General aspects

Hormone replacement therapy for the aging male has become a major issue for our patients, as well as in andrology and endocrinology. Since life expectancy is increasing, the likelihood of developing androgen deficiency symptoms and age-associated hypogonadism is rather high. The U.S. Food and Drug Administration (FDA) estimates that four to five million American men may suffer from low testosterone or hypogonadism, but only 5% are currently being treated.

Whether men have a clinically significant decline in testosterone levels with advancing age is controversial. Recent studies in healthy men show that testosterone levels, in particular free bioactive levels of testosterone, decline with age, although there is considerable individual variation. There are two elements in the decline of the bioavailability of androgens with age: the decline in androgen production per se, and the increase in serum hormone binding globulins (SHBG) that firmly bind circulating testosterone. The net result is that there is less free testosterone available for biological action.

While it's been shown that plasma testosterone (and particularly free testosterone) levels decline with age, it's unclear what percentage of men actually become "truly testosterone-deficient". Strict criteria for testosterone deficiency have not been defined. In a study of 300 healthy men aged between 20 and 100, Kaufman and Vermeulen (who defined their reference range for testosterone to be between 11 and 40 nmol/L) found subnormal testosterone levels in more than 20% of men over 60. It should be mentioned that 15% over 80 still had testosterone values in the normal range, over 20 nmol/L.

The signs of aging itself are similar to the aging-male symptoms of testosterone deficiency - diminished interest in sex, erectile dysfunction, reduced muscle mass and strength, decreased bone density, depression and fatigue. This fact is important in trying to distinguish between normal aging and a partial androgen deficiency in the aging male (PADAM).

The symptoms of depression in the aging male are nearly identical to those of testosterone deficiency. Very often, therefore, only a long-standing testosterone deficiency will be detected clinically. Is a patient whose plasma levels of testosterone decrease from the upper to the lower range of normal testosterone levels, possibly constituting a drop of as much as 50%, testosterone deficient? Even with such a quantitative fall, levels can remain within the reference range. Therefore the diagnosis of PADAM requires a much wider range of symptoms than a mere change in hormone levels.

If the lower limit of normal (and the threshold level for a partial androgen deficiency) were to be conservatively estimated at 11 nmol/L for testosterone and 0.225 nmol/L for free testosterone, which represent the lower 1% value of healthy young males, it seems that over 30% of men over 75 years have subnormal free testosterone levels.¹ Androgens have numerous non-reproductive effects; they are important anabolic factors in the maintenance of muscle mass, bone mass and in non-sexual mental functioning, and stimulate the formation of red blood cells. A small portion of secreted androgens in the male are aromatized to estrogenic hormones. These estrogens are significant for the health of the skeleton, brain and the cardiovascular system in men. A literature review by Alexandersen suggests either a neutral or a favorable effect of normal testosterone values on cardiovascular disease in males.² In recent years several studies have shown that testosterone supplementation has favorable effects on the fibrinolytic system, the lipid status, and a vasodilatory effect on the coronary arteries.

The essential questions in hormone replacement therapy

Who needs testosterone replacement therapy, for how long, and how should this therapy be applied?

Identifying individuals who require supplementation is a difficult task. As far as we know, only testosterone-deficient men require testosterone supplementation. However, as discussed above, the clinical signs and symptoms of aging overlap with those of testosterone deficiency.

There are only a few validated, clinically usable questionnaires for this purpose. The St. Louis ADAM (Androgen Deficiency in the Aging Male) questionnaire investigates the following symptoms:

1. Decrease in sex life
2. Lack of energy
3. Decrease in strength and/or endurance
4. Loss of height
5. Reduced enjoyment of life
6. Sad and/or grumpy
7. Erections less strong
8. Deterioration in sports ability
9. Falling asleep after dinner
10. Decreased work performance

Patients experiencing problems in items 1, 7, or a combination of any four or more items might be candidates for replacement therapy. The specificity of these questionnaires is rather high (>70%), but the selectivity is low (approx. 30%). Finally, it is the physician and the patient who ultimately decide whether replacement therapy should be done.

Practical aspects of testosterone substitution

An immediate concern for androgen supplementation in old age is the development and/or progression of prostate diseases such as benign prostatic hyperplasia (BPH) or prostate carcinoma. Androgens do not directly cause BPH or prostate carcinoma, but they may have a permissive role, as evidenced by the beneficial effects of treatment aimed at reducing the biological effects of androgens on both conditions. The results of the Massachusetts Male Aging Study (MMAS) showed that sex steroids only account for 11% of prostate cancer risks; 30% are related to nutrition and 40% to other factors such as height, weight and family history. With regard to BPH, there is no evidence that androgen administration to hypogonadal men increases the incidence of BPH over that observed in control eugonadal men.

Although there is no reason for immediate concern, testosterone should be administered with caution to aging men. According to our current knowledge, not every hypogonadotropic individual is symptomatic and has need of replacement therapy.

According to WHO requirements, an ideal mode of androgen application would mimic physiological testosterone levels, effectively correct symptoms, and be acceptable and safe for the user. To date, only a few application modes fulfill these criteria.

a.) Orally administered androgens
The liver has a very high capacity to break down circulating testosterone so that the half-life of free testosterone in the serum is only about 10 min. Therefore, oral administration of testosterone leads to a very brief, clinically-ineffectual increase in serum testosterone. In addition to various modes of administration being developed, numerous modifications in the chemical structure of the testosterone molecule are being undertaken to achieve a longer effect than by the administration of native testosterone.

Esterification in the 17ß-position, e. g., prevents premature metabolism. Oral testosterone undecanoate, made by esterification with a medium long-chain fatty acid, is not transported via the portal vein to the liver, but enters the lymph pathways of the intestine within chlylomicrons, reaching the blood via the thoracic duct. Thus the first-pass effect of the liver and thereby hepatic toxicity is avoided. Enteral uptake is improved by the dissolution of testosterone undecanoate in oil and taking it with a fat-rich meal. Even after 180-240 mg, distributed over three daily doses, the patient may have long phases of low testosterone levels. A new formulation of testosterone undecanoate will be marketed shortly. Two tablets of Testocaps® 40 mg taken twice daily show favorable hormone values over 24 hours, with supra-physiological hormone levels for less than 8% of the time.

b.) Intramuscular application
Regular intramuscular injections of 250 mg testosterone enanthate (e.g. Testoviron®) every 3 weeks are not suitable for long-term substitution. Two to four days after the injection, non-physiological high testosterone serum concentrations (up to 400 % of normal values) occur, followed by an exponential fall to subnormal values before the next injection. Physiological testosterone levels are only achieved for 12-14 days within a time span of 21 days. These large fluctuations, with initially supraphysiological testosterone values which then fall into the hypogonadal region until the next injection, are perceived as unpleasant by many patients in terms of performance, mood change and sexual function. Therefore this form of therapy is now considered inappropriate.

Testosterone undecanoate and testosterone buciclate - Data from phase II and phase III studies clearly show the intramuscular formulations of these drugs have a longer half-life and duration of action. Injection of 1000 mg and 600 mg, respectively, can keep serum testosterone levels in the normal range for about 12 weeks, while avoiding non-physiological peak levels; in the case of long-term substitution with testosterone undecanoate, only four intramuscular injections per year are required. Intramuscular testosterone undecanoate or buciclate will probably become the standard substitution therapy for male hypogonadism in the future.

c.) Testosterone implants (pellets)
These consist of pure crystalline testosterone (Testimplants®) without additives, and are implanted under sterile conditions, after a puncture incision under local anesthesia, deep into the subcutaneous fatty tissue of the abdominal skin. Of all substitution methods available, the testosterone pellets possess the longest duration of action. The implantation of six pellets, each containing 100 mg, maintains serum testosterone levels in the normal range for about 4-5 months. Because of their long-lasting and uniform testosterone levels, testosterone pellets proved to be superior to oral or intramuscular application of testosterone in a randomized, comparative study in hypogonadal men. Currently this is the most cost-effective physiological testosterone supplementation, but it involves an invasive procedure of implantation.

d.) Transdermal applications
Two types of testosterone patch delivery systems are available. The scrotal patch consists of a carrier film containing 15 mg testosterone (Testoderm®). With good skin contact, about 6 mg testosterone are administered every 24 hours. If the patch is applied daily in the late evening or in the early hours of the morning, maximum testosterone levels are achieved in the morning and thus the natural physiological circadian rhythm is well-simulated. Scrotal testosterone patches are very expensive compared to the cost of other substitution preparations, and are currently not available in Europe.

Second-generation testosterone dermal patches (Androderm®) are applied to the upper arms, thighs or torso and have a gel-containing reservoir in which 12.2 mg testosterone are dissolved. The addition of an absorption enhancer makes an administration rate of 2.5 mg per 24 hours possible. With daily application, the physiological rhythm is very well-simulated. Most patients have to wear two patches in order to achieve an adequate level of active testosterone. Contact dermatitis occurs rather frequently, causing 15% to 30% of patients to suspend treatment.

e.) Testogels
An easy-to-use testosterone-containing hydroalcoholic gel (AndroGel1%®) has recently been developed which, after daily application of 50-100 mg gel on the skin of the upper arms, shoulders or abdomen, provides physiological serum levels of testosterone, DHT and estradiol. The gel dries within 5 min; a shower taken 30 min later does not affect the blood levels. In an open, randomized comparative study with the non-scrotal patch, comparably good improvements in mood, sexual activity and performance, muscle strength, erythropoiesis and body composition were observed in hypogonadal men. Owing to its simple and practical application, testosterone-containing gel has achieved a high market share shortly after its introduction three years ago in the USA. It will probably become a permanent component of the therapeutic arsenal in the treatment of androgen deficiency. Intensive skin contact with sexual partners and children should be avoided for the first 3-5 hours after application.

Preliminary date presented at the AUA 2003 in Chicago showed that testosterone replacement therapy with Testosterone-gel 1% improves the erectile response to sildenafil and may be considered for the treatment of ED in men with low to low-normal testosterone who failed prior treatment with sildenafil alone.

Contraindications to androgen substitution

Diagnosed prostate carcinoma is an absolute contraindication to androgen therapy. Therefore, before starting treatment in men over 50, the prostate-specific antigen (PSA) should be determined, transrectal sonography should be performed to establish the prostate size, and a digital rectal examination should be conducted to detect focal changes.

Mammary carcinoma in men, though very rare, is also a contraindication. Androgens are aromatized into estrogens so that the growth of estrogen receptor-positive mammary carcinoma is promoted by androgen therapy. BPH is a relative contraindication. In the presence of a clearly enlarged prostate gland and residual urine formation, restraint should be exercised (IPPS >16). If the patient has erythrocytosis with an increased hematocrit count, treatment with androgens should be withheld. Many questions still remain unanswered. Further well-conducted long-term studies and evidence-based information are clearly required.

Summary

The fact that men with primary or secondary hypogonadism should be given testosterone substitution is well accepted. However, if the patient has no clinical signs of an androgen deficiency, testosterone replacement therapy will have no clinical effect. The use of testosterone in men with age-associated hypogonadism is still under debate. Restraint is indicated even in the presence of low serum testosterone levels, as, of course, with normal testosterone levels as well. From time to time, a 3- to 6-month trial treatment with testosterone and subsequent renewed evaluation of the complaints will help the decision regarding long-term treatment. Owing to potentially disadvantageous effects on the prostate, it is important to follow up patients regularly. The dose of testosterone and/or the application interval should be adjusted to the overall trough testosterone levels, serum LH, blood analysis and the clinical status.

Because of its unfavorable pharmacokinetics, testosterone enanthate is no longer recommended for this use. Present and future testosterone replacement therapies e.g. testosterone implants, tablets, intramuscular testosterone undecanoate and gels, have to be considered when determining "optimal" hormonal therapy.

Large, controlled, long-term studies are required to evaluate the future role of hormone replacement therapies for age-associated male hypogonadism.