The physiologic aspects of aging are presented in the myth of Tithonus, the lover of Aurora, goddess of dawn. Aurora loved Tithonus so much that she asked her father, Zeus, to grant him eternal life. Unfortunately she forgot to request eternal youth for her lover, who began to experience the failure of his libido at approximately age 50 years and at age 60 to 70 years was somewhat impotent. By the age of 80 years, Tithonus had lost much of his muscle strength, and by the time he turned 90, he walked around stooped, because his bone was disappearing and he had some kyphosis.

By the time he reached 100 years, he had developed some age-related cognitive dysfunction, which was shown in the myth by the fact that he babbled incessantly. At this stage, love's sweet bloom had wilted, and Aurora just wanted to be rid of him. But Tithonus was immortal. Since she could not make him disappear, Aurora changed him into a cicada instead. Thus, the chirping of a cicada is actually the incessant babbling of a senile old man.

Many of the changes cited in this myth are associated with declining testosterone production. They include age-related disturbances in memory, muscle mass, and strength. Clearly, loss of libido and impotence are testosterone effects, and osteopenia may be another. There is evidence to suggest that disturbances in balance and declines in maximal oxygen uptake capacity (VO2max) also relate to declines in testosterone levels, although these effects have been understudied. Changes in food intake may also be effects of testosterone loss.

Today scientists are looking for hormonal substances that will rejuvenate human beings and allow them to live longer. Can this be done with testosterone? Probably not, but the full range of its potential may be under appreciated. Twenty years of clinical experience and current research findings provide a convincing argument that testosterone replacement has a role to play in improving the quality of life in older men.

EVIDENCE FOR AN AGE-RELATED DECLINE IN TESTOSTERONE

One of the early studies that has helped to define an age-related decrease in testosterone levels was done in healthy men aged 20-45 years compared with those aged 50 to 70 years. Levels of bioavailable testosterone were variable in the group of young individuals, who all were in robust health, with no levels measuring below 70 ng/dL. When these findings were compared with measurements in healthy men aged 50 to 70 years who had no known disease or medications, no longer were there any men with very high bioavailable testosterone levels, and approximately half of the group had levels below those of the younger individuals.

Importantly, luteinizing hormone (LH) levels were not elevated in the older populations. Additional confirmation came from an Australian study by Wishart and colleagues. Using a free androgen index, these investigators reported a decline in testosterone after age 31 years that continued each decade.

Longitudinal Study

The current understanding is that declines in free and bioavailable testosterone levels are related to a failure of the gonadotropin-releasing hormone pulse generator; whether it is pulse frequency or some other cause at that level is unknown. There also appears to be a malfunction at the pituitary level.

CLINICAL IMPLICATIONS OF TESTOSTERONE DEFICIENCY

Currently, the key questions involve whether declining testosterone levels as a function of age are clinically relevant and whether testosterone replacement may be beneficial in some older individuals. On both issues, the data are beginning to say "yes."

Libido and Sexual Functioning

In As You Like It, William Shakespeare described a 60-year-old in "lean and slipped pantaloon" and with a "big, manly voice, turning again towards childish treble pipes." An endocrinologist seeing a 30-year-old man who looked and spoke like that would diagnose "hypogonadism." This illustrates the point that testosterone deficiency is relatively easy to diagnose in the young but more difficult to define in the 70- or 80-year-old.

Studies have provided evidence of a strong correlation between bioavailable testosterone and a variety of sexual behaviors. Testosterone levels correlate more strongly with libido effects than with erections. These effects were seen in a retrospective study in which a two-year follow-up was conducted of individuals (both testosterone-treated subjects and untreated controls) who presented initially with low levels of bioavailable testosterone. Libido increased in these subjects, which is not surprising.

Morales et. al., reported similar findings using testosterone enanthate or testosterone undecanoate. That double-blind trial showed a 61% increase in sexual interest and performance in treated individuals. A number of other studies have shown similar results over time.

Our clinical experience has suggested that men treated with sildenafil (Viagra) do not obtain an adequate erection if their testosterone level is low, but will respond to testosterone treatment. Testosterone seems to be required for the last stage of the erection, possibly because of the hormone's effect on nitric oxide synthase (unpublished data).

Memory Effects

One recent study showed strong relationships between bioavailable testosterone and performance on a number of different memory tests. Similar results have been published by Janowsky and colleagues and by Herbst et. al., in abstract form.

Strength and Muscle Functioning

Furthermore, both bioavailable and total testosterone levels correlated extremely well with functional status.

Body Fat

From these findings, it appears that testosterone and SHBG levels together are the major predictors of skeletal mass. However, a relationship with IGF-1 and physical activity is not ruled out . Furthermore, two studies have demonstrated that testosterone administration results in an improvement in upper grip strength. Testosterone deficiency will cause a decline in muscle mass, as well as sarcopenia, and frailty, with numerous interactions between these effects.

Bone Density

It should be recognized also that mortality from hip fractures is higher in men with low testosterone. Deficiency is associated with minimal trauma hip fracture. In addition, there are very positive data from Tenover and colleagues showing an association of testosterone with lumbar spine density.

SAFETY ISSUES IN TESTOSTERONE REPLACEMENT

In a study of replacement therapy for 1 year, several tests were performed routinely, including prostate-specific antigen determination, liver function tests, and triglyceride levels. Blood pressure, fructosamine, and osteocalcin levels did not change over the course.

Hematopoiesis

Studies have shown that testosterone supplementation increases hematocrit approximately 1%. As they age, men, but not women, have a decline in hemoglobin of 1 to 2 g/dL, most likely related to the decline in testosterone. Replacement dosages can lead to very high hematocrit in some individuals, however, and this must be monitored every four to six months.

Prostate Cancer

There is no clinical evidence that the risk of either prostate cancer or benign prostatic hyperplasia (BPH) increases with testosterone replacement. In the study by Hajjar et. al., both BPH and prostate cancer tended to decline, but not to a statistically significant degree. A larger study did show similar results, with a significant decline in BPH and prostate cancer (and also angina).

Cardiovascular Risk

The lower the level of free testosterone in an individual, the more likely he is to have coronary artery disease. In the 1940's, testosterone was used to treat angina. The results from a double-blind study were reported by Jaffe. This investigator showed that testosterone improves exercise-induced ST depression. There are also data showing that testosterone will relax the coronary arteries by liberating nitric oxide, an effect very similar to that of estrogen.

A Chinese study by Wu and Weng reported on 62 older men treated for ten weeks with testosterone undecanoate. Angina was relieved in 77% of subjects, there were positive lipid studies, and data suggested improvement in myocardial ischemia. Changes in lipids with testosterone replacement are quite variable; however, clinical evidence shows only no change or a slightly positive change.

SCREENING AND TESTING FOR TESTOSTERONE DEFICIENCY IN CLINICAL PRACTICE

Some years ago a screening questionnaire was developed to help diagnose testosterone deficiency. Among other things, it identified candidates for testosterone testing. The questionnaire consisted of the following 10 items:

1. Do you have a decrease in libido or sex drive?

2. Do you have a lack of energy?

3. Do you have a decrease in strength or endurance?

4. Have you lost weight?

5. Have you noticed a decreased enjoyment of life?

6. Are you sad or grumpy?

7. Are your erections less strong?

8. Have you noted a recent deterioration in your ability to play sports?

9. Are you falling asleep after dinner?

10. Has there been any recent deterioration in your work performance?

The questionnaire was tested on 310 Canadian physicians (the same sample mentioned earlier) and was shown to have a high degree of sensitivity and specificity-one equivalent to that of doing stress testing for myocardial ischemia risk. Risk-factor analysis showed a positive correlation between results and all questions, with the exception of those regarding decreased strength and endurance. However, such decreases have been objectively shown to be symptoms of testosterone deficiency, even though they were not recognized in this population. A positive score on the questionnaire is an affirmative answer to question one or seven or any three others.

Currently, Saint Louis University and the University of Adelaide are involved in a 12-month double-blind study of testosterone undecanoate, 80 mg twice a day, vs. oleic acid. A dose-response method is being employed, so subjects will build up to the 80-mg dose depending on their testosterone levels. Men older than 60 years who have a free testosterone index below the normal range for young adults will be enrolled. The hypothesis is that replacement dosage will decrease leptin and increase IGF-1, bone density, muscle mass, and strength. Multiple measures of strength will be used, involving both upper and lower extremities, with the additional hypothesis that upper extremity strength will be improved to a greater degree than lower extremity strength. A battery of tests will measure improvement in cognitive function, mood, dysphoria, and quality of life. A year's therapy may be too short to achieve positive results in all of these areas.

CONCLUSION

Testosterone replacement, given at the time of male andropause, or "viropause," has shown many positive results. Data show increases in strength, memory, hematocrit, and libido. In addition to the research data, clinical experience has shown that testosterone in replacement dosage clearly improves quality of life and function in middle-aged and older men.