Safety and efficacy of testosterone gel in the treatment of male hypogonadism

Figures & data

Figure 1 Serum T concentrations (mean ± SEM) over 24 h after first application of 100 mg T gel. Reproduced with permission from Wang C, et al. J Clin Endocrinol Metab. 2000;85:964–969. © The Endocrine Society.

Figure 2 Serum T concentrations (mean 6SE) before (day 0) and after transdermal T applications on days 1, 30, 90, and 180. Reproduced with permission from Swerdloff RS, et al. J Clin Endocrinol Metab. 2000;85:4500–4510. © The Endocrine Society.

Table 1 Summary of efficacy data from testosterone trials using T gel in hypogonadal men

First author, Ref	Patient details	Blinding	Control group	Regimen	Duration	Results
Wang et al^Citation42	227 hypogonadal men aged 19–68 years (Total T < 10.4 nmol/L)	Androgel treatments were double-blinded but Androderm was open-labeled	None	Randomized to receive – 1% Androgel (5 g/day) + placebo (1 + 1 pump) 1% Androgel (10 g/day) (2 pumps) or Andropatch (5 mg/day). Androgel doses were adjusted in future visits based on T levels and clinical symptoms	180 days	At 90 days of treatment, lean body mass increased more in the 100 mg/day T gel group (2.74 ± 0.28 kg; P = 0.0002) than in the 50 mg/day T gel (1.28 ± 0.32 kg) and T patch groups (1.20 ± 0.26 kg). Fat mass and percent fat were not significantly decreased in the T patch group, but showed decreases in the T gel groups (50 mg/day, −0.90 ± 0.32 kg; 100 mg/day, −1.05 ± 0.22 kg). Sexual function and mood improved maximally on day 30 of treatment, without differences across groups, and showed no further improvement with continuation of treatment. Mean muscle strength in the leg press exercise increased by 11 to 13 kg in all treatment groups by 90 days and did not improve further at 180 days of treatment. Moderate increases were also observed in arm/chest muscle strength
Wang et al^Citation52	227 hypogonadal men aged 19–68 years (Total T < 10.4 nmol/L)	Androgel treatments were double-blinded but Androderm was open-labeled	None	Randomized to receive – 1% Androgel (5 g/day) + placebo (1 + 1 pump) 1% Androgel (10 g/day) (2 pumps) or Andropatch (5 mg/day). Androgel doses were adjusted in future visits based on T levels and clinical symptoms	180 days	Urine N-telopeptide/creatinine ratio, a marker for bone resorption, decreased significantly (P = 0.0019) only in the T gel 100 mg/day group. Serum bone osteoblastic activity markers (osteocalcin, procollagen and skeletal alkaline phosphatase) increased significantly during the first 90 days of treatment without intergroup differences but declined to baseline thereafter. BMD increased significantly both in the hip (+1.1 ± 0.3%) and spine (+2.2 ± 0.5%) only in the T gel 100 mg/day group (P = 0.0001)
McNicholas et al^Citation27	208 hypogonadal men aged 31–80 years (Total T < 10.4 nmol/L)	Testim treatments were double-blinded but Androderm was open-labeled	None	Randomized to receive – 1% Testim (5 mg/day) or 1% Testim (10 mg/day) or Matching placebo gel or Androderm (5 mg/day)	90 days	Both doses of Testim significantly improved positive and negative mood over baseline; Andropatch did not. All three treatments increased lean body mass, and the higher dose of Testim produced a significant decrease in percentage body fat (−0.12%, P < 0.01). At all sample times both doses of Testim significantly improved sexual performance, sexual motivation, sexual desire and spontaneous erections. Andropatch provided insignificant improvements from baseline at all sample times for sexual desire, an inconsistent improvement in sexual motivation, but no effect on spontaneous erections
Steidle et al^Citation29	406 hypogonadal men aged 20–80 years (Total T < 10.4 nmol/L)	Testim treatments were double-blinded but Androderm was open-labeled	Placebo	Randomized to receive – 1% Testim (5 g/day) or 1% Testim (10 g/day) or Matching placebo gel or Androderm (5 mg/day)	90 days	At day 90, the 100 mg/day Testim treatment improved lean body mass by 1.7 kg and percentage of body fat by 1.2% to a significantly greater degree than either control treatment. Reductions in fat mass of 0.8 ± 2.4, 0.8 ± 2.0, 0.4 ± 1.8, and 0.1 ± 1.5 kg were noted in the 50 mg/day Testim gel, 100 mg/d Testim gel, Androderm patch, and placebo treatment groups, respectively. Reductions in % fat were evidenced in all treatment groups, with the Testim treatments yielding the most notable decreases. The 100 mg/day Testim treatment resulted in a 1.2 ± 1.9% reduction at d 90, which was not only parison with the T patch treatment (0.5 ± 1.6%, P 0.05). Significant improvements in spontaneous erections, sexual desire, and sexual motivation were also evidenced with the 100 mg/d Testim dose in comparison with placebo
Loizides et al^Citation54	638 hypogonadal men aged 18–86 (T < 300 ng/dL)	Open	None	Single group study receving 1% Testim (50 mg/day) and could increase up to 100 mg/day at the discretion of theinvestigator	30 days	Average score for sexual desire, sexual motivation, spontaneous erections (daytime and nighttime), sexual performance, sexual enjoyment, and satisfaction showed a significant increase from baseline by the end of the first week and generally reached a maximal response by the end of the second week, which was maintained for the remainder of the month of therapy with Testim. Both measures of positive mood and negative mood improved significantly, beginning with the first week of therapy and reaching and maintaining a maximal response at the second week
Dean et al^Citation30	371 hypogonadal men aged 21–81 (Total T < 300 ng/dL) were recruited from those who had completed two short-term double-blind studies with Testim	Open	None	Single group study receving 1% Testim (5 g/day) and could increase up to 100 mg/day based on serum T levels and clinical symptoms	12 months	Testim treatment resulted in significant changes in body composition at months 6 and 12 (Figures 5–7). These changes included significant increases in lean body mass 1.7 kg [month 6] and 2.2 kg [month 12]), significant decreases in fat mass (1.2 kg [month 6] and 1.8 kg [month 12]), and % fat (1.4% [month 6], and 2.1% [month 12]) but with no significant change in total body mass. Long-term treatment with Testim resulted in a significant (P < 0.001) percent change increase from baseline in BMD of the lumbar spine as measured by DEXA scan, reaching 2.58% at month 12. In addition, significant improvements in mood and sexual function were maintained for up to 12 months of treatment
Wang et al^Citation26	163 hypogonadal men (mean age 51.4 yrs) were recruited form those who were in the six-month study using Androgel or Androderm to continue for an additional 36 months	Open	None	Those who were receving 5 g/day or 10 g/day of Androgel continued in the same group. Men receiving Androderm were assigned to Androgel, 5 g/day. Dose were adjusted in future visits based on T levels and clinical symptoms	42 months	Lean body mass increased (P = 0.0001) and fat mass decreased (P = 0.0001), and these changes were maintained with treatment but were not accompanied by significant increases in muscle strength. Increases in serum bone markers suggestive of increased bone formation were followed by gradual and progressive increases in bone mineral density more in the spine (P = 0.0001) than the hip (P = 0.0004). Sexual function and mood parameters improved rapidly and were maintained throughout T treatment
Steidle et al^Citation43	151 hypogonadal men (Total T < 10.4 nmol/L pre-treatment) who failed to experience satisfactory symptom relief of sexual dysfunction after treatment with Androgel	Open	Androgel 5 g/day	Testim 5 g/day (treatment group) or Androgel 5 gm/day (control group)	4 weeks	Changes from baseline in the 5 domains of the Brief Male Sexual Function Inventory were compared between groups. The mean percentage improvement favored Testim treatment in sexual drive (23% vs 16%, P < 0.3), erectile function (32% vs 8%, P < 0.03), ejaculatory function (11% vs 9%, P < 0.4), problem assessment (47% vs 12%, P < 0.01), and sexual satisfaction (62% vs 23%, P < 0.02). A greater percentage of subjects also reported satisfaction with the experimental treatment (55% vs 33%, P < 0.02), and these subjects were less likely to require upward dose titration at the final follow-up visit (53% vs 72%,P < 0.03)
Kuhnert et al^Citation28	162 hypogonadal men over 18 years (Total T < 10 nmol/L)	Open	None	Randomized to receive 1 g/day of 2.5% T gel (Testocur) applied to scrotal skin or 5 g/day to nonscrotal skin or 5 mg Androderm patch applied to nonscrotal skin daily	24 weeks	Whereas serum testosterone levels and the pre-post changes of the areas under the curve of testosterone and free testosterone between weeks 0 and 24 indicated equivalent treatment success for the patch and scrotal groups, the dermal gel group was significantly superior to the other twogroups
Schrader et al^Citation61	48 HIV-positive hypogonadal males who failed to experience satisfactory symptom relief following prior treatment with Androgel 1%	Open	Androgel 5 g/day	Testim 5 g/day (treatment group) or Androgel 5 gm/day (control group)	4 weeks	The average percentage improvement favored the experimental treatment in all five comparisons of the BMSFI, including sexual drive (53% vs 18%, P < 0.001), erectile function (49% vs 7%, P < 0.004), ejaculatory function (15% vs 8%, P < 0.14), problem assessment (59% vs 12%, P < 0.003), and sexual satisfaction (58% vs 9%, P < 0.006). A greater percentage of subjects also reported satisfaction with the experimental treatment (85% vs 48%, P < 0.03), and these subjects were less likely to require upward dose titration at the final follow-up visit (30% vs 74%,P = 0.01)
Scott et al^Citation32	30 HIV-positive hypogonadal males over aged 31–66 years who were alredy receving IM testoster-one with T levels in the Eugonadal range	Open	Internal cross-over	IM Testosterone cypionate 100–200 mg every 1–2 weeks 1% Androgel 5 g/day. Both doses were adjusted in future visits based on T levels and clinical symptoms	16 weeks	Mean peak free testosterone concentrations with IM testosterone and T gel were 42 pg/mL and 23 pg/mL, respectively, and mean peak trough fluctuations in free testosterone were 26.7 ± 12.8 pg/mL and 2.7 ± 10.7 pg/mL, respectively (P < 0.001). Quality-of-life scores indicated more improved physical and emotional well-being with gel versus intramuscular testosterone. No significant changes in laboratory parameters or lean body mass were noted
Shabsigh et al^Citation57	75 hypogonadal men aged 17–80 years (TT < 400 ng/dL) with confirmed lack of response to ED to sildenafil	Double-blind	Placebo	5 g/day of 1% Androgel or placebo gel + 100 mg of sildenafil/day	12 weeks	Androgel treated subjects had greater improvement in erectile function compared to those who received placebo, reaching statistical significance at week 4 (4.4 vs 2.1, P = 0.029, 95.1% CI: 0.3, 4.7). Similar trends were observed for improvements in orgasmic function, overall satisfaction, total IIEF score and percentage of IIEF responders. T-gel significantly (P ≤ 0.004) increased total and free T levels throughout the study, although no significant correlations were made between testosterone levels and the IIEF at end point. Mean total QOL scores were similar between groups at baseline. Throughout the study changes in QOL were generally small but were consistently better in subjects who received T-gel versus placebo reaching significance at week 12 (P = 0.028) 95.1% CI: 0.0, 0.5) and approaching significance at end point

Abbreviations: CI, confidence interval; T, Testosterone; IIEF, International Index of Erectile Function; QOL, Quality of life; BMSFI, Brief Male Sexual Function Inventory; BMD, Bone Mineral Density; IM, Intramuscular.

Figure 3 Changes in body composition A) and muscle strength B) during treatment with Androgel. Reproduced with permission from wang C, et al. J Clin Endocrinol Metab. 2004;89:2085–2098. © The Endocrine Society.

Figure 4 Changes in hip and spine bone mineral density (BMD) in hypogonadal men treated with Androgel. Reproduced with permission from wang C, et al. J Clin Endocrinol Metab. 2004;89:2085–2098. © The Endocrine Society.

Figure 5 Total serum testosterone levels pre- and post-gel substitution. Reproduced with permission from Grober ED, et al. Efficacy of changing testosterone gel preparations (Androgel or Testim) among suboptimally responsive hypogonadal men. Int J Impot Res. 2008;20:213–217. © Nature Publishing Group.

WangCSwerdloffRSIranmaneshATestosterone Gel Study GroupTransdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal menJ Clin Endocrinol Metab20008582839285310946892

 PubMed Web of Science ®Google Scholar

WangCSwerdloffRSIranmaneshAEffects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal menClin Endocrinol (Oxf)200154673975011422108

 PubMed Web of Science ®Google Scholar

McNicholasTADeanJDMulderHCarnegieCJonesNAA novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual functionBJU Int2003911697412614254

 PubMed Web of Science ®Google Scholar

SteidleCSchwartzSJacobyKSebreeTSmithTBachandRAA2500 Testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual functionJ Clin Endocrinol Metab20038862673268112788872

 PubMed Web of Science ®Google Scholar

LoizidesESwierzewskiMJO’NeillCGriesserJSmithTEarly response time in sexual activity and mood following testosterone gel replacement in hypogonadal males from the Testim(R) START StudyRev Urol20046Suppl 6S16S2116985907

 PubMedGoogle Scholar

DeanJDCarnegieCRodzvillaJSmithTLong-term effects of testim(r) 1% testosterone gel in hypogonadal menRev Urol20046Suppl 6S22S2916985908

 PubMedGoogle Scholar

WangCCunninghamGDobsALong-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal menJ Clin Endocrinol Metab20048952085209815126525

 PubMed Web of Science ®Google Scholar

SteidleCWittMAMatriscianoJBlockJESexual functioning and satisfaction in nonresponders to testosterone gel: Potential effectiveness of retreatment in hypogonadal malesClin Cornerstone20057Suppl 4S20S2516651204

 PubMedGoogle Scholar

KuhnertBByrneMSimoniMTestosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trialEur J Endocrinol2005153231732616061839

 PubMed Web of Science ®Google Scholar

SchraderSMillsAScheperleMBlockJEImprovement in sexual functioning and satisfaction in nonresponders to testosterone gel: clinical effectiveness in hypogonadal, HIV-positive malesClin Cornerstone20057Suppl 4S26S3116651205

 PubMedGoogle Scholar

ScottJDWolfePRAndersonPCohanGRScarsellaAProspective study of topical testosterone gel (AndroGel) versus intramuscular testosterone in testosterone-deficient HIV-infected menHIV Clin Trials20078641242018042506

 PubMed Web of Science ®Google Scholar

ShabsighRKaufmanJMSteidleCPadma-NathanHRandomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil aloneJ Urol20081795 SupplS97S10218405769

 PubMed Web of Science ®Google Scholar