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Endocrine Care |
Department of Andrology (L.P.L., M.J., T.N.Z., A.J.C., D.J.H.), Concord Hospital and ANZAC Research Institute, Concord, New South Wales 2139, Australia; and Department of Cardiology (D.S.C.), Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW 2006, Australia
Address all correspondence and requests for reprints to: Prof D. J. Handelsman, ANZAC Research Institute, Concord, NSW 2139, Australia. E-mail: djh{at}med.usyd.edu.au
Abstract
The efficacy and safety of androgen supplementation in older men
remains controversial. Despite biochemical evidence of partial androgen
deficiency in older men, controlled studies using T demonstrate
equivocal benefits. Furthermore, the importance of aromatization and
5
reduction in androgen actions among older men remains unclear.
Dihydrotestosterone is the highest potency natural androgen with the
additional features that it is neither aromatizable nor susceptible to
potency amplification by 5 reduction. Therefore, the effects of
dihydrotestosterone may differ from those of T in older men. This study
evaluated the efficacy and safety of 3 months treatment with
transdermal dihydrotestosterone gel on muscle strength, mobility, and
quality of life in ambulant, community-dwelling men aged 60 yr or
older. Eligible men (plasma T 
15 nmol/liter) were randomized to
undergo daily dermal application of 70 mg dihydrotestosterone gel
(n = 18) or vehicle (n = 19) and were studied before, monthly
during, and 1 month after treatment. Among 33 (17 dihydrotestosterone,
16 placebo) men completing the study with a high degree of compliance,
dihydrotestosterone had significant effects on circulating hormones
(increased dihydrotestosterone; decreased total and free testosterone,
LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased
total and low-density lipoprotein cholesterols; unchanged high-density
lipoprotein cholesterol and triglycerides), hematopoiesis (increased
hemoglobin, hematocrit, and red cell counts), and body composition
(decreased skinfold thickness and fat mass; unchanged lean mass and
waist to hip ratio). Muscle strength measured by isokinetic peak torque
was increased in flexion of the dominant knee but not in knee extension
or shoulder contraction, nor was there any significant change in gait,
balance, or mobility tests, in cognitive function, or in quality of
life scales. Dihydrotestosterone treatment had no adverse effects on
prostate (unchanged prostate volumes and prostate-specific antigen) and
cardiovascular (no adverse change in vascular reactivity or lipids)
safety markers. We conclude that 3 months treatment with transdermal
dihydrotestosterone gel demonstrates expected androgenic effects,
short-term safety, and limited improvement in lower limb muscle
strength but no change in physical functioning or cognitive
function.
MALE AGING IS associated with a gradual, progressive decline in circulating T concentrations suggestive of partial androgen deficiency (1). After decades of controversy, epidemiological studies show clearly that in the general male population total T concentrations decrease by up to 1% per year (1) or more by various ad hoc adjusted forms (free, bioavailable) of T measurements. Although age-related deterioration in organ function is nearly ubiquitous, consequential hormonal deficits may provide an opportunity to ameliorate apparently age-related changes. The striking benefits in younger hypogonadal men of androgen replacement therapy on the structure and/or function of muscle, bone, and brain as well as quality of life suggests that androgen therapy might be beneficial for partially androgen-deficient older men. Such benefits require that the endocrine deficit is sufficiently severe and that aging tissues remain sufficiently androgen responsive. Hence, the significance of the partial androgen deficiency in aging men hinges on whether androgen therapy can make a significant, objective improvement in meaningful health outcomes.
Several controlled clinical trials of androgen supplementation in aging men have reported only equivocal benefits. Snyder et al. (2, 3) showed that T did not improve either muscle strength or bone density compared with placebo and that benefits were restricted to the most androgen deficient. Other smaller studies have shown that T supplementation in older men produced only modest and inconsistent benefits for muscle, bone, and mental functioning or quality of life (4, 5, 6). A key aspect of T’s biological activity is that not only does it act directly on androgen receptors but its hormonally active metabolites, dihydrotestosterone (DHT) and estradiol, have additional effects on androgen and estrogen receptors, respectively. Hence, if estrogen has deleterious effects on prostate and other diseases (7, 8, 9, 10), particularly when coincident with declining T secretion in older men, a nonaromatizable androgen such as DHT might have advantages that are obscured by aromatization and estrogenic effects.
DHT, the most potent natural androgen, is little used therapeutically (11, 12, 13). It has been administered intramuscularly or transdermally for the treatment of micropenis (14), growth delay (12), or gynecomastia (15) in boys as well as for replacement therapy in androgen-deficient men (16, 17) and in experimental studies of abdominal obesity (18). A preliminary, uncontrolled study reported that DHT is useful in treating older men with partial androgen deficiency (19, 20), for whom the higher potency and freedom from estrogenic side effects may be beneficial. For these reasons, the present study was designed to evaluate the efficacy and safety of 3 months of transdermal DHT treatment in men older than 60 yr using a modified formulation of a hydroalcoholic gel (21) that has been used in France for decades (11, 16, 17).
Patients and Methods
Study design
This study had a double blind, placebo-controlled, randomized clinical trial design. All study procedures were approved by the Central Sydney Area Health Service Ethics Committee (RPAH zone) within the National Health and Medical Research Council Guidelines for Human Experimentation. The primary end point was muscular strength measured as peak torque by isokinetic dynamometry in the knee and shoulder joints with the underlying hypothesis that DHT treatment would increase strength. The secondary end points included evaluation of the efficacy and safety effects of DHT treatment on muscular function (gait, balance, mobility), body composition, reproductive hormones, hematopoiesis, prostate size and prostate-specific antigen (PSA), and vascular reactivity.
Subjects and treatment
Generally, healthy men older than 60 yr of age were recruited if
they had a plasma T 15 nmol/liter on two separate occasions.
Men were excluded if they 1) had prostate cancer or disease requiring
further treatment; 2) had unstable, uncontrolled, or severe chronic
medical disease; 3) had medical conditions that interfered with muscle
testing; 4) used medication that interacted with sex steroid action; or
5) had skin disease that would interfere with topical drug
delivery.
Study procedures
Volunteers were recruited through advertisement. Respondents were provided with an explanation of the study and a written information sheet and were required to sign a consent form before screening. At entry, standardized medical history, physical examination, and blood samples were obtained. Eligible subjects who satisfied all entry criteria and provided written informed consent were randomized by being assigned a study number that corresponded with individually numbered drug supplies. The randomization code was broken only at the end of all data collection. Fasting blood samples were taken between 0830 and 1030 h after application of the gel and at a fixed time for each participant. Participants were requested not to vary their diet or exercise patterns.
Participants were studied twice at baseline before commencing treatment and then at monthly intervals for 4 months (3 months of treatment and 1 month after cessation of treatment). Treatment included daily application of the 0.7% hydroalcoholic dermal gel (Andractim; Laboratoires Besins-Iscovesco, Paris, France). At each monthly visit, participants were supplied with a box containing 60 sachets each containing 35 mg DHT or placebo vehicle. Subjects were instructed to apply 2 sachets (70 mg DHT/placebo) of the gel on the skin of their chests every day after a morning shower. Boxes were returned at each monthly visit, and medication compliance was based on counting the unused sachets returned.
Assays
Hormones and biochemical variables were measured as described previously (22, 23, 24, 25, 26). Briefly, plasma LH (Axsym; Abbott Laboratories, Chicago, IL) [coefficient of variation (CV) 5.0–7.4%], FSH (Axsym, Abbott Laboratories) (CV 3.5–7.4%), total T (Immulyte, Los Angeles, CA) (CV 7.8–12.7%), and SHBG (Immulyte) (CV 6.1–7.9%) were measured by commercial immunoassays. Free T (CV 9.6–11.7%) was measured by an in-house centrifugal ultrafiltration assay using Centrifree columns (Millipore Corp., Bedford, MA) and tritiated T to estimate percentage of unbound T, from which actual free T was calculated using total T concentration. DHT was measured by the permanganate method using a T antibody (C0457, Bioquest, North Ryde, Australia) (CV 3.8–4.6%). Ether extracts of plasma samples were oxidized by exposure to 0.5% potassium permanganate for 30 min, which was terminated by ether extraction. Full procedural recovery was calculated for each sample using tritiated DHT. Estradiol was measured in unextracted plasma samples using a DELFIA assay (Perkin-Elmer Corp., Rowville, Australia) (CV 1.2–5.8%). Hormones were measured within the same assay where feasible. Biochemical variables (hemoglobin, creatinine, alkaline phosphatase, osteocalcin, PSA, total and high-density lipoprotein cholesterols, and triglycerides) were measured by routine autoanalyzer methods.
Muscle strength
Muscle strength was measured as peak torque estimated from repetitive isokinetic contractions on a Cybex NORM dynamometer (Cybex, Ronkonkoma, NY). Each testing session evaluated two joints (knee and shoulder) in extension and flexion for both dominant and nondominant sides. Subjects were positioned comfortably with proper alignment of the limb and dynamometer axes, as recommended by the manufacturer. Joints were tested isokinetically through their full ranges of motion with gravity correction for the effect of limb weight on torque production calculated by proprietary software. For each participant, the order of testing the joint and lateral side was selected at random at the first testing session and the same testing order was followed in all subsequent sessions. For each joint movement, the testing comprised five repetitions of submaximal extension-flexion at 90 degrees/sec followed by rest of 1 min, then five maximal repetitions at 90 degrees/sec and rest for 30 sec, and finally five maximal repetitions at 120 degrees/sec. The peak torque was recorded as the test outcome.
Muscle strength was analyzed by normalizing peak torque for differences
in body size by using body surface area (BSA), which we have validated
(Ly, L. P., and D. J. Handelsman, submitted for publication)
as producing the least residual variance in preliminary reproducibility
studies. BSA was calculated as follows (27):
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Functional assessment tests
Gait and balance were evaluated by four functional tests. Functional reach was measured (in millimeters) as the mean of three trials of the maximal horizontal forward reach of the outstretched right arm without losing balance (28). Standing balance was measured (in seconds) as the mean of three trials of length of time the participant could stand with feet in tandem with eyes closed (29). For analysis, times were categorized as 10 sec or less, 10–30 sec, and more than 30 sec. Eighteen-meter fast walk was measured (in seconds) as the mean of two trials to walk as fast as possible (without running or terminal deceleration) a distance of 18 m (29). Five-time chair rise was measured (in seconds) and the mean of three trials of the time to stand up and sit down five times from a standard 43-cm-high chair as fast as possible without hand support (29).
Anthropometric measurements
Height was measured to the nearest 0.5 cm using a standard stadiometer, and weight was measured to the nearest 0.1 kg with subjects lightly dressed. Skinfold thicknesses were assessed at biceps, triceps, subscapular, and suprailiac positions at standard sites on the right side of the body (30) with a Harpenden Skinfold Caliper (British Indicators Ltd., Bedfordshire, UK).
Bioelectrical impedance was measured with a SEAC model BIM 3.0
bioimpedance meter (Inderlec, Brisbane, Australia). Whole body
resistance, reactance, and impedance were measured from four electrodes
placed on fasting supine subjects. Electrodes were placed at the
pisiform prominence of the wrist, at the distal metacarpal on the
dorsal surface of the right hand, between the medial and lateral
malleoli of the ankle, and at the distal metatarsal of the dorsal
surface of the right foot. Lean mass was estimated from bioimpedance
readings according to the formula of Lukaski and Bolonchuk
(31) for men and fat mass, obtained by subtraction from
body weight. Using BIA readings (all in ohms) for resistance
(R), reactance (Xc), and impedance (Z)
with height (H, cm) and weight (W, kg) and S = 1 for male gender
(32), fat-free mass (FFM) was calculated as follows:
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Cognitive function
The Modified Mini-Mental State Examination (35) was administered before and at the end of treatment. Results were grouped into six categories: 1) temporal and spatial orientations; 2) registration of three words; 3) attention and calculation/mental reversal; 4) three-word recall; 5) language in five components (naming, repeating, following a three-stage command, reading and obeying, and writing); and 6) visual construction (copying two pentagons). Changes in cognitive function of participants were evaluated by total and individual category scores.
Quality of life
Quality of life was quantified by the British version of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) (36). The questionnaire was administered before entry and at each monthly visit. The instrument includes nine measures of functioning relating to 1) physical and emotional concepts (physical functioning); 2) physical role; 3) bodily pain; 4) general health perception; 5) vitality; 6) social functioning; 7) emotional role; 8) general mental health; and 9) reported health transition from the last month (modified from the original 1 year ago). Raw scores are transformed to a standardized scale ranging from 0 to 100, with the higher score representing better status. At the end of treatment, an extra health transition question was added regarding the subjects’ health compared with 3 months previously.
Ultrasonography
Prostate volumes were measured using a 7.5-megahertz sector scanner (Opus 1; Ausonics, Sydney, Australia) before and at the end of treatment. Transrectal ultrasonography to estimate total, central, and peripheral prostate volumes was performed by a single operator (T.N.Z.) using both planimetric and ellipsoidal methods as described previously (10, 37).
Endothelial function
Arterial endothelial function was measured noninvasively by the method of Celermajer and colleagues (38). Brachial artery diameter was measured on B-mode ultrasound images with a 7.0-megahertz linear array transducer (model 128XP/10, Acuson, Mountain View, CA) at rest after flow-mediated dilatation and in response to a 400-µg spray of sublingual glyceryl trinitrate. Flow-mediated dilatation measures the vascular dilatation caused by vascular hyperemia after release of high-pressure occlusion of the brachial artery by an inflated sphygmomanometer cuff. Increased blood flow shear leads to endothelial release of nitric oxide, which is compared with direct, endothelial-independent effects of direct nitric oxide delivery by glyceryl trinitrate.
Statistical analysis
Response variables were calculated as the difference from baseline values of one’s own group (DHT or placebo). DHT effects on continuous response variables were estimated by the main effects of treatment (DHT vs. placebo), time, and treatment x time interaction terms using an ANOVA for repeated measures followed by a post hoc one-tailed t test (P = 0.05). DHT treatment effects were identified from treatment main effects or interactions and reversibility of treatment effects by appropriate linear contrast. Small amounts of missing data during the treatment period was imputed by the last-observation-carried-forward technique to allow full repeated-measures ANOVA analysis. Categorical variables were analyzed by exact contingency table methods. Data were analyzed and graphed by using StatXact version 4, SPSS version 10 (SPSS, Inc.), and SigmaPlot.
Results
Characteristics and disposition of participants
From recruitment advertising, 145 men contacted the study investigators with interest to participate. Of these, 31 failed to make contact after being sent the study information sheet, 23 attended but chose not to participate, and 54 were eliminated through the screening process. Exclusions at screening included 23 men for T levels, 17 with joint problems (7 hip, 2 patella, and 1 humeral head replacements, 2 intervertebral disc protrusions, 5 arthritis), 6 with prostate disorders (1 cancer and 5 with increased PSA), 6 with recent androgen use (5 T, 1 mesterolone), and 2 with cardiovascular disorders (1 untreated aortic aneurysm, 1 recent coronary bypass operation).
Ultimately, 37 eligible men aged 68.2 ± 1.15 (SEM)
years were selected to participate in the study (Table 1
). The treatment groups were well
matched by randomization for all variables except for the placebo group
having higher fat mass and weight and lower plasma T concentration. At
randomization, 18 men were assigned to DHT and 19 were assigned to
placebo, with 17 and 16 men, respectively, completing the study. Of the
4 subjects discontinued after randomization, 2 did so soon after
baseline (1 on DHT after a single day of use of the gel, which he
disliked, and the other on placebo who was lost to follow-up) and 2,
both on placebo, did so after 1 month of treatment (1 attributed
worsened knee arthritis to treatment, and 1 was lost to follow-up).
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The number of sachets provided was calculated so as to finish on the morning of the next appointment, when subjects were asked to return unused sachets. Compliance of subjects’ gel use was assessed by counting the number of unused sachets. Compliance was 100% for all participants. Apart from the four men who discontinued, the remaining subjects completed all scheduled appointments. Among men who completed the study, 189 of 198 (95%) of dynamometry and 195 of 198 (98%) of functional tests were completed, with omissions attributable to incidental reasons (injuries, flu, incidental procedures) in seven men.
Hormonal and biochemical effects
Hormones. Plasma DHT concentrations increased during
treatment, and treatment produced a marked decrease in plasma total and
free T, LH, and FSH (Fig. 1). SHBG
decreased in both groups with time but more so in the DHT group
(DHT x time interaction, P = 0.05). All hormonal
changes had returned to baseline at 1 month after cessation of
treatment. Plasma estradiol concentrations were unchanged by DHT
treatment.
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). High-density lipoprotein cholesterol
and triglycerides were unchanged by DHT treatment. DHT treatment
increased hemoglobin, hematocrit, and red cell count, although values
remained within the normal range at all times; hemoglobin and red cell
count but not hematocrit returned to baseline 1 month after cessation
of treatment. None of the participants was discontinued because of
polycythemia. There were no significant changes in osteocalcin or
bone alkaline phosphatase.
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There were no significant differences in any biochemical or hormonal findings using either baseline T or T + DHT as covariates except for total or high- density lipoprotein cholesterol and hematocrit, which were no longer different when adjusted for baseline T or T + DHT.
Efficacy parameters
Muscle strength. Peak torque developed during isokinetic
dynamometry was increased significantly for dominant knee flexion at
the second month of treatment and remained consistent without return to
baseline after 1 month after cessation of treatment (Fig. 3). None of the other isokinetic
contractions (knee and shoulder, extension and flexion, dominant and
nondominant limb) exhibited any differences in isokinetic peak torque.
Reanalysis of the data according to the baseline T concentration using
either T or T + DHT as covariate did not change the findings.
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Functional tests. There were no significant changes in maximal reach, standing balance, fast walk, or chair rise. The results of the fast walk and chair rise were significantly changed over time (P < 0.001) but equally in both groups, consistent with a training effect.
Anthropometric measures. Despite randomization, subjects in
the DHT group had significantly lower adiposity, as indicated by body
weight, waist to hip ratio, skinfold thickness, and fat mass at entry
to the study. During treatment, DHT decreased skinfold thickness,
weight gain, and fat mass but had no effects on waist to hip ratio or
lean mass (Fig. 4). The effects of DHT
treatment on body composition persisted at 1 month after cessation of
treatment. There was no significant differences in findings using
either baseline testosterone or testosterone + DHT as covariate.
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Quality of life. Only one SF-36 scale (emotional role) improved slightly but significantly, whereas none of the other scales was influenced by DHT treatment (data not shown).
Safety parameters
Prostate. Three months of DHT treatment did not significantly
increase total, central, or peripheral prostate volumes measured by
either planimetric (Table 2) or
ellipsoidal (data not shown) methods. Both total and central prostate
volumes increased significantly in the placebo-treated men, whereas
this did not occur in men treated with DHT (Table 2).
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). Discussion
The clinical benefits of androgen supplementation in older men remain controversial. Well-controlled, prospective studies are limited, and suitable target populations as well as therapeutic means and objectives remain to be clearly identified. The most extensive study has shown that 3 yr of transdermal T did not significantly increase muscle strength or bone density compared with placebo (2, 3). Previous smaller studies of shorter duration (3–12 months) produced inconsistent benefits in muscle, bone, and mental function and quality of life (4, 5, 6, 18, 39). Nevertheless, in the study by Snyder et al. (2, 3), a pattern of potential benefit was observed in that bone density increased most in those with the lowest pretreatment bone density. This suggests that older men with sufficient androgen deficiency might benefit from androgen therapy if they remain androgen responsive, an issue that can only be resolved by prospective, placebo-controlled clinical trials.
At present, controlled studies of androgen therapy in older men have
used T exclusively (2, 3, 4, 5, 6, 18, 39). However, T has both
direct and indirect modes of action. In addition to direct activation
of the androgen receptor (40), T has potent bioactive
steroidal metabolites that temper its overall androgenic effects.
The two major metabolites are DHT, a more potent and nonaromatizable
androgen, formed by the enzyme 5-reductase, and estradiol, a potent
estrogen produced by the enzyme aromatase that acts via estrogen
receptors. These ramifications of androgen action serve to amplify and
diversify, respectively, T’s biological effects. The present study
aimed to determine whether the most potent naturally occurring and pure
androgen, DHT, might have therapeutic advantages in older men. The
theoretical basis for this supposition is that, unlike T, DHT cannot be
further amplified in androgenic potency by 5 reduction. Hence,
exogenous DHT will have consistent androgenic effects on all tissues,
in contrast to androgens such as T, which can be 5 reduced to more
potent androgens (a process occurring avidly within the prostate), thus
having disproportionately greater androgenic effects on the prostate
than on other tissues. This reasoning has been supported by a
preliminary, uncontrolled study suggesting that DHT administration
reduces prostate size in older men without known prostate disease
(20). Furthermore, DHT administration might also be
beneficial in reducing net estrogen production, because the majority of
circulating estradiol in men is derived from peripheral conversion of
androgenic precursors, including T, androstenedione, and
DHEA (41). There is evidence that estrogen
accumulation with advancing age may be deleterious to the prostate or
other organs (7, 8, 9, 10). On the other hand, recent evidence
suggests that aromatization of T to estradiol may be important at least
in part in maintaining some aspects of normal function of the brain
(42) and bone (43). Hence, the effects of a
pure androgen without estrogenic effects in older men are of
considerable interest.
In this study, daily dermal application of 70 mg DHT gel for 3 months
produced expected hormonal changes of increased plasma DHT together
with negative feedback suppression of the pituitary-testicular axis
(plasma total and free T, LH, FSH). The effects of the reformulated
hydroalcoholic DHT gel were consistent with its short-term (14-d)
pharmacokinetics and pharmacodynamics in healthy older men
(21). Plasma DHT was increased by 15–20 nmol/liter over
baseline, levels that are comparable with short-term use of a similar
dose (64 mg) and that remained stable throughout the study,
demonstrating the consistent pharmacokinetics of this DHT gel in older
men for at least 3 months. The reduced plasma total and free T as well
as LH and FSH were fully reversed 1 month after cessation of treatment.
The magnitude of these effects were similar to the reductions in plasma
total T (
60%), LH (60%), and FSH (25–30%) concentrations
observed in the short-term study (21), demonstrating the
reproducibility of DHT gel pharmacodynamics. The decrease in plasma
SHBG over time in both groups (but unrelated to DHT treatment) is
consistent with the lack of effect of DHT in the short term
(21). The reason for the time-related reduction in SHBG
concentrations in this study is unclear but may reflect unrecognized
changes in diet and/or exercise associated with participation in the
study (44), highlighting the need for placebo controls in
such studies. Unlike a previous study using T (2, 3),
there was no consistent effect of baseline T on outcomes in this study.
Furthermore, we also observed the phenomenon of "regression to the
mean" (45) in baseline T concentrations, whereby despite
screening requirements of less than 15 nmol/liter, the subsequent
pretreatment baseline T concentrations were moderately higher;
equivalent regression to the mean has been observed in similar studies
(46).
The relative importance of T’s bioactive metabolites in its net
effects may vary between tissues (47). Thus, most T
entering the prostate is converted to DHT by type II 5-reductase
(48), whereas T effects on brain (42) and
bone (43) may involve local aromatization. Although whole
body conversion of T to estradiol represents a very minor proportion
(<1%) of T metabolism (41), estradiol’s molar potency
is 2 orders of magnitude higher than T’s, so that the proportion of
androgen action mediated via estrogen receptors may be appreciable. The
changes in body composition observed in this study—selective decrease
in body fat without increase in lean mass (muscle)—differs from the
effects of T administration in older men, which more consistently
increase lean mass with more variable reduction in fat mass
(49). These systematic differences suggest that both DHT
and T effects of reducing fat mass may primarily involve the androgen
receptor, whereas the divergence of effects on lean muscle suggests
greater involvement of aromatization and estrogen receptor in mediating
T-induced muscular hypertrophy.
The modest gain in muscular strength only in limb joint contractions together with the lack of change in gait, mobility, or other tests of muscular function is consistent with the unchanged muscle mass. The consistency of the changes over monthly time points makes this unlikely to be simply a chance finding attributable to the number of contractions studied. The finding that the only significant strength effect occurred in the lower limb is at variance with the expectation that regional effects of androgens would be more prominent on the upper trunk and limbs (50). Together with its more consistent effects on muscle mass, T may also have more consistent effects on muscular strength, although the study design confounds interpretation of these findings. For example, in controlled T studies of older men, handgrip strength was reported improved in nonmasked studies (5, 6), whereas a blinded cross-over study showed no benefit (4). Similarly, more sophisticated muscular strength testing by isokinetic dynamometry showed improvement in muscular strength in a small, short-term, uncontrolled study (51), whereas a well-controlled, larger, long-term study failed to show any significant change in muscular strength during 3 yr of transdermal T administration compared with placebo (2). An important caveat on muscle function testing is its effort dependence. Because the primary end point (peak torque) depends on maximal exertion, variability in motivation and effort may introduce variability despite efforts to standardize the testing, including encouragement. This inflation of the measurement variance tends to produce null results and requires large sample sizes to show even modest effects, particularly with less well-standardized tests (39). Hence, although our study is unable to exclude additional effects of DHT on muscular strength in large limb joints, the effect size is likely to be quite small.
Apart from learning (time-related) effects, there were no significant benefits of DHT treatment on functional tests. This lack of benefit in tests of gait, balance, and mobility is consistent with the lack of increases in muscle size and strength. In addition, the high level of function maintained by the participants at entry into this study may have undermined the sensitivity of such testing. The study inclusion criteria requiring that participants be community dwelling, ambulant, and able to complete muscle testing selects for older men with better preservation of lower limb strength. Thus, functional tests of gait, balance, and mobility, which primarily examine physical functioning of the lower limbs, were accomplished at higher performance levels incapable of further improvement. Further studies would be required to evaluate whether DHT or other androgens might improve gait, balance, or mobility among older men with greater functional impairment before treatment.
Cognitive function appeared to be slightly impaired by DHT treatment according to testing by the Modified Mini Mental Status Examination. This small change has little clinical significance because the baseline scores on this test, developed originally to distinguish organic from functional brain impairment (35, 52), were close to maximal. Nevertheless, further studies of sex steroid effects on cognitive function in older men are needed to identify whether the putative protective effects of estrogens against dementia in women (53) are also evident in men. Similarly, quality of life, as measured by the SF-36 scale, which scored highly at entry, was not influenced by DHT treatment with the exception that a single scale (role performance limited by emotional problems) was slightly, but significantly, improved. This scale is designed to estimate problems with work or other regular daily activities as a result of emotional problems that happened in the preceding 4 wk (36). The significance of this isolated findings requires further elucidation.
The hematological changes attributable to DHT treatment were consistent
with the magnitude and reversibility of the hematological effects of T
(54). A striking feature was that, unlike the effects on
hematocrit, the effects on hemoglobin and red cell count were not fully
reversed at 1 month after cessation of DHT treatment. In contrast to
one retrospective study of injectable T (55), none of the
men treated prospectively with DHT developed polycythemia. If the true
prevalence of polycythemia was the 25% reported in that study, it is
unlikely that our study would have missed this finding
(P = 0.015; power of 69% to exclude a true prevalence
of 25%). This suggests that the true prevalence is lower than
estimated by the retrospective study, that the longer duration of
treatment in the retrospective study may have been important, or that
this dose of transdermal DHT has lesser hemopoietic effects than
conventional doses of injectable T esters (54). It is
notable that it has long been claimed that androgen effects on
hemopoiesis are related to 5ß-reduced rather than 5-reduced
androgens (56). The potential for precipitation of sleep
apnea by androgen administration (57) was not observed in
this study, perhaps because this idiosyncratic effect of T is
restricted to men with marked obesity or subclinical sleep apnea, who
were excluded (57, 58, 59).
The safety experience with 3 months of DHT treatment proved
satisfactory. There were no discontinuations for adverse medical events
(notably polycythemia, sleep apnea, or lower urinary tract symptoms)
attributable to DHT treatment. The only discontinuation, for
aggravation of arthritis, occurred in the placebo group. The effects of
3 months of DHT treatment on the prostate in this study were minimal or
even potentially beneficial, because there was no evidence of
stimulatory effects on prostate volumes or PSA concentrations. Indeed,
the underlying tendency toward prostate volume growth in older men, as
evident in the placebo-treated group, was absent in the DHT-treated
men. This raises the possibility that DHT treatment, because of its
inability to exhibit intraprostatic amplification, has less selective
prostate growth effects than would T. Whether such effects are
beneficial in retarding age-related benign prostate growth or even
prostate cancer remain to be further investigated. Positive findings in
the large-scale ongoing prostate cancer chemoprevention studies using a
5-reductase inhibitor (60) may increase interest in use
of the non-5-reducible DHT, although the potential utility of this
approach has been questioned (61). In contrast, most but
not all studies using T in older men showed no changes in prostate size
or PSA (62).
The short-term effects of DHT on vascular reactivity and lipids showed no evidence of potentially deleterious effects; indeed, the decreased total and low-density lipoprotein cholesterol could be considered potentially beneficial, although the magnitude of the effects was modest. Arterial endothelial dysfunction is an early marker of presymptomatic vascular damage, preceding overt atherosclerosis (63, 64). Because we have previously shown that androgen deprivation in older men with prostate cancer might be associated with improved endothelial function (65), we included assessment of this parameter in DHT-treated older men to evaluate any potential deleterious effects on arterial physiology, which were not detectable in this study. Similarly, the unchanged biochemical markers of bone turnover support the contention that DHT supplementation may maintain bone mass despite the reduction in net estrogen exposure. Although congenital estrogen deficiency has striking effects on male bone (66, 67), androgen receptor-mediated effects are also important (43), and the balance of effects on bone mass in older men remains to be established. Further longer studies would be required to determine the net effects of DHT on bone mass and fracture rates in older men. As with other safety issues, this short-term study is encouraging but highlights the need for continued surveillance of all androgen use in older men because the long-term safety data are still very limited (62).
We conclude that 3 months treatment with transdermal DHT gel at a relatively high dose demonstrates stable pharmacological features with consistent negative feedback effects on the pituitary-testicular axis and reduced body fat but minimal effects on muscle mass, strength, or function. The short-term safety of DHT in older men was supported by the lack of increase in prostate volumes or PSA or on vascular reactivity and lipids. The potential for DHT therapy to limit age-related prostate growth and to decrease cholesterol warrants further study with larger sample sizes and longer treatment periods.
Acknowledgments
We thank Laboratoires Besins-Iscovesco (Paris, France) for providing the DHT (Andractim) and matching placebo gel. We are grateful to the participants whose interest, patience, and good humor made this study possible. We are also indebted to the staff of the Department of Andrology (Concord Hospital) and the Cardiovascular Research Laboratory and Metabolism Unit (Royal Prince Alfred Hospital) for valued help. We thank Peter Liu for helpful discussion.
Footnotes
This study was supported by the National Health and Medical Research Council.
Abbreviations: CV, Coefficient of variation; DHT, dihydrotestosterone; PSA, prostate-specific antigen; SF-36, 36-Item Short Form Health Survey.
Received November 30, 2000.
Accepted May 1, 2001.
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). Measurements of peak torque were made in
knee and shoulder in the dominant and nondominant sides at each visit.
For further details see text. Data are plotted as mean and
SEM of differences from each individual’s own baseline.
Dashed lines indicate no change from baseline.
Asterisks indicate differences due to DHT treatment.