The use of hormonal therapy in “andropause”: the pro side

“An error is the more dangerous the more truth it contains.”

— Henri-Frédéric Amiel

Although the discovery and synthesis of testosterone and other androgens took place more than 80 years ago, the controversy over their significance, applications and use is no less intense today than it was then. The introduction of injectable forms of testosterone in the first half of the 20th century created great expectations and a rush to treat all sorts of disparate conditions unrelated to a deficiency in testosterone production. The false hopes and misunderstandings due to androgen use and abuse in the absence of hypogonadism resulted in frustration and disappointment for all concerned and seriously interfered with proper scientific evaluation of gonadal steroids, the causes and consequences of their deficiency as well as their treatment. The rumbles from that distant “big bang” still resonate today. And, probably no syndrome experiences the influx of “expert” views from all sorts of walks of life: from endocrinologists and psychiatrists to urological surgeons and gerontologists, from the lay press to the regulatory agencies and from the pharmaceutical to the entertainment industries. The dismal result of all this free-for-all cacophony of opinions is a great deal of confusion, erroneous information and significant detriment to patients and physicians alike.¹

Both my opponent and I are believers in the concept of testosterone deficiency syndrome (TDS) and prescribers of testosterone therapy. We may argue about issues of limited consequence such as taxonomy and semantics, but on the fundamental ones (e.g., clinical relevance of the syndrome, its assessment and monitoring therapy), I wish to reiterate that a “con” position is defensible only when TDS is diagnosed and managed incompetently.

The absurd view that TDS is an invention of industry blatantly and conveniently ignores medical observations and reports going back 500 years and accelerating since the mid 20th century. It does not merit further discussion.

Medical progress brings honest disagreements and evolving opinions. The controversy about TDS spans the whole spectrum, from diagnosis to treatment. Two areas are particularly unsettled: the biochemical diagnosis and the effect of testosterone on prostate health. Two other subjects are relatively new but gaining relevance and importance: the contribution of TDS to the development of the metabolic syndrome and erectile dysfunction and their treatment. But heavily debated issues also include the contribution of diagnostic questionnaires, the most effective delivery forms for testosterone, the long-term efficacy and safety of current preparations, standards for monitoring men receiving exogenous testosterone and, most unfortunately, the unwarranted extrapolation of the results of the Women's Health Initiative (WHI) to the use of testosterone treatment in adult men. Although much has been learned over the last 6 decades about the manifestations of TDS, the efficacy of testosterone treatment and its potential adverse outcomes, most studies have been relatively short or insufficiently powered to reach definitive conclusions.

Volumes could be written just to address the issues listed above. Allow me to tackle some of the more relevant ones.

Diagnosis

In addition to an adequate history and physical examination, physicians have several specific options to reach a diagnosis of TDS: questionnaires and a biochemical assessment from peripheral blood (the efficacy of salivary testosterone measurements is currently not fully recognized).

A variety of questionnaires are available at present. Some are more elaborate than others. They are appropriate purely as screening instruments and are documented for their significant sensitivity but rather poor performance with regard to specificity.² Three questionnaires are most widely recognized: the St. Louis University ADAM, the Massachusetts Male Aging Study (MMAS) and the Aging Male Survey (AMS). Owing to their simplicity and sensitivity, the ADAM and the AMS have gained most popularity. Dr. Casey and I share the view that they are helpful for screening purposes but that they fall short in their use as definitive clinical diagnosis or as outcome measures for treatment.³

The biochemical diagnosis is another sore point of controversy and confusion, but it is simpler than it has been made out to be: liquid chromatography tandem spectrometry remains the gold standard, and free testosterone by equilibrium dialysis and measured bioavailable testosterone, properly performed, are reliable assays.⁴ These methods, however, are either cumbersome, difficult to reproduce, expensive or not readily available. Calculated free testosterone and bioavailable testosterone are considered accurate and can be carried out with equipment and expertise available in most clinical laboratories. It must be emphasized that the measurement of total testosterone is adequate for the determination of androgenicity in nearly all clinical situations as long as the blood sampling is done in the morning (another point of contention). One must remember the circadian and ultradian variations in testosterone levels. Therefore, the performance of repeated measurements is recommended to confirm the diagnosis. It would be unforgivable to subject a man to a lifetime of testosterone treatment on the basis of a single faulty biochemical test. We should not ignore the small but convincing evidence that assessment of testosterone from samples of peripheral blood might be a poor reflection of androgen levels in tissues.⁵ One last word to the wise on this, from a recent publication:

We have the technology to improve the accuracy and precision of testosterone assays and must choose these properties over simplicity and economy.⁶

Although this is an accurate statement, it is a hard pill to swallow with the realities of our health care system.

Prostate health

Prominent among the concerns regarding testosterone treatment is its effect on prostate health. For decades, the concept that testosterone is “bad for the prostate” has gone unchallenged. More research and clinical experience are seriously and fundamentally revisiting these notions.⁷ Basic investigations have shown that the development and growth of prostate cancer are much more complex than simply an excess of lack of androgens: nonsteroidal hormones (e.g., insulin, leptin, glucocorticoids and growth hormone), genetic susceptibility, inflammation and environmental factors appear to be significant contributors. Further, and despite the large body of support for a positive relation between male sex steroids and growth of prostate cells, there are a number of puzzling situations that are under active study. For instance, a prostate cancer cell line that requires initial stimulation by androgens to grow is eventually suppressed by them. These and other observations must not be interpreted as a green light for the indiscriminate use of testosterone treatment in adult men. Appropriate assessment of the prostate before and during treatment remains a mandatory responsibility for the treating physician.⁸

I trust that Dr. Casey joins me⁹ in supporting the recommendation that known or suspected prostate carcinoma is a contraindication for testosterone products. This has been reiterated, unambiguously, by the recent Endocrine Society Guideline.¹⁰ Administration of testosterone and other steroids to men suspected of having prostate cancer, at this time, should be considered only as part of properly sponsored, well designed and organized, rigidly controlled and carefully monitored clinical trials. To do otherwise can easily be construed as reckless behaviour that would potentially endanger the patient's health and the clinician's reputation and result in further detriment to a field already replete with myths, misinformation and dubious evidence. To the objective observer, it is clear that further “critical assessment” of the available information on the relation between testosterone and prostate health will not significantly enhance our knowledge on this topic. Only a fresh approach with good studies will lead to the answers that we all yearn for.⁹

Sexual dysfunction

An evolving concept in the field of erectile dysfunction is the relevance of androgens in general and testosterone in particular. Experimental evidence for the fundamental importance of androgens in the maintenance of the anatomic and histological integrity of the penile cavernosal structures is overwhelming.¹¹ Several clinical studies have confirmed an improvement in sexual desire and erectile quality in testosterone deficient men treated with exogenous testosterone. In addition, there is an ever increasing number of reports indicating that testosterone deficiency interferes not only with normal function but also with the response to treatments specifically aimed at correcting the inadequate mechanisms of erection. The studies are still limited in number and insufficiently powered but intriguing, if not yet totally convincing. Suffice it to say that after several years of doubts and controversy it appears that a simple testosterone determination should be part of the initial work up of most men with erectile dysfunction. If TDS is documented, it should be treated initially; it may be all that is necessary. If, on the other hand, the response is inadequate, the addition of a specific agent (i.e., a PDE5 inhibitor) can be added.¹²

Cardiovascular health

Significant benefits in some aspects of lipid profile, prevention of atheromas deposition, coronary vasculature and in exercise performance in men with heart failure have been clearly documented. The studies are still few in number^13,14 or involve small populations.¹⁵ But, if we are going to reject the results of these well thought out and executed studies, I would say “show me the contrary evidence” or even better, “where is the beef?”

There are many other issues of relevance when dealing with TDS that require the serious attention of the medical and scientific communities. Regulatory agencies base their decisions on published information and expert opinions. Contradictory information from discrepant or poorly developed guidelines and recommendations, studies of questionable design or execution, and the erroneous or tendentious interpretation of their data do not advance our search for answers. The lay media has had a field day pointing to the honest doubts and concerns of serious clinicians and researchers as examples of blatant ignorance at best and dishonesty at worst. Although to a great extent it has been our own fault, the patients and the physicians themselves have ultimately become the victims of this regrettable state of affairs.