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LETTERS TO THE EDITOR Toward Personalized Sexual Medicine: Where is the Evidence? DOI: 10.1111/jsm.12619 Last year, this journal published three articles of the same research group on the potential efficacy of two different drug combinations (testosterone/phosphodiesterase inhibitor [T + PDE5i] and testosterone/buspirone [T + HT1ara]), in women with hypoactive sexual desire disorder [1–3]. T + PDE5i is hypothesized to activate excitatory mechanisms in the brain during sexual stimulation, and T + HT1ara is thought to block a hypothesized phasic increase in inhibitory serotonergic activity in the prefrontal cortex in response to negatively valenced sexual stimuli. The Dual Control model is used as a theoretical framework for this study [4]. A close reading of the three articles revealed a number of concerns that seriously question the validity of both the theoretical claims and the findings. We will address the following issues: (i) statistical analysis strategy; (ii) clinical significance of findings; (iii) placebo control; and (iv) conflicts of interest.
Statistical Analysis Strategy The authors merely present data from subgroup analyses reporting on differential drug effects in high and low inhibitors and in high and low sensitive women [1,2]. There are several problems with this strategy. High and low sensitive subgroups were based on participants mean reaction times to erotic and neutral words on an emotional Stroop task ([1], p. 815). To support the validity of this division into subgroups, the authors reported an increase of preconscious attention allocation in the low sensitive women during active treatment, relative to placebo (p. 817). Judging from the degrees of freedom in this ANOVA (dfs 1,54), however, this test cannot refer to the low sensitive women only. Yet figure 3 ([1], p. 819) repeats the associated P value of 0.001, which raises doubts about the accuracy of this analysis. Besides, it is entirely unclear what the findings on the Stroop task were in the high sensitive women, a crucial piece of information to verify the authors’ claim that the Stroop task meaningfully measures sensitivity to sexual cues. Was preconscious attention to sexual cues during T + PDE5i treatment not enhanced in the high sensitive group? These data are lacking. High- and low-inhibitor subgroups were based on scores of diaries obtained during T + PDE5i treatment [2]. Women who failed to respond to this treatment were labeled “high inhibitors,” and women who did respond were “low inhibitors” (p. 828). In other words, inhibition was defined as a lack of sexual activation. This conflicts with the basic tenet of the Dual Control model which assumes that the inhibitory and excitatory components that mediate sexual response are relatively independent neurophysiological systems [4]. Also, no attempts were made to support this differentiation in subgroups with neurophysiological data, validated questionnaires, or even clinical and anamnestic data. The table 1 ([2], p. 829) reveals only a few demographic and baseline differences between subgroups. High inhibitors had significantly more children and had relationships of significantly longer duration than low inhibitors. These variables are known to be related to the decline in sexual desire in women [5], and to reduced quality of marital sex [6], and may, as such, be an alternative explanation for the lack of response to PDE5i. The actual significance of the higher prevalence of negative sexual experiences in the high inhibitors group, a finding that the authors consider being supportive of an inhibitory
© 2014 International Society for Sexual Medicine
neurophysiological mechanism, is unclear. The negative sexual experiences varied from inappropriate touching to rape, and slightly less than half of the high inhibitors did not have those experiences. Also, it is unknown to what extent those experiences led to posttraumatic stress [7]. The picture gets even more clouded when looking at some of the findings more closely. For instance, figure 5 ([1], p. 820) shows a differential effect of T + PDE5i between low and high sensitive women on feelings of sexual desire and experienced genital arousal [1]. While the authors focus on the absence of a drug effect in high sensitive women (who are not expected to benefit from a drug that increases sensitivity to sexual stimuli), and the presence of a drug effect in low sensitive women (who are expected to benefit from a drug that increases their sensitivity to sexual stimuli), inspection of the means shows that low sensitive women on placebo reported, on average, equal levels of sexual desire and genital arousal than the high sensitive women on placebo. What dysfunction is being treated here? A clear understanding of the validity of the division in subgroups is extremely pertinent, because analyses looking at efficacy of both drugs in the total sample are also lacking. Why are these data not reported? Is it because no significant effect of drug was found? This is not entirely imaginary, because why would authors voluntarily choose not to report significant findings if they are there? A recent review by Sun showed that in trials in which the primary end points designed to show efficacy of active treatment over placebo did not demonstrate significance, sponsoring of the trial by a pharmaceutical company enhanced the likelihood of publication of subgroup analyses with a factor 2,3 relative to studies that were carried out without industry money [8]. Also, subgroups were not randomized at baseline, which is an important requirement for reliable subgroup analysis, to prevent confounding of the results [9]. For instance, the strikingly low confidence intervals within the relatively small subgroups may well be a confound of the strategy to divide the sample into low and high scorers on a measure that is one of the dependent variables of the study. A final point of concern regarding the statistical analysis scheme is that the data were not analyzed according to intention to treat, which does not conform to internationally accepted guidelines [10].
Clinical Significance In accordance with requirements of the Food and Drug Administration, the authors placed great significance on patient-reported outcomes such as the SEI (subjective evaluation of improvement) and SEG (subjective evaluation of gain), both measures being the sum of two no (0)/yes (1) questions, resulting in 0–2 scales. In both studies, increases relative to placebo within subgroups varied from 0.2 to 0.4. What is the clinical significance of such a finding? Similarly, patient-reported sexual improvement (measured on a 1–4 scale, 1 = nothing, 4 = much) during active treatment was less than 1.5 in both studies. Is it unfair to say that this mean amounts to showing “no improvement”? To judge the clinical significance of significant findings, effect sizes are valuable. Because no effect sizes were reported in the studies, we calculated effect sizes of comparisons that showed significance. Only a handful of effect sizes were large
J Sex Med 2014;11:2357–2363
2358 (0.80 < Cohen’s d > 1.29), with most of these large effect sizes being related to the SEI and SEG outcomes, the means of which tended toward “no improvement.”
Letters to the Editor (b) Analysis and Interpretation of Data Peter Leusink; A. Joan P. Boeke; Ellen Laan
Category 2 Placebo Control In the two empirical studies, two active treatments were compared with placebo. Due to the lack of a placebo control for each of the treatment components, it is unclear which component of the treatment, T or PDE5i in the study that compared low and high sensitive women [1], and T and HT1ara in the study that compared low and high inhibitors [2], would actually be the effective treatment ingredient. Theoretically, women may be using an inactive treatment ingredient, which is undesirable. In addition, active treatment ingredients may have had physiological side effects which would allow women to determine whether they had had active treatment or placebo. Facial flushing and nasal congestion are well-known side effects of PDE5 inhibitors. It is therefore recommended that active placebos be used in PDE5i trials [11]. Also lacking is the actual quantity of drug that the participants used during the trials, because they were allowed to use treatments on demand. It is relevant to know whether placebo treatments were used on demand in similar quantities as active treatment. How many women actually did use placebo treatment? Did they do so in similar amounts as active treatment? If not, how did this influence their patient-reported outcome scores? For buspirone, no studies have been published that showed a positive effect on sexual behavior or sexual experience. Also, no data for on-demand treatment are available for this drug. The question therefore is which component in the T + HT1ara combination would be responsible for any positive effects.
Conflicts of Interest Nowhere in any of the three articles is the conflict of interest reported by one of the authors who is also editor-in-chief of the Journal of Sexual Medicine. Who reviewed the manuscripts and who made the final decision to accept the articles for publication? In addition, 8 of 11 authors have financial interests in the drug developing company, and the four authors who analyzed the data were owner or employee of the pharmaceutical company that sponsored the study. What did the editorial board of the Journal of Sexual Medicine do to make sure that these conflicts of interest were not affecting the presentation of the findings or the publication policy?
Conclusion Given the problems pointed out in this editorial, we raise the question of whether these articles should have been published in their current form. Peter Leusink, MD,* A. Joan P. Boeke, MD PhD,† and Ellen Laan, PhD‡ *Department of Sexology, Groene Hart Hospital, Gouda, The Netherlands; †General Practice Postjesweg, Amsterdam, The Netherlands; ‡Department of Sexology and Psychosomatic Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Statement of Authorship
Category 1 (a) Conception and Design Peter Leusink; A. Joan P. Boeke; Ellen Laan
J Sex Med 2014;11:2357–2363
(a) Drafting the Article Peter Leusink; A. Joan P. Boeke; Ellen Laan (b) Revising It for Intellectual Content Peter Leusink; A. Joan P. Boeke; Ellen Laan
Category 3 (a) Final Approval of the Completed Article Peter Leusink; A. Joan P. Boeke; Ellen Laan References 1 Poels S, Bloemers J, van Rooij K, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, Tuiten A. Toward personalized sexual medicine (Part 2): Testosterone combined with a PDE5 inhibitor increases sexual satisfaction in women with HSDD and FSAD, and a low sensitivity system for sexual cues. J Sex Med 2013;10:810–23. 2 Rooij K, van Poels S, Bloemers J, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, Tuiten A. Toward personalized sexual medicine (Part 3): Testosterone combined with a serotonin1a receptor agonist increases sexual satisfaction in women with HSDD and FSAD, and dysfunctional activation of sexual inhibitory mechanisms. J Sex Med 2013;10:824–37. 3 Bloemers J, van Rooij K, Poels P, Goldstein I, Everaerd W, Koppeschaar H, Chivers M, Gerritsen J, van Ham D, Olivier B, Tuiten A. Toward personalized sexual medicine (Part 1): Integrating the “dual control model” into differential drug treatments for hypoactive sexual desire disorder and female sexual arousal disorder. J Sex Med 2013;10:791–809. 4 Bancroft J, Janssen E. The dual control model of male sexual response: A theoretical approach to centrally mediated erectile dysfunction. Neurosci Biobehav Rev 2000;24:571–9. 5 Klusmann D. Sexual motivation and the duration of partnership. Arch Sex Behav 2002;31:275–87. 6 Liu C. Does quality of marital sex decline with duration? Arch Sex Behav 2003;32:55–60. 7 Letourneau EJ, Resnick HS, Kilpatrick DG, Saunders BE, Best CL. Comorbidity of sexual problems and post-traumatic stress disorder in female crime victims. Behav Ther 1996;27:321–36. 8 Sun X, Briel M, Busse JW, You JJ, Akl EA, Mejza F, Bala MM, Bassler D, Mertz D, Diaz-Granados N, Vandvik PO, Malaga G, Srinathan SK, Dahm P, Johnston BC, Alonso-Coello P, Hassouneh B, Truong J, Dattani ND, Walter SD, Heels-Ansdell D, Bhatnagar N, Altman DG, Guyatt GH. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: Systematic review. BMJ 2011;342:d1569. 9 Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ 2010;340:c117. 10 Moher D, Schulz KF, Altman DG; CONSORT GROUP (Consolidated Standards of Reporting Trials). The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 2001;134:657–62. 11 Feys F, Bekkering GE, Singh K, Devroey D. Do randomized clinical trials with inadequate blinding report enhanced placebo effets for intervention groups and nocebo effects for placebo groups? A protocol for a mata-epidemiological study of PDE-5 inhibitors. Syst Rev 2012;1:54.
LETTERS TO THE EDITOR Toward Personalized Sexual Medicine: Where is the Evidence? DOI: 10.1111/jsm.12619 Last year, this journal published three articles of the same research group on the potential efficacy of two different drug combinations (testosterone/phosphodiesterase inhibitor [T + PDE5i] and testosterone/buspirone [T + HT1ara]), in women with hypoactive sexual desire disorder [1–3]. T + PDE5i is hypothesized to activate excitatory mechanisms in the brain during sexual stimulation, and T + HT1ara is thought to block a hypothesized phasic increase in inhibitory serotonergic activity in the prefrontal cortex in response to negatively valenced sexual stimuli. The Dual Control model is used as a theoretical framework for this study [4]. A close reading of the three articles revealed a number of concerns that seriously question the validity of both the theoretical claims and the findings. We will address the following issues: (i) statistical analysis strategy; (ii) clinical significance of findings; (iii) placebo control; and (iv) conflicts of interest.
Statistical Analysis Strategy The authors merely present data from subgroup analyses reporting on differential drug effects in high and low inhibitors and in high and low sensitive women [1,2]. There are several problems with this strategy. High and low sensitive subgroups were based on participants mean reaction times to erotic and neutral words on an emotional Stroop task ([1], p. 815). To support the validity of this division into subgroups, the authors reported an increase of preconscious attention allocation in the low sensitive women during active treatment, relative to placebo (p. 817). Judging from the degrees of freedom in this ANOVA (dfs 1,54), however, this test cannot refer to the low sensitive women only. Yet figure 3 ([1], p. 819) repeats the associated P value of 0.001, which raises doubts about the accuracy of this analysis. Besides, it is entirely unclear what the findings on the Stroop task were in the high sensitive women, a crucial piece of information to verify the authors’ claim that the Stroop task meaningfully measures sensitivity to sexual cues. Was preconscious attention to sexual cues during T + PDE5i treatment not enhanced in the high sensitive group? These data are lacking. High- and low-inhibitor subgroups were based on scores of diaries obtained during T + PDE5i treatment [2]. Women who failed to respond to this treatment were labeled “high inhibitors,” and women who did respond were “low inhibitors” (p. 828). In other words, inhibition was defined as a lack of sexual activation. This conflicts with the basic tenet of the Dual Control model which assumes that the inhibitory and excitatory components that mediate sexual response are relatively independent neurophysiological systems [4]. Also, no attempts were made to support this differentiation in subgroups with neurophysiological data, validated questionnaires, or even clinical and anamnestic data. The table 1 ([2], p. 829) reveals only a few demographic and baseline differences between subgroups. High inhibitors had significantly more children and had relationships of significantly longer duration than low inhibitors. These variables are known to be related to the decline in sexual desire in women [5], and to reduced quality of marital sex [6], and may, as such, be an alternative explanation for the lack of response to PDE5i. The actual significance of the higher prevalence of negative sexual experiences in the high inhibitors group, a finding that the authors consider being supportive of an inhibitory
© 2014 International Society for Sexual Medicine
neurophysiological mechanism, is unclear. The negative sexual experiences varied from inappropriate touching to rape, and slightly less than half of the high inhibitors did not have those experiences. Also, it is unknown to what extent those experiences led to posttraumatic stress [7]. The picture gets even more clouded when looking at some of the findings more closely. For instance, figure 5 ([1], p. 820) shows a differential effect of T + PDE5i between low and high sensitive women on feelings of sexual desire and experienced genital arousal [1]. While the authors focus on the absence of a drug effect in high sensitive women (who are not expected to benefit from a drug that increases sensitivity to sexual stimuli), and the presence of a drug effect in low sensitive women (who are expected to benefit from a drug that increases their sensitivity to sexual stimuli), inspection of the means shows that low sensitive women on placebo reported, on average, equal levels of sexual desire and genital arousal than the high sensitive women on placebo. What dysfunction is being treated here? A clear understanding of the validity of the division in subgroups is extremely pertinent, because analyses looking at efficacy of both drugs in the total sample are also lacking. Why are these data not reported? Is it because no significant effect of drug was found? This is not entirely imaginary, because why would authors voluntarily choose not to report significant findings if they are there? A recent review by Sun showed that in trials in which the primary end points designed to show efficacy of active treatment over placebo did not demonstrate significance, sponsoring of the trial by a pharmaceutical company enhanced the likelihood of publication of subgroup analyses with a factor 2,3 relative to studies that were carried out without industry money [8]. Also, subgroups were not randomized at baseline, which is an important requirement for reliable subgroup analysis, to prevent confounding of the results [9]. For instance, the strikingly low confidence intervals within the relatively small subgroups may well be a confound of the strategy to divide the sample into low and high scorers on a measure that is one of the dependent variables of the study. A final point of concern regarding the statistical analysis scheme is that the data were not analyzed according to intention to treat, which does not conform to internationally accepted guidelines [10].
Clinical Significance In accordance with requirements of the Food and Drug Administration, the authors placed great significance on patient-reported outcomes such as the SEI (subjective evaluation of improvement) and SEG (subjective evaluation of gain), both measures being the sum of two no (0)/yes (1) questions, resulting in 0–2 scales. In both studies, increases relative to placebo within subgroups varied from 0.2 to 0.4. What is the clinical significance of such a finding? Similarly, patient-reported sexual improvement (measured on a 1–4 scale, 1 = nothing, 4 = much) during active treatment was less than 1.5 in both studies. Is it unfair to say that this mean amounts to showing “no improvement”? To judge the clinical significance of significant findings, effect sizes are valuable. Because no effect sizes were reported in the studies, we calculated effect sizes of comparisons that showed significance. Only a handful of effect sizes were large
J Sex Med 2014;11:2357–2363
2358 (0.80 < Cohen’s d > 1.29), with most of these large effect sizes being related to the SEI and SEG outcomes, the means of which tended toward “no improvement.”
Letters to the Editor (b) Analysis and Interpretation of Data Peter Leusink; A. Joan P. Boeke; Ellen Laan
Category 2 Placebo Control In the two empirical studies, two active treatments were compared with placebo. Due to the lack of a placebo control for each of the treatment components, it is unclear which component of the treatment, T or PDE5i in the study that compared low and high sensitive women [1], and T and HT1ara in the study that compared low and high inhibitors [2], would actually be the effective treatment ingredient. Theoretically, women may be using an inactive treatment ingredient, which is undesirable. In addition, active treatment ingredients may have had physiological side effects which would allow women to determine whether they had had active treatment or placebo. Facial flushing and nasal congestion are well-known side effects of PDE5 inhibitors. It is therefore recommended that active placebos be used in PDE5i trials [11]. Also lacking is the actual quantity of drug that the participants used during the trials, because they were allowed to use treatments on demand. It is relevant to know whether placebo treatments were used on demand in similar quantities as active treatment. How many women actually did use placebo treatment? Did they do so in similar amounts as active treatment? If not, how did this influence their patient-reported outcome scores? For buspirone, no studies have been published that showed a positive effect on sexual behavior or sexual experience. Also, no data for on-demand treatment are available for this drug. The question therefore is which component in the T + HT1ara combination would be responsible for any positive effects.
Conflicts of Interest Nowhere in any of the three articles is the conflict of interest reported by one of the authors who is also editor-in-chief of the Journal of Sexual Medicine. Who reviewed the manuscripts and who made the final decision to accept the articles for publication? In addition, 8 of 11 authors have financial interests in the drug developing company, and the four authors who analyzed the data were owner or employee of the pharmaceutical company that sponsored the study. What did the editorial board of the Journal of Sexual Medicine do to make sure that these conflicts of interest were not affecting the presentation of the findings or the publication policy?
Conclusion Given the problems pointed out in this editorial, we raise the question of whether these articles should have been published in their current form. Peter Leusink, MD,* A. Joan P. Boeke, MD PhD,† and Ellen Laan, PhD‡ *Department of Sexology, Groene Hart Hospital, Gouda, The Netherlands; †General Practice Postjesweg, Amsterdam, The Netherlands; ‡Department of Sexology and Psychosomatic Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Statement of Authorship
Category 1 (a) Conception and Design Peter Leusink; A. Joan P. Boeke; Ellen Laan
J Sex Med 2014;11:2357–2363
(a) Drafting the Article Peter Leusink; A. Joan P. Boeke; Ellen Laan (b) Revising It for Intellectual Content Peter Leusink; A. Joan P. Boeke; Ellen Laan
Category 3 (a) Final Approval of the Completed Article Peter Leusink; A. Joan P. Boeke; Ellen Laan References 1 Poels S, Bloemers J, van Rooij K, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, Tuiten A. Toward personalized sexual medicine (Part 2): Testosterone combined with a PDE5 inhibitor increases sexual satisfaction in women with HSDD and FSAD, and a low sensitivity system for sexual cues. J Sex Med 2013;10:810–23. 2 Rooij K, van Poels S, Bloemers J, Goldstein I, Gerritsen J, van Ham D, van Mameren F, Chivers M, Everaerd W, Koppeschaar H, Olivier B, Tuiten A. Toward personalized sexual medicine (Part 3): Testosterone combined with a serotonin1a receptor agonist increases sexual satisfaction in women with HSDD and FSAD, and dysfunctional activation of sexual inhibitory mechanisms. J Sex Med 2013;10:824–37. 3 Bloemers J, van Rooij K, Poels P, Goldstein I, Everaerd W, Koppeschaar H, Chivers M, Gerritsen J, van Ham D, Olivier B, Tuiten A. Toward personalized sexual medicine (Part 1): Integrating the “dual control model” into differential drug treatments for hypoactive sexual desire disorder and female sexual arousal disorder. J Sex Med 2013;10:791–809. 4 Bancroft J, Janssen E. The dual control model of male sexual response: A theoretical approach to centrally mediated erectile dysfunction. Neurosci Biobehav Rev 2000;24:571–9. 5 Klusmann D. Sexual motivation and the duration of partnership. Arch Sex Behav 2002;31:275–87. 6 Liu C. Does quality of marital sex decline with duration? Arch Sex Behav 2003;32:55–60. 7 Letourneau EJ, Resnick HS, Kilpatrick DG, Saunders BE, Best CL. Comorbidity of sexual problems and post-traumatic stress disorder in female crime victims. Behav Ther 1996;27:321–36. 8 Sun X, Briel M, Busse JW, You JJ, Akl EA, Mejza F, Bala MM, Bassler D, Mertz D, Diaz-Granados N, Vandvik PO, Malaga G, Srinathan SK, Dahm P, Johnston BC, Alonso-Coello P, Hassouneh B, Truong J, Dattani ND, Walter SD, Heels-Ansdell D, Bhatnagar N, Altman DG, Guyatt GH. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: Systematic review. BMJ 2011;342:d1569. 9 Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ 2010;340:c117. 10 Moher D, Schulz KF, Altman DG; CONSORT GROUP (Consolidated Standards of Reporting Trials). The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 2001;134:657–62. 11 Feys F, Bekkering GE, Singh K, Devroey D. Do randomized clinical trials with inadequate blinding report enhanced placebo effets for intervention groups and nocebo effects for placebo groups? A protocol for a mata-epidemiological study of PDE-5 inhibitors. Syst Rev 2012;1:54.
