Lisette Hilton

Transitional zone sampling might not be necessary for prostate cancer detection in men with exclusively peripheral prostate cancer–suspicious lesions on multiparametric magnetic resonance imaging (mpMRI) who undergo targeted and systematic prostate biopsies, according to a study published in the 

The study of 863 men found peripheral targeted and systematic prostate biopsies without transitional zone sampling yielded similar cancer detection to the sampling protocol with transitional zone sampling. And the “zone-dependent” approach might reduce biopsy-related morbidity, the authors wrote.

Researchers in Germany and Australia studied men who underwent extended systematic biopsies and transitional zone sampling, in addition to mpMRI/ultrasound fusion targeting of at least one mpMRI categorized suspicious lesion in the peripheral zone. The men had no suspicious lesions on mpMRI in the transitional zone.

The authors defined clinically significant prostate cancer as a Gleason score of more than or equal to 3+4.

They retrospectively compared clinically significant prostate cancer detection rates between two biopsy protocols. One was a combination of peripheral mpMRI targeted and extended systematic prostate biopsy, including transitional zone sampling. The other was peripheral mpMRI targeted plus systemic prostate biopsy without transitional zone sampling.

The extended protocol yielded prostate cancer detection for clinically significant prostate cancer at 48% versus 47% among those who did not have transitional zone sampling.

Gleason score 3+3 in the extended protocol group was 21% versus 20% with omission of systematic transitional zone sampling.

Transitional zone systematic prostate cancer sampling detected an additional 2.0% of cancer.

“This zone-dependent biopsy strategy warrants prospective evaluation to optimize the extent of systematic biopsies in presence of suspicious mpMRI lesions,” the authors wrote.

Michael S. Cookson, MD, professor and chairman of the Department of Urology at the University of Oklahoma Health Sciences Center, and co–editor-in-chief of 

 that there is debate about how extensive and how many biopsies need to be obtained in the era of mpMRI.

“When lesions are easily visible on MRI, particularly Prostate Imaging-Reporting and Data System [PI-RADS] 4 and 5 lesions, the cancer diagnosis is almost always found in the target,” said Cookson, who is not an author on the paper. “There are, however, questions about the additional information gain from systematic biopsies. In this retrospective study in patients with peripheral zone target lesions, there did not appear to be any significant yield to routine sampling of the transitional zone.”

The study is important because each biopsy adds to the potential morbidity of the procedure, including bleeding infection and urinary retention, according to Cookson.

“The transition zone is an area that is particularly susceptible to urinary bleeding and outlet obstruction, so avoidance of this at least has the potential to reduce the risk of this post-biopsy complication. In addition, transition zone–only tumors are relatively rare, and in the absence of any demonstrable suspicion on mpMRI could probably be avoided,” Cookson said.

While not addressed in this paper, future analyses should look at the potential for reducing complications by avoiding transition zone biopsies in this setting, noted Cookson.

Kachanov M, Leyh-Bannurah SR, Roberts MJ, at al. Optimizing combined magnetic resonance imaging-targeted and systematic biopsy strategies: Sparing the multiparametric magnetic resonance imaging-negative transitional zone in presence of exclusively peripheral multiparametric magnetic resonance imaging-suspect lesions [published online ahead of print September 24, 2021]. 

Articles

Transitional Zone sampling can be spared in some men with suspicious prostate cancer lesions on mpMRI

Refractory overactive bladder patients treated with 100 units of intradetrusor onabotulinumtoxinA (BTX-A) reported a median time to improvement at 3 days post treatment, with maximum improvement at 7 days, according to research presented at the 2021 American Urological Association Annual Meeting.

“Prior to this study, there was really no data on exactly how long it takes until Botox begins to take effect in the bladder. Patients always ask the question, ‘How many days till I will notice an improvement?’ The original studies could really only give us an idea that it should happen by two weeks,” said study author Howard B. Goldman, MD, professor and vice chair, Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

Cleveland Clinic investigators conducted a prospective, non-randomized study of 51 patients (including 3 males) with non-neurogenic, refractory urgency-frequency syndrome and urgency urinary incontinence undergoing first-time BTX-A injection. Patients’ median age was about 72 years with an average body mass index of 33.8. All stopped taking overactive bladder medications and completed a daily Patient Global Impression of Improvement diary for 3 weeks following BTX-A treatment.

“We chose non-neurogenic patients with refractory overactive bladder and at least one overactive bladder medication for a number of reasons. First of all, insurance will only cover Botox for the bladder if a patient has tried and failed conservative treatments and at least one…medication. So, those are the patients that get Botox, in general,” Goldman said. “We chose non-neurogenic patients because the cause of overactive bladder in neurogenic patients may be different and, thus, we wanted to use a homogeneous population.”

Forty-eight patients reported symptom improvement according to Patient Global Impression of Improvement scores.

“We can now tell patients that most of them will notice some improvement by 3 days, a lot of improvement by 5 days and that maximum improvement is generally at 7 days and then continues,” Goldman said.

There were a few adverse events. Three patients had urinary tract infections (UTIs) and 2 had symptomatic retention.

“The fact that patients noted improvement by 3 days and a lot of improvement by 5 days was earlier than we had really expected. We also had a very high rate of overall improvement, with 92% of the patients having improvement,” Goldman said. “The rate of urinary tract infections was quite low, at 6%, which is less than we had expected. And 80% of patients did not restart previous overactive bladder medications during the study time period.”

The findings change how Goldman counsels patients.

“I can reassure them of excellent success, low urinary tract infection rate and can let them know that by 5 days, they should be noting significant improvement in their symptoms. I can also tell them that the majority do not need to take the overactive bladder medication anymore after the Botox treatment,” he said. “We would not, however, utilize Botox in patients who had difficulty emptying their bladders or in patients that also have bowel problems. Those patients might be better served with sacral neuromodulation.”

1. Kocher NJ, Zillioux Z, Martin S, et al. Patient-reported onset of symptom improvement following initial intradetrusor onabotulinumtoxina injections for overactive bladder. Paper presented at: 2021 American Urological Association Annual Meeting; September 10-13; virtual. Abstract MP52-11.

"Prior to this study, there was really no data on exactly how long it takes until Botox begins to take effect in the bladder," said Howard B. Goldman, MD. 

Refractory overactive bladder symptoms improve days after Botox injection

Women with overactive bladder (OAB) often use compensatory behaviors, or coping, to manage symptoms. Ironically, coping strategies are associated with more severe urinary symptoms and higher anxiety and stress, according to a study published in 

Most women with OAB do not seek or receive care for their symptoms. Anecdotally, urologists know that women with OAB figure out ways in which to cope with those symptoms to lessen the burden of OAB on their lives, according to study author W. Stuart Reynolds MD, MPH, associate professor of urology and fellowship director of Female Pelvic Medicine and Reconstructive Surgery Fellowship at Vanderbilt University Medical Center.

“Sometimes, these behaviors, which we are calling compensatory bladder behaviors, can have a big impact on day-to-day activities, and, maybe even more significantly, can really add to the psychological and social burden in the form of increased anxiety and stress symptoms,” Reynolds said.

Increased anxiety and stress also can cause or worsen urinary symptoms. A typical scenario is having an urgent need to urinate but not finding a restroom.

“This makes people anxious to go places or do certain things. To further complicate matters, feeling anxious can make the urinary symptoms worse. There may be a vicious cycle between anxiety and stress, urinary symptoms, and coping behaviors,” Reynolds said. “While this scenario likely makes sense…there is not much scientific or medical literature on this.”

Reynolds and colleagues examined how often women with OAB use coping behaviors and whether the behaviors are associated with psychosocial factors. They studied 120 adult women with OAB who completed questionnaires on OAB quality of life, anxiety and depression, and stress. The investigators used the subjects’ responses to the OAB-q Quality-of-Life Scale to generate coping scores, with higher scores representing greater negative effects on quality of life.

They found that 88% of women reported using at least 1 compensatory coping behavior at least “a little of the time,” with “locating the nearest restroom in a new place” being the most frequent, according to the study.

Factors associated with higher coping scores were higher body mass index, lower education, using overactive bladder medication, urgency incontinence, and urinary symptom severity.

Depression was not associated with higher total coping scores, but overactive bladder severity, higher anxiety and stress were significantly associated with higher scores.

“We found that not only was a higher coping score associated with greater urinary symptom severity, but a higher score was also associated with greater anxiety and stress symptoms, even after adjusting for the OAB symptom severity,” Reynolds said.

The findings have prompted Reynolds to ask patients with overactive bladder more directly about how their symptoms impact day-to-day activities and how that impacts their psychological state.

“Often, their treatment goals are specifically related to these activities, such as, ‘I would really like to just be able to do ….’ Rather than just ‘leak less’ or ‘urinate less frequently.’ This helps me tailor the treatment approach more specifically to the patient’s expectations,” Reynolds said.

Behavioral therapy and lifestyle changes are recommended first-line interventions for OAB patients. Technically, behavioral treatment is usually by 1 of 2 approaches: trying to modify bladder function by changing voiding habits, such as with bladder training and delayed voiding, or through behavioral training, which focuses on the bladder outlet and includes pelvic floor muscle training to improve strength and control and techniques for urge suppression.

Lifestyle modifications include fluid management, caffeine reduction, dietary changes (avoiding bladder irritants), and weight loss, according to Reynolds.

“While effective, these interventions are often under-utilized in patients with OAB and often with poor compliance,” he said. “The implication of our findings is that the concept of ‘behavioral therapy’ likely needs to be expanded to incorporate additional behavioral therapy, such as cognitive behavioral therapy, as well as other interventions that address psychologic impacts directly.”

More research is needed to understand how the relationship between coping behaviors and psychosocial factors might offer opportunities for OAB interventions, the authors wrote.

1. Reynolds WS, Kaufman MR, Bruehl S, et al. Compensatory bladder behaviors (“coping”) in women with overactive bladder. 

Published online September 15, 2021. https://pubmed.ncbi.nlm.nih.gov/34524704/

These compensatory behaviors are associated with more severe urinary symptoms and higher anxiety and stress.

Coping behaviors common in women with overactive bladder

Studies are beginning to suggest that COVID-19’s impact on men’s health might go beyond the lungs, heart, and kidneys. According to recently published studies, having COVID-19 could have lasting impacts on fertility and sexual function.

Ranjith Ramasamy, MD, associate professor and director of the University of Miami Miller School of Medicine’s Reproductive Urology Program, is uncovering what he says are clear links between COVID-19 infection and men’s sexual health.

“We know the COVID-19 virus can remain inside the testis long after the initial infection in asymptomatic men. We know the COVID-19 virus can decrease sperm count for up to 3 to 6 months. And we know the COVID-19 virus can affect the blood vessels and be present in the penis up to 7 to 9 months after the initial infection and can lead to erectile dysfunction,” Ramasamy said.

Getting the mRNA COVID-19 vaccine does not appear to impact fertility and should be encouraged, according to Ramasamy, who has published several articles on COVID-19 and men’s sexual health, including the research letter, “Sperm parameters before and after COVID-19 mRNA vaccination” published June 17 in

Findings from early studies looking at male infertility post–COVID-19 infection are concerning, reassuring, conflicting, and inconclusive.

COVID-19 does not appear to get into the semen, according to urologist James M. Hotaling, MD, MS, FECSM, medical director of the fertility integrated practice unit and director of the Men’s Health program at the University of Utah, Salt Lake City.

Hotaling and coauthors in China conducted an observational study of 34 adult Chinese males who received a diagnosis of COVID-19 and found severe acute respiratory syndrome (SARS)-CoV-2 was not detected in the men’s semen 1 month after COVID-19 diagnosis.

Current evidence suggests a low likelihood of SARS-CoV-2 transmission through the seminal fluid. There are limited data characterizing SARS-CoV-2 infection’s impact on male reproductive hormones and semen parameters. And data suggesting SARS-CoV-2 gets into testes are inconclusive, according to Hotaling.

Data regarding the short- and long-term impacts of SARS-CoV-2 on male reproductive health remain largely inconclusive and need further long-term study, Hotaling and colleagues reported in a review of the literature published April 2021 in 

But Ramasamy and other investigators are finding causes for concern.

A study published earlier this year in the 

 by Ramasamy et al looked at testis tissue collected from autopsies of 6 COVID-19 positive and 3 COVID-19 negative men. The investigators found 3 of the 6 COVID-19–positive biopsies had normal spermatogenesis and 3 had impaired spermatogenesis. Electron microscopy showed the COVID-19 virus in testis tissue of 1 COVID-19–positive autopsy case.

The novel COVID-19 virus has an affinity for angiotensin converting enzyme-2 (ACE-2) receptors. Since ACE-2 receptor expression is high in the testes, the study authors hypothesized that COVID-19 can be present in testes tissue of infected patients. This study suggests that the male reproductive tract, specifically the testes, may be the target of COVID-19 infection. They found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility, according to the study.

Investigators in China also found evidence that SARS-CoV-2 can infect the testis and germ cells, suggesting a potential impact on spermatogenesis and male fertility.

“Nevertheless, further study is essential to reveal the underlying mechanism of SARS-CoV-2 infection of testicular cells and the correlation of testis infection with the clinical course of COVID-19,” according to the correspondence published December 14, 2020, in 

Although more quality research is needed to confirm these results, the findings make sense when one thinks about COVID-19 infection basics, according to Hossein Sadeghi-Nejad, MD, FACS, professor of Surgery/Urology at Rutgers New Jersey Medical School and Hackensack University Medical Center.

Infection from SARS-CoV-2 causes an exaggerated inflammatory response leading to immunosuppression. The body releases cytokines that mainly affect lung tissue but also lead to extrapulmonary effects, he said.

For example, some studies are showing overall testosterone levels can be lower in patients who get COVID-19. Investigators of a single-center cohort study of patients with COVID-19 found lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men.

Still unclear is whether the decrease in testosterone is an adaptive or maladaptive COVID-19 response.

The reason for the likelihood of lower testosterone levels in COVID-19 patients is that SARS CoV-2 gets into the system is through ACE-2, which has been expressed in Leydig cells and Sertoli cells, according to Sadeghi-Nejad.

Damage to Leydig cells may lead to testosterone deficiency, he said.

There are about 2 dozen peer-reviewed articles containing research or findings regarding COVID-19 and erectile dysfunction (ED), according to Martin Gross, MD, assistant professor at Dartmouth-Hitchcock Medical Center and codirector of the Dartmouth-Hitchcock Men’s Health Center.

“They predominantly include case reports, observational studies, survey data, expert opinions, and review articles. These types of articles tend to be on the lower end of scientific rigor,” Gross said. “We don’t know much about the relationship between ED and COVID-19 at this point.”

A study by Ramasamy et al, published in July in the 

nalyzing penile tissue from COVID-19 patients who recovered and subsequently developed ED, was novel and interesting, according to Gross.

It was the first study to demonstrate the presence of the COVID-19 virus in the penis up to 9 months after the initial infection and suggests that endothelial dysfunction from the virus could contribute to ED.

Omer Raheem, MD, MSc, assistant professor of urology and director of men’s health at Tulane University School of Medicine, New Orleans, Louisiana, said he found it interesting that 1 of the 2 men Ramasamy and colleagues studied was hospitalized for COVID-19 infection, whereas the other had only mild COVID-19 symptoms, yet both men developed severe erectile dysfunction.

This study suggests that widespread endothelial cell dysfunction from COVID-19 infection can contribute to erectile dysfunction. Larger prospective studies are warranted to further validate this finding, Raheem said.

“From patient’s perspective, albeit not conclusive, there is some evidence suggesting the potentially negative impact of COVID-19 infection on male reproductive function and overall men’s health. Likewise, COVID-19–infected or COVID-19–recovered men should be aware of the possible risk of developing erectile dysfunction, male infertility, and hypogonadism, owing to the adverse effect of the SARS-CoV-2 virus on testicular Sertoli and Leydig cells via ACE-2 binding. And obviously those symptomatic men should seek urologic consultation to evaluate and treat these conditions,” Raheem said.

Although the link between COVID-19 infection, endothelial damage, and ED is interesting, the finding should be further evaluated in larger studies and viewed cautiously, according Sadeghi-Nejad.

“Endothelial damage is not restricted to COVID-19. Endothelial dysfunction is seen in many of our patients who have erectile dysfunction, which we know to be a neurovascular problem,” Sadeghi-Nejad said.

There are conflicting data about whether sexual activity increased or decreased during the pandemic, according to Sadeghi-Nejad.

Many surveys on sexual activity during quarantining suggest decreased activity, possibly because the studies included younger patients with children living at home. Other studies on older patients showed increased activity.

Interestingly, investigators studying US sales of phosphodiesterase-5 (PDE5) inhibitors show sales of the medications spiked during lockdowns.

Turkish authors of a paper published earlier this year in 

 reported a significant increase in andrological diagnoses during the pandemic, compared with before it.

“There was a statistically significant increase in the number of patients diagnosed with male reproductive or sexual health problems during the COVID-19 pandemic period,” according to the authors. “The number of patients diagnosed with erectile dysfunction during the pandemic was also significantly higher than [in] the pre–COVID-19 pandemic period.”

The paper’s authors suggest that although these problems are multifactorial, psychogenic factors might be a significant trigger.

In other research, the PDE5 inhibitors men use to treat erectile dysfunction could also treat COVID-19. These medications, the authors wrote, have anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties.

“A lot of the paper was theoretical but solidly grounded in physiology and pharmacology,” Gross said. “These studies are all interesting to some degree, but they are snapshots in time that may lose relevance down the road.”

Counseling patients about COVID-19’s potential impact on sexual health and fertility might start with encouraging patients to get vaccinated.

“I recommend that all couples trying to conceive get the vaccine. And that it is safe,” Hotaling said.

Men who have acute COVID-19 infections and see a decline in spermatogenesis should consider waiting 3 to 6 months before planning fertility treatment so their sperm counts can recover, according to Ramasamy.

Sadeghi-Nejad cites American Society of Reproductive Medicine recommendations regarding shared decision-making and detailed discussions, including not withholding the vaccine from patients who are planning to conceive, those who are already undergoing fertility treatment, and pregnant patients. These groups should be encouraged to receive vaccination if there are no other contraindications.

Gross, however, said he questions the value of further research on the link between ED and COVID-19, and a COVID-19 diagnosis does not change his approach to ED treatment.

“It would be presumptuous to think that our little corner of medicine has any relevance to the bigger COVID-19 picture. And lots of conditions cause ED; let’s try and tackle those first,” Gross said. “I have never found a good reason to wait to treat any patient’s erectile dysfunction. If a patient has a problem, hears his options, and is healthy enough and wants to proceed with some or all of these options, then I’m happy to help. If patients aren’t healthy enough or otherwise prepared to move forward with treatment, then we can wait until they’re ready.”

Questions remain about how the virus invades the immune system and can stay in organs for such a long time, as well as whether any impact from COVID-19 on male fertility or sexual function is permanent, according to Ramasamy.

More data should be coming out soon, according to Hotaling.

“Some of the big IVF groups are tracking their outcomes where the men or women have had COVID-19. A lot of these big claims databases will release their data from 2020 sometime between now and the end of the year,” Hotaling said. “There are a lot of studies out of Europe that I’ve seen tracking cohorts of patients who had COVID-19.”

Ongoing and long-term studies to evaluate the potential impact of the COVID-19 infection on men’s health are needed as we emerge from COVID-19 pandemic and monitor the novel COVID-19 Delta variant, Raheem said.

1. Gonzalez DC, Nassau DE, Khodamoradi K, et al. Sperm parameters before and after COVID-19 mRNA vaccination.

 Published online June 17, 2021. doi:10.1001/jama.2021.9976

2. Pan F, Xiao X, Guo J, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. 

 2020;113(6):1135-1139. doi:10.1016/j.fertnstert.2020.04.024

3. Patel DP, Punjani N, Guo J, Alukal JP, Li PS, Hotaling JM. The impact of SARS-CoV-2 and COVID-19 on male reproduction and men’s health. 

 2021;115(4):813-823. doi:10.1016/j.fertnstert.2020.12.033

4. Achua JK, Chu KY, Ibrahim E, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. 

 2021;39(1):65-74. doi:10.5534/wjmh.200170

5. Ma X, Guan C, Chen R, et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. 

. 2021;18(2):487-489. doi:10.1038/s41423-020-00604-5

6. Dhindsa S, Zhang N, McPhaul MJ, et al. Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19.

. 2021;4(5):e2111398. doi:10.1001/jamanetworkopen.2021.11398

7. Stolk RF, van Leeuwen HJ, Kox M, et al. The chicken or the egg: low testosterone predisposes for COVID-19 or COVID-19 induces a decrease in testosterone? 

 2021;25(1):237. doi:10.1186/s13054-021-03664-9

8. Kresch E, Achua J, Saltzman R, et al. COVID-19 endothelial dysfunction can cause erectile dysfunction: histopathological, immunohistochemical, and ultrastructural study of the human penis. 

. 2021;39(3):466-469. doi:10.5534/wjmh.210055

9. Hernandez I, Gul Z, Gellad WF, Davies BJ. Marked increase in sales of erectile dysfunction medication during COVID-19. 

10. Duran MB, Yildirim O, Kizilkan Y, et al. Variations in the number of patients presenting with andrological problems during the coronavirus disease 2019 pandemic and the possible reasons for these variations: a multicenter study. 

 2021;9(1):100292. doi:10.1016/j.esxm.2020.100292

11. Mostafa T. Could oral phosphodiesterase 5 inhibitors have a potential adjuvant role in combating COVID-19 infection?. 

2021;9(1):15-22. doi:10.1016/j.sxmr.2020.08.006

12. ASRM issues statement on COVID-19 vaccines, joins other OB/GYN groups on community-wide statement. News release. American Society for Reproductive Medicine. Dec 16, 2020. Accessed July 13, 2021. https://bit.ly/3BbJ5Bq

According to recently published studies, having COVID-19 could have lasting impacts on fertility and sexual function.

Lisette Hilton

Articles

Transitional Zone sampling can be spared in some men with suspicious prostate cancer lesions on mpMRI

Refractory overactive bladder symptoms improve days after Botox injection

Coping behaviors common in women with overactive bladder

COVID-19 and men’s health: What we know so far