A Randomized, Doubleblind, Placebocontrolled Trial on the Effect

Home , Jenapharm

A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male BJUI Symptoms scale BJU INTERNATIONAL Christopher C.K. Ho , Seng Fah Tong * , Wah Yun Low† , Chirk Jenn Ng ‡ , Ee Ming Khoo‡ , Verna K.M. Lee § , Zulkiﬂ i Md Zainuddin and Hui Meng Tan† ¶ Departments of Surgery and * Family Medicine, Universiti Kebangsaan Malaysia Medical Centre, † Medical Research and Development Unit and ‡ Department of Primary Care Medicine, Faculty of Medicine, University of Malaya , § Department of Family Medicine, Faculty of Medicine, International Medical University, Kuala Lumpur and ¶ Sime Darby Medical Centre, Selangor, Malaysia Accepted for publication 9 August 2011

Study Type – Therapy (RCT) What’ s known on the subject? and What does the study add? Level of Evidence 1b Testosterone defi ciency syndrome can be treated with testosterone replacement in the form of injectable, transdermal, buccal and oral preparations. Long-acting i.m. testosterone undecanoate 1000 mg, which is given at 10− 14 week intervals, has been OBJECTIVE shown to be adequate for sustaining normal testosterone levels in hypogonadal men. This study confi rms that long-acting i.m. testosterone undecanoate is effective in • To evaluate the effect of i.m. injection of improving the health-related quality of life in men with testosterone defi ciency testosterone undecanoate 1000 mg over 12 syndrome as assessed by the improvement in the Aging Male Symptoms scale. months on the Aging Male Symptom (AMS) Testosterone treatment can be indicated in men who have poor health-related quality scale scores in men with testosterone of life resulting from testosterone defi ciency syndrome. defi ciency syndrome (TDS).

RESULTS than in the placebo group (− 2.8 vs − 1.2, PATIENTS AND METHODS P = 0.03; and − 3.2 vs − 1.8, P = 0.016). • Improvement in the total AMS score • The difference in change between the • A total of 120 men > 40 years old was signifi cantly greater in the treatment randomized groups for the sexual domain with TDS (total testosterone < 12 nmol/L group than in the placebo group (F: 4.576, scores followed the same trend, though the and total AMS scores ≥ 27) were P = 0.017) over the 48-week period. difference was not signifi cant. randomized into i.m. injection of either • The mean (SD ) total AMS score was placebo or testosterone undecanoate 38.46 (11.85) at baseline and 33.59 (1.69) CONCLUSION 1000 mg. at 48 weeks for the placebo group, • In all, 56 and 58 participants from the and 41.73 (12.73) at baseline and 32.61 • Long-acting testosterone is effective in active treatment and placebo groups, (9.67) at 48 weeks for the treatment improving health-related quality of life as respectively completed the study. group. assessed by the AMS scale in men with TDS. • An i.m. injection of either placebo or • The mean change in the total AMS score testosterone undecanoate 1000 mg was was − 12.6% in the placebo group and KEYWORDS given at weeks 0, 6, 18, 30 and 48. − 21.9% in the treatment group. • Self-administered AMS questionnaires • The mean psychological and testosterone defi ciency , hypogonadism , were completed at weeks 0, week 18 and somatovegetative domain scores decreased testosterone undecanoate , injectable , week 48. signifi cantly more in the treatment group long-acting , AMS scale

INTRODUCTION healthcare issues of the 21st century are have reported that there is a consistent those related to aging and, with regard to decline in total testosterone levels at a rate Men ’ s health has become a key concern and men ’ s health, the aging male. Worldwide, of 1 – 2% per year starting from a man ’ s late challenge for healthcare professionals and the elderly population is growing faster than 30 s [ 1 ] .Testosterone deﬁ ciency syndrome policy makers. Amongst the most prominent any other age group. Observational studies (TDS) in adult males is associated with

numerous physical, psychological and sexual treatment) decreased after 12 weeks of RESEARCH TOOL symptoms. Testosterone replacement treatment, indicating a signifi cant therapy has been shown to improve improvement in symptoms and in HRQoL. We used the AMS scale, which measures symptoms as well as health-related quality These authors also showed that AMS severity of subjectively perceived complaints of life (HRQoL) related to TDS [ 2,3 ] . scale scores can predict subjective clinical in each of the 17 items on a scale of 1 – 5, a expert opinion on the effi cacy of the higher score meaning greater symptom There are many tools for the measurement treatment. severity [ 16 ] . The composite scores for each of HRQoL in hypogonadal men. These of the domains is based on adding up the include the Aging Male Symptom (AMS) Recently, a new preparation of long-acting scores of the items of the respective scale, the WHO quality-of-life scale, the injectable testosterone undecanoate domains. The composite score (total score) 12- and 36-item short-form health surveys, (Nebido ® , Bayer Schering, Leverkusen, is the sum of the domain scores. The and the androgen defi ciency in adult males Germany) has been brought onto the cumulative score can range from 17 to 85 (ADAM) scale. The AMS scale was originally market. This undecanoate ester formulation points. The severity of the symptoms are developed in Germany in 1991 [ 4 ] , with the of testosterone with castor oil, extends the defi ned as: no/low (17 – 26 points), mild aim of assessing aging symptoms among maximum dosing interval by about fourfold (27– 36 points), moderate (37 – 49 points) and groups of males under different conditions, compared with that of other injectable severe (≥ 50 points). The three domains evaluating the severity of symptoms over formulations of testosterone [ 17 ] . Studies of the AMS scale are psychological, time, and measuring changes before and in Europe have reported that 1000 mg somatovegetative and sexual. Heinemann after androgen replacement therapy [ 5 ] . The testosterone undecanoate as an i.m. et al . [ 6 ] translated the original German development of the AMS scale at that time injection at 10– 14-week intervals is AMS scale into the culturally adapted was in response to the lack of fully adequate for sustaining normal testosterone English-language scale and showed that standardized scales to measure the severity levels in hypogonadal men [ 18 ] . Similar there was cross-cultural equivalence. of aging symptoms and their impact on fi ndings were found in studies done in Asia HRQoL in males, specifi cally [ 6,7 ] . and Australia. SUBJECTS

Many studies have shown that the AMS The objective of the present study was to Participants were recruited by phone-call scale correlates with testosterone levels and investigate the effect of i.m. injection of invitation to form a cohort of randomly predicts hypogonadism [ 8 – 13 ] . It also meets testosterone undecanoate 1000 mg over 12 selected men aged ≥ 40 years from an urban the requirements of clinical utility and months on the AMS scores for Malaysian community. Participants, who gave written outcomes sensitivity [ 8 ] . Heinemann et al . men with low serum testosterone levels. informed consent to participate, underwent [ 8 ] have also convincingly shown that the initial screening tests which included an AMS scale has the ability to measure early morning total testosterone test and treatment effects on HRQoL across the full PATIENTS AND METHODS the completion of the AMS questionnaire. If range of severity of complaints. In addition, the participant ’ s total testosterone level was the results of the AMS scale can predict STUDY DESIGN < 12 nmol/L and total AMS score was ≥ 27 subjective clinical expert opinion on (corresponding to mild to severe symptoms treatment effi ciency [ 14 ] . Weak correlations The present study was a double-blind, of TDS), he was called back for a formal were also reported between AMS scale parallel, randomized, placebo-controlled trial screening visit to establish whether he domain scores (psychological, somatic and with an allocation ratio of 1:1. It was fulfi lled the study criteria. The inclusion sexual) and testosterone levels [ 9,10 ] . approved by the Medical Ethics Committee, criteria were: age 40 – 70 years; having University of Malaya Medical Centre at least ‘ mild ’ symptoms for all three There are very few studies reporting the (approval number: 631.11) and was AMS domains (scores of ≥ 9 in the effect of testosterone therapy using the conducted in accordance with the ethical somatovegetative, ≥ 6 in the psychological AMS scale. In one of the largest placebo- principles of the Malaysian Good Clinical and ≥ 6 in the sexual domain) or total AMS controlled studies of testosterone therapy in Practice Guidelines that are based on the scores ≥ 27; having early morning total late-onset hypogonadism, it was found that Declaration of Helsinki and the International testosterone level < 12 nmol/L on two the effect of oral testosterone undecanoate Conference on Harmonization guideline E6: occasions; and a PSA level of < 4 ng/mL. The (Andriol TestocapsTM , Merck, Sharp and Good Clinical Practice. The primary endpoint exclusion criteria were: uncontrolled Dohme, Whitehouse Station, NJ, USA) on of the present study was treatment effect diabetes mellitus (HbA1c > 8%); clinical total AMS scores during 12 months of on AMS scores. The secondary endpoints hypothyroidism or hyperthyroidism; treatment was not signifi cantly different were adverse events, anthropometric haematocrit > 55%; known prostate cancer; from placebo, except for sexual symptoms, changes and changes in laboratory blood androgen-dependent carcinoma of the male where a modest improvement was reported results, i.e fasting lipid, fasting blood mammary gland; past or present liver with oral testosterone undecanoate 160 mg/ glucose, liver function tests, total tumours; other signifi cant medical day [ 15 ] . In a study by Moore et al . [ 16 ] on testosterone and serum hormone binding conditions (American Society of an injectable testosterone enanthate product globulin levels, and International Prostate Anaesthetists score > 3) or psychological (Testosterone-Depot, Jenapharm, Jena, Symptoms Score (IPSS) and 12-item conditions (psychosis, schizophrenia or Germany), it was found that the increased short-form health survey (SF-12) manic depression); or clinically diagnosed mean total AMS score at baseline (before questionnaire results. sleep apnoea. Participants were also

FIG. 1. • Recruitment of participants 48 weeks as measured by the total AMS Excluded, n = 164 Enrolment and randomization of score (at screening, 18 and 48 weeks) and Invited, n = 284 • S. Ts > 12 nmol/L (104) study participants. MI, • Uninterested (26) individual domain scores. The secondary myocardial infarction. • comorbidities (26) endpoints were adverse events, = = < Treatment, n 60 Placebo, n 60 • AMS 27 (7) anthropometric changes, laboratory blood • Age > 70 (1) results, and IPSS and SF-12 scores. The 1 died (MI) 3 withdrew: 1 died (MI) secondary endpoints will be reported in a 1 withdrew: • chest pain (1) separate paper. • chest pain • Relocated (2) SAFETY MONITORING AND WITHDRAWAL = = Completed, n 56 Completed, n 58 Participants ’ safety was monitored by scheduled assessment and self-reporting of excluded if they were on medication known medication, prepared in an identical form. adverse events. Scheduled assessment to interfere with testosterone metabolism, Each serial number with its code for either included a clinical assessment (with a repeat had hypersensitivity to the active substance placebo or active medication was kept in a DRE at week 30) for every visit and or excipients of the study medication, sealed envelope. The supplier of the monitoring of biochemistry profi les at weeks testosterone treatment (transdermal, oral or intervention packages and the envelopes 18 and 48. Every participant was asked to i.m.) within the previous 6 months or was not involved in any stage of the trial. report any symptom after commencement testosterone implants within the previous Hence, the participants, clinical investigators of the intervention. Mandatory reviews and 12 months. and trial site manager were all blinded to consideration for withdrawal from the study the types of intervention until the trial were undertaken if any of the following SAMPLE SIZE period was over, when only then, the codes criteria were noted: a rise in PSA level of were revealed. Revealing the codes within ≥50% from the baseline or to > 4 ng/mL, any The sample size was calculated based on the the trial period was permitted only when clinical abnormality on DRE, a signifi cant improvement in AMS score, the primary there was an occurrence of serious adverse worsening of IPSS, a rise in haematocrit of endpoint of the study. With a two-sided α event. > 55% or any report of adverse event. value of 0.05 and a power of 80%, a sample size of 60 subjects per arm would be able to Repeat physical assessments (except DRE) STATISTICAL ANALYSES detect a 4.64 reduction in the AMS scores were done for every encounter with from the baseline (30.8) at 48 weeks after participants, at weeks 6, 18, 30, 42 and 48 Descriptive statistics were used for baseline intervention with a population SD of 8.98 after the fi rst intervention. Serum total demographics, outcome measurements and [ 19 ] . This sample size would be able to testosterone and biochemistry profi les adverse events. In comparing the baseline detect a minimum point difference of 8.78 were repeated at weeks 18 and 48; DRE, profi les and adverse events between the in HRQoL score with an estimated administration of IPSS, AMS and SF-12 active treatment and placebo groups, exact population SD of 17 [ 20 ] . questionaires was done at weeks 18 and 48. contingency table methods were used for The serum testosterone results were not categorical data, and an independent sample STUDY PROTOCOL revealed to participants or investigators t -test was used for continuous data. until the trial period was over. All laboratory Responses to outcome measures for each The study was conducted at a tertiary investigation was carried out by a single group were calculated as the difference medical centre in Malaysia. All participants laboratory to maintain standardization of from their baseline values. The effects of who fulfi lled the study criteria were measurement and reference points. active treatment on HRQoL scores were assessed by clinical investigators (certifi ed estimated using repeated measure ANOVA medical doctors) to establish their baseline INTERVENTION by including the intervention x time profi les, which included a physical interaction terms. The two-sided level of assessment of their weight, height, blood All participants received fi ve injections from signifi cance (P ) was set at 0.05. Data pressure and prostate (by DRE), a recording the package allocated to them at weeks 0, 6, analysis was done using the Statistical of current medications and concurrent 18, 30 and 42 after formal enrolment. Package for the Social Sciences (SPSS Inc., illnesses, recording biochemistry profi les The active treatment was 1000 mg of Chicago IL, USA) version 15. (total testosterone, haematocrit and serum testosterone undecanoate in 4 mL of castor PSA levels and liver function test results) oil, and placebo was just castor oil of the and recording their IPSS, and AMS scale and same volume and appearance. The injection RESULTS SF-12 questionnaire scores. was given as slow bolus i.m. at the gluteal region over 1 min. The present study was carried out between After reviewing the baseline assessment May 2008 and February 2010. A total of 284 results, each participant received an OUTCOME MEASUREMENTS men were invited to participate in the study intervention package indexed with a serial ( Fig. 1 ). After excluding 164 men, 120 men number at visit 1. Each package contained The primary endpoint was the improvement were recruited and randomized equally into fi ve vials of either all placebo or active in symptoms and HRQoL from baseline to the treatment and placebo groups, but only

FIG. 2. Comparison of serum testosterone levels in TABLE 1 Baseline characteristics of the placebo and testosterone undecanoate groups the testosterone undecanoate group vs the placebo group from baseline to week 48 using repeated Testosterone measure ANOVA . Placebo undecanoate Mean (SD ) body mass index, kg/m2 28.2 (4.5)30.4 (5.2) (F = 62.001, P < 0.011) Mean (SD ) waist circumference, cm 96.3 (10.7) 102.7 (12.3) 25.0 Placebo Mean (SD ) systolic blood pressure, mmHg 127.9 (10.4) 132.5 (14.6) 20.0 n = 58 15.0 Mean (SD ) diastolic blood pressure, mmHg 81.4 (6.4) 84.1 (7.4) Testosterone 10.0 undecanoate Mean (SD ) total testosterone level (nmol/L) 9.1 (1.8) 8.9 (2) 5.0 n = 56 Mean (SD ) serum hormone binding globulin level, nmol/L 20.9 (6.9) 21.6 (7) 0.0 Baseline week-18 week-48 Mean (SD ) total AMS score 38.2 (11.9) 42.9 (13.2) (week-0) somatic subscale 15.8 (5.4) 17.6 (5.6) Serum Testosterone, nmol/L Serum Testosterone, Period after the first injection psychological subscale 10.0 (4.0) 11.6 (4.5) sexual subscale 12.4 (4.3) 13.7 (4.4) Ethnicity , n (%) Malay 15 (25.0) 16 (26.7) 56 participants in the treatment and 58 in the placebo group completed the study. In Chinese 25 (41.7) 25 (41.7) the treatment group, one patient died from Indian 17 (28.3) 17 (28.3) myocardial infarction while three withdrew Others 3 (5.0) 2 (3.3) from the study (one because of chest pain Comorbidities, n (%) and another two because of relocation to Hypertension 20 (3.3) 29 (48.3) another state). In the placebo group, one Diabetes mellitus 9 (15.0) 14 (23.3) patient died from myocardial infarction and Dyslipidemia 20 (33.3) 22 (36.7) another withdrew because of chest pain. The Coronary artery disease 3 (5.0) 6 (10.0) two patients who withdrew because of myocardial infarction had a history of ischaemic heart disease. The other two who FIG. 3. Comparison of changes in the total AMS and domain scores in the testosterone undecanoate group withdrew because of chest pain refused vs the placebo group. further investigation. week 18 week 48 Table 1 shows the baseline characteristics of the treatment and placebo groups. Despite Psychological AMS Somatovegetative Sexual AMS Total AMS the randomization there were signiﬁ cant Domain Score Domain Score Domain Score Testosterone Testosterone Testosterone Testosterone differences between the two groups in the Placeboundecanoate Placeboundecanoate Placeboundecanoate Placebo undecanoate following: body mass index, waist .00 circumference, diastolic blood pressure, total −1.00 AMS score and the AMS psychological −2.00 domain score. −3.00 = P = (F = 2.512, P = 0.092) The participants ’ mean (SD ) age was 53.4 −4.00 (F 3.922, 0.030) (7.4) years in the treatment group and 53.0 −5.00 (F = 26.174, P < 0.001) (8.2) years in the placebo group. At 48 − weeks, administration of testosterone 6.00 undecanoate 1000 mg signiﬁ cantly −7.00 increased mean serum testosterone levels −8.00 from 8.9 to 23.8 nmol/L compared with −9.00 placebo, which increased them from 9.1 to − 11.2 nmol/L (F = 62.001, df = 2.000, P < Change in AMS scores from baseline 10.00 (F = 4.576, P = 0.017) 0.001 [ Fig. 2 ] ).

The improvement in the total AMS score was signifi cantly greater in the treatment the 48-week period, the mean AMS difference in the change in sexual subscale arm compared with the placebo arm (F: psychological and somatovegetative domain scores between the two groups ( Table 2 ). 4.576, df = 2.000, P = 0.017) over the scores decreased signifi cantly more in the 48-week period ( Fig. 3 ). The change in mean testosterone undecanoate 1000 mg arm DISCUSSION total AMS score was − 12.6% in the placebo than in the placebo arm (− 2.8 vs − 1.2, group and − 21.9% in the testosterone P = 0.03 and − 3.2 vs − 1.8, P = 0.016, The present study showed that long-acting undecanoate 1000 mg group. Similarly, over respectively), but there was no signifi cant testosterone undecanoate treatment

TABLE 2 Comparison of total AMS scores and AMS domain scores of the placebo and testosterone undecanoate groups

Repeated measure AMS score Intervention group Baseline Week 18 Week 48 ANOVA , FP Mean (SD ) total AMS sum score Placebo 38.46 (11.85) 34.66 (10.06) 33.59 (10.69) 4.576 0.017 Testosterone undecanoate 41.73 (12.73) 32.73 (9.71) 32.61 (9.67) Mean (SD ) psychological domain score Placebo 10.03 (3.98) 8.88 (3.38) 8.81 (3.30) 3.922 0.03 Testosterone undecanoate 11.11 (4.30) 8.61 (3.41) 8.27 (3.05) Mean (SD ) somatovegetative domain score Placebo 15.93 (5.34) 14.58 (4.58) 14.12 (5.05) 26.174 < 0.001 Testosterone undecanoate 17.18 (5.52) 13.43 (4.67) 13.89 (4.48) Mean (SD ) sexual domain score Placebo 12.49 (4.29) 11.20 (3.42) 10.66 (3.95) 2.512 0.092 Testosterone undecanoate 13.45 (4.34) 10.70 (3.63) 10.45 (3.69)

signifi cantly improved total AMS scores. improvement in the AMS sexual domain The interesting thing to note in the Italian On analysis of the AMS domain scores, score. Another difference to note is that the study was that those on oral testosterone we found that the psychological and present study was a randomized controlled undecanoate for 6 months did not show somatovegetative scores also improved trial comparing testosterone undecanoate signifi cant changes in all AMS scores, signifi cantly with treatment. The sexual against placebo. We also assessed the AMS but when they switched to the i.m. domain scores also improved with score over a longer period of time (48 preparation, the total and somatovegetative testosterone undecanoate treatment but the weeks) than the authors of the Korean study domain scores improved signifi cantly. The improvement was not signifi cant. Cultural (24 weeks). sexual and psychological domain score factors could have infl uenced the outcome changes were not signifi cant, although the as the AMS questionnaire could have been The Russian study was a randomized, sexual domain score did show an interpreted differently by the Malaysian placebo-controlled trial assessing the effects improvement. population in the present study as compared of testosterone supplementation on to a Western population. depressive symptoms and sexual dysfunction In the study from Thailand, the scores in men with both hypogonadism and of all domains of the AMS questionnaire The present fi ndings concurred with four metabolic syndrome [ 21 ] . Similarly to the decreased with i.m. testosterone other studies from Korea, Russia, Italy and present study, the testosterone undecanoate undecanoate but only the psychological Thailand, which included the assessment of group had slightly higher AMS scores at domain score improvement was signifi cant AMS score after treatment with testosterone baseline but the difference was not ( P = 0.044) [ 23 ] . The improvement in the undecanoate. signifi cant. In the present study, the sexual and somatovegetative domain scores difference was signifi cant. In the Russian were not signifi cant (P = 0.200 and P = In the Korean study [ 3 ] , the main aim was to study, as compared with placebo, there were 0.071, respectively). The present study, assess the effi cacy and safety of long-acting improvements in total AMS score over time. however, was not a randomized prospective injectable testosterone undecanoate. The time x group effect was largely trial. Secondary effi cacy was measured using AMS negligible after adjustment for age, and scores. The participants ’ characteristics were baseline body mass index, smoking status, In the present study, adverse coronary similar to those in the present study; total testosterone level, and prevalent events were noted but at the beginning of participants were Asian and their mean (SD ) diabetes mellitus. The AMS subscale scores the study period, no adverse coronary events age was 54 (9.6) years. In the Korean study, were not analysed. after treatment with testosterone were however, if the treating physician felt that reported in the literature. A history of there was no clinical improvement in The Italian study was a randomized, ischaemic heart disease was, therefore, not erectile function within 18 weeks of the double-blind, double-dummy study that one of our exclusion criteria. Basaria et al. treatment period, phosphodiesterase-5 investigated the effi cacy and safety of oral [ 24 ] reported the adverse coronary events inhibitor medication (vardenafi l 20 mg) was and i.m. testosterone undecanoate in associated with testosterone only in July used along with testosterone replacement hypogonadal men with metabolic syndrome 2010, after our study had concluded. therapy from the 18th week to the end [ 22 ] . Only 32 men were randomized to Needless to say, the present study adds to of the follow-up period. As a result, receive i.m. testosterone undecanoate. In the evidence that adverse coronary events 17 patients were prescribed concomitant contrast to the present study, there was are associated with testosterone. phosphodiesterase-5 inhibitor medication signifi cant improvement in the sexual from 18 – 24 weeks. This could have domain subscores with i.m. testosterone In conclusion, long-acting testosterone is improved the AMS sexual domain score undecanoate at 6 and 12 months. The effective in improving the HRQ oL in men signifi cantly compared with the present present study also showed an improvement with TDS as assessed by improvement in results, which showed a nonsignifi cant in this domain but this was not signifi cant. AMS scale scores. Testosterone treatment

can be indicated in men who have poor androgen defi ciency? Aging Male 2004 ; 18 Schubert M , Minnemann T , Hubler D HRQoL resulting from TDS. 7 : 211 – 8 et al . Intramuscular testosterone 9 Morley JE , Perry HM , Kevorkian RT , undecanoate: pharmacokinetic aspects Patrick P. Comparison of screening of a novel testosterone formulation CONFLICT OF INTEREST questionnaires for the diagnosis of during long-term treatment of men with hypogonadism . Maturitas 2006 ; 53 : hypogonadism . J Clin Endocrinol Metab None declared. This study was supported 424 – 9 2004 ; 89 : 5429 – 34 fi nancially by Bayer Schering Pharma. 10 Kratzik CW , Reiter WJ , Riedl AM et al . 19 Tan HM , Khoo EM , Ng CJ , Low WY , Hormone profi les, body Ma ß Index and Yap PK , Tan WS. The Aging Males ’ aging male symptoms – results of the Symptoms ’ Scale (AMS) – a general REFERENCES androx Vienna municipality study . Aging screening instrument for aging males ’ Male 2004 ; 7 : 188 – 96 health problem? Eur Urol 2007 ; ( Suppl ) 1 Feldman HA , Longcope C , Derby CA 11 Itoh N , Hisasue S , Kato R et al . 6 : 107 et al . Age trends in the level of serum Comparison of Morley ’ s ADAM 20 Sararaks S , Azman AB , Low LL et al . testosterone and other hormones in questionnaire and Heinemann ’ s Aging Validity and reliability of the SF-36: the middle-aged men: longitudinal results Male Symptoms (AMS) rating scale to Malaysian context . Med J Malaysia 2005 ; from the Massachusetts male aging screen andropause symptoms in 60 : 163 – 79 study . J Clin Endocrinol Metab 2002 ; 87 : Japanese males . Aging Male 2004 ; 7 : 49 21 Giltay EJ , Tishova YA , Mskhalaya GJ , 589 – 98 12 Soh J , Ishida Y , Naito Y et al . Gooren LJG , Saad F , Kalinchenko SY . 2 Yassin A , Saad F . Treatment of sexual Correlations of AMS score, depression Effects of testosterone supplementation dysfunction of hypogonadal patients score and hormonal levels with the on depressive symptoms and sexual with long acting testosterone manifestation of partial androgen dysfunction in hypogonadal men with undecanoate (Nebido ® ) . World J Urol decline in the aging male (PADAM) . the metabolic syndrome . J Sex Med 2006 ; 24 : 639 – 44 Aging Male 2004 ; 7 : 83 2 0 1 0 ; 7 : 2572 – 82 3 Moon DG , Park MG , Lee SW et al . The 13 Jankowska EJ , Szklarska A , 22 Aversa A , Bruzziches R , Francomano D , effi cacy and safety of testosterone Lopuszanska M , Medras M . Hormonal Spera G , Lenzi A . Effi cacy and safety of undecanoate (nebido ® ) in testosterone determinants of andropausal symptoms two different testosterone undecanoate defi ciency syndrome in korean: a in Polish men . Aging Male 2004 ; 7 : 2 1 formulations in hypogonadal men with multicenter prospective study . J Sex Med 14 Heinemann LA , Moore C , Dinger JC , metabolic syndrome . J Endocrinol Invest 2 0 1 0 ; 7 : 2253 – 60 Stoehr D . Sensitivity as outcome 2 0 1 0 ; 33 : 776 – 83 4 Heinemann LAJ , Zimmermann T , measure of androgen replacement: the 23 Permpongkosol S , Tantirangsee N , Vermeulen A , Thiel C. A new aging AMS scale . Health Qual Life Outcomes Ratana-olarn K. Treatment of 161 men male ’ s symptoms ’ (AMS) rating scale . 2006 ; 4 : 23 with symptomatic late onset Aging Male 1999 ; 2 : 105 – 14 15 Legros JJ , Meuleman EJ , Elbers JM , hypogonadism with long-acting 5 Badia X , Herdman M. The importance Geurts TB , Kaspers MJ , Bouloux PM . parenteral testosterone undecanoate: of health-related quality-of-life data in Study 43203 Investigators. Oral effects on body composition, lipids, and determining the value of drug therapy . testosterone replacement in psychosexual complaints . J Sex Med Clin Ther 2001 ; 23 : 168 – 75 symptomatic late-onset hypogonadism: 2 0 1 0 ; 7 : 3765 – 74 6 Heinemann LAJ , Saad F , Thiele K , effects on rating scales and general 24 Basaria S , Coviello AD , Travison TG Wood-Dauphinee S . The Aging safety in a randomized, placebo- et al . Adverse events associated with Males ’ Symptoms (AMS) rating scale. controlled study . Eur J Endocrinol 2009 ; testosterone administration . N Engl J Cultural and linguistic validation into 160 : 8 2 1 – 3 1 Med 2 0 1 0 ; 363 : 109 – 22 English . Aging Male 2001 ; 3 : 14 – 16 Moore C , Huebler D , Zimmermann T , 22 Heinemann LAJ , Saad F , Thai DM. The Correspondence: Christopher C. K. Ho, 7. Heinemann LAJ , Saad F , P ö ll ä nen P . aging males ’ symptoms scale (AMS) as Department of Surgery, Universiti Measurement of quality of life specifi c outcome measure for treatment of Kebangsaan Malaysia Medical Centre, Jalan for aging males . Schneider HPG eds, In androgen defi ciency . Eur Urol 2004 ; 46 : Yaacob Latif, Bandar Tun Razak, 56000 Hormone Replacement Therapy and 80 – 7 Cheras, Kuala Lumpur, Malaysia. Quality of Life , London, New York, 17 Morgentaler A , Dobs AS , Kaufman JM e-mail: [email protected] . Washington : Parthenon Publishing et al . Long acting testosterone Group , 2002 : 63 – 83 undecanoate therapy in men with Abbreviations : AMS , Aging Male Symptoms ; 8 Heinemann LA , Saad F , Heinemann K , hypogonadism: results of a TDS , testosterone defi ciency syndrome ; Thai DM. Can results of the AMS scale pharmacokinetic clinical study . J Urol HRQoL , health-related quality of life ; SF-12 , predict those of screening scales for 2008 ; 180 : 2307 – 13 12-item short-form health survey.