Irwin Goldstein

International Society for Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation.

INTRODUCTIONnOver the past 20 years our knowledge of premature ejaculation (PE) has significantly advanced. Specifically, we have witnessed substantial progress in understanding the physiology of ejaculation, clarifying the real prevalence of PE in population-based studies, reconceptualizing the definition and diagnostic criterion of the disorder, assessing the psychosocial impact on patients and partners, designing validated diagnostic and outcome measures, proposing new pharmacologic strategies and examining the efficacy, safety and satisfaction of these new and established therapies. Given the abundance of high level research it seemed like an opportune time for the International Society for Sexual Medicine (ISSM) to promulgate an evidenced-based, comprehensive and practical set of clinical guidelines for the diagnosis and treatment of PE.nnnAIMnDevelop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Method.u2002 Review of the literature.nnnRESULTSnThis article contains the report of the ISSM PE Guidelines Committee. It affirms the ISSM definition of PE and suggests that the prevalence is considerably lower than previously thought. Evidence-based data regarding biological and psychological etiology of PE are presented, as is population-based statistics on normal ejaculatory latency. Brief assessment procedures are delineated and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients.nnnCONCLUSIONnDevelopment of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. Therefore, it is strongly recommended that these guidelines be re-evaluated and updated by the ISSM every 4 years.

Clinical Efficacy, Safety and Tolerability of Collagenase Clostridium Histolyticum for the Treatment of Peyronie Disease in 2 Large Double-Blind, Randomized, Placebo Controlled Phase 3 Studies

PURPOSEnIMPRESS (Investigation for Maximal Peyronies Reduction Efficacy and Safety Studies) I and II examined the clinical efficacy and safety of collagenase Clostridium histolyticum intralesional injections in subjects with Peyronie disease. Co-primary outcomes in these identical phase 3 randomized, double-blind, placebo controlled studies included the percent change in the penile curvature abnormality and the change in the Peyronie disease questionnaire symptom bother score from baseline to 52 weeks.nnnMATERIALS AND METHODSnIMPRESS I and II examined collagenase C. histolyticum intralesional injections in 417 and 415 subjects, respectively, through a maximum of 4 treatment cycles, each separated by 6 weeks. Men received up to 8 injections of 0.58 mg collagenase C. histolyticum, that is 2 injections per cycle separated by approximately 24 to 72 hours with the second injection of each followed 24 to 72 hours later by penile plaque modeling. Men were stratified by baseline penile curvature (30 to 60 vs 61 to 90 degrees) and randomized to collagenase C. histolyticum or placebo 2:1 in favor of the former.nnnRESULTSnPost hoc meta-analysis of IMPRESS I and II data revealed that men treated with collagenase C. histolyticum showed a mean 34% improvement in penile curvature, representing a mean ± SD -17.0 ± 14.8 degree change per subject, compared with a mean 18.2% improvement in placebo treated men, representing a mean -9.3 ± 13.6 degree change per subject (p <0.0001). The mean change in Peyronie disease symptom bother score was significantly improved in treated men vs men on placebo (-2.8 ± 3.8 vs -1.8 ± 3.5, p = 0.0037). Three serious adverse events (corporeal rupture) were surgically repaired.nnnCONCLUSIONSnIMPRESS I and II support the clinical efficacy and safety of collagenase C. histolyticum for the physical and psychological aspects of Peyronie disease.

The Erection Hardness Score and Its Relationship to Successful Sexual Intercourse

INTRODUCTIONnThe Erection Hardness Score (EHS), recently validated, was developed in 1998 as a simple (one-item) method to quantify erection outcome data. Although it is intuitive that erection hardness and successful sexual intercourse (SSI) are related, the link has not been directly established.nnnOBJECTIVEnTo evaluate the relationship between erection hardness (assessed by EHS) and SSI, establishing the EHS as a clinically useful tool.nnnMETHODSnThe data set (N = 307) was from a multinational, double-blind, placebo-controlled trial (with open-label extension) of sildenafil citrate in men with erectile dysfunction.nnnMAIN OUTCOME MEASURESnEvent-based modeling used every intercourse attempt and the EHS to estimate the odds ratio of SSI between adjacent EHS categories. Mean-based modeling used mean EHS per patient to determine its relationship to percentage of SSI. Mediation-based modeling used mean EHS and mean percentage of SSI over the double-blind phase to estimate the direct effect of sildenafil treatment on SSI and the indirect effect of sildenafil treatment on SSI via erection hardness.nnnRESULTSnThe odds of SSI for EHS 3 (hard enough for penetration but not completely hard) were 41.9 times (95% confidence interval [CI], 33.0-53.2; P < 0.0001) that for EHS 2 (hard but not hard enough for penetration), and the odds of SSI for EHS 4 (completely hard and fully rigid) were 23.7 times (95% CI, 19.5-28.9; P < 0.0001) that for EHS 3. The percentage of SSI increased approximately curvilinearly with the increase in mean EHS, from almost 60% at EHS 3 to 78.5% at EHS 3.5 and to 93.1% at EHS 4. The indirect effect of sildenafil treatment on SSI via erection hardness accounted for almost 90% of the total effect on SSI (P < 0.0001).nnnCONCLUSIONnThe close and direct relationship between erection hardness and SSI supports the broader use of the EHS-a simple, valid, reliable, and responsive measure-in clinical practice.

ORIGINAL ARTICLE: The Current Outlook for Testosterone in the Management of Hypoactive Sexual Desire Disorder in Postmenopausal Women

INTRODUCTIONnHypoactive sexual desire disorder (HSDD) is a common clinical problem in women, especially those who have experienced surgical menopause. Because androgen levels decline with age and drop dramatically following bilateral oophorectomy, it has been hypothesized that reduced levels of testosterone are related to diminished desire.nnnAIMnAs presented at a continuing medical education satellite symposium during the 2008 annual meeting of the International Society for the Study of Womens Sexual Health, to review the current state of knowledge about the physiologic effects of testosterone in postmenopausal women, the effects of transdermal testosterone delivery in surgically menopausal women with HSDD, and ongoing studies of a transdermal testosterone gel.nnnMETHODSnA review of the pertinent literature, including recent presentations.nnnMAIN OUTCOME MEASURESnResults from the Womens International Study of Health and Sexuality; and studies utilizing the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and validated instruments that assess female sexual function: the Sexual Activity Log, the Profile of Female Sexual Function, and the Personal Distress Scale.nnnRESULTSnSurgically menopausal women receiving testosterone experience significant increases in total satisfying sexual activity vs. women receiving placebo, significant improvement in all domains of sexual function, and decreases in personal distress, with a favorable safety profile.nnnCONCLUSIONSnTestosterone deficiency may be considered among the underlying causes of HSDD. Currently, testosterone is available to women in the United States only via off-label prescribing or by unregulated compounding of testosterone preparations. New safety trials will examine the long-term safety of testosterone gel in surgically menopausal women with HSDD who are at high risk of cardiovascular disease or breast cancer.

Controversies in Sexual Medicine: Use and Abuse of Rigiscan in the Diagnosis of Erectile Dysfunction

INTRODUCTIONnNocturnal penile tumescence and rigidity (NPTR, or, more simply, NPT) studies, with or without the help of a recording computer (Rigiscan), have been traditionally positioned at the head of several erectile dysfunction (ED) diagnostic flowcharts with the aim to distinguish between psychogenic and organic etiology. Shall we continue to consider these tools as a diagnostic gold standard in ED diagnosis?nnnMETHODSnFour scientists with expertise and/or interest in the area of ED pathophysiology and diagnosis were asked to contribute their opinions.nnnMAIN OUTCOME MEASUREnTo give to The Journal of Sexual Medicines reader new stimuli to reexamine a still largely utilized tool utilized in sexual medicines clinical practice.nnnRESULTSnOf the four experts discussing the topic, the first who is the section editor of the Controversy section, believes that NPT/Rigiscan cannot be considered a useful diagnostic tool for differential diagnosis in ED. He is supported by the physiological considerations of the second expert and by the experimental evidence produced and discussed by the expert number four who questions the accuracy, reliability, and usefulness of these tools to measure a critical aspect of the erection physiology which is the adequate rigidity. In contrast, with several good arguments, the third expert still suggests the use of these tools, perhaps not for every man presenting with ED, but at least for the patient with no neurovascular risk factors who presents with a history suggestive of a psychogenic cause.nnnCONCLUSIONnThe reader will judge if the expensive, complicated, and time-consuming effort to record nocturnal erectile activity is or is not useful anymore for the patient and for orienting the treatment choices.

A Multi‐Institutional Observational Study of Testosterone Levels after Testosterone Pellet (Testopel®) Insertion

INTRODUCTIONnImplantable testosterone pellets were approved by the Food and Drug Administration in 1972 for the treatment of testosterone deficiency syndrome (TDS). Clinical use of this testosterone delivery modality has been limited until its recent reintroduction (Testopel(®) , Slate Pharmaceuticals, Durham, NC, USA). Six academic institutions collaborated and combined their databases to more fully characterize serum testosterone levels after the pellet implantations.nnnAIMSnTo assess the time-dependent serum testosterone levels after subcutaneous testosterone pellets in clinical practice for the treatment of TDS.nnnMETHODSnData were retrospectively pooled and analyzed from data in six academic institutions. Variables included patient age, total testosterone concentrations before and after implantation, the number of testosterone pellets implanted, and the time from implantation to measurement of serum testosterone concentrations. Three hundred eighty men undergoing 702 insertions were included for analysis using JMP (version 4.0.4; SAS Institute, Cary, NC, USA).nnnMAIN OUTCOME MEASURESnMain outcome measures were postimplantation total testosterone levels and investigator-reported adverse events. Testosterone levels as a function of the number of pellets implanted and time from implantation were assessed.nnnRESULTSnImplantation of six to ≥10 testosterone pellets (450 to ≥750 mg) increased total testosterone into the therapeutic range at 1 month postimplantation and sustained therapeutic levels (>300) for 4-6 months. Higher pellet numbers (10-12 pellets) were associated with higher, more consistent, and longer maintenance of testosterone levels within the therapeutic range. Four extrusions and three hematomas were reported early in our experience; other investigator-reported adverse events were generally mild to moderate in nature and transient in duration. No subjects required analgesics.nnnCONCLUSIONSnTestosterone pellets (Testopel(®) , Slate Pharmaceuticals) provide sustained levels of testosterone for at least 4 months and up to 6 months in men with TDS. Implantation of ≥8 pellets achieved optimal results with respect to peak mean testosterone level and duration of effect. Testosterone pellets were generally well tolerated.

Interrelationship of Sildenafil Treatment Effects on the Physiological and Psychosocial Aspects of Erectile Dysfunction of Mixed or Organic Etiology

INTRODUCTIONnIn a previous paper using mediation modeling, the direct and indirect effects of sildenafil on erection maintenance were demonstrated.nnnOBJECTIVEnIn an extension of this previous work, the historical psychosocial paradigm of ED, which focuses on performance anxiety, is tested by using mediation modeling to define the relationship of the physiological aspects (hardness and maintenance) and the associated psychosocial aspects (confidence, sexual relationship satisfaction, and performance anxiety) of ED.nnnMETHODSnStatistical mediation analysis using the following outcomes from a double-blind placebo-controlled trial of fixed-dose sildenafil 100 mg or 50 mg: Erection Hardness Score; the 15-item International Index of Erectile Function (IIEF), including item 4 (frequency of erection maintenance after penetration) and item 5 (difficulty of erection maintenance to intercourse completion); the Self-Esteem And Relationship questionnaire; and the question, Do you feel anxious about your next attempt at sexual intercourse?nnnMAIN OUTCOME MEASURESnEstimated percentages of direct and indirect effects of sildenafil on psychosocial aspects of ED (95% confidence intervals).nnnRESULTSnThe model estimated that erection hardness mediated 43.7% (29.3%, 62.4%) of the effect of treatment onto confidence and 45.9% (32.2%, 61.8%) of the effect of treatment onto sexual relationship satisfaction, and that erection maintenance (using IIEF item 4 as a proxy) mediated 23.0% (10.1%, 39.1%) and 22.4% (10.1%, 36.5%), respectively. Similar results were obtained when IIEF item 5 was used as the proxy for measurement of maintenance. Of all possible paths to performance anxiety, only that from treatment via confidence was statistically significant, mediating an estimated 88.6% (55.5%, 146.2%; item 4 model) or 74.9% (47.0%, 121.0%; item 5 model) of the effect of treatment onto anxiety. The direct path to anxiety from treatment was not statistically significant.nnnCONCLUSIONSnIn men treated with sildenafil for ED, performance anxiety might be ameliorated by improved confidence. Improved confidence might be mainly mediated via increased erection hardness.

Persistent Genital Arousal Disorder (PGAD): Case Report of Long-Term Symptomatic Management with Electroconvulsive Therapy

INTRODUCTIONnThis is the second case report of a woman with bipolar disorder type I who noted the onset of persistent genital arousal disorder (PGAD) symptoms after abrupt cessation of paroxetine. With the worsening of PGAD symptoms, she developed severe depression and suicidal thoughts, resulting in her undergoing electroconvulsive therapy (ECT) as management.nnnAIMnTo describe a case of PGAD and develop hypotheses to explain the beneficial actions of ECT on PGAD based on 4 years of ECT administration.nnnMETHODSnPatient self-report after obtaining consent, as well as literature review.nnnRESULTSnAfter the fourth ECT, the patients PGAD symptoms abated serendipitously. She was placed on ECT on demand for the treatment of her PGAD. With each ECT treatment, PGAD symptoms immediately disappeared, relapsing slowly over time until the next ECT was administered. The patient has, thus far, received a total of 30 treatments of ECT. Side effects continue to be minimal and include brief short-term memory loss, headache, and muscle aches.nnnCONCLUSIONnECT is known to induce cerebral excitatory and inhibitory neurotransmitter changes after acute and chronic administration. Sexual arousal is stimulated by the action of hypothalamic and limbic dopamine, noradrenaline, melanocortin, and oxytocin, and inhibited by serotonin, cerebral opioids, and endocannabinoids. Based on the patients bipolar disorder, the mechanism of action of ECT and the observation of ECT effectiveness on her PGAD, we hypothesize the following: (i) bipolar disorder led to central hyperactive dopamine release, an important component in the pathophysiology of her PGAD; (ii) central serotonin deficiency after selective serotonin-reuptake inhibitor (SSRI) withdrawal resulted in a lack of inhibition of sexual excitement; (iii) ECT resulted in lowering of the hyperstimulated central dopamine release; and (iv) ECT led to an increase in sexual inhibition by stimulating serotonin activity. Further research in the central control of sexual arousal is needed.

Does radical nephrectomy increase the risk of erectile dysfunction compared with partial nephrectomy? A cohort analysis.

Study Type – Therapy (prospective cohort)

COMMENTARY: Transfer of Topical Testosterone Preparations to Children or Spouses

T gel (1%) products have been approved by government regulation agencies for use in men with testosterone deficiency syndrome since 2000 and 2003 [1,2]. Efficacy studies have shown topical testosterone preparations to improve such outcomes as sexual function, libido, mood, muscle mass, muscle strength, and energy [3–7]. Topical 1% testosterone gel is also associated with eugonadal testosterone values, unlike the peaks and troughs related to intramuscular testosterone enanthate or cypionate injections [1,2]. Topical 1% testosterone gel is further associated with fewer reactions at the application site compared to testosterone patch therapy [1,2]. As a result of the benefits of topical testosterone gel over intramuscular and patch testosterone alternatives, topical gel products have become a widely utilized therapeutic option for men with testosterone deficiency syndrome, especially those with hypogonadism and sexual health concerns. On May 6, 2009, however, the Food and Drug Administration (FDA) notified health care professionals that prescription testosterone gel products will be required to include a boxed warning on product labels after the FDA received a number of reports of adverse events in children and spouses. To date, reports concerning drug transfer to children and spouses have been primarily published in endocrinology and pediatric journals, with only two reports in The Journal of Sexual Medicine published in 2005 [8,9]. Patients with sexual health complaints frequently have low levels of testosterone, and as a result, sexual medicine health care providers are large prescribers of topical testosterone replacement products [10–16], including approved testosterone gels and non-approved testosterone creams, ointments, and sprays. It is important that sexual medicine health care providers be familiar with the issues of hyperandrogenism in women and virilization in young children secondary to drug transfer from topical testosterone preparations. The case of a 2-year-old boy who came into skin contact with testosterone gel presents some of the negative implications associated with exposure to topical testosterone [17]. The boy was taken to his pediatrician because of pubic hair growth. It was discovered that this pubic hair growth was not accompanied by testicular enlargement, acne, or body odor. Further investigation revealed that the pubic hair growth had been present for 4 months, and neither parent had a history of precocious sexual development. However, it was discovered that the child’s father had been using testosterone cream for the previous 12 months to treat his testosterone deficiency syndrome. The child’s father applied the cream to his forearms nightly, but did not usually have contact with his son until the following morning. When the father ceased use of the testosterone cream, the boy demonstrated no progression of puberty [17]. Similar results were found among other exposed children. An 18-month-old girl was taken to her doctor following pubic hair growth and clitoromegaly [18]. Her stepfather applied testosterone cream to his thighs and then allowed the child to sit on his lap. When the girl was examined, it was revealed that her bone age was 3 years, while her chronological age was 18 months. Her serum testosterone level wasmeasured at 390 ng/dLwhen the desired measurement for children is less than 2649