refractory, we stated that these children had been on anticholinergicor antispasmodic medications before undergoing urodynamic testing.In addition, we reiterated that point in the results by stating, “A totalof 18 children had previously been treated medically and 7 requiredadditional medication in the regimen during treatment.” Thus, themajority of these patients were truly refractory for their daytimesymptoms.

We agree that the term “refractory” is highly questionable whenreferring to the nocturnal enuresis portion of the symptom complexonly. Because the patients had refractory daytime symptoms weperformed urodynamic studies and not because of the nighttimesymptoms only. We completely agree that urodynamic testing is notneeded in the overwhelming majority of patients who have nighttimeor even night and daytime symptoms unless medical therapy hasfailed.

RE: ANDROPAUSE: A MISNOMER FOR A TRUE CLINICALENTITY

A. Morales, J. P. W. Heaton and C. C. Carson, III

J Urol, 163: 705–712, 2000

To the Editor. Given the likely multifactorial etiology of this clin-ical entity, including but not limited to, multiple endocrine changes,androgen decline in the aging male (ADAM) remains a confusingmisnomer. If an acronym is essential then perhaps changing hor-mones in the aging man (CHAM) would be more accurate, since notall hormones decline, for example insulin often increases in produc-tion but is relatively ineffective.

My primary disappointment was that the recommendations didnot address the frequent clinical dilemma of the man in his 40s or50s with somewhat low free testosterone but normal luteinizing andfollicle-stimulating hormones. The algorithm states in that situationto investigate the hypothalamus and pituitary but we simply cannotafford to do so in all of these men, especially without any evidence ofthe frequency of hypothalamic or pituitary disease as opposed toidiopathic blunting of the response. Of course, when the luteinizinghormone is low, the investigations are mandatory but our growingclinical experience and the literature1 suggest that a normal lutein-izing hormone response to subnormal free testosterone is common inthis age group.

Respectfully,Rosemary BassonDepartments of Psychiatry, and Obstetrics and GynecologyVancouver Hospital and Health Sciences CenterEchelon Building855 West 12th Ave.Vancouver, British Columbia, Canada V5Z 1M9

1. Korenman, S. G., Morley, J. E., Mooradian, A. D. et al: Second-ary hypogonadism in older men: its relation to impotence.J Clin Endocrinol Metabol, 71: 963, 1990

To the Editor. To an extent I agree that andropause is a truemisnomer and that ADAM is clinically more appropriate terminol-ogy, especially because of the gradual decline in the hormonal statusin males rather than the sharp decline in females at the time ofmenopause. ADAM is also associated with a decrease of other hor-mones besides testosterone, and a direct causality between manifes-tation and alteration of specific hormones has not been fully estab-lished.

Our research reveals that not all men undergo male menopause tothe same degree or extent. In a study of 302 older men who describedchanges of andropause 46% had erectile dysfunction, 41% weaknessand 36% memory loss.1 The age of onset of andropause is alsovariable with men presenting between ages 51 and 60 years, followedby those 61 to 70 years old.

This entity seems to develop in some men more than others. Theauthors report that ADAM is unpredictable, and its manifestationssubtle and variable. However, smokers are more likely than non-smokers to report symptoms related to andropause.1 Multivariateanalysis revealed that smoking more than 10 cigarettes a day wasindependently associated with an earlier onset of andropause (oddsratio 2.5, confidence interval 1.2 to 5.3, p 5 0.01). Nicotine can havea negative effect on the gonadotropin releasing hormone pulse gen-erator, thereby affecting the hormonal mileu.2

Clearly, more research is needed to establish the definition ofandropause. Much research has been conducted on female meno-pause and much needs be done in understanding andropause, espe-cially regarding hormone replacement for men. Some of the symp-toms related to andropause can be easily reversed with testosteronereplacement.3

Respectfully,Robert TanGeriatrics SectionDepartment of Family PracticeUniversity of TexasHouston, Texas 77030

1. Tan, R. S., and Philip, P. S.: Perceptions of and risk factors forandropause. Arch Androl, 43: 97, 1999

2. Vermuelen, A.: Environment, human reproduction, menopauseand andropause. Environ Health Perspect, suppl., 101: 91,1993

3. Tan, R. S. and Bransgrove, L.: Testosterone replacement ther-apy. What is its potential in elderly men? Postgrad Med, 103:249, 1998

RE: CHRONIC TREATMENT WITH FINASTERIDE DAILYDOES NOT AFFECT SPERMATOGENESIS OR SEMEN

PRODUCTION IN YOUNG MEN

J. W. Overstreet, V. L. Fuh, J. Gould, S. S. Howards,M. M. Lieber, W. Hellstrom, S. Shapiro, P. Carroll,

R. S. Corfman, S. Petrou, R. Lewis, P. Toth, T. Shown, J. Roy,J. P. Jarow, J. Bonilla, C. A. Jacobsen, D. Z. Wang and

K. D. Kaufman

J Urol, 162: 1295–1300, 1999

To the Editor. The conclusion of the authors minimizes the effect of1 mg. finasteride on semen production. In this study ejaculate vol-ume was analyzed in a placebo controlled trial for daily finasterideuse (1 mg. formulation only) in young men. The authors state, “Forassessing ejaculatory volume a 10% equivalency criterion based onthe 90% confidence interval (CI) around the difference between treat-ment effects was prespecified.” The results indicated that at the endof the 48-week treatment period the 90% CI for the difference be-tween 1 mg. finasteride and placebo groups with respect to themedian percent reduction in ejaculate volume was 210.4% to 13.1%.However, the authors suggest that chronic treatment with finas-teride daily does not affect semen production in young men, based onthe fact that a comparison of this reduction between the finasterideand placebo treatment groups did not reach statistical significance(p 5 0.915).

Concluding equivalence based on observing a nonsignificant testresult is inappropriate.1 In equivalence studies “statistical analysisshould be based on the use of CIs. Equivalence is inferred when theentire CI falls within the equivalence margins.”1 In this study the90% CI for the difference between treatment groups falls outside theprespecified equivalence margin of 610%. Thus, the findings do notsupport equivalence between 1 mg. finasteride and placebo in termsof reduction of ejaculate volume. Also, to estimate equivalence a 95%CI is commonly used, which would be even wider than the reported90% CI of 210.4% to 13.1%.

To calculate the power of the study with respect to ejaculatevolume reduction, it is necessary to know the number of patientshaving such measurements at the end of treatment. This informa-tion is not available in the article, although table 1 shows that atbaseline 1 mg. finasteride and placebo groups included 40 and 39patients, respectively. A rough estimate suggests that assuming asignificance level of 5%, the study had approximately 30% to 35%power to detect a difference of 10% between treatments for ejaculatevolume change. Thus, if there was an actual difference of 10%, thenthere is a 65% to 70% probability that this difference would not bedetected, because of sample size inadequacy. Therefore, it is prema-ture for the authors to imply that finasteride products, when givendaily, would not affect semen production. The proper conclusionshould be, “As the 90% CI falls outside the prespecified equivalencemargin of plus or minus 10%, the study does not support or excludeequivalence between 1 mg. finasteride and placebo for changes inejaculate volume.” The views in this letter are solely those of the

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authors and are not necessarily the views of the Food and DrugAdministration.

Respectfully,Valeria Freidlin, Hon-Sum Ko and Jonathan K. WilkinCenter for Drug Evaluation and ResearchUnited States Food and Drug AdministrationRockville, Maryland

1. International Conference on Harmonisation: Guidance on statis-tical principles for clinical trials. Fed Regist, 63: 49583, 1998

Reply by Authors. This critique focuses almost exclusively on sta-tistical methodology and the calculations are technically correct.However, we believe it is appropriate to evaluate the data in thecontext of the clinical study as a whole, which was designed todetermine the clinical safety of 1 mg. finasteride in young men. Inprevious studies treatment with finasteride at the higher 5 mg. doseproduced a transient, approximately 25% median reduction in ejac-ulate volume that reversed on discontinuation of the drug.1 A goal ofour study was to determine whether a similar reduction occurredduring treatment with 1 mg. finasteride. The estimate of variabilityfor ejaculate volume was based on the variability observed previ-ously.

In our study both treatment groups had measured decreases frombaseline in ejaculate volume at the end of the 48-week treatmentperiod.1 At the heart of the critique by Freidlin et al is that, while themeasured between treatment group difference for these changes inejaculate volume was only 1% (20.03 ml., p 5 0.915), the lowerboundary of the 90% CI extended outside of the predefined 10%margin by 0.4%. To put this 0.4% into perspective, had the medianejaculate volume in the placebo group decreased only 0.01 ml. (0.4%of 2.7 ml.) more from baseline, or that of the finasteride groupdecreased 0.01 ml. (0.4% of 2.8 ml.) less, then the predefined criterionrelated to reduction in ejaculate volume would have been satisfied.Thus, the predefined criterion was missed by an amount (0.01 ml.)that was well below, by an order of magnitude, resolution of theassay (0.1 ml.) that was used to measure ejaculate volume in thestudy.

Freidlin et al also criticize our use of a 90% CI to define theequivalence criterion and power of the study. They are correct that inthe present regulatory environment equivalence criteria are com-monly estimated using a 95% CI (reference 1 in letter). However, the1 mg. finasteride study was initiated in 1995 before adoption of theseguidelines and a 90% CI was commonly used at the time. In addition,the study was designed to have 80% power to detect a 20% differencein ejaculate volume between treatment groups, and any differencebetween groups of 14% or more would yield statistical significance atthe 5% (2-sided) level. Had the actual variability in ejaculate volume(standard deviation of 34%) been more consistent with the variabilityestimate applied prospectively in planning the study (29%), thepredefined equivalence criterion (10% margin) would have been met.

Because our study was a clinical trial evaluating the safety of adrug, it is important to evaluate the numerical data on ejaculatevolume from a clinical perspective. Of interest, 2 recent prospectivestudies on the predictive value of semen parameters indicated thatejaculate volume was not related to subsequent fertility, except incases in which volume was below 1 ml.2, 3 In our study there were nosubjects in the finasteride group who reached this level of clinicalconcern. However, 2 patients receiving placebo had ejaculate vol-umes below 1 ml. during treatment. These observations reinforce ourconclusion that the changes observed for ejaculate volume in thestudy for either treatment group were consistent with normal bio-logical variability. This normal variability was especially evident onreview of the results of the 60-week followup. The narrow focus of thetechnical issue raised by Freidlin et al obscures the fact that 1 mg.finasteride demonstrated no clinically significant effects on sperma-togenesis or semen production in healthy young men.

1. United States package circular for 1 mg. finasteride tablets,1999

2. Bonde, J. P. E., Ernst, E., Jensen, T. K. et al: Relation betweensemen quality and fertility: a population-based study of 430first-pregnancy planners. Lancet, 352: 1172, 1998

3. Zinaman, M. J., Brown, C. C., Selevan, S. G. et al: Semen qualityand human fertility: a prospective study with healthy couples.J Androl, 21: 145, 2000

RE: TRANSURETHRAL HOLMIUM LASER RESECTION OFTHE PROSTATE

K. Matsuoka, S. Iida, K. Tomiyasu, A. Shimada and S. Noda

J Urol, 163: 515–518, 2000

To the Editor. We question the scientific value of this series. Laserprostatectomy in all of its various guises has been described as atreatment option for benign prostatic enlargement for some yearsand, although the authors state that they did not perform a compar-ative study, when randomized controlled trials have been previouslypublished the scientific merit of a series is open to question. Morespecifically, the prostate volumes treated with the holmium laserwere small, the operating times were prolonged (83 6 35 minutes)and 11% of the patients had urinary retention after the initialcatheter was removed. Of the patients 46% were lost to followup at1 year and 89% were lost to followup at 3 years postoperatively.Based on this article we would dispute the statement that holmiumlaser prostatectomy is effective for the treatment of benign prostatichyperplasia.

Respectfully,Stephen R. Keoghane and Adam J. JonesDepartment of UrologyThe Battle HospitalReading, United Kingdom

Reply by Authors. For any new surgical method to become acceptedtrials should first be performed a number of times at a large numberof institutions, and satisfactory results from a significant majority ofthese procedures should be validated. Next, problematic points thatarise during evaluation should be carefully recorded and analyzed.Finally, assuming satisfactory results from the first 2 steps, statis-tically significant, random sampled, comparative studies should beperformed, comparing and contrasting the new surgical method tocommonly accepted current surgical methods.

We tested and attempted to validate the findings of Gilling et alregarding holmium laser resection of the prostate.1–3 Following theirmethodology exactly, our goal was to determine to what extentfindings similar to theirs could or could not be validated at a differentinstitution. Considering that the ethnicity of the patients, the coun-try of testing and the treating physicians were different, we believethat our study was a significant and valid evaluation of the tech-nique.

Although the originators of the holmium laser resection of theprostate subsequently performed randomized controlled trials, validdisagreement exists as to whether researchers performing originaltrials should also perform trials comparing the new method to exist-ing therapies. Such disagreement centers on 2 equally valid con-cerns. First, unless trials are performed at a number of differentinstitutions other than those where the originators performed them,then problematic points related to the surgical method may notsurface. Second, if randomized controlled trials are performed with-out the experience of a certain number of cases, as noted by Gillinget al, the results will have built-in bias favoring existing methodol-ogies. These points notwithstanding, our research at least providesan index for researchers who are attempting to validate this methodas an alternative treatment. In addition to validating the findings ofGilling et al, we described in detail the deficiencies we encountered.

Mean prostate volume in the cases in question was 37 ml. butwhen considering the Japanese physique this volume is not small.The long operating time was problematic and we explained that workis under way to reduce this time. In addition, regarding the 11% ofpatients who had trial failure without catheterization after the firstpostoperative day, Gilling et al obtained satisfactory results withextraction the day following the operation. However, when this pro-tocol was executed in the same way at our institution a significantminority of patients complained of urinary retention. To eliminate ordrastically reduce this possibility, we determined that 2-day cathe-terization was appropriate and urinary retention did not recur. Thisis an example of problems/differences we noted that were not re-ported by Gilling et al.

Our series did not continue with long-term results, since satisfac-tory results were obtained after the early postoperative stages and,just as importantly, the study was not designed to be a long-term(greater than 1 year) evaluation. Rather, the technique in questionwas evaluated first and foremost for safety and efficacy immediatelyand 1 week postoperatively. The 1 and 3-year data were presented on

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