Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part III.

INTRODUCTION: In 2016 the International Society for the Study of Women's Sexual Health (ISSWSH) published an expert consensus report on new nomenclature that addressed the need for comprehensive, evidence-based criteria for new diagnoses in desire, arousal, and orgasm, with the definition on arousal focusing exclusively on female genital arousal disorder (FGAD). AIM: A new expert panel solely focused on mechanisms of arousal disorders convened to revise the nomenclature to include female cognitive arousal disorder (FCAD) and FGAD. METHODS: The ISSWSH co-chairs identified experts on arousal disorders in women. The 10 participants included clinicians, researchers, and educators, representing a diverse, multidisciplinary group. Pre-meeting preparation included evidence-based literature review as the basis of presentations panelists made at the meeting on the current knowledge in cognitive arousal. Consensus was reached using a modified Delphi method. Writing assignments were made as a basis of manuscript development. MAIN OUTCOME MEASURES: The new definition of FCAD is characterized by distressing difficulty or inability to attain or maintain adequate mental excitement associated with sexual activity, as manifested by problems with feeling engaged and mentally turned on or sexually aroused for a minimum of 6 months. RESULTS: Female sexual arousal disorder encompasses both FGAD (revised definition) and FCAD (new definition). Recommendations regarding diagnosis include a clinical interview to assess for FCAD using targeted questions. Patient-reported outcomes that contain questions to assess FCAD are described, including limitations for differentiating between cognitive arousal, genital arousal, and sexual desire. Laboratory measures of cognitive and genital arousal are discussed, including the relationships between genital and cognitive arousal patterns. Biopsychosocial risk factors for FCAD and FGAD, as well as exclusionary conditions, are presented. CLINICAL IMPLICATIONS: The revision of the ISSWSH nomenclature regarding the criteria for the 2 arousal categories, FCAD and FGAD, and the recommended diagnostic strategies offers a framework for management of women with arousal disorders. STRENGTHS & LIMITATIONS: This nomenclature allows for basic science and clinical research in subtypes of arousal in order to develop better diagnostic and treatment options for use by clinicians, scientists, and regulatory agencies. There are limited validated measures of cognitive arousal, including the Female Sexual Function Index, the most commonly used measure, which does not effectively distinguish between cognitive excitement, genital sensations, and event-related desire. CONCLUSION: Future directions include the refinement of FCAD and FGAD and development and validation of patient-reported outcomes that distinguish between the cognitive processes and genital responses to enhance clinical care and research in this area. Parish SJ, Meston CM, Althof SE, et al. Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions-Part III. J Sex Med 2019;16:452-462.

An update of the International Society of Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE).

INTRODUCTION: In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts. AIM: The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. METHOD: A comprehensive literature review was performed. RESULTS: This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. 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. CONCLUSION: Development 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. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years.

An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation.

INTRODUCTION: The International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation developed the first evidence-based definition for lifelong premature ejaculation (PE) in 2007 and concluded that there were insufficient published objective data at that time to develop a definition for acquired PE. AIM: The aim of this article is to review and critique the current literature and develop a contemporary, evidence-based definition for acquired PE and/or a unified definition for both lifelong and acquired PE. METHODS: In April 2013, the ISSM convened a second Ad Hoc Committee for the Definition of Premature Ejaculation in Bangalore, India. The same evidence-based systematic approach to literature search, retrieval, and evaluation used by the original committee was adopted. RESULTS: The committee unanimously agreed that men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Men with acquired PE are older, have higher incidences of erectile dysfunction, comorbid disease, and cardiovascular risk factors, and have a longer intravaginal ejaculation latency time (IELT) as compared with men with lifelong PE. A self-estimated or stopwatch IELT of 3 minutes was identified as a valid IELT cut-off for diagnosing acquired PE. On this basis, the committee agreed on a unified definition of both acquired and lifelong PE as a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. CONCLUSION: The ISSM unified definition of lifelong and acquired PE represents the first evidence-based definition for these conditions. This definition will enable researchers to design methodologically rigorous studies to improve our understanding of acquired PE.

Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene.

We show here that quantitative measurement of DNA copy number across amplified regions using array comparative genomic hybridization (CGH) may facilitate oncogene identification by providing precise information on the locations of both amplicon boundaries and amplification maxima. Using this analytical capability, we resolved two regions of amplification within an approximately 2-Mb region of recurrent aberration at 20q13.2 in breast cancer. The putative oncogene ZNF217 (ref. 5) mapped to one peak, and CYP24 (encoding vitamin D 24 hydroxylase), whose overexpression is likely to lead to abrogation of growth control mediated by vitamin D, mapped to the other.

High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.

Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes. Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies. Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments. We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.

Assembly of microarrays for genome-wide measurement of DNA copy number.

We have assembled arrays of approximately 2,400 BAC clones for measurement of DNA copy number across the human genome. The arrays provide precise measurement (s.d. of log2 ratios=0.05-0.10) in cell lines and clinical material, so that we can reliably detect and quantify high-level amplifications and single-copy alterations in diploid, polyploid and heterogeneous backgrounds.

Sexual arousal and lubrication problems in women with clinically diagnosed hypoactive sexual desire disorder: preliminary findings from the hypoactive sexual desire disorder registry for women.

Sexual desire and arousal difficulties are often correlated in women. However, no studies have examined characteristics of women with clinically diagnosed hypoactive sexual desire disorder (HSDD) that increase the likelihood of co-occurring arousal difficulties. The authors examined combined HSDD and arousal/ lubrication problems using baseline cross-sectional data from the HSDD Registry for Women. Their analyses were restricted to women who could be classified with certainty as having arousal or lubrication difficulties by the Female Sexual Function Index (requiring sexually activity in the past 4 weeks). Results showed that among 426 premenopausal women with HSDD, 50.2% had arousal problems, 42.5% lubrication problems, 39.0% combination, and 46.2% neither. Among 174 postmenopausal women, prevalence percentages were 58.0% arousal, 56.9% lubrication, 49.4% combined, and 34.5% neither. The strongest predictor of combined arousal/lubrication problems was self-reported severity of HSDD. Among premenopausal women, race/ethnicity, depression, and lower relationship happiness were also associated with combined arousal/lubrication problems. Among postmenopausal women, surgical menopause and use of selective serotonin reuptake inhibitors were positively associated with arousal problems. Arousal and lubrication problems were present in approximately half of this subsample of HSDD Registry participants, with distinctions in prevalence and predictors by menopausal status and type of arousal difficulty (arousal vs. lubrication).

Survey of treatment practices for sexual dysfunction(s) associated with anti-depressants.

There are many management strategies and antidotes available for sexual dysfunction associated with antidepressants available. However, only a few of these strategies and antidotes were tested in rigorous trials and most of them probably will not be rigorously tested. Surveying the prescribing practices of experts in this area provides another opportunity to evaluate these strategies and antidotes. The authors surveyed 29 (of 50) "expert" psychiatrists in the area of sexual dysfunction associated with antidepressants. Switching to another antidepressant, decreasing the dose of an antidepressant, and adding oral agents such as bupropion, phosphodiesterase-5 inhibitors, and some dopaminergic agents (dextroamphetamine, methylphenidate) and a testosterone patch in some dysfunctions (libido, orgasm) are management strategies most frequently used by the experts. The experts also consider these strategies as the most effective ones. These findings are compared with other studies and discussed with regard to the evidence from clinical trials.

A large field CCD system for quantitative imaging of microarrays.

We describe a charge-coupled device (CCD) imaging system for microarrays capable of acquiring quantitative, high dynamic range images of very large fields. Illumination is supplied by an arc lamp, and filters are used to define excitation and emission bands. The system is linear down to fluorochrome densities <<1 molecule/microm2. The ratios of the illumination intensity distributions for all excitation wavelengths have a maximum deviation approximately +/-4% over the object field, so that images can be analyzed without computational corrections for the illumination pattern unless higher accuracy is desired. Custom designed detection optics produce achromatic images of the spectral region from approximately 450 to approximately 750 nm. Acquisition of a series of images of multiple fluorochromes from multiple arrays occurs under computer control. The version of the system described in detail provides images of 20 mm square areas using a 27 mm square, 2K x 2K pixel, cooled CCD chip with a well depth of approximately 10(5) electrons, and provides ratio measurements accurate to a few percent over a dynamic range in intensity >1000. Resolution referred to the sample is 10 microm, sufficient for obtaining quantitative multicolor images from >30,000 array elements in an 18 mm x 18 mm square.

Rapid ejaculation: a review of nosology, prevalence and treatment.

Information concerning the epidemiology, etiology and treatment of premature (rapid) ejaculation is reviewed. Evidence concerning the prevalence of premature ejaculation indicates that subjective concern about rapid ejaculation is a common concern worldwide. Hypotheses concerning the pathogenesis of premature ejaculation include: (1) that it is a learned pattern of ejaculation maintained by interpersonal anxiety, (2) that it is the result of dysfunction in central or peripheral mechanisms regulating ejaculatory thresholds and (3) that it is a normal variant in ejaculatory latency. Current evidence based treatment interventions include behavioral psychotherapy and the use of pharmacological agents, including topical anesthetic agents and selective serotonin reuptake inhibitors.

Conjoint marital therapy: a cognitive behavioral model.

This article presents an integrated cognitive-behavioral model for conjoint therapy of chronic marital discord. The model is based on eight empirically testable hypotheses that are clinically relevant and integrate contributions from general systems theory, behavioral marital therapy, and psychoanalysis. Disproof of cognitive schemas for the perception of the opposite sex (transference reactions) is hypothesized to be a common therapeutic mechanism in the dissimilar models of marital therapy.

Effects of psychotropic drugs on human erection and ejaculation.

Evidence concerning pharmacological effects on human sexuality suggests that dopaminergic receptor activation may be associated with penile erection. Erection also appears to involve inhibition of alpha-adrenergic influences and beta-adrenergic stimulation plus the release of a noncholinergic vasodilator substance, possibly vasoactive intestinal peptide. Ejaculation appears to be mediated primarily by alpha-adrenergic fibers. Serotonergic neurotransmission may inhibit the ejaculatory reflex. An understanding of the neurobiological substrate of human sexuality may assist clinicians in choosing psychotropic agents with minimal adverse effects on sexual behavior and may also contribute to the development of pharmacological interventions for sexual difficulties.

Concurrent psychotherapy and behavior therapy. Treatment of psychoneurotic outpatients.

The feasibility and effects of treating psychoneurotic outpatients with concomitant but separate treatment programs of psychoanalytically oriented psychotherapy and behavior therapy was investigated in three cases, utilizing detailed clinical observations and questionnaire responses. The two treatment regimens appeared to have synergistic effects, and anticipated difficulties, such as a split therapeutic alliance, symptom substitution, or preciptious withdrawal from psychotherapy after symptom removal, did not occur. Although there was no evidence of symptom substitution after the behavioral removal of the "target symptom," both clinical observations and questionnaire responses indicated that successful behavior therapy had many unanticipated effects on the patient's nontarget behaviors and cognitions.

BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications.

Chromosome 15q11-q13 is one of the most variable regions of the human genome, with numerous clinical rearrangements involving a dosage imbalance. Multiple clusters of segmental duplications are found in the pericentromeric region of 15q and at the breakpoints of proximal 15q rearrangements. Using sequence maps and previous global analyses of segmental duplications in the human genome, a targeted microarray was developed to detect a wide range of dosage imbalances in clinical samples. Clones were also chosen to assess the effect of paralogous sequences in the array format. In 19 patients analysed, the array data correlated with microsatellite and FISH characterisation. The data showed a linear response with respect to dosage, ranging from one to six copies of the region. Paralogous sequences in arrayed clones appear to respond to the total genomic copy number, and results with such clones may seem aberrant unless the sequence context of the arrayed sequence is well understood. The array CGH method offers exquisite resolution and sensitivity for detecting large scale dosage imbalances. These results indicate that the duplication composition of BAC substrates may affect the sensitivity for detecting dosage variation. They have important implications for effective microarray design, as well as for the detection of segmental aneusomy within the human population.

Three cases of female anorgasmia associated with MAOIs.

Monoamine oxidase inhibitors have been associated with male retarded ejaculation and impotence. The authors describe three cases of female anorgasmia secondary to this class of antidepressants. To the author's knowledge only one incidental finding of this kind has been reported.

Synthesis of Y chromosome-specific labeled DNA probes by in vitro DNA amplification.

We describe the use of in vitro DNA amplification for production of double-stranded, biotin-labeled DNA probes. Specifically, a 124 BP DNA segment of the Y chromosome-specific 3.4 KB repeat was amplified in preparations of human genomic DNA using the polymerase chain reaction (PCR) and a thermostable DNA polymerase. The PCR products were amplified further in the presence of a molar excess of biotin-11-dUTP. The resulting double-stranded DNA segments showed a high amount of incorporated biotin-11-dUTP. The probes were used in DNA-DNA hybridization experiments without further purification. When DNA sequences flanking the target region are known, probe generation by enzymatic amplification offers a rapid and efficient alternative to molecular cloning and nick translation.