Benefits of TRT in Hypogonadal men

0021-972X/00/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2000 by The Endocrine Society Vol. 85, No. 8 Printed in U.S.A. Transdermal Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and Body Composition Parameters in Hypogonadal Men* CHRISTINA WANG, RONALD S. SWERDLOFF, ALI IRANMANESH, ADRIAN DOBS, PETER J. SNYDER, GLENN CUNNINGHAM, ALVIN M. MATSUMOTO, THOMAS WEBER, NANCY BERMAN, AND THE TESTOSTERONE GEL STUDY GROUP† Divisions of Endocrinology, Depar
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  Transdermal Testosterone Gel Improves SexualFunction, Mood, Muscle Strength, and Body CompositionParameters in Hypogonadal Men* CHRISTINA WANG, RONALD S. SWERDLOFF, ALI IRANMANESH, ADRIAN DOBS,PETER J. SNYDER, GLENN CUNNINGHAM, ALVIN M. MATSUMOTO,THOMAS WEBER, NANCY BERMAN, AND THE T ESTOSTERONE G EL S TUDY G ROUP †  Divisions of Endocrinology, Departments of Medicine/Pediatrics, Harbor-University of California-Los Angeles Medical Center and Research and Education Institute (C.W., R.S.S., N.B.), Torrance,California 90509; Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; The Johns HopkinsUniversity (A.D.), Baltimore, Maryland 21287; University of Pennsylvania Medical Center (P.J.S.), Philadelphia, Pennsylvania 19104; Veterans Affairs Medical Center, Baylor College of Medicine (G.C.), Houston, Texas 77030; Veterans Affairs Puget Sound Health Care System, University of Washington(A.M.M.), Seattle, Washington 98108; and Duke University Medical Center (T.W.), Durham, North Carolina 27705  ABSTRACT Testosterone (T) therapy for hypogonadal men should correct theclinical abnormalities of T deficiency, including improvement of sex-ual function, increase in muscle mass and strength, and decrease infat mass, with minimal adverse effects. We have shown that admin-istration of a new transdermal T gel formulation to hypogonadal menprovided dose proportional increases in serum T levels to the normaladult male range. We now report the effects of 180 days of treatmentwith this 1% T gel preparation (50 or 100 mg/day, contained in 5 or10 g gel, respectively) compared to those of a permeation-enhanced Tpatch (5 mg/day) on defined efficacy parameters in 227 hypogonadalmen. In the T gel groups, the T dose was adjusted up or down to 75mg/day (contained in 7.5 g gel) on day 90 if serum T concentrationswere below or above the normal male range. No dose adjustment wasmadewiththeTpatchgroup.Sexualfunctionandmoodchangesweremonitored by questionnaire, body composition was determined bydualenergyx-rayabsorptiometry,andmusclestrengthwasmeasuredby the one repetitive maximum technique on bench and leg pressexercises. Sexual function and mood improved maximally on day 30of treatment, without differences across groups, and showed no fur-ther improvement with continuation of treatment. Mean musclestrength in the leg press exercise increased by 11 to 13 kg in alltreatment groups by 90 days and did not improve further at 180 daysof treatment. Moderate increases were also observed in arm/chestmuscle strength. At 90 days of treatment, lean body mass increasedmore in the 100 mg/day T gel group (2.74  0.28 kg; P  0.0002) thanin the 50 mg/day T gel (1.28  0.32 kg) and T patch groups (1.20  0.26kg).Fatmassandpercentfatwerenotsignificantlydecreasedinthe T patch group, but showed decreases in the T gel groups (50mg/day,  0.90  0.32 kg;100 mg/day,  1.05  0.22 kg).Theincreasein lean mass and the decrease in fat mass were correlated with thechanges in average serum T levels attained after transdermal T re-placement. These beneficial effects of T replacement were accompa-nied by the anticipated increases in hematocrit and hemoglobin butwithout significant changes in the lipid profile. The increase in meanserum prostate-specific antigen levels (within the normal range) wascorrelated with serum levels of T. The greatest increases were notedin the 100 mg/day T gel group. Skin irritation was reported in 5.5%ofsubjectstreatedwithTgelandin66%ofsubjectsinthepermeation-enhanced T patch group.We conclude that T gel replacement improved sexual function andmood, increased lean mass and muscle strength (principally in thelegs), and decreased fat mass in hypogonadal men with less skinirritation and discontinuation compared with the recommended doseof the permeation-enhanced T patch. (  J Clin Endocrinol Metab 85: 2839–2853, 2000) A NDROGEN REPLACEMENT therapy in hypogonadalmen improves sexual function, decreases body fat,and increases lean muscle mass and function and bone mass(1–3). These beneficial effects of testosterone (T) replacementtherapy are accompanied by slight lowering of high densitylipoprotein (HDL) cholesterol levels, increase in hematocrit(Hct)/hemoglobin (Hgb), and increase in the size of theprostate gland to within the normal adult male range (2, 3).Recentdevelopments inthedelivery ofadequateamounts ofT to mimic the daily production rate use the skin as the routeof administration. The transdermal T patches, including thescrotal patch (Testoderm), the nonscrotal permeation-enhanced patch with an alcohol-based reservoir (Andro- Received February 15, 2000. Revision received April 20, 2000. Ac-cepted May 12, 2000.Address allcorrespondenceandrequestsforreprintsto:Dr.ChristinaWang, Division of Endocrinology, Department of Medicine, Harbor-University of California-Los Angeles Medical Center, 1000 West CarsonStreet, Torrance, California 90509.* This work was supported by grants from Unimed Pharmaceuticals,Inc.ThestudiesatHarbor-UniversityofCalifornia-LosAngelesMedicalCenter were supported by NIH Grant M0-00543 (to the General ClinicalResearch Center).† The Testosterone Gel Study Group includes: S. Berger, ChicagoCenter for Clinical Research (Chicago, IL); E. Dula, West Coast ClinicalResearch (Van Nuys, CA); J. Kaufman, Urology Research Options (Au-rora, CO); G. P. Redmond, Center for Health Studies (Cleveland, OH);S. Scheinman and H. W. Hutman, South Florida Bioavailability Clinic(Miami,FL);S.L.Schwartz,Diabetes andGlandular DiseaseClinic,P.A.(San Antonio, TX); C. Steidle, Northeast Indiana Research (Fort Wayne,IN); J. Susset, MultiMed Research (Providence, RI); G. Wells, AlabamaResearch Center, L.L.C. (Birmingham, AL); and R. E. Dudley, S.Faulkner, N. Rohowsky, G. Ringham, W. Singleton, J. Longstreth, andK. Zunich, Unimed Pharmaceuticals, Inc. (Deerfield, IL). 0021-972X/00/$03.00/0 Vol. 85, No. 8The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2000 by The Endocrine Society 2839  by on November 11, 2008 jcem.endojournals.orgDownloaded from   derm), and the nonscrotal patch without a reservoir (Testo-derm TTS), deliver 5–6 mg/day T to the body and providea relative steady state level of T at the low to midnormalrange(4–13).HigherserumTlevelscanbeachievedbyusingmore than one transdermal patch. Long term use of thesepatches (3–10 yr) has been shown to be effective in main-taining sexual function and bone and muscle mass in youngas well as elderly hypogonadal men (14–18). Nonetheless,one of the permeation-enhanced T patches is associated withskin irritation in about a third of the subjects and has a10–15% discontinuation rate despite the use of local preap-plication of corticosteroid cream (19–21). The scrotal patchrequires a large surface of scrotal skin and clipping or shav-ing of the hair. The nonscrotal body patches do not adhereoptimally in some patients.WehavereportedthatTwhenappliedasageloveralargerarea of skin in an open system rarely produces problems ofskin irritation (22). We have also shown that this new T gel(AndroGel) formulation can efficiently and rapidly increaseserum T levels into the normal range in hypogonadal men. 1 About 9–14% of T applied to the skin as the gel is bioavail-able. Pharmacokinetic analyses of T gel vs. T patch showedthat the average serum T levels over the 180-day treatmentperiodwerehighestinthe100mg/dayTgelgroup,andtheselevels were 1.4- and 1.9-fold higher than those achieved bythe 50 mg/day T gel and the T patch (Androderm) groups,respectively. The daily application of the gel resulted insteady state serum T pharmacokinetics with dose propor-tional increases in serum estradiol and suppression of LHand FSH levels. Serum 5  -dihydrotestosterone concentra-tions were elevated, but 5  -dihydrotestosterone to T ratiosincreased slightly after T gel application. Daily T gel appli-cation provided more flexibility in dosing, dose proportion-ality in T gel pharmacokinetics, and less discontinuation ratethanthepermeation-enhancedpatch(22;seeFootnote1).Wenow report the efficacy and safety of 2 doses of T gel (An-droGel, 50 and 100 mg T/day, contained in 5 and 10 g gel,respectively) vs. T patch (Androderm, 2 patches delivering 5mgT/day)in227hypogonadalmen.Wemonitoredtheeffectof T replacement on sexual function, mood changes, bodycomposition, muscle strength, red cell indexes, lipid profile,prostate dysfunction indexes, skin problems, and other po-tential side-effects. Subjects and Methods  Subjects Hypogonadal men were recruited and studied in 16 centers in theUnited States. The patients were between 19–68 yr old and had singlemorning serum T levels at screening of 10.4 nmol/L (300 ng/dL) or less.Previously treated hypogonadal men were withdrawn from T esterinjectionforatleast6weeksandfromoralortransdermalandrogensfor4 weeks before the screening visit. Aside from the hypogonadism, thesubjects were in good health, as evidenced by medical history, physicalexamination,completebloodcount,urinalysis,andserumbiochemistry.If the subjects were taking lipid-lowering agents or tranquilizers, thedoses were stabilized for at least 3 months before enrollment. The sub- jects had no history of chronic medical illness or alcohol or drug abuse.They had normal rectal examination, prostate-specific antigen (PSA)level of less than 4 ng/mL, and urine flow rate of 12 mL/s or greater before enrollment in the study. They were excluded if they had a gen-eralized skin disease that might affect the T absorption or prior historyof skin irritability with Androderm patch. Subjects weighing less than80% or more than 140% of their ideal body weight were also excluded.A total of 227 patients were enrolled; 73, 78, and 76 were randomizedto receive 50 mg/day T gel (contained in 5 g gel), 100 mg/day T gel(contained in 10 g of gel), or the T patch, respectively. There were nosignificantgroup-associateddifferencesinthepatients’characteristicsat baseline (age, height, weight, cause of hypogonadism, and previous Ttreatment). About 3.9–11.0% of the subjects were less than 35 yr of age,23.3–36.8% were between 35–49 yr of age, 55.1–57.5% were between50–64yrofage,and3.9–8.2%were65yroroverinthe3initialtreatmentgroups. About 35–45% of the patients had primary hypogonadism(Klinefelter’s syndrome, anorchia, or testicular failure), and 15–25% hadsecondary hypogonadism (Kallman’s syndrome, hypothalamic pitu-itary disease, or pituitary tumor). Hypogonadism in the remaining menwas attributed to aging or normogonadotropic hypogonadism (symp-toms of hypogonadism with low serum T but normal LH). Forty-onepercent of the subjects had not received prior T replacement.  Study design The study was a randomized, multicenter (16 centers), parallel studycomparing 2 doses of T gel with a T patch. The study was double blindwith respect to the T gel dose and open label for the T patch group. Forthefirst3monthsofthestudy(days1–90),thesubjectswererandomizedto receive 50 mg/day T gel in 5 g gel, 100 mg/day T gel in 10 g gel, or2 nonscrotal patches delivering 5 mg/day (T patch). In the following 3months (days 91–180), the subjects were administered 1 of the followingtreatments: 50 mg/day T gel, 100 mg/day T gel, 5.0 mg/day T patch,or 75 mg/day T gel in 7.5 g gel. Patients who were applying T gel hada single, preapplication serum T measurement on day 60, and if thelevels were within the normal range of 10.4–34.7 nmol/L (300–1000ng/dL) they remained on their srcinal dose. Patients with T levels lessthan10.4nmol/Landwhowereoriginallyassignedtoapply50mg/dayT gel and those with T levels more than 34.7 nmol/L who had received100 mg/day T gel were then reassigned to administer 75 mg/day T gelfor days 91–180.Subjects returned to the study center on days 0 (baseline), 30, 60, 90,120, 150, and 180 for a clinical examination and skin irritation andadverse event assessments. Fasting blood samples were drawn on alldays. Hematology and clinical biochemistry, including electrolytes, glu-cose, renal and liver function tests, and lipid profile, were performed atall clinic visits. T gel and patch Testosterone gel (AndroGel) was manufactured by Besins Iscovesco(Paris, France) and supplied by Unimed Pharmaceuticals, Inc. (BuffaloGrove, IL). The formulation is a hydroalcoholic gel containing 1% (10mg/g) T. Approximately 250 g gel were packaged in multidose glass bottles that delivered 2.25 g of the gel for each actuation of the pump.Patients assigned to apply 50 mg/day T were given one bottle of T gelandonebottleofplacebogel(vehicleonly);thoseassignedtoreceive100mg/day T gel were dispensed two bottles of the active T gel. On themorning of day 1 of the study, the patients were instructed to depressthe pump of one of the bottles once. The gel was applied to the rightupper arm/shoulder. Then, using the same bottle, a second dose of gelwas delivered and applied to the left upper arm/shoulder. The second bottle was then used, with gel from the actuation of the pump appliedtotherightabdomenandthesecondactuationtotheleftabdomen.Thus,each patient randomized to T gel applied gel to four application siteseach day. On the following day, the application sites were reversed.Alternate application sites continued throughout the study. After ap-plication of the gel to the skin, the gel dried within a few minutes.Patients washed their hands thoroughly with soap and water immedi-ately after gel application. After 90 days, for the subjects titrated to the75 mg/day dose of T gel, the patients were supplied with three bottles,one containing placebo and the other two containing T gel. The subjectswereinstructedtoapplyoneactuationfromtheplacebobottleandthreeactuations from a T gel bottle to four different sites of the body as 1 Swerdloff, R. S., C. Wang, G. Cunningham, A. Dobs, A. Iranmanesh,A. Matsumoto, P. Snyder, T. Weber, N. Berman, and T-gel Study Group,submitted for publication. 2840 WANG ET AL. JCE & M ã 2000 Vol 85 ã No 8  by on November 11, 2008 jcem.endojournals.orgDownloaded from   described above. The sites were rotated each day, using the same se-quence as that described above.Testosterone patches (Androderm) delivering 2.5 mg/day T wereprovided.Thepatients wereinstructedtoapply twoTpatches toacleandry area of skin on the back, abdomen, upper arms, or thighs once perday. Application sites were rotated with approximately a 7-day interval between applications to the same site. T gel or patches were applied atapproximately 0800 h each morning for 180 days.  Methods Body composition (total body mass, lean body mass, fat mass, andpercent fat) was measured by dual energy x-ray absorptiometry withHologic, Inc., 2000 or 4500A series on days 0, 90 and 180. These assess-ments were performed in 168 of 227 subjects because the Hologic, Inc.,dual energy x-ray absorptiometry equipment was not available at 3 ofthe16studycenters.Allbodycompositionmeasurementswerecentrallyanalyzed and processed by Hologic, Inc. (Waltham, MA). The data for bonemineraldensityandbonemarkerswillbereportedinasubsequentreport.Muscle strength was assessed on days 0, 90, and 180 with the one-repetitive maximum technique in bench press and seated leg pressexercises. The one-repetitive maximum technique assesses the maximalforce-generatingcapacityofthemusclesusedtoperformthetest.Musclestrength was assessed in 167 of the 227 patients. Four of the 16 centersdid not participate in the muscle strength testing because of lack of therequired equipment.Sexual function and mood were assessed by questionnaires the pa-tients answered daily for 7 consecutive days before clinic visits on day0 and on days 30, 60, 90, 120, 150, and 180 days during gel and patchapplication.Thesubjectsrecordedwhethertheyhadsexualdaydreams,anticipation of sex, flirting, sexual interaction (sexual motivation pa-rameters) and orgasm, erection, masturbation, ejaculation, and inter-course (sexual performance parameters) on each of 7 days. The valuewasrecordedas0(none)or1(any)foranalyses,andthenumbersofdaysthe subjects noted a parameter were summed for the 7-day period. Theaverageofthefoursexualmotivationparameterswastakenasthesexualmotivation score, and that of the five sexual performance parameterswas used as the sexual performance mean score (0–7). The subjects alsoassessed their level of sexual desire, sexual enjoyment, and satisfactionof erection using a seven-point Likert-type scale (0–7), and assessed thepercentage of full erection from 0–100%. The subjects rated their moodusing a 0–7 score. The parameters assessed included positive moodresponses (alert, friendly, full of energy, well/good feelings) and neg-ative mood responses (angry, irritable, sad, tired, nervous). Weeklyaverage scores were calculated. The details of this questionnaire weredescribed previously (24–26).Skin irritation assessment were measured at every clinic visit usingthe following scale: 0  no erythema, 1  minimal erythema, 2  moderate erythema with sharply defined borders, 3  intense erythemawith or without edema, and 4  intense erythema with edema and blistering/erosion. When subjects developed skin irritation, pretreat-ment with corticosteroid cream was advised. The Prostate SymptomScorewereassessedondays0,30,and90usingtheInternationalProstateSymptom Score (I-PSS) (27, 28). The maximum score for I-PSS is 35.Complete blood counts, serum clinical chemistry, and serum PSA levelswere measured at each center’s laboratory.The study protocol was approved by the institutional review boardof each study center. Written consent was obtained from each subject.  Statistical analyses Descriptive statistics for each parameter were calculated. All data inthe figures and tables show the treatment mean (  sem ) by day for eachof the three groups of subjects based on the treatment pattern from days0–90 ( left panels ) and for each of the five groups from days 91–180 ( right panels ). However, as the final treatment groups (five groups) for thesubjects using T gel were no longer randomized, between-group com-parisons were made only up to day 90 using the srcinal treatmentassignments, 50 or 100 mg T gel or T patch, as the independent groups.Theprimarymodelforanalysisofthevariableswasatwo-wayANOVAmodel,includingallsubjectsasagroupwithonerepeatedmeasureeffect(study day), one independent group effect (treatment), and their inter-action. If none of the effects was statistically significant, then no furthertestingwasperformed.Ifthestudydayeffectwassignificant,thenitwastested using contrasts comparing the results at follow-up visits to base-line measurements. If the treatment effect was significant, then groupmeans were compared using pairwise methods. If the interaction wassignificant, then both the more detailed evaluation of study day withintreatment and treatment differences within study day was made.Changesinthesexualfunctionvariableswereanalyzedusingequivalentrepeated measures models for categorical variables. Analyses of changefrom days 0 to 180 within treatment groups were made within each ofthe five groups based on pattern using paired t tests or Wilcoxon’s test.Comparisons resulting in a P  0.05 were considered statistically sig-nificant. SAS version 6.12 (SAS Institute, Inc., Cary, NC) was used forall analyses. Results  Subjects Two hundred and twenty-seven subjects were initiallyrandomized to 73 in the T gel 50 mg/day (in 5 g gel), 78 inthe T gel 100 mg/day (in 10 g gel), and 76 in the T patchgroups, respectively. At 90 days, dose adjustments weremade in the T gel groups based on the preapplication serumT levels on day 60. Twenty subjects in the 50 mg/day T gelgroup had the T gel dose increased to 75 mg/day, and 20 inthe T gel 100 mg/day group had the T gel dose reduced to75 mg/day. There were 3 patients in the T patch group whowere switched to 50 mg/day T gel because of patch intol-erance,one100mg/dayTgelsubjectwasadjustedtoreceive50 mg/day, and one 50 mg/day T gel subject had the doseadjusted to 25 mg/day. The number of subjects enrolled indays 91–180 of the study consisted of 51 continuing 50 mg/day T gel, 40 receiving 75 mg/day T gel, 52 receiving 100mg/day T gel, and 52 continuing on the patch.T patch compliance, assessed by counting returnedpatches, was 65% during days 1–90 and 74% during days91–180 days. The T gel compliance rate, assessed by theweight of the T gel bottles, was over 93% and 96% for 50 and100 mg T gel groups, respectively, during days 1–90 andremained at that level from days 91–180. TABLE 1. Average serum T levels (during 24 h) after transdermal application of T gel or patch T patch T gel (50 mg/day) T gel (100 mg/day) Day 0 8.22  0.55 a 8.22  0.53 8.60  0.55Day 90 14.46  0.68 19.17  1.06 27.46  1.12 T patch T gel 50 T gel 50 3  75 b T gel 100 3  75 b T gel 100 Day 180 14.14  0.88 19.24  1.18 15.60  3.68 25.79  2.55 24.72  1.05 a Mean  SE . b In subjects receiving T gel, if serum T on day 60 is higher or lower than the normal range, the dose is adjusted downward from 100 mgto 75 mg/day or upward from 50 to 75 mg/day on day 91, respectively. EFFICACY OF T GEL IN HYPOGONADAL MEN 2841  by on November 11, 2008 jcem.endojournals.orgDownloaded from    Serum T concentrations Atthescreeningvisit,meanserumTconcentrations(singlesample) were 5.9  0.36, 4.1  0.51, 7.7  0.27, and 8.0  0.51nmol/L, respectively, in the subjects diagnosed with pri-mary,secondary,normogonadotropic,andaging-relatedhy-pogonadism. At baseline (day 0) mean serum T concentra-tions (average values over 24 h) were 7.9  0.52, 4.9  0.55,10.5  0.43, and 10.7  0.80 nmol/L in the subjects withprimary, secondary, normogonadotropic, and aging-relatedhypogonadism. These differences in baseline serum T levelswere observed in all three treatment groups. Although base-line serum T levels were different in the four hypogonadalsubcategories, the responses of sexual function, musclestrength, and body composition to T treatment were inde-pendent of initial diagnostic classification. Average serum Tconcentrations over 24 h at baseline (day 0) and on days 90and 180 after treatment are summarized in Table 1. Theseresults have been previously reported as a detailed pharma-cokinetic report (see Footnote 1). After transdermal applica-tion on day 90, the average serum T concentration in the 100mg/day T gel group was 1.4-fold higher than that in the 50mg/day T gel group and 1.9-fold higher than that in the Tpatch group. Dose adjustment from 50 to 75 mg/day did notincrease the average serum T concentration, but decreasingthe dose from 100 to 75 mg/day lowered the average serumT concentration (see Footnote 1).  Sexual function (Fig. 1) Atbaseline,thesexualmotivationandperformancescoreswere similar across groups. After transdermal T treatment, F IG . 1. Effects of transdermal T geland T patch treatment on sexual moti- vation ( top ) and performance ( bottom )summary scores in hypogonadal men.In this and subsequent figures, the left panel shows the subjects initially ran-domized to three treatment groups: Tpatch ( Œ ), 50 mg/day T gel ( f ), and 100mg/day T gel ( F ). Based on the serum Tlevels,thedoseofTgelwasadjustedupor down (from days 91–180) to 75 mg/ day if the serum T level was below orabove the adult male range, respec-tively. The right panel shows the sub- jects in the final five treatment groups(three srcinal treatment groups plusthe additional two groups of subjectswhose T gel doses were adjusted): 50 to75 mg/day T gel (  ) and 100 to 75 mg/ day T gel ( E ). 2842 WANG ET AL. JCE & M ã 2000 Vol 85 ã No 8  by on November 11, 2008 jcem.endojournals.orgDownloaded from 
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