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VII. If Testosterone, Which Testosterone? Which Androgen Regimen Should be Used for Supplementation in Older Men? Formulation, Dosing, and Monitoring Issues

Institute of Reproductive Medicine of the University D-48129 Münster, Germany

	Introduction

Top Introduction Unsuitable androgens Therapeutic goal Choice of testoserone... Evaluation of effects and... Key messages Outlook References

 
MALE HYPOGONADISM is the prime indication for testosterone treatment (1, 2). Male senescence as such is not an indication for this treatment. However, there are hardly any reasons to withhold testosterone substitution from a senescent hypogonadal man and, indeed, the incidence of hypogonadism increases with advancing age. Therefore if, in an aging male, symptoms of hypogonadism and subnormal serum testosterone levels are diagnosed, testosterone substitution should be considered and implemented, if there is no contraindication (3). The question then arises, which androgen preparation is best suited for substitution in aging hypogonadal men?

	Unsuitable androgens

Top Introduction Unsuitable androgens Therapeutic goal Choice of testoserone... Evaluation of effects and... Key messages Outlook References

 
In the past numerous androgenic steroids have been synthesized and used clinically. The synthetic androgens were produced to selectively enhance certain biologic effects of testosterone, e.g. the anabolic effect on muscles and bones or the hematopoietic effect. Often the desired effects were never ascertained in controlled clinical trials (as requested today by evidence-based medicine), and some of these molecules had toxic side-effects, particularly in long-term use, as usually occurs in substitution therapies for hypogonadism. In particular, 17-methyltestosterone, fluoxymesterone, and other 17-alkylated androgens (such as stanozolol) should be avoided. All the 17-substituted steroids can cause increase in liver enzymes, cholestasis, and peliosis of the liver, and even liver tumors (for review, see ref. 2). These steroids are therefore considered obsolete today and have—at least in Europe—disappeared from the market. However, many physicians not familiar with the field retain a long-lasting, negative impression of these steroids, believing that testosterone may disturb liver function, although this in fact only applies to those obsolete androgens.

Furthermore, some of the synthetic androgens cannot be converted to 5-dihydrotestosterone (DHT) or to estrogens, as testosterone can be, and therefore they cannot develop the full spectrum of testosterone activities, including effects on the brain and on bones. For the same reason, DHT, which is commercially available as a gel to be applied to the trunk skin, is not suitable for substitution, at least not on a long-term basis, as it cannot be converted to testosterone or estrogen.

Hence it appears that testosterone, as produced by the testis, is the best androgen for substitution and for substitution in senescent hypogonadal men. The next therapeutic consideration then focuses on selection of the testosterone preparation most suited for senescent hypogonadal men.

	Therapeutic goal

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Today oral, injectable, implantable, and transdermal testosterone preparations are available for clinical use, and further preparations are under development (1, 2). They all produce distinct but widely differing pharmacokinetic profiles of serum testosterone. However, the biological significance of these various profiles is not fully appreciated, as we are only beginning to understand which serum levels and metabolites are required to achieve the various biological effects of testosterone and to avoid untoward side-effects. In particular, little is known about the long-term effects of testosterone therapy performed by different preparations, different routes of application, and different kinetic profiles. Under these circumstances, the consensus reached by a Workshop Conference on Androgen Therapy organized jointly by the World Health Organization, National Institutes of Health, and the U.S. Federal Drug Administration in 1990, still provides the best therapeutic guideline: "The consensus view was that the major goal of therapy is to replace testosterone levels at as close to physiologic concentrations as is possible" (4). Until other facts are provided, all testosterone preparations should be judged by this principle. Needless to say, a consensus is not necessarily evidence-based, but rather reflects an opinion, albeit an opinion of experts.

	Choice of testoserone preparation

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Of the available testosterone preparations the older injectable esters, testosterone enanthate and cypionate, continue to be the most widely used for substitution purposes and result in identical serum profiles. Their disadvantage is that, if injected at 2- to 3-week intervals, they initially produce supraphysiologically high serum testosterone levels, which then slowly decline, so that before the next injection subnormally low levels may be reached. Patients recognize and dislike these ups and downs of testosterone levels, paralleled by variations of well-being, sexual activity, and emotional stability.

Subdermal testosterone implants produce a similar pattern, but the profile of high initial peaks and decline thereafter extends over a much longer period of up to 6 months. Because of the longer timespan, the patient hardly recognizes the slow swings of serum testosterone.

Testosterone undecanoate administered orally produces short-lived peaks of a few hours duration, so that three doses have to be taken daily to administer enough testosterone for substitution, resulting in an irregular serum testosterone pattern during the course of the day.

Finally, transdermal testosterone has recently become available. Testosterone is administered either through scrotal or nongenital skin. Both systems produce serum testosterone profiles in the lower to medium normal range, mimicking the physiological diurnal variations of testosterone. Due to the necessity of using enhancers to facilitate absorption through the skin, nongenital systems cause a higher rate of skin reactions, but some patients consider it inconvenient to shave the scrotum occasionally to assure adhesion of the transcrotal patch. Hence, while the pharmacokinetic profile fulfills the consensus goal, the mode of application may prevent some patients from reaping the benefit.

	Evaluation of effects and side-effects

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Testosterone substitution in young as well as in older hypogonadal men requires regular surveillance to assure that the patient is well-adjusted and that possible side-effects are avoided. In addition to occasional serum testosterone determinations to assure the proper pitch of serum levels before administering the next dose, general well-being, vigour, alertness, mood, and sexual activity are parameters by which to judge the adequacy of treatment. Because hypogonadism is characterized by mild anemia, hematocrit and red blood cells are important criteria to monitor. Persistent anemia indicates too low a level of substitution. Older patients, however, react quite sensitively to higher doses by developing polycythemia. This may be observed particularly under testosterone enanthate or cypionate treatment, with temporarily supraphysiological serum testosterone levels (5, 6).

Sufficient substitution maintains or normalizes bone density, which should therefore be monitored before treatment and at least biannually thereafter. Transdermal testosterone appears to be equally as effective as testosterone enanthate (7).

The most important absolute contraindication against testosterone treatment is a prostate carcinoma. While the incidence of subclinical prostate carcinoma is high in older men, it is unclear whether testosterone treatment will stimulate progression of a subclinical carcinoma, and there are no data indicating that testosterone treatment will activate a subclinical carcinoma (8). Because of the incidence of prostate carcinoma and benign prostatic hyperplasia increasing with age, patients should be examined carefully before onset of testosterone therapy, and those over 45 yr of age receiving testosterone treatment should be monitored at least yearly. Rectal palpation and serum PSA are the standard procedures to perform at these check-ups. Increasing experience will show whether the blind finger palpating only part of the surface of this organ can be assisted for diagnostic acccuracy by transrectal ultrasonography. In addition to this valuable tool, undergoing continuous improvement, we use uroflow as a functional parameter for the routine evaluation of the prostate in patients undergoing testosterone substitution.

It is reassuring that a recent study on long-term testosterone enanthate treatment of men around 70 yr found a lower rate of benign prostatic hypertrophy (BPH) in the treatment group than in the control group over a 2-yr observation period (5). Because transcrotal testosterone produces somewhat higher serum DHT levels, it was speculated that it might induce a higher rate of BPH. However, in a crossectional study (9) and in our follow-up for up to 11 years (E. Nieschlag, unpublished data), prostate volumes and uroflow were no different in controls or in men treated with testosterone enanthate. Similarly, patients under nongenital transdermal testosterone substitution did not show higher prostate volumes than patients given testosterone enanthate (10). Because older men generally do not take advantage of regular check-ups for prostate disease, those on testosterone may benefit from regular monitoring, as a spontaneously developing prostate carcinoma is more likely to be discovered and treated early in these patients. In all events, discovery of a prostate carcinoma requires immediate cessation of testosterone substitution. If substitution is performed by long-acting esters or implants, such immediate withdrawal is not possible and, depending on the kinetics of the preparations used, disappearance of testosterone has to be awaited. In contrast, transdermal systems have the advantage that they can be removed immediately, and testosterone levels drop within minutes.

	Key messages

Top Introduction Unsuitable androgens Therapeutic goal Choice of testoserone... Evaluation of effects and... Key messages Outlook References

 
Considering the special precautions required by older hypogonadal men and following the general principles for testosterone substitution outlined above, namely · use natural testosterone, · aim at physiologic serum testosterone profiles, and · allow immediate withdrawal if necessary,

one would preferentially use transdermal testosterone for substitution therapy in older hypogonadal men. Oral testosterone undecanoate and intramuscular testosterone enanthate or cypionate would be second choices, whereas testosterone implants would appear unsuitable. While this is the physician’s rational ranking, the actual selection may be influenced by the patient’s preference and life-style.

	Outlook

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New developments may give reason to modify the above conclusion. While longer-acting testosterone preparations such as testosterone buciclate (11) and testosterone microspheres (12) may be more suitable for younger hypogonadal patients and for male contraception, testosterone cyclodextrins are potentially a good second choice, or even a first, once their kinetics are adjusted to produce physiologic serum levels (13).

New insights into the molecular mechanisms of androgen action may lead to the development of steroids suited for specific purposes. 7-methyl-19-nortestosterone may be an example, as it is experiencing renewed interest because of its high androgenicity combined with low prostatotropic effects shown in animal experiments (14). Whether such steroids will become useful and safe for clinical application in senescence remains to be seen.

Some experts advocate the use of estrogens in male senescence, in particular because of anticipated positive cardiovascular effects. However, estrogens would cover only one of the three metabolic facets of testosterone action and, according to the above principles, would not be suitable for substitution in male hypogonadism.

Finally, dehydroepiandrosterone (DHEA), when administered to patients with low adrenal and gonadal steroids, may function as a precursor for sex steroids including testosterone (15). However, the advantage of using a precursor instead of real testosterone in the treatment of male hypogonadism remains to be established.

	References

Top Introduction Unsuitable androgens Therapeutic goal Choice of testoserone... Evaluation of effects and... Key messages Outlook References

 

1. Nieschlag E, Behre HM, eds. 1997 Andrology: male reproductive health and dysfunction. Heidelberg/New York: Springer; 297–309.
2. Nieschlag E, Behre HM, eds. 1998 Testosterone: action, deficiency, substitution, 2nd ed. Heidelberg/New York: Springer.
3. Kaufman M, Vermeulen A. 1998 Androgens in male senescence. In: Nieschlag E, Behre HM, eds. Testosterone: action, deficiency, substitution, 2nd ed. Heidelberg/New York: Springer; 437–471.
4. Nieschlag E, Wang C, et al, eds. 1992 Guidelines for the use of androgens. Geneva:World Health Organization.
5. Hajjer RR, Kaiser FE, Morley JE. 1997 Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 82:3793–3796.[Abstract/Free Full Text]
6. Sih R, Morley JE, Kaiser FE, Perry HM, Patrick P, Ross C. 1996 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661–1667.[Abstract/Free Full Text]
7. Behre HM, Kliesch S, Leifke E, Link TM, Peters PE, Nieschlag E. 1997 Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 82:2386–2390.[Abstract/Free Full Text]
8. Schröder FH. 1996 The prostate and androgens: the risk of supplementation. In: Oddens B, Vermeulen A, eds. Androgens and the aging male. London, New York: Parthenon Publishing Group; 223–226.
9. Behre HM, Bohmeyer J, Nieschlag E. 1994 Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). 40:341–349.[Medline]
10. Meikle AW, Arver S, Dobs AS, et al. 1996 Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology. 49:191–196.
11. Behre HM, Nieschlag E. 1992 Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab. 75:1204–1210.[Abstract]
12. Bhasin S, Swerdloff RS. 1996 Sustained delivery of testosterone by a long acting, biodegradable testosterone microsphere formulation in hypogonadal men. In: Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C, eds. Pharmacology, biology and clinical applications of androgens. Current status and future prospects. New York: Wiley-Liss; 481–486.
13. Salehian B, Wang C, Alexander G, et al. 1996 Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate—a clinical research center study. J Clin Endocrinol Metab. 80:3567–3575.[Abstract]
14. Suvisaari J, Sundaram K, Noé G, et al. 1997 Pharmacokinetics and pharmacodynamics of 7-methyl-19-nortestosterone after intramuscular administration in healthy men. Hum Reprod. 12:967–973.
15. Young J, Couzinet B, Nahoul K, et al. 1997 Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrinol Metab. 82:2578–2585.[Abstract/Free Full Text]

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