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Current Literature Review
© 2011 International Society for Sexual Medicine
Survey of Literature Current Literature Review
jsm_2203
660..665
Basic Science
Activated RhoA/Rho kinase impairs erectile function after cavernous nerve injury in rats. C Gratzke, TD Strong, MA Gebska, HC Champion, CG Stief, AL Burnett, TJ Bivalacqua. J Urol 2010;184:2197–204. Pentoxifylline promotes recovery of erectile function in a rat model of postprostatectomy erectile dysfunction. M Albersen, TM Fandel, H Zhang, L Banie, G Lin, D De Ridder, CS Lin, TF Lue. Eur Urol 2011;59:286–96. Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. NL Angeloni, CW Bond, Y Tang, DA Harrington, S Zhang, SI Stupp, KE McKenna, CA Podlasek. Biomaterials 2011;32:1091–101. Editorial Comment: Despite the increasing use of techniques that are designed to be less invasive and minimize damage to nerves associated with the pelvic plexus, the occurrence of erectile dysfunction after surgical procedures, such as prostatectomy, remains an important consideration in postsurgical care. These three studies investigate various aspects of cavernous nerve damage and recovery. In the first, Gratzke and colleagues used a bilateral cavernous nerve crush injury rat model to examine alterations in the contractile regulatory proteins RhoA and rho kinase. In smooth muscle cells, RhoA and rho kinase act in tandem to sustain the contractile state. Protein levels and functional activity of both of these key enzymes were significantly upregulated 14 days after bilateral cavernous nerve injury. Consistent with previous studies, erectile function and neuronal nitric oxide synthase (nNOS) protein was decreased in nerveinjured animals. Importantly, intracavernosal administration of the rho kinase inhibitor Y-27632 enhanced erectile function in nerve-injured animals. These data reveal yet another molecular consequence after cavernous nerve injury that may contribute to erectile dysfunction. However, targeting the Rho A/rho kinase pathway to treat nerve injury-associated erectile dysfunction 660
remains a difficult proposition due to the ubiquitous tissue distribution of these critical proteins, as well as their broader involvement in cell growth and differentiation. Interestingly, RhoA and rho kinase have also been shown to be upregulated in the spinal cord after nerve injury. Whether this is a beneficial or deleterious process may be tissue and context dependent. Thus, our perspective on Rho A and rho kinase continues to evolve as more data come to light. In the second study, Albersen and colleagues also used a bilateral cavernous nerve crush injury rat model to investigate the effects of chronic pentoxifylline treatment. Pentoxifylline was administered daily by oral gavage immediately after nerve injury at doses of 25, 50, and 100 mg/kg of body weight for a total of 28 days. Erectile function was assessed after a 72-hour washout period (no pentoxifylline treatment) and penile tissue was harvested for histochemical analyses. Nerve-injured rats treated with pentoxifylline exhibited enhanced erectile responses, compared to animals receiving vehicle only. Tissue from pentoxifylline-treated animals had decreased collagen deposition and increased smooth muscle content in the corpus cavernosum and increased nNOS content in the dorsal nerve. Pentoxifylline treatment also prevented the loss of nNOS-containing small nerve fibers surrounding the helicine arterioles and decreased parameters associated with degeneration in the cavernous nerve (i.e., axonal swelling, vacuolization, perturbations in overall neuronal morphology). In cultures of isolated major pelvic ganglia, pentoxifylline treatment for 48 hours increased neurite outgrowth. Since pentoxifylline is a nonspecific inhibitor of phosphodiesterases and cytokine signaling, it remains unclear how it may mediate all of these observed effects. However, these findings are generally consistent with previously reported results of similar studies using phosphodiesterase type 5 inhibitors and immunophilins. The authors argue that the current clinical experience with pentoxifylline suggests a more acceptable safety profile, making it a J Sex Med 2011;8:660–665
reasonable candidate for development as a treatment option in penile rehabilitation regimens. Further characterization of pentoxifylline’s multiple modes of action should help to discern its efficacy and any potential adverse effects. Lastly, Angeloni and colleagues present a specific strategy to stimulate cavernous nerve regeneration using chemically engineered biodegradable peptide nanofibers that elute the morphogenic protein sonic hedgehog (SHH). SHH has been previously shown to be a critical factor in maintaining corpus cavernosum tissue structure and composition. In animal models, cavernous nerve damage can lead to decreased SHH expression. Inhibition of anterograde neuronal transport in the cavernous nerve reduced SHH protein in the penis. Furthermore, blockade of SHH binding to its receptor resulted in progressive cavernous nerve degeneration. In rats subjected to cavernous nerve crush injury, application of SHH-containing peptide nanofibers directly onto the injured nerve enhanced erectile function, promoted nerve regeneration, and reduced apoptosis in penile tissue, compared to vehicle-treated animals. SHHcontaining peptide nanofibers were deemed to be more effective than the use of SHH-containing beads since erectile function was not improved after bead application despite decreased apoptosis in penile tissue. The additional benefit of the peptide nanofibers was postulated to be their ability to form a scaffold around the cavernous nerve to guide axonal regrowth. While many questions remain unanswered, this is a promising new technology that is likely to have therapeutic application in numerous areas. These findings also reinforce the importance of SHH in the penis and raise some interesting questions on whether other growth factors or drugs have the ability to stimulate the expression of SHH in the cavernous nerve or cavernosal tissue. Noel N. Kim, PhD Psychology
Role of androgens in women’s sexual dysfunction. R Basson, LA Brotto, AJ Petkau, F Labrie. Menopause 2010;17:962–71. Level of Evidence: 3. Editorial Comment: Nondepressed women with acquired sexual disorders were compared with control subjects (women without sexual problems; N = 124) on measures of serum sex steroids (taken on menstrual cycle days 8–10 in the premenoJ Sex Med 2011;8:660–665
pausal women), sexual function, relationship satisfaction, and mood. Women diagnosed with sexual disorders were categorized into the following groups: (i) hypoactive sexual desire disorder (HSDD), N = 58; (ii) women with HSDD and female sexual arousal disorder (FSAD), N = 52; and (iii) women with FSAD alone, N = 11. The clinical group was older with poorer sexual function than the controls. Of the sex steroid measures, only dehydroepiandrosterone sulfate (P = 0.006) and androstenediol (P = 0.020), sex hormone precursors, were lower in the dysfunctional group. No significant differences were demonstrated for androgen metabolites. No sexual dysfunction subgroup differences were found. Variability in the serum measures between women was seen in all groups. Limitations include the cross-sectional design, lack of control for menopausal status in the analyses limiting specificity of results, and noninclusion of obese women, which limit generalizability. These results suggest that lower levels of androgen and estrogen precursors rather than differences in sex hormones or their metabolites are associated with desire and arousal dysfunction. The wide variability in measures of sex steroids suggests that change in levels may play a greater role in the onset of sexual dysfunction than absolute levels. Anita H. Clayton, MD Genital appearance dissatisfaction: Implications for women’s genital image selfconsciousness, sexual esteem, sexual satisfaction, and sexual risk. VR Schick, SK Calabrese, BN Rima, AN Zucker. Psychol Women Q 2010;34:394–404. Level of Evidence: 3. Editorial Comment: Body image selfconsciousness and sexual self-esteem may impact cognitive distraction during sexual activity and influence motivation to avoid risky behavior. Perceptions related to genital appearance may have specific effects in this context. Female undergraduate students (N = 188), age 18–28 years (mean = 19.39 years), completed scales modified to address vulva appearance satisfaction using a labeled anatomical diagram, genital image selfconsciousness, motivation to avoid risky sex, sexual esteem, and sexual satisfaction. Eighty percent were white, 96% self-identified as mostly or exclusively heterosexual, over 60% were freshmen or sophomores, and 63% reported having ever engaged in vaginal intercourse. Subjects were 661
recruited through the university psychology participant pool and completed the questionnaires as a Web-based survey. Greater dissatisfaction with genital appearance was associated with higher genital image self-consciousness during physical intimacy, and lower sexual esteem, sexual satisfaction, and motivation to avoid risky sexual behavior. Sexual esteem did not mediate genital self-image and risky sexual behavior, but did affect genital self-image and sexual satisfaction. This was true for women who had previously engaged in vaginal intercourse and in women who had not. Limitations of this study include the cross-sectional design, failure to access for possible affect of other sexual activities that might increase visualization of the external genitalia or other aspects of genital dissatisfaction (e.g., smell, taste, etc.), evaluation of a fairly homogenous population, lack of accounting for phase of menstrual cycle at assessment, and failure to control for other influences on behavior and satisfaction, such as mood symptoms and substance use, thus limiting generalizability. These findings suggest a negative effect of vulva appearance dissatisfaction on sexual self-consciousness, sexual esteem, sexual satisfaction, and motivation to avoid risky sexual behavior. Interventions that educate about the variability in genital appearance and reduce comparisons with an unreal ideal may facilitate the development of a healthy sexual self-concept. Anita H. Clayton, MD Clinical Research—Female
Effects of two combined hormonal contraceptives with the same composition and different doses on female sexual function and plasma androgen levels. R Strufaldi, LM Pompei, ML Steiner, EP Cunha, JA Ferreira, S Peixoto, CE Fernandes. Contraception 2010;82:147–54. Level of Evidence: 1b. Editorial Comment: Sex steroids such as estrogen and testosterone are well known to influence female sexual function. Hormonal contraception through birth control pills increases sex hormonebinding globulin (SHBG) and decreases circulating androgens, a phenomenon which may negatively impact sexuality. Despite this, some studies have shown sexual symptoms improve with hormonal contraception. These authors performed a randomized, controlled trial of 101 women treated with either ethinyl estradiol (EE) 662
30 mg/levonorgestrel (LNG) 150 mg or EE 20 mg/ LNG 100 mg for six cycles. The Female Sexual Function Index (FSFI) was utilized. Blood work was performed at baseline and after the sixth cycle to assess total testosterone and Free Androgen Index (FAI). Ninety-seven women completed the study. At baseline, the only significant difference between the groups was a higher SHBG level in the EE 30/LNG 150 subpopulation, whereas FSFI scores and sexual frequency were similar. After six cycles, FAI decreased and SHBG increased in both groups, with significant differences seen in EE 30/LNG 150 users. Only the FSFI desire domain changed significantly during the study period, improving in the EE 20/LNG 100 group. However, nonsignificant increases were noted in other domains of sexual function, with overall scores improving in both groups. Multiple regression analysis revealed that desire, at the end of treatment, was only explained by desire at baseline. The authors conclude that contraceptive pills cause reduction in plasma androgen levels significant only in EE 30/LNG 150 users. However, this did not appear to negatively impact female sexual function. Strengths of this work include the randomized prospective nature with validated indices and laboratory data. Unfortunately, this study was not blinded, and does not provide a physiological explanation for these findings. Further research to establish the mechanism behind these improvements would be of benefit to the literature. Rachel N. Pauls, MD Sexual dysfunction among women of lowincome status in an urban setting. B Worly, M Gopal, L Arya. Int J Gynaecol Obstet 2010;111: 241–4. Level of Evidence: 3. Editorial Comment: FSD is a common problem; however, little epidemiologic research has concentrated on low-income populations. These subgroups often have higher poverty, violence, and sexual crime rates, as well as comorbidities such as depression and urge incontinence, which may place them at higher risk for sexual disorders. These authors performed a prospective study of women presenting to an urban gynecology clinic in order to ascertain rates of sexual dysfunction and potential risk factors. The Female Sexual Function Index (FSFI), Center for Epidemiologic Studies Depression Scale (CES-D), questionnaire for urinary incontinence diagnosis, demographic information, as well as partners’ sexual function J Sex Med 2011;8:660–665
were ascertained. A sample size calculation determined a necessary sample size of 101 women in order to detect an odds ratio of >3.5 for depression in women with sexual dysfunction. One hundred and two women were ultimately included and 38 (37.3%) met criteria for sexual dysfunction. The mean age of all subjects was 31. Women with sexual dysfunction had lower scores in all domains of the FSFI, were more likely to be older, unemployed, and African American. Clinical factors significantly associated with sexual dysfunction, after multivariant analysis, included depression and urge urinary incontinence. The strengths of this study include recruitment of low-income women as a different focus from other reported data in the literature. However, the findings are limited by a relatively small sample size and young age of the population. Further studies of this demographic population would be of interest in order to better address challenges specific to these female patients. Rachel N. Pauls, MD Medical student sexuality: How sexual experience and sexuality training impact U.S. and Canadian medical students’ comfort in dealing with patients’ sexuality in clinical practice. AW Shindel, KA Ando, CJ Nelson, BN Breyer, TF Lue, JF Smith. Acad Med 2010;85:1321–30. Level of Evidence: 3. Editorial Comment: While sexual problems may significantly impact patients’ quality of life, several studies have suggested medical students receive poor training, and are inadequately prepared to address these complaints. In addition, little is known regarding medical students’ quality of life and their own sexual function. These authors performed a survey of medical students in the United States and Canada. Participants responded to a yes/no question assessing comfort level talking to patients about their sexual practices and problems, and the Center for Epidemiologic Studies Depression Scale (CES-D). Males completed the International Index of Erectile Function (IIEF) and Premature Ejaculation Diagnostic Tool (PEDT), while females completed the Female Sexual Function Index (FSFI) and the Index of Sex Life (ISL). Other questions queried about demographics, sexual experience and satisfaction, and perception of the adequacy of their human sexuality training. Out of 2,261 surveys that were completed, 1,343 were from women. Of the females surveyed, J Sex Med 2011;8:660–665
87.5% had engaged in sexual intercourse with a mean age of 18.6 for their first encounter. While 49.1% of the females had FSFI scores suggestive of sexual dysfunction, only 312 (23.2%) reported unhappiness with their sexual function. With respect to adequacy of training, more dissatisfaction was noted in those who were unmarried and in the first year of medicine. When queried regarding comfort level talking to patients about their sexuality, the vast majority of participants (81.1%) reported feeling comfortable. Less comfort was associated with poor sexual function scores, depression, Asian race, and perceived inadequacy of their training. These findings are of interest in understanding predictive factors for comfort of providing physicians, as well as to ascertain discrepancies in medical school curriculum. In addition, female medical students appear to be at risk for sexual dysfunction, and open discussions of these issues may be of benefit. Future research, with more detailed questions regarding deficiencies in the curriculum would be of use in further describing this phenomenon. Rachel N. Pauls, MD Clinical Research—Male
Evidence for geographical and racial variation in serum sex steroid levels in older men. ES Orwoll, CM Nielson, F Labrie, E Barrett-Connor, JA Cauley, SR Cummings, K Ensrud, M Karlsson, E Lau, PC Leung, Ö Lunggren, D Mellström, AL Patrick, ML Stefanick, K Nakamura, N Yoshimura, J Zmuda, L Vandenput, C Ohlsson for the Osteoporotic Fractures in Men (MrOS) Research Group. J Clin Endocrinol Metab 2010; 95:E151–60. Level of Evidence: 3. Editorial Comment: Serum androgens, estrogens, and sex steroid precursors/metabolites were measured in 5,003 older men from five countries using mass spectrometry, except for sex hormone binding globulin (SHBG) levels which were assessed using radioimmunoassay. Substantial geographical variation in the levels of sex steroids, precursors, and metabolites, as well as SHBG, was found among the different countries. For instance, Asian men in Hong Kong and Japan, but not in the United States, had levels of total testosterone approximately 20% higher than in other groups. Even greater variation was observed concerning levels of estradiol, SHBG, and dihydrotestosterone. Group differences in body mass index did not 663
explain most geographical differences. Moreover, body mass index-independent racial differences were present. In black men, higher levels of estrogens (estradiol, estrone) were found, whereas lower levels of glucuronidated androgen metabolites were seen in Asian men. To the knowledge of the reviewer, this is the first cohort study pointing to the fact that there are clinically meaningful ethnic differences in elderly men regarding various sex steroid levels. This observation may have clinical consequences not only in terms of multinational studies where the values of steroid levels play a role but also in the judgment of clinical effects regarding medications, which impact the various sex steroid levels investigated in this cohort study. Hartmut Porst, MD Efficacy of tadalafil in secondary Raynaud’s phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial. PD Shenoy, S Kumar, LK Jha, SK Choudhary, U Singh, R Misra, V Agarwal. Rheumatology 2010;49:2420–8. Level of Evidence: 1b. Editorial Comment: This study (ClinicalTrials. gov database # NCT00626665) enrolled 25 patients suffering from scleroderma and secondary Raynaud’s phenomenon (RP) with at least four attacks per week and with a secondary resistance to vasodilator therapy. Study participants were randomized either to tadalafil 20 mg or placebo on alternate days as add-on therapy to their current vasodilators for 6 weeks. After a 7-day washout, patients were crossed over to the other arm. Primary end points were improvement in the daily frequency and duration of RP episodes and RP condition score (RCS). Secondary outcome measures were healing of existing and appearance of new digital ulcers (DUs) and improvement in scleroderma-specific Health Assessment Questionnaire (SHAQ), quality of life (QoL), flowmediated dilatation (FMD), and patient and physician global assessment. Twenty-four of 25 patients completed the study. While on tadalafil therapy, significant improvement in mean daily frequency, mean daily duration of RP, and mean daily RCS were observed, compared with baseline and placebo. All the 24 digital lesions healed during tadalafil therapy, compared with three out of 13 during the placebo treatment (P < 0.0001). One new DU was reported during tadalafil therapy vs. 13 during placebo therapy (P = 664
0.0005). QoL, SHAQ, FMD, and patient and physician global assessment significantly improved while on tadalafil. Although the number of patients investigated in this trial is relatively small, the findings regarding the impact of tadalafil on the negative clinical consequences of secondary Raynaud’s phenomenon are indeed impressive. This small but well-designed clinical study provides further evidence on the anti-fibrotic properties of tadalafil, which may apply for all phosphodiesterase 5 inhibitors, and on the clinical benefits of their use in conditions linked to increased collagen turnover with subsequent fibrosis. In this regard, besides Raynaud’s phenomenon, other pathologic conditions such as Dupuytren’s contraction or Peyronie’s disease may be target indications with the latter one showing favorable responses to daily tadalafil 5 mg according to the personal experience in those patients. Hartmut Porst, MD Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. SD Beck, AL Bey, R Bihrle, RS Foster. J Urol 2010;184:2078–80. Level of Evidence: 3. Editorial Comment: This study consisted of analysis of a monocenter database from January 1, 2000 to December 31, 2005 regarding the outcome of primary retroperitoneal lymph node dissection because of testicular cancer in terms of fertility and ejaculatory/orgasmic function. Of 280 patients identified, 176 were finally eligible for follow-up between 3 and 9 years after surgery. One hundred seventy-one (97%) of 176 patients who underwent primary retroperitoneal lymph node dissection reported preserved antegrade emission. Of the 135 men who had undergone nerve-sparing procedure, 134 (99%) could ejaculate, as could 33 of 37 (89%) who underwent non-nerve-sparing surgery. Forty-seven (73%) out of 64 men were able to successfully father a child. Another three patients fathered children via in vitro fertilization. This retrospective analysis of the outcome of retroperitoneal lymph node dissection due to testicular cancer is a testimonial of the impressive progress we made in our surgical techniques over the past three decades regarding the management of testicular cancer. This applies both for more sophisticated nerve-sparing techniques, as well as for so-called non-nerve-sparing procedures in which the overwhelming majority of the responsible nerve fibers is also being preserved, thanks to J Sex Med 2011;8:660–665
better anatomical understanding and knowledge. Dating back to the early 1980s where the reviewer was introduced to this kind of surgery, the majority of these young patients was suffering from either loss of emission or ejaculation. Hartmut Porst, MD
Level of evidence 1a 1b 2a 2b
Editor’s Note
Commentaries on clinical studies include a “level of evidence” rating to assist readers in evaluating the significance of the findings and conclusions. The simplified rating scale below is adapted from the more complete recommendations of the Centre for Evidence-Based Medicine (http:// www.cebm.net/index.aspx?o=1025).
J Sex Med 2011;8:660–665
3
4
Type of evidence Evidence from systematic reviews or meta-analysis of randomized controlled trials Evidence from at least one randomized control trial Evidence from at least one controlled study without randomization Evidence from at least one other type of quasi experimental study Evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case control studies Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
665
Survey of Literature Current Literature Review
jsm_2203
660..665
Basic Science
Activated RhoA/Rho kinase impairs erectile function after cavernous nerve injury in rats. C Gratzke, TD Strong, MA Gebska, HC Champion, CG Stief, AL Burnett, TJ Bivalacqua. J Urol 2010;184:2197–204. Pentoxifylline promotes recovery of erectile function in a rat model of postprostatectomy erectile dysfunction. M Albersen, TM Fandel, H Zhang, L Banie, G Lin, D De Ridder, CS Lin, TF Lue. Eur Urol 2011;59:286–96. Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. NL Angeloni, CW Bond, Y Tang, DA Harrington, S Zhang, SI Stupp, KE McKenna, CA Podlasek. Biomaterials 2011;32:1091–101. Editorial Comment: Despite the increasing use of techniques that are designed to be less invasive and minimize damage to nerves associated with the pelvic plexus, the occurrence of erectile dysfunction after surgical procedures, such as prostatectomy, remains an important consideration in postsurgical care. These three studies investigate various aspects of cavernous nerve damage and recovery. In the first, Gratzke and colleagues used a bilateral cavernous nerve crush injury rat model to examine alterations in the contractile regulatory proteins RhoA and rho kinase. In smooth muscle cells, RhoA and rho kinase act in tandem to sustain the contractile state. Protein levels and functional activity of both of these key enzymes were significantly upregulated 14 days after bilateral cavernous nerve injury. Consistent with previous studies, erectile function and neuronal nitric oxide synthase (nNOS) protein was decreased in nerveinjured animals. Importantly, intracavernosal administration of the rho kinase inhibitor Y-27632 enhanced erectile function in nerve-injured animals. These data reveal yet another molecular consequence after cavernous nerve injury that may contribute to erectile dysfunction. However, targeting the Rho A/rho kinase pathway to treat nerve injury-associated erectile dysfunction 660
remains a difficult proposition due to the ubiquitous tissue distribution of these critical proteins, as well as their broader involvement in cell growth and differentiation. Interestingly, RhoA and rho kinase have also been shown to be upregulated in the spinal cord after nerve injury. Whether this is a beneficial or deleterious process may be tissue and context dependent. Thus, our perspective on Rho A and rho kinase continues to evolve as more data come to light. In the second study, Albersen and colleagues also used a bilateral cavernous nerve crush injury rat model to investigate the effects of chronic pentoxifylline treatment. Pentoxifylline was administered daily by oral gavage immediately after nerve injury at doses of 25, 50, and 100 mg/kg of body weight for a total of 28 days. Erectile function was assessed after a 72-hour washout period (no pentoxifylline treatment) and penile tissue was harvested for histochemical analyses. Nerve-injured rats treated with pentoxifylline exhibited enhanced erectile responses, compared to animals receiving vehicle only. Tissue from pentoxifylline-treated animals had decreased collagen deposition and increased smooth muscle content in the corpus cavernosum and increased nNOS content in the dorsal nerve. Pentoxifylline treatment also prevented the loss of nNOS-containing small nerve fibers surrounding the helicine arterioles and decreased parameters associated with degeneration in the cavernous nerve (i.e., axonal swelling, vacuolization, perturbations in overall neuronal morphology). In cultures of isolated major pelvic ganglia, pentoxifylline treatment for 48 hours increased neurite outgrowth. Since pentoxifylline is a nonspecific inhibitor of phosphodiesterases and cytokine signaling, it remains unclear how it may mediate all of these observed effects. However, these findings are generally consistent with previously reported results of similar studies using phosphodiesterase type 5 inhibitors and immunophilins. The authors argue that the current clinical experience with pentoxifylline suggests a more acceptable safety profile, making it a J Sex Med 2011;8:660–665
reasonable candidate for development as a treatment option in penile rehabilitation regimens. Further characterization of pentoxifylline’s multiple modes of action should help to discern its efficacy and any potential adverse effects. Lastly, Angeloni and colleagues present a specific strategy to stimulate cavernous nerve regeneration using chemically engineered biodegradable peptide nanofibers that elute the morphogenic protein sonic hedgehog (SHH). SHH has been previously shown to be a critical factor in maintaining corpus cavernosum tissue structure and composition. In animal models, cavernous nerve damage can lead to decreased SHH expression. Inhibition of anterograde neuronal transport in the cavernous nerve reduced SHH protein in the penis. Furthermore, blockade of SHH binding to its receptor resulted in progressive cavernous nerve degeneration. In rats subjected to cavernous nerve crush injury, application of SHH-containing peptide nanofibers directly onto the injured nerve enhanced erectile function, promoted nerve regeneration, and reduced apoptosis in penile tissue, compared to vehicle-treated animals. SHHcontaining peptide nanofibers were deemed to be more effective than the use of SHH-containing beads since erectile function was not improved after bead application despite decreased apoptosis in penile tissue. The additional benefit of the peptide nanofibers was postulated to be their ability to form a scaffold around the cavernous nerve to guide axonal regrowth. While many questions remain unanswered, this is a promising new technology that is likely to have therapeutic application in numerous areas. These findings also reinforce the importance of SHH in the penis and raise some interesting questions on whether other growth factors or drugs have the ability to stimulate the expression of SHH in the cavernous nerve or cavernosal tissue. Noel N. Kim, PhD Psychology
Role of androgens in women’s sexual dysfunction. R Basson, LA Brotto, AJ Petkau, F Labrie. Menopause 2010;17:962–71. Level of Evidence: 3. Editorial Comment: Nondepressed women with acquired sexual disorders were compared with control subjects (women without sexual problems; N = 124) on measures of serum sex steroids (taken on menstrual cycle days 8–10 in the premenoJ Sex Med 2011;8:660–665
pausal women), sexual function, relationship satisfaction, and mood. Women diagnosed with sexual disorders were categorized into the following groups: (i) hypoactive sexual desire disorder (HSDD), N = 58; (ii) women with HSDD and female sexual arousal disorder (FSAD), N = 52; and (iii) women with FSAD alone, N = 11. The clinical group was older with poorer sexual function than the controls. Of the sex steroid measures, only dehydroepiandrosterone sulfate (P = 0.006) and androstenediol (P = 0.020), sex hormone precursors, were lower in the dysfunctional group. No significant differences were demonstrated for androgen metabolites. No sexual dysfunction subgroup differences were found. Variability in the serum measures between women was seen in all groups. Limitations include the cross-sectional design, lack of control for menopausal status in the analyses limiting specificity of results, and noninclusion of obese women, which limit generalizability. These results suggest that lower levels of androgen and estrogen precursors rather than differences in sex hormones or their metabolites are associated with desire and arousal dysfunction. The wide variability in measures of sex steroids suggests that change in levels may play a greater role in the onset of sexual dysfunction than absolute levels. Anita H. Clayton, MD Genital appearance dissatisfaction: Implications for women’s genital image selfconsciousness, sexual esteem, sexual satisfaction, and sexual risk. VR Schick, SK Calabrese, BN Rima, AN Zucker. Psychol Women Q 2010;34:394–404. Level of Evidence: 3. Editorial Comment: Body image selfconsciousness and sexual self-esteem may impact cognitive distraction during sexual activity and influence motivation to avoid risky behavior. Perceptions related to genital appearance may have specific effects in this context. Female undergraduate students (N = 188), age 18–28 years (mean = 19.39 years), completed scales modified to address vulva appearance satisfaction using a labeled anatomical diagram, genital image selfconsciousness, motivation to avoid risky sex, sexual esteem, and sexual satisfaction. Eighty percent were white, 96% self-identified as mostly or exclusively heterosexual, over 60% were freshmen or sophomores, and 63% reported having ever engaged in vaginal intercourse. Subjects were 661
recruited through the university psychology participant pool and completed the questionnaires as a Web-based survey. Greater dissatisfaction with genital appearance was associated with higher genital image self-consciousness during physical intimacy, and lower sexual esteem, sexual satisfaction, and motivation to avoid risky sexual behavior. Sexual esteem did not mediate genital self-image and risky sexual behavior, but did affect genital self-image and sexual satisfaction. This was true for women who had previously engaged in vaginal intercourse and in women who had not. Limitations of this study include the cross-sectional design, failure to access for possible affect of other sexual activities that might increase visualization of the external genitalia or other aspects of genital dissatisfaction (e.g., smell, taste, etc.), evaluation of a fairly homogenous population, lack of accounting for phase of menstrual cycle at assessment, and failure to control for other influences on behavior and satisfaction, such as mood symptoms and substance use, thus limiting generalizability. These findings suggest a negative effect of vulva appearance dissatisfaction on sexual self-consciousness, sexual esteem, sexual satisfaction, and motivation to avoid risky sexual behavior. Interventions that educate about the variability in genital appearance and reduce comparisons with an unreal ideal may facilitate the development of a healthy sexual self-concept. Anita H. Clayton, MD Clinical Research—Female
Effects of two combined hormonal contraceptives with the same composition and different doses on female sexual function and plasma androgen levels. R Strufaldi, LM Pompei, ML Steiner, EP Cunha, JA Ferreira, S Peixoto, CE Fernandes. Contraception 2010;82:147–54. Level of Evidence: 1b. Editorial Comment: Sex steroids such as estrogen and testosterone are well known to influence female sexual function. Hormonal contraception through birth control pills increases sex hormonebinding globulin (SHBG) and decreases circulating androgens, a phenomenon which may negatively impact sexuality. Despite this, some studies have shown sexual symptoms improve with hormonal contraception. These authors performed a randomized, controlled trial of 101 women treated with either ethinyl estradiol (EE) 662
30 mg/levonorgestrel (LNG) 150 mg or EE 20 mg/ LNG 100 mg for six cycles. The Female Sexual Function Index (FSFI) was utilized. Blood work was performed at baseline and after the sixth cycle to assess total testosterone and Free Androgen Index (FAI). Ninety-seven women completed the study. At baseline, the only significant difference between the groups was a higher SHBG level in the EE 30/LNG 150 subpopulation, whereas FSFI scores and sexual frequency were similar. After six cycles, FAI decreased and SHBG increased in both groups, with significant differences seen in EE 30/LNG 150 users. Only the FSFI desire domain changed significantly during the study period, improving in the EE 20/LNG 100 group. However, nonsignificant increases were noted in other domains of sexual function, with overall scores improving in both groups. Multiple regression analysis revealed that desire, at the end of treatment, was only explained by desire at baseline. The authors conclude that contraceptive pills cause reduction in plasma androgen levels significant only in EE 30/LNG 150 users. However, this did not appear to negatively impact female sexual function. Strengths of this work include the randomized prospective nature with validated indices and laboratory data. Unfortunately, this study was not blinded, and does not provide a physiological explanation for these findings. Further research to establish the mechanism behind these improvements would be of benefit to the literature. Rachel N. Pauls, MD Sexual dysfunction among women of lowincome status in an urban setting. B Worly, M Gopal, L Arya. Int J Gynaecol Obstet 2010;111: 241–4. Level of Evidence: 3. Editorial Comment: FSD is a common problem; however, little epidemiologic research has concentrated on low-income populations. These subgroups often have higher poverty, violence, and sexual crime rates, as well as comorbidities such as depression and urge incontinence, which may place them at higher risk for sexual disorders. These authors performed a prospective study of women presenting to an urban gynecology clinic in order to ascertain rates of sexual dysfunction and potential risk factors. The Female Sexual Function Index (FSFI), Center for Epidemiologic Studies Depression Scale (CES-D), questionnaire for urinary incontinence diagnosis, demographic information, as well as partners’ sexual function J Sex Med 2011;8:660–665
were ascertained. A sample size calculation determined a necessary sample size of 101 women in order to detect an odds ratio of >3.5 for depression in women with sexual dysfunction. One hundred and two women were ultimately included and 38 (37.3%) met criteria for sexual dysfunction. The mean age of all subjects was 31. Women with sexual dysfunction had lower scores in all domains of the FSFI, were more likely to be older, unemployed, and African American. Clinical factors significantly associated with sexual dysfunction, after multivariant analysis, included depression and urge urinary incontinence. The strengths of this study include recruitment of low-income women as a different focus from other reported data in the literature. However, the findings are limited by a relatively small sample size and young age of the population. Further studies of this demographic population would be of interest in order to better address challenges specific to these female patients. Rachel N. Pauls, MD Medical student sexuality: How sexual experience and sexuality training impact U.S. and Canadian medical students’ comfort in dealing with patients’ sexuality in clinical practice. AW Shindel, KA Ando, CJ Nelson, BN Breyer, TF Lue, JF Smith. Acad Med 2010;85:1321–30. Level of Evidence: 3. Editorial Comment: While sexual problems may significantly impact patients’ quality of life, several studies have suggested medical students receive poor training, and are inadequately prepared to address these complaints. In addition, little is known regarding medical students’ quality of life and their own sexual function. These authors performed a survey of medical students in the United States and Canada. Participants responded to a yes/no question assessing comfort level talking to patients about their sexual practices and problems, and the Center for Epidemiologic Studies Depression Scale (CES-D). Males completed the International Index of Erectile Function (IIEF) and Premature Ejaculation Diagnostic Tool (PEDT), while females completed the Female Sexual Function Index (FSFI) and the Index of Sex Life (ISL). Other questions queried about demographics, sexual experience and satisfaction, and perception of the adequacy of their human sexuality training. Out of 2,261 surveys that were completed, 1,343 were from women. Of the females surveyed, J Sex Med 2011;8:660–665
87.5% had engaged in sexual intercourse with a mean age of 18.6 for their first encounter. While 49.1% of the females had FSFI scores suggestive of sexual dysfunction, only 312 (23.2%) reported unhappiness with their sexual function. With respect to adequacy of training, more dissatisfaction was noted in those who were unmarried and in the first year of medicine. When queried regarding comfort level talking to patients about their sexuality, the vast majority of participants (81.1%) reported feeling comfortable. Less comfort was associated with poor sexual function scores, depression, Asian race, and perceived inadequacy of their training. These findings are of interest in understanding predictive factors for comfort of providing physicians, as well as to ascertain discrepancies in medical school curriculum. In addition, female medical students appear to be at risk for sexual dysfunction, and open discussions of these issues may be of benefit. Future research, with more detailed questions regarding deficiencies in the curriculum would be of use in further describing this phenomenon. Rachel N. Pauls, MD Clinical Research—Male
Evidence for geographical and racial variation in serum sex steroid levels in older men. ES Orwoll, CM Nielson, F Labrie, E Barrett-Connor, JA Cauley, SR Cummings, K Ensrud, M Karlsson, E Lau, PC Leung, Ö Lunggren, D Mellström, AL Patrick, ML Stefanick, K Nakamura, N Yoshimura, J Zmuda, L Vandenput, C Ohlsson for the Osteoporotic Fractures in Men (MrOS) Research Group. J Clin Endocrinol Metab 2010; 95:E151–60. Level of Evidence: 3. Editorial Comment: Serum androgens, estrogens, and sex steroid precursors/metabolites were measured in 5,003 older men from five countries using mass spectrometry, except for sex hormone binding globulin (SHBG) levels which were assessed using radioimmunoassay. Substantial geographical variation in the levels of sex steroids, precursors, and metabolites, as well as SHBG, was found among the different countries. For instance, Asian men in Hong Kong and Japan, but not in the United States, had levels of total testosterone approximately 20% higher than in other groups. Even greater variation was observed concerning levels of estradiol, SHBG, and dihydrotestosterone. Group differences in body mass index did not 663
explain most geographical differences. Moreover, body mass index-independent racial differences were present. In black men, higher levels of estrogens (estradiol, estrone) were found, whereas lower levels of glucuronidated androgen metabolites were seen in Asian men. To the knowledge of the reviewer, this is the first cohort study pointing to the fact that there are clinically meaningful ethnic differences in elderly men regarding various sex steroid levels. This observation may have clinical consequences not only in terms of multinational studies where the values of steroid levels play a role but also in the judgment of clinical effects regarding medications, which impact the various sex steroid levels investigated in this cohort study. Hartmut Porst, MD Efficacy of tadalafil in secondary Raynaud’s phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial. PD Shenoy, S Kumar, LK Jha, SK Choudhary, U Singh, R Misra, V Agarwal. Rheumatology 2010;49:2420–8. Level of Evidence: 1b. Editorial Comment: This study (ClinicalTrials. gov database # NCT00626665) enrolled 25 patients suffering from scleroderma and secondary Raynaud’s phenomenon (RP) with at least four attacks per week and with a secondary resistance to vasodilator therapy. Study participants were randomized either to tadalafil 20 mg or placebo on alternate days as add-on therapy to their current vasodilators for 6 weeks. After a 7-day washout, patients were crossed over to the other arm. Primary end points were improvement in the daily frequency and duration of RP episodes and RP condition score (RCS). Secondary outcome measures were healing of existing and appearance of new digital ulcers (DUs) and improvement in scleroderma-specific Health Assessment Questionnaire (SHAQ), quality of life (QoL), flowmediated dilatation (FMD), and patient and physician global assessment. Twenty-four of 25 patients completed the study. While on tadalafil therapy, significant improvement in mean daily frequency, mean daily duration of RP, and mean daily RCS were observed, compared with baseline and placebo. All the 24 digital lesions healed during tadalafil therapy, compared with three out of 13 during the placebo treatment (P < 0.0001). One new DU was reported during tadalafil therapy vs. 13 during placebo therapy (P = 664
0.0005). QoL, SHAQ, FMD, and patient and physician global assessment significantly improved while on tadalafil. Although the number of patients investigated in this trial is relatively small, the findings regarding the impact of tadalafil on the negative clinical consequences of secondary Raynaud’s phenomenon are indeed impressive. This small but well-designed clinical study provides further evidence on the anti-fibrotic properties of tadalafil, which may apply for all phosphodiesterase 5 inhibitors, and on the clinical benefits of their use in conditions linked to increased collagen turnover with subsequent fibrosis. In this regard, besides Raynaud’s phenomenon, other pathologic conditions such as Dupuytren’s contraction or Peyronie’s disease may be target indications with the latter one showing favorable responses to daily tadalafil 5 mg according to the personal experience in those patients. Hartmut Porst, MD Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. SD Beck, AL Bey, R Bihrle, RS Foster. J Urol 2010;184:2078–80. Level of Evidence: 3. Editorial Comment: This study consisted of analysis of a monocenter database from January 1, 2000 to December 31, 2005 regarding the outcome of primary retroperitoneal lymph node dissection because of testicular cancer in terms of fertility and ejaculatory/orgasmic function. Of 280 patients identified, 176 were finally eligible for follow-up between 3 and 9 years after surgery. One hundred seventy-one (97%) of 176 patients who underwent primary retroperitoneal lymph node dissection reported preserved antegrade emission. Of the 135 men who had undergone nerve-sparing procedure, 134 (99%) could ejaculate, as could 33 of 37 (89%) who underwent non-nerve-sparing surgery. Forty-seven (73%) out of 64 men were able to successfully father a child. Another three patients fathered children via in vitro fertilization. This retrospective analysis of the outcome of retroperitoneal lymph node dissection due to testicular cancer is a testimonial of the impressive progress we made in our surgical techniques over the past three decades regarding the management of testicular cancer. This applies both for more sophisticated nerve-sparing techniques, as well as for so-called non-nerve-sparing procedures in which the overwhelming majority of the responsible nerve fibers is also being preserved, thanks to J Sex Med 2011;8:660–665
better anatomical understanding and knowledge. Dating back to the early 1980s where the reviewer was introduced to this kind of surgery, the majority of these young patients was suffering from either loss of emission or ejaculation. Hartmut Porst, MD
Level of evidence 1a 1b 2a 2b
Editor’s Note
Commentaries on clinical studies include a “level of evidence” rating to assist readers in evaluating the significance of the findings and conclusions. The simplified rating scale below is adapted from the more complete recommendations of the Centre for Evidence-Based Medicine (http:// www.cebm.net/index.aspx?o=1025).
J Sex Med 2011;8:660–665
3
4
Type of evidence Evidence from systematic reviews or meta-analysis of randomized controlled trials Evidence from at least one randomized control trial Evidence from at least one controlled study without randomization Evidence from at least one other type of quasi experimental study Evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case control studies Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
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