US Pharm. 2023;48(6):31-35.

Study: Physically Demanding Work Tied to Higher Male Fertility

A study by researchers from Brigham and Women’s Hospital suggests that men who regularly lift heavy objects at work have higher sperm counts. The study, published in Human Reproduction, is part of the Environment and Reproductive Health (EARTH) cohort, a clinical study that aims to explore how exposure to environmental chemicals and lifestyle choices affects reproductive health.

“We already know that exercise is associated with multiple health benefits in humans, including those observed on reproductive health, but few studies have looked at how occupational factors can contribute to these benefits,” said first author Lidia Mínguez-Alarcón, a reproductive epidemiologist in Brigham’s Channing Division of Network Medicine and coinvestigator of the EARTH study. “What these new findings suggest is that physical activity during work may also be associated with significant improvement in men’s reproductive potential.”

Infertility is a growing problem, and it can be caused by a wide variety of complex factors. However, about 40% of infertility cases can be traced to male factors, such as sperm count, semen quality, and sexual function. In particular, sperm count and semen quality are thought to be the major drivers of growing infertility rates among males—a previous analysis led by the EARTH study team found that among men seeking fertility treatment, sperm count and quality declined by as much as 42% between 2000 and 2017.

“Further, there is increasing evidence that male infertility is associated with common chronic diseases such as cardiovascular disease and autoimmune disease, highlighting the broader importance of male reproductive health,” added Dr. Mínguez-Alarcón.

The EARTH study is a collaboration between the Harvard T. Chan School of Public Health and Mass General Brigham to evaluate the effect of environment and lifestyle factors on fertility. EARTH has collected samples and survey data from over 1,500 men and women, and the current study focused on a subset of these participants, including 377 male partners in couples seeking treatment at a fertility center.

The researchers found that men who reported often lifting or moving heavy objects at work had 46% higher sperm concentration and 44% higher total sperm count compared with those with less physical jobs. Men who reported more physical activity at work also had higher levels of the male sex hormone testosterone and, counterintuitively, the female hormone estrogen.

“Contrary to what some people remember from biology class, ‘male’ and ‘female’ hormones are found in both sexes, but in different amounts,” said Dr. Mínguez-Alarcón. “In this case, we hypothesize that excess testosterone is being converted into estrogen, which is a known way for the body to keep normal levels of both hormones.”

While the current study found a relationship between physical activity and fertility in men seeking fertility treatment, it will take further research to confirm if these findings hold true for men from the general population. The researchers also hope that future studies will reveal the underlying biological mechanisms at play.

“Reproductive health is important in its own right, but more and more evidence suggest that male infertility can give us insight into broader public health issues, including the most common chronic diseases,” concluded Dr. Mínguez-Alarcón. “Uncovering actionable steps people can take to improve their fertility stands to benefit all of us, not just couples trying to conceive.”

Novel Immunotherapy Promising Against High-Risk Prostate Cancers

A new monoclonal antibody drug known as enoblituzumab is safe in men with aggressive prostate cancer and may induce clinical activity against cancer throughout the body, according to a phase II study led by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. If confirmed in additional studies, enoblituzumab could become the first promising antibody-based immunotherapy agent against prostate cancer.

In a clinical trial, 32 men with high-risk or very high–risk prostate cancers scheduled for prostate cancer surgery were treated with six weekly infusions of enoblituzumab prior to surgery and were followed for an average of 30 months. Twenty-one patients, or 66%, had an undetectable prostate-specific antigen (PSA) level 12 months following surgery, suggesting that there was no sign of residual disease. Additionally, the drug was well-tolerated overall; no patients had any surgical delays or medical complications during or after the operation. A description of the work was published in the Nature Medicine.

If enoblituzumab continues to perform well in further larger randomized studies, it could represent a new pathway for immunotherapy against multiple cancers and the first one that may have a role for prostate cancer, said lead study author and cancer immunology researcher Eugene Shenderov, MD, PhD, assistant professor of oncology at the Johns Hopkins University School of Medicine. Other existing antibody-based immunotherapy drugs have targeted immune checkpoints, natural on/off switches mediating immune responses, such as CTLA-4, PD-1, and LAG-3. Cancer cells hijack these checkpoints, turning off the immune response to cancer. “Drugs that block these checkpoints have had success in other types of cancers, including lung cancer and melanoma, but not in prostate cancer,” said Dr. Shenderov.

Enoblituzumab works by binding to a protein called B7-H3 that is overexpressed on prostate cancer cells and is believed to impede the immune system’s ability to attack cancer cells. The new therapy could pack a one-two punch against cancer, Dr. Shenderov said, by blocking B7-H3’s inhibition of the immune system’s recognition and elimination of cancer cells and also triggering a process called antibody-dependent cellular cytotoxicity, which leads to tumor cell destruction by activating additional immune cells such as macrophages and natural killer cells.

“Enoblituzumab appears safe and seems to activate the immune system in a way that involves both T cells and myeloid cells,” Dr. Shenderov said. “What this means is if these results can be replicated in a larger, randomized study, it opens the possibility that combining this therapy with local, curative-intent therapies like surgical prostate removal or radiation therapy would allow this drug to potentially kill micrometastatic disease hiding elsewhere in the body, and therefore prevent a significant number of men from experiencing recurring disease. That could be a paradigm shift in prostate cancer.”

The median age of study participants was 64 years (age range 48-74 years). About half (47%) had a PSA greater than 10 ng/mL at diagnosis, which is abnormally high, and 50% had Gleason grade group 5 at biopsy, meaning that they had highly aggressive disease. Patients were enrolled from February 2017 through June 2019. Enoblituzumab was confirmed to penetrate into prostate tumors and to bind to B7-H3 in the vast majority of participants, according to prostate samples studied after surgery.

Side effects of enoblituzumab were generally mild and included fatigue, neurologic symptoms such as headache or dizziness, and flu-like or cold symptoms. One patient developed inflammation of the heart (myocarditis), which fully resolved with steroid treatment and is a known side effect of other immune checkpoint drugs.

Beyond safety and antitumor activity based on PSA dropping to undetectable levels, investigators also looked for changes in the tumor microenvironment before and after enoblituzumab treatment. They found increased markers of cytotoxicity after treatment, consistent with the concept that the immune system was activated against tumor cells. The tumors showed increased infiltration with granulocytes, leukocytes, and effector T cells, and there was roughly a doubling of the density of cytotoxic T cells after treatment.

“The findings are exciting but exploratory and need to be confirmed in larger study cohorts,” cautioned senior study author Emmanuel S. Antonarakis, MD, the Clark Endowed Professor of Medicine and director of Genitourinary Oncology for the University of Minnesota Masonic Cancer Center.  Dr. Antonarakis was the senior investigator of the study while he was at the Johns Hopkins Kimmel Cancer Center.

“However, these results in high-risk prostate cancer patients, and the broader need for immunotherapeutic strategies with efficacy in prostate cancers, provide justification to further develop multipronged approaches that include targeting B7-H3 to optimize antitumor activity in prostate cancers and other solid malignancies,” he said.

Investigators are planning a larger, randomized trial of enoblituzumab in newly diagnosed prostate cancer patients to assess clinical activity of the drug compared with current standards of care.


New Genetic Target for Male Contraception Identified

Discovery of a gene in multiple mammalian species could pave the way for a highly effective, reversible, and nonhormonal male contraceptive for humans and animals.

Washington State University (WSU) researchers identified expression of the gene Arrdc5 in the testicular tissue of mice, pigs, cattle, and humans. When they knocked out the gene in mice, it created infertility only in the males, impacting their sperm count, movement, and shape. The researchers detailed their findings in Nature Communications.

“The study identifies this gene for the first time as being expressed only in testicular tissue, nowhere else in the body, and it’s expressed by multiple mammalian species,” said Jon Oatley, senior author and professor in WSU’s School of Molecular Biosciences. “When this gene is inactivated or inhibited in males, they make sperm that cannot fertilize an egg, and that’s a prime target for male contraceptive development.”

While other molecular targets have been identified for potential male contraceptive development, the Arrdc5 gene is specific to the male testes and found in multiple species. Importantly, lack of the gene also causes significant infertility, creating a condition called oligoasthenoteratospermia. This condition, the most common diagnosis for human male infertility, shows a decrease in the amount of sperm produced, slowed mobility, and distorted shape so that the sperm are unable to fuse with an egg.

In the WSU study, the male mice lacking this gene produced 28% less sperm that moved 2.8 times slower than in normal mice—and about 98% of their sperm had abnormal heads and midpieces.

The study indicates that the protein encoded by this gene is required for normal sperm production. Dr. Oatley’s team will next work on designing a drug that would inhibit production or function of that protein.

Disrupting this protein would not require any hormonal interference, a key hurdle in male contraception since testosterone plays other roles beyond sperm production in men, including building bone mass and muscle strength as well as red blood cell production. Designing a drug to target this protein would also make it easily reversible as a contraceptive.

“You don’t want to wipe out the ability to ever make sperm—just stop the sperm that are being made from being made correctly,” he said. “Then, in theory, you could remove the drug and the sperm would start being built normally again.”

Dr. Oatley and study first author Mariana Giassetti have filed a provisional patent for the development of a male contraceptive based on this gene and the protein it encodes.

Because the gene is found across mammalian species, this knowledge also holds promise for use in animals, Dr. Oatley said. The team analyzed available biological data on DNA and protein sequences in mammals and found the gene in almost every known mammal species. This opens the potential to develop male contraception for use in livestock, perhaps replacing castration in some instances to control reproduction, and in wildlife when managers seek to limit overpopulation of a species.

The initial focus, however, is on giving humans more control over their own reproduction. While there are many forms of birth control for women, they are not always effective or widely available, and more than half of pregnancies worldwide are still unintended, according to the United Nations.

“Developing a way to curb population growth and stop unwanted pregnancies is really important for the future of the human race,” said Dr. Oatley. “Right now, we don’t really have anything on the male side for contraception other than surgery, and only a small percentage of men choose vasectomies. If we can develop this discovery into a solution for contraception, it could have far-ranging impacts.”


Mediterranean Diet Best Prostate Cancer Prevention, Studies Find

Men who consume colorful fruits and vegetables on a regular basis are less likely to be diagnosed with prostate cancer (PC), according to new research by University of South Australia scientists. A rainbow of foods rich in certain micronutrients helps to prevent PC as well as speed up recovery among men who undergo radiation treatment for the disease. The findings, from two studies published in the journal Cancers, highlight the importance of a Mediterranean or Asian diet that includes these foods.

Researchers compared micronutrient plasma concentrations of PC patients with a healthy control group, revealing low levels of lutein, lycopene, alpha-carotene, and selenium in PC patients and high levels of iron, sulfur, and calcium in the same group, relative to controls. Increased DNA damage after radiation exposure was also associated with low lycopene and selenium in blood plasma.

Men with plasma concentrations lower than 0.25 μg/mL for lycopene and/or lower than 120 μg/L for selenium have an increased risk of PC and are likely to be more sensitive to the damaging effects of radiation. Foods that are rich in lycopene include tomatoes, melons, papayas, grapes, peaches, watermelons, and cranberries. Selenium-rich foods include white meat, fish, shellfish, eggs, and nuts.

Study coauthor Permal Deo said that eating foods that are naturally rich in lycopene and selenium is preferable to taking supplements, in which the benefits are limited, according to previous studies.

“Our recommendation is to adopt a Mediterranean diet enlisting the help of a dietician because people absorb nutrients in different ways, depending on the food, the digestive system, the person’s genotype and possibly their microbiome,” Dr. Deo said.

PC remains one of the most common and fatal cancers in men, but the nutritional deficiencies associated with it remain largely unknown. Other risk factors, such as ethnicity, family history, and age, have previously been linked to prostate cancer.

“There is strong evidence that being overweight and tall increases the risk of prostate cancer. Diets high in dairy products and low in vitamin E may also increase the risk but the evidence is less clear,” said Dr. Deo. Vitamin E is found in plant-based oils, nuts, seeds, fruits, and vegetables.

The research is the first to evaluate plasma concentrations of micronutrients and trace elements with respect to PC in the South Australian population.

Why Obesity Is More Dangerous for Men

A study from York University in Toronto, Ontario, sheds light on the biological underpinnings in sex differences in obesity-related disease, with researchers observing “striking” differences in the cells that build blood vessels in the fatty tissue of male versus female mice.

Men are more likely than women to develop conditions associated with obesity, such as cardiovascular disease, insulin resistance, and diabetes, said York Professor Tara Haas with the Faculty of Health’s School of Kinesiology and Health Science.

“People have used rodent models to study obesity and the diseases that are associated with obesity—like diabetes—but they’ve typically always studied male rodents, because females are resistant to developing the same kinds of diseases,” said Dr. Haas, lead author. “We were really interested in exploring that difference because, to us, it spoke of something really fascinating happening in females that protects them.”

Dr. Haas and her team observed in an earlier study that when mice become obese, females grow a lot of new blood vessels to supply the expanding fat tissue with oxygen and nutrients, whereas males grow a lot less. In this latest study published in iScience, Dr. Haas and her coauthors, including York PhD student Alexandra Pislaru, Faculty of Health Assistant Professor Emilie Roudier, and former York postdoctorate student Martina Rudnicki, focused on differences in the endothelial cells that make up the building blocks of these blood vessels in fat tissue.

The team used software to help sift through thousands of genes to zero in on the ones that would be associated with blood vessel growth. They discovered that processes associated with the proliferation of new blood vessels were high in the female mice, whereas the males had a high level of processes associated with inflammation.

“It was very striking the extent of inflammation-associated processes that were prevalent in the males,” Dr. Haas recalled. “Other studies have shown that when endothelial cells have that kind of inflammatory response, they’re very dysfunctional, and they don’t respond to stimuli properly.”

Ms. Pislaru, who works in Dr. Haas’ laboratory and is a co–first author of the study, participated in this project as part of her dissertation.

“It is exciting to observe the continuing resilience that female endothelial cells display even when stressed by a long-term high-fat diet,” Ms. Pislaru said. “The findings from our study can help researchers to get a better understanding of why obesity manifests differently in men and women.”

The researchers also examined the behavior of the endothelial cells when they were taken out of the body and studied in petri dishes.

“Even when we take them out of the body where they don’t have the circulating sex hormones or other kinds of factors, male and female endothelial cells still behave very differently from each other,” Dr. Haas explained.

Female endothelial cells replicated faster, while male endothelial cells displayed greater sensitivity to an inflammatory stimulus. By comparing with previously published data sets, the researchers found endothelial cells from aged male mice also displayed a more inflammatory profile compared with female cells.

“You can’t make the assumption that both sexes are going to respond to the same series of events the same way,” said Dr. Haas. “This isn’t just an obesity-related issue—I think it’s a much broader conceptual problem that also encompasses healthy aging. One implication of our findings is that there will be situations where the treatment that is ideal for men is not going to be ideal for women and vice versa.”

The study was funded by a grant through the Canadian Institutes of Health Research, as well as the Natural Sciences and Engineering Research Council of Canada and York’s Faculty of Health.

While humans and mice have different genes that may be turned up or down, Dr. Haas believes that the general findings would likely apply and is interested in studying the same cells in humans in future research.

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