male infertility

Tiny lab-grown testicles look remarkably like the real thing under the microscope

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The first-ever 3D model of testicles, made using mouse cells, could improve our understanding of sex development disorders and male infertility.

Black and white microscope image of an artificial testicle which looks like a bundle of noodles

The new model testicles could have important health implications, the researchers who made them say. One of the artificial testicles is pictured above in high detail under the microscope after 14 days of development. 

For the first time, scientists have grown three-dimensional, miniature versions of testicles in the lab, using mouse cells. 

The lab-grown testicles survived in a dish for up to nine weeks and closely resembled natural mouse testicles, even developing tubelike structures equivalent to those that produce sperm in the testes of mice and humans. The cells within the model testicles also expressed genes similar to those that are active in regular mouse testicles. 

The replica testicles are so-called organoids — self-organizing 3D structures that are grown to resemble full-size tissues in the body. Scientists have created organoids of many organs, including the human heart and brain, with the aim of better capturing the complexities of these tissues in 3D and in a way that represents human biology better than animal models do. Organoids are usually created by coaxing stem cells to develop into tissue-like structures by exposing them to specialized growth chemicals in a dish. 

The researchers behind the new testicle organoids described their achievement in a paper published Jan. 12 in the International Journal of Biological Sciences. They say the organoids could help improve our understanding of the testicles, or testes, whose main job is to produce the male sex hormone testosterone and sperm needed for reproduction. As such, the organoids could also provide valuable insight into conditions that are linked to improper testicle functioning, such as sex development disorders and male infertility, the scientists say.  

“Once we have an in vitro [petri dish] cellular model of the testis, we can start exploring how the testes function, how different cell types within the testis interact with each other, and also try to explore whether sperm can be generated in vitro,” Nitzan Gonen, co-senior study author and a researcher in biomedicine at Bar-Ilan University in Israel, told Live Science in an email.  

Gonen and colleagues study a process called sex determination, whereby either male or female reproductive organs — the testicles and ovaries, respectively — form during embryonic development. The researchers were inspired to create the new testicle organoids after realizing there was a lack of lab models that closely resembled these organs in the human body. 

In the new study, the team extracted immature testicle cells from newborn mice and, with the help of growth-stimulating signaling proteins, drove them to form organoids. The organoid cells organized themselves in a similar way to what is seen in a normal mouse testicle. 

The team was also able to grow testicle organoids from mouse testicle cells drawn from developing embryos. Many diseases that are tied to testicle development and dysfunction occur during embryonic development, so being able to model this stage of testicle growth may be particularly important, the team wrote in the paper. 

The newly made testicle organoids didn’t produce sperm. However, there were early signs that the cells might be able to take part in meiosis, a type of cell division that is used to produce various sex cells, including sperm. Going forward, the team wants to explore whether the organoids can be made to make sperm and hormones. 

They also aspire to grow testicle organoids from human cells, and they already have one specific use in mind. Male children with cancer who are undergoing chemotherapy often lose the stem cells that will go on to form sperm after puberty begins and can, therefore, become infertile, Gonen said. The hope is that, eventually, testicle organoids could be grown from a child’s stem cells before cancer treatment begins and be used to produce fertile sperm, she said. These sperm could then be available for future fertility treatments, such as in vitro fertilization (IVF.)

Focusing on male infertility.

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The burden of male infertility is often unrecognized and its causes are poorly understood. Efforts to increase awareness and understanding are being undertaken to improve fertility outcomes and overall health for affected men.

Globally, at least one in seven heterosexual couples of reproductive age is affected by infertility1. Infertility is often perceived as an issue that affects women, but male factor infertility contributes to approximately half of instances2. Unfortunately, the burden of male infertility is often unrecognized and its causes are poorly understood, meaning men can be sidelined during treatment and the burden of medically assisted reproductive techniques falls on the woman, even if she herself has no reproductive issues. This lack of understanding and information means that substantial emotional stress is put on both members of the couple seeking infertility treatment.

For most men with infertility, no cause of the issue is given, which can add further stress and uncertainty. However, men usually receive a classification based on their semen phenotype, such as azoospermia (no sperm in the ejaculate), oligozoospermia (<15 million sperm per ml), asthenozoospermia (reduced sperm motility), teratozoospermia (abnormal sperm morphology) or a combination of these phenotypes. These categories are defined according to criteria outlined by the WHO in their laboratory manual for processing human semen3. Semen analysis is essential for infertility evaluation and subsequent referral, diagnosis and treatment, but tests to provide a precise diagnosis of male infertility are rare. Thus, the best pathway to fertility can be missed, and few targeted treatment options exist4.

The presence of male infertility could be an indicator of men’s health in general5,6. Evidence suggests that an infertility diagnosis is associated with an increased risk of current comorbidities, future diagnosis of metabolic diseases and cancer and even of mortality5. Thus, all men dealing with couple infertility should undergo a full andrological assessment by a reproductive urologist that includes a detailed history, physical examination, semen analysis, endocrine assessment and other tests if required. This assessment should also involve lifestyle counselling and information on chronic disease prevention, disease management and health maintenance4,5. This undertaking has the potential to improve men’s health outcomes overall.

Knowledge and understanding of male fertility issues are poor in the general public, but some efforts to improve public awareness have been made, such as the HIMfertility campaign in the UK, which provides men faced with this issue with information and a support network. Despite these efforts, the personal and societal burdens of male infertility are underappreciated6,7. In this environment, organizations, such as the Male Reproductive Health Initiative and the International Male Infertility Genomics Consortium, and researchers are working to advance knowledge and understanding. By investigating the underlying causes of male infertility — from the genetic and epigenetic to the physiological — discerning the most pressing questions in male infertility research and providing standardized terminology, outstanding questions concerning male infertility can be answered and new treatment options developed.

“the personal and societal burdens of male infertility are underappreciated”

At Nature Reviews Urology, we want to support these endeavours and are proud to publish articles from experts in this field that raise awareness and improve knowledge and comprehension of male infertility. In doing so, we hope that we can contribute to enhancing collaboration and progressing research in this area, ultimately improving options and outcomes for men with a diagnosis of male infertility.

Male infertility: the driver behind our team’s new study

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Commentary on a 12-week double-blind placebo-controlled trial to see if raising blood lycopene levels improves sperm quality – by Dr Elizabeth Williams, a senior lecturer in the Human Nutrition Unit, Department of Oncology & Metabolism at the University of Sheffield.

Most young men are more than surprised when they are told that 25% of them will have poor sperm quality and that it is one of the major causes of infertility in couples.

These days young men are exposed to many factors that affect male fertility. This includes obesity, smoking, stress, alcohol abuse, environmental toxins, sexually transmitted diseases and many more factors that mean our body’s ability to produce healthy sperm is impaired.

Britain is facing an epidemic of childlessness with one in six couples unable to conceive and men having poor-quality sperm causing over half of the problem.

That is why we decided to undertake what I feel is an important study which is being led by our own well-respected UK expert in fertility, Allan Pacey, Professor of Andrology in the Academic Unit of Reproductive and Developmental Medicine.

Following the findings of a previous study at Cleveland Clinic’s Center for Reproductive Medicine in the USA, which indicated lycopene supplementation could raise sperm count by up to 70%, we decided to undertake our own lycopene study at the University of Sheffield.

There are a number of research papers that have also shown lycopene may slow the progression of cancer of the prostate, the gland that makes seminal fluid, so it is logical that lycopene may improve sperm quality.

Allan and I agreed that little work has been done in this area, but if lycopene has a beneficial effect on the prostate, it is reasonable to think it might also improve sperm function.

We have designed a double-blind placebo-controlled trial to investigate the effect of lycopene on sperm function. We are recruiting 60 healthy male students and university staff aged 18-30 to take part in the three-month study.

We are using an over-the-counter lactolycopene supplement, called XY Pro®, for the study because previous scientific papers showed its lycopene formulation is very readily absorbed.

Half of the study volunteers will take two 7 mg capsules per day of a lycopene supplement containing lactolycopene while the other half will take identical dummy capsules.

To avoid the risk of bias, neither the volunteers nor the researchers will know who has received the active capsules and who has received the dummy treatment, until the results are analysed. Volunteers will not be given any personal information about their sperm count or potential fertility.

There is enough evidence out there to suggest this study is worthwhile and I am cautiously optimistic. If it works in the volunteers we would then consider testing it in infertile patients.

What Causes Male Infertility? Sperm Cells With Poorly Packaged Genes, Researchers Say

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The human genome would span nearly six feet if unfurled, yet every cell in your body contains a complete copy. How does that work? The DNA wraps itself like thread around protein spools called histones, and these genes and proteins combined form a complex referred to as achromatin. Yet sperm (a man’s reproductive cells) are much smaller than most cells, so early in their development, the histone spools are replaced by even tinier proteins called protamines. Now, researchers from Cold Spring Harbor Laboratory (CSHL) discovered that this moment of substitution — referred to as chromatin remodeling — is essential for male fertility, and when this process somehow goes awry, the result is infertility.

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Male Infertility

When people think of fertility, they most often think of women, yet men play an equal role in fertility and may be the cause of childlessness. In fact, more than three million American men also experience infertility. Male infertility can be a temporary issue caused by a reaction to certain conditions, say, a sexually transmitted disease or even a tumor. On the other hand, infertility may be a permanent condition caused by a fundamental issue with the sperm itself, including too few sperm produced, misshapen sperm, motility (when sperm that cannot swim properly), or blockages that prevent sperm from joining with semen.

To better understand infertility, then, scientists commonly investigate sperm, the specialized cell that is so small — 30 times more petite than the female egg — it contains little more than DNA and molecular motors. From head to tail, a sperm cell is invisible to the naked eye, just about 1/500th of an inch. For this reason, even more than other cells, DNA must be tightly packaged to fit within its miniscule boundaries.

CSHL Professor Dr. Alea Mills and Dr. Wangzhi Li, lead author of a new study published Tuesday in Nature Communications, identified a role played in male infertility by Chd5, the protein that regulates chromatin remodeling, the moment when protamines replace histones.  The team discovered Chd5 as a potential cause of sterility when they analyzed data from testes biopsies obtained from men with sperm defects causing infertility. “We found that men with more severe defects had the lowest levels of Chd5,” Mills said.

To learn more about Chd5, the team of researchers removed copies of the Chd5 gene from male mice. They discovered this resulted in the male mice having severe fertility defects, ranging from low sperm counts to decreased motility. In fact, when the researchers performed in vitro fertilization (IVF), the defective sperm from these mice were unable to fertilize eggs.

Exploring further, the researchers discovered that when Chd5 is missing, chromatin remodeling is entirely disrupted. Protamines do not efficiently replace histones, resulting in a less condensed genome. In turn, when the genome was not packaged correctly within sperm cells, the DNA itself dramatically changed — the double helix became damaged and broke at multiple points throughout the genome.

“So in addition to infertility, loss of Chd5 may put future generations — the rare embryos that do get fertilized with defective sperm — at risk for disease,” Mills said. “Chd5 may protect a person from medical conditions related to DNA damage and spontaneous mutations, like cancer and autism.” The team of researchers is continuing to explore the effects of Chd5 in human fertility.

Toiletry chemicals linked to testicular cancer and male infertility cost EU millions, report says

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Nordic Council calls on EU to ban damaging compounds found in household products that cost millions due to their harmful impact on male reproductive health
endocrine disruptor chemicals ( EDC ) hormone-mimicking chemicals : cleaning products placed shelf
Endocrine disruptor compounds (EDCs) routinely used in household items could cause serious health damage, a study has found.

endocrine disruptor chemicals ( EDC ) hormone-mimicking chemicals : cleaning products placed shelf
The hormone-mimicking chemicals used routinely in toiletries, cosmetics, medicines, plastics and pesticides cause hundreds of millions of euros of damage to EU citizens every year, according to the first estimate of their economic impact.

The endocrine disruptor compounds (EDCs) are thought to be particularly harmful to male reproductive health and can cause testicular cancer, infertility, deformation of the penis and undescended testicles.

The new report, from the Nordic Council of Ministers, focuses on the costs of these on health and the ability to work but warns that they “only represent a fraction of the endocrine-related diseases” and does not consider damage to wildlife. Another new study, published in a medical journal, showed an EDC found in anti-perspirants reduced male fertility by 30%.

The Nordic Council, representing the governments of governments of Denmark, Finland, Iceland, Norway and Sweden, is demanding the European Union speeds up its plan to identify, assess and ban harmful EDCs. Sweden is already taking legal action against the EU over its missed deadlines, which it blamed on lobbying by the European chemical industry.

“I am not happy that taxpayers have to pay for the damage caused by EDCs, while industry saves money by not investigating their chemicals properly,” said Danish environment minister Kirsten Brosbøl on publication of the new report.

Michael Warhurst, of campaign group Chem Trust, said: “Companies should focus on developing and producing products that don’t contain hormone disruptors and other problem chemicals. This will give them a competitive advantage as controls on these chemicals become stricter around the world – and as consumers become more aware of this issue.”

The report, called The Cost of Inaction, uses the extensive health records collected by the Nordic countries to determine the incidence of the male reproductive health problems linked to EDCs and then uses Swedish data to estimate costs. These are extrapolated to the population of the EU’s 28 nations.

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The report also assesses the proportion of the health problems attributable to EDCs, with a central estimate of 20%, leading to a conclusion that the male reproductive health problems cost the EU €592m (£470m) a year. The report states: “Minimising exposure to endocrine disruptors will not only remove distress and pain for the persons (and the wildlife) affected, it will also save the society from considerable economic costs.”

The EU, which would be the first authority in the world to regulate EDCs, is currently conducting a public consultation on a scientific method to identify the chemicals, which ends on 16 January. In 2011, the UK and German governments lobbied to EU to restrict the definition of EDCs to only the most potent chemicals, a proposal described as a “loophole” by critics.

Peter Smith, executive director for product stewardship at CEFIC, which represents the European chemical industry, said the Nordic report attribution of health problems to EDCs was “arbitrary”. He said: “The link between exposure to a chemical and an illness has not been shown in many cases. The authors themselves say they have some trouble with causality.”

Smith said the delays to EDC regulation in the EU did not suit the industry. “Nobody is happy with the delays. But we would prefer it to be permanent and right rather than temporary and wrong.” He said case-by-case rigorous assessment was needed and that any precautionary action had to be proportional to the evidence of harm.

However, Professor Andreas Kortenkamp, a human toxicologist at Brunel University London in the UK, said the epidemiological work needed to prove causation is very difficult. For example, he said, analysing links to birth defects would having taken tissue samples from mothers before they gave birth.

“Hard evidence for effects in humans is difficult to demonstrate, though there are some exceptions,” he said. “But there is very good, strong evidence from animal and cell line test systems. The chemical industry only likes to emphasis the first part of that.” He said precaution was the only safe approach and said the Nordic report was good work.

“Industry lobbying has put regulation back by 3-5 years, which was entirely the intention,” said Kortenkamp, who led a 2012 review of EDCs for the EU which found new regulations were needed. “Every year of no regulation means millions of euros to the industry. That is what it is all about.”

In 2012, the World Health Organiation and the UN environment programme published a major report on the state of EDC science, which concluded that communities across the globe were being exposed to EDCs and their associated risks and that urgent research on the health and environmental impacts was needed. Dr Maria Neira, the WHO’s director for public health and environment said at the time: “We all have a responsibility to protect future generations.” Another review in 2012 by the European Environment Agency advised “a precautionary approach to many of these chemicals until their effects are more fully understood.”

Chemicals found in common household products may affect human sperm.

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In 1991 a study showed that human sperm counts had fallen by almost 50 percent in less than 50 years, which increased the cases of male infertility due to lower sperm count.

Toothpaste and sunscreen could be two of the reasons why male infertility is on the rise.

Sebastian_Tomus_sperm_shutterstock
A few years later researchers discovered that common chemicals used in everyday day items such as soap and toothpaste have a negative effect in the male reproductive system – and a new study has found a way of testing the impact of household products on human sperm.
Some chemical substances mimic either male sex hormones or female sex hormones and both interfere with the male reproductive system by slowing down sperm, explains Steve Connor over at the Independent.
The chemicals commonly found in detergents, plastics, toothpaste and even sunscreen also make sperm release enzymes needed to fertilise the egg cell before it reaches it, which may also be a cause of infertility.
In their study the researchers found that these chemicals have what Connor describes as a “cocktail effect”, meaning the presence of one amplifies the effects of others.
“For the first time, we have shown a direct link between exposure to endocrine-disrupting chemicals from industrial products and adverse effects on human sperm function,” said Professor Niels Skakkebaek, of Copenhagen University Hospital in Denmark, to the Independent.
A report from the Centre of Advanced European Studies and Research found that out of 96 common household chemicals, a third had an effect on the protein that controls sperm motility and swimming agility.
“In my opinion, our findings are clearly a concern as some endocrine-disrupting chemicals are possibly more dangerous than previously thought,” said Skkakkebaek. “However, it remains to be seen from forthcoming clinical studies whether our findings may explain reduced couple fertility which is very common in modern society.”
This study is the first one that highlights how common lifestyle or environmental changes affect male fertility.

Protein linked to male infertility .

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In a study published in the journal PLoS Genetics, researchers from Monash University, the University of Newcastle, John Curtin School of Medical Research and Garvan Institute of Medical Research, in Australia; and the University of Cambridge, in the UK, have shown how a protein called RABL2 affects the length of sperm tails, crippling their motility (or swimming ability), and decreases sperm production.

Professor Moira O’Bryan from Monash University’s School of Biomedical Sciences (SOBS) led the research. In laboratory tests, the team found that a mutation in RABL2 resulted in sperm tails that were 17 per cent shorter than normal. Dysfunctioning RABL2 also negatively affected sperm production, resulting in a 50 per cent decrease.

Professor O’Bryan said the research fitted another piece in the jigsaw puzzle of sperm development.

“The mutations in the RABL2 gene are very likely to cause infertility,” Professor O’Bryan said.

“Further, as motility is absolutely essential for fertility, insights into tail function may reveal options for urgently needed male-based contraception.”

Lead author and PhD student Jennifer Lo, also from the School of Biomedical Sciences, said RABL2 worked with other molecules known as intraflagellar transport proteins that carry genetic cargo along the sperm tail.

“Intraflagellar transport proteins are like a train. Our data suggests that the reloading of the train is defective if RABL2 dysfunctions,” Ms Lo said.

“The train is still running in sperm tails with dysfunctional RABL2, but it contains fewer passengers. The end result is that sperm formation and motility are abnormal.”

Ms Lo said that as mutations in RABL2 decrease sperm count and sperm swimming ability, it may be possible to inhibit this protein in a future male pill.

However, as RABL2 is also found, albeit in lower concentrations, in other tissues, such as the brain, kidney and liver, an inhibitor specific to the testes would need to be developed.

Professor O’Bryan said that male infertility was often the canary in the coal mine of general health.

“Many of the basic processes of sperm development occur at lower levels in other organs of the body. As such, the presentation of a man for infertility treatment offers the opportunity not only to give him the children he desires but also to mitigate future disease,” Professor O’Bryan said.

Source: http://www.sciencealert.com.au