The Health Consequences of Testosterone Deficiency
Controversies and Advances With Testosterone Therapy: A 40-Year Perspective
Abraham Morgentaler, M.D., F.A.C.S | Associate Clinical Professor of Surgery (Urology) | Harvard Medical School, Beth Israel Deaconess Medical Center
Boston, Massachusetts
Published: December 09, 2015 DOI: https://doi.org/10.1016/j.urology.2015.11.034
There is level 1 evidence that Testosterone Therapy (TTh) improves sexual function and desire, body composition, and bone density. Concerns regarding cardiovascular risk were based on two deeply flawed retrospective studies and are contradicted by dozens of studies showing cardiovascular benefits of TTh or higher endogenous testosterone, including placebo-controlled studies in men with known heart disease (angina, heart failure).
Prostate cancer should no longer be considered a risk of TTh. Testosterone is neither scourge nor panacea—it is just good medicine.
After nearly 40 years working with testosterone (T)—first, as a basic science researcher and, for the last 27 years, as a clinician and investigator—I have been a witness to a considerable number of advances and controversies in the diagnosis and management of testosterone deficiency (TD), also known as hypogonadism. I have been honored to be able to contribute to the field, particularly in the understanding of the biological relationship of androgens to prostate cancer (PCa). As physicians and the public have come to increasingly recognize the benefits of testosterone therapy (TTh), there has also developed a powerful backlash against the use of TTh. Today, the topic of TTh generates as much passion as any other topic in medicine.
Unfortunately, passion makes dispassionate analysis impossible. Today, there is a dominant narrative that the benefits of TTh are unproven, the risks are substantial, and TTh is abused and overused because of physicians yielding to unwarranted demand by misguided patients who are unwilling to accept normal aging. Although there is no evidence to support this position, and considerable evidence to the contrary, this narrative has trumped the facts within the public media. The impact of this vilification of TTh has been substantial, discouraging symptomatic patients from accepting a potentially beneficial treatment, and generating suspicion of physicians offering TTh by their colleagues, for questionable medical practices. This is unfair to patients and physicians alike.
Once a narrative is established, it influences how we view new information.
Below, I present information regarding several of the key topics in Testosterone Therapy today.
Terminology
Testosterone Deficiency (TD) is now increasingly preferred over the older term, hypogonadism, to describe the clinical syndrome in which low levels of testosterone lead to clinical signs and symptoms. Hypogonadism technically refers also to the impaired testicular production of sperm, which is not of immediate relevance to most men with low testosterone levels. For this reason, TD is considered simpler and more accurate than hypogonadism and is the terminology used in this review. Testosterone Therapy (TTh) is preferred over testosterone replacement therapy for similar reasons, as testosterone is not “replaced” in men, unlike hormone replacement therapy in women.
Benefits of Testosterone Therapy
The frequently stated assertion that the benefits of Testosterone Therapy are unproven is simply false. There is level 1 evidence that TTh improves erection quality, libido, sexual frequency; increased lean mass and bone density; improves lipid parameters; causes reduced fat mass; and improves glycemic control.
Who is a Candidate for Testosterone Therapy (TTh)?
There is consensus that candidates for treatment with TTh should have signs or symptoms of TD combined with biochemical evidence of low T levels.
The challenge, however, is deciding what T level is considered low. For the first 40 years after the commercial availability of T products, the diagnosis was made entirely on clinical presentation. With the introduction of readily available testing with the development of radioimmunoassays in the 1970s, the emphasis shifted to documentation of low blood levels. Today, it is becoming increasingly clear that symptoms and clinical presentation should once again take priority, with blood test results an important, yet secondary confirmation.
The difficulty with arriving at a reasonable threshold value for biochemical confirmation of TD is underscored by the wide range of recommended thresholds offered by various professional groups and experts, ranging from 200 ng/dl (approximately 7 nmol/l) to 400 ng/dl (approximately 14 nmol/l).
This confusing situation is worsened by the recommendation by the Endocrine Society in 2010 to follow reference ranges provided by the laboratory performing the testosterone testing, because there is so much variation in reference ranges across laboratories that one survey revealed that 17 of 25 laboratories had different reference ranges.
This means that the same test result may be categorized as normal by one laboratory and low by another.
The explanation for the wide range in threshold recommendations is that there is no specific T value that reliably separates men who may benefit from treatment from those who will not.
Threshold recommendations are therefore arbitrary. The application of lower thresholds means that a higher rate of treated men are likely to experience benefits, but at the cost of denying treatment to many men who may also benefit. Higher thresholds allow for inclusion of more candidates who may benefit, yet overall response rates may be lower.
Moreover, there is a substantial degree of inter-individual variability with regard to symptoms and response to treatment, due at least, in part, to two known confounders—the binding of androgen to sex hormone binding globulin and genetic variability with regard to the number of CAG repeats in the androgen receptor gene, with larger numbers of repeats associated with reduced sensitivity.
This means that healthcare providers must decide on whether a course of treatment is indicated based on the totality of clinical presentation rather than by a blood test result alone.
In our practice, we have found free testosterone to be more clinically useful than total testosterone, as it is independent of sex hormone binding globulin variability.
We routinely measure both total and free testosterone during the evaluation and also to monitor response to treatment.
The current widespread practice by health insurance companies, including Medicare, to restrict coverage based on specific testosterone threshold values therefore lacks a scientific basis and is contrary to good medical practice. The diagnosis of TD requires clinical judgment, and attempts to replace this with irrational adherence to arbitrarily selected values prevent healthcare providers from offering important treatments to appropriately selected patients.
Testosterone and Prostate Cancer
Until recently, the greatest concern regarding TTh among physicians has been the risk of PCa.
This concern was based on the androgen hypothesis, which posited that ever-greater androgen concentrations led to ever-greater PCa risk and growth.
Arguably, the greatest advancement in the field of T therapy over the last twenty years has been the conceptual revolution regarding the relationship of androgens to PCa. Today, the androgen hypothesis can no longer be seriously considered as it is contradicted by a substantial body of evidence.
It has been replaced by the saturation model, which describes an exquisite sensitivity to changes in serum androgen concentrations at very low androgen concentrations, and an indifference to changes at higher concentrations.Finally, Marks et al showed that intra-prostatic concentrations of T and dihydrotestosterone failed to increase significantly with T therapy, despite large increases in serum T, suggesting alternative mechanisms by which a maximal androgenic effect may be achieved.
The importance of the saturation model is that it provides a theoretical foundation for the relatively new practice of offering TTh to selected men with PCa. Although there are no controlled studies to date to offer definitive assessment of risk, a moderate number of case series have demonstrated minimal risk of PCa recurrence or progression with T therapy beyond what would be expected without T therapy.
Does High Endogenous T or TTh Increase the Risk of PCa?
In 2004, my fellow, Ernani Rhoden, and I published the first in-depth analysis of the risk of TTh with regard to PCa.
Until that time, it was axiomatic that higher T concentrations predisposed men to PCa development and growth. We were therefore stunned to discover that we were unable to find any solid evidence that higher endogenous T levels or TTh itself were associated with increased risk of PCa or of high-grade PCa. More recent evidence confirms this. A prospective longitudinal study involving 3886 men with PCa and 6448 age-matched controls showed no relationship between serum androgens and PCa risk.
In the placebo arm of the REDUCE trial, 3255 men underwent prostate biopsy at years 2 and 4, revealing no association between PCa risk and serum T or dihydrotestosterone.
In a meta-analysis of 22 RCTs involving 2351 men, those who received TTh were at no greater risk of developing PCa compared with men who received placebo.
Recently, Baillargeon et al investigated the SEER database and reported that among 52,579 men with PCa, those with exposure to TTh were at no greater risk for high-grade PCa than untreated men.
Low T Levels are Associated With Worse Prognosis for PCa
Remarkably, the weight of evidence today strongly indicates an association between low T levels and worse PCa disease and prognosis. In 1996, my colleagues and I reported PCa rates of 14% using sextant biopsies in men with low T and normal PSA and DRE, a rate similar to men known to be at increased risk based on elevated PSA of 4-10 ng/ml.
Subsequent studies have shown that low T levels are associated with higher Gleason score, greater stage at RP, increased SV involvement, higher biochemical recurrence rates, and reduced survival.
In a cohort of men undergoing active surveillance, low values of free T were found to be an independent predictor of progression.
Cardiovascular Risk
In November 2013 and January 2014, two retrospective studies reported increased CV risks associated with T prescriptions.
This message was amplified in the US by television ads by plaintiff attorneys seeking cases for class action lawsuits. Health Canada and the FDA announced concerns and added new warnings regarding CV risk with TTh products. In addition, the FDA announced a new warning regarding the risk of venous thromboembolic events.
These reports of increased risk were surprising to experts in the field, since there had been accumulating evidence over two decades that higher levels of endogenous T appeared to be protective against CV risk, and TTh had been shown to be associated with reduced mortality and clear evidence of improved CV risk factors, such as fat mass and glycemic control.
These two articles reporting risks merit closer inspection, since they received so much media attention and anchored many critical commentaries on the use of TTh, despite the fact that their findings ran counter to a large body of evidence.
The first of these, by Vigen et al, was a retrospective study of 8709 men in the VA healthcare system who underwent coronary angiography and had T levels <300 ng/dl. Some of these men eventually received a prescription for TTh, and the rest went untreated. The authors reported that the absolute rate of adverse events [cumulative for stroke, myocardial infarction (MI), and death] was 25.7% in the T-treated group and only 19.9% in the untreated group. However, these results were misreported. The correct absolute rate of events was lower by half in the T-treated group compared with the untreated group, at 10.1% and 21.2%, respectively.
The article was subsequently revised to change “absolute rate of events” to “estimated cumulative probability of events” based on adjustment for 54 factors. This fundamental error was not noted in the media. A second major error was discovered several months later, when the journal published a second correction revealing the authors had made an error involving more than 1000 men, and discovered that their all-male population was contaminated by nearly 10% women.
More than 160 leading scientific figures and 29 medical societies have called for retraction of the article, concluding that these errors rendered the results “no longer credible”.
The second article, by Finkle et al, was an analysis of a large insurance database. The authors reported a 36% increase in nonfatal MI in the 90 days following receipt of a T prescription compared with the 12 months prior to the prescription. There was no control group, so it is unknown whether untreated men with TD would have had a higher, lower, or similar rate of MI. In addition, the comparison of the two periods is invalid, since the retrospective nature of this study means that the 12-month period prior to the prescription represents how often physicians were willing to prescribe TTh to men with a recent MI, rather than representing a true rate of MI. It makes no sense to compare physician prescription patterns with true MI rates following receipt of the prescription. Importantly, the actual rate of MI following a T prescription was very low, at approximately one-third the expected MI rate using the NIH Heart Attack Calculator.
In contrast, several dozen articles strongly suggest that low levels of T represent a risk factor for CV disease and mortality, and that T administration may be beneficial or protective (reviewed in Ref. ). In particular, the literature demonstrates that low T levels are associated with increased mortality, atherosclerosis, incident coronary artery disease, severity of coronary artery disease, and carotid plaque or intima-media thickness. In two observational studies of T-deficient men, mortality was reduced by half among men that received T therapy compared with untreated men. In addition, several RCTs in men with known heart disease have shown improved exercise capacity with TTh compared with placebo. This has been shown in men with angina and in men (and one study in women) with heart failure.
Finally, TTh has been shown to improve known CV risk factors, such as reducing fat mass, resolving the metabolic syndrome, and improving glycemic control.
Recently, Sharma et al investigated 83,010 men with documented low T levels, and categorized them into three groups.
Group 1 received T therapy with normalization of T levels, group 2 received T therapy but failed to achieve normalized T levels, and group 3 did not receive T therapy. Results revealed that all-cause mortality, MI, and stroke were all significantly reduced in men who achieved normalization of T levels compared with men who did not receive TTh, or who did not achieve normalization. Importantly, those in group 2 (inadequate TTh) had no greater risk of stroke or MI than untreated men in group 3.
In summary, there appears to be no solid evidence supporting the concern that TTh is associated with increased CV risk. On the contrary, there is an as yet underappreciated awareness that TD itself increases CV risk, and that treatment is associated with CV benefits, especially in at-risk populations. In addition, the first large-scale study of venous thromboembolism risk with TTh has now been published, revealing no increased rate of venous thromboembolism among men who received a T prescription.
It is a peculiarity of our time that these rare studies reporting increased risk receive considerably more media attention than the numerous studies reporting reassuring results.
Future Directions
Over the course of its history, the value of TTh has been tainted: first by its implication with PCa, and more recently with concerns regarding CV risk. Yet as these concerns fade, there are a number of areas where current and future research may provide important clinical advances with TTh. One group recently reported phase 1 data in which men with metastatic castrate-resistant PCa were treated to monthly cycles of intermittently high-dose T injections followed by extremely low T levels due to androgen deprivation.
Positive clinical responses were noted in several men, providing a rationale for considering the possibility that TTh may have a future role in the treatment of PCa.
Substantial data have accumulated that TTh improves body composition and glycemic control in obese or diabetic men with TD. An observational study over 5 years showed remarkable progressive improvement in waist circumference and weight of men who received long-acting T injections.
Given the relative ineffectiveness of nonsurgical treatments for obesity, it may be that TTh will have a future role in weight loss management, if these findings are supported by prospective, controlled studies.
Perhaps most importantly, the current controversy regarding possible CV risks with TTh has led to the recent publication of a number of observational studies that suggest there may be a protective benefit of TTh with regard to CV events, including MI, stroke, and mortality.
The implications of this for future generations are substantial, but will require the performance of a very large prospective trial over several years.
Discussion
The advantage of spending many years in a field is that one develops an appreciation for the ebb and flow of medical and scientific opinion. Testosterone has always been controversial, based on its designation as “the male hormone,” and its promotion in some quarters as an antiaging tonic. The ubiquitous advertising by for-profit clinics and especially by supplement companies making over-the-top claims have created a reactionary atmosphere where a skeptical public, including physicians, is ready to seize upon negative stories that suggest there is something wrong with TTh. It is thus curious, but not altogether surprising, that just as the fear of prostate cancer is waning, we find ourselves concerned with a new “crisis” related to testosterone, namely, CV risk. There is no good evidence for either of these, yet once a dominant narrative has been established, it can be exceedingly difficult to return to an objective stance where the evidence again becomes paramount.
If one examines the evidence dispassionately, what is clear is that TD creates important medical and quality of life issues for men. Symptoms that arise from a deficiency of T will respond nicely to treatment. For some men, treatment can be experienced as life changing. Others will describe the benefits as solid. Some men will not respond at all even after a reasonable trial of treatment, which can be considered 3-6 months with T levels in the upper third of the normal range. In these cases, TTh may be discontinued.
The risks of TTh include erythrocytosis, peripheral edema, acne, breast tenderness or enlargement, and testicular atrophy. Men must be questioned whether they wish to preserve fertility, since treatment with exogenous T reduces sperm concentrations, often to zero.
The most difficult decision for clinicians is to determine who to treat. In general, the likelihood of benefit is greater for those with more severe degrees of TD, yet there is enormous interindividual variability for any given T level with regard to symptoms and to response to treatment. This means that there is an important role for the “art” of medicine in decision-making regarding TTh. Men are not defined by their T values. The clinical presentation is most important. The denial of healthcare coverage by insurance companies based on requirements to meet specific T thresholds is unscientific and replaces clinical judgment with an arbitrary threshold for an imprecise test. This is a transplant attempt by health insurance companies to deny treatment and thereby reduce costs. This practice should be condemned.
After 40 years in the field, this is what I see. Testosterone Therapy for men with Testosterone Deficiency is neither a panacea nor a scourge. It is simply good medicine.
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