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Original Research |

Effect of Testosterone Replacement on Response to Sildenafil Citrate in Men With Erectile Dysfunction: A Parallel, Randomized Trial

Matthew Spitzer, MD; Shehzad Basaria, MD; Thomas G. Travison, PhD; Maithili N. Davda, MPH; Amanda Paley, BA; Beth Cohen, MD; Norman A. Mazer, MD, PhD; Philip E. Knapp, MD; Samson Hanka, MD; Kishore M. Lakshman, MD; Jagadish Ulloor, PhD; Anqi Zhang, PhD; Katie Orwoll, BS; Richard Eder, BA; Lauren Collins, RNP; Nurahmed Mohammed, MD; Raymond C. Rosen, PhD; Leonard DeRogatis, PhD; and Shalender Bhasin, MD
[+] Article and Author Information

From the Boston University School of Medicine, Boston Medical Center, and Boston University School of Public Health, Boston, and New England Research Institutes, Watertown, Massachusetts; F. Hoffmann-La Roche, Basel, Switzerland; and Johns Hopkins University, Baltimore, Maryland.

Acknowledgment: The authors thank the members of the Data and Safety Monitoring Board (Abraham Morgentaler, MD [Chair]; Leonard Marks, MD; Andre Guay, MD; and Ridwan Shabsigh, MD) and the staff of the Boston University Clinical and Translational Science Institute for their help with these studies.

Grant Support: By the National Institute of Child Health and Human Development (5R01HD047722). Additional support was provided by the Boston University Clinical and Translational Science Institute (1UL1RR025771) and Boston Claude D. Pepper Older Americans Independence Center (grant 5P30AG031679 from the National Institute on Aging).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0805.

Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Bhasin (e-mail, bhasin@bu.edu). Data set: Portions available through written agreements with Dr. Bhasin (e-mail, bhasin@bu.edu) and the research sponsor (National Institute of Child Health and Human Development).

Requests for Single Reprints: Matthew Spitzer, MD, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118; e-mail, matthew.spitzer@bmc.org.

Current Author Addresses: Drs. Spitzer, Basaria, Travison, Cohen, Knapp, Hanka, Lakshman, Ulloor, Zhang, Mohammed, and Bhasin; Ms. Davda; Ms. Paley; Ms. Orwoll; Mr. Eder; and Ms. Collins: Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine and Boston Medical Center, 670 Albany Street, Boston, MA 02118.

Dr. Mazer: F. Hoffmann-La Roche Ltd, Pharma Research and Early Development, Malzgasse 30, 4070 Basel, Switzerland.

Dr. Rosen: New England Research Institutes, 9 Galen Street, Watertown, MA 02472.

Dr. DeRogatis: Maryland Center for Sexual Health, Johns Hopkins University School of Medicine, Suite 140, Building A, 1300 York Road, Lutherville, MD 21093.

Author Contributions: Conception and design: S. Basaria, N.A. Mazer, P.E. Knapp, N. Mohammed, R.C. Rosen, S. Bhasin.

Analysis and interpretation of the data: M. Spitzer, S. Basaria, T.G. Travison, M.N. Davda, N.A. Mazer, S. Hanka, J. Ulloor, A. Zhang, N. Mohammed, R.C. Rosen, S. Bhasin.

Drafting of the article: M. Spitzer, S. Basaria, T.G. Travison, A. Zhang, N. Mohammed, R.C. Rosen, S. Bhasin.

Critical revision of the article for important intellectual content: M. Spitzer, S. Basaria, T.G. Travison, N.A. Mazer, P.E. Knapp, N. Mohammed, R.C. Rosen, S. Bhasin.

Final approval of the article: M. Spitzer, S. Basaria, T.G. Travison, M.N. Davda, N. Mohammed, R.C. Rosen, L. DeRogatis, S. Bhasin.

Provision of study materials or patients: K.M. Lakshman, R. Eder, N. Mohammed.

Statistical expertise: M. Spitzer, T.G. Travison, M.N. Davda, N. Mohammed.

Obtaining of funding: N. Mohammed, S. Bhasin.

Administrative, technical, or logistic support: A. Paley, P.E. Knapp, S. Hanka, K.M. Lakshman, K. Orwoll, R. Eder, L. Collins, N. Mohammed, L. DeRogatis.

Collection and assembly of data: M. Spitzer, S. Basaria, A. Paley, B. Cohen, P.E. Knapp, S. Hanka, K.M. Lakshman, J. Ulloor, K. Orwoll, R. Eder, L. Collins, N. Mohammed, S. Bhasin.


Ann Intern Med. 2012;157(10):681-691. doi:10.7326/0003-4819-157-10-201211200-00004
Text Size: A A A

This article has been corrected. The original version (PDF) is appended to this article as a supplement.

Background: Erectile dysfunction and low testosterone levels frequently occur together.

Objective: To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels.

Design: Randomized, double-blind, parallel, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00512707)

Setting: Outpatient academic research center.

Participants: Men aged 40 to 70 years with scores of 25 or less for the erectile function domain (EFD) of the International Index of Erectile Function, total testosterone levels less than 11.45 nmol/L (<330 ng/dL), or free testosterone levels less than 173.35 pmol/L (<50 pg/mL).

Intervention: Sildenafil dose was optimized, and 140 participants were then randomly assigned to 14 weeks of daily transdermal gel that contained 10-g testosterone for 70 participants and placebo for the remaining 70 participants. All participants were included in the primary analysis, although 10 in the testosterone group and 12 in the placebo group did not complete the study.

Results: At baseline, the 2 groups had similar EFD scores. Administration of sildenafil alone was associated with a substantial increase in EFD score (mean, 7.7 [95% CI, 6.5 to 8.8]), but change in EFD score after randomization did not differ between the groups (difference, 2.2 [CI, −0.8 to 5.1]; P = 0.150). The findings were similar for other domains of sexual function in younger men, more obese men, and men with lower baseline testosterone levels or an inadequate response to sildenafil alone. Frequency of adverse events was similar for testosterone and placebo groups.

Limitation: Whether testosterone could improve erectile function without sildenafil was not studied.

Conclusion: Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels.

Primary Funding Source: National Institute of Child Health and Human Development.

Figures

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Figure 1.

Study flow diagram.

* Percentages may not sum to 100 due to rounding.

† 70 participants were included in the primary analysis.

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Appendix Figure 1.

Change in serum total testosterone, serum free testosterone, hematocrit, and PSA levels with addition of testosterone.

The day of randomization was designated as day 0. The shaded areas represent the sildenafil dose-optimization phase (weeks −7 to 0). Appendix Table 1 displays between-group comparisons for these data. PSA = prostate-specific antigen.

* To convert ng/dL to nmol/L, multiply by 0.0347.

† To convert pg/mL to pmol/L, multiply by 3.467.

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Figure 2.

Change in IIEF scores with sildenafil alone or in combination with testosterone or placebo.

The study included assessments during week −13, a sildenafil dose-optimization phase (weeks −7 to 0) (shaded areas), and a 14-week postrandomization period. The day of randomization was designated as day 0. Higher IIEF scores reflect better erectile function. IIEF = International Index of Erectile Function.

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Appendix Figure 2.

Change in sexual encounter frequency and success using Sexual Encounter Profile diaries with sildenafil alone or in combination with testosterone or placebo.

The day of randomization was designated as day 0. The shaded areas represent the sildenafil dose-optimization phase (weeks −7 to 0).

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Appendix Figure 3.

Change in MSHQ scores with sildenafil alone or in combination with testosterone or placebo.

The day of randomization was designated as day 0. The shaded areas represent the sildenafil dose-optimization phase (weeks −7 to 0). Higher MSHQ scores suggest improved sexual function. MSHQ = Male Sexual Health Questionnaire.

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Figure 3.

Change in quality of life, vitality, affect, and marital relationship with sildenafil alone or in combination with testosterone or placebo.

The day of randomization was designated as day 0. The shaded areas represent the sildenafil dose-optimization phase (weeks −7 to 0). Higher QOL-MED, PGWBI, and DABS scores reflect better quality of life, vitality, and affect, respectively, than lower scores. Lower CARES-SF scores correspond with improved marital interaction. Appendix Table 1 displays the results of the unadjusted linear regression to compare mean changes in each group with missing records treated by using multiple imputation. CARES-SF = Cancer Rehabilitation Evaluation System—Short Form; DABS = Derogatis Affects Balance Scale; PAR = positive affects ratio; PGWBI = Psychological General Well-Being Index; QOL-MED = Quality of Life Specific to Male Erection Difficulties.

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Tables

References

Letters

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Comments

Submit a Comment
Testosterone Measurement
Posted on November 26, 2012
Steven Smoger, MD,FACP
Veterans Affairs, Louisville
Conflict of Interest: None Declared
I read with interest the article by Spitzer et al regarding the combination of testerone replacement with sildenafil. In their discussion they do not comment on the variabilty of testosterone measurements as a potential explanation for the lack of effect of testosterone replacement. From clinical experience this seems to be a common occurrence and has the potential to influence the decision to consider hormone replacement. In addition, the baseline BMI was over 31 in both groups, raising the question of whether the sex hormone binding protein levels could explain the lower average testosterone level. A comment on these would be appreciated.
letter to the editor: testosterone does improve sexual function
Posted on December 10, 2012
Allen D. Seftel, MD, FACS; Geoffrey Hackett MD FRCPI MRCGP
Professor, Cooper Medical School of Rowan University, Cooper University Hospital, CAmden, NJ; Consultant in Andrology, Good Hope Hospital, Birmingham UK and Professor of Men's Health, University o
Conflict of Interest: seftel- consultant to Lilly, Endo, Auxilium, Abbott, Actient, Journal of Urology-editorial boardhackett- speakers bureau-lilly, bayer

To the editor:

The manuscript by Spitzer el al (1), purports to demonstrate that in men with erectile dysfunction (ED), the addition of testosterone replacement therapy to a successful course of PDE5i therapy (oral sildenafil) to further augment male erectile function, was not beneficial. The IIEF-erectile function domain (EFD) was used to assess baseline and post –treatment erectile function, with a mean baseline EFD score of 12.2 for the testosterone arm and 12.0 for the placebo arm. A score of 12.0 places these men into the “moderate” ED category (2).

Sildenafil administration alone was associated with substantial increases in all domains of the IIEF in both groups, including the EFD. Mean EFD score increased by 7.7 for all participants, from 12.1 to 19.8. The mean change of 7.7 is greater than the 5 point change required to verify minimal clinically important differences (MCID) in men with baseline moderate ED (3). The primary analysis indicated that 14-week change in EFD score of 2.2 after randomization (primary outcome) did not differ significantly between the testosterone and placebo groups. In a previous study, sildenafil 50 mg, was found to be similarly efficacious in treating 476 men with ED, as evidenced by a similar rise in EFD score (4). Patients receiving sildenafil 50 mg had an increase in the mean (SD) baseline EF domain score from 12.8 (5.2) to 22.5 (6.6) (P < 0.001), in a placebo-controlled trial (4).

Interestingly, a subset of patients (237 men) titrated to a 100-mg sildenafil dose, demonstrated a significantly greater improvement in EFD (2.2 points) above that EFD score for those who continued on the 50-mg dose (n=240; P < 0.001). The rise of greater than 2 points in EFD in men with mild ED (EFD 22 post 50 sildenafil) satisfies the criteria for MCID in mild ED (3). Of further interest, the primary analysis in the current study indicated that the 14-week increase in EFD score after randomization was also 2.2, though these data were not statistically significant. Nonetheless, the mean change of 2.2 in the current study (1) equals the improvement noted with sildenafil 100mg (4).

Thus, it appears that testosterone supplementation did positively impact erectile function, similar to the effects seen with sildenafil 100 mg (4). The benefit in EFD to the cohort with testosterone supplementation may not have been statistically different due to the smaller sample size vs. the sildenafil trial (4).

1. Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, Mazer NA, Knapp PE, Hanka S, Lakshman KM, Ulloor J, Zhang A, Orwoll K, Eder R, Collins L, Mohammed N, Rosen RC, Derogatis L, Bhasin S. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med. 2012 Nov 20;157(10):681-91. doi:10.7326/0003-4819-157-10-201211200-00004. PubMed PMID: 23165659.

2. Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology. 1999 Aug;54(2):346-51. PubMed PMID: 10443736.

3. Rosen RC, Allen KR, Ni X, Araujo AB. Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale. Eur Urol. 2011 Nov;60(5):1010-6. Epub 2011 Jul 30. PubMed PMID: 21855209.

4. Buvat J, Hatzichristou D, Maggi M, Farmer I, Martínez-Jabaloyas JM, Miller PJ, Schnetzler G. Efficacy, tolerability and satisfaction with sildenafil citrate 100-mg titration compared with continued 50-mg dose treatment in men with erectile dysfunction. BJU Int. 2008 Dec;102(11):1645-50. Epub 2008 Aug 14. PubMed PMID: 18710446.

Is testosterone important in sildenafil non-responders?
Posted on December 19, 2012
Antonio Aversa MD PhD, Emmanuele A Jannini MD, Mario Maggi MD, Andrea Lenzi MD
Department of Experimental Medicine, Sapienza University of Rome, Italy
Conflict of Interest: None Declared

Dear Sir,

We have read the article by Spitzer et al. (1) with great interest. In this elegant article the authors fail to demonstrate any additive effect of testosterone (T) on erection in men treated for erectile dysfunction (ED) with the phosphodiesterase type-5 inhibitor (PDE5i), sildenafil. The study is well designed but we believe it misses to discuss some critical points that are milestones in the field. First of all, as the same authors state in the discussion, they had an increase in testosterone levels of 3.47 nmol/L (100 ng/dL) during the sildenafil run-in period alone. This is indeed expected when an impotent men become again sexually active, as previously suggested by Carosa et al (2) who demonstrated that this is not a direct PDE5i effect, but instead it is mediated by a neuroendocrine response occurring with recovered sexual motivation. Second point is that TRT is commenced when plasma T levels are already within the normal range (about 12 nmol/L), so that the failure in response to T in terms of erection is well expected. Aversa et al (3) examined sildenafil non-responders to 100 mg and arterial insufficiency then supplemented with TRT starting from a baseline T level of 12 nmol/L. They found a positive response for two main reasons: a peak plasma testosterone level after one month administration of transdermal patch (23.7 nmol/L) that was paralleled by an increase in penile arterial function. Shabsigh et al confirmed same results (4). In the article by Spitzer, the patients were responders to sildenafil and, mostly, they were not investigated by penile Duplex ultrasound, so that we cannot argue anything about the penile vascular circulation. Testosterone is one of the major determinants of PDE5 expression at the cavernous levels, as suggested by Morelli et al (5). A threshold level for testosterone to determine this effect is not established yet so that the Authors should reconsider their negative results keeping in mind that for the abovementioned reasons they were someway expected. The demonstration that their findings are true, needs more to be more circumstantiated by the proof-of-fact of a in-depth vascular examination of their patients at baseline.

References

1. Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, Mazer NA, Knapp PE, Hanka S, Lakshman KM, Ulloor J, Zhang A, Orwoll K, Eder R, Collins L, Mohammed N, Rosen RC, Derogatis L, Bhasin S. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med. 2012 Nov 20;157(10):681-91.

2. Carosa E, Martini P, Brandetti F, Di Stasi SM, Lombardo F, Lenzi A, Jannini EA. Type V phosphodiesterase inhibitor treatments for erectile dysfunction increase testosterone levels.Clin Endocrinol (Oxf). 2004 Sep;61(3):382-6.

3. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf). 2003 May;58(5):632-8.

4. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol. 2008 May;179(5 Suppl):S97-S102.

5. Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M, Orlando C, Vannelli GB, Aversa A, Natali A, Forti G, Giorgi M, Jannini EA, Ledda F, Maggi M. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology. 2004 May;145(5):2253-63.

Author's Reply
Posted on February 6, 2013
Matthew Spitzer, MD; Shehzad Basaria, MD; Thomas G. Travison, PhD; Shalender Bhasin, MD
Boston University
Conflict of Interest: None Declared

We agree with Dr. Smoger’s comment that testosterone measurements vary due to multiple factors including assay variation, diurnal and pulsatile secretory rhythms, and variations in sex hormone binding globulin levels. We measured testosterone between 7:30 and 10:00 am by liquid chromatography-tandem mass spectrometry, widely considered the reference method with the highest sensitivity and specificity, but agree that additional measurements of testosterone during screening would have been of value. Obesity is associated with decreased sex hormone binding globulin, and we agree that it might have played some role in the low total testosterone values.(1) Accordingly, we included participants with total testosterone less than 330 ng/dl and/or free testosterone less than 50 pg/ mL, well below the reference ranges established in healthy young men using liquid chromatography-tandem mass spectrometry.(2)

We thank Drs. Seftel and Hackett for underlining the importance of clinical meaningfulness. A change of 4 points has been deemed by many experts as the Minimal Clinically Important Difference (MCID) in the International Index of Erectile Function (IIEF) Erectile Function Domain (EFD) based on receiver operating characteristic analyses.(3) In this trial, our analyses did not find either statistically or clinically meaningful differences in the change in EFD score between the testosterone and placebo groups arguing against a clinically important difference. We acknowledge that the MCID is inversely associated with baseline EFD scores, however the totality of evidence argues against a substantial effect from adding testosterone to sildenafil in this trial.(3) Absence of benefit was consistently observed for all measures of sexual function, including satisfaction with sexual intercourse, frequency of sexual intercourse, and frequency of satisfactory sexual encounters.

We appreciate comments by Aversa et al. We agree that the increase in serum total testosterone levels might be secondary to increases in sexual activity. There is increasing evidence that phosphodiesterase-5 inhibitors directly act on Leydig cells and stimulate testosterone production.(4) We acknowledge that vascular examinations were not performed in our study. However, the IIEF is a standard measure of erectile function that has been widely used to determine treatment efficacy in registration trials of erectile dysfunction therapies and is a validated tool that conveys information regarding the efficacy and clinical meaningfulness of the intervention.(5) Thus, we submit that the IIEF is a more clinically meaningful and patient-important outcome than vascular studies.

References

1. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-59.

2. Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96(8):2430-9.

3. Rosen RC, Allen KR, Ni X, Araujo AB. Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale. Eur Urol. 2011;60(5):1010-6.

4. Janjic MM, Stojkov NJ, Bjelic MM, Mihajlovic AI, Andric SA, Kostic TS. Transient rise of serum testosterone level after single sildenafil treatment of adult male rats. J Sex Med. 2012;9(10):2534-43.

5. Rosen RC, Cappelleri JC, Gendrano N, 3rd. The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res. 2002;14(4):226-44.

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Summary for Patients

Effect of Testosterone on Response to Sildenafil in Men With Erectile Dysfunction

The full report is titled “Effect of Testosterone Replacement on Response to Sildenafil Citrate in Men With Erectile Dysfunction. A Parallel, Randomized Trial.” It is in the 20 November 2012 issue of Annals of Internal Medicine (volume 157, pages 681-691). The authors are M. Spitzer, S. Basaria, T.G. Travison, M.N. Davda, A. Paley, B. Cohen, N.A. Mazer, P.E. Knapp, S. Hanka, K.M. Lakshman, J. Ulloor, A. Zhang, K. Orwoll, R. Eder, L. Collins, N. Mohammed, R.C. Rosen, L. DeRogatis, and S. Bhasin.

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