It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
Friday, January 19, 2024
Infertility: Sperm need a breakthrough for fertilization
Defective ion channel in sperm flagellum renders men infertile and frustrates medically assisted reproduction
In half of the couples that are unable to conceive a child, the infertility is due to the man. A new study identifies the defective function of ‘CatSper’, an ion channel controlling calcium levels in sperm, as a common cause of seemingly unexplained male infertility. CatSper-deficient human sperm fail to fertilize the egg, because they cannot penetrate its protective vestments. Thus far, this sperm channelopathy has remained undetectable. Scientists from Münster, Germany, have unravelled CatSper´s role in infertility using a novel laboratory test that identifies affected men. Based on the results of the study, which has been published in the scientific journal ‘The Journal of Clinical Investigation’, diagnostics and care of infertile couples can be improved.
One in six couples fail to conceive a child. The underlying cause often remains unresolved. In fact, in about one third of infertile couples, the man´s semen analysis yields no abnormalities in the number, motility, or morphology of the sperm. This poses a problem: the lack of a clear diagnosis prevents an evidence-based selection of a therapy option. As a result, affected couples often experience unsuccessful treatments.
How do men fail to conceive a child despite normal semen parameters? An interdisciplinary team of scientists from the University of Münster in Germany, set out to answer this question. ‘For quite a while, we have considered CatSper a prime suspect’ says Prof. Timo Strünker from the Centre of Reproductive Medicine and Andrology (CeRA). Some years ago, Strünker and colleagues revealed that sperm use CatSper as a sensor to detect messenger molecules released by the egg. These molecules activate CatSper, which leads to an influx of calcium into the flagellum, changing its beating pattern.
To scrutinize whether this is essential for fertilization, the researchers developed a simple laboratory test that enabled them to determine the activity of CatSper in sperm from almost 2300 men. This revealed that about one in a hundred infertile men with unremarkable semen parameters indeed features a loss of CatSper function. ‘The most common cause is genetic variants in genes encoding one of CatSper’s components’, adds the Reproductive Geneticist Prof. Frank Tüttelmann, Münster.
Sperm require the changes in flagellar beating mediated by CatSper to break through the egg´s protective coat. Another important finding of the study: CatSper-related male infertility also involves failure of medically assisted reproduction via intrauterine insemination, involving the application of sperm via a catheter into the uterus right before ovulation, or classical in-vitro fertilization (fertilization in the petri dish). This is not surprising, considering that these treatments still require the sperm to break through the egg coat. Affected men/couples could only conceive a child via the ICSI method, which involves the manual injection of a sperm cell into the egg.
‘Thanks to this comprehensive research endeavour, we can now identify and diagnose this channelopathy, enabling evidence-based treatment of affected couples’, summarizes Prof. Sabine Kliesch, Head of the Department of Clinical and Surgical Andrology at the CeRA. ‘Thereby, we minimize the medical risk for the couples and maximize the chances of success’.
The function of sperm is not only controlled by CatSper but also various other proteins. These are also in the focus of the Clinical Research Unit (CRU326) ‘Male Germ Cells‘, which, funded by the German Research Council, provided the collaborative framework for the current study. The overarching aim of the researchers in Münster is to systematically elucidate the role of these proteins in (in)fertility, improving diagnostics and care of affected couples.
In half of the couples that are unable to conceive a child, the infertility is due to the man. A new study identifies the defective function of ‘CatSper’, an ion channel controlling calcium levels in sperm, as a common cause of seemingly unexplained male infertility. CatSper-deficient human sperm fail to fertilize the egg, because they cannot penetrate its protective vestments. Thus far, this sperm channelopathy has remained undetectable. Scientists from Münster, Germany, have unravelled CatSper´s role in infertility using a novel laboratory test that identifies affected men. Based on the results of the study, which has been published in the scientific journal ‘The Journal of Clinical Investigation’, diagnostics and care of infertile couples can be improved.
One in six couples fail to conceive a child. The underlying cause often remains unresolved. In fact, in about one third of infertile couples, the man´s semen analysis yields no abnormalities in the number, motility, or morphology of the sperm. This poses a problem: the lack of a clear diagnosis prevents an evidence-based selection of a therapy option. As a result, affected couples often experience unsuccessful treatments.
How do men fail to conceive a child despite normal semen parameters? An interdisciplinary team of scientists from the University of Münster in Germany, set out to answer this question. ‘For quite a while, we have considered CatSper a prime suspect’ says Prof. Timo Strünker from the Centre of Reproductive Medicine and Andrology (CeRA). Some years ago, Strünker and colleagues revealed that sperm use CatSper as a sensor to detect messenger molecules released by the egg. These molecules activate CatSper, which leads to an influx of calcium into the flagellum, changing its beating pattern.
To scrutinize whether this is essential for fertilization, the researchers developed a simple laboratory test that enabled them to determine the activity of CatSper in sperm from almost 2300 men. This revealed that about one in a hundred infertile men with unremarkable semen parameters indeed features a loss of CatSper function. ‘The most common cause is genetic variants in genes encoding one of CatSper’s components’, adds the Reproductive Geneticist Prof. Frank Tüttelmann, Münster.
Sperm require the changes in flagellar beating mediated by CatSper to break through the egg´s protective coat. Another important finding of the study: CatSper-related male infertility also involves failure of medically assisted reproduction via intrauterine insemination, involving the application of sperm via a catheter into the uterus right before ovulation, or classical in-vitro fertilization (fertilization in the petri dish). This is not surprising, considering that these treatments still require the sperm to break through the egg coat. Affected men/couples could only conceive a child via the ICSI method, which involves the manual injection of a sperm cell into the egg.
‘Thanks to this comprehensive research endeavour, we can now identify and diagnose this channelopathy, enabling evidence-based treatment of affected couples’, summarizes Prof. Sabine Kliesch, Head of the Department of Clinical and Surgical Andrology at the CeRA. ‘Thereby, we minimize the medical risk for the couples and maximize the chances of success’.
The function of sperm is not only controlled by CatSper but also various other proteins. These are also in the focus of the Clinical Research Unit (CRU326) ‘Male Germ Cells‘, which, funded by the German Research Council, provided the collaborative framework for the current study. The overarching aim of the researchers in Münster is to systematically elucidate the role of these proteins in (in)fertility, improving diagnostics and care of affected couples.
IT WAS FOUND THAT MALE MICE WITH NO ABILITY TO PRODUCE THE MC2 PROTEIN WERE UNABLE TO FORM THE CONNECTION BETWEEN THE TAIL AND THE HEAD OF THE SPERM AND THE MICE BECAME INFERTILE. THE MICROSCOPE IMAGES CLEARLY SHOW THE DIFFERENCE IN THE SPERM.
Mice lacking a certain gene are unable to produce offspring because their sperm lack the connection between the tail and the head. A new thesis from the University of Gothenburg indicates a probable cause of male infertility.
Researchers at the University of Gothenburg have identified a new protein, dubbed by them as “MC2”, that plays a crucial part in the formation of swimmable sperm in mice. This protein is needed to create a functional connection between the head and the tail of the sperm.
“The connection is located in the ‘neck’ of the sperm head and facilitates coordinated movement and function as the sperm swims towards the egg. Certainly, the tail and head will each be created perfectly without such a connection – but to no avail, as they will be unable to reach their target,” says Kexin Zhang, a doctoral student at the Department of Chemistry and Molecular Biology at the University of Gothenburg.
Gene of no importance for females
Experiments on mice indicated to Kexin Zhang and her research colleagues that production of the MC2 protein was controlled by a specific gene in the genome. When the gene was removed using genetic scissors, the researchers saw that the mice stopped producing the protein and became completely infertile. It is already known that genetic factors are responsible for 15 to 30 per cent of infertility in men. The gene is not on the sex chromosome and had no impact on the females’ ability to produce offspring.
“My research helped to enhance understanding of the causes of infertility due to the absence of the head of the sperm, which is known as acephalic spermatozoa syndrome. The underlying cause of this diagnosis has been unknown until now,” says Kexin Zhang.
Contraceptive
The discovery of the MC2 protein provides new insights into the molecular structure of sperm cells that then develop into spermatozoa. Researchers will be able to study these insights further.
“It is estimated that some 15 per cent of all heterosexual couples have problems with having children. The man is responsible for the problems in about half of these cases. I hope our research will eventually lead to new diagnostic methods and new treatments for male infertility. It may also be possible to create a male contraceptive by switching off this gene,” says Kexin Zhang.
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
Preserving Genetic Integrity in Reproduction: Insights from Telomere Protection and Sperm Head-Tail Junctions
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