Ability of sperm to sense determines how well they function

Diet and lifestyle 23. jul 2021 3 min PhD student Ida Marie Boisen Written by Morten Busch

Sperm are subjected to enormous changes on a journey from a man’s testicles to an egg in a woman’s uterus. Evidence indicates that the ability to fertilise an egg largely depends on the sperm’s ability to sense various factors – such as the concentration of calcium. A new study of sperm with changes in their calcium-sensing receptor shows that this affects their ability to sense the major differences between the environments sperm encounter and thereby affects their functioning. The new finding may influence the understanding of male infertility.

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On paper, it mostly looks like a good old-fashioned race. The sperm that wriggles the fastest fertilises the egg. However, this is apparently not that simple, because some sperm may scarcely be able to move in the right direction and some act as if they have reached the target long before they get there. A new study reveals that sperm can sense the major differences between the environments in a man’s testicles and a woman’s cervix.

“The sperm move from a quiet and peaceful environment in the man to a significantly different one in the woman, where they are activated and thus enabled to find and penetrate the egg. Our experiments show that the sperm’s calcium-sensing receptor is crucial for this process and that small changes can be crucial for how the sperm function. This knowledge may mainly indicate why some men are infertile, but it can potentially also enable us to find the cause more quickly and easily,” explains main author Ida Marie Boisen, PhD student, Department of Growth and Reproduction, Rigshospitalet, Copenhagen.

Ready for the journey

Fertilisation is the last step in a complex series of events starting with spermatogenesis and sperm maturation in the testis and epididymis. After they mature, sperm remain in a kind of hibernation in which many systems are dormant. However, this is broken abruptly when the sperm are ejaculated towards a woman’s uterus.

“Here, the sperm are exposed to an increase in calcium concentration and also major changes in the concentrations of magnesium, phosphate and bicarbonate and especially changes in pH. This causes the sperm to undergo several processes required for fertilisation, such as hyperactivation to cause them to wriggle towards the egg and carry out the acrosome reaction, which enables the sperm to bind to the egg,” says Ida Marie Boisen.

In particular, the calcium-sensing receptor is considered essential in helping sperm to sense the enormous changes in the concentrations of calcium, magnesium and bicarbonate to which they are exposed during maturation, in the male semen and later in the female vagina and uterus. However, the role of the calcium-sensing receptor in human sperm was virtually unknown.

“To investigate the role of the calcium-sensing receptor in sperm, we measured how it reacted to several of the substances with which it is naturally in contact during the journey towards the egg – that apparently both activate and inhibit the sperm. We tested them in sperm from healthy donors and from people with abnormal changes in their calcium-sensing receptor protein, which we know either reduces or enhances the functioning of the protein,” explains Ida Marie Boisen.

Hyperactive receptor

In the healthy sperm, the activators of the calcium-sensing receptor worked completely as expected, so they helped to amplify the sperm’s effect by activating signals such as response to the more bicarbonate-containing environment in the uterus and the acrosome reaction binding the sperm to the egg.

“This applied to the men with healthy and normal sperm, but men with a loss-of-function mutation in the calcium-sensing receptor had a reduced response to the changes in bicarbonate and the changes in calcium concentration, so changing the calcium-sensing receptor affects these sperm,” says Ida Marie Boisen.

The calcium-sensing receptor may enable the sperm to swim in the direction of altered calcium concentration, and thus weakening the receptor may lead to impaired wriggling ability. This was apparently intact among the men with a hyperactivated receptor. Nevertheless, they seem to have another problem that is at least as serious.

“Our experiments suggest that the overactive receptor causes the sperm to sense that they have reached the egg before they do, so they initiate the acrosome reaction before they reach the egg. They will probably therefore die before they reach the target,” explains Ida Marie Boisen.

The new experiments mainly provide new and important insight into the journey of the sperm and their sensing apparatus but also provide unprecedented insight into how concentrations of substances can orient the sperm so that they can turn the necessary functions on and off. Although this is primarily fascinating basic research, it also has immediate applications.

“The calcium-sensing receptor is important for sperm to sense calcium, magnesium and bicarbonate. Since loss of this function can impair sperm functioning, we can potentially use changes in calcium-sensing receptor proteins to detect and especially explain some men’s infertility. This is important, since there has been far too little knowledge about and understanding of why men have poor sperm quality. Here, a logical explanation often helps in accepting the problem,” concludes Ida Marie Boisen.

The calcium-sensing receptor is essential for calcium and bicarbonate sensitivity in human spermatozoa” has been published in The Journal of Clinical Endocrinology & Metabolism. In 2018, the Novo Nordisk Foundation awarded a grant to main author Martin Blomberg Jensen for the project Clinical Relevance of the Calcium-sensing Receptor in Reproduction.

Our research is inspired by the realities we face in our outpatient clinic: an increased prevalence of reproductive disorders without known aetiology....

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