IVF News

Crucial role of sperm DNA-packaging protein has been identified in mice, which causes infertility when truncated.

During sperm production in humans, 23 DNA chromatin strands must be tightly wound into the head of the sperm. Because sperm cells are significantly smaller than typical human cells, sperm-specific proteins called protamines are required to tightly package and protect DNA during this process. Now, researchers from Germany have identified a previously unknown mechanism by which protamine 2 (PRM2) is required for fertility in mice.

'Most mammals seem to produce only one type of protamine, PRM1. In humans, but also rodents like mice, it's different – they have a second type, PRM2', said first-author of the study, Dr Lena Arevalo, University of Bonn, Germany.

DNA is normally packaged more loosely around histone proteins, however, during sperm generation, histones are replaced by protamines. The N-terminal domain of PRM2 is normally cleaved during sperm DNA packaging. In this study, published in PLOS Genetics, the authors generated a mouse model in which the PRM2 N-terminal domain was absent, leaving only a truncated protein behind. This led to inefficient transfer of DNA from histones to protamines, and ineffective DNA packaging into sperm.

Importantly, when mutant male mice which have only the truncated form of PRM2 were mated with healthy female mice, no offspring were produced. The mice were infertile.

'Proper PRM2 cleaving, therefore, seems to be crucial for successful reproduction, yet, the function of the [PRM2 N-terminal] domain and PRM2 processing are unknown to date' the authors explained in their paper.

Further biochemical analysis showed that the sperm of these mice had impaired motility, abnormal shape and their DNA was fragmented, highlighting the importance of an intact N-terminal domain of PRM2.

Unlike other species, having this second protamine is specific to mice and primates. As this DNA packaging process is thought to occur using similar mechanisms in humans, the researchers hypothesise that having a faulty PRM2 protein may cause infertility in men.

'We were able to provide a first glimpse into the function of cleaved PRM2 and PRM2 processing, that opens up multiple avenues for further investigation', concluded the authors.

Sources and References

• 12 July 2022. University Hospital Bonn
  Sperm are masters of tetris packing

• 28 June 2022. PLOS Genetics
  Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice

• 12 July 2022. Crast.net
  It turns out that your sperm is packed with DNA as tightly as a Tetris block

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With consumer DNA testing growing in popularity, it is becoming increasingly difficult to ensure the anonymity of both donors and donor-conceived children.

According to the ongoing Connecte DNA study, there have been more people using consumer genetic testing to reveal information about genetic relatives. With large commercial DNA databanks, the parties involved in donation and conception can now bypass the regulated channels of receiving donor information. Dr Lucy Frith, reader in bioethics at the University of Manchester, presented the findings at the annual meeting of the European Society of Human Reproduction and Embryology (ESHRE).

According to Dr Frith, 'donor-conceived people can use these services to conduct a DNA test to search for their genetic parent; recipient parents can test the child to identify the donor and any other half-siblings; and donors themselves can also take a DNA test to search for the offspring of their donations.' She added: 'the donor (or the donor-conceived child) need not be in a database to be identified – as a close genetic relative may be in the database and thereby traceable.'

Researchers involved in the ConnecteDNA study conducted interviews with sperm, egg and embryo donors, parents through donor conception, and donor-conceived adults. Interim results suggest that commercial DNA testing services, and social media, are being used to find genetic relatives as well as, or instead of, 'official' routes. In the UK, information about donors and donor-conceived people is held on a central register managed by the Human Fertilisation and Embryology Authority (HFEA). Donor-conceived children born after 2005 can request information from the HFEA about their donor when they turn 18.

Professor Joyce Harper, from the Institute for Women's Health at University College London, told BioNews: '...Dr Frith's study interviewing donors and donor-conceived children and their parents is important to understand what drives them to find genetic relatives. As she reports – all options are possible; from donors trying to find their offspring, to parents who are using these tests to trace people related to their own donor-conceived children.'

According to an ESHRE survey in 2015, there are still a dozen European countries that have laws mandating donor anonymity. The ConnecteDNA study is set to focus on the legal regulations that currently govern the access to and storage of donor information in the UK, the Netherlands, Sweden and Victoria, Australia. Ultimately, the study aims to find solutions and make recommendations about how to keep and reveal donor information.

Dr Frith concluded 'that the fertility sector itself is now suddenly faced with a new responsibility to ensure that both gamete recipients and donors are aware of the wide-ranging possibilities of identification.'

Sources and References

• 6 July 2022. 38th annual meeting of the European Society of Human Reproduction and Embryology
  How consumer DNA testing is changing the landscape of egg and sperm donation

The largest study of its kind has found no difference in pregnancy rates between intrauterine insemination (IUI) cycles using fresh or frozen sperm.

The research was presented at the annual meeting of the European Society of Human Reproduction and Embryology by Dr Panagiotis Cherouveim from Massachusetts General Hospital and Harvard Medical School.

'The fact that our data did not reveal any significant difference in success between the utilisation of fresh ejaculated and frozen sperm, except in a subgroup of patients given oral ovulation-inducing agents, is very reassuring to all involved,' said Dr Cherouveim. 'No detrimental effect of sperm cryopreservation on IUI outcomes was noted.'

The study looked at outcomes from 5335 IUI treatments that took place from 2004-2021. Overall there was no significant difference in pregnancy rates, but some differences were observed in patients who had ovarian stimulation prior to insemination, versus those who did not.

'Although, specific subgroups might benefit from fresh sperm utilisation and time-to-pregnancy might be shorter with fresh than frozen sperm, patients should be counselled about the non-inferiority of frozen sperm,' said Dr Cherouveim.

One limitation of the study is that most of the frozen sperm came from anonymous donors, who tend on average to be younger, and healthier than the partners providing fresh sperm, and usually have good quality sperm. 

'On the face of it, it's reassuring to find that there is no material difference in the success of fresh or frozen sperm during an IUI procedure,' andrologist Professor Allan Pacey from the University of Sheffield told BioNews. 'However, in this study, the frozen sperm was from donors who are highly selected men precisely because their sperm can survive the freezing process. Therefore, is there really any surprise that the authors found no difference?'

Sources and References

• 4 July 2022. 38th annual meeting of the European Society of Human Reproduction and Embryology
  Frozen sperm just as effective as fresh for insemination treatments

Pregnancies resulting from frozen embryo transfers are at greater risk of complications related to high blood pressure, according to new research.

High blood pressure (hypertension) in pregnancy can have serious consequences for both the mother and the fetus and complications such as pre-eclampsia. Dr Sindre Petersen from the Norwegian University of Science and Technology, Trondheim, Norway presented the findings at the annual meeting of the European Society of Human Reproduction and Embryology.

'This study was by far the largest sibling analysis to date investigating the association between assisted reproduction treatments and hypertensive disorders in pregnancy,' said Dr Petersen. 'Our findings are important because the number of [frozen embryo transfers] is rapidly increasing throughout the world.'

The study, by the Committee of Nordic Assisted Reproductive Technology and Safety, used data from more than 4.5 million pregnancies across three Nordic countries between 1988 and 2015. Pregnancies that resulted from frozen embryo transfers had almost double the chance of hypertensive disorders compared to those resulting from natural conception or fresh embryo transfers.

To exclude parental factors, the researchers were able to repeat the finding in a smaller group of 33,000 women who had two or more pregnancies – comparing pregnancies from frozen embryo transfers with those from fresh transfers or natural conception in the same woman. Researchers have not yet addressed the potential impact of maternal age, as a frozen embryo transfer would be likely to follow a fresh or natural embryo transfer at a later date.

Dr Peterson pointed out that the findings must be balanced against the fact that frozen embryo transfers facilitate transferring one embryo at a time, reducing the number of multiple pregnancies which are associated with greater risk for mothers and babies.

'I am confident that a well-grounded and individualised decision of whether to go for a fresh or a frozen cycle can be made after dialogue between the clinician and the couple, just as in all clinical decision making,' he said.

Professor Abha Maheshwari, clinical director of the Aberdeen Fertility Centre and lead clinician at Fertility Scotland told BioNews: 'Hypertensive disorders in pregnancy don't just affect outcomes for mother and baby in that pregnancy but have long-term implications for the mother. Hence, we as a community, have to do everything to minimise the risks.'

Sources and References

• 6 July 2022. 38th annual meeting of the European Society of Human Reproduction and Embryology
  Frozen embryo transfers in IVF linked to greater risk of maternal hypertension in pregnancy