Androgen Replacement

Michael Scally MD

Doctor of Medicine
10+ Year Member
Evaluation and treatment of males suspected of having testosterone deficiency entails multiple controversial issues. Recognition of the high prevalence of low testosterone levels in many men with common chronic diseases, an aging population, and greater recognition that testosterone levels fall with aging have greatly expanded the number of men who are diagnosed to have low testosterone levels. The development of new delivery systems and increased marketing of these delivery systems have combined with the larger number of potential patients to make testosterone replacement more common. It is a hot topic for the lay press and primary care clinicians, as well as for urologists and endocrinologists.

Modern medicine is striving to provide evidence-based care. To do this we need large, randomized, placebo-controlled trials (RPCTs), preferably multicentered, and preferably government funded. Treatment of testosterone deficiency due to classical diseases affecting the hypothalamus, pituitary, and/or testes has been accepted for decades, although there were no multicenter trials. Some of the testosterone delivery systems predate the requirement for multicenter studies, and most of the more recently developed testosterone delivery systems were approved by the Food and Drug Administration on the basis of their pharmacokinetic profile and their ability to achieve physiological blood levels. Approval was not based on long-term studies of efficacy and risk. Some outcome studies have provided sufficient data to permit meta-analyses. However, most of these analyses have relied on a limited number of small clinical trials of short duration, and they have used a variety of testosterone delivery systems. Thus, their conclusions often are compromised. This review identifies many of the issues that continue to challenge clinicians, investigators, and patients. This is even truer for most busy primary care clinicians who write a large percentage of the prescriptions for testosterone treatment.


Cunningham GR, Toma SM. Why Is Androgen Replacement in Males Controversial? J Clin Endocrinol Metab:jc.2010-0266. http://jcem.endojournals.org/cgi/rapidpdf/jc.2010-0266v1 (JCEM -- Sign In Page)

Context: Symptoms and signs consistent with androgen deficiency and low testosterone levels are recognized frequently in clinical practice. Recent population-based epidemiological studies indicate that low testosterone levels in men are associated with increased morbidity and mortality. The clinician must be able to counsel patients to help them determine whether testosterone replacement therapy is appropriate for them.

Evidence Acquisition: The authors have conducted a literature search in PubMed, and we have reviewed references in the multiple systematic reviews and meta-analyses that have been published on this topic.

Evidence Synthesis: We have attempted to provide the reader with an appreciation of the evidence that can be used to support the diagnosis of androgen deficiency, the efficacy of treatment, the potential risks of treatment, the therapeutic options, and the recommendations for monitoring treatment.

Conclusions: We think that published clinical experience justifies testosterone replacement therapy in males who have not initiated puberty by age 14 and in males with low testosterone levels due to classical diseases of the hypothalamic-pituitary-gonadal axis. The benefit:risk ratio is less certain in older men and in those with chronic diseases associated with low testosterone levels. The decision to treat in this setting is much more controversial because there are few large clinical trials that have demonstrated efficacy and no large clinical trials that have determined potential risks of increasing the incidence of clinical prostate cancers or cardiovascular events. We provide a critical review of the evidence that supports treatment and potential risks and ways to reduce the risks if the physician and patient elect testosterone replacement.
 
Drug firms and doctors tout treatments for 'male menopause'; others are cautious
http://www.washingtonpost.com/wp-dyn/content/article/2010/10/04/AR2010100405856.html (washingtonpost.com)

Monday, October 4, 2010; 5:56 PM

When it comes to the peculiar burdens of womanhood, menopause has to be somewhere near the top of the list, right alongside childbirth and bikini waxes.

But it seems that midlife hot flashes, mood swings and dwindling libidos may not be entirely female concerns after all: Doctors, researchers and drug companies have begun making the case that men also experience a change of life. This male menopause - "manopause, " if you will - is said to stem from an age-related decline in testosterone, the hormone that plays a key role in everything from puberty to maintaining muscle strength and bone mass to sex drive.

"What we see is that for men, often beginning in their late 30s or early 40s, there is a gradual drop in testosterone of about 1 to 2 percent a year," explains Robert Brannigan, a urologist at Northwestern Memorial Hospital in Chicago who has been researching the phenomenon. "It's not as dramatic or as abrupt a change as is often the case in women, but there is this subtle shift in hormone levels that can result, over time, in a man crossing a threshold where he then has a deficit of testosterone."

This can result in a range of symptoms that "have a huge overall impact on day-to-day life," he says, including depression, irritability, low energy, decreased muscle mass, weight gain, sexual dysfunction and even the occasional hot flash or night sweats.

"We're talking about a lot of men here," adds Brannigan, who estimates that at least 5 million U.S. men are affected by late-onset hypogonadism, which is the clinical term for the condition. "Unfortunately, the vast majority are undiagnosed."

That's partly because this newly recognized condition is hard to identify given it's laundry list of possible symptoms. But research published recently in the New England Journal of Medicine definitively linked low testosterone levels to low sexual desire, and erectile dysfunction, and a poor morning erection, and concluded that these three symptoms must be present to diagnose late-onset hypogonadism. The study, which tracked 3,369 European men between the ages of 40 and 79, also showed that low testosterone was only somewhat related to such physical and psychological problems as an inability to engage in vigorous activity, sadness and fatigue.

Still, the notion of male menopause remains controversial. In fact, a recent article in the Drug and Therapeutics Bulletin that reviewed dozens of studies found that men's testosterone levels do not always drop with age, that low levels in older men do not necessarily produceany specific symptoms and that men with normal hormone levels experience many of the problems commonly associated with low testosterone, including sexual dysfunction, diminished strength and depression.

Indeed, critics suggest that most of the symptoms that have been blamed on "low T" are normal consequences of aging.

"It's still controversial as to whether low levels of testosterone represent a medical problem," says Jason Wexler, an endocrinologist at Washington Hospital Center, who notes that issues such as a lack of energy and motivation, poor memory and weight gain are "highly nonspecific" and can also be related to a slew of other medical conditions. . In most cases, he said, "I don't think there's a direct correlation between the way men feel as they get older and their testosterone levels. So for me, there is great reluctance to call that a disease."

Such informed skepticism hasn't stopped some pharmaceutical companies from marketing the bejesus out of the concepts of low T and male menopause - and it hasn't stopped men from seeking tests and receiving testosterone prescriptions, which have skyrocketed from 2.4 million in 2005 to nearly 3.9 million in 2009, according to the consulting firm IMS Health.

"I think the problem is that you have a captive audience," says Andrew Kramer, a University of Maryland School of Medicine urologist and surgeon. "When a commercial [for low-testosterone-related products] asks, 'Do you have lower energy? Are you not sleeping as well? Is your libido down? Are your erections not as good as they used to be?' every man, of course, is like, 'Yeah, that fits.' "

The fear is that this sort of hyper-awareness will lead to an overscreening of the aging male population, either because patients demand it or because doctors feel they must cover all their bases in this litigious age.

"There is this potential setup for men to be screened when they shouldn't be, and for low testosterone levels that don't represent a problem to be 'discovered' on lab testing and then get misinterpreted as being a low level that requires some intervention," says Wexler. "And that men who should never have been screened, whose testosterone levels have nothing to do with how they feel, are now going to get supplementation, when we really don't have a good body of scientific literature to tell us whether testosterone supplementation in aging men is even safe in the long run." He wonders if the cost and risks of this hormone replacement are worth it, when the benefits are also largely unknown at this point.

Northwestern's Brannigan says yes, largely because of the potential impact on a man's quality of life.

"The question is this: Do patients sit back and let these changes occur and deal with the change in how they feel and function, or do they actually pursue available treatments that in many cases can help?" he says, noting that he has had great success in his clinical practice with topical, injectable and implanted testosterone supplements as well as with medications that stimulate the body's production of testosterone.

Still, Brannigan stresses that men with prostate cancer, a history of breast cancer or untreated sleep apnea and those who are trying to conceive a baby shouldn't use the synthetic hormone. "It's not the answer for everybody, but I find that for many patients, it can restore or optimize how they feel on a day-to-day basis, and in many instances it's not only impacting [a man] but also his relationship with an intimate partner, who is also a part of this equation."

Regardless of where they stand on the matter, experts seem to agree on one thing: Though catchy and hard to ignore, terms such as "male menopause" and "manopause" send the wrong message.

" 'Male menopause' is a loaded term, " says Wexler. "It's got so much baggage, this idea that there's this condition that is somehow equivalent to the female menopause.

"There are definitely men out there who have symptoms, who have low testosterone levels and can benefit from therapy, but the term 'male menopause' or 'andropause' implies that this happens to all men as they age, like menopause happens to all women as they get older, and that's just not the case."
 
Evaluation and treatment of males suspected of having testosterone deficiency entails multiple controversial issues. Recognition of the high prevalence of low testosterone levels in many men with common chronic diseases, an aging population, and greater recognition that testosterone levels fall with aging have greatly expanded the number of men who are diagnosed to have low testosterone levels. The development of new delivery systems and increased marketing of these delivery systems have combined with the larger number of potential patients to make testosterone replacement more common. It is a hot topic for the lay press and primary care clinicians, as well as for urologists and endocrinologists.

Modern medicine is striving to provide evidence-based care. To do this we need large, randomized, placebo-controlled trials (RPCTs), preferably multicentered, and preferably government funded. Treatment of testosterone deficiency due to classical diseases affecting the hypothalamus, pituitary, and/or testes has been accepted for decades, although there were no multicenter trials. Some of the testosterone delivery systems predate the requirement for multicenter studies, and most of the more recently developed testosterone delivery systems were approved by the Food and Drug Administration on the basis of their pharmacokinetic profile and their ability to achieve physiological blood levels. Approval was not based on long-term studies of efficacy and risk. Some outcome studies have provided sufficient data to permit meta-analyses. However, most of these analyses have relied on a limited number of small clinical trials of short duration, and they have used a variety of testosterone delivery systems. Thus, their conclusions often are compromised. This review identifies many of the issues that continue to challenge clinicians, investigators, and patients. This is even truer for most busy primary care clinicians who write a large percentage of the prescriptions for testosterone treatment.


Cunningham GR, Toma SM. Why Is Androgen Replacement in Males Controversial? J Clin Endocrinol Metab:jc.2010-0266. http://jcem.endojournals.org/cgi/rapidpdf/jc.2010-0266v1 (JCEM -- Sign In Page)

Context: Symptoms and signs consistent with androgen deficiency and low testosterone levels are recognized frequently in clinical practice. Recent population-based epidemiological studies indicate that low testosterone levels in men are associated with increased morbidity and mortality. The clinician must be able to counsel patients to help them determine whether testosterone replacement therapy is appropriate for them.

Evidence Acquisition: The authors have conducted a literature search in PubMed, and we have reviewed references in the multiple systematic reviews and meta-analyses that have been published on this topic.

Evidence Synthesis: We have attempted to provide the reader with an appreciation of the evidence that can be used to support the diagnosis of androgen deficiency, the efficacy of treatment, the potential risks of treatment, the therapeutic options, and the recommendations for monitoring treatment.

Conclusions: We think that published clinical experience justifies testosterone replacement therapy in males who have not initiated puberty by age 14 and in males with low testosterone levels due to classical diseases of the hypothalamic-pituitary-gonadal axis. The benefit:risk ratio is less certain in older men and in those with chronic diseases associated with low testosterone levels. The decision to treat in this setting is much more controversial because there are few large clinical trials that have demonstrated efficacy and no large clinical trials that have determined potential risks of increasing the incidence of clinical prostate cancers or cardiovascular events. We provide a critical review of the evidence that supports treatment and potential risks and ways to reduce the risks if the physician and patient elect testosterone replacement.

Great post Dr. Scally. As you know, because you worked with me before, I have 25 stents. In my particular case, I believe TRT is extremely beneficial. When my T is low I have exercise induced angina. This tells me one thing - if I were to undergo a nuclear stress test it would indicate a need for at a minimum a Percutaneous Coronary Intervention with a high probability of another stent. If I report no angina during the stress test, any abnormalities are always - 100% of the time - either nonexistent or marked as an area to watch (the blockage is not seen as significant enough to warrant intervention). I truly believe TRT has saved my life. Even after your protocol for renormalization, my levels were high enough to stave off additional stents. As soon as my levels dropped due to my own non-compliance with diet the angina returned. Thankfully I re-initiated TRT and the exercise induced angina is once again gone.

So TRT does three things - it helps me stay complaint by giving me the energy to work out while boosting my mood (I just wish I could figure out the ED and libido issues), it dilates my arteries and lowers my inflammation as indicated by my hsCRP.

I have had a CT scan of the pelvis area and there is no blockages. I have had additional tests done for ED (I can't even begin to remember their name) and I have no venous leakage or nerve damage. It is hormonal or, more likely, both hormonal and mental (although the two in my opinion are inseparable).

However, something you wrote did jump out at me: We think that published clinical experience justifies testosterone replacement therapy in males who have not initiated puberty by age 14 and in males with low testosterone levels due to classical diseases of the hypothalamic-pituitary-gonadal axis.

My hypogonadism is idiopathic. As you know I did respond to your treatment protocol and when my numbers came back low normal you asked me to re-initiate TRT for 1 year and try again. Being a stubborn idiot I just stopped everything as I was tired of TRT which I had been doing for four years. I think I can trace it all back to a collapse I had while on an ACE inhibitor that caused a complete endocrine crash in my body. At the time everything was out of whack - I failed a Dexamethasone test, met three of the four criterion for diabetes on a GTT. had very low IGF-1, very low testosterone, lost over 20lbs in two weeks, and needed to use a velcro weight belt around my mid-section to provide support for my diaphragm so I could breath correctly (my CO2 levels were climbing fast). I went from doing 100 pushups to, quite literally, struggling to do 10. Nobody to date or at that time has been able to tell me what happened and I had over $50,000 in tests done - neurological, kidneys, liver, checked for rhabdomyolysis, had MRIs done of my entire spine, brain, adrenals, pituitary, and a CT of the lungs. Only the endocrine systems were shown to be basically trashed.

They picked on T because it was the easiest to treat. Six months later and I went to bed still feeling like sh*t and woke up the next day feeling normal. Suddenly all my endocrine systems that they could reasonably measure were normal. I sometimes wonder if I would just have stayed the course if my testosterone would have re-normalized as well. I had a spontaneous recovery, but the damage was probably already done. This episode may be the very reason I am in the shape I am in today with my heart.

In closing, at least in my case with idiopathic hypogonadism, the TRT has staved off more than a few stents and allowed me to live a relatively normal life. While there is not any large scale studies about people like me, I think this sub-population cannot be ignored. If I was to guess, TRT has saved my insurance company at least $120,000 (this is the cost of two angiograms without the stents). In an era of cost savings, looking at TRT to mitigate disease pathology in a positive manner to save costs should also be a focus of research.
 
In the New York Times (10/12, D7) "Personal Best" column, Jane E. Brody writes, "A $45 million study financed by the National Institute on Aging (NIA) is under way at 12 medical centers to see if a year of treatment with testosterone will help 800 men aged 65 and older with low levels of the hormone and problems with physical functioning, fatigue and sexual or cognitive performance." This "study, in which the men are being randomly assigned to receive the hormone or a look-alike placebo, will also evaluate the hormone's effects on cardiac risk factors." However, it "will not answer the question of whether it is safe to use the hormone for years, even decades, which would be necessary to maintain any benefits."


Hormone Replacement for Men? Perhaps
http://www.nytimes.com/2010/10/12/health/12brody.html?_r=1&ref=health

October 11, 2010
By JANE E. BRODY

Women are way ahead of men in knowing the benefits and risks of hormone replacement. There has yet to be a large study spanning years, comparable to the Women’s Health Initiative, of the safety and effectiveness of hormone therapy for aging men who have signs and symptoms of testosterone deficiency.

Despite beliefs based on observational evidence that estrogen therapy enhanced the health and well-being of menopausal women, when a definitive study was finally done, clinicians and researchers were shocked to discover that the risks of long-term hormone replacement could outweigh its benefits.

Would a similar study of testosterone therapy for men experiencing “andropause” likewise reveal more hazard than help? The answer would be welcomed by an estimated four million men in the United States who have subnormal levels of this important hormone, a common result of advancing age.

But these men, as well as those already receiving testosterone therapy and the baby boomers who may soon develop symptoms of low testosterone, may never know whether adding to their bodies’ waning supply will improve or detract from the quality and length of their lives. Rather, they may have to base a decision about therapy on confusing and conflicting evidence.

Late last year, for example, a six-month federally financed study of a testosterone gel put a surprising hitch in efforts to improve the lives of aging men who experience a decline in energy, mood, vitality and sexuality as a result of low testosterone levels. The study, conducted among 209 men 65 and older who had difficulty walking, was abruptly halted when those using the hormone had an unexpectedly high rate of cardiac problems.

The researchers, who published their findings in The New England Journal of Medicine, noted that the deck might have been stacked in favor of a hazardous outcome because study participants, especially the group that received testosterone, had high rates of high blood pressure, diabetes, obesity and elevated blood lipids. Then again, this may be a realistic population to study, given that many candidates for hormone therapy are likely to have such health issues.

Advisement ‘in Limbo’

A $45 million study financed by the National Institute on Aging is under way at 12 medical centers to see if a year of treatment with testosterone will help 800 men aged 65 and older with low levels of the hormone and problems with physical functioning, fatigue and sexual or cognitive performance. The study, in which the men are being randomly assigned to receive the hormone or a look-alike placebo, will also evaluate the hormone’s effects on cardiac risk factors.

Still, this study will not answer the question of whether it is safe to use the hormone for years, even decades, which would be necessary to maintain any benefits. A major concern is whether long-term use would promote the growth of prostate cancer, which is present but hidden in as many as half of older men.

“There are not many good studies of testosterone in older men,” Dr. William J. Bremner, a urologist at the University of Washington in Seattle, said in an interview. “The studies are small and the longest of them lasted only three years. We need the same kind of study for testosterone as the Women’s Health Initiative — several thousand men followed for maybe 10 years. Currently, we’re in limbo as to how to advise patients.”

He acknowledged that the need for such a study for men is “less compelling” because, in contrast to women, who experience an abrupt drop in estrogen at menopause, often with disruptive symptoms, hormone decline in aging men is far more gradual, and symptoms, when they occur, are commonly viewed as normal signs of aging, not hormone deficiency.

A large European study published in the same issue of the journal sought to better determine who, among middle-aged and elderly men, might be candidates for testosterone replacement. Among a sample of 3,369 men aged 40 to 79, researchers at eight European medical centers found that “limited physical vigor” and three sexual symptoms — diminished sexual thoughts and morning erections and erectile dysfunction — were most closely linked to low levels of testosterone.

Although low hormone levels are widely thought to increase a man’s risk of depression, the researchers found that “psychological symptoms had little or no association with the testosterone level.”

There are four main approaches to testosterone therapy available in this country: intramuscular injections every one to three weeks; skin applications through a patch or gel; and pellets implanted under the skin that last for months. The patch can cause skin irritation, and the gel can be transferred to others through skin contact unless care is taken to cover the area where it is applied. But oral administration is rarely used because of toxic effects on the liver.

Weighing Help vs. Harm

The most common reason men seek testosterone therapy is waning sexual desire or performance, although the ability of the hormone to relieve sexual symptoms is unpredictable. More than one-quarter of men with normal testosterone levels have such symptoms, and many men with subnormal levels do not. Dr. Bremner said he typically suggests a trial of therapy for up to a year to see if sexual function or other symptoms improve.

Citing the results of many small studies, Dr. Bremner said, “There is good evidence that testosterone administration can improve muscle mass and strength and increase bone density” in men with subnormal levels. Dr. Abraham Morgentaler, a urologist at Harvard Medical School and author of “Testosterone for Life” (McGraw-Hill, 2009), said in an interview that other noted benefits include a decrease in body fat and total cholesterol and improved blood sugar metabolism.

In a report on the risks of testosterone therapy, written with Dr. Ernani Luis Rhoden and published in 2004 in The New England Journal of Medicine, Dr. Morgentaler noted that testosterone has widespread effects throughout the body, but he and Dr. Rhoden concluded that with proper monitoring, any looming hazards can be readily detected.

Before the most recent study, at doses considered normal, the testosterone gel showed little or no effect on cardiovascular risk, the two doctors reported. Injections could result in harmful thickening of the blood, however, especially if above-normal blood levels of the hormone result.

Although testosterone can cause overgrowth of the prostate, studies have not shown harm to urinary function, Dr. Morgentaler said. The risk of prostate cancer is of greater concern, given that suppressing the body’s natural production of testosterone can cause this cancer to regress. Men considering treatment should first undergo a full prostate exam and PSA measurement, with periodic prostate checkups during therapy, Dr. Bremner said.
 
On February 18 and 19, 2010, The Endocrine Society, in partnership with the Centers for Disease Control and Prevention (CDC), convened a meeting of representatives of multiple professional societies, government, and industry who have a stake in ensuring that testosterone levels are measured accurately and reliably. This objective is necessary to meet research, patient care, and public healthneeds.

The spectrum of conference participants was designed to ensure that a broad range of perspectives informed the identification of goals and objectives and the development of a consensus on the issue of testosterone assay standardization. Organizations interested in steroid hormone testing in the United States were invited and were represented at the meeting. (For a list of meeting participants and organizations represented, see Supplemental Appendix I, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org (Journal of Clinical Endocrinology & Metabolism).) The findings of the group were summarized by the two authors and circulated to all participants for comments and suggestions. Revisions representing the consensus of the group were incorporated into this statement.

The final consensus statement was sent to interested organizations for consideration of endorsement, whether or not they participated in the meeting. Some organizations that participated in the conference chose not to endorse the statement for a variety of reasons. However, nonendorsement does not imply, nor should it be interpreted to mean, that these organizations disagree with all statements in the document. The final manuscript was approved by all the endorsing organizations; hence, the consensus should be considered as summarizing the views of those organizations.

The overarching goal of this collaborative effort is to improve the quality of research, patient care, and public health through broad implementation of standardized testosterone measurements that are accurate, reliable, and comparable over time. This document presents all stakeholders with a call to action to actively participate in this effort.

In brief, the following recommendations represent the consensus of the assembled group of stakeholders (see Recommendations for a more detailed explanation of the recommendations, and see Supplemental Appendix II for a list of organizations that have endorsed this report).

All stakeholders [physicians, other health care providers, laboratories, diagnostic manufacturers, health care organizations, professional societies, pharmaceutical companies, insurance companies, the National Institutes of Health (NIH) and other government agencies] should acknowledge the importance of testosterone assay standardization and of the current standardization effort and should work closely with the CDC to formulate plans to implement accuracy-based, calibrated testing across the entire community of providers and users of these assays.

The expert scientific and medical communities (individuals with scientific and medical expertise in the measurement of testosterone and its clinical application) should work to define performance criteria that cover the full range of expected values, from children to adult males and females.

The expert scientific and medical communities should work together to define reference intervals for testosterone in adults and children of both sexes.

The expert scientific and medical communities should develop guidelines and protocols to ensure uniform patient preparation and handling of samples before they are assayed.

Third-party payers and health care organizations should promote the use of assays that have been standardized through the above-mentioned efforts and should work with relevant organizations and agencies to enable payment only for such standardized assays.

Funding entities, journals, and others involved in research should support the standardization of assays.

Manufacturers and laboratories should continue to work to develop new methodological approaches for ensuring the sensitive, specific, accurate, and cost-effective measurement of testosterone.


Rosner W, Vesper H, on behalf of The Endocrine Society the endorsing o. Toward Excellence in Testosterone Testing: A Consensus Statement. J Clin Endocrinol Metab 2010;95(10):4542-8. http://jcem.endojournals.org/cgi/content/abstract/95/10/4542 (Toward Excellence in Testosterone Testing: A Consensus Statement -- Rosner et al. 95 (10): 4542 -- Journal of Clinical Endocrinology & Metabolism)

Background: Testosterone assays are widely used. However, deficiencies in these assays limit their broad and effective implementation and threaten the health of those patients whose medical care relies upon its accurate measurement. Furthermore, the translation of research findings into information useful for patient care, such as new evidence-based clinical guidelines, is not possible unless both research and clinical assays are held to higher standards than are currently required. A group of concerned stakeholders was convened to address this problem.

Methods: Representatives of multiple professional societies, government, and industry, having a stake in ensuring that testosterone levels are measured accurately and reliably, met to identify goals, objectives, and actions necessary to bring about the standardization of assays for testosterone.

Results: To ensure highly accurate testosterone testing that will result in improved diagnosis, treatment, and prevention of disease through the use of standardized assays, a series of recommendations were agreed upon. The recommendations included the following: technical improvements for assay standardization; education of health care providers, patients, and all others concerned with testosterone testing; plans to encourage all concerned journals, government agencies, and health insurance companies to support this effort; and encouragement to manufacturers to develop better and more cost effective assays.

Conclusion: A preliminary timeline was set out to implement the recommendations of the Group.
 

Attachments

What is settled is unsettled! The controversy continues.


Wartofsky L, Handelsman DJ. Standardization of Hormonal Assays for the 21st Century. J Clin Endocrinol Metab 2010;95(12):5141-3.

We write to reprise and expand the theme of a consensus statement on the subject of standardization of testosterone measurement published in the October issue of the JCEM (1) and encourage your review of that article. The statement from The Endocrine Society and the Centers for Disease Control and Prevention (CDC), with the endorsement of many other groups, addresses the impactof currently available, often inaccurate testosterone assays on clinical care, research, and health care expenditures. The concern is rooted in the fact that there is no recognized reference standard for the assay. Absent such a standard, trustworthy age- and sex-specific reference ranges for testosterone are not attainable. Inaccuracies in plasma testosterone measurement have been noted in ourJournal for several years (2, 3, 4) and apply to both total and free hormone measurements, particularly at the lower levels. The major problems with sensitivity and specificity of the assays have related to current immunoassay methodology, particularly those that are automated (platform-based), although variability has also been shown with analysis by mass spectrometry (5, 6).

There are other problems that are unique to the validity of so-called free testosterone assays. For the most part, free testosterone "measurements" are rarely actually measured but reflect instead derived or calculated values by one or another method that has never been thoroughly validated or standardized. As a result, large errors in this calculation of 20–40% may exist (7, 8, 9), typically overestimating values obtained by equilibrium dialysis. The concept of measuring "bioavailable" testosterone is no less conceptually flawed and also provides values of questionable validity (10). Consequently, a calculated free testosterone measurement can in no way substitute for a total testosterone measured in a validated mass spectrometry-based method.

An Endocrine Society Position Statement in 2007 warned of the significant limitations of testosterone assays (11). The lack of a "gold standard" test and the implications of inaccurate hormonal assays should be obvious and include mistaken diagnosis with subsequent inappropriate care, misleading research findings, and unnecessary health care costs, to name a few. Indeed, given that we strive to base our clinical practice guidelines (3, 12) upon the results of clinical investigation and clinical trials, such guidelines could be worthless to dangerous when rooted in inaccurate laboratory measurements. A recent study documented adverse cardiovascular events associated with testosterone administration; in that study, both initial participation and subsequent dosage adjustments of testosterone were based upon measurements of total and free testosterone (13). How reliable were those measurements, and how might they have influenced dosage changes directly linked to the observed adverse outcomes?

The current consensus statement (1) reflects an ongoing initiative of the CDC (14, 15) in partnership with The Endocrine Society to illuminate this problem. The stated goal of the collaboration is "to improve the quality of research, patient care, and public health through broad implementation of standardized testosterone measurements that are accurate, reliable, and comparable over time." Although the efforts cited above to standardize testosterone assays are both necessary and laudable, they represent an initiative based on only one hormone. At this time, the best results are achieved by methods based on tandem mass spectrometry. However, the issue is not the specific method, but rather the recognition that an assay’s accuracy be traceable to a scientifically arrived at, universally recognized standard. Do all of our other routinely employed hormonal assays provide truly accurate and precise measurements? The wide variation in plasma thyroglobulin and antithyroglobulin antibody levels in different laboratories comes immediately to mind, but similar variations are commonly seen with assays of the serum estrogens and other steroids (16), vitamin D, free T3 or free T4, GH (17), ACTH, salivary cortisol, etc., the measurements of which form the basis for so many of our clinical decisions. The growing use and availability of tandem mass spectrometry has led to more reliable results for 25-OH-vitamin D (18) and has proven specific and reliable for estradiol and progesterone as well as for testosterone (19). Thus, the recommendations proposed by Rosner and Vesper (1) to those having a stake in the quality of testosterone assays could be applied as well to stakeholders in the measurement of several other hormones. These stakeholders include laboratory directors, regulatory agencies, professional societies, pharmaceutical companies, the National Institutes of Health and other research funding agencies, third party payers for health care, and of course patients and their physicians.

If you missed their article in the October issue of JCEM (1), we invite you to read and consider the recommendations and the proposed process for standardization that they suggest, which we will not repeat here. Rather, we will close by mentioning another important stakeholder on the issue of reliable assay results—our medical and scientific journals. Just as journals have collaborated to develop guidelines for clinical trials, standardized nomenclature, aspects of ethical publishing, etc., we can, as a body, insist that research published in our pages must present hormone data measured by assays with the highest standards of accuracy and precision as certified by appropriate bodies. To do so effectively, the JCEM acknowledges that more work would be required by journal staff, manuscript reviewers, and the editors to assure compliance, but the outcome will be well worth the labor. The effective standardization of assays of testosterone and other hormones will be a work in progress, conservatively speaking, over perhaps the next decade. The proximate effort is the standardization of the total testosterone assays, but we should not ignore the inherent conceptual flaws in methods for the estimation of free testosterone as well as the imprecision of these assays. The CDC/Endocrine Society initiative has provided the start, with an emphasis on the importance of mass spectrometry-based testosterone assays. It will take time and dollars for hospital and commercial clinical pathology laboratories to upgrade their technology and methodology. Given the importance of this initiative to both hormone research and clinical care, we hope that the CDC will monitor the quality control of these assays on an ongoing basis as a public service. Once these assays are clearly and optimally standardized, the JCEM pledges to require that all testosterone data submitted by authors will have been measured by laboratories employing the requisite optimal methodology. We will call upon our sister journals to adopt the same policy.
 

Attachments

Standardization: The Future of Testosterone Testing

Standardization: The Future of Testosterone Testing - Renal and Urology News

The Endocrine Society and various endorsing organizations recently published recommendations for improving and standardizing testosterone testing. “Toward Excellence in Testosterone Testing: A Consensus Statement” asserts that urologists and other health-care providers must understand the importance of using accurately calibrated testosterone tests—a process that the groups hope to have fully in place in 2012 (J Clin Endocrinol Metab. 2010;95:4542-4548; available at jcem.endojournals.org/cgi/reprint/95/10/4542, accessed November 12, 2010 ). Endocrinologist William Rosner, MD—professor of medicine at Columbia University in New York, and a lead author of the consensus statement—explains to Renal & Urology News what impending testosterone-testing standardization—and the current lack of it—means to urology practice and research

http://jcem.endojournals.org/cgi/content/full/95/10/4542 (Toward Excellence in Testosterone Testing: A Consensus Statement -- Rosner et al. 95 (10): 4542 -- Journal of Clinical Endocrinology & Metabolism)

Toward Excellence in Testosterone Testing: A Consensus Statement

Background: Testosterone assays are widely used. However, deficiencies in these assays limit their broad and effective implementation and threaten the health of those patients whose medical care relies upon its accurate measurement. Furthermore, the translation of research findings into information useful for patient care, such as new evidence-based clinical guidelines, is not possible unless both research and clinical assays are held to higher standards than are currently required. A group of concerned stakeholders was convened to address this problem.

Methods: Representatives of multiple professional societies, government, and industry, having a stake in ensuring that testosterone levels are measured accurately and reliably, met to identify goals, objectives, and actions necessary to bring about the standardization of assays for testosterone.

Results: To ensure highly accurate testosterone testing that will result in improved diagnosis, treatment, and prevention of disease through the use of standardized assays, a series of recommendations were agreed upon. The recommendations included the following: technical improvements for assay standardization; education of health care providers, patients, and all others concerned with testosterone testing; plans to encourage all concerned journals, government agencies, and health insurance companies to support this effort; and encouragement to manufacturers to develop better and more cost effective assays.

Conclusion: A preliminary timeline was set out to implement the recommendations of the Group.
 
Good thing I have not been reading here lately. I might have been hindered in my recent free thought blaster. :D But my rants serve other personal needs I assure... :rolleyes: Good stuff and great thread!, and nice to see you on top of the real deal thus presenting all aspects founded to current available information.

I find it funny how when I first came to this forum, and blasting current medical standards with accusations of ignorance and negligent disregard. As time passes I find myself drawn closer and closer to the reality that things are already as they should be. However, I still disclaim money and politics as poor influential factors improperly skewing progress.....:drooling: Time will tell.

One of my favorite sayings, that "everythnig has already been thought, and that things are the way they are for reasons not completely expounded, but properly based", seems to again prove.
 
The following commentary from November/December 2010 shows that the controversy about TRT is alive and well. The pendulum has swung far to the direction in prescribing for the simple reason it is desired, which is wrong. I sense a backlash amongst the medical community that will be hard pressed to present its case due to the commercialization of testosterone. However, I am more concerned that this will once again hamper the proper research, education, treatment, and care of AAS users. AAS continue to be the most politicized class of drugs ever prescribed. And this politicization creates fear and ignorance. Despite these problems and the decades lost, AAS/SARMs will become a hot area of R&D for the $$$ potential alone.

Handelsman DJ. An old emperor finds new clothing: rejuvenation in our time. Asian J Androl 2010;13(1):125-9. http://www.nature.com/aja/journal/v13/n1/full/aja2010154a.html

“Those who don't understand their history are condemned to repeat it (Santayana)

History repeats itself, first as tragedy and then as farce (Marx)

To cast this sage historical advice into contemporary terms, the eternal human predisposition to believe in flimsy promises of rejuvenation needs to be well understood, or repeated. As an ingenious species, we have made grand advances in overcoming the physical limits of our biology. Yet while technology has overcome our native ponderous, gravity- and land-bound locomotion with air, land and sea travel, the irreversibility of time and inevitability of death remain stubbornly unyielding. Even such prolongation of lifespan that we have achieved only reveals more starkly the progressive somatic decay and waning of virility which erode dreams of enduring youthful vigour. Lurking just below the conscious horizon, wishful thinking about rejuvenation regularly resurfaces whenever social conditions favour such indulgence. This ancient latent desire to reverse the effects of ageing, most prominently focused on male virility, has led to periodic eruptions of rejuvenation folly—false hopes, built from dreams and armed with futile means, intent on reversing ageing. The epitome of rejuvenation follies is depicted in Lucas Cranach's sixteenth century fantasy landscape of the Fountain of Youth, the legendary spring waters that restore youthfulness, portraying wizened old crones entering a bathing pool to emerge as nubile youthful figures. Curiously, the painter's imagination considers it sufficient to rekindle flagging male virility for the object of libidinal interest to be rejuvenated without needing to revitalise the male body. The latter aspiration, however, gained greater attention in the most florid historical outburst of rejuvenation quackery originating over the turn of the twentieth century reaching an apogee over the next three decades before its rapid extinction. Serious, but self-deluded, doctors announced to great public acclaim various fanciful schemes starting with Brown-Sequard's injections of non-human testis extracts1, 2 and soon joined by Steinach's ‘autoplastic’ procedure (unilateral vasectomy) and Voronoff's testis grafts (stitching non-human testis slices onto the human testicular capsule).3 With the earnest self-belief of pioneers proclaiming scientific triumphs, these doctors published their methods to allow for others to replicate reflecting fidelity in their motivation rather than hunger for limelight or enrichment. However, decades later, once the testosterone content of testes could be measured it was easily calculated or shown directly4 that Brown-Sequard's aqueous extract could yield no hydrophobic constituents such as testosterone. Like much good science, this realisation came too late to derail the flashy transit of hollow fashion. Consequently, Brown-Sequard's, as well as the associated millenarian fads, were simply placebos, mass delusions flourishing amongst a credulous public in thrall to the hubris of early medical science with its new temptation of scientific rejuvenation. Instinctively, contemporary medical journals deplored Brown-Sequard's claims as ‘… recalling …with an incredulous smile …the wild imagings of medieval philosophers in search of an elixir vitae …’, disdaining his discovery as a ‘Pentacle of Rejuvenescence’5, 6(an ancient magical talisman consisting of a five-pointed star believed to summon energy.) and, presciently anticipating the placebo effects of expectation, recording that that the dramatic effects claimed in public displays could not be replicated in hospitalized patients.5 Nevertheless, the promise of revitalisation ensured enormous popularity for rejuvenation quackery1, 2 until its abrupt eclipse in the 1930s. Thoughtful, scholarly scepticism is never much of a match for turbocharged optimism in the public arena regardless of the truth; and doctors, who always remain members of the community, are vulnerable to popular fashion and expectation. The demise and disappearance of rejuvenation quackery in the mid-1930s was due to the advent of the modern science of androgen pharmacology. This was signified by the 1935 virtual dead-heated race between three industrial scientific groups, crowned by Nobel Prize recognition for two but curiously not the third, to fully characterize the major mammalian male hormone, which came to be named testosterone.7, 8, 9 Hope never springs eternal more, it seems, than when it comes to rejuvenation.

An illusion finds a definition

A recent issue of New England Journal of Medicine (NEJM) publishes two closely related studies bookending the issue of testosterone administration to older men. This modern medical (re)incarnation of hormonal rejuvenation, with its scientific fixation on testosterone, has diverged during the last century from the ongoing non-medical lineage of rejuvenation follies which continue in the form of the expensive placebos of the Western health food supplement industry and Asian medicinal use of exotic animal body parts.

The concept of testosterone treatment for older men is based on considering male ageing as analogous to either menopause or pathologically-based hypogonadism. The former is a false analogy as menopause has a unique natural history featuring relatively abrupt and complete cessation of ovarian estrogen secretion in mid-adult life. This is contrary to all other human hormonal systems which decline gradually, modestly and inconsistently with ageing. This dichotomy always provided a firm basis for empirically testing the value of estrogen replacement for a state of uniform, complete estrogen deficiency. Nevertheless, the first randomized placebo-controlled clinical trial10 was preceded by decades of widespread overuse of estrogens for menopause which declined by 80% after the study's publication.11 This exuberant use was based on overinterpreted observational studies and fuelled by inflated expectations of not just symptomatic benefit, but of fundamental health benefits by modifying the natural history of major late-life fatal diseases of women. For all other age-related declines in pituitary hormonal axes, there is no convincing evidence of medical benefit, and notably less enthusiasm, for correcting the modest age-related decreases in thyroid, adrenal or growth hormones compared with the popularity of testosterone for both men and women.

The other analogy, with pathologically based hypogonadism, is based on the superficial resemblance of non-specific symptoms of ageing but which are equally apparent in many other hormonal deficiency states as well as chronic non-gonadal diseases. This ‘andropause hypothesis’, known also by various synonyms ‘male menopause’, ‘viropause’, ‘partial androgen deficiency of the ageing male’ and ‘late onset hypogonadism’ or ‘late-life onset hypogonadism’ was so poorly substantiated that the authoritative 2004 US Institute of Medicine's review12 concluded that better preliminary evidence was required to warrant a large-scale prospective study comparable to the Women's Health Initiative for estrogen replacement in menopause. Nevertheless, the last two decades have seen a ~20-fold increase in testosterone prescribing in the absence of any proven new indications for testosterone treatment. This increase is largely confined to the United States with minimal changes in other regional markets;13 however, the ‘andropause’ bandwagon has undoubtedly left the station propelled by direct-to-public drug advertising.

One of the NEJM paper is from the European Male Ageing Study (EMAS), a large, well-designed observational study of male ageing involving over 3300 men drawn from population-based sources in eight European cities. EMAS is the European counterpart of the seminal Massachusetts Male Ageing Study (MMAS) from the New England Research Institute in Boston which, in a series of memorable and widely cited papers (250 papers, with over 9000 citations so far) over the last two decades created the first sound basis for population-based research into reproductive and related general health aspects of male ageing. EMAS has now begun reporting a series of studies covering much the same territory with similar means but using a larger, multicentre approach in diverse European populations.14,15

This EMAS paper evaluated a wide range of non-specific physical and mental symptoms that accumulate during male ageing and focused on their relationship with blood testosterone levels. The approach of relating non-specific symptoms to serum testosterone levels originates from clinical studies that defined thresholds for symptoms of androgen deficiency in classical pathologically based hypogonadism using clinic-based, convenience populations16, 17 an approach that was extended to population-based analysis of MMAS data seeking to define symptomatic age-related androgen deficiency among older men.18, 19 An important caveat arising from detailed studies of individual men with authentic androgen deficiency is that, although individuals have highly consistent blood testosterone thresholds for symptoms, neither thresholds nor symptoms are consistent between individuals.16 Thus grouping individuals according to symptom(s) would encompass a wide range of individual blood testosterone thresholds so that averaged between-individual estimates of threshold would provide only a crude representation of the component, divergent individual thresholds.

On this background, the EMAS paper introduces a large, multicentre sample size; however, statistical power cannot overcome logical flaws. Examining a wide array of physical and questionnaire measures they found no significant association between physical or psychological features and blood testosterone levels. The analysis then focused on three sexual symptoms (erectile dysfunction, frequency of morning erections or sexual thoughts). Each exhibited a weak association with blood testosterone consisting of a shallow breakpoint (at levels of 8.0, 8.5 and 11 nmol l?1) together with high rates of false positive (25–50%) and negatives (40–50%) indicative of a weak positive and negative predictive values, although that predictive analysis was not reported. The only consistently significant association was between all three sexual symptoms and a blood total testosterone concentration threshold of <8 nmol l?1, but not <11 nmol l?1. Yet, the paper proposes ‘definition’ that requires three sexual symptoms plus a higher blood testosterone, <11 nmol l?1. Furthermore, these associations were all nullified by adjustment for age, obesity and coexisting illnesses indicating that they are due to confounding effects of underlying pathology rather than authentic relationships between those sexual symptoms and blood testosterone levels. A practical implication of this finding is that, among older men without known pituitary or testicular pathology, reduced blood testosterone is due to, and a marker for, their obesity and/or coexisting illnesses. Hence to rectify any deficit in blood testosterone levels, if that is warranted, should be directed towards ameliorating the underlying cause rather than administration of testosterone.

The proposed definition of ‘andropause’ also relies on calculation of a ‘free’ testosterone. This variable has an unearned and largely unquestioned reputation as a superior measure of testosterone action. In reality it has a flimsy biological rationale and is usually derived from inaccurate and misleading calculations rather than actual measurements. The concept of ‘free’ testosterone arose in the 1970s as a term borrowed from the early days of modern clinical pharmacology when mutual displacement of drugs from circulating binding proteins was a contemporaneous explanation for drug interactions. Although that concept of ‘free’ drugs has long been superseded by more physiological explanations for drug interactions such as reciprocal effects on drug metabolizing enzymes, drug transporters and orphan receptors,20 the concept of ‘free’ hormones persisted in endocrinology where it passed from being an illustrative heuristic speculation to become an almost mystical axiom. In the EMAS paper, like most others using ‘free’ testosterone, this derived variable is calculated from the blood total testosterone and SHBG levels by a formula, often glorified as calculations using the ‘Laws of Mass Action’. In reality, these calculations are poorly validated in large scale practical usage with substantial inaccuracies (20–40% overestimation) compared with laboratory measurements of dialysable testosterone, the gold standard.21, 22,23 Similar inaccuracies are present in the son-of-free testosterone, the ‘bioavailable’ testosterone.24 Such systematic errors are due to violations of the many assumptions in practical application of theoretical equilibrium binding equations, particularly inaccurate plug-in stoichiometry and binding affinity estimates although several other assumptions are questionable and unverified. Such errors render these convenient formulae unsuitable for use in individual diagnosis as the definition envisages21, 22, 23 although the systematic error is better tolerated in self-contained research studies. The computational artefact of ‘free’ testosterone has introduced nothing but confusion into the field of male ageing. The heavy reliance of ‘free’ testosterone on blood SHBG levels which increases with age (and decrease with obesity, which in turn increases in prevalence with age) means that including ‘free’ testosterone in any model or formula merely re-introduces ‘age’ in a masked form that undoes attempts to adjust the models fully for confounding effects of age. Consequently, including ‘free’ testosterone in the proposed criteria for age-related androgen deficiency simply turns it into a circular definition.

The counterpart MMAS study shows that blood testosterone levels in older men are quite variable18 due to regression to the mean and other biological and measurement variability. This, together with common experience, has led to all clinical guidelines requiring at least two blood samples weeks apart to confirm sustained low blood testosterone.25, 26, 27 Hence, a proposed definition of age-related androgen deficiency based on a single blood sample is likely to be error-prone. Generally such observational studies are best considered hypothesis generating for an interventional study featuring randomization and placebo controls. In that context this proposed definition is premature as a longitudinal counterpart with serial blood sampling together with symptoms would be required to form more reliable and robust testable criteria than a cross-sectional snapshot based on a single blood sample. Beyond the difficulties of reliance on a single blood sample, the proposed definition requires testosterone measurements by mass spectrometry, a superior technology not yet widely available in routine pathology laboratories despite the established limitations of testosterone immunoassays.28, 29, 30

As men with pathologically-based androgen deficiency were excluded, the proposed definition of age-related androgen deficiency is inherently a pathologizing or medicalizing of ageing. As dubious as this may be, it might be substantiated if the key defining variable, blood testosterone levels, displayed a distinct bimodality with age; otherwise, such pursuit must revert to creating arbitrary cutpoints in a unimodal distribution as ultimately transpired in this paper.

Additional important feature of this analysis is its reliance on adjustment of models. The eight European cities contributing equally to EMAS include more (the United Kingdom, Belgium, Sweden, Italy and Spain) and less (Estonia, Poland and Hungary) affluent countries. The pooling of populations so widely divergent in culture, economic development and health profiles into a single quasi-national entity is more a political identity statement, a genuflection to the EU funding agency, than fact or reasonable assumption. Elimination of important between-centre differences as mere nuisance variables may obscure more than it reveals, missing the trees for all that forest. The influence of this dubious homogenisation on the findings remains unclear.

Finally, a major issue is the overinterpretation of cross-sectional data to imply causality. Although quasi-longitudinal interpretation of cross-sectional studies is a major temptation in telescoping time into a quick snapshot compared with slow, costly longitudinal observations. Such transmutation of cross-sectional data into quasi-longitudinal is especially unsound when the population is not at steady-state as blood testosterone levels show a downward temporal trends in European31 and American32 populations, probably due to the progressive increases in population obesity. The impact of the implied causality of this study should not be underestimated. Despite the ritual demurrals of not recommending testosterone for older men, this paper would inevitably encourage greater use of testosterone as an anti-ageing tonic. One needs to wait no longer to verify this prediction than to read the accompanying editorial which now considers it possible to make a ‘well-established’ diagnosis of age-related androgen deficiency.33

And the consequences

The second NEJM paper reports the premature termination of a randomized, placebo-controlled clinical trial of testosterone treatment in older men with limited mobility (Testosterone in Older Men (TOM)) for an excess of adverse cardiovascular effects in testosterone treated men. It is an interesting reflection on the contemporary risk-averse environment dominating clinical research and medical publishing that the adverse TOM study findings were published within 6 months of study termination whereas the EMAS study spent 2 years in revision.

The TOM study aimed to evaluate somatic benefits of 6 months of testosterone treatment in older men focusing on the muscular and motivational effects of testosterone in frail men over 65 years with lowered serum testosterone. As expected, such a group of frail, elderly men had high background prevalence of pre-entry cardiovascular disorder. This underlying cardiovascular disease is itself responsible for lowering the blood testosterone levels as a non-specific consequence of any chronic illness. Ultimately the TOM study was terminated by its Data Safety and Monitoring Board due to the progressive excess of cardiovascular (23 versus 5 discontinuations in a final study population of 209) as well as other adverse effects in the testosterone-treated men. Although the study's definition of cardiovascular safety was broad (including unexplained syncope and peripheral edema), the unexpected findings were consistent using various alternative definitions.

As the TOM study design was based on conventional masking, entry criteria, individual dose titration and monitoring, these findings can be reasonably interpreted as a low cardiovascular safety margin for frail, elderly men. This differs from previous placebo-controlled studies of testosterone in older men, comprising younger and less frail study populations, that did not report excess cardiovascular adverse events as summarized in systematic reviews34, 35, 36 or even in small 3-month37, 38 and 12-month39 studies of men with cardiac failure. Nevertheless, these testosterone-related adverse findings cannot be regarded as entirely surprising given the well-known male excess of earlier onset, more severe cardiovascular disease40 together with the comprehensive refutation of the long dominant estrogen protection hypothesis.41

These cautionary findings put into perspective the frequently misinterpreted finding of low serum testosterone in men with cardiovascular disease. This regular association in observational studies has become overinterpreted as a risk factor (rather than a consequence), leading to prediction of beneficial (rather than adverse) effects of testosterone treatment.42, 43, 44, 45 This complacency led to a misplaced focus on prostate cancer as the major risk of testosterone treatment in older men.35, 36

This paper saliently highlights the important principle that relatively small adverse effects involving the most common cause of death—cardiovascular disease—overwhelms even substantial benefits on less common or non-fatal disorders. Hence, the TOM study's confirmation of improved limb muscular strength is overshadowed just as were proven reduction in bone fractures and colorectal cancer in the Women Health Initiative, the loss of highly effective, gastric sparing COX2 analgesics and restrictions on oral antidiabetic glitazones due to their adverse cardiovascular effects.

Reflections

These papers resonate with echoes of past mistakes. The focus of the EMAS paper on rejuvenating sexual function can be viewed as a reversion to historical type. Both papers are sadly redolent of the HRT saga in which excessive estrogen prescribing was encouraged for decades by overinterpreted observational studies which led to inflated expectations of improved cardiovascular and other objective health benefits rather than mere symptomatic relief. This exuberance was only curbed by the Women Health Initiative study,10 the first placebo-controlled randomized controlled trial, which provided a sharp reality check in refuting net health benefits and reducing recommended post-menopausal estrogen usage to symptomatic relief for the shortest time necessary.11 Lest we sleepwalk down that same path, hopefully it will not take decades before the ‘andropause hypothesis’ undergoes analogous rigorous testing.

Another historical echo is from the long-range consequence of using, and inevitably then overusing, clinical diagnostic tests simply because they are available. Decades ago when thyroid function tests first became widely available to evaluate thyroid disorders using immunoassays established in specialist hospital laboratories, inevitably out of curiosity these tests were used in hospitalized patients without thyroid disease. Many proved to have low serum thyroxine (T4) and even lower serum triiododthyronine (T3) without having any known thyroidal disease; furthermore when the patients recovered from the underlying illness, the thyroid function tests reverted to normal. In a classical confusion of means and ends, this came to be known as the ‘sick euthyroid syndrome’, loosely defined as a patient with abnormal thyroid function tests and a non-thyroidal illness, but without intrinsic thyroid disease. This terminology reflected a natural reluctance to treat such patients with thyroid hormones despite clearly abnormal blood thyroid function tests when there was no authentic thyroid pathology. It is now generally recognized that abnormal thyroid function tests in non-thyroidal illness are due to the effects of chronic illness and not hypothyroidism warranting replacement therapy.46, 47 The increasing use of testosterone assays in non-reproductive disorders appears to be unwittingly repeating this misadventure with the invention of a ‘sick eugonadal syndrome’, yet another name for ‘andropause’. The main difference is that the interest in rectifying reproductive function, with its immediate misidentification with male virility, attracts much greater popular attention than for hypothyroidism.

These papers shine a spotlight on the limitations of clinical best practice guidelines over the last decade. Rather than serving to strengthen evidence-based medicine by restraining unproven overuse, they have become weakened and even eventually a collusive means of sanctioning it. Whereas the first national guidelines for testosterone use published at the start of the decade25 aimed to restrict testosterone prescribing for the unproven age-related androgen deficiency without hindering prescribing for pathologically based androgen deficiency, these were followed by European-based guidelines in 2005 and US guidelines in 2006, republished recently essentially unchanged.26, 27 The latter blurred the distinction between pathologically-based and age-related androgen deficiency, loosening the diagnostic criteria and lacking regulatory force. As such they came to constitute a minimal diagnostic barrier that tacitly collude with rather than deter testosterone misuse. Whether this perverse outcome is an unintended consequence of the failures of the guideline mechanism,48 or to the connivance of industry-friendly lobbying eroding guideline development is unclear.

These studies are a reminder of the undesirability of direct-to-public advertising of testosterone. Among all therapeutics, the advertising maxim that ‘sex sells’ makes testosterone the most vulnerable to the distortions and confected needs, which are the stock-in-trade of professional marketing of drugs to a public lacking the crucial and technical awareness required to appraise such manipulation. Without protection against this form of manipulative marketing, an avalanche of misguided testosterone prescribing awaits to distort the health and medical care of ageing men.

Ultimately, testosterone prescribing for older men should be restricted to careful clinical trials where diligent ethical oversight will ensure adequate design and suitable warnings to participants. The lowering of blood testosterone in older men due to their concomitant illnesses provides simultaneously both the opportunity for benefit as well as the risk of adverse cardiovascular outcomes. Nevertheless, such concerns should not be a barrier to necessary further research aiming to better define the benefits and risks of testosterone in older men. While age alone may not prove a valid indication for testosterone treatment, more specific studies examining the effects of testosterone on the co-morbidities of ageing such as obesity, diabetes and metabolic syndrome are still warranted. Crucially there is no reason to doubt they can still be safely performed within the framework of placebo-controlled, randomized clinical trials. Rather than the dubious pursuit of pathologizing of ageing, the evaluation of whether testosterone may have a role in adjunctive treatment of obesity, diabetes, metabolic syndrome or other chronic non-gonadal diseases by rigorous interventional studies featuring randomisation and placebo controls, appear justified by a variety of observational studies.49, 50,51

In their wider impact, these two studies can be construed as pressing the accelerator and the brakes at the same time on testosterone prescribing for older men... with probably the same effect of spinning wheels without moving forward.52 The challenge remains whether we can break free from the seemingly irresistible pull into a familiar downward spiral to learn from history rather than blindly repeating it.


References - See Link Above


Professor David Handelsman (MB BS, PhD, FRACP) is the Inaugural Professor/Director of the ANZAC Research Institute. His expertise is in all aspects of male reproductive health, medicine and biology. He was appointed Associate Professor of Medicine in 1989 and then becoming Australia’s first Professor of Andrology in 1996 at the University of Sydney. He is a past President of the Endocrine Society of Australia, has served as a member of the Australian Drug Evaluation Committee and numerous NHMRC grant evaluation committees and panels, is an expert adviser to the Australian Sports Drug Medical Advisory Committee and member of the Commonwealth’s Anti-Doping Research Panel. He was awarded the 1994 Susman Prize for original research by the Royal Australasian College of Physicians and the inaugural AMA Men’s Health Award in 2003. Over a 20 years career he made over 560 scientific contributions including over 270 scientific papers. Editorial Board 12 journals (9 current) and ad hoc peer reviewer for over 70 scientific journals. Supervised 17 PhD and 10 other graduate students. Continuous peer-reviewed grant funding and industry contracts since 1980. His research interests are in the areas of physiology and pharmacology of androgens; genetic mouse models in male reproductive biology; hormonal male contraception; sports doping; male ageing as well as public health policy relevant to male reproductive health.
http://www.asiaandro.com/Editor/David_J_Handelsman.asp (:: Asian Journal of Andrology ::)
 
You know, I can just hear it now as the argument ensues. Logic suggest TRT is no good 98% of the future cases and that it would be only harmful restoration of what was lowered for a reason (IMO). The proponents will say that it has to be taken on a per case basis, that perhaps a 65 year old male who is ideal weight and just failing testicles needs some kick, right. Well then tell me why the 95 year old grandmother still cuts the grass? Its because her body is responding to a demand that has been kept in place for the most part. The 65 year old guy lacks the demand or he would not be in his current set of shoes. And shoes change about like Zebra Stripes. So whats pouring a little SynT on him gonna do? Either kill his heart with excess androgens, or rot his prostate out with Estrogens (probably both in his case), but without demand, hes got about as much use for it as a big Ol set of titties on a boar hog....

The following commentary from November/December 2010 shows that the controversy about TRT is alive and well. The pendulum has swung far to the direction in prescribing for the simple reason it is desired, which is wrong. I sense a backlash amongst the medical community that will be hard pressed to present its case due to the commercialization of testosterone. However, I am more concerned that this will once again hamper the proper research, education, treatment, and care of AAS users. AAS continue to be the most politicized class of drugs ever prescribed. And this politicization creates fear and ignorance. Despite these problems and the decades lost, AAS/SARMs will become a hot area of R&D for the $$$ potential alone.

Handelsman DJ. An old emperor finds new clothing: rejuvenation in our time. Asian J Androl 2010;13(1):125-9. http://www.nature.com/aja/journal/v13/n1/full/aja2010154a.html

“Those who don't understand their history are condemned to repeat it (Santayana)

History repeats itself, first as tragedy and then as farce (Marx)

To cast this sage historical advice into contemporary terms, the eternal human predisposition to believe in flimsy promises of rejuvenation needs to be well understood, or repeated. As an ingenious species, we have made grand advances in overcoming the physical limits of our biology. Yet while technology has overcome our native ponderous, gravity- and land-bound locomotion with air, land and sea travel, the irreversibility of time and inevitability of death remain stubbornly unyielding. Even such prolongation of lifespan that we have achieved only reveals more starkly the progressive somatic decay and waning of virility which erode dreams of enduring youthful vigour. Lurking just below the conscious horizon, wishful thinking about rejuvenation regularly resurfaces whenever social conditions favour such indulgence. This ancient latent desire to reverse the effects of ageing, most prominently focused on male virility, has led to periodic eruptions of rejuvenation folly—false hopes, built from dreams and armed with futile means, intent on reversing ageing. The epitome of rejuvenation follies is depicted in Lucas Cranach's sixteenth century fantasy landscape of the Fountain of Youth, the legendary spring waters that restore youthfulness, portraying wizened old crones entering a bathing pool to emerge as nubile youthful figures. Curiously, the painter's imagination considers it sufficient to rekindle flagging male virility for the object of libidinal interest to be rejuvenated without needing to revitalise the male body. The latter aspiration, however, gained greater attention in the most florid historical outburst of rejuvenation quackery originating over the turn of the twentieth century reaching an apogee over the next three decades before its rapid extinction. Serious, but self-deluded, doctors announced to great public acclaim various fanciful schemes starting with Brown-Sequard's injections of non-human testis extracts1, 2 and soon joined by Steinach's ‘autoplastic’ procedure (unilateral vasectomy) and Voronoff's testis grafts (stitching non-human testis slices onto the human testicular capsule).3 With the earnest self-belief of pioneers proclaiming scientific triumphs, these doctors published their methods to allow for others to replicate reflecting fidelity in their motivation rather than hunger for limelight or enrichment. However, decades later, once the testosterone content of testes could be measured it was easily calculated or shown directly4 that Brown-Sequard's aqueous extract could yield no hydrophobic constituents such as testosterone. Like much good science, this realisation came too late to derail the flashy transit of hollow fashion. Consequently, Brown-Sequard's, as well as the associated millenarian fads, were simply placebos, mass delusions flourishing amongst a credulous public in thrall to the hubris of early medical science with its new temptation of scientific rejuvenation. Instinctively, contemporary medical journals deplored Brown-Sequard's claims as ‘… recalling …with an incredulous smile …the wild imagings of medieval philosophers in search of an elixir vitae …’, disdaining his discovery as a ‘Pentacle of Rejuvenescence’5, 6(an ancient magical talisman consisting of a five-pointed star believed to summon energy.) and, presciently anticipating the placebo effects of expectation, recording that that the dramatic effects claimed in public displays could not be replicated in hospitalized patients.5 Nevertheless, the promise of revitalisation ensured enormous popularity for rejuvenation quackery1, 2 until its abrupt eclipse in the 1930s. Thoughtful, scholarly scepticism is never much of a match for turbocharged optimism in the public arena regardless of the truth; and doctors, who always remain members of the community, are vulnerable to popular fashion and expectation. The demise and disappearance of rejuvenation quackery in the mid-1930s was due to the advent of the modern science of androgen pharmacology. This was signified by the 1935 virtual dead-heated race between three industrial scientific groups, crowned by Nobel Prize recognition for two but curiously not the third, to fully characterize the major mammalian male hormone, which came to be named testosterone.7, 8, 9 Hope never springs eternal more, it seems, than when it comes to rejuvenation.

An illusion finds a definition

A recent issue of New England Journal of Medicine (NEJM) publishes two closely related studies bookending the issue of testosterone administration to older men. This modern medical (re)incarnation of hormonal rejuvenation, with its scientific fixation on testosterone, has diverged during the last century from the ongoing non-medical lineage of rejuvenation follies which continue in the form of the expensive placebos of the Western health food supplement industry and Asian medicinal use of exotic animal body parts.

The concept of testosterone treatment for older men is based on considering male ageing as analogous to either menopause or pathologically-based hypogonadism. The former is a false analogy as menopause has a unique natural history featuring relatively abrupt and complete cessation of ovarian estrogen secretion in mid-adult life. This is contrary to all other human hormonal systems which decline gradually, modestly and inconsistently with ageing. This dichotomy always provided a firm basis for empirically testing the value of estrogen replacement for a state of uniform, complete estrogen deficiency. Nevertheless, the first randomized placebo-controlled clinical trial10 was preceded by decades of widespread overuse of estrogens for menopause which declined by 80% after the study's publication.11 This exuberant use was based on overinterpreted observational studies and fuelled by inflated expectations of not just symptomatic benefit, but of fundamental health benefits by modifying the natural history of major late-life fatal diseases of women. For all other age-related declines in pituitary hormonal axes, there is no convincing evidence of medical benefit, and notably less enthusiasm, for correcting the modest age-related decreases in thyroid, adrenal or growth hormones compared with the popularity of testosterone for both men and women.

The other analogy, with pathologically based hypogonadism, is based on the superficial resemblance of non-specific symptoms of ageing but which are equally apparent in many other hormonal deficiency states as well as chronic non-gonadal diseases. This ‘andropause hypothesis’, known also by various synonyms ‘male menopause’, ‘viropause’, ‘partial androgen deficiency of the ageing male’ and ‘late onset hypogonadism’ or ‘late-life onset hypogonadism’ was so poorly substantiated that the authoritative 2004 US Institute of Medicine's review12 concluded that better preliminary evidence was required to warrant a large-scale prospective study comparable to the Women's Health Initiative for estrogen replacement in menopause. Nevertheless, the last two decades have seen a ~20-fold increase in testosterone prescribing in the absence of any proven new indications for testosterone treatment. This increase is largely confined to the United States with minimal changes in other regional markets;13 however, the ‘andropause’ bandwagon has undoubtedly left the station propelled by direct-to-public drug advertising.

One of the NEJM paper is from the European Male Ageing Study (EMAS), a large, well-designed observational study of male ageing involving over 3300 men drawn from population-based sources in eight European cities. EMAS is the European counterpart of the seminal Massachusetts Male Ageing Study (MMAS) from the New England Research Institute in Boston which, in a series of memorable and widely cited papers (250 papers, with over 9000 citations so far) over the last two decades created the first sound basis for population-based research into reproductive and related general health aspects of male ageing. EMAS has now begun reporting a series of studies covering much the same territory with similar means but using a larger, multicentre approach in diverse European populations.14,15

This EMAS paper evaluated a wide range of non-specific physical and mental symptoms that accumulate during male ageing and focused on their relationship with blood testosterone levels. The approach of relating non-specific symptoms to serum testosterone levels originates from clinical studies that defined thresholds for symptoms of androgen deficiency in classical pathologically based hypogonadism using clinic-based, convenience populations16, 17 an approach that was extended to population-based analysis of MMAS data seeking to define symptomatic age-related androgen deficiency among older men.18, 19 An important caveat arising from detailed studies of individual men with authentic androgen deficiency is that, although individuals have highly consistent blood testosterone thresholds for symptoms, neither thresholds nor symptoms are consistent between individuals.16 Thus grouping individuals according to symptom(s) would encompass a wide range of individual blood testosterone thresholds so that averaged between-individual estimates of threshold would provide only a crude representation of the component, divergent individual thresholds.

On this background, the EMAS paper introduces a large, multicentre sample size; however, statistical power cannot overcome logical flaws. Examining a wide array of physical and questionnaire measures they found no significant association between physical or psychological features and blood testosterone levels. The analysis then focused on three sexual symptoms (erectile dysfunction, frequency of morning erections or sexual thoughts). Each exhibited a weak association with blood testosterone consisting of a shallow breakpoint (at levels of 8.0, 8.5 and 11 nmol l?1) together with high rates of false positive (25–50%) and negatives (40–50%) indicative of a weak positive and negative predictive values, although that predictive analysis was not reported. The only consistently significant association was between all three sexual symptoms and a blood total testosterone concentration threshold of <8 nmol l?1, but not <11 nmol l?1. Yet, the paper proposes ‘definition’ that requires three sexual symptoms plus a higher blood testosterone, <11 nmol l?1. Furthermore, these associations were all nullified by adjustment for age, obesity and coexisting illnesses indicating that they are due to confounding effects of underlying pathology rather than authentic relationships between those sexual symptoms and blood testosterone levels. A practical implication of this finding is that, among older men without known pituitary or testicular pathology, reduced blood testosterone is due to, and a marker for, their obesity and/or coexisting illnesses. Hence to rectify any deficit in blood testosterone levels, if that is warranted, should be directed towards ameliorating the underlying cause rather than administration of testosterone.

The proposed definition of ‘andropause’ also relies on calculation of a ‘free’ testosterone. This variable has an unearned and largely unquestioned reputation as a superior measure of testosterone action. In reality it has a flimsy biological rationale and is usually derived from inaccurate and misleading calculations rather than actual measurements. The concept of ‘free’ testosterone arose in the 1970s as a term borrowed from the early days of modern clinical pharmacology when mutual displacement of drugs from circulating binding proteins was a contemporaneous explanation for drug interactions. Although that concept of ‘free’ drugs has long been superseded by more physiological explanations for drug interactions such as reciprocal effects on drug metabolizing enzymes, drug transporters and orphan receptors,20 the concept of ‘free’ hormones persisted in endocrinology where it passed from being an illustrative heuristic speculation to become an almost mystical axiom. In the EMAS paper, like most others using ‘free’ testosterone, this derived variable is calculated from the blood total testosterone and SHBG levels by a formula, often glorified as calculations using the ‘Laws of Mass Action’. In reality, these calculations are poorly validated in large scale practical usage with substantial inaccuracies (20–40% overestimation) compared with laboratory measurements of dialysable testosterone, the gold standard.21, 22,23 Similar inaccuracies are present in the son-of-free testosterone, the ‘bioavailable’ testosterone.24 Such systematic errors are due to violations of the many assumptions in practical application of theoretical equilibrium binding equations, particularly inaccurate plug-in stoichiometry and binding affinity estimates although several other assumptions are questionable and unverified. Such errors render these convenient formulae unsuitable for use in individual diagnosis as the definition envisages21, 22, 23 although the systematic error is better tolerated in self-contained research studies. The computational artefact of ‘free’ testosterone has introduced nothing but confusion into the field of male ageing. The heavy reliance of ‘free’ testosterone on blood SHBG levels which increases with age (and decrease with obesity, which in turn increases in prevalence with age) means that including ‘free’ testosterone in any model or formula merely re-introduces ‘age’ in a masked form that undoes attempts to adjust the models fully for confounding effects of age. Consequently, including ‘free’ testosterone in the proposed criteria for age-related androgen deficiency simply turns it into a circular definition.

The counterpart MMAS study shows that blood testosterone levels in older men are quite variable18 due to regression to the mean and other biological and measurement variability. This, together with common experience, has led to all clinical guidelines requiring at least two blood samples weeks apart to confirm sustained low blood testosterone.25, 26, 27 Hence, a proposed definition of age-related androgen deficiency based on a single blood sample is likely to be error-prone. Generally such observational studies are best considered hypothesis generating for an interventional study featuring randomization and placebo controls. In that context this proposed definition is premature as a longitudinal counterpart with serial blood sampling together with symptoms would be required to form more reliable and robust testable criteria than a cross-sectional snapshot based on a single blood sample. Beyond the difficulties of reliance on a single blood sample, the proposed definition requires testosterone measurements by mass spectrometry, a superior technology not yet widely available in routine pathology laboratories despite the established limitations of testosterone immunoassays.28, 29, 30

As men with pathologically-based androgen deficiency were excluded, the proposed definition of age-related androgen deficiency is inherently a pathologizing or medicalizing of ageing. As dubious as this may be, it might be substantiated if the key defining variable, blood testosterone levels, displayed a distinct bimodality with age; otherwise, such pursuit must revert to creating arbitrary cutpoints in a unimodal distribution as ultimately transpired in this paper.

Additional important feature of this analysis is its reliance on adjustment of models. The eight European cities contributing equally to EMAS include more (the United Kingdom, Belgium, Sweden, Italy and Spain) and less (Estonia, Poland and Hungary) affluent countries. The pooling of populations so widely divergent in culture, economic development and health profiles into a single quasi-national entity is more a political identity statement, a genuflection to the EU funding agency, than fact or reasonable assumption. Elimination of important between-centre differences as mere nuisance variables may obscure more than it reveals, missing the trees for all that forest. The influence of this dubious homogenisation on the findings remains unclear.

Finally, a major issue is the overinterpretation of cross-sectional data to imply causality. Although quasi-longitudinal interpretation of cross-sectional studies is a major temptation in telescoping time into a quick snapshot compared with slow, costly longitudinal observations. Such transmutation of cross-sectional data into quasi-longitudinal is especially unsound when the population is not at steady-state as blood testosterone levels show a downward temporal trends in European31 and American32 populations, probably due to the progressive increases in population obesity. The impact of the implied causality of this study should not be underestimated. Despite the ritual demurrals of not recommending testosterone for older men, this paper would inevitably encourage greater use of testosterone as an anti-ageing tonic. One needs to wait no longer to verify this prediction than to read the accompanying editorial which now considers it possible to make a ‘well-established’ diagnosis of age-related androgen deficiency.33

And the consequences

The second NEJM paper reports the premature termination of a randomized, placebo-controlled clinical trial of testosterone treatment in older men with limited mobility (Testosterone in Older Men (TOM)) for an excess of adverse cardiovascular effects in testosterone treated men. It is an interesting reflection on the contemporary risk-averse environment dominating clinical research and medical publishing that the adverse TOM study findings were published within 6 months of study termination whereas the EMAS study spent 2 years in revision.

The TOM study aimed to evaluate somatic benefits of 6 months of testosterone treatment in older men focusing on the muscular and motivational effects of testosterone in frail men over 65 years with lowered serum testosterone. As expected, such a group of frail, elderly men had high background prevalence of pre-entry cardiovascular disorder. This underlying cardiovascular disease is itself responsible for lowering the blood testosterone levels as a non-specific consequence of any chronic illness. Ultimately the TOM study was terminated by its Data Safety and Monitoring Board due to the progressive excess of cardiovascular (23 versus 5 discontinuations in a final study population of 209) as well as other adverse effects in the testosterone-treated men. Although the study's definition of cardiovascular safety was broad (including unexplained syncope and peripheral edema), the unexpected findings were consistent using various alternative definitions.

As the TOM study design was based on conventional masking, entry criteria, individual dose titration and monitoring, these findings can be reasonably interpreted as a low cardiovascular safety margin for frail, elderly men. This differs from previous placebo-controlled studies of testosterone in older men, comprising younger and less frail study populations, that did not report excess cardiovascular adverse events as summarized in systematic reviews34, 35, 36 or even in small 3-month37, 38 and 12-month39 studies of men with cardiac failure. Nevertheless, these testosterone-related adverse findings cannot be regarded as entirely surprising given the well-known male excess of earlier onset, more severe cardiovascular disease40 together with the comprehensive refutation of the long dominant estrogen protection hypothesis.41

These cautionary findings put into perspective the frequently misinterpreted finding of low serum testosterone in men with cardiovascular disease. This regular association in observational studies has become overinterpreted as a risk factor (rather than a consequence), leading to prediction of beneficial (rather than adverse) effects of testosterone treatment.42, 43, 44, 45 This complacency led to a misplaced focus on prostate cancer as the major risk of testosterone treatment in older men.35, 36

This paper saliently highlights the important principle that relatively small adverse effects involving the most common cause of death—cardiovascular disease—overwhelms even substantial benefits on less common or non-fatal disorders. Hence, the TOM study's confirmation of improved limb muscular strength is overshadowed just as were proven reduction in bone fractures and colorectal cancer in the Women Health Initiative, the loss of highly effective, gastric sparing COX2 analgesics and restrictions on oral antidiabetic glitazones due to their adverse cardiovascular effects.

Reflections

These papers resonate with echoes of past mistakes. The focus of the EMAS paper on rejuvenating sexual function can be viewed as a reversion to historical type. Both papers are sadly redolent of the HRT saga in which excessive estrogen prescribing was encouraged for decades by overinterpreted observational studies which led to inflated expectations of improved cardiovascular and other objective health benefits rather than mere symptomatic relief. This exuberance was only curbed by the Women Health Initiative study,10 the first placebo-controlled randomized controlled trial, which provided a sharp reality check in refuting net health benefits and reducing recommended post-menopausal estrogen usage to symptomatic relief for the shortest time necessary.11 Lest we sleepwalk down that same path, hopefully it will not take decades before the ‘andropause hypothesis’ undergoes analogous rigorous testing.

Another historical echo is from the long-range consequence of using, and inevitably then overusing, clinical diagnostic tests simply because they are available. Decades ago when thyroid function tests first became widely available to evaluate thyroid disorders using immunoassays established in specialist hospital laboratories, inevitably out of curiosity these tests were used in hospitalized patients without thyroid disease. Many proved to have low serum thyroxine (T4) and even lower serum triiododthyronine (T3) without having any known thyroidal disease; furthermore when the patients recovered from the underlying illness, the thyroid function tests reverted to normal. In a classical confusion of means and ends, this came to be known as the ‘sick euthyroid syndrome’, loosely defined as a patient with abnormal thyroid function tests and a non-thyroidal illness, but without intrinsic thyroid disease. This terminology reflected a natural reluctance to treat such patients with thyroid hormones despite clearly abnormal blood thyroid function tests when there was no authentic thyroid pathology. It is now generally recognized that abnormal thyroid function tests in non-thyroidal illness are due to the effects of chronic illness and not hypothyroidism warranting replacement therapy.46, 47 The increasing use of testosterone assays in non-reproductive disorders appears to be unwittingly repeating this misadventure with the invention of a ‘sick eugonadal syndrome’, yet another name for ‘andropause’. The main difference is that the interest in rectifying reproductive function, with its immediate misidentification with male virility, attracts much greater popular attention than for hypothyroidism.

These papers shine a spotlight on the limitations of clinical best practice guidelines over the last decade. Rather than serving to strengthen evidence-based medicine by restraining unproven overuse, they have become weakened and even eventually a collusive means of sanctioning it. Whereas the first national guidelines for testosterone use published at the start of the decade25 aimed to restrict testosterone prescribing for the unproven age-related androgen deficiency without hindering prescribing for pathologically based androgen deficiency, these were followed by European-based guidelines in 2005 and US guidelines in 2006, republished recently essentially unchanged.26, 27 The latter blurred the distinction between pathologically-based and age-related androgen deficiency, loosening the diagnostic criteria and lacking regulatory force. As such they came to constitute a minimal diagnostic barrier that tacitly collude with rather than deter testosterone misuse. Whether this perverse outcome is an unintended consequence of the failures of the guideline mechanism,48 or to the connivance of industry-friendly lobbying eroding guideline development is unclear.

These studies are a reminder of the undesirability of direct-to-public advertising of testosterone. Among all therapeutics, the advertising maxim that ‘sex sells’ makes testosterone the most vulnerable to the distortions and confected needs, which are the stock-in-trade of professional marketing of drugs to a public lacking the crucial and technical awareness required to appraise such manipulation. Without protection against this form of manipulative marketing, an avalanche of misguided testosterone prescribing awaits to distort the health and medical care of ageing men.

Ultimately, testosterone prescribing for older men should be restricted to careful clinical trials where diligent ethical oversight will ensure adequate design and suitable warnings to participants. The lowering of blood testosterone in older men due to their concomitant illnesses provides simultaneously both the opportunity for benefit as well as the risk of adverse cardiovascular outcomes. Nevertheless, such concerns should not be a barrier to necessary further research aiming to better define the benefits and risks of testosterone in older men. While age alone may not prove a valid indication for testosterone treatment, more specific studies examining the effects of testosterone on the co-morbidities of ageing such as obesity, diabetes and metabolic syndrome are still warranted. Crucially there is no reason to doubt they can still be safely performed within the framework of placebo-controlled, randomized clinical trials. Rather than the dubious pursuit of pathologizing of ageing, the evaluation of whether testosterone may have a role in adjunctive treatment of obesity, diabetes, metabolic syndrome or other chronic non-gonadal diseases by rigorous interventional studies featuring randomisation and placebo controls, appear justified by a variety of observational studies.49, 50,51

In their wider impact, these two studies can be construed as pressing the accelerator and the brakes at the same time on testosterone prescribing for older men... with probably the same effect of spinning wheels without moving forward.52 The challenge remains whether we can break free from the seemingly irresistible pull into a familiar downward spiral to learn from history rather than blindly repeating it.


References - See Link Above


http://www.asiaandro.com/Editor/David_J_Handelsman.asp (:: Asian Journal of Andrology ::)
 
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The aim of this study was to seek objective evidence of androgen deficiency based on pertinent biochemical, end organ, disease state, and quality-of-life alterations in middle- aged and elderly men classified as having Late-Onset Hypogonadism (LOH) according to the criteria previously defined in a general population study. In addition, they examined whether the observed associations could be explained by other factors that vary concurrently with gonadal status.

In summary, LOH, as defined by the presence of three sexual symptoms and low T in a small minority of aging men, showed consistent associations with multiple objective features compatible with androgen deficiency: lower hemoglobin, BMD, and lean body mass as well as reduced physical quality of life. These features were more marked in severe than moderate LOH, suggesting a graded relationship with the degree of T deficiency. The same features were less marked in men with low T only, irrespective of symptoms emphasizing the relevance of sexual symptoms in LOH. The present results further highlight the important confounding influence of obesity and age in a number of metabolic and physical function end points frequently found to be abnormal in LOH. These observations impart new insights into the pathophysiology of LOH that could inform the design of future clinical trials and potentially improve current management of symptomatic aging men with low or borderline T.


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). Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2012/03/09/jc.2011-2513.abstract (Characteristics of Androgen Deficiency in Late-Onset Hypogonadism: Results from the European Male Aging Study (EMAS))

Context: Late-onset hypogonadism (LOH) has been defined as a syndrome in middle-aged and elderly men reporting symptoms in the presence of low testosterone (T).

Objective: The objective of the study was to seek objective biochemical and end-organ evidence of androgen deficiency in men classified as having LOH according to our previously published criteria.

Design, Setting, and Participants: The design of the study included cross-sectional data from the European Male Aging Study on 2966 community-dwelling men aged 40–79 years in eight European countries.

Main Outcome Measure(s): Waist circumference, body mass index, muscle mass, estimated heel bone mineral density (eBMD), hemoglobin, insulin sensitivity, physical activity, metabolic syndrome, insulin resistance index, and cardiovascular disease were measured.

Results: Sixty-three men (2.1%) were classified as having LOH: 36 moderate and 27 severe. They were older and more obese than eugonadal men and had, in proportion to the graded T deficiency, lower muscle mass, eBMD, and hemoglobin, with poorer general health. Both moderate and severe LOH was associated with lower hemoglobin, mid-upper arm circumference, eBMD, physical function (measured by the Short Form-36 questionnaire), slower gait speed and poorer general health. Only men with severe LOH showed significant associations with larger waist circumference (?= 1.93cm; 0.04–3.81), insulin resistance (?= 2.81; 1.39–4.23), and the metabolic syndrome (odds ratio 9.94; 2.73–36.22) after adjustments for confounders. Men with low testosterone only (irrespective of symptoms) showed lesser magnitudes of association with the same end points.

Conclusions: LOH is associated with multiple end-organ deficits compatible with androgen deficiency. These data support the existence of a syndrome of LOH in only a minority of aging men, especially those with T below 8 nmol/liter.
 
The controversy continues ...

Nigro N, Christ-Crain M. Testosterone treatment in the aging male: myth or reality? Swiss Med Wkly 2012;142:0. Testosterone treatment in the aging male: myt... [Swiss Med Wkly. 2012] - PubMed - NCBI

The definition of late onset hypogonadism in the aging male is controversially debated, and according to the latest literature consists of at least three especially sexual symptoms such as loss of morning erection, low sexual desire and erectile dysfunction as well as a total testosterone <8-11 nmol/l. Testosterone replacement therapy in the aging male has been shown to have a beneficial effect on muscle and fat mass as well as on bone mineral density, with more conflicting effects observed on muscle strength, sexual function, mood and quality of life.

The prescriptions for testosterone products for the aging male increased by over 170% in the previous five years. Furthermore, there is a lot of epidemiological data showing an inverse relationship between testosterone levels and obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. However, only few small randomised placebo-controlled studies have investigated the effect of testosterone replacement therapy on insulin resistance and HbA1c levels, with controversial results.

Importantly, so far the long-term safety and efficacy of testosterone replacement therapy has not been established. Although until now no clear evidence has been found that testosterone replacement therapy has a causative role in prostate cancer or indeed in changes of the biology of the prostate, in a recent meta-analysis a 4-fold increased risk of prostate-associated event rates in testosterone treated elderly men sounds a note of caution. Also the risk for cardiovascular events is still not clear and caution is warranted especially in elderly men with cardiovascular disease and limited mobility.

In summary, the actual available evidence of long-term risks and outcome of testosterone replacement therapy is still very limited and carefully designed placebo-controlled trials of testosterone administration to assess the risks and benefits of such a therapy are required. Until then, testosterone treatment in elderly men should be restricted to elderly men with clearly low testosterone levels in the presence of clinical symptoms, and the advantages and disadvantages need to be accurately weighted. A careful monitoring of potential side effects is necessary.
 
Giannoulis MG, Martin FC, Nair KS, Umpleby AM, Sonksen P. Hormone Replacement Therapy and Physical Function in Healthy Older Men. Time to Talk Hormones? Endocr Rev. http://edrv.endojournals.org/content/early/2012/03/19/er.2012-1002.abstract

Improving physical function and mobility in a continuously expanding elderly population emerges as a high priority of medicine today. Muscle mass, strength/power, and maximal exercise capacity are major determinants of physical function, and all decline with aging. This contributes to the incidence of frailty and disability observed in older men. Furthermore, it facilitates the accumulation of body fat and development of insulin resistance.

Muscle adaptation to exercise is strongly influenced by anabolic endocrine hormones and local load-sensitive autocrine/paracrine growth factors. GH, IGF-I, and testosterone (T) are directly involved in muscle adaptation to exercise because they promote muscle protein synthesis, whereas T and locally expressed IGF-I have been reported to activate muscle stem cells. Although exercise programs improve physical function, in the long-term most older men fail to comply. The GH/IGF-I axis and T levels decline markedly with aging, whereas accumulating evidence supports their indispensable role in maintaining physical function integrity.

Several studies have reported that the administration of T improves lean body mass and maximal voluntary strength in healthy older men. On the other hand, most studies have shown that administration of GH alone failed to improve muscle strength despite amelioration of the detrimental somatic changes of aging. Both GH and T are anabolic agents that promote muscle protein synthesis and hypertrophy but work through separate mechanisms, and the combined administration of GH and T, albeit in only a few studies, has resulted in greater efficacy than either hormone alone. Although it is clear that this combined approach is effective, this review concludes that further studies are needed to assess the long-term efficacy and safety of combined hormone replacement therapy in older men before the medical rationale of prescribing hormone replacement therapy for combating the sarcopenia of aging can be established.
 
...As time passes I find myself drawn closer and closer to the reality that things are already as they should be. However, I still disclaim money and politics as poor influential factors improperly skewing progress.....:drooling:

I'm not sure I follow that second sentence. If I take it literally it sounds like you are saying you reject the fact that money and politics are "poor influential factors". In other words, you think they *are* influential.

If so, I agree.

And let me run this by the forum for its consideration. Its a hypothesis for why the politics is making TRT controversial not only in the medical community and society as a whole but, surprisingly, among the community of guys receiving TRT. (Surprising because you'd think there would be sympathy among this crowd -- my experience is there isn't always.)

It goes like this. Big Nanny Government, tells us kids we can't have candy. It's very bad for us, and although we might want it, we can't have it. People plead for candy, but no one gets it. As a result, everyone is grumpy with Nanny.

But then she decides to relent a little. She decides that if certain conditions are met, then the kids meeting them *can* have candy. Needless to say, lots of kids try to show that they meet those conditions. Some actually do; some are borderline; some clearly don't. And a strange thing happens. The kids who clearly do meet her conditions start berating the borderline kids and the kids who clearly do not meet the conditions. They start acting on Nanny's behalf. In fact, they grow to love Nanny. It becomes important to *their* justification for having candy that the other kids are *not* allowed to have it.

The tragedy is, in those circumstances, that everyone forgets the problem in the first place. Why the f*ck is it any business of Nanny's *at all* whether any given person has candy?
 
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No, I think we are on the same page. The issue is political ranging from fear of unknown to fear of social insurrection. The truth is that it has been prethought that you can dose folks with SynT till it bubbles out of their skin, and the most likely outcome is that they are going to start crying like a bitch!!. Testosterone as a hormone is the POOREST alternative there is... Its like throwing gas on a bon fire of bitch titties...

True and good replacement notion would be strick androgens, which testosterone is not. THEN YOU WOULD HAVE SOME REAL ABUSE. I have not studied on SARMS yet, but I suspect in principle they may be far superior as a cure for the ever Popular LOW T MALE... LOL

To give a fat middle aged sedentary man SynT is like the fucking biggest joke on the planet. Its opportune in these IGNORANT ROMAN TIMES cause you can eat all ya want and not get sick for MANY YEARS. It does nothing unless the subject puts down the twinkees.....:)

So to address yur analogy. They are giving them the candy now, but the joke is that is is SUGAR FREE>... LOL[:o)]

Its so easy to amuze myself. I believe they call that INSANITY... .LOL

I'm not sure I follow that second sentence. If I take it literally it sounds like you are saying you reject the fact that money and politics are "poor influential factors". In other words, you think they *are* influential.

If so, I agree.

And let me run this by the forum for its consideration. Its a hypothesis for why the politics is making TRT controversial not only in the medical community and society as a whole but, surprisingly, among the community of guys receiving TRT. (Surprising because you'd think there would be sympathy among this crowd -- my experience is there isn't always.)

It goes like this. Big Nanny Government, tells us kids we can't have candy. It's very bad for us, and although we might want it, we can't have it. People plead for candy, but no one gets it. As a result, everyone is grumpy with Nanny.

But then she decides to relent a little. She decides that if certain conditions are met, then the kids meeting them *can* have candy. Needless to say, lots of kids try to show that they meet those conditions. Some actually do; some are borderline; some clearly don't. And a strange thing happens. The kids who clearly do meet her conditions start berating the borderline kids and the kids who clearly do not meet the conditions. They start acting on Nanny's behalf. In fact, they grow to love Nanny. It becomes important to *their* justification for having candy that the other kids are *not* allowed to have it.

The tragedy is, in those circumstances, that everyone forgets the problem in the first place. Why the f*ck is it any business of Nanny's *at all* whether any given person has candy?
 
To give a fat middle aged sedentary man SynT is like the fucking biggest joke on the planet.

Exactly why is it a joke to do that? Why, for example, is it a joke to give the fat middle aged sedentary man testosterone but it is not a joke to give him ACE inhibitors to control hypertension? Both hypertension and low T can be helped by losing weight, but we don't say the fat guy has to lose weight *first* and then he can have some Ramipril. Why is T different?

Isn't this precisely an example of what I'm talking about. It serves the purpose of the slim and clearly-low hypogonadism sufferers to villify the fat, only-low-normal "sufferers", because it places them (the "real" sufferers) further along the scale of "I really *need* T" than they otherwise would be. By pointing to the fat middle-aged sedentary person the slim younger active person can say:

"Look, I don't approve of *them* having T, so that proves I have a balanced view. T isn't for everyone. Now I, on the other hand, am a real sufferer, and since you know I don't think anyone and everyone should get T, you can be sure that when I say *I* need T, that I'm telling the truth."

I'm not saying this is the only reason for controversy, and I don't think everyone who is on T thinks like that. But it seems plausible that it is a factor. Getting on side of the prison guards by snitching on and oppressing your fellow prisoners is an ancient game.
 
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