Serum DHT and DHT/T Ratios in Men After Transdermal DHT Administration
Data regarding the clinical impact of sustained supraphysiologic concentrations of DHT in men repeatedly exposed to daily transdermally administered DHT gel provide valuable clinical safety information. Here we summarize the findings from three placebo-controlled studies in which men were treated with a transdermal DHT gel formulation for 3, 6, or 24 months.
Transdermal DHT gel in older men with partial androgen deficiency treated for 3 and 6 months
The efficacy and safety of a transdermal DHT gel was studied by Ly et al. (51) and Kunelius et al. (52) in placebo-controlled studies in older men with partial androgen deficiency who were treated for 3 and 6 months, respectively. Table 1 summarizes the effect of DHT treatment on serum T, DHT, and DHT/T ratio in response to DHT gel. T and DHT concentrations and DHT/T ratios remained stable in the placebo gel group. As would be expected, serum T concentrations in men treated with DHT gel were significantly suppressed to about one-third of baseline whereas serum DHT concentrations increased dramatically, rising about 10-fold. In parallel, the DHT/T ratio increased about 16- to 40-fold across the two studies. Despite such high serum DHT levels, DHT gel treatment did not significantly increase total, central, or peripheral prostate volumes, as measured by ultrasonography, nor was serum prostate-specific antigen (PSA) elevated. In addition, International Prostate Symptom Scores (IPSS) remained unchanged in men treated with DHT gel for 6 months. Exogenous DHT therapy was associated with a modest increase in hematocrit (without exceeding the normal upper limit) but was without effect on serum lipids or other parameters of cardiovascular (CV) risk.
Table 1.
Effect of DHT Treatment on Mean (± Standard Deviation) Serum T and DHT Concentrations and Prostate and CV Risk Factors
Study Description and Population |
Duration (Months) |
N (Completed) |
T (ng/dL) [nmol/L] |
DHT (ng/dL) [nmol/L] |
DHT/T[SUP]c[/SUP] |
Assay Method |
Effect of DHT on Prostate and CV Risk Factors |
|---|
Daily application of DHT gel (70 mg/d)
|
3
|
17[SUP]a[/SUP], DHT gel
|
Baseline: 432 ± 89 [14.98 ± 3.09]
|
Baseline: 41 ± 12 [1.41 ± 0.41]
|
0.09
|
RIA
|
Increase in Hgb/HCT but remained in normal range
|
Older men; age, >60; T <450 ng/dL (51, 53)
|
1 mo: 210 ± 14 [7.28 ± 0.49]
|
1 mo: 490 ± 58 [16.87 ± 2.0]
|
2.44
|
HDL cholesterol did not change
|
|
|
|
2 mo: 187 ± 14 [6.48 ± 0.49]
|
2 mo: 505 ± 58 [17.39 ± 2.0]
|
2.70
|
No evidence of stimulatory effects on prostate volume or PSA concentrations
|
|
|
|
|
3 mo: 144 ± 57 [4.99 ± 1.98]
|
3 mo: 534 ± 99 [18.39 ± 3.41]
|
3.71
|
No impairment in brachial artery size or flow in response to glyceryl trinitrate–induced dilatation
|
|
|
|
|
No change in inflammatory biomarkers (CRP, sVCAM, and sICAM)
|
|
|
|
|
|
|
|
Daily application of DHT gel (125–250 mg/d)
|
6
|
54[SUP]b[/SUP], DHT gel
|
Baseline: 464 ± 132 [16.26 ± 4.58]
|
Baseline: 44 ± 17 [1.51 ± 0.59]
|
Baseline: 0.09
|
RIA
|
No effect on serum lipids
|
|
3 mo: 270 ± 136 [9.36 ± 4.68]
|
|
|
|
|
|
|
|
6 mo: 170 ± 112 [5.89 ± 3.88]
|
6 mo: 238 ± 133 [8.19 ± 4.58]
|
6 months: 1.4
|
|
|
|
|
|
14, DHT gel (125 mg/d)
|
|
Baseline: 44 ± 20 [1.51 ± 0.69]
|
|
|
|
|
3 mo: 276 ± 200 [9.50 ± 6.89]
|
Increase in HCT (2.3%) and Hgb (0.9 g/L) at 6 months
|
|
|
|
|
|
|
6 mo: 247 ± 189 [8.50 ± 6.51]
|
|
|
|
|
|
|
|
Older men; mean age, 58 (52)
|
|
27, DHT gel (187.5 mg/d)
|
|
Baseline: 44 ± 17 [1.51 ± 0.59]
|
|
|
|
3 mo: 261 ± 113 [8.99 ± 3.89]
|
|
|
|
|
|
|
|
6 mo: 238 ± 139 [8.19 ± 4.79]
|
Serum PSA, prostate volume, and IPSS remained unchanged
|
|
|
|
|
|
|
|
19, DHT gel (250 mg/d)
|
|
Baseline: 44 ± 20 [1.51 ± 0.69]
|
|
|
|
|
3 mo: 267 ± 119 [9.19 ± 4.10]
|
|
|
|
|
|
|
|
6 mo: 232 ± 81 [7.99 ± 2.79]
|
|
|
|
|
|
|
|
Daily application of DHT gel (70 mg/d)
|
24
|
37, DHT gel
|
Baseline: 493 ± 176 [17.1 ± 6.1]
|
Baseline: 64 ± 61 [2.2 ± 2.1]
|
Baseline: 0.13
|
LC-MS/MS
|
No effect on lipids
|
No effect on carotid IMT
|
|
|
|
|
|
|
|
Decreased (–1.1 kg) fat mass by DEXA
|
|
|
|
|
|
|
|
Healthy men older than 50 years with no known prostate disease (54)
|
Increased HCT > 50% in 8 subjects who discontinued
|
|
|
|
|
|
|
24 mo: 69.2 ± 43.5 [2.4 ± 1.5]
|
24 mo: 733 ± 497 [25.2 ± 17.1]
|
24 months: 10.6
|
Although both increased, neither PSA nor central prostate volume growth increased significantly; no change in IPSS score
|
|
|
|
|
Daily application of DHT gel (10 g of 0.7% DHT gel)
|
1
|
12, DHT gel
|
210 ± 20 [7.3 ± 0.7]
|
210 ± 50 [7.2 ± 1.7]
|
1
|
LC-MS/MS
|
No effects on serum lipids
|
HDL did not change
|
|
|
|
|
|
|
|
Healthy men; age 35–55 (55)
|
All subjects had PSA <1.5-fold baseline at end of study, and none had a PSA >4.0 ng/mL at any time during the study
|
|
|
|
|
|
|
Prostate volume and IPSS unaffected by DHT treatment
|
|
|
|
|
|
|
|
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Abbreviations: DEXA, dual-energy X-ray absorptiometry; HCT, hematocrit; HGB, hemoglobin; IMT, initma-media thickness; sICAM, soluble intercellular adhesion molecule; sVCAM, soluble vascular cell adhesion molecule.
a18 enrolled.
b60 enrolled.
cCalculated from T and DHT provided by authors.
Transdermal DHT gel in middle-aged eugonadal men treated for 24 months
A placebo-controlled trial of DHT gel to evaluate the effect of DHT specifically on prostate growth rate has been published and is arguably the most significant report concerning the longer-term effects of supraphysiologic DHT exposure (54). DHT administration yielded a sustained increase in mean serum levels of DHT with a parallel decrease in mean concentrations of serum T. No changes in androgen levels were observed after placebo (Fig. 2). For men using DHT gel, mean serum DHT increased about 10-fold and mean serum T levels decreased by about 86% after 24 months of daily DHT gel application (Table 1).
Figure 2.
Mean (± standard error of the mean) serum DHT and T response to transdermal DHT therapy over 24 months of treatment in middle-aged men. Shaded region of each graph represents normal ranges for DHT or T. To convert T and DHT to ng/dL, values must be divided by 0.0347 or 0.0345, respectively. Redrawn from Idan et al. (54).
The effect of sustained serum DHT levels resulted in only minor changes to serum PSA and prostate volume, none of which were statistically or clinically significant. Three men in the DHT-treated group were discontinued due to a rise in PSA to >4 ng/mL, but none was diagnosed with prostate cancer. One man in the placebo group required a transurethral resection of the prostate for BPH. Discontinuation of men treated with DHT occurred primarily due increased hematocrit (>50%), which was asymptomatic and resolved after stopping treatment. No serious adverse effects due to DHT occurred.
Overall, these studies of men treated with supraphysiologic doses of DHT do not support the hypothesis that modest elevations of DHT and DHT/T ratios observed with commonly used TRT preparations (including injectable T esters, transdermal T, and oral TU) will yield deleterious effects in men, particularly in androgen-sensitive tissues like prostate. Consistent with this conclusion are recent data from a longitudinal, observational cohort study of 3638 men in which circulating DHT (measured by LC-MS/MS) was not associated with incident prostate cancer (56).
