The Debate Over Testosterone Replacement in Aging Men

Testosterone replacement is at the center of intense debate for its proper uses, its benefits, and its potential long-term side effects. With the growing number of US Food and Drug Administration (FDA)-approved methods for testosterone replacement in deficient men, particularly the aging male population, the subject has taken on growing importance that impacts every specialty. Lacking in the debate are the scientific answers derived from long-term, randomized, controlled studies.

Testosterone replacement is at the center of intense debate for its proper uses, its benefits, and its potential long-term side effects. With the growing number of US Food and Drug Administration (FDA)-approved methods for testosterone replacement in deficient men, particularly the aging male population, the subject has taken on growing importance that impacts every specialty. Lacking in the debate are the scientific answers derived from long-term, randomized, controlled studies. The media blitz regarding health issues for both men and women, particularly regarding hormone replacement therapy and new questions of safety for different hormonal treatments spurred by the Women’s Health Initiative, leaves clinicians and patients struggling with the decision of whether to use these methods of replacement to relieve the many troubling symptoms of deficiency that significantly impair quality of life during the aging years. The key question of any treatment regards the risk/benefit ratio for a given patient and whether the treatment provides reasonable expectation of improvement in symptoms or disease state with reasonable risks of adverse events.

Over the years, it is surprising that the need for studies to answer these issues has been, by and large, ignored by the specialties that were most highly impacted when the first reports of significant benefits began to appear in the 1940s, particularly in the cardiovascular arena. This does not mean that there have been no adequate studies investigating the physiologic effects of testosterone. Medline lists over 60,000 testosterone references since 1966. What has been clearly demonstrated by 65 years of availability is that treatment in physiologic doses to correct deficiency in young men has clear physiologic benefits and has rarely shown any serious side effects during replacement for long periods. With use in older men over 50, mostly derived from studies of the newer treatment methods, the potential side effects of testosterone are relatively mild, dose-related and reversible, at least over the short- or medium-term periods of one to five years. However, the risks or benefits of long-term use in aging men for five to 10 years or longer remain unknown.

Potential Adverse Effects
Common potential adverse effects, usually only seen with excessive doses, include:

• polycythemia;
• fluid retention; and
• worsening of sleep apnea.

Also included are other less serious effects such as:

• irritability or aggressive behavior;
• increasing benign prostate hyperplasia (BPH) symptoms;
• gynecomastia; or
• hair loss.

In the younger population these effects may be easily reversed with dosage changes and have little risk of serious sequelae. However, in the older age groups (over 50) with significant co-morbidities, such as vascular disease, congestive heart failure, renal insufficiency, or undiagnosed sleep apnea, some of these effects might have serious adverse outcomes, even over shorter time intervals. Potential for increasing growth of existing prostate cancer may be the most highly debated issue. Awareness of these potential effects, careful monitoring after initiating treatment, and cautious treatment doses may allow treatment in most age groups to be prescribed safely even when some of these diseases are present.

Problems Interpreting the Past Literature
With aging, the decline in androgens, both adrenal and testicular, is well established and appears gradual when statistical analyses are applied to large populations. However, when analyzed for individuals within this population, large variations from little change to dramatic declines are observed. The presence of disease states results in significant reduction and more rapid decline in testosterone levels in longitudinal studies than has been predicted by the statistical models derived from cross-sectional data. This observation and the growing list of medications and environmental chemicals that may further reduce testosterone levels or impact the cellular effects suggest that testosterone deficiency may be more common today than has been recognized in the past. Differences in androgen receptor sensitivity due to genetic polymorphisms, cytosine-adenine-guanine (CAG) length and wide variation in sex hormone binding globulin (SHBG) levels result in significant variations of ‘normal’ testosterone requirements between individuals.The ‘normal range’ established for populations is not a dose response curve for testosterone benefits or deficiency.

What is lacking in the currently available studies is the analysis of the ‘relative decline’ of testosterone in individuals over time and the development of disease pathologies. The ‘relative decline’ in any individual may be a more important variable than the actual testosterone level. The past studies should also be viewed with caution based on the present recognition of wide variation in testosterone levels reported utilizing different testing methods, a problem that was found in the initial Massachusetts Male Aging Study (MMAS). This is further confounded by the fact that a large percentage of testosterone production is due to peripheral conversion of adrenal precursors not represented by circulating testosterone levels, used to analyze relationships between testosterone levels and disease associations.

Future studies will need to address the circulating levels of the major androgens as well as the urinary excretion rates, which better reflect the total androgen production. Adding to the complexity of the problems of understanding pathologic correlates is the issue of estrogen conversion and the estrogen/androgen ratio, particularly related to cardiovascular diseases. Potential Benefits of Testosterone—Important New Findings
The importance of testosterone and aging disease changes is not insignificant. The lists of benefits from testosterone replacement continues to grow in significant areas that affect both the quality of life and the physiologic aspects of aging. Reported improvements in mood and cognitive function, energy, strength, bone density, and lean body mass suggest that functional capacities that increase the ability to remain independent may be improved or maintained for longer. Reduction in beta amyloid production experimentally with testosterone suggests the possibility that there may be a protective effect of replacement on the development or progression of Alzheimer’s disease, a highly important, devastating disease of aging. Newly reported relationships of testosterone deficiency to the aging diseases most likely to result in increasing healthcare costs and higher mortality rates, diabetes, hypertension, coronary artery disease (CAD), and stroke makes the issue of replacement even more critical.

The symptoms of changing sexuality, reduced libido, and erectile dysfunction (ED) have become the most widely popularized indicators of decreasing testosterone levels. The presence of ED has been associated with a two- to three-fold increased risk for both stroke and myocardial infarction (MI). Interestingly, the central arteries in the pelvic area, the heart, and the brain have endothelial nitric acid synthase (eNOS) enzymes that are more dependant on testosterone than the peripheral arteries. Improved libido and sexual function with treatment have been shown in recent studies. Additionally, improved response to phosphodiesterase inhibitors in conjunction with testosterone replacement suggests that sexuality may be maintained for longer throughout life, a clear quality of life improvement for many men and probably the single most common reason for men seeking hormone replacement from their physicians. Sexuality may, in fact, be the least important variable from a morbidity and mortality standpoint, but it can lead to increased testing and treatment that leads to these other important benefits more frequently than any other medical issue. Still, when confronted with the patient who needs treatment, the clinician is faced with the risk/benefit issue. The most highly debated of these is whether testosterone replacement may significantly increase morbidity or mortality from cardiovascular events or from prostate cancer in the older age group (over 50).
Cardiovascular Issues
The issue of cardiovascular risk seems predominantly to have been derived from either reports from steroid abuse at excessive levels or from expected increased risk from reports of reduction in high-density lipoprotein (HDL) cholesterol or possibly polycythemia seen mostly at supra-physiologic doses.^19,20 The perception of increased risk has meagre literature support, if any, but seems to be mentioned frequently when the issues of adverse effects are listed. There are no reported increases in cardiovascular events, such as MI, congestive heart failure, or stroke, in any long-term use for replacement in younger men, or from shorter replacement studies in older men using the newer approved formulations.

The most interesting research regarding cardiac benefits dates back to the 1940s, when case reports of improvement in angina, shortness of breath, and electrocardiogram (ECG) changes resulted in a larger study by Lesser of 100 men, using placebo controls and crossover treatment, which showed significant improvements in 90% over three months.²¹ More recently, controlled studies using testosterone patches confirmed the earlier reports, demonstrating significantly improved treadmill tests and reduced symptoms over nine months.²² In three short-term studies, intravenous (IV) testosterone resulted in immediate improvement of over one minute in treadmill time to the appearance of ECG changes in two studies, and no improvement in the other.^23–25 Additionally, a recent study indicated improvement in congestive heart failure symptoms and brain natriuretic peptide (BNP) levels with testosterone treatment.²⁶ Two studies by Phillips indicated a high inverse correlation of coronary plaque severity to free testosterone levels, a significantly stronger relationship than well accepted risk factors.^27,28 Phillips also recently published an interesting review of the relationships of testosterone and estrogen in men that suggests deficiency of these hormones may be major factors in the etiology of cardiovascular diseases.²⁹

Testosterone deficiency is associated with increased intra-abdominal fat, insulin resistance and smaller highly dense LDL/HDL particle size associated with syndrome X.³⁰ Improvement in these changes with treatment suggests that the increased incidence of this syndrome and the increased cardiovascular risks associated with it may be reversed or reduced with long-term treatments.³¹ Other studies indicate inverse relationships between adverse cardiac risk factors— type 1 plasminogen activator inhibitor (PAI-1), fibrinogen, C-reactive protein (CRP)—and testosterone levels.^32,33 The expanding literature supporting positive benefits from testosterone in cardiovascular disease and the importance of this area to major morbidity and mortality in aging men suggests that improved symptoms and quality of life may also be associated with reduced healthcare costs and improved health outcomes.
Does Testosterone Replacement Significantly Increase Risk of Prostate Cancer?
This is the most critical question relating to the risk of prostate cancer with testosterone treatment, querying whether testosterone replacement results in either the increased incidence of cancer or accelerates growth of existing disease resulting in increased mortality. A few studies have indicated that higher levels of testosterone may be associated with increased prostate cancer incidence.^34,35 However, the vast majority of studies show no increase in the incidence of prostate cancer with varying levels of testosterone in men.^36–38 A growing literature now suggests that the risk of aggressive prostate cancer may, in fact, be associated with lower levels or deficiency.^39,40 Supporting this observation are studies of the use of five alpha reductase inhibitors that reduce the most potent form of testosterone, dihydrotestosterone (DHT), for use in prostate hypertrophy and hair loss, which have resulted in increased aggressiveness of biopsy proven prostate cancers found after long-term, seven-year use.⁴¹ Additionally, the long-term analyses of aging men in the MMAS not only confirms that lower levels of testosterone are associated with more aggressive prostate cancer, but they also increase from both prostate cancer and overall cancer mortality. This study also suggests that low testosterone is associated with increased incidence of diabetes, hypertension, cardiovascular diseases, and overall mortality rates.⁴² Although the MMAS analyses support a role for maintaining testosterone within normal ranges for all these issues, they still do not fully answer the question of whether long-term replacement of testosterone will result in all the suggested benefits.

Although there are occasional reports of prostate cancer diagnosed during testosterone treatment, there are no large studies showing an unusual increase in incidence above expected levels.There is, at least, one well documented database of clinical monitoring of 1,500 aging men given testosterone replacement for up to 10 years that suggests that the rates of newly diagnosed prostate cancers are well below the expected rates.⁴³ Active prostate cancer is an absolute contraindication for testosterone treatment, but some experts suggest that testosterone replacement can be used cautiously in successfully treated men after a reasonable time interval if deficiency is established and symptoms warrant treatment.^44,45

Summary
For every physician facing the decision of whether initiate treatment with testosterone, the choice requires knowledge of the risks and benefits and of the necessary testing and monitoring required for safely and effectively administering treatment. Sadly, this information has been minimal or lacking in the training of physicians in specialties most likely to be faced with these patients. Several diagnostic and treatment protocols have recently been published by expert panels and are available to any physician.^46–48 Given the relative safety and significant potential health benefits of testosterone replacement with careful patient selection and properly monitored treatment, testosterone has gained a permanent place in the medical armamentarium. With the increased number of approved treatment modalities available, the need for long-term, prospective studies of testosterone replacement in aging males becomes more urgent in order to better answer the risk/benefit ratio questions.■