Testosterone Transdermal System Research Articles

Ambulatory Blood Pressure Parameters Among Men With Hypogonadism Treated With Testosterone Transdermal Therapy

ObjectiveStudies are needed to examine the effects of testosterone replacement therapy on ambulatory blood pressure (BP) parameters. This study assessed a testosterone transdermal system (TTS) using 24-hour ambulatory BP monitoring. MethodsIn a single-arm, noninferiority trial conducted at 41 US sites, 168 men (mean age: 56.2 years) with hypogonadism not receiving testosterone replacement therapy in the past 6 months were enrolled and received ≥1 study drug dose. Nightly TTS treatment was administered for 16 weeks (starting dose: 4 mg/d; min, max dose: 2, 6 mg/d) to achieve testosterone concentration of 400−930 ng/dL. The primary endpoint was mean change from baseline to week 16 in 24-hour systolic BP (SBP). Noninferiority was determined based on the upper bound of the 2-sided 95% CI <3.0 mmHg. ResultsSixty-two men had ≥85% study drug compliance and a valid week 16 ambulatory BP monitoring session. Mean change from baseline to week 16 in 24-hour average SBP was 3.5 mmHg (95% CI, 1.2−5.8 mmHg; n = 62). Since the upper limit of the CI was >3 mmHg, an effect of TTS could not be ruled out. Mean changes were larger at daytime vs nighttime and in subgroups of men with vs without hypertension. Cardiovascular adverse events were rare (<2%) and nonserious; no major cardiovascular adverse events were reported. ConclusionA meaningful effect of 16-week TTS treatment on 24-hour average SBP among men with hypogonadism could not be ruled out based on the study’s noninferiority criterion. The magnitude of mean changes observed may not be clinically meaningful regarding cardiovascular events.

Contact Dermatitis to Medications and Skin Products.

Consumer products and topical medications today contain many allergens that can cause a reaction on the skin known as allergic contact dermatitis. This review looks at various allergens in these products and reports current allergic contact dermatitis incidence and trends in North America, Europe, and Asia. First, medication contact allergy to corticosteroids will be discussed along with its five structural classes (A, B, C, D1, D2) and their steroid test compounds (tixocortol-21-pivalate, triamcinolone acetonide, budesonide, clobetasol-17-propionate, hydrocortisone-17-butyrate). Cross-reactivities between the steroid classes will also be examined. Next, estrogen and testosterone transdermal therapeutic systems, local anesthetic (benzocaine, lidocaine, pramoxine, dyclonine) antihistamines (piperazine, ethanolamine, propylamine, phenothiazine, piperidine, and pyrrolidine), topical antibiotics (neomycin, spectinomycin, bacitracin, mupirocin), and sunscreen are evaluated for their potential to cause contact dermatitis and cross-reactivities. Finally, we examine the ingredients in the excipients of these products, such as the formaldehyde releasers (quaternium-15, 2-bromo-2-nitropropane-1,3 diol, diazolidinyl urea, imidazolidinyl urea, DMDM hydantoin), the non-formaldehyde releasers (isothiazolinones, parabens, methyldibromo glutaronitrile, iodopropynyl butylcarbamate, and thimerosal), fragrance mixes, and Myroxylon pereirae (Balsam of Peru) for contact allergy incidence and prevalence. Furthermore, strategies, recommendations, and two online tools (SkinSAFE and the Contact Allergen Management Program) on how to avoid these allergens in commercial skin care products will be discussed at the end.

In vitro and in vivo evaluation of a novel testosterone transdermal delivery system (TTDS) using palm oil base.

Transdermal preparations for testosterone are becoming popular because of their unique advantages such as avoidance of first-pass effect, convenience, improved bioavailability, and reduction of systemic side effects. A novel testosterone transdermal delivery system (TDDS) was developed using a palm oil base called HAMIN™ (a commercial product) and tested using in vitro and in vivo skin permeability test methods. The physical characteristics of the formulation such as particle size and viscosity were determined by using Franz diffusion cell and Brookfield viscometer, respectively. In vivo skin permeability test was performed on healthy rabbits through the skin. Testosterone in serum was analyzed using the validated Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) technique. In vitro study showed that the cumulative amount of testosterone diffused was between 40 to 1400 ngcm(-)² over a period of five hr after application of TDDS through the artificial Strat-M™ membrane. In the in vivo rabbit skin permeability test, the results indicated that testosterone was well absorbed with a mean Cmax and Tmax of 60.94 ngml(-1) and 2.29 hr after application of TDDS while no increase was observed in placebo treatment. Particle size analysis ranged from 79.4 nm to 630.0 nm for placebo and 97 to 774.0 nm for TDDS. The formulation was successfully prepared using HAMIN™, which has demonstrated great potential for topical delivery of testosterone.

Addressing Andropause in Older Men in Long-Term Care

Addressing Andropause in Older Men in Long-Term Care

Changes in Prostate Specific Antigen in Hypogonadal Men After 12 Months of Testosterone Replacement Therapy: Support for the Prostate Saturation Theory

We measured prostate specific antigen after 12 months of testosterone replacement therapy in hypogonadal men. Data were collected from the TRiUS (Testim® Registry in the United States), an observational registry of hypogonadal men on testosterone replacement therapy (849). Participants were Testim naïve, had no prostate cancer and received 5 to 10 gm Testim 1% (testosterone gel) daily. A total of 451 patients with prostate specific antigen and total testosterone values were divided into group A (197 with total testosterone less than 250 ng/dl) and group B (254 with total testosterone 250 ng/dl or greater). The groups differed significantly in free testosterone and sex hormone-binding globulin, but not in age or prostate specific antigen. In group A but not group B prostate specific antigen correlated significantly with total testosterone (r=0.20, p=0.005), free testosterone (r=0.22, p=0.03) and sex hormone-binding globulin (r=0.59, p=0.002) at baseline. After 12 months of testosterone replacement therapy, increase in total testosterone (mean±SD) was statistically significant in group A (+326±295 ng/dl, p<0.001; final total testosterone 516±28 ng/dl) and group B (+154±217 ng/dl, p<0.001; final total testosterone 513±20 ng/dl). After 12 months of testosterone replacement therapy, increase in prostate specific antigen was statistically significant in group A (+0.19±0.61 ng/ml, p=0.02; final prostate specific antigen 1.26±0.96 ng/ml) but not in group B (+0.28±1.18 ng/ml, p=0.06; final prostate specific antigen 1.55±1.72 ng/ml). The average percent prostate specific antigen increase from baseline was higher in group A (21.9%) than in group B (14.1%). Overall the greatest prostate specific antigen was observed after 1 month of treatment and decreased thereafter. Patients with baseline total testosterone less than 250 ng/dl were more likely to have an increased prostate specific antigen after testosterone replacement therapy than those with baseline total testosterone 250 ng/dl or greater, supporting the prostate saturation hypothesis. Clinicians should be aware that severely hypogonadal patients may experience increased prostate specific antigen after testosterone replacement therapy.

Sexual Function in Chronic Kidney Disease

Endocrine abnormalities are common in patients with chronic kidney disease (CKD) and lead to sexual dysfunction, anemia, hyperparathyroidism, and altered mineral metabolism. Common clinical problems include disturbances in menstruation in women, erectile dysfunction in men, and decreased libido and infertility in both sexes. Organic factors tend to be prominent and are related to uremia and other comorbid illnesses. Psychological factors and depression may exacerbate the primary problem. Alterations in the hypothalamic-pituitary axis are seen early in CKD and tend to worsen after patients start dialysis. Hypogonadism plays a dominant role in male sexual function, whereas changes in hypothalamic-pituitary function predominate in female sexual dysfunction. In patients on dialysis, treatment strategies include optimizing dose of dialysis, correction of anemia with erythropoietin, and correction of hyperparathyroidism. Successful kidney transplantation may restore normal sexual function, especially in younger patients.

New testosterone transdermal delivery system is effective in healthy men

New testosterone transdermal delivery system is effective in healthy men

New testosterone transdermal delivery system is effective in healthy men

New testosterone transdermal delivery system is effective in healthy men

Testosterone Replacement Therapy for Older Men

Summary A review of the currently published data indicates thattestosterone replacement therapy in older men may beadvantageous in terms of improving bone mineral density,increasing muscle mass and strength, and, in some men,improving libido and mood. However, the long-term clin-ical significance of these effects is still uncertain, as largerand longer-term studies are needed. In the short term (upto 3 years), the adverse effects of testosterone replace-ment therapy in older men seem predictable and manage-able, but the longer-term effects on target organs, such asthe cardiovascular system and the prostate, are yet to bedetermined. References AACE Hypogonadism Task Force. American Association of Clinical En-docrinologists medical guidelines for clinical practice for the evalu-ation and treatment of hypogonadism in adult male patients—2002update. Endocr Pract. 2002;8:439–456.Anonymous. Incidence of vertebral fracture in Europe: results from theEuropean Prospective Osteoporosis Study (EPOS). J Bone Miner Res.2002;17:716–724.Arver S, Dobs AS, Meikle AW, Caramelli KE, Rajaram L, Sanders SW,Mazer NA. Long-term efficacy and safety of a permeation-enhancedtestosterone transdermal system in hypogonadal men. Clin EndocrinolOxford. 1997;47:727–737.Baker HW, Burger HG, de Kretser DM, Hudson B, O’Connor S, WangC, Mirovics A, Court J, Dunlop M, Rennie GC. Changes in the pi-tuitary-testicular system with age.Clin Endocrinol Oxford. 1976;5:349–372.Basaria S, Dobs AS. Hypogonadism and androgen replacement therapyin elderly men. Am J Med. 2001;110:563–572.Bhasin S, Bagatell CJ, Bremner WJ, Plymate SR, Tenover JL, KorenmanSG, Nieschlag E. Issues in testosterone replacement in older men. JClin Endocrinol Metab. 1998;83:3435–3448.Bhasin S, Bremner WJ. Emerging issues in androgen replacement ther-apy. J Clin Endocrinol Metab. 1997;82:3–8.Bhasin S, Gabelnick HL, Spieler JM, Swerdloff RS, Wang C, Kelly C,eds. Pharmacology, Biology and Clinical Applications of Androgen.New York, NY: Wiley Liss; 1996.Bhasin S, Swerdloff RS, Steiner B, Peterson MA, Meridores T, GalmiriniM, Pandian MR, Goldberg R, Berman N. A biodegradable testoster-one microcapsule formulation provides uniform eugonadal levels oftestosterone for 10–11 weeks in hypogonadal men. J Clin EndocrinolMetab. 1992;74:75–83.Blum J, Harris RH. Diagnosis and treatment of hypogonadism with em-phasis on erectile dysfunction and osteoporosis. Prim Care Case Rev.2003;6:97–109.Bouloux P. Testim 1% testosterone gel for the treatment of male hypo-gonadism. Clin Ther. 2005;27:286–298.Bremner WJ, Prinz PN. A loss of circadian rhythmicity in blood testos-terone levels with aging in normal men. J Clin Endocrinol Metab.1983;56:1278–1281.Brocks DR, Meikle AW, Boike SC, Mazer NA, Zariffa N, Audet PR,Jorkasky DK. Pharmacokinetics of testosterone in hypogonadal menafter transdermal delivery: influence of dose. J Clin Pharmacol. 1996;36:732–739.Cunningham GR, Cordero E, Thornby JI. Testosterone replacement withtransdermal therapeutic systems. JAMA. 1989;261:2525–2530.Davidson JM, Chen JJ, Crapo L, Gray GD, Greenleaf WJ, Catania JA.Hormonal changes and sexual function in aging men. J Clin Endo-crinol Metab. 1983;57:71–77.Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA.Pharmacokinetics, efficacy, and safety of a permeation-enhanced tes-tosterone transdermal system in comparison with bi-weekly injectionsof testosterone enanthate for the treatment of hypogonadal men. J ClinEndocrinol Metab. 1999;84:3469–3478.Ferrini RL, Barrett-Connor E. Sex hormones and age: a cross-sectionalstudy of testosterone and estradiol and their bioavailable fractions incommunity-dwelling men.Am J Epidemiol. 1998;147:750–754.Findlay JC, Place V, Snyder PJ. Treatment of primary hypogonadism inmen by the transdermal administration of testosterone. J Clin Endo-crinol Metab. 1989;68:369–373.

Pharmacokinetics of a new testosterone transdermal delivery system, TDS®‐testosterone in healthy males

The Transdermal Delivery System (TDS) is a liquid formulation that can be applied to the skin via a metered pump spray to deliver drug to the systemic circulation. The aims of this study were to assess the ability of the TDS preparation to deliver testosterone systemically, and to characterize the pharmacokinetic profiles of the hormone in healthy males. An open label, comparative, randomized placebo controlled study involving three treatments and three periods with a minimum of a 1 week washout period was conducted. Twelve healthy males received 50 mg TDS-testosterone, TDS-placebo, and 50 mg of a commercially available topical testosterone preparation (Androgel, 1% topical testosterone gel). The mean AUC(0,12 h) was higher following application of TDS-testosterone (61.8 ng ml-1 h), compared with Androgel (57.7 ng ml-1 h) and TDS-placebo (50.7 ng ml-1 h. The mean Cmax (0,12 h) was similar for TDS-testosterone (6.6 ng ml-1) and Androgel (6.5 ng ml-1) and these values were higher than those for TDS-placebo (5.7 ng ml-1). Analysis of variance showed that the 90% confidence intervals on the relative difference of the ratio for the AUC(0,12 h) and the Cmax (0,12 h) between TDS-testosterone and Androgel, were contained within the bioequivalence limit (80, 125%) (Cmax 89.2, 112.3% and AUC 93.5, 120.5%). Serum testosterone concentrations were lower following TDS-Placebo and were not bioequivalent either to the gel or spray. The TDS preparation was shown to deliver testosterone systemically to humans and the concentrations of the hormone in the 12 h following TDS administration were bioequivalent to an existing topical delivery gel.

A Pilot Study of an Investigational Testosterone Transdermal Patch System in Young Women with Spontaneous Premature Ovarian Failure

Evidence suggests that young women with spontaneous premature ovarian failure (sPOF) have significantly lower androgen levels than age-matched regularly menstruating women. The objective of the study was to evaluate an investigational testosterone transdermal patch (TTP) designed to deliver the normal ovarian production rate of testosterone. This was an open-label study (2-month baseline period followed by 2-month treatment period). Nine women with sPOF and a history of regular bleeding patterns on standard estrogen/progestogen cyclic treatment participated in the study. One subject with abnormal baseline levels was excluded. Four consecutive 28-d cycles of transdermal estradiol (E2; 0.1 mg/d) and sequential oral medroxyprogesterone acetate (MPA; 10 mg/d for the last 12 d of each cycle). During cycles 3 and 4, an investigational TTP (nominal delivery 150 microg/d) was applied twice weekly to the abdomen. Steady-state pharmacokinetic profiles of free and total testosterone and scheduled vaginal bleeding patterns were studied. The mean (95% confidence interval) of the time-average free testosterone levels during TTP treatment was 7.5 (4.9-9.9) pg/ml; 26.0 (17.2-34.6) pmol/liter (with E2), and 6.9 (4.9-8.8) pg/ml; 23.9 (17.2-30.5) pmol/liter (with E2 and MPA). The confidence intervals of the means include the upper limit of normal for premenopausal women, i.e. 6.8 pg/ml (23.5 pmol/liter), although the mean values are slightly above this. The addition of TTP to cyclic E2/MPA therapy in women with sPOF produced mean free testosterone levels that approximate the upper limit of normal. A 3-yr study to assess safety and effectiveness in this population is in progress.

In Vitro and In Vivo Evaluation of a Novel Nonscrotal Matrix-Type Transdermal Delivery System of Testosterone

A matrix-type testosterone (TS) transdermal delivery system for nonscrotal skin was developed with DuroTak® 87-2510 as an adhesive polymer. When 3% dodecylamine was used in combination with 10% span 80, the in vitro rat permeation rate increased from 2.29 µg/cm2/hr to 6.51 µg/cm2/hr as the TS loading dose increased from 2% to 6%. The maximum flux of experimental patch was about 14-fold higher than that of Testoderm®. Release kinetics of TS from the patches was proportional to t1/2 following the Higuchi equation, and the release rate of TS increased as TS loading dose increased. Also, a good linear relationship between the skin permeation rate and the release rate was observed, which implies that the release rate is the rate-limiting process of the skin permeation. In vivo study showed that the plasma concentration of TS promptly increased and reached the peak level within 3–6 hours of application of the experimental patch. Area under the curve (AUC0 ~ 48) and Cmax also linearly increased in a dose-dependent manner up to 6% of TS. These results demonstrate the feasibility of developing a nonscrotal matrix-type transdermal delivery system of TS.

Formulation of a reservoir-type testosterone transdermal delivery system

A reservoir-type transdermal delivery system of testosterone (TS) was developed using an ethanol/water (70:30) cosolvent system as the vehicle. The maximum permeation rate achieved by 70% (v/v) of ethanol was further increased from 2.69 to 47.83 μg/cm 2/h with the addition of 1.0% dodecylamine as the skin permeation enhancer. The permeation rate of TS through the ethylene vinyl acetate (EVA) membrane was observed to increase as the vinyl acetate content in the copolymer increased. Addition of 1.0% (w/w) gelling agent, hydroxypropyl methlycellulose (HPMC), in the reservoir formulation resulted in desirable rheological properties with an insignificant effect on the skin permeation rate of TS. Thus, a new transdermal delivery system for TS was formulated using EVA membrane coated with a pressure-sensitive adhesive (Duro-Tak 87-2510) and HPMC as a gelling agent. This experimental patch showed comparable plasma concentration profiles in the in vivo study when compared with a commercial product, Androderm®. Moreover, the results suggested the possibility of further enhancing the permeation rate of TS by controlling the composition of the reservoir formulation.

Interrelationships among Lipoprotein Levels, Sex Hormones, Anthropometric Parameters, and Age in Hypogonadal Men Treated for 1 Year with a Permeation-Enhanced Testosterone Transdermal System1

Serum lipoproteins and cardiovascular risk are affected by endogenous and exogenous sex hormones. As part of a multicenter evaluation of a permeation-enhanced testosterone transdermal system (TTD), the interrelationships among serum lipoproteins, hormone levels, anthropometric parameters, and age were investigated in 29 hypogonadal men. Subjects (aged 21-65 yr) were first studied during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with the TTD. Compared with treatment with IM-T, the HG period produced increases in high density lipoprotein [HDL; 12.0 +/- 1.6% (+/-SEM); P<0.001] and total cholesterol (4.2 +/- 1.9%; P: = 0.02) and a decrease in the cholesterol/HDL ratio (-9.7 +/- 2.8%; P = 0.02). Compared with the HG period, TTD treatment produced decreases in HDL (-7.6 +/- 2.5%; P = 0.002) and increases in the cholesterol/HDL ratio (9.0 +/- 2.5%; P = 0.01) and triglycerides (20.7 +/- 6.4%; P: = 0.03). Small decreases in total cholesterol (-1.2 +/- 1.8%; P: = 0.1) and low density lipoprotein (-0.8 +/- 2.6%; P = 0.07) were also observed during TTD, but did not reach statistical significance. Likewise, there were no significant differences between the IM-T and TTD treatments. Serum HDL levels showed a strong negative correlation with body mass index and other obesity parameters in all three study periods (r < -0.45; P < 0.02). During treatment with TTD, serum testosterone levels also correlated negatively with body mass index (r = -0.621; P < 0.001). As a consequence of these relationships, a positive trend was observed between HDL and testosterone levels during TTD treatment (r = 0.336; P = 0.07). Interestingly, the changes in lipoprotein levels during TTD treatment indicated a more favorable profile (decrease in cholesterol and low density lipoprotein levels) with increasing age of the patients. In hypogonadal men the effects of transdermal testosterone replacement on serum lipoproteins appear consistent with the physiological effects of testosterone in eugonadal men.

Interrelationships among Lipoprotein Levels, Sex Hormones, Anthropometric Parameters, and Age in Hypogonadal Men Treated for 1 Year with a Permeation-Enhanced Testosterone Transdermal System

Interrelationships among Lipoprotein Levels, Sex Hormones, Anthropometric Parameters, and Age in Hypogonadal Men Treated for 1 Year with a Permeation-Enhanced Testosterone Transdermal System

New clinical applications of transdermal testosterone delivery in men and women

This paper reviews recent progress in the development and clinical application of testosterone transdermal delivery systems designed for physiological replacement therapy in men and women. The biopharmaceutic goal of physiologic replacement therapy is to produce serum levels and circadian patterns of testosterone and its active metabolites that mimic the normal physiology of testosterone in the particular target population. For the treatment of adult hypogonadal men, the nightly 24 h application of the Androderm ® testosterone transdermal system (5 mg per day) achieves this goal – as demonstrated in a series of clinical pharmacokinetic studies. For the treatment of adolescent males, physiologic replacement can be approximated by modifying the dose and duration of Androderm ® application so as to mimic the patterns of nocturnal testosterone secretion observed during puberty. With the objective of providing physiological replacement for women with diminished testosterone production, an experimental testosterone matrix transdermal system (TMTDS) has been developed and is currently undergoing clinical evaluation. In parallel with the development of testosterone transdermal systems, physicians have been investigating a number of conditions, in both males and females, where testosterone production is diminished and replacement therapy may be beneficial. Three of these new clinical applications will be illustrated – the use of Androderm ® for the treatment of adolescent males with β-thalassemia, the use of Androderm ® for the treatment of HIV+ men, and the use of the TMTDS for the treatment of HIV+ women. From the biopharmaceutic and clinical perspectives, the development of testosterone transdermal systems represents an important achievement in controlled drug delivery.

Pharmacokinetics, Efficacy, and Safety of a Permeation-Enhanced Testosterone Transdermal System in Comparison with Bi-Weekly Injections of Testosterone Enanthate for the Treatment of Hypogonadal Men

Pharmacokinetics, Efficacy, and Safety of a Permeation-Enhanced Testosterone Transdermal System in Comparison with Bi-Weekly Injections of Testosterone Enanthate for the Treatment of Hypogonadal Men

Transdermal Testosterone Delivery: Comparison Between Scrotal and Nonscrotal Delivery Systems

The purpose of this investigation was to study the bioequivalence of two testosterone transdermal delivery systems (T-TDSs), Testoderm®, designed to deliver testosterone through scrotal skin, and Androderm®, designed for nonscrotal permeation. In vitro permeation and release kinetics as well as in vivo pharmacokinetics in the castrated Yucatan miniature swine (minipigs) model of both T-TDSs were studied side by side under the same experimental conditions. In vitro skin permeation kinetics studies demonstrated that testosterone permeates through minipig dorsal skin at zero-order kinetics from both T-TDSs. The nonscrotal T-TDS, however, has a permeation rate which is ∼13 times higher than that for the scrotal T-TDS. The release of testosterone from the nonscrotal T-TDS showed a biphasic release profile between cumulative amount released and time, whereas a monophasic release profile between cumulative amount released and square root of time was observed for the scrotal T-TDS. Pharmacokinetic analysis of plasma testosterone profiles in minipigs indicated a significant difference (p < 0.001) in daily dose of testosterone delivered (1.20 versus 4.83 mg/day), maximum concentration (Cmax) (54.2 versus 218.0 ng/dl), and area under concentration–time curve (AUC0–28) [665 versus 3208 (ng/dl) × hr] between these T-TDSs. However, there is no difference in time to reach Cmax, mean residence time, and daily-delivered-dose-normalized Cmax and AUC0–28. The difference in pharmacokinetic profiles resulted from the difference in daily doses delivered, which could be attributed remarkably to the difference in permeation rate (∼13-fold) between the nonscrotal and scrotal T-TDSs.

A burn-like lesion caused by a testosterone transdermal system

A wide range of drugs are capable of being administered as transdermal drug delivery systems (TDDS). Despite their advantages, these systems are known to have adverse effects. This report describes localised skin reactions with reference to a burn-like lesion on the shoulder of a patient caused by a testosterone TDDS. Patients should be advised of the potential adverse effects of these systems and also of suitable application sites, avoiding areas liable to prolonged pressure.

Transdermal testosterone.

Nightly application of testosterone transdermal (TTD) system to nonscrotal sites in men with hypogonadism results in a 24-hour serum testosterone concentration profile which mimics the circadian pattern observed in healthy young men. The system also normalises dihydrotestosterone/testosterone and estradiol/testosterone ratios and reduces luteinising hormone levels towards the normal range. A multicentre, open-label study demonstrated that nocturnal erectile response and overall sexual function improved during 12 months' treatment with the TTD system (5 mg/day) in men with hypogonadism. Individual variables of sexual desire, arousal, frequency of sexual activity, orgasm and satisfaction also improved. The TTD system is well tolerated, with application site reactions such as pruritus, burn-like blisters and erythema being the most commonly reported events. Prostate-specific antigen levels and prostate volume remain in the normal range during long term treatment.