Well known mineral has surprising role in men’s fertility

Male infertility is a growing challenge globally, and researchers are seeking an explanation behind this trend. An interesting angle is serum phosphate concentrations, which have been overlooked in connection with fertility. With declining birth rates in high-income countries, understanding the regulators of infertility is more important than ever. Phosphate is vital for many bodily processes, and new research suggests that it also crucially affects men’s sperm quality. Recent studies have shown that infertile men tend to have phosphate deficiency more frequently, which may indicate new treatment options.

“Our data from 1,242 men show that nearly one third have substantially lower serum phosphate concentrations than average, a startling finding that could lead to new treatment approaches. This opens the possibility of interventions specifically targeting phosphate deficiency, possibly by changing diet or taking supplements. However, more research is needed to understand exactly how phosphate affects fertility and how best to target treatments to improve male reproductive health,” explains Sam Kafai Yahyavi, PhD Fellow, Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark.

Infertility has many causes

Male infertility is a growing problem in high-income countries. Researchers are therefore striving to understand new factors that can affect men’s fertility. The body’s mineral balance has received little attention so far – especially serum phosphate concentrations. Phosphate is essential for many biological processes, but its role in reproduction is largely unknown. For many years, research primarily focused on vitamin D and how it affects bones and fertility.

“Researchers previously thought that vitamin D only affected bones and not fertility. Our group researched vitamin D for many years but then discovered that the testicles and bones may cross-talk more than we thought. This changed the understanding of how fertility is connected to the body’s mineral balance,” says Martin Blomberg Jensen, Head of Research, Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Herlev and Gentofte Hospital, Denmark.

An important part of fertility is sperm quality: not only the number of sperm but also motility.

“Sperm quality is not just quantitative. We also assess how they swim – both motility in general and progressive motility: whether the sperm cells can swim purposefully forward and thus reach the egg. Their shape also plays a role,” explains Sam Kafai Yahyavi.

“We discovered that minerals such as calcium and phosphate are not only essential for bones but also affect testicular function. What really caught our interest was that we found bone signalling in the testes – a connection we had not previously considered,” he says.

Infertility can have many causes: genetic, lifestyle-related and physical, such as blockages in the vas deferens. But the researchers discovered a new factor.

“Infertility can result from heredity, lifestyle or physical problems such as blocked sperm ducts. But we found a new factor: phosphate deficiency, which can strongly affect sperm quality. Studies have never explored this in depth before. It opens new opportunities to better understand and perhaps even treat certain types of male infertility,” notes Sam Kafai Yahyavi.

Assembling a jigsaw puzzle

To investigate the relationship between phosphate concentrations and sperm quality, the researchers analysed data from 1,242 men examined for infertility at Rigshospitalet in Copenhagen. Each participant underwent a fertility examination; blood samples were taken to measure mineral and hormone concentrations and sperm samples were analysed for quality.

The sperm samples were assessed according to WHO guidelines: the number of sperm cells, their shape and their general and progressive motility.

“When we examine men with infertility, we consider several parameters. This is like assembling a jigsaw puzzle and finding patterns that can enhance knowledge about fertility,” says Martin Blomberg Jensen.

The researchers were especially interested in phosphate, which strongly affects energy production and bone strength. The men were divided into three groups based on their serum phosphate concentrations. About 10% were moderately deficient and 25% were mildly deficient. The rest had normal phosphate concentrations. The researchers investigated whether the men with phosphate deficiency also had poorer sperm quality.

“Men and women differ markedly in relation to phosphate. If you measure phosphate concentrations in the blood and locally around the germ cells, women have the same concentrations. But the phosphate concentration in men’s seminal fluid is extremely high and far more regulated. This suggests that phosphate plays a special role in male reproduction that we are only just beginning to understand,” notes Martin Blomberg Jensen.

Surprising

Substantially more infertile men had phosphate deficiency than in the general population. When the researchers analysed the blood samples from the 1,242 men, it was found that a significant proportion had lower phosphate levels than expected.

“One third of the men had such severe phosphate deficiency that it would be considered clinically low. This was unexpected,” explains Martin Blomberg Jensen.

About 1–5% of the general population has clinical deficiency. In this study, however, the figure exceeded 30%, which piqued the researchers’ interest.

“About 2% of the general population has clinical deficiency. Other studies mention 1–5%. We exceeded 30%, which is surprising. This suggests that something here has not been investigated enough,” says Sam Kafai Yahyavi.

To ensure that the result was not a coincidence, the researchers examined two more cohorts of infertile men.

“In two other cohorts we found the same pattern: about 25–27%. The exact number may not be 30% but is considerably higher than for the general population,” adds Sam Kafai Yahyavi.

Very striking effect

Phosphate deficiency was not associated with sperm count but with progressive motility, which is essential for fertilisation.

“These men do not necessarily have few sperm, but they swim poorly or are deformed. The association is not based on the number but on motility. And the differences are great – the article’s tables show differences between 32% and 41%, which corresponds to an increase of 40–50%,” explains Sam Kafai Yahyavi.

Another noteworthy finding was the association between phosphate deficiency and higher concentrations of estradiol, a hormone that may affect fertility. The researchers wonder whether mineral imbalances can affect sperm’s ability to develop properly or swim optimally. The results suggest that phosphate may affect male fertility more than previously thought.

“We were quite surprised by the association. We are further investigating whether lowering the phosphate concentration in the fluid around the sperm can affect motility. The interesting thing is that serum phosphate concentrations also seem to affect this and could possibly be changed,” says Martin Blomberg Jensen.

Motility is the key

Male infertility is complex and affected by many factors, and phosphate concentrations have an important role. This finding is particularly noteworthy since previous studies focused primarily on hormonal and genetic causes without assessing how minerals affect fertility.

“Serum phosphate concentrations are about 1 millimole per litre. But the concentration is extremely high in the testicular fluid in which the sperm swim. This is incredibly exciting, because there must be a transport mechanism, and this raises several questions: why does this happen? And will manipulating serum phosphate concentrations affect fertility?” exclaims Martin Blomberg Jensen.

By focusing on phosphate concentrations and how they affect sperm function, researchers have identified a previously overlooked and new dimension of reproductive health.

“You could think that the key was the number of sperm cells, but we found something else: motility. And this is extremely exciting, because sperm go through several stages before they become fully functional. When they are produced in the testicles, they are not ready to fertilise – they go to the epididymis and mature. If the phosphate concentration affects that process, then this might also be therapeutic for infertile men,” adds Martin Blomberg Jensen.

Not healthy men who happen to be infertile

The research is very significant for how infertile men are understood and treated in the future.

“This surprised us. Infertile men are generally considered healthy except for being infertile. And yet no one has described this before. Phosphate is not routinely measured in fertility clinics or in assessing these men – but perhaps should be examined more closely,” says Sam Kafai Yahyavi.

These observations also raise new questions about how modern lifestyles and diet affect the mineral balance and thus potentially fertility.

“From a societal perspective, our findings raise massive questions. We strongly suspect that more people today have lower serum phosphate concentrations than in the past – and the paradox is that people are not eating less phosphate, quite the opposite. This suggests that the serum concentration is not solely related to intake but how the body manages and distributes phosphate, and this can strongly affect fertility and general health,” explains Martin Blomberg Jensen.

The findings emphasise the need for broader understanding and approaches to studying infertility.

“This is precisely the core of our approach. Infertile men are not healthy men who happen to be infertile – they should be considered a distinct group with specific biological challenges. Infertility has many causes – genetic factors, hormonal imbalances and nutrient deficiencies – and we need to understand these much better to offer more targeted treatment,” concludes Sam Kafai Yahyavi.

Research on how phosphate affects male fertility highlights its importance in reproduction.

“If our hypothesis holds – and we have not yet fully proven this – then at least 25% of infertile men have phosphate deficiency, which makes phosphate especially interesting. If this turns out to be important, you could in principle just give them phosphate supplements,” explains Martin Blomberg Jensen.

Potential for bone medicine

The latest discoveries show treatments for men who have trouble conceiving children may be improved by precisely targeting specific chemical imbalances, such as phosphate. Phosphate is important for many functions in the body, including reproduction, and research now suggests that directly increasing phosphate concentrations can improve male fertility.

“We want to understand how the body controls the phosphate concentration and are investigating whether we can increase or decrease the concentration, specifically in the parts of the body that carry out reproduction, to better understand how this may affect men’s fertility. In some of our studies we increase how much phosphate people consume, and in others we use a phosphate binder, which prevents absorption, to determine how this affects fertility,” says Martin Blomberg Jensen.

These new approaches to treatment transcend traditional methods and open new possibilities. In addition to adjusting phosphate concentrations, the researchers are investigating using existing drugs that are not usually used to treat people with infertility.

“We are also considering using bone medicine and hormones, which we think can help up to 20% of infertile men. This is especially relevant for men who still have well-functioning Sertoli cells, which are key in supporting and nurturing the developing sperm cells. This treatment improves sperm production but not necessarily motility. If we can understand exactly how these mechanisms work together, we may be able to use these types of medicine optimally for infertility,” concludes Martin Blomberg Jensen.