23 March 2020

The vexed question of Western male fertility

Clinical Men

Men can sometimes seem like an afterthought when trying to find out why couples are having trouble conceiving. But now the technology industry has caught on and is starting to pay attention to this lucrative, untapped market.

Last year, venture capital firms poured millions of dollars into companies such as sperm storage startup, Dadi, and sperm testing and freezing service, Legacy, according to TechCrunch.

Just like direct-to-consumer genetic tests, these start-ups are offering low-cost kits that men can order online and use in the comfort and anonymity of their own homes. Some let men look at their sperm quality using slides and a smartphone, while others allow men to collect semen samples at home, and mail them back to be frozen and stored by the company.

US consumers are typically the first on the receiving end of Silicon Valley innovations, but you may soon see Australian patients asking about the same thing.

And while there is plenty of support for democratising fertility and raising awareness of the male role in fertility, experts aren’t necessarily sold on this latest trend.

“That’s just opportunistic commercialisation,” says Professor Rob McLachlan, medical director of the male reproductive and sexual health andrology education service, Healthy Male (formerly known as Andrology Australia).

The opportunity they are cashing in on is a growing fear around what some have dubbed “spermaggedon”. This is the alarm that sperm counts are plummeting in Western men, possibly rendering more males infertile and portending a “Children of Men”-style future where our species is rendered unable to reproduce. (Children of Men is an apocalyptic science fiction novel and movie where years of infertility has left mankind on the verge of exteinction).

Already, one in six couples are unable to conceive on their own, and in around half of those cases, there is a problem with the man.

But this may not be a new problem. Experts are increasingly convinced that sperm counts, an important marker of male fertility, have been declining over the last half century.

Those in the reproductive research field have been debating the question since at least the 1970s, with studies producing conflicting results. What’s more, they are often hampered by the small size of the studies, their observational methods and unrepresentative samples.

However, this changed with the publication of a meta-analysis in 2017.

“I no longer think that there is much debate or controversy about this,” says Professor Richard Sharpe, a male reproductive health expert at the University of Edinburgh.

The analysis of more than 185 studies of more than 40,000 men living in Western countries, as well as in South America, Asia and Africa, was enough to convince many in the field that the trend was legitimate.

According to the paper, published in Human Reproduction Update, semen counts in men living in Australia, North America, Europe and New Zealand have halved since the 1970s. In 1973, men had an average of 99 million sperm per millilitre of semen, but by 2011 this had dropped to 47 million per millilitre. That’s a decline of around 1% a year.

“Given the importance of sperm counts for male fertility and human health, this study is an urgent wake-up call for researchers and health authorities around the world to investigate the causes of the sharp ongoing drop in sperm count, with the goal of prevention,” said lead author Dr Hagai Levine, of the Hebrew University of Jerusalem, in a media release for the study.

Importantly, Dr Levine’s study suggested that the decrease was still happening.

There was no big drop followed by a plateau, and nothing to suggest the trend would do anything other than decline further.

“The high proportion of men from Western countries with concentration below 40 million/mL is particularly concerning given the evidence that sperm count below this threshold is associated with decreased monthly probability of conception,” said Dr Levine.

Declining sperm counts may not only herald a growing demand for fertility services in the community, but it’s also a marker of health. Poor quality sperm has been linked to conditions such as diabetes, cancer and heart disease, suggesting this finding may be a canary in a coal mine for men’s overall health.

Curiously, the study found that rates hadn’t declined as significantly outside of Western countries and, in fact, even increased among men who had already become a father.

Now researchers are trying to understand why.

WHY IS THIS HAPPENING?

The reasons for the decline in sperm counts are probably multifactorial, and involve genetics, the environment and behaviour changes, says reproduction expert Professor Tina Kold Jensen, at the University of Southern Denmark.

Chromosomal and genetic abnormalities certainly play a role, and are thought to be responsible for around 50% of male infertility cases.

We have also seen soaring rates of obesity and overweight in the last few decades, which are factors known to harm sperm quality.

Western lifestyles often coincide with other harmful factors such as sedentary behaviour, smoking, alcohol consumption, drug use and stress.

But this doesn’t tell the whole story, according to Professor Jensen.

“We just find it interesting that when we study sperm count in young men, there are many young men who are healthy, they’re not overweight – they’re fine – and nevertheless they have a poor sperm count.”

What she thinks may be to blame is the fact that our society is awash in synthetic chemicals, specifically endocrine disrupting chemicals, that are found throughout the household products we use daily.

“These endocrine disrupting chemicals are found in all sorts of everyday products, like plastic bottles, Coca Cola cans, wrapping paper for burgers, pizza trays, microwave popcorn, Teflon and hard plastic,” says Professor Jensen.

Exposures to chemicals such as phthalates, bisphenol A (BPA), parabens and fluorinated organic compounds are common, and studies have found levels of some of these potentially endocrine disrupting chemicals in 90% or more of blood samples.

Some of these mimic hormones that naturally occur in our bodies, and research has linked exposure to these chemicals to a range of health problems throughout different parts of the body.

“We believe that exposure of the testes in utero, as a fetus, is very important for the sperm count as an adult,” Professor Jensen says. That means that the pregnant mothers’ exposure could determine her son’s sperm count.

“We have found in animal studies that maternal exposure to some of these endocrine disrupting chemicals has an impact on the offspring of these rats and mice.”

Professor Sharpe says that while this is a popular explanation – and one he previously held – he’s increasingly sceptical about it.

“I think the majority lean towards thinking that the effect has its origins in fetal life (probably in the first trimester), which would be my first choice; however, this is incredibly difficult to put to the test in man,” he says.

However, instead of it arising from endocrine disruptors, Professor Sharpe now believes it more likely results from the huge dietary and lifestyle changes occurring in both pregnant women and young men.

“But the reality is that we do not know, and if anyone tells you differently they are not basing it on hard evidence from human studies.

Proving that adverse events in early human pregnancy might affect reproductive health in adult men is “a Herculean task”, he says.

This may be interesting from a population point of view, but men who currently have a low sperm count are probably more interested in what they can do now to improve their fertility.

This growing interest partly explains the booming global fertility supplements market, which is projected to reach $US2.39 billion by 2025, according to a 2019 report by business consulting firm Grand View Research.

“Unfortunately, we have no treatments for the vast majority (not helped by us not knowing the cause) and what is available over the counter is unproven to work, and is largely a waste of money in my opinion,” says Professor Sharpe.

There has been some promising research linking sperm quality to the consumption of omega-3 fatty acids, such as those found in seafood and fish oil supplements. In particular, fish and fish liver oil contain essential nutrients such as retinoic acid, which may help improve semen quality.

Professor Jensen decided to collect blood and semen samples from 1700 young Danish men to see whether the supplements they had taken in the previous three months were tied to differences in their sperm quality.

“Men who took multivitamin, vitamin D or other vitamins didn’t have a better sperm count, but fish oil intake did increase their counts,” Professor Jensen says.

The study, published in JAMA Open Network earlier this year, found that men who reported taking fish oil supplements also had larger testicular size and improved levels of sex hormones compared to their counterparts who didn’t take the supplements.

The relationship held true even after adjusting for age, smoking, fitness level, ejaculation abstinence and fever in the three months prior.

Professor Jensen says she was surprised to find fish oil had this association, especially given they found no improvements among men taking other supplements.

Nevertheless, she notes that it wasn’t a randomised control trial and stresses that this isn’t sufficient to recommend fish oil supplementation to men who want to improve their sperm counts.

In contrast, two favourites of the male fertility supplement industry haven’t had as promising news.

Zinc and folic acid are commonly sold as male fertility supplements, because zinc is a mineral essential for sperm development and folate helps to form the sperm’s DNA.

However, a large, controlled, randomised study also published earlier this year suggests the supplements have failed to live up to the hype.

More than 2000 US couples planning to undertake infertility treatments were randomly assigned to take a daily supplement of either a placebo or a pill containing 5 milligrams of folic acid and 30 milligrams of zinc.

The JAMA paper showed that after six months of supplementation, there was no difference in either semen quality or live birth rates among the two groups. In fact, those who took the supplements were at a greater risk of DNA fragmentation compared to those in the placebo group, and were more likely to report side-effects such as abdominal pain and other gastrointestinal problems.

“The take-home message for men is that, for the first time, there is high-quality data that zinc and folic acid do not improve live birth outcomes or semen function,” study author Dr James M. Hotaling, at University of Utah Health, said in a statement at the time.

All is not lost for those who want to boost their semen quality, however.

Dr Albert Salas-Huetos, who researches the role of genetics and nutrition in male fertility at the University of Utah, says that a growing body of evidence supports the benefit of a good diet.

“There are a lot of observational studies with food and dietary patterns that clearly show us that following a healthy diet, for instance the Mediterranean diet with plenty of vegetables, fruit, fish and poultry, are positively associated with sperm quality parameters,” Dr Salas-Huetos says.

The cross-sectional study of 3000 young Danish men published in JAMA Network Open only last month supports this recommendation.

The men were being screened for entry into the armed forces, and this allowed Professor Jensen and her colleagues to analyse semen qualities such as sperm count, motility and shape and overall volume.

When the researchers compared the sperm quality with survey data about the men’s eating habits over the three months prior, they found that those eating mainly a Western diet had the lowest sperm counts of between 109 million to 138 million/mL.

Unlike those eating a Western diet, which was full of red meat, fried food, desserts and sugary drinks, those who ate a diet rich in fruits, vegetables, fish and chicken had the best sperm quality and a count of 167 million/mL on average.

A vegetarian-like diet, with little meat and a high intake of vegetables, eggs and milk, was the next best for sperm count, and appeared to produce the best shaped sperm. And those who ate a traditional Danish “open-sandwich” diet, with plenty of whole grains, cold cuts and dairy, had the fastest sperm.

SO IS THE FUTURE BARREN?

The debate about falling sperm counts isn’t quite settled, according to Professor McLachlan.

Some high-quality studies have shown the complete opposite of that 2017 meta-analysis, indicating that sperm counts haven’t dropped at all. In fact they may have risen.

For example, one study of 5000 young Danish men showed that sperm counts increased modestly between 1996 and 2010. Other studies have found no difference over time, and others have shown a decline.

Nor is there strong evidence to suggest that a fall in sperm count has translated into a harder time for couples to naturally conceive, he says.

For starters, sperm counts of 15 million/mL or more are considered normal – and it only takes one sperm to fertilise an egg. So a drop from 99 million to 47 million/mL still leaves men within a healthy range.

“In fact, I’ve heard it argued that time-to-pregnancy for the average young couple now may be shorter than in the past, because now – hopefully – people are more aware of their sexual health, about the fertile time and risks to their fertility,” Professor McLachlan says.

He also cautions against viewing the rising use of reproductive assistance as a marker of declining fertility.

Around one in 20 Western children are now born thanks to these technologies, but this has been underpinned by social changes and technological advancements.

The industry is growing, people are becoming more aware of interventions available and technology is improving – all factors that explain rising uptake, Professor McLachlan says.

This makes it hard to determine what effect lower sperm counts are having, if any.

Nevertheless, Professor Sharpe believes we could be seeing the effects of lower sperm counts across the community.

“Simple logistics suggest that in a modern setting, lower sperm counts will have negatively impacted couple fertility,” says Professor Sharpe.

“Take the example of Northern Europe. Here, one in five or six young men now has a sperm count low enough that we know it will negatively impact their fertility.This does not mean that they cannot father a child, just that it will take them longer to impregnate their partner.

“But here’s the problem. Couples are waiting ever longer to try for a pregnancy, so that often the woman is in her 30s or even 40s.”

By age 35, female fertility in a “normal woman” is reduced 35 to 40% compared with her early 20s and her fertility continues to decline thereafter, declining precipitously beyond age 40, Professor Sharpe says.

“So when you add a male partner with a low sperm count into the mix, you can see that achieving a pregnancy is going to take longer, but for such couples, time is a hugely limiting factor; time is not on their side. So having a low sperm count matters more today, in terms of couple fertility, than it did in the recent past.

“Of course there is always assisted reproduction, but this is a bruising process physically, mentally and financially and involves invasive treatment of the female partner even when it is the male who has the fertility problem.

“Plus, it still only works in a minority of cases and the biggest negative factor is female, and to some extent also male, age.”

Professor McLachlan says the most important thing is that men who are concerned about their fertility see their local doctor for testing and advice, not use a sperm count test performed at home.

“Male fertility is not just about sperm count,” he says. “There could be other factors in fertility that are at play, and just looking at the sperm count is just one of a whole number of things that have to be done.”

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