Emmanuele A. Jannini

Neuroendocrine control of male reproductive function. The opioid system as a model of control at multiple sites

It is known that the same peptide can be identified in different secretory tissues and in the central nervous system (CNS). We now provide evidence that the same peptides can be found in different organs related to the control of a single function, and speculate on the possibility that this reflects a common neuroendocrine programming. Endogenous opioid peptides (EOP) inhibit the reproductive function acting via the CNS. EOP inhibit gonadotropin secretion in rodents and humans via inhibition of GnRH release and have direct inhibitory actions at the pituitary level via specific binding sites on the gonadotrophs. However, EOP can also be synthesized in the testis and in different compartments of the male genital tract. Several findings indicate that EOP of the reproductive tract have a local, paracrine role. These include: (1) the detection of significant beta-endorphin (beta-EP) production by rat Leydig cells (Lc) in cultures; (2) the hormonal regulation of Lc beta-EP production by positive (gonadotropins) and negative (steroids, glucocorticoids, GnRH) factors; (3) the presence of opioid binding sites (Kd in the nanomolar range) in tubular homogenates and Sertoli cells (Sc) in culture of adult and immature rat testes; (4) the inhibition of basal and FSH-stimulated ABP production by Sc in culture when chronically exposed to beta-EP treatment; (5) the detection of high levels of beta-EP and met-enkephalin in human semen with values 6-12 times higher than in plasma; (6) the evidence for inhibitory functions of seminal opioids on sperm motility, vas deferens muscle contraction and partner immune system. Thus the same peptides, i.e. EOP, may control the reproductive function at multiple sites, operating as a multimessenger system in which the central and peripheral level are unified by the common chemical and inhibitory nature of the message.

Sexual inactivity results in reversible reduction of LH bioavailability

We have recently documented significantly reduced serum testosterone (T) levels in patients with erectile dysfunction (ED). To understand the mechanism of this hypotestosteronemia, which was independent of the etiology of ED, and its reversibility only in patients in whom a variety of nonhormonal therapies restored sexual activity, we measured serum luteinizing hormone (LH) in the same cohort of ED patients (n=83; 70% organic, 30% nonorganic). Both immunoreactive LH (I-LH) and bioactive LH (B-LH) were measured at entry and 3 months after therapy. Based on outcome (ie number of successful attempts of intercourse per month), patients were categorized as full responders (namely, at least eight attempts; n=51), partial responders (at least one attempt; n=20) and non-responders (n=16). Compared to 30 healthy men with no ED, baseline B-LH (mean±s.d.) in the 83 patients was decreased (13.6±5.5 vs 31.7±6.9 IU/L, P<0.001), in the face of a slightly increased, but in the normal range, I-LH (5.3±1.8 vs 3.4±0.9 IU/L, P<0.001); consequently, the B/I LH ratio was decreased (3.6±3.9 vs 9.7±3.3, P<0.001). Similar to our previous observation for serum T, the three outcome groups did not differ significantly for any of these three parameters at baseline. However, outcome groups differed after therapy. Bioactivity of LH increased markedly in full responders (pre-therapy=13.7±5.3, post-therapy=22.6±5.4, P<0.001), modestly in partial responders (14.8±6.9 vs 17.2±7.0, P<0.05) but remained unchanged in non-responders (11.2±2.2 vs 12.2±5.1). The corresponding changes went in the opposite direction for I-LH (5.2±1.7 vs 2.6±5.4, P<0.001; 5.4±2.2 vs 4.0±1.7, P<0.05; 5.6±1.2 vs 5.0±1.2, respectively), and in the same direction as B-LH for the B/I ratio (3.7±4.1 vs 11.8±7.8, P<0.001; 4.2±4.3 vs 5.8±4.2, P<0.05; 2.1±0.7 vs 2.6±1.3, respectively). We hypothesize that the hypotestosteronemia of ED patients is due to impaired bioactivity of LH. This reduced bioactivity is reversible, provided that resumption of sexual activity is achieved regardless of the therapeutic modality. Because biopotency of pituitary hormones is controlled by the hypothalamus, LH hypoactivity should be due to the hypothalamic functional damage associated to the psychological disturbances which unavoidably follow sexual inactivity.

Endorphins in male impotence: evidence for naltrexone stimulation of erectile activity in patient therapy

In the present study we evaluated whether naltrexone administration could stimulate sexual function in 30 male patients, ages 25 to 50 years, with idiopathic impotence of at least one years duration and not of organic etiology. The patients received naltrexone (50 mg/day) or placebo, on a random basis for two weeks. Sexual performance, expressed as the number of full coitus/week, was assessed before (time 0) and during (on days 7 and 15) each treatment. The naltrexone therapy significantly increased the number of successful coitus compared to placebo after 7 and 15 days of treatment: improvement of sexual performance was evident in 11 out of the 15 treated patients. All the patients experienced a significant increase in morning and spontaneous full penile erections/week. No significant side effects were reported. Endocrine studies revealed no significant modification of plasma LH, FSH or testosterone by naltrexone, suggesting that the positive effect of the drug on sexual behavior was exerted at a central level. A two-month follow-up, at which time patients were off treatment, erectile capacity had returned to baseline in 10 patients, while five reported complete recovery of their sexual ability. We hypothesize that an alteration in central opioid tone is present in idiopathic impotence and is involved in the impairment of sexual behavior.

The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men

INTRODUCTION In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to develop an evidence-based process of care for the diagnosis and management of testosterone deficiency (TD) in adult men. The panel considered the definition, epidemiology, etiology, physiologic effects, diagnosis, assessment and treatment of TD. It also considered the treatment of TD in special populations and commented on contemporary controversies about testosterone replacement therapy, cardiovascular risk and prostate cancer. AIM The aim was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of diagnosis and management of TD for clinicians without expertise in endocrinology, such as physicians in family medicine and general urology practice. METHOD A comprehensive literature review was performed, followed by a structured, 3-day panel meeting and 6-month panel consultation process using electronic communication. The final guideline was compiled from reports by individual panel members on areas reflecting their special expertise, and then agreed by all through an iterative process. RESULTS This article contains the report of the ISSM TD Process of Care Committee. It offers a definition of TD and recommendations for assessment and treatment in different populations. Finally, best practice treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with TD. CONCLUSION Development of a process of care is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to new insights into the pathophysiology of TD, as well as new, efficacious and safe treatments. We recommend that this process of care be reevaluated and updated by the ISSM in 4 years.

Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis

BACKGROUND Specific factors underlying successful surgical sperm retrieval rates (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in adult patients with Klinefelter syndrome (KS) have not been completely clarified. OBJECTIVE AND RATIONALE The aim of this review was to meta-analyse the currently available data from subjects with KS regarding SRRs as the primary outcome. In addition, when available, PRs and live birth rates (LBRs) after the ICSI technique were also investigated as secondary outcomes. SEARCH METHODS An extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR for conventional-TESE (cTESE) or micro-TESE (mTESE) and its specific determinants without any arbitrary restriction were included. OUTCOMES Out of 139 studies, 37 trials were included in the study, enrolling a total of 1248 patients with a mean age of 30.9 ± 5.6 years. The majority of the studies (n = 18) applied mTESE, 13 applied cTESE and in one case testicular sperm aspiration (TESA) was used. Additionally, four studies used a mixed approach and in one study, the method applied for sperm retrieval was not specified. Overall, a SRR per TESE cycle of 44[39;48]% was detected. Similar results were observed when mTESE was compared to cTESE (SRR 43[35;50]% vs 45[38;52]% for cTESE vs micro-TESE, respectively; Q = 0.20, P = 0.65). Meta-regression analysis showed that none of the parameters tested, including age, testis volume and FSH, LH and testosterone (T) levels at enrollment, affected the final SRR. Similarly, no difference was observed when a bilateral procedure was compared to a unilateral approach. No sufficient data were available to evaluate the effect of previous T treatment on SRR. Information on fertility outcome after ICSI was available for 29 studies. Overall a total of 218 biochemical pregnancies after 410 ICSI cycles were observed (PR = 43[36;50]%). Similar results were observed when LBR was analyzed (LBR = 43[34;53]%). Similar to what was observed for SRR, no influence of KS age, mean testis volume, LH, FSH or total T levels on either PR and LBR was observed. No sufficient data were available to test the effect of the womens age or other female fertility problems on PR and LBR. Finally, no difference in PR or LBR was observed when the use of fresh sperm was compared to the utilization of cryopreserved sperm. WIDER IMPLICATIONS The present data suggest that performing TESE/micro-TESE in subjects with KS results in SRRs of close to 50%, and then PRs and LBRs of close to 50%, with the results being independent of any clinical or biochemical parameters tested.

The safety and efficacy of Avanafil, a new 2nd generation PDE5i: comprehensive review and meta-analysis

ABSTRACT Introduction: The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. Recently, a new PDE5ì, avanafil, has become available worldwide. Areas covered: All placebo-controlled randomized clinical trials (RCTs) on the effect of avanafil in patients with ED were reviewed and meta-analyzed. So far, 5 different RCTs on avanafil have been published, including 1379 and 605 patients in active and placebo groups, respectively. Avanafil was up to 3-fold superior to placebo in determining successful sexual intercourse. Although head-to-head comparative studies are still lacking, re-analyses of available data, showed that avanafil had comparable efficacy, but lower incidence of drug-related side effects, compared to first-generation PDE5is. Expert opinion: Avanafil specific and peculiar pharmacological profile, addresses several problems that have been documented with first-generation PDE5is. Avanafil should theoretically guarantee a low dropout incidence by ensuring a natural profile of action and a low incidence of side effects. Longer studies and head-to-heard trials are advisable to clarify these issues.

Attachment styles and sexual dysfunctions: A case-control study of female and male sexuality

The aim of this study was to investigate attachment styles in a group of women and men with sexual dysfunction. We recruited 44 subjects (21 women and 23 men) with sexual dysfunction and 41 subjects (21 women and 20 men) with healthy sexual function as the control group. Validated instruments for the evaluation of male and female sexual dysfunctions (M/F SD) and a psychometric tool specifically designed to investigate attachment style were administered. In women, significant differences were found between subjects with sexual dysfunction and healthy controls. The scales indicating an insecure attachment showed: discomfort with closeness (FSD=42.85±11.55 vs CTRL=37.38±8.54; P<0.01), relationship as secondary (FSD=26.76±2.60 vs CTRL=18.42±7.99; P<0.01), and need for approval (FSD=26.38±3.61 vs CTRL=20.76±7.36; P<0.01). Healthy women also had significantly higher scores in secure attachment (confidence: FSD=24.57±3.89 vs CTRL=33.42±5.74; P<0.01). Men with sexual dysfunctions differed from healthy men in confidence (MSD=30±6.33 vs CTRL=36.05±5.26; P<0.01) and in discomfort with closeness (MSD=39.08±8 vs CTRL=34.25±7.54; P<0.05). These results suggest that particular aspects related to insecure attachment have a determinant role in people with sexual dysfunctions. It is therefore fundamental to identify the attachment styles and relational patterns in patients receiving counselling and psychological treatments focussed on sexual problems.

Premature ejaculation: old story, new insights

Conventional theories and therapies for premature ejaculation (PE) are based on assumptions not always supported by evidence. This review of the current literature on the physiology of the ejaculatory control, pathogenesis of PE, and available therapies shows that PE is still far from being fully understood. However, several interesting hypotheses have been formulated, and solid, evidence-based clinical data are currently available for dapoxetine, the unique, first-line, officially approved pharmacotherapy for PE. Further growth in the field of PE will occur only when we shift from opinion-based classifications, definitions, and hypotheses to robust, noncontroversial data grounded on evidence.

Hormonal correlations of premature ejaculation

Premature ejaculation is the most frequent male sexual dysfunction, significantly impairing quality of life of both the patient and the partner and affecting up to one-third of men of every age. In the last years, our knowledge about this topic has greatly increased, and studies on the causes and treatments related to ejaculatory disorders have shed a light on previously uncharted territory. Public interest on sexual dysfunctions has likewise increased in the general population: the time lapse between the first symptoms of sexual dysfunction and the seeking of medical advice has been significantly reduced, whereas demand for a treatment has markedly increased. A role of endocrine regulation has been established in all the aspects of male reproduction; however, the endocrine control of ejaculation is not fully understood. Sex steroid, pituitary, and thyroid hormones have all been advocated as potential candidates in the regulation of the ejaculatory process, but exact mechanisms are not clear yet and further studies are required in order to identify potential targets for treatment.

Psychoticism, Immature Defense Mechanisms and a Fearful Attachment Style are Associated with a Higher Homophobic Attitude

INTRODUCTION Homophobic behavior and a negative attitude toward homosexuals are prevalent among the population. Despite this, few researches have investigated the psychologic aspects associated with homophobia, as psychopathologic symptoms, the defensive system, and attachment styles. AIM The aim of this study was to investigate the psychologic factors mentioned earlier and their correlation with homophobia. METHODS Five hundred fifty-one university students recruited, aged 18-30, were asked to complete several psychometric evaluation. MAIN OUTCOME MEASURES In particular, Homophobia Scale (HS) was used to assess homophobia levels, the Symptoms Check List Revised (SCL-90-R) for the identification of psychopathologic symptoms, the Defence Style Questionnaire (DSQ-40) for the evaluation of defense mechanisms and the Relationship Questionnaire (RQ) for attachment styles. RESULTS After a regression analysis, we found a significant predictive value of psychoticism (β = 0.142; P = 0.04) and of immature defense mechanisms (β = 0.257; P < 0.0001) for homophobia, while neurotic defense mechanisms (β = -0.123; P = 0.02) and depressive symptoms (β = -0.152; P = 0.04) have an opposite role. Moreover, categorical constructs of the RQ revealed a significant difference between secure and fearful attachments styles in levels of homophobia (secure = 22.09 ± 17.22 vs. fearful = 31.07 ± 25.09; P < 0.05). Finally, a gender difference to HS scores and a significant influence of male sex was found (β = 0.213; P < 0.0001). CONCLUSIONS We demonstrated the involvement of psychoticism and immature defense mechanisms in homophobic attitudes, while a contrasting role is played by neurotic defense mechanisms and depressive symptoms. Moreover, secure attachment is an indicator of low levels of homophobia compared with the subjects demonstrating a fearful style of attachment. Hence, in the assessment of homophobia and in the relevant programs of prevention, it is necessary to consider the psychologic aspects described earlier.