IVF News

Germline cells seem to reset their biological clocks around the time of embryo implantation, not when generating gametes, as previously thought.

Scientists measured an increase in genetic damage in embryonic cells during the early stages of embryogenesis in mice before undergoing a total reset within a 'rejuvenation period', reversing any cell damage.

'This study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal ageing,' wrote the researchers from Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts.

Previously, it was thought that, unlike the somatic cells which form our bodies, germline cells – which differentiate into either sperm or eggs – were ageless and did not inherit genetic damage from their parent organisms. However, recent research has shown that germline cells do age and display hallmarks of genetic damage. Yet, babies do not inherit their parents' age, and start again from zero.

The team employed machine-learning algorithms as 'ageing clocks' to calculate the ages of human and mouse embryonic tissue by measuring the prevalence of methylation – an epigenetic marker. These markers accumulate with age on certain sections of DNA and are influenced by environmental factors. Although these markers do not affect the DNA sequence, they can alter the way a gene is expressed and modify proteins produced.

Genetic data sets collected from mouse embryos during different stages of embryonic development were analysed by these epigenetic ageing clocks. Data sets recorded from mouse embryos following fertilisation showed increased epigenetic ageing with time during the first six days of cell division. But, during its implantation within the uterus wall, the embryonic cells displayed a decrease in epigenetic damage, characteristic of a reversal in ageing. 

The team were unable to perform the same experiment in human embryos but were able to compare methylation in human induced pluripotent stem cells and embryonic stem cell lines and datasets detailing methylation in human fetal tissue samples and see that a similar reset appeared to have occurred. 

The findings, published in the journal Science Advances, have wide-reaching implications for aiding the treatment of age-related illnesses such as Alzheimer's and Parkinson's disease. These diseases feature cells with accelerated epigenetic ageing and through a greater understanding of these biological reset mechanisms, it is thought that epigenetic damage to these cells could be reversed. However, achieving this in practice may be challenging since knowledge of other causes of cellular ageing is needed. 

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An essential component of how sperm move has been discovered, opening up new avenues for the understanding and treatment of male infertility.

Scientists at the University of Toledo, Ohio, have made a new discovery about the function of a part of the sperm that was previously thought to only act as a 'shock absorber'. What was believed to be a rigid structure in the neck of the sperm, the atypical centriole, has now been discovered to be essential for sperm movement.

Corresponding author Professor Tomer Avidor-Reiss now believes that the atypical centriole 'is an evolutionary innovation whose function is to make your sperm move better'.

For a sperm to successfully fertilise an egg in the reproductive tract, it needs powerful motility. It was previously thought that this motility was driven by another set of centrioles sliding together in the sperm's tail. This new finding, published in Nature Communications, instead showed that the atypical centriole in the sperm's neck acts as a transmission centre, coordinating the response from the tail with a 'kinking' action in the sperm's head, powering the sperm's movement. This finding challenged the belief that the head is passive as the sperm moved.

Professor Avidor-Reiss hopes that this research will open up new avenues to understanding why some men are infertile. 'If the centriole is defective, this coupling between the sperm tail and head is going to be defective... This knowledge allows us to identify a subgroup of infertile men that was not revealed before.'

The researchers involved in the study, led by PhD candidate Sushil Khanal, used a state-of-the-art technique called STORM microscopy to look at the structure of the sperm in high definition. By identifying what the function of these components is within the sperm cells, they can also understand what to expect in healthy sperm. They suggested that the kinking action of the sperm head could be responsible for sensing the reproductive tract environment whilst the swimming motion may enhance the ability of the sperm to get through the protective outer layers of the egg for fertilisation.

Professor Avidor-Reiss added that 'these studies call for a revision in our understanding of sperm centrioles both in sperm movement and in the early embryo'.

With this new understanding, the movement of the sperm and function of the centriole could be used as a test for diagnosing the cause of male infertility. Furthermore, therapies could be developed for patients that have sperm with dysfunctional centrioles.

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A protocol involving two egg collections in the same menstrual cycle may reduce the time to pregnancy for IVF patients who respond poorly to ovarian stimulation. 

Results from a Spanish study presented at the meeting of the European Society of Human Reproduction and Embryology 2021 showed that in patients with low ovarian reserve, the protocol – called DuoStim – resulted in a comparable number of eggs and embryos as two rounds of egg collection in separate cycles. However, with DuoStim the average time it took to have an embryo ready for transfer was reduced. 

'We think it's a great alternative for predicted poor responders who might otherwise have difficulties reaching blastocyst transfer from just one egg pick-up' said Dr Maria Cerrillo Martinez from IVIRMA in Madrid, Spain who presented the findings. 

DuoStim entails two ovarian stimulations and egg collections during a single menstrual cycle. Historically, fertility treatment has involved a single ovarian stimulation and egg retrieval in a given cycle. This would normally be during the first half of the cycle (the 'follicular' phase) but there is precedent for collecting eggs in the second 'luteal' phase, such as for women needing fertility preservation prior to cancer treatment, when delaying treatment until the next cycle would not be justifiable.

Dr Cerrillo and her team conducted a randomised trial, comparing DuoStim with results from two rounds of stimulation and egg collection on separate cycles. All 80 participants were aged 38 or older and had predicted low ovarian response to stimulation. The DuoStim group had a chromosomally-normal embryo ready for transfer on average 23 days after the start of stimulation, whereas the average was 44 days in the conventional method group. 

The researchers do not recommend DuoStim for patients who respond well to ovarian stimulation, as they are likely to produce enough good-quality eggs. However, Dr Cerrillo recommended several classes of patients who could benefit:  

'It may be a good alternative in poor responders, in fertility preservation patients with time constraints, or even in egg donors, whose aim is to maximise the number of eggs retrieved in a single treatment,' she said.

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Antibodies, resulting from either vaccination against or infection with COVID-19 do not impact female fertility, according to new research.

No statistically significant differences in women's rates of embryo implantation were found between those who had antibodies to COVID-19 and those who did not.

'We hope that all reproductive-aged women will be more confident getting the COVID-19 vaccine, given Dr Morris's findings that the vaccine does not cause female sterility' said Dr Hugh Taylor, president of the American Society for Reproductive Medicine (ASRM).

Concerns over a potential autoimmune response towards a protein involved in embryo implantation, called syncytin-1, arose due to its structural similarities with the SARS-CoV-2 spike proteins, the virus that leads to COVID-19. Such an immune response, if present, would inhibit the syncytin-1 protein which helps blastocysts attach to the endometrium and develop the placenta.

Previous research had yet to show any reactivity between syncytin-1 and the SARS-CoV-2 spike proteins. However, this study, published in ASRM's Fertility & Sterility Reports, by Dr Randy Morris, head of the IVF1 fertility clinic in Chicago, Illinois was the first to use human data.

The pregnancy rates of 143 women were examined, 88 of whom had tested negative for COVID-19 antibodies, and 55 women who had tested positive. Twenty of the women with antibodies had been previously infected with COVID-19 whilst 35 had received the Pfizer or Moderna mRNA COVID-19 vaccines.

In vitro frozen embryo transfer was used as a model to assess the impact of COVID-19 on the rates of embryo implantation within the endometrium. Before the transfer of a blastocyst-stage embryo into their uterus, each woman underwent treatments to raise their oestrogen and progesterone levels in order to thicken their endometrium linings. Successful embryo implantation was characterised with elevated levels of human chorionic gonadotropin, a hormone produced by the placenta during pregnancy, recorded eight days after the transfer.

The reaction of over 3000 proteins found in humans, including syncytin-1, with SARS-CoV-2  antibodies was investigated in a separate study performed by scientists at Yale University School of Medicine, New Haven, Connecticut. The research, headed by Dr Akiko Iwasaki, found no such reactivity between syncytin-1 and the SARS-CoV-2 antibodies.

It is hoped that the new clinical research by Dr Morris, coupled with laboratory studies such as that of Dr Iwasaki, will provide further reassurance to many women who wish to have children, that the COVID-19 vaccines are safe with no short or long-term effects on fertility.

'This, and other studies of this nature, further reinforce the ASRM COVID Task Force guidance that, no matter where you are in the family-building process, the COVID-19 vaccine is safe and saves lives' concluded Dr Taylor.

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Fertility drugs do not increase the risk of developing breast cancer, a UK study has shown.

Using records from 1.8 million women who received fertility treatment in the last 30 years, researchers from King's College London assessed whether routinely used fertility drugs increase breast cancer risk.  

'Fertility treatment can be an emotional experience. Patients often ask us if taking ovarian stimulating drugs will put them at increased risk of developing cancers, including breast cancer,' said study author Dr Yusuf Beebeejaun from King's Fertility. 'To answer that important clinical question, we undertook this review that reports data from nearly 2 million people.'

The study, published in Fertility and Sterility is the largest of its kind ever carried out. The researchers analysed patient records from 1990 to 2020, including women of all reproductive ages who were followed up for an average of 27 years after undergoing fertility treatments. The participants, all of whom had no previous history of breast cancer, were treated with ovulation stimulants gonadotrophins and/or clomiphene citrate. 

The study reported no significant increase in breast cancer risk to women treated with either drug alone or in combination when compared to both healthy and infertile untreated women.

'Our study showed that the use of drugs to stimulate ovaries in fertility treatment did not put women at increased risk of breast cancer,' said senior author Dr Sesh Sunkara, lecturer in women's health at King's. 'This study provides the evidence needed to reassure women and couples seeking fertility treatments.'

Fertility drugs stimulating the release of eggs from a patient's ovaries have been used since the early 1960s and can be part of a range of fertility treatments including IVF. Both investigated drug types - clomiphene and gonadotrophins – stimulate the production of follicles in the ovaries, which contain the eggs. Alongside, ovulation stimulation medication typically increases the production of oestrogen, a hormone that can act on breast cells. Researchers were concerned that this effect could increase the risk for breast cancer formation in treated women.

Dr Kotryna Temcinaite from the charity Breast Cancer Now, said: 'Previously it was unclear whether fertility drugs affect breast cancer risk, and we do receive calls to our helpline from women who are concerned that their breast cancer has been caused by fertility treatment. While this analysis of existing published studies does provide welcome reassurance that fertility treatment is unlikely to increase breast cancer risk, further long-term and detailed studies are now needed to confirm these findings.' 

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No differences were identified between IVF cycles taking place before and after the patients received the Pfizer COVID-19 vaccine.

In an observational study, the characteristics of the ovarian stimulation cycle, and outcome in terms of the proportion of high-quality embryos, were compared across two successive IVF cycles: pre- and post-vaccination. 

Professor Raoul Orvieto, who led the study at the Sheba Medical Centre in Tel Hashomer, Israel, told the Jerusalem Post: 'Comparing two IVF cycles was the best way to see if the vaccine would have any impact in terms of number of eggs or any other factors. It did not.'

The 36 couples in the study were all undergoing fertility treatment prior to receiving two doses of the Pfizer mRNA COVID-19 vaccination. Both partners received the vaccine, with the subsequent IVF treatment cycle taking place between 7-85 days post-vaccination. 

Published in Reproductive Biology and Endocrinology, the study observed no differences in cycle characteristics including length of stimulation, and peak estradiol and progesterone levels. Further, no differences were observed in the number of oocytes (immature egg cells) retrieved, fertilisation rate, or the proportion of high-quality embryos formed. 

Professor Orvieto and his colleagues previously published results on the effect of SARS-CoV-2 infection on outcomes of patients undergoing IVF treatment. There was no decrease in patients' performance or ovarian reserve in IVF cycles following recovery from COVID-19, however, a reduction in the proportion of high-quality embryos was seen. 

'We decided to carry out this research because many people are scared of the possible effects of the vaccines on fertility,' said Professor Orvieto. 'I hope this will help fight misconceptions about the vaccine.'

Semen analysis was also included in the study, with no effect observed in key measures including sperm concentration and total motile sperm count. These observations support the findings of a separate study on male fertility published recently, which compared sperm samples of 45 participants taken before and after receiving two doses of either the Pfizer or Moderna vaccine. 

Professor Orvieto said 'We are the first to demonstrate and publish that the vaccine has no effect on both male and female fertility.'

The authors note that validation of their observations is required by larger studies with longer follow-up times. 'However, I do not expect any different results,' said Professor Orvieto.

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Tuesday 22nd June, 2021. 3PM EST/ 8PM GMT / 9PM CET

Moderators:

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Presenters:

Dr. Roger Sturmey: The Embryo in Culture- Metabolism

Dr. Jason Swain: The Embryo in Culture- Culture Conditions

Dr. Kay Elder: The Embryo in Culture: Imprinting, Oxidative Stress and Epigenetic Homeostasis

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Key molecular events regulating early embryo development have been revealed for the first time.

University of Cambridge researchers have created a detailed profile of molecular signals governing embryo implantation during the second week of embryo development. This crucial stage is the point at which many early pregnancy failures occur.

Lead author Professor Magdalena Zernicka-Goetz said: 'Implantation is a milestone in human development as it is from this stage onwards that the embryo really begins to take shape and the overall body plans are decided. It is also the stage of pregnancy at which many developmental defects can become acquired.'

Ethical and practical constraints have meant that, until now, very little had been discovered about this step because development has only been possible inside the womb. However, using a technique to culture human embryos in vitro for up to 14 days, pioneered by the same group, and the latest sequencing technology, the team were able to identify the 'molecular conversations' between embryonic cells.

'Embryo development is an extremely complex process and while our system may not be able to fully reproduce every aspect of this process, it has allowed us to reveal a remarkable self-organising capacity of human blastocysts that was previously unknown,' said co-author Dr Marta Shahbazi.

The study, published in Nature, revealed that some cells release signals instructing other groups of cells to form either the head or tail end of the developing embryo, marking the very earliest stages of body-plan coordination. These cells then respond to their instructions by transitioning out of pluripotency – the state in which cells can take on any identity – before going on to become defined parts of the developing embryo's body.

The findings, which bridge a knowledge gap in embryology, could lead to a greater understanding of why some pregnancies fail early after conception and offer insight into the causes of some developmental defects.

Co-author Dr Simon Fishel, director of CARE Fertility said 'This is about much more than just understanding the biology of implantation embryo development. Knowledge of these processes could help improve the chances of success of IVF), of which only around one in four attempts are successful.'

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No significant differences were found in a study assessing the effect of the mRNA COVID-19 vaccines on key measures of male fertility.

Forty-five male participants, aged between 18 and 35, took part in a study which compared sperm samples of participants before and after administration of two COVID-19 vaccine doses. Each participant provided a sperm sample before, and approximately 70 days after, receiving two doses of either the Pfizer or Moderna COVID-19 vaccine.

Lead author of the study Daniel Gonzalez from the University of Miami Miller School of Medicine, Florida said: 'This is the full life cycle of sperm and 70 days is sufficient time to see if the vaccine impacts semen parameters'.

When the COVID-19 vaccines were evaluated in clinical trials, their effects on fertility and reproduction were not studied.

Dr Ranjith Ramasamy, director of the Miller School's Reproductive Urology Programme, was the first to demonstrate that SARS-Cov-2, the virus which leads to COVID-19, can affect male fertility. He said 'we are now the first to examine if there is any impact of the COVID vaccine on male fertility potential, which we did not find.'

In this study, published as a research letter in JAMA, Dr Ramasamy and colleagues investigated measures of fertility, including semen volume, sperm concentration, sperm motility, and total motile sperm count. They concluded that no significant difference was found for any measure across the cohort.

According to a report led by Imperial College London's Institute of Global Health Innovation, the top reasons for vaccine refusal are 'concerns about side effects' and 'concerns that there has not been enough testing of vaccines'. Furthermore, the effect on fertility is also often reported as a concern among those worried about potential side effects of the COVID-19 vaccine.

Professor Allan Pacey, professor of andrology at the University of Sheffield who was not involved in the study, told CNN: 'I hope this provides some reassurance to any men who may be concerned about their fertility if they accept one of these types of vaccines.' 

The study did not test COVID-19 vaccines not based on mRNA platforms, such as the AstraZeneca or Johnson & Johnson vaccine. 'However, we think the mechanism of how these vaccines work is all fairly similar despite different genetic material, so based on biology, we don't think there should be anything different with the other two vaccines,' explained Dr Ramasamy.

The authors note the study limitations, including the small number of participants, and the age restriction to young men. Professor Pacey concluded: 'Additional larger studies with men of different ages are needed to affirm the study's results.'

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