Steroidogenic factor-1 inverse agonists as a treatment option for canine hypercortisolism: in vitro study.

Hypercortisolism is one of the most commonly diagnosed endocrinopathies in dogs, and new targeted medical treatment options are desirable. Steroidogenic factor-1 (SF-1), an orphan nuclear hormone receptor, is a key regulator of adrenal steroidogenesis, development, and growth. In pituitary-dependent hypercortisolism (PDH), high plasma ACTH concentrations increase the transcriptional activity of SF-1. In adrenal-dependent hypercortisolism, SF-1 expression is significantly greater in dogs with recurrence after adrenalectomy than in those without recurrence. Inhibition of SF-1 could therefore be an interesting treatment option in canine spontaneous hypercortisolism. We determined the effects of 3 SF-1 inverse agonists, compounds IsoQ A, #31, and #32, on cortisol production, on the messenger RNA (mRNA) expression of steroidogenic enzymes and SFs, and on cell viability, in primary adrenocortical cell cultures of 8 normal adrenal glands and of 3 cortisol-secreting adrenocortical tumors (ATs). To mimic PDH, the normal adrenocortical cell cultures were stimulated with ACTH. The results show that only compound #31 inhibited cortisol production and SF-1 target gene expression in non-ACTH-stimulated and ACTH-stimulated normal adrenocortical cells but did not affect cell viability. In the AT cell cultures, the effects of #31 on cortisol production and target gene expression were variable, possibly caused by a difference in the SF-1 mRNA expressions of the primary tumors. In conclusion, inhibition of SF-1 activity shows much promise as a future treatment for canine hypercortisolism.

New Insights in the Functional Zonation of the Canine Adrenal Cortex.

BACKGROUND: Current understanding of adrenal steroidogenesis is that the production of aldosterone or cortisol depends on the expression of aldosterone synthase (CYP11B2) and 11ß-hydroxylase cytochrome P450 (CYP11B1), respectively. However, this has never been studied in dogs, and in some species, a single CYP11B catalyzes both cortisol and aldosterone formation. Analysis of the canine genome provides data of a single CYP11B gene which is called CYP11B2, and a large sequence gap exists near the so-called CYP11B2 gene. OBJECTIVES: To investigate the zonal expression of steroidogenic enzymes in the canine adrenal cortex and to determine whether dogs have 1 or multiple CYP11B genes. ANIMALS: Normal adrenal glands from 10 healthy dogs. METHODS: Zona fasciculata (zF) and zona glomerulosa (zG) tissue was isolated by laser microdissection. The mRNA expression of steroidogenic enzymes and their major regulators was studied with RT-qPCR. Southern blot was performed to determine whether the sequence gap contains a CYP11B gene copy. Immunohistochemistry (IHC) was performed for 17α-hydroxylase/17,20-lyase (CYP17). RESULTS: Equal expression (P = .62) of the so-called CYP11B2 gene was found in the zG and zF. Southern blot revealed a single gene. CYP17 expression (P = .05) was significantly higher in the zF compared with the zG, which was confirmed with IHC. CONCLUSIONS AND CLINICAL IMPORTANCE: We conclude that there is only 1 CYP11B gene in canine adrenals. The zone-specific production of aldosterone and cortisol is probably due to zone-specific CYP17 expression, which makes it an attractive target for selective inhibition of cortisol synthesis without affecting mineralocorticoid production in the zG.

Internet-based brief sex therapy for heterosexual men with sexual dysfunctions: a randomized controlled pilot trial.

INTRODUCTION: Internet-based sex therapy for men with erectile dysfunction has been advocated as an easily accessible and cost-effective treatment. AIM: To test whether Internet-based sex therapy is superior to waiting list. METHODS: Internet-based therapy was administered to heterosexual men with erectile dysfunction or premature ejaculation, without face-to-face contact, in a waiting-list controlled design, with pre-, post-, and follow-up measurements at 3 and 6 months posttreatment. Treatment was based on the sensate-focus model of Masters and Johnson, and supplemented with cognitive restructuring techniques. MAIN OUTCOME MEASURES: Self-reported improvement of sexual functioning, erectile functioning (men with ED), premature ejaculation (men with PE), sexual desire, overall sexual satisfaction, and sexual self-confidence. RESULTS: Ninety-eight men participated (58 ED, 40 PE). Sexual functioning was much or somewhat improved in 40 participants (48%). In participants with ED, a near significant effect of treatment was found (P = 0.065), with higher levels of sexual desire (P < 0.05) and sexual self-confidence (P = 0.05) in treated men, in addition to improved erectile functioning (P = 0.01) and overall sexual satisfaction (P < 0.001) in both groups. In participants with PE, treatment was not superior to waiting list. In participants with ED, erectile functioning (P < 0.05) and overall sexual satisfaction (P = 0.002) improved significantly. In participants with PE, latency to ejaculation (P < 0.001), sexual desire (P < 0.05), and overall sexual satisfaction (P < 0.05) improved significantly from baseline to posttreatment, with no further changes at both follow-ups. Sexual self-confidence in men with PE remained unchanged during treatment until follow-up at 3 months posttreatment, and then was found to be improved at 6-months follow-up (P < 0.05). CONCLUSION: Internet-based sex therapy for male erectile dysfunction was efficacious for male erectile disorder. For men with premature ejaculation, however, treatment was not superior to waiting list.

Tadalafil (Cialis) and erectile dysfunction after radiotherapy for prostate cancer: an open-label extension of a blinded trial.

OBJECTIVES: To determine the efficacy of tadalafil (Cialis) in patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy for prostate cancer in an extended open-label phase of the blinded trial. METHODS: Sixty patients entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received tadalafil 20 mg or placebo for 6 weeks and then crossed over to the alternate medication. Of these 60 patients, 51 (85%) entered a 6-week open-label extension phase. The data were collected using the International Index of Erectile Function (IIEF) questionnaire. Side effects were also recorded. RESULTS: All patients completed the double-blind cross-over study. The 9 patients who did not wish to enter the open-label phase had had significantly worse scores statistically on the erectile function domain of the IIEF with tadalafil in the blinded trial (P = 0.03). For all IIEF domains, except for sexual desire, tadalafil was equally effective in the double-blind phase as in the open-label phase. For nearly all the IIEF questions, tadalafil caused a significant increase in the mean scores from baseline in the run-in period of the blinded trial. The side effects were mild or moderate and had significantly decreased compared with tadalafil in the blinded trial. CONCLUSIONS: Tadalafil is effective in many patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy for prostate cancer. In the open-label extension of the trial, tadalafil showed the same efficacy as in the blinded phase.

Challenges of linking scientific knowledge to river basin management policy: AquaTerra as a case study.

The EU Project AquaTerra generates knowledge about the river-soil-sediment-groundwater system and delivers scientific information of value for river basin management. In this article, the use and ignorance of scientific knowledge in decision making is explored by a theoretical review. We elaborate on the 'two-communities theory', which explains the problems of the policy-science interface by relating and comparing the different cultures, contexts, and languages of researchers and policy makers. Within AquaTerra, the EUPOL subproject examines the policy-science interface with the aim of achieving a good connection between the scientific output of the project and EU policies. We have found two major barriers, namely language and resources, as well as two types of relevant relationships: those between different research communities and those between researchers and policy makers.

Sex therapy through the internet for men with sexual dysfunctions: a pilot study.

Results are described of a pilot study of the efficacy of sex therapy through the Internet for thirty-nine men with erectile dysfunction or rapid ejaculation. Treatment consisted of sex therapy (Masters & Johnson, 1970), had a duration of three months, and was conducted entirely through e-mail. Forty-six percent of the participants dropped out. Fourteen (67%) participants reported an improvement of their sexual functioning. Seven (47%) participants reported the improvement had sustained one month after termination, eight (53%) participants reported no further change. We conclude that sex therapy through the Internet may yield positive results and that further controlled studies are warranted.

The integrated project AquaTerra of the EU sixth framework lays foundations for better understanding of river-sediment-soil-groundwater systems.

The integrated project "AquaTerra" with the full title "integrated modeling of the river-sediment-soil-groundwater system; advanced tools for the management of catchment areas and river basins in the context of global change" is among the first environmental projects within the sixth Framework Program of the European Union. Commencing in June 2004, it brought together a multidisciplinary team of 45 partner organizations from 12 EU countries, Romania, Switzerland, Serbia and Montenegro. AquaTerra is an ambitious project with the primary objective of laying the foundations for a better understanding of the behavior of environmental pollutants and their fluxes in the soil-sediment-water system with respect to climate and land use changes. The project performs research as well as modeling on river-sediment-soil-groundwater systems through quantification of deposition, sorption and turnover rates and the development of numerical models to reveal fluxes and trends in soil and sediment functioning. Scales ranging from the laboratory to river basins are addressed with the potential to provide improved river basin management, enhanced soil and groundwater monitoring as well as the early identification and forecasting of impacts on water quantity and quality. Study areas are the catchments of the Ebro, Meuse, Elbe and Danube Rivers and the Brévilles Spring. Here we outline the general structure of the project and the activities conducted within eleven existing sub-projects of AquaTerra.

A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma.

PURPOSE: Erectile dysfunction after three-dimensional conformal external-beam radiotherapy (3DCRT) for prostatic carcinoma is reported in as many as 64% of those patients. The purpose of this study was to determine the efficacy of the oral drug tadalafil (Cialis) in patients with erectile dysfunction after radiotherapy for prostatic carcinoma. METHODS AND MATERIALS: Patients (N=358) who completed radiotherapy at least 12 months before the study were approached by mail. All patients had been treated by 3DCRT; 60 patients were included and entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received 20 mg of tadalafil or placebo for 6 weeks. Drug or placebo was taken on demand at patient's discretion, with no restrictions regarding the consumption of alcohol or food, at least once a week and no more than once daily. At 6 weeks patients crossed over to the alternative treatment. Data were collected using the Sexual Encounter Profile (SEP) and the International Index of Erectile Function (IIEF) questionnaires. Side effects were also recorded. RESULTS: Mean age at study entry was 69 years. All patients completed the study. For almost all questions of the IIEF questionnaire there was a significant increase in mean scores from baseline with tadalafil, but not with placebo. Sixty-seven percent of the patients reported an improvement of erectile function with tadalafil (placebo: 20%), and 48% reported successful intercourse with tadalafil (placebo: 9%) (p<0.0001). Side effects were mild or moderate. CONCLUSIONS: Tadalafil is an effective treatment for erectile dysfunction after 3DCRT for prostatic carcinoma with successful intercourse reported in almost 50% of the patients, and it is well tolerated.

Aging and sexual response in the laboratory in patients with erectile dysfunction.

Aging places men at increased risk for erectile problems, particularly beginning around their fifties and sixties. Using a psychophysiological assessment procedure that included visual erotic stimulation, vibrotactile stimulation, and intracavernosal injection, this study tested for possible age effects on erectile response and self-reported sexual arousal in a group of men clinically diagnosed with erectile dysfunction. We controlled for three factors of purported importance to erectile functioning: existing comorbidities, use of specific medications, and current tobacco and alcohol use. Results indicated effects from both age and tobacco use on erectile response, although these effects were not uniform across age groups. For example, age had inconsistent effects on erectile response in patients aged 50 to 90 years; tobacco use had its strongest effect on patients under 50 years of age. In general, such covariates were less able to account for variation in erectile response among patients with more-severe ED. Despite these effects, ED men even in the oldest group showed average penile circumference increases of 28 mm under ICI, an erectile response typically sufficient for vaginal intercourse.

Psychosexual factors that differentiate men with inhibited ejaculation from men with no dysfunction or another sexual dysfunction.

AIM: Inhibited or retarded ejaculation (IE) is an uncommon male sexual dysfunction that may result in a lack of sexual fulfillment for both the man and his partner. In this study, we attempted to identify factors that differentiate men with IE from sexually functional controls or from men with other sexual dysfunctions and to specify whether such factors predict self-reported sexual arousal during psychophysiological assessment. METHODS: Each patient underwent psychophysiological assessment and a structured clinical interview based on a standardized questionnaire that included demographic information, psychosexual and medical history, and assessment of current sexual, erectile, and ejaculatory function, including relationship quality and characteristics. RESULTS: Men with IE resemble men with other dysfunctions but are differentiated from controls, in their lower level of relationship satisfaction, greater level of distress, and higher level of health-related problems. Men with IE were further characterized by lower levels of self-reported subjective sexual arousal, despite exhibiting strong penile response during psychophysiological testing and reporting high quality erections across a variety of situations. Also notable, however, were the many factors on which men with IE did not differ from controls. CONCLUSIONS: Taken together, this research helps specify directions for future investigations of men with IE.

Predicting responsiveness to the treatment of rapid ejaculation with 25 mg clomipramine as needed.

Clomipramine (25 mg) taken as needed increases ejaculatory latency in men with rapid ejaculation (RE), although only about half the men treated respond to this regimen. It would therefore be clinically advantageous to know the patient's potential responsiveness to an 'as needed' regimen prior to treatment. The present study attempted to identify a priori factors that might enable prediction of patients' response or nonresponse to 'as needed' clomipramine. Variables relevant to rapid ejaculation were examined in 23 men with RE, 12 of whom had responded to clomipramine. Logistic regression indicated that three factors assessed prior to treatment--initial ejaculation latency, overall sexual satisfaction, and ejaculation frequency each week--significantly improved the prediction of responsiveness to this treatment regimen. Specifically, RE men with initial ejaculatory latencies over 60 s, self-reported sexual satisfaction of 5 or higher (on a seven-point scale), and ejaculation frequency of twice or more weekly were more likely to benefit from 25 mg 'as needed' clomipramine. As such, men meeting these criteria might be considered for this treatment regimen. Those not matching these characteristics might better be considered for 20 or 30 mg clomipramine given on a daily basis.

Sexual response in men with inhibited or retarded ejaculation.

Inhibited ejaculation (IE) is a poorly understood male sexual dysfunction having both somatic and psychological etiologies. This study investigated sexual response in 25 IE men with no probable somatic cause. Using a standard psychophysiological assessment procedure, these men were compared with sexually functional and other dysfunctional groups on two measures of sexual response: erectile response and self-reported sexual arousal. Within the sample of IE men, sexual response was investigated as a function of both diagnostic classification and relationship factors. Differences occurred between IE men and the other groups on erectile response and self-reported sexual arousal during psychosexual stimulation in the lab, with IE men reporting lowest levels of sexual arousal. Within the IE group, diagnostic classifications and relationship variables were also related to self-reported sexual arousal. These findings suggest that inhibited arousal may be fairly common among IE men having no apparent somatic etiology, and further that several specific relationship factors may provide potential strategies for enhancing arousal in these men.

[Favorable effect of sildenafil on erectile dysfunction in patients after radiotherapy for prostate cancer; randomised, double-blind, placebo-controlled crossover study]. / Gunstig effect van sildenafil op erectiele disfunctie bij patiënten na radiotherapie voor prostaatkanker; gerandomiseerd, dubbelblind, placebogecontroleerd en gekruist onderzoek.

OBJECTIVE: To determine the efficacy of sildenafil in patients with erectile dysfunction after external beam radiotherapy for prostate cancer. DESIGN: Randomised, double-blind, placebo-controlled, crossover study. METHOD: A total of 406 patients with erectile dysfunction reported in their medical records who had completed external beam radiotherapy at least 6 months prior to the study, were approached by letter. Sixty patients were included in a study which lasted 12 weeks. They received 50 mg of sildenafil citrate or placebo for two weeks; during week 2 the dose could be increased to 100 mg in the case of unsatisfactory erectile response. At week 6 patients crossed over to the alternative treatment. Data were collected using the validated 'International index of erectile function' (IIEF) questionnaire, and side-effects were recorded. Patients were given the possibility of continuing to a 6-week open-label phase. RESULTS: The mean age of those participating was 68 years. All patients completed the double-blind phase. For the majority f questions in the IIEF questionnaire, there was a significant increase in mean scores from baseline with sildenafil, but of the patients with sildenafil, versus 18% with placebo. Ninety percent of the patients required a dose adjustment to 100 mg sildenafil, and 100% of the patients in the placebo group increased the dose. Side-effects were mild or moderate. Patients who proceeded to the open-label phase reported the same results as in the double-blind phase. CONCLUSION: Sildenafil improved erectile function in about half of the patients with erectile dysfunction after external beam radiotherapy for prostate cancer, and it was well tolerated.

Efficacy of sildenafil in an open-label study as a continuation of a double-blind study in the treatment of erectile dysfunction after radiotherapy for prostate cancer.

OBJECTIVES: To determine the efficacy of sildenafil citrate (Viagra) in patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy for prostate cancer. METHODS: Sixty patients treated with radiotherapy for prostate cancer at least 6 months previously, complaining of erectile dysfunction, and not using nitrates were entered into a double-blind, placebo-controlled, crossover study lasting 12 weeks. They received 50 mg of sildenafil or placebo for 2 weeks; at week 2, the dose was increased to 100 mg in the case of an unsatisfactory erectile response. At week 6, patients crossed over to the alternative treatment. Patients were then allowed to enter a 6-week open-label phase using 50 mg of sildenafil in the first 2 weeks, increasing the dose to 100 mg in the case of an insufficient erectile response in the following 4 weeks. Data were collected before trial entry (baseline evaluation) and every 2 or 4 weeks using the International Index of Erectile Function questionnaire. Any side effects were recorded. Two years later, all patients were approached by mail to evaluate their current sexual functioning and possible use of sildenafil. RESULTS: All patients completed the double-blind, crossover study. For nearly all the International Index of Erectile Function questions, sildenafil caused a significant increase in mean scores from baseline. Placebo had no effect. Seventy-seven percent entered the open-label phase; they were the better responders in the double-blind phase. Sildenafil was as equally effective as in the double-blind phase. The side effects were mild or moderate and significantly decreased in the open-label period. Two years after trial entry, 24% still used sildenafil. CONCLUSIONS: Sildenafil is relatively effective in patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy for prostate cancer. New drugs and combination therapies are needed to improve outcome.

An exploration of emotional response to erotic stimulation in men with premature ejaculation: effects of treatment with clomipramine.

Emotions presumably play an important role in sexual response and dysfunction in men. Yet, few studies have investigated differences in affect between sexually dysfunctional and functional men or changes in dysfunctional men resulting from successful treatment. We compared men having premature ejaculation (PE) with sexually functional counterparts on positive and negative affects, and examined changes in their affective response to pharmacotherapeutic treatment with clomipramine, an ejaculation-retarding agent. Results indicated higher levels of specific negative affects in PE men than controls. Positive affect also differed among groups, and showed variation in response to erotic stimulation and drug treatment. When specific positive affects were analyzed, they diverged in their response to stimulus and drug manipulations. For example, all groups exhibited a decrease in arousal/sensual during clomipramine treatment, but only PE men who responded positively to pharmacological treatment exhibited significant elevation in their enjoyment of the sexual experience. The fact that alleviation of the dysfunction improved positive affect in PE men responsive to clomipramine argues for the efficacy of pharmacotherapy in promoting positive emotional experiences associated with sexual response. But the failure of negative affects to approximate the low levels typical of sexually functional men also suggests the need to consider nonpharmacological methods to ensure complete reinstatement of healthy sexual response.

The plication procedure for penile curvature: surgical outcome and postoperative sexual functioning.

OBJECTIVE: This study evaluates the patients' judgement of the surgical outcome of the plication procedure, as described by Schröder and Essed, and the postoperative sexual functioning of patients with congenital curvatures and Peyronie's disease. PATIENTS AND METHODS: Of 98 patients treated for penile curvatures between 1985 and 1996, 85 patients received postoperatively a 'Questionnaire Assessing the Outcome of Surgery' and a short version of the 'Questionnaire for Screening Sexual Dysfunctions'. RESULTS: 28 patients with congenital curvatures and 31 with Peyronie's disease were evaluated. 75% of the patients with congenital curvatures and 58% of the patients with Peyronie's disease were satisfied with the result. Patients treated for Peyronie's disease reported diminished penile length and inability to have sexual intercourse more often than patients with congenital curvatures (90 vs. 64%, and 29 vs. 0%). After correction for age, patients with Peyronie's disease were less satisfied with their present sex life, had more frequent erectile problems and more trouble with considerable sexual desire than a group of 42 controls. For patients with Peyronie's disease satisfaction with the result was positively correlated with satisfaction with their present sex life and negatively correlated with the frequency of erectile problems. For patients with congenital curvatures satisfaction with the result was negatively correlated with both a postoperative curvature and a repeat operation. CONCLUSIONS: Some patients with Peyronie's disease may not benefit from surgical correction (alone). Because of the occurrence of sexual problems, future evaluation of the role of pre- and postoperative sexological counselling in achieving better results is recommended.

Treatment outcome, body image, and sexual functioning after orchiectomy and radiotherapy for Stage I-II testicular seminoma.

PURPOSE: Orchiectomy followed by infradiaphragmatic irradiation is the standard treatment for Stage I-II testicular seminoma in The Netherlands. Because body image and sexual functioning can be affected by treatment, a retrospective study was carried out to assess treatment outcome, body image, and changes in sexuality after orchiectomy and radiotherapy. METHODS AND MATERIALS: The medical charts of 166 patients with Stage I-II testicular seminoma were reviewed. A questionnaire on body image and current sexual functioning regarding the frequency and quality of erections, sexual activity, significance of sex, and changes in sexuality was sent to 157 patients (at a mean of 51 months after treatment). RESULTS: Seventy-eight percent (n = 123, mean age 42 years) completed the questionnaire. During irradiation, almost half of patients experienced nausea and 19% nausea and vomiting. Only 3 patients had disease relapse. After treatment, about 20% reported less interest and pleasure in sex and less sexual activity. Interest in sex, erectile difficulties, and satisfaction with sexual life did not differ from age-matched healthy controls. At the time of the survey, 17% of patients had erectile difficulties, a figure that was significantly higher than before treatment, but which correlated also with age. Twenty percent expressed concerns about fertility, and 52% found their body had changed after treatment. Cancer treatment had negatively influenced sexual life in 32% of the patients. CONCLUSIONS: Orchiectomy with radiotherapy is an effective and well-tolerated treatment for Stage I-II testicular seminoma. Treatment-induced changes in body image and concerns about fertility were detected, but the sexual problems encountered did not seem to differ from those of healthy controls, although baseline data are lacking.

The limited practical value of color Doppler sonography in the differential diagnosis of men with erectile dysfunction.

From the files of the outpatient urology department 44 men with ED had undergone both psychophysiological diagnostic screening (PDS, VSS, VSS+VIB, ICI+VSS+VIB) and color Doppler sonography testing (CDS, including VSS). PDS was carried out by one medical physiologist, CDS by one urologist. The diagnoses reached could be compared. This study revealed that CDS in ED-patients often resulted in an incorrect diagnosis, that is a presumed vascular abnormality while many such patients demonstrated firm erections under PDS-laboratory test conditions. Thus, it was concluded that CDS as a (first) screening test in ED-patients is of limited value. It was further emphasized that PDS, although giving quite relevant information about possible etiology and therapeutic treatment, is not a necessary first screen. Good history taking, preferably of the man and his partner, is still the basic first screen and quite often offers enough information to make a treatment plan with reasonable likelihood of success.