Aging in males is accompanied by a steady decline of bioavailable testosterone levels, reaching, in 20-30% of men over 65 years old, levels below the reference range for young males. In the presence of signs and symptoms suggestive of androgen deficiency, subnormal levels of androgen may justify androgen supplementation.
The effects of this treatment are modest, characterized by an increase in lean body mass and decrease in fat mass (with little or no effects on muscle strength), a small increase in bone mineral density, increase in libido but little or no effect on erectile dysfunction, improvement of spatial cognition and verbal fluency, of mood and possibly of general well-being, the favorable effects being the more pronounced the lower the basal testosterone levels. The potential benefits of androgen supplementation in elderly men should, however, be weighed against the possible side-effects and risks, the most important concerning the prostate. Prostatic carcinoma is androgen-responsive and an absolute contraindication for androgen supplementation. Whether androgens might accelerate the transition of a subclinical carcinoma, highly prevalent in elderly men, to a clinical carcinoma is unclear for the moment, although the limited experience so far with androgen supplementation in elderly men is rather reassuring; androgens slightly increase levels of plasma prostate-specific antigen (PSA) and increase prostatic volume modestly.
As there is some evidence that estrogens, originating in males to a large extent from plasma testosterone, play a role in the development of benign prostatic hyperplasia, it has been suggested that non-aromatizable androgens might cause less prostate stimulation. Whereas 7α-methyl-19-nortestosterone (MENT) is just such a synthetic selective androgen receptor modulator (SARM), with less stimulating effects than testosterone on the prostate1,2, dihydrotestosterone (DHT) may be considered a natural selective androgen receptor modulator, as it cannot be aromatized. At first sight, it is surprising that DHT might have less prostate- stimulating effects than testosterone, as it is known that patients with congenital 5α-reductase 2 deficiency, and hence low DHT levels, have hypoplastic prostates. However, it seems that not plasma DHT but intratissular DHT, locally formed from testosterone, determines prostate growth. Due to the feed-back effect of DHT on pituitary secretion of luteinizing hormone (LH), plasma testosterone and estradiol levels decrease during DHT treatment3 and intraprostatic DHT may be decreased via decreased precursor testosterone levels.
Recently, Ly and colleagues4, as well as Kunelius and colleagues5, reported the effects of transdermal DHT treatment in placebo-controlled trials. Ly and colleagues4 administered DHT for 3 months at a dose of 70 mg/day as a 0.7% gel, whereas Kunelius and colleagues5 administered DHT 125-250 mg/day as a gel containing 2.596 of DHT. Based on the inclusion criteria (T
In the study of Ly and colleagues4, which did not require the presence of symptoms of partial androgen deficiency of aging male (PADAM) for inclusion, DHT levels increased to the normal concentration range of testosterone; levels of LH, follicle stimulating hormone (FSH), testosterone and free testosterone decreased as the consequence of the expected feed-back effect of DHT. Levels of total and low density lipoprotein cholesterol decreased without significant effect on the level of high density lipoprotein cholesterol. As to the clinical effects, lower limb muscle mass and strength increased, whereas fat mass decreased modestly, but no effects were seen in mobility tests, cognitive function or quality of life. However, Kunelius and colleagues5 included in their study men with clinical symptoms of androgen deficiency and, although using higher doses of DHT than Ly’s group, obtained lower DHT levels, and no tight correlation between dose and DHT was observed. Although the cumulated androgen levels, corresponding to the sum of testosterone and dihydrotestosterone, remained within the physiological range, there was a significant decrease in LH levels and a 50% decrease in estradiol levels. As to the clinical effects, the only statistically significant effect was an improvement in early morning erections and ability to maintain erections; effects on body composition were not studied, and no effects on well-being or vitality were observed. Prostate volume remained unchanged. It is interesting to mention that, in an earlier study, De Lignires6 had observed a modest decrease of prostate volume.
In so far as these short-term studies permit, it can be cautiously concluded that DHT treatment produces the expected androgen effects, whereas the absence of acute adverse effects may seem reassuring. The studies do not permit or even suggest that DHT treatment would have less effect on the prostate than testosterone. The studies do show, however, that the high concentrations of DHT do not have evident acute adverse effects on the prostate. The decrease in estrogen levels is not without concern, in view of the well- known role of estrogens in bone metabolism, as is evident in patients with estrogen resistance or aromatase deficiency who show significant osteopenia and delayed epiphyseal closure. Moreover, in elderly men, the correlation of bone mineral density is much stronger with estradiol than with testosterone, indicating a role for estradiol in maintaining bone mass. This was recently confirmed by a study by Meier and colleagues7 showing that chronic rhCG treatment (which increases estradiol levels), but not dihydrotestosterone, stimulates osteoblastic collagen synthesis in older men with partial androgen deficiency. Hence, it can be questioned whether treatment with the non-aromatizable DHT will maintain bone mass. As to the effect on the central nervous system, it seems that the effects of testosterone on cognitive functions are mediated via estradiol formed locally. Hence, whether DHT will have similar effects as testosterone on cognitive functions remains unknown. In conclusion, available data so far do not support the use of DHT in preference over testosterone in elderly men. Nevertheless, studies of longer duration, involving a large number of elderly men with subnormal androgen levels and clinical signs of androgen deficiency, comparing the effects of DHT to those of testosterone are certainly warranted in order to permit an answer to the question whether DHT has advantages over testosterone in the androgen replacement therapy of elderly men.
References
1. Cummings DE, Kuniar N, Bardin CW, Sundaram K, Brmner WJ. Prostate-sparing effects in primates of the potent androgen 7-alpha- methyl-19-nortestosterone: a potential alternative to testosterone for androgen replacement and male contraception. J CMn Endocrinol Metab 1998;83:4212-19
2. Anderson RA, Wallace AM, Sattar N, Kumar N, Sundaram K. Evidence for tissue selectivity of the synthetic androgen 7 alpha- methyl-19-nortestosterone in hypogonadal men. J CUn Endocrinol Metab 2003;88:2784-93
3. Wang C, Iranmanesh A, Berman N, et al. Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men. A clinical research center study. J Clin Endocrinol Metab 1998;83:2749-57
4. Ly LP, Jimenez M, Zhuang N, Celermajer DS, Conway J, Handelsman DJ. A double blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001;86:4078-88
5. Kunelius SP, Lukkarinen O, Haimuksela MI, Ikonen O, Tapanainen JS. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab 2002;87:1462-6
6. De Lignires B. Transdermal dihydrotestosterone treatment of andropause. Ann Med 1993;25:235-41
7. Ly LP, Jiminez M, Zhuang TN, et al. A double blind, placebo- controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility and quality of life in older men with partial androgen deficiency. J Clin Hudocniiol Metab 2001;86:4078-88
A. Vermeiden
Section of Endocrinology, Medical Clinic, University Hospital Gent, Belgium
Correspondence: Professor A. Vermeiden, section of Endocrinology, Department of Internal Medicine, University Hospital, De Pintelaan 185, 9000 Gent, Belgium
2004 Parthenon Publishing. A member of the Taylor & Francis Group
DOI: 10.1080/13685530400016672
Copyright CRC Press Dec 2004
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