is limited evidence to support an association of estradiol with CVD.

    Interventional studies of T therapy in men with coronary artery disease have shown beneficial effects on exercise-induced myocardial ischemia. However, placebo-controlled, randomized clinical trials (RCTs) of T therapy in men with the prespecified outcomes of cardiovascular events or deaths are lacking. Meta-analyses of randomized controlled trials of T published up to 2010 found no increase in cardiovascular events, mortality, or prostate cancer with therapy.

    Recently, in a trial of older men with mobility limitations, men randomized to receive a substantial dose of T reported cardiovascular adverse effects. This phenomenon was not reported from a comparable trial where men received a more conservative dose of T, suggesting a prudent approach should be adopted when considering therapy in frail older men with existing CVD. Adequately powered RCTs of T in middle-aged and older men are needed to clarify whether or not hormonal intervention would reduce the incidence of CVD.
     
  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Huhtaniemi I. Late-onset hypogonadism: Current concepts and controversies of pathogenesis, diagnosis and treatment. Asian J Androl. Late-onset hypogonadism: Current concepts and controversies of pathogenesis, diagnosis and treatment Huhtaniemi I, - Asian J Androl

    Although suppressed serum testosterone (T) is common in ageing men, only a small proportion of them develop the genuine syndrome of low T associated with diffuse sexual (e.g., erectile dysfunction), physical (e.g. loss of vigor and frailty) and psychological (e.g., depression) symptoms. This syndrome carries many names, including male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late-onset hypogonadism (LOH) describes it best and is therefore generally preferred.

    The decrease of T in LOH is often marginal, and hypogonadism can be either due to primary testicular failure (low T, high luteinizing hormone (LH)) or secondary to a hypothalamic-pituitary failure (low T, low or inappropriately normal LH). The latter form is more common and it is usually associated with overweight/obesity or chronic diseases (e.g., type 2 diabetes mellitus, the metabolic syndrome, cardiovascular and chronic obstructive pulmonary disease, and frailty). A problem with the diagnosis of LOH is that often the symptoms (in 20%-40% of unselected men) and low circulating T (in 20% of men >70 years of age) do not coincide in the same individual.

    The European Male Ageing Study (EMAS) has recently defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum T (total T <11 nmol l-1 and free T <220 pmol l-1 ) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections).

    By these criteria, only 2% of 40- to 80-year-old men have LOH. In particular obesity, but also impaired general health, are more common causes of low T than chronological age per se.

    Evidence-based information whether, and how, LOH should be treated is sparse. The most logical approach is lifestyle modification, weight reduction and good treatment of comorbid diseases.

    T replacement is widely used for the treatment, but evidence-based information about its real benefits and short- and long-term risks, is not yet available. In this review, we will summarize the current concepts and controversies in the pathogenesis, diagnosis and treatment of LOH.
     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Vesper HW, Botelho JC, Wang Y. Challenges and improvements in testosterone and estradiol testing. Asian J Androl. http://www.ajandrology.com/preprintarticle.asp?id=122338

    Assays that measure steroid hormones in patient care, public health, and research need to be both accurate and precise, as these criteria help to ensure comparability across all clinical and research applications.

    This review addresses major issues relevant to assay variability and describes recent activities by the US Centers for Disease Control and Prevention (CDC) to improve assay performance. Currently, high degrees of accuracy and precision are not always met for testosterone and estradiol measurements; although technologies for steroid hormone measurement have advanced significantly, measurement variability within and across laboratories has not improved accordingly. Differences in calibration and specificity are discussed as sources of variability in measurement accuracy.

    Ultimately, a combination of factors appears to cause inaccuracy of steroid hormone measurements, with nonuniform assay calibration and lack of specificity being two major contributors to assay variability. Within-assay variability for current assays is generally high, especially at low analyte concentrations.

    The CDC Hormone Standardization (HoSt) Program is improving clinical assays, as evidenced by a 50% decline in mean absolute bias between mass spectrometry assays and the CDC reference method from 2007 to 2011. This program provides the measurement traceability to CDC reference methods and helps to minimize factors affecting measurement variability.