Experimental Evidence for Sildenafil’s Action in the Central Nervous System: Dopamine and Serotonin Changes in the Medial Preoptic Area and Nucleus Accumbens During

Christos Kyratsas, MD,* Christina Dalla, PhD,* Elmira Anderzhanova, MD, PhD,*§ Alexia Polissidis, PhD,* Nikolaos Kokras, MD, PhD,*† Konstantinos Konstantinides, MD,‡ and Zeta Papadopoulou-Daifoti, PhD*

*Department of Pharmacology, Medical School, University of Athens, Athens, Greece; †First Department of Psychiatry, Eginition Hospital, Medical School, University of Athens, Athens, Greece; ‡Andrology Institute of Athens, Athens, Greece

J Sex Med 2013;10:719–729

Abstract

Introduction. Sildenafil is the first effective oral treatment for male . Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc). Aim. The aim of this study was to determine whether sildenafil administration alters dopaminergic and serotonergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal. Methods. An acute (2 days) or chronic (21 days) sildenafil regimen (1 mg/kg) was administered intraperitoneally to male rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time. Main Outcome Measures. Tissue levels of DA and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as serotonin (5-HT) and its metabolite 5-HIAA, were measured in the mPOA and NAcc with high-performance liquid chromatography with electrochemical detector. Dopamine ([DOPAC+HVA]/DA) and serotonin (5-HIAA/5-HT) turnovers were also calculated as indices of neurotransmission. Results. In nontrained males, acute and chronic sildenafil treatment increased DA and 5-HT turnover rates in the mPOA and NAcc. In trained rats, acute sildenafil also increased DA and 5-HT turnover rates in both structures, whereas chronic treatment enhanced 5-HT turnover rate only in the mPOA and DA turnover rate only in the NAcc. Conclusions. Our data confirm that sildenafil enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil-induced effects on serotonergic activity in these brain regions as well. Therefore, present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal.

Editorial comment: This paper investigated if sildenafil administration influences central neural pathways, namely dopaminergic and serotonergic activity in the nucleus accumbens (NAcc) and the medial preoptic area (mPOA), in a model of sexual arousal. It is well established the peripheral role of the phosphodiesterase type 5 inhibitor (PDE5I) sildenafil in inducing corpus cavernosum relaxation events. However and since sildenafil has the ability to cross the blood-brain barrier, a central action for this drug has been hypothesized. In fact, it has been reported a positive effect of sildenafil administration on dopaminergic pathways in the NAcc. However, less information is available on the regulatory effects of this PDE5I in other brain areas involved in male sexual behavior, as the mPOA, or in other pathways, as the serotonergic system. The authors verified if sildenafil treatment would alter dopaminergic and serotonergic activity in the mPOA and NAcc using a model of “noncontact” sexual encounter. Given that sexually trained rats may differ from nontrained rats in terms of treatment response, it was also examined whether previous sexual experience could influence the effects of sildenafil on the neurochemical measurements. Male and female Wistar rats were used. Male animals were divided in two groups: 1) sexually trained rats (two sessions of “noncontact” exposure to inaccessible estrous females); 2) nontrained rats (without female stimulus). Both trained and nontrained groups received either daily intraperitoneal injections of sildenafil (1 mg/kg) for 2 days (acute) or for 21 days (chronic). Nontrained and trained control groups were injected acutely or chronically with vehicle. After these treatment timepoints all the groups had a final “noncontact” session, during which the number of was recorded. Immediately after, the animals were sacrificed, the brain removed for dissection of the NAcc and the mPOA, which were processed for the chromatographic detection of DA and 5-HT. Results showed that previously trained rats generally displayed more erections than nontrained rats. Sildenafil administration increased the number of noncontact erections, as well as the percentage of male rats that displayed noncontact erections. No significant differences were detected between acute and chronic sildenafil-treated rats. Regarding DA levels, in the mPOA there was a significant interaction of sildenafil treatment with previous training. In nontrained and trained rats, both acute and chronic sildenafil treatments decreased DA levels, in comparison to the respective vehicle groups. DA metabolites were not significantly affected in any of the groups by the treatments. In nontrained rats the DA turnover rate ([DOPAC+HVA]/DA) was increased, both in acute and chronic sildenafil treated groups. In trained rats, only acute sildenafil administration significantly enhanced the DA turnover rate. 5-HT levels were not affected by previous training. Only acute administration of sildenafil reduced 5-HT in both groups, whereas chronic therapy did not produce an effect. 5-HT metabolite remained unaffected by PDE5I administration. Both acutely and chronically sildenafil-treated rats had higher serotonergic turnover (5-HIAA/5-HT), in comparison to controls. In the NAcc, DA tissue levels were decreased following acute and chronic sildenafil treatment. There were no significant effects of previous training or sildenafil treatment in DA metabolites. Analysis of the DA turnover rate ([DOPAC+HVA]/DA) revealed an enhancement in acute and chronic sildenafil-treated rats, irrespectively of previous training. Concerning 5-HT tissue levels in the NAcc, there was an interaction between previous training and sildenafil treatment. Both acute and chronic sildenafil treatment decreased 5-HT tissue levels in nontrained and trained rats. 5-HT’s metabolite was enhanced in rats treated acutely or chronically with sildenafil, irrespective of previous training. Consequently, serotonergic turnover was enhanced after PDE5I treatment. Overall, these studies show that centrally administered sildenafil increases dopaminergic neurotransmission in the NAcc and extend these findings to the mPOA. Furthermore, they demonstrate similar sildenafil- induced effects regarding serotonergic activity in these brain regions. The putative underlying mechanism for these neurochemical effects could involve the modification of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway since DA release in the mPOA is most likely mediated by glutamatergic-mediated NO activity. Given that sildenafil acts via the NO/cGMP pathway, it could be hypothesized that this pathway is activated in order to enhance central dopaminergic activity and male sexual response. From a clinical standpoint, it is known that many cases of erectile dysfunction either coexist with or cause secondary libido/sexual motivation disorders. This observation, along with the presented results, could potentially explain the effects of PDE5I in patients with psychogenic erectile dysfunction, when no organic disorder is confirmed.

Affiliation:

Carla Costa Professor of Cell and Molecular Biology Faculty of Medicine of the University of Porto, Portugal E-mail: [email protected]

Long-term changes of sexual function in men with obstructive sleep apnea after initiation of continuous positive airway pressure.

Budweiser S, Luigart R, Jörres RA, Kollert F, Kleemann Y, Wieland WF, Pfeifer M, and Arzt M. J Sex Med 2013;10:524–531.

Introduction. Obstructive sleep apnea (OSA), particularly intermittent nocturnal hypoxemia, is associated with erectile dysfunction (ED). Aim. We investigated in patients with OSA whether continuous positive airway pressure (CPAP) therapy has a long-term effect on sexual function, including ED, in the presence of other risk factors for ED. Methods. Within a long-term observational design, we reassessed 401 male patients who had been referred for polysomnography, with respect to erectile and overall sexual function. Mean _ standard deviation follow- up time was 36.5 _ 3.7 months. Patients with moderate to severe ED were stratified according to the regular use of CPAP. Main Outcome Measure. Changes of sexual function were assessed by the 15-item International Index of Erectile Function (IIEF-15) questionnaire, including the domains erectile function (EF), intercourse satisfaction, orgasmic function (OF), sexual desire (SD), and overall satisfaction (OS). Results. Of the 401 patients, 91 returned a valid IIEF-15 questionnaire at follow-up. Their baseline characteristics were not different from those of the total study group. OSA (apnea–hypopnea index >5/hour) had been diagnosed in 91.2% of patients. In patients with moderate to severeED(EF domain <17), CPAP users (N = 21) experienced an improvement in overall sexual function (IIEF-15 summary score; P = 0.014) compared with CPAP non-users (N = 18), as well as in the subdomains OF (P = 0.012), SD (P = 0.007), and OS (P = 0.033). Similar results were obtained in patients with poor overall sexual dysfunction (IIEF-15 summary score <44). In patients with moderate to severeEDand low mean nocturnal oxygen saturation (_93%, median), also the EF subdomain improved in CPAP users vs. non-users (P = 0.047). Conclusions. These data indicate that long-term CPAP treatment of OSA and the related intermittent hypoxia can improve or preserve sexual function in men with OSA and moderate to severe erectile or sexual dysfunction, suggesting a certain reversibility of OSA-induced sexual dysfunctions.

Comments Clinical investigations suggest that also OSA is strongly associated with ED. Recently, articles’ authors demonstrated that this association remains significant even if other, known risk factors for ED are present Whether the effects on ED or sexual function are reversible by therapy of OSA and its related intermittent hypoxia has not been explored in detail. Most of the studies addressing the effects of CPAP in patients with OSA and ED investigated only short-term effects over 1–3 months or were based on small numbers of patients prospectively investigated whether CPAP therapy exerts a longterm effect on sexual function, including ED, even in the presence of other risk factors for ED. Limitation of study have been reported : changes in body weight, medication, or comorbidities could have contributed to the measured effect, but according to the study design, these were not systematically assessed ; the response rate to the questionnaire was not fully satisfying and could have biased results, although the baseline characteristics of participants did not differ from those of the initial study group. Nevertheless, thisprospective investigation provides evidence that in patients with OSA and moderate to severe ED, the regular, long-term use of CPAP has a beneficial effect on erectile and overall sexual function even in the presence of other risk factors predisposing for ED. But the evaluation of the effects of CPAP on ED in large clinical trials, including objective measures of ED and adherence to CPAP therapy, is needed.

Habituation of sexual responses in men and women: A test of the preparation hypothesis of women’s genital responses.

Dawson SJ, Suschinsky KD, and Lalumière ML. J Sex Med 2013;10:990–1000.

Introduction. Laboratory studies have revealed two well-replicated sex differences in sexual arousal patterns: category specificity and sexual concordance. Men’s genital responses are dependent on specific sexual cues and are concordant with subjective reports of arousal.Women’s genital responses are much less dependent on specific sexual cues and are much less concordant with their subjective reports. The preparation hypothesis provides a functional explanation for these sex differences and posits that women’s genital responses are not tied to sexual preferences but rather occur automatically in the presence of any sexual cue to protect the genital tissues from injuries incurred through sexual activity. This hypothesis leads to the expectation that women’s genital responses may not habituate as quickly or as completely as men’s. Aim. To determine whether there is a sex difference in the habituation of genital responses and to further test the preparation hypothesis of women’s genital responses. Methods. Twenty men and 20 women had their genital responses measured while they were exposed to nine consecutive presentations of the same erotic film clip (habituation), followed by two presentations of different erotic film clips (novelty), and followed by two presentations of the original erotic film clip (dishabituation). Main Outcome Measures. Genital responses were measured continuously using penile strain gauges (assessing penile circumference) and vaginal probes (assessing vaginal pulse amplitude). Participants reported subjective sexual arousal, perceived genital arousal, and attention after each film clip presentation. Results. Men and women displayed very similar patterns of genital responses, consistent with habituation and novelty effects. Effects of habituation and novelty were eliminated once subjective reports of attention were covaried. Conclusion. Contrary to the prediction from the preparation hypothesis of women’s genital responses, men’s and women’s responses showed similar patterns of habituation upon repeated exposure. Future research should attempt to maintain participants’ attention in order to further test the preparation hypothesis.

Comments It is unclear whether habituation of genital responses occurs similarly in both sexes: men appear to be more likely to habituate than women. Only one study has used the same experimental procedure on both sexes produced a very unusual result for men; the three studies conducted with women have produced very different results and used different methodologies, thus it remains unsure whether women’s genital responses habituate. The first goal of this study was to determine whether a sex difference exists in the habituation of genital responses. The second goal was to further test a prediction generated from the preparation hypothesis, that is, to determine whether women’s genital responses are more resistant than men’s to repeated stimulation. This study is the first to find no sex difference in the patterns of habituation of genital responses when men and womenare tested with the same experimental design. The patterns of habituation across the three measures of arousal were strikingly similar. It is thus possible that the sexual responses of men and women are similarly malleable and equally subject to learning processes, similar to studies investigating other forms of learning on genital responses (e.g., conditioning). In addition to the limitation of not assessing lubrication in the current study, the use of the exact same erotic stimulus repeatedly may not provide an optimal test of the preparation hypothesis of women’s genital responses. Future studies should attempt to manipulate attention and investigate the role of appraisal in order to extricate the relationship between learning, sexual responses, and attentional commitment. Research using other technologies to assess attention, such as eye tracking, in concert with penile plethysmography and women’s genital responses with vaginal photoplethysmography may aid in explaining the cognitive processes involved in the processing of visual stimuli mediating sexual responses.

Affiliation:

Beatrice Cuzin Head of Andrology Unit Department of and Transplantation E Herriot Universitary Hospital Lyon, France Email: Beatrice.cuzin[at]chu-lyon.fr Surgical Solutions for the Complications of the Vaseline Self-Injection of the Penis

Zoltán Bajory, MD, PhD,* Gábor Mohos, MD,† Ágnes Rosecker, MD,* Noémi Bordás, MD,* and László Pajor, MD, PhD*

*Department of Urology, University of Szeged, Szeged, Hungary; †Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary

J Sex Med 2013;10:1170–1177

Introduction. Penile girth enhancement by the injection of Vaseline is an existing practice. Many cases develop severe complications that need surgery. Aim. To report on the reconstructive surgical solutions of the complications of Vaseline self-injection and the outcomes. To develop a modification of a one-step reconstruction method involving the use of pedicled scrotal flaps. Main Outcome Measures. The complications and their surgical solutions were classified as regards severity and difficulty. The outcomes were observed and a newly introduced one-step surgical method was investigated. Methods. Seventy-eight consecutive patients (87.2% of them with a history of imprisonment) were divided into three groups. In group A, aesthetic penile defects or phimosis caused by the Vaseline necessitated or local excision. In group B, the whole penile skin was involved, and total skin removal and two- or (a newly modified) one-step reconstructive surgery were performed. In group C, both the whole penile skin and the scrotum were involved: complete skin removal and skin grafting or skin pedicled flap transplantation were carried out.

Results. In five cases in group B, postoperative skin necrosis made a second operation necessary. There was one intraoperative urethral injury, where a urethral fistula developed and a second urethral reconstruction was performed. There was no major complication with the newly developed one-stage pedicled flap procedure. At the end of the therapy, all the cases were healed. All of the patients reported successful sexual intercourse after the operations and 91% were satisfied with the result.

Conclusions. The complications depend mainly on the amount of Vaseline injected, the hygienic circumstances, and the personal tolerability. In the worst cases, only radical skin removal and skin transplantation can solve the problem. The newly developed one-step arterial branch-preserving scrotal skin flap reconstruction appears to be a suitable and cost-effective solution for these patients.

Editorial comment: The injection of warmed Vaseline beneath the penile skin is an existing practice, mostly in Eastern European countries, and in special subpopulations (prisoners, low social class, etc.). This report is particularly interesting as immigrants from these countries are currently living all around Europe, and seeking help in our departments.

Complications of self-injected Vaseline in the penis (usually under unhygienic conditions) include penile pain, genital skin inflammation, difficulties during sexual intercourse, granuloma, ulcer, skin necrosis, and gangrene. Surgical genital repair and reconstruction procedures very often include total penile skin removal, skin grafts and flaps. In severe cases more complicated two-or-more-step reconstructive surgery is needed. It is always a challenging procedure, which puts the skill of the surgical team to the test. Authors propose an advanced one-step method of reconstructive surgery, which can make the procedures more effective, more acceptable, and cheaper. They stress in the conclusions that the earlier the surgery is performed, the lower the number of postoperative complications and the better the aesthetic result of the surgery.

Affiliation: Natalio Cruz Head of the Andrology Unit Department of Urology and Nephrology Virgen del Rocío University Hospital Sevilla, E-mail: [email protected]