The upcoming 29th Annual EAU Congress will address a number of challenging topics which currently raise much discussion in the international urological community. One of such topics is testosterone replacement therapy in older men. Prof. Jens Sonksen (DK), member of the EAU Scientific Congress Office, outlined the main controversy on this subject and talked about the developments that we can expect in the near future.What is the main controversy in this field today? What is its history?
There are several issues regarding testosterone replacement therapy (TRT) in older men.
First, there remains some discussion about whether the drop in testosterone with aging, shown in numerous studies, is a normal physiological change that is to be expected with aging, or if hypogonadism is the direct cause of the many of the changes seen with aging.
There are many signs of deterioration with aging that occur at the same time as the drop in testosterone. It is tempting to conclude, because of this time relationship, that development of heart disease, cancer, bone and joint deterioration as well as mental status changes are caused by the drop in testosterone. However, the other opinion is that these conditions are simply caused by the aging process itself and the drop in testosterone has nothing to do with it. The impact of this discussion is defining which aging males need to be treated and which men do not.
Second, because of some recent report of testosterone replacement seemingly causing increased cardiovascular events and mortality in certain patient groups, the safety of testosterone replacement in older men has been called into question. However, one has to examine studies closely as to who the patient population consists of, whether the replacement dose is physiologic or supraphysiologic and how end-points in the studies are defined.
For instance, in one study , men disabled due to cardiac problems, bed-ridden and placed in extended care facilities were treated with higher than normal doses of testosterone, with the end-point of the study set as an increase in vigour and ambulation. The end-point of the study was actually proven, in that the men became more vigorous, but this then led to an increase in cardiac events and death due to the increased activity. Therefore, when looking at safety of testosterone replacement, there may be certain groups that would not be candidates for treatment. The derogatory information from these recent studies, however, need to be balanced with a great deal of information that men with hypogonadism have a higher all-cause mortality than men with a normal testosterone level.
Finally, I believe the most controversial topic is the relationship between TRT and prostate cancer. We have known for years, based on the Nobel Prize winning work of Huggins and Hodges, that the majority of prostate cancers are androgen dependent. It is known that when men are either surgically or chemically castrated, prostate cancer usually regresses for a period of time until the tumour becomes androgen insensitive.
Huggins and Hodges, in a limited number of patients showed that testosterone administration in castrated prostate cancer patients led to a resurgence of tumour growth. Therefore, there have been fears, for many years, that men with a high testosterone are at risk for development of prostate cancer, that TRT can induce cancer formation in men without prostate cancer, and that TRT given to men previously treated for prostate cancer will lead to recurrences.
These long held views are being called into question with published work from Abraham Morgantaler and others. In a health fair setting, with randomly recruited men found to have a low testosterone and a normal prostate specific antigen level and a normal digital rectal examination, Morgantaler found an extremely high rate of prostate cancer on random biopsies. This is in a group with low testosterone, who ostensibly should have a low rate of prostate cancer.
There are number of publications that have put forth a ”saturation model” of the androgen dependence of prostate cancer. This theory suggests that the stimulation of prostate cancer growth occurs with a relatively low serum testosterone level, possibly even as low as 100 to 150 ng/L. Therefore, at castrate levels, there is limitation of tumour growth, which is reversed as the testostone level rises to the saturation level, at which point all the prostatic androgen receptors are occupied. The theory suggests that raising serum testosterone above this level, say from 150 ng/L to 500 ng/L (the middle of the normal range) will allow hypogonadal symptoms to resolve and have absolutely no effect on the prostate cancer.
Proponents of the saturation model have been rather freely giving TRT to men who have had a prior radical prostatectomy and/or radiation therapy for prostate cancer. There are even limited reports now of men with untreated prostate cancer, on a ”watchful waiting” protocol, being treated with TRT without adverse outcomes.
However, one must remember that all testosterone preparations carry a warning that administration is contraindicated in men with known or suspected carcinoma of the prostate or breast.
What knowledge are we lacking and which issues do we need to address to resolve this controversy?
More epidemiological studies looking at testosterone levels and mortality and morbidity are necessary to help define the impact of dropping testosterone levels with age. Long-term studies of physiological TRT replacement on health issues associated with aging are necessary. Most studies to date have been relatively short-term, although some longer duration series have been reported recently.
On the prostate cancer issue, I believe this is a situation where a mix of basic science and clinical studies is necessary to resolve the issue.
Basic tumor biology studies can test whether the saturation model is valid. Cell culture would seem to be a very valuable tool in this regard. One could also test the hormonal environment in the genesis of prostate cancer in cell culture or in animal model of implanted human prostate cancer, testing to see what hormonal levels might be associated with local progression or even metastasis. The impact of hormones on gene fusions described by Chinnaiyan would be interesting.
Clinical studies in men have thus far not demonstrated that TRT is associated with a higher rate of prostate cancer, but more long term studies are needed. Although the vast majority of urologists are approaching TRT very cautiously in men with previously treated or untreated prostate cancer, some adventurous researchers will continue to push the limits of what we can do, and we certainly look forward to see if the initial promising results will continue.
What new developments can we expect in the upcoming years?
I expect we will see several things in the future, as a result of ongoing studies.
First of all, a firm direction on indications for hormone replacement therapy in older men. This may even amount to general administration of testosterone in hypogondal men for the purpose of health maintenance, even in men with no symptomatology. Secondly, I believe that we will achieve an understanding of the long-term safety profile of TRT.
Furthermore, we are looking forward to an establishment or rejection of the saturation model of androgen drive of prostate cancer and the definition of guidelines for treating hypogonadal symptoms in men with a diagnosis of current of previously treated prostate cancer. Last but not least, we will be learning more about the role of TRT in penile rehabilitation after radical prostatectomy.
Please visit the congress website to view the scientific programme online.