The mechanism causing PLS is not known, but may be related to anatomic changes or fibrosis and scaring in the retropubic space. Studies suggest that men are more concerned with penile length than women, and that men desiring penile lengthening actually have normal penile length. The goal of this study that appears in the European Journal of Oncology Nursing was to determine patients’ perceptions and responses to PLS after RP.

Six participants were recruited by open invitation from a CaP support group. The main criterion for inclusion was perception of PLS at least one year after undergoing RP. Five of the six men were married. Most were of Caucasian descent and had completed secondary education. None of the men reported to be able to achieve adequate erections for penetrative sex. Participants underwent one-on-one semi-structured interviews and a second interview with the principal investigator to confirm findings. Interview analysis followed a substantive theory, within the grounded theory method. In this process, data collection, coding and analysis occur simultaneously and coding and analysis continue after the interview.

The central theme to emerge from the study was “resignation”, a conveyed awareness of their inability to return to a pre-cancerous lifestyle. Men adapted to the changes of having CaP. All participants focused on the bigger picture and this allowed them to coexist with a diagnosis of CaP. To focus on the bigger picture, they took into consideration past experiences, current state of affairs and hypothesized how potential outcomes would impact upon them. Family relations were prioritized, especially spousal communication. In addition, three sub-themes were identified; unaltered masculinity, the unimportance of PLS and erectile dysfunction as a speed bump. None of the men perceived changes in their own evaluation of masculinity after noticing PLS after RP. While men saw themselves as being unable to perform a “masculine” role in procuring coitus, this did not mean that they saw themselves as unmanly. The men also felt that PLS was unimportant, in part due to the fact that they all experienced erectile dysfunction. It is unclear how PLS might impact potent men in this regard. Finally, all men identified return of erectile function as the event that would improve satisfaction with penile function.

Yu Ko WF, Degner LF, Hack TF, Schroeder G

Eur J Oncol Nurs. 2009 Oct 5. Epub ahead of print.
doi:10.1016/j.ejon.2009.09.001

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

UroToday – the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice. To access the latest urology news releases from UroToday, go to: www.urotoday.com

Copyright 2009 – UroToday

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PSD502, a product in development for the treatment of PE, is a proprietary formulation of the two marketed drugs lidocaine and prilocaine dispensed by a metered dose aerosol. PSD502 works selectively on non-keratinized skin on the glans penis (head of the penis).

“Premature ejaculation can have a powerful negative impact on the emotional and sexual lives of men and their partners,” said Professor Stanley E. Althof, PhD, Center for Marital and Sexual Health of South Florida, West Palm Beach, Florida. “Recently, the international sexual health community agreed that PE should be defined as ejaculation occurring within approximately one minute of penetration that causes the patient distress. Now we need to work to develop treatments, and these encouraging results with PSD502 seem to be a step in the right direction.”

Both pivotal trials showed clinically and statistically significant efficacy in the treatment of premature ejaculation, as measured by changes in Intravaginal Ejaculatory Latency Time (IELT) and Index of Premature Ejaculation (IPE), a patient-reported outcome of ejaculatory control, sexual satisfaction, and distress.

“We are excited that results from two pivotal studies have shown that PSD502 was effective for men with PE, and we look forward to the opportunity to help patients who have had no real options to date,” said Patrick Fourteau, Chief Executive Officer of Sciele Pharma, Inc. “This data will support the New Drug Application for PSD502 that we are planning to submit to the U.S. Food & Drug Administration (FDA), which upon FDA approval would make PSD502 be the first prescription treatment in the U.S. for premature ejaculation.”

Pivotal Study Details

The new study, the second of two major pivotal trials, was designed to assess the clinical benefit and safety of PSD502 in men with PE. The trial, which randomized 256 patients across 38 investigational centers in the U.S., Canada and Poland, also assessed the safety and tolerability of the therapy. Final analyses of the three months data confirmed that PSD502 produced a clinically and statistically significant increase from baseline in all study primary and secondary endpoints. The time for IELT for PSD502 group increased 4.7-fold compared to 1.5-fold in placebo (p

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“Flibanserin was a poor antidepressant,” Thorp said. “However, astute observers noted that it increased libido in laboratory animals and human subjects. So, we conducted multiple clinical trials and the women in our studies who took it for hypoactive sexual desire disorder reported significant improvements in sexual desire and satisfactory sexual experiences.

“It’s essentially a Viagra-like drug for women in that diminished desire or libido is the most common feminine sexual problem, like erectile dysfunction is in men,” Thorp said.

Studies have shown that the prevalence of hypoactive sexual desire disorder in the U.S. ranges from 9 percent to 26 percent of women, depending on age and menopausal status. Flibanserin is currently an investigational drug and is available only to women taking part in clinical trials.

The results were reported on Nov. 16, at the Congress of the European Society for Sexual Medicine in Lyon, France. The presentation was given by Elaine E. Jolly, M.D., overall principal investigator and a professor at the University of Ottawa in Canada.

Jolly, Thorp and colleagues pooled data from four clinical trials of flibanserin conducted in the U.S., Canada and Europe. A total of 1,946 pre-menopausal women ages 18 and older were randomized to receive either flibanserin or placebo for 24 weeks, with 4 weeks of pre-treatment baseline measurement and 4 weeks of post-treatment follow-up.

Initially, four different dosing regimens were used in the trials: 25 milligrams twice a day, 50 milligrams once a day at bedtime, 50 milligrams twice a day and 100 milligrams once a day at bedtime. The dosing regimens totaling 50 milligrams a day were not effective while the regimens totaling 100 milligrams were. So, the results being reported are from only three of the four trials and are based on the 100 milligrams once a day dosing regimen only.

The trials measured mean changes from baseline on the following six variables as reported by the women each week: number of satisfying sexual events (SSE), electronic diary (eDiary) desire score, female sexual function index (FSFI) desire domain score, FSFI total score, female sexual distress scale-revised (FSDR-R), and FSDR-R Item 13 (which focuses specifically on desire/libido).

The researchers concluded that treatment with 100 milligrams of flibanserin once a day was associated with significant improvements versus placebo in the number of satisfying sexual events (SSE) reported, sexual desire (as measured by eDiary and FSFI desire domain), a reduction in distress associated with sexual dysfunction (as measured by FSDS-R and its Item 13), and sexual functioning as measured by FSFI.

“These results point to a novel approach to pharmacologic treatment of the sexual problem that plagues reproductive age women the most, and may over time prove to be an effective treatment without the side effects of androgen replacement therapy, which is the only treatment currently available,” Thorp said.

The trials were funded by Boehringer Ingelheim Pharmaceuticals, the manufacturer of flibanserin.

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The researchers behind the study, from Imperial College London, King’s College London and Royal Holloway, University of London, say their findings mean scientists may have to rethink other vaccines they are developing for diseases like HIV, tuberculosis and malaria, which are delivered in the same way, using the same virus ’shell’.

The vaccine used an adenovirus, which normally causes the common cold, to enable the vaccine therapy to travel around the body. Harmless HIV genes were then inserted into the virus. It was thought that this would help the immune system to learn to recognise and fight off HIV.

The new study suggests that after receiving the trial vaccination, people who had previously built up immunity to the adenovirus had an influx of immune cells called CD4 T-cells homing in on their mucous membranes, as these cells prepared to fight off a new adenovirus infection. Mucous membranes are found in areas including the nose, mouth, vagina and gut. HIV naturally infects CD4 T-cells, so this inadvertently provided HIV with an abundance of potential new homes at the sites where the virus would naturally enter the body during sexual intercourse, thereby increasing people’s risk of infection.

The researchers say their findings are a warning for scientists developing adenovirus vaccines against other diseases, as the same effect occurs with other, perhaps all, adenovirus subtypes.

Adenovirus infection is common and there are 51 known human strains. Around half of all adults in the developed world and about 90 percent of individuals in sub-Saharan Africa, where HIV is most prevalent, have built up immunity to the subtype of adenovirus used in STEP.

Preliminary results of the vaccine trial showed that people who had previously been infected with the adenovirus used in the trial had a significantly higher risk of being infected with HIV following the vaccine compared to people who were given a placebo.

Dr Steven Patterson, who is the corresponding author of the study from the Division of Investigative Science at Imperial College London, said: “HIV is a huge threat to global health, with 2.7 million people becoming infected every year. We were all hopeful that the STEP trial would be a success, so when the researchers published their results and the trial was halted, we were all very surprised and disappointed. Scientists use adenoviruses in all sorts of vaccines and we did not expect this result. It was vital to discover what caused this increase in HIV infection risk so we could avoid the same problem in future trials.

“Our research suggests that the adenovirus-based HIV vaccine effectively instructs the cells that HIV infects to gather round exactly where HIV is likely to be introduced. This is clearly worrying for this kind of vaccine. Scientists are currently developing adenovirus-based vaccines to protect people against TB and malaria as well as HIV, but they may have to rethink these vaccines if the effect we describe in our new paper is a problem for all of them,” added Dr Patterson.

The researchers measured antibodies against adenovirus type 5 (Ad-5) and adenovirus type 11 (Ad-11) in 20 healthy volunteers to determine who had been infected. They then took samples of the volunteers’ immune cells and grew them in the laboratory to see whether their CD4 cells would recognise Ad-5 and Ad-11. When the researchers added adenoviruses to the tissue cultures, they found that the viruses activated the CD4 cells and caused them to grow and replicate. They found that the newly generated CD4 cells had particular kinds of molecules on their surface that enabled them to migrate to mucosal membranes.

The results also showed that CD4 cells can recognise and react to another distinct subtype of adenovirus, regardless of which subtype the person was infected with initially. The authors say this means all subtypes of adenovirus are likely to be unsuitable in HIV vaccines.

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Because testosterone produces the masculine brain, researchers are concerned that fetal exposure to anti-androgens such as phthalates — which are pervasive in the environment — has the potential to alter masculine brain development, said lead author Shanna H. Swan, Ph.D., professor of Obstetrics and Gynecology, director of the URMC Center for Reproductive Epidemiology, and an expert in phthalates.

“Our results need to be confirmed, but are intriguing on several fronts,” Swan said. “Not only are they consistent with our prior findings that link phthalates to altered male genital development, but they also are compatible with current knowledge about how hormones mold sex differences in the brain, and thus behavior. We have more work to do, but the implications are potentially profound.”

Phthalates are chemicals used to soften plastics. Recent studies have shown that the major source of human exposure to the two phthalates of most concern (DEHP and DBP) is through food. These phthalates are used primarily in polyvinyl chloride (PVC), so any steps in the processing, packaging, storage, or heating of food that use PVC-containing products can introduce them into the food chain.

Phthalates are also found in vinyl and plastic tubing, household products, and many personal care products such as soaps and lotions. Phthalates are becoming more controversial as scientific research increasingly associates them with genital defects, metabolic abnormalities, and reduced testosterone in babies and adults. A federal law passed in 2008 banned six phthalates from use in toys such as teethers, play bath items, soft books, dolls and plastic figures.

In Swan’s study, higher concentrations of metabolites of two phthalates, di(2-ethylhexyl) phthalate (DEHP), and dibutyl phthalate (DBP), were associated with less male-typical behavior in boys on a standard play questionnaire. No other phthalate metabolites measured in-utero was linked to the less-masculine behavior. Girls’ play behavior was not associated with phthalate levels in their mothers, the study concluded.

Swan’s interest in phthalates stems from an investigation into the environmental causes of reproductive health problems. Since 1998 she has led the federally funded, multi-center Study for Future Families (SFF), which established a large database from which to explore various scientific questions about toxins.

The current study focused on a small sample of SFF mothers who delivered children between 2000 and 2003. The mothers provided urine samples around the 28th week of pregnancy. The urine was analyzed for phthalate metabolites by the Centers for Disease Control and Prevention (CDC).

Swan hypothesized that phthalates may lower fetal testosterone production during a critical window of development — somewhere within eight to 24 weeks gestation, when the testes begin to function — thereby altering brain sexual differentiation.

To explore the question, researchers reconnected with mothers from the SFF sample and asked them to complete a standard research questionnaire, called the Preschool Activities Inventory (PSAI), for their children ages 3 1/2 to 6 1/2 years.

The PSAI is designed to discriminate play behavior within and between the sexes, and in the past has been shown to reflect the endocrine-disrupting properties of other toxins, such as PCBs and dioxins. The PSAI addressed three aspects of play: types of toys children choose (trucks versus dolls), activities (rough-and-tumble play, for example), and child characteristics.

However, researchers were concerned about how the choice of toys available in any given household might skew results, so in addition they asked about parental views toward atypical play. For example, the survey asked, “What would you do if you had a boy who preferred toys that girls usually play with?” The possible answers included “strongly encourage” (him to play this way) to “strongly discourage.”

The final survey scores are designed to reflect sex-typical play. Higher scores meant more male-typical play and lower scores meant more female-typical play.

Researchers then examined boys play-behavior scores in relation to the concentration of phthalate metabolites in their mothers’ prenatal urine samples, finding that higher concentrations of DEHP and DBP metabolites were associated with less masculine play behavior scores.

Earlier studies by Swan and others have shown that phthalate exposure during pregnancy might affect the development of genitals of both male rodents and baby boys. Scientists refer to this cluster of genital alterations as the “phthalate syndrome,” and research suggests that in rodent pups, the syndrome can have adverse consequences for later sexual development.

If endocrine disrupters such as phthalates can impair genital development and hormone levels in the body, the play-behavior study noted, then a deeper examination of how these chemicals impact the brain is warranted.

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The studies researchers found that teens who screened positive for substance use had significantly greater odds of having sexual contact after using drugs or alcohol. According to the findings, these teens were more likely to have unprotected sex, multiple sexual partners and even a sexually transmitted illness. The cross-sectional survey consisted of 305 adolescents from ages 12- to 18-years-old in 3 different urban clinics. Participants were asked the CRAFFT questions, and also completed a self-administered questionnaire about high risk sexual behaviors. Of those who screened positive, 42.6% reported having sexual contact without a condom, 26.1% after drinking alcohol, 15.6% after drug use and 21.7% with a partner who had been drinking alcohol.

Developed by the Children’s Center for Adolescent Substance Abuse Research, the CRAFFT screen, which refers to the mnemonic acronym in the six screening questions, includes questions such as “do you ever use alcohol or drugs to relax, feel better about yourself, or fit in?” and “do you ever forget things you did while using alcohol or drugs?” Answering “yes” to two or more questions is highly predictive of an alcohol or drug-related disorder and now at-risk sexual behavior.

“Primary care physicians are on the frontline of identifying adolescents who are at-risk and all should be screened with questions like these at every routine medical visit,” says Sharon Levy, MD, co-author of the study and physician in the Adolescent Substance Abuse Program at Children’s. “Clinicians should be prepared to discuss high risk sexual behaviors with their patients along with the dangers of engaging in sexual activity while intoxicated. Something as simple as asking an adolescent a few questions during a clinical appointment might make the difference.”

The CRAFFT test is routinely administered during adolescent clinical appointments at Children’s. All adolescents who take the test receive brief advice on alcohol and drug use, and those who test positive are recommended to further assessment for substance use disorders. The authors suggest that these adolescents also receive counseling to avoid high risk sexual behaviors and sexual activity after alcohol or drug use.

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To get around that problem, Dr. Smithgall’s team developed an assay to measure Nef function indirectly by coupling it to another protein, called Hck, which Nef activates in HIV-infected cells. Because Hck activity can be easily measured, the investigators were able to use it as a reporter for Nef activity in an automated high-throughput screening process. In collaboration with the University of Pittsburgh Drug Discovery Institute, they screened a library of 10,000 chemical compounds against the coupled proteins to see which ones influenced Nef-induced activation of Hck.

After further testing, they confirmed that three compounds inhibited the activity of the Nef-Hck complex and, more importantly, all of them also interfered with HIV replication. One compound was so effective that it suppressed HIV replication to undetectable levels in cell culture experiments.

“So we now have a way to rapidly and efficiently screen for inhibitors of Nef signaling through Hck,” Dr. Smithgall said. “But the surprise was that some of those inhibitors also showed strong antiviral activity in cell culture models.”

There is evidence that people infected with HIV variants that have mutations in the Nef gene take substantially longer to develop disease symptoms or AIDS, he said. In animal models, disrupting the production of Nef from the virus or its interaction with Hck also delays or prevents disease symptoms. The next challenge for the researchers will be to determine whether these compounds also interfere with progression of AIDS-like disease in animal models by blocking Nef function.

“Most current therapies for HIV infection use drugs that interfere with the function of viral enzymes such as reverse transcriptase or with the interaction of the virus and the host cell,” Dr. Smithgall said. “Targeting Nef represents an entirely new approach that could be useful to deal with issues such as drug-resistant HIV strains, and may slow the progression to AIDS.”

He added that Nef is just one of several so-called “accessory proteins” encoded by HIV which are important virulence factors in AIDS. Inhibitory compounds against some of the others might be revealed using a similar coupled protein approach for high throughput screening.

Co-authors of the paper include Lori Emert-Sedlak, Ph.D., Toshiaki Kodama, Ph.D., and Edwina C. Lerner, Ph.D., Department of Microbiology and Molecular Genetics, School of Medicine; Weixiang Dai, Ph.D., and Billy Day, Ph.D., Department of Pharmaceutical Sciences, School of Pharmacy; and John S. Lazo, Ph.D., Department of Pharmacology and Chemical Biology, School of Medicine. Drs. Day and Smithgall also are members of the Drug Discovery Institute, which is directed by Dr. Lazo.

The research was supported by grants from the National Institutes of Health.

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This is the first research study to look at the effect of BPA on the male reproductive system in humans. Previous animal studies have shown that BPA has a detrimental effect on male reproductive system in mice and rats.

Funded by the U.S. National Institute of Occupational Safety and Health, this study adds to the body of evidence questioning the safety of BPA, a chemical made in the production of polycarbonated plastics and epoxy resins found in baby bottles, plastic containers, the lining of cans used for food and beverages, and in dental sealants.

The BPA levels experienced by the exposed factory workers in the study were 50 times higher than what the average American male faces in the United States, the researchers said.

“Because the BPA levels in this study were very high, more research needs to be done to see how low a level of BPA exposure may have effects on our reproductive system,” said the study’s lead author. De-Kun Li, MD, Ph.D., a reproductive and perinatal epidemiologist at Kaiser Permanente’s Division of Research in Oakland, Calif. “This study raises the question: Is there a safe level for BPA exposure, and what is that level? More studies like this, which examine the effect of BPA on humans, are critically needed to help establish prevention strategies and regulatory policies.”

The researchers explained that BPA is believed by some to be a highly suspect human endocrine disrupter, likely affecting both male and female reproductive systems. This first epidemiological study of BPA effects on the male reproductive system provides evidence that has been lacking as the U.S. Food and Drug Administration, and various U.S. government panels have explored this controversial topic.

This study is the first of series of studies that examine the BPA effect in humans and are to be published by Dr. Li and his colleagues.

The study finding, Dr. Li also points out, may have implications of adverse BPA effects beyond male sexual dysfunction. Male sexual dysfunction could be a more sensitive early indicator for adverse BPA effects than other disease endpoints that are more difficult to study, such as cancer or metabolic diseases.

For this study, researchers compared 230 workers exposed to high levels of BPA in their jobs as packagers, technical supervisors, laboratory technicians and maintenance workers in one BPA manufacturing facility and three facilities using BPA to manufacture epoxy resin, in several regions near Shanghai, to a control group of 404 workers in the same city from factories where no BPA exposure in the workplace was recorded. The factories with no BPA exposure produced construction materials, water supplies, machinery, garments, textiles, and electronics. The workers from the two groups were matched by age, education, gender, and employment history.

Researchers gauged BPA levels by conducting spot air sampling, personal air sample monitoring and walk-through evaluations, by reviewing factory records and interviewing factory leaders and workers about personal hygiene habits, use of protective equipment, and exposures to other chemicals. A subset of workers also provided urine samples for assaying urine BPA level to confirm the higher BPA exposure level among the workers with occupational BPA exposure.

Researchers measured sexual function based on in-person interviews using a standard male sexual function inventory that measures four categories of male sexual function including erectile function, ejaculation capability, sexual desire, and overall satisfaction with sex life.

After adjusting for age, education, marital status, current smoking status, a history of chronic diseases and exposure to other chemicals, and employment history, the researchers found the BPA-exposed workers had a significantly higher risk of sexual dysfunction compared to the unexposed workers.

The BPA-exposed workers had a nearly four-fold increased risk of reduced sexual desire and overall satisfaction with their sex life, greater than four-fold increased risk of erection difficulty, and more than seven-fold increased risk of ejaculation difficulty.

A dose-response relationship was observed with an increasing level of cumulative BPA exposure associated with a higher risk of sexual dysfunction. Furthermore, compared to the unexposed workers, BPA-exposed workers reported significantly higher frequencies of reduced sexual function within one year of employment in the BPA-exposed factories.

Other authors on this study include: X. Weng, Ph.D., J.R. Ferber, MPH, and L.J. Herrinton of the Kaiser Permanente Division of Research; Z. Zhou, Ph.D., MD, Y. He, Ph.D., and T. Wu MD, Ph.D. of the Department of Occupational Health and Toxicology, School of Public Health & WHO Collaborating Center for Occupational Health, Fudan University, Shanghai, China; D. Qing, , M. Miao, PhD, J. Wang, Ph.D, Q. Zhu, MD, E. Gao, MD, MPH, Ph.D., and W. Yuan of Shanghai Institute of Planned Parenthood Research and National Population & Family Planning Key Laboratory of Contraceptive Drugs and Devices; and H. Checkoway, Ph.D. of Department of Environmental Health, University of Washington, Seattle.

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The research is reported in the Journal of Clinical Investigation.

The pivotal experiments demonstrated that neonatal exposure to DES led to a much more dramatic reduction in fertility in male mice with the protein NR0B2 than it did in male mice lacking the protein because NR0B2 deficiency protected male mice against the negative effects of DES on testis development and function. NR0B2 deficiency also protected male mice from the detrimental effects of postnatal and adult exposure to DES.

Future work will determine whether similar pathways link human exposure to molecules such as DES that disrupt normal hormone functioning to the increased incidence of male reproductive disorders.

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