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12 November 2018 - by Dr Geeta Nargund, Professor Stuart Campbell, Dr Svend Lindenberg, Dr Pasquale Patrizio, Professor Rene Frydman
Over the last ten years, the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) has campaigned worldwide to put the welfare of women at the heart of fertility treatment.
IVF has been transformed over the last 40 years. One of the most startling changes is that a treatment which was originally intended to address the problem of tubal infertility is now regularly used to treat women who are both healthy and fertile. From male factor infertility, to elective egg freezing or same-sex couples wishing to start a family, the contexts of our practice have been irreversibly changed. These should rightly be regarded as advances, but with every step forward, we have an increasing responsibility to ensure that no healthy woman is made ill from fertility treatment.
Women undergoing IVF can experience a wide range of side effects, the most serious of which is Ovarian Hyperstimulation Syndrome (OHSS). In its mild form this affects as many as one third of cycles, with 3.1 to 8 percent being moderately or severely affected, according to the Royal College of Obstetricians and Gynaecologists.
Research has shown that if more than 15 eggs are collected during one cycle, women are at increased risk of OHSS without any increase in IVF success rates. The data from the Human Fertilisation and Embryology Authority (HFEA), released in response to parliamentary questions by MP Siobhain McDonagh between April to June 2018, revealed that between 2013 and 2017, 20 or more eggs were collected in 21,244 cycles, approximately 6.5 percent of total cycles in that period. Further, in 1860 cycles, more than 30 eggs and in some cases more than 50 eggs were collected in a single cycle.
At the same time, NHS data has recorded 836 emergency hospital admissions as a result of OHSS in a single year; a stark difference to the 60 cases reported directly to the HFEA. The true picture about hospital admissions can only be obtained if we link the HFEA registry with that of the NHS registry as is done in Scandinavia, Australia, USA and many other countries.
OHSS is often presented to women as a 'no pain, no gain' reality, yet it must be at least presented to patients that OHSS is a largely preventable condition and that the mild stimulation IVF treatment strategy delivers equivalent success rates per cycle while significantly reducing the risk of OHSS.
The aim of conventional IVF is to stimulate the ovaries to maximise the egg numbers, while in mild IVF, the aim is to obtain a mild response that will produce an adequate number of quality eggs to produce equivalent success rates. If the ideal number of eggs per live birth with conventional IVF in women with normal ovarian reserve is 15, with mild IVF it is about half that number and can be as few as five. The battle lines are drawn squarely between quantity and quality.
Statements that there is 'little doubt' that the conventional approach gives a woman a 'significantly better chance' must be challenged (see BioNews 973). The classic paper by Valerie Baker and colleagues who studied over 650,000 consecutive cycles from the American Society of Reproductive Medicine database demonstrated that there was an inverse relationship between the stimulating dose of follicle stimulating hormone and live birth throughout all age groups, including among women under the age of 35.
There are numerous papers confirming that mild IVF gives comparable success rates in terms of live births as conventional IVF. At present there is no large randomised study directly comparing the two methods, but that does not justify defenestrating the significant body of evidence demonstrating equivalence of success rates. This is not to mention the significant benefits that mild IVF brings in relation to health outcomes for women and children, and reduction in the burden of both treatment and the total cost.
The number of eggs collected per cycle in the UK is increasing annually with the risk of OHSS contained by the use of agonist trigger and 'freeze-all embryos' in the case of high oestradiol levels. While this strategy is an important emergency tool in reducing OHSS complications, it is not prevention and it should not be taken as a licence to ignore the dangers of ovarian stimulation, nor subjecting women to the concomitant side effects. True prevention is not placing women at OHSS risk in the first place by avoiding aggressive protocols of ovarian stimulation.
It must always be remembered that the protection of the welfare of women in IVF is a wider concept beyond OHSS prevention. There are additional treatments, such as the administration of intravenous immunology drugs, which may have potentially harmful effects and are in desperate need of more oversight. At present, lack of data collection and database linkage restrictions are obscuring our ability to determine the size of problem.
Instead of large-scale, rigorous analysis, we are often given bland reassurances that all is well with the state of IVF in the UK. Sensible proposals to protect the welfare of women are currently being put forward in Parliament by McDonagh and should be supported whatever one's view on the best stimulation strategy.
We surely all agree that the aim of IVF treatment should be to achieve a singleton, healthy, full term, normal weight baby, without putting a woman's health at risk in the short or long term. With the additional oversight and data, we will be able to speak confidently as one voice that we are protecting the welfare of women during IVF treatment.

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Bring on the bots: 22 October 2018 - by Tara Schmidlen and Amy Curry Sturm
It's 2018, and Alexa has become a common household name. The iPhone has turned 10 and roughly two-thirds of adults worldwide own a smartphone. About 84 percent of the global population lives in an area where mobile broadband access is available. At the same time, genetic testing has become more affordable and accessible to consumers, with direct-to-consumer genetic testing pioneer, 23andMe, now boasting five million users in over 50 countries.
As the interest in and demand for genetic testing has increased, the demand for genetic counsellors – experts trained to help patients understand and make use of genetic information – is increasing. There are currently over 4800 certified genetic counsellors in North America. Clear Genetics, a healthcare technology company based in San Francisco, has collaborated with genetic counsellors working in a variety of patient-care settings to develop a chatbot named GIA (Genetic Information Assistant). GIA is a clinical-grade chatbot who assists patients pursuing genetic counselling, risk assessment and testing.
For those of you wondering what a bot, or chatbot, is – these are software-based simulated conversation tools. Chatbots use artificial intelligence and natural language processing to answer simple questions, increase and maintain consumer engagement, promote services, and provide convenient, easy access between consumers and service providers. Bots often handle repetitive questions from users, such as, 'Is my flight on time?' In the field of genetics, they can respond to questions like, 'Should my children also be tested?'
One American health entity using chatbot technology is Geisinger, a non-profit integrated health system serving over three million residents in Pennsylvania and southern New Jersey. Geisinger and Clear Genetics have collaborated to develop chatbots for communication with patients enrolled in the MyCode Community Health Initiative. MyCode is a large research biobank returning genetic test results for genes known to be associated with an increased risk for treatable and preventable heritable heart diseases and cancers.
Over 210,000 Geisinger patients are enrolled in MyCode, with at least 2 percent expected to have a disease-causing genetic variant for which there are potential treatment options. With so many patients enrolled, automation of some repetitive, scriptable communications would free up staff members and genetic counsellors for tasks that require human interaction.
To recruit patients into the MyCode study, Geisinger and Clear Genetics developed a consent chatbot that walks patients through components of the consent form, allowing them to opt to receive more or less detail on key topics (goals, benefits, risks, and so on). The tool is compliant with the Health Insurance Portability and Accountability Act 1996, and can be used on any mobile device. It is designed to record the decision (consent, considering, decline) in the patient's electronic health record. Geisinger patients who tested the consent chatbot in focus groups reacted positively, favoring the more informative and customisable chatbot experience to an in-person approach.
In addition to the consent chatbot, a patient 'follow-up' chatbot was developed to remind MyCode participants of suggested actions after they got their results. Via the follow-up chatbot, MyCode participants could indicate whether they had received a result packet, gathered their family history data, met with a provider to review results, and shared results with relatives. Patients could also request a genetic counselling visit and type in questions.
To help patients communicate their genetic test results with at-risk family members, a family sharing tool was developed as an easy mechanism to electronically share results and inform family members of the importance of genetic counselling and testing. The tool allows the patient to send their relatives a link to a 'cascade' genetic counselling chatbot by text message, email or Facebook messenger. The cascade chatbot describes the patient's result, associated disease risks and recommended management.
The patient's at-risk relative can request a genetic counselling visit via the chatbot and ask questions. Geisinger patients who have interacted with the family sharing tool and cascade chatbot report that they have enjoyed the ability to preview what their relative will see and welcome a tool that 'has the detailed information' and 'answers that wouldn't be on the tip of the tongue' when talking with family members about genetic test results.
Beyond the consent, follow up and cascade use cases described here, a chatbot like Clear Genetics' GIA, can free up genetic counsellors by automating many other routine tasks, such as delivering negative results and providing standard pre-test education.
Sceptics may lament that 'the bots are taking over'. But the goal is not to replace genetic counsellors with chatbots. Rather, the goal is to delegate important tasks that are repetitive, time-consuming and scriptable to a chatbot, like GIA, to leave genetic counsellors more time for more valuable and highly skilled patient care. More counsellor time will lead to greater accessibility of genetic counselling services. To that we enthusiastically say, bring on the bots.
Click here to view SOURCES & REFERENCES and RELATED ARTICLES from the BIONEWS ARCHIVE or to leave a comment about this article.

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24 September 2018 - by Rachel Siden
The UK's Human Fertilisation and Embryology Authority (HFEA) is urging companies that offer direct-to-consumer DNA testing to provide more comprehensive warnings to customers.
A recent paper presented to the HFEA board, oulined how egg and sperm donors, as well as donor-conceived people, could be impacted by direct-to-consumer DNA testing and 'matching' services which offer to connect customers who are genetically related to each other. DNA testing services could reveal someone's unknown donor-conceived status, or uncover the identity of a donor who believed they had anonymity.
'Donors who think the anonymity can be protected are suddenly discovering they can't,' said Nina Barnsley, director of the Donor Conception Network. 'Even if you don't upload your DNA anywhere, you can still be found. It's a new world and we are all playing catch-up,' she told The Guardian newspaper.
While popular DNA testing companies such as 23andMe,, and can only 'match' users within their databases, customers could still use a single match to track down other relatives through social media or birth and marriage records. And while these companies may disclose that unexpected genetic information may be discovered 'in the small print', the HFEA paper argues that customers may not be adequately warned of the risks, nor offered any support.
'We found no DNA testing and matching services that mention that a need for professional emotional support may arise from relatedness matching, or via further inference from matching,' stated the HFEA paper. 'No service offers professional emotional support to users, nor signposts to other available support.'
While the HFEA does not have the authority to force companies to provide warnings, the HFEA paper outlines a response plan that includes raising awareness of these risks and providing information and support through the HFEA website and clinics, and reaching out to DNA testing companies to have a dialogue about why greater warning should be provided on their websites.
HFEA Chair Sally Cheshire has pledged that the websites will be contacted and that these issues will be discussed with the UK's Department of Health, The Guardian reported.
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Prenatal tests are misused for sex-selection in the UK
24 September 2018 - by Rikita Patel
Prenatal tests offered by private UK clinics are misused for sex-selection and could lead to abortions of female fetuses, according to a BBC investigation.
Non-invasive prenatal testing (NIPT) involves screening fetal DNA in the mother's blood to identify genetic abnormalities, such as Down's syndrome. The technique also enables mothers to find out their baby's sex as early as nine to 10 weeks into pregnancy. However, when the test is implemented within the NHS  next month, patients will not be provided with this information.
In contrast, private clinics are revealing gender information from NIPT to expectant mothers. An investigation by BBC Two's Victoria Derbyshire programme has found that thousands of pregnant women are using online forums to discuss sex-selection through NIPT and their concerns about having a baby girl. Further, it found that clinics in Slough, Berkshire, were openly advertising gender determination testing.
Due to concerns that pregnancies could be aborted based on preference for a male child, the Labour Party has called for a ban on parents being told the sex of their baby.
Naz Shah, Labour MP for Bradford and shadow minister for women and equalities, told the programme that 'cultural practices in some communities, like the South Asian community, have a preference for boys' which is 'forcing them to adopt methods such as NIPT to live up to expectations of family members'.
In UK law, the sex of the baby is not one of the permitted grounds for abortion. However, if a woman is likely to face violence or abuse as a result of giving birth to a baby girl, a termination in the first 24 weeks could be lawful, as the Abortion Act states, if 'continuance of the pregnancy would involve risk, greater than if the pregnancy were terminated, of injury to the physical or mental health of the pregnant woman'. The act allows that 'account may be taken of the pregnant woman’s actual or reasonably foreseeable environment'.
Speaking to the BBC, Tom Shakespeare, professor of disability research at Norwich Medical School and chair of the Nuffield Council on Bioethics' NIPT working group, said: 'The desire for sex-selection is a major driver of private-sector testing.
'But countries like China and India have recognised the problem of sex-selective abortion and so it's very difficult to get this information – in India it is illegal.'
If the UK permits the practice of releasing this information, nationals from those countries may travel to the UK for medical tourism, Professor Shakespeare said.
A Department of Health and Social Care spokesman told the BBC: 'The prenatal test is never meant to be used for determining the sex of a child. We will continue to review the evidence.'
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Frequent sex – not abstinence – is better for sperm quality
24 September 2018 - by Christie Whitehouse
Sperm quality and pregnancy outcomes in IVF may be improved with frequent ejaculation, a new study suggests.
Research carried out at the Centre for Reproductive Medicine in Shenyang, China, aimed to determine the effects of a short period of abstinence on the quality of ejaculated sperm, as well as its effect on the pregnancy outcomes of 500 couples undergoing IVF. Major molecular differences were seen between samples of semen depending on the duration of abstinence.
Specifically, semen samples collected after only one to three hours of abstinence contained more motile sperm with a higher reproductive potential than samples collected after men had abstained for three to seven days.
'For years, men have usually been advised to limit sexual activity to increase the chances of pregnancy. However, it’s time to change our minds,' said Dr Da Li, who led the study along with Dr XiuXia Wang.
'Our data indicates couples with relatively normal semen parameters should have frequent sex around the ovulation period. This could make all the difference to their efforts to start a family.'
Mass spectrometry used to analyse the protein content of semen showed that proteins involved in cell adhesion (important for fusing with the egg), motility and metabolism were increased when men abstained for only a few hours compared with days. The total antioxidant capacity of sperm was also significantly improved after reduced abstinence, leading to reduced genetic damage by oxidative stress and increasing the chance of viable proteins being formed.
Encouraging results were also seen in the couples undergoing IVF treatment. Typically, the live birth rate in a cohort of this size would be around 30 percent, said Dr Li. However, live births in the group using semen provided only a few hours after previous ejaculation were increased by one third compared with the group using semen ejaculated after a longer period of abstinence.
These results collectively suggest that having more frequent sex produces sperm of a better quality and increases the likelihood of a successful pregnancy.
The researchers now plan to carry out further research into the protein composition of semen, specifically looking at the post-translational modifications of the different samples. The Centre for Reproductive Medicine is also updating its IVF protocols to use semen from shorter periods of abstinence.
The study was published in Molecular and Cellular Proteomics.
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24 September 2018 - by Dr Anna Smajdor
In the wake of a recent Mail on Sunday article, one might wonder if there are grounds for moving from a small-scale subsistence-type approach to the harvest, to a more industrial approach. No, we are not talking about vegetables here, but… sperm.
Yet again, a case has emerged in which a man's sperm has been 'harvested' without his consent. The incident in question happened in the UK in 2014, according to the Mail on Sunday. The newspaper reported that a UK couple had had sperm taken from their son who had died in a motorbike accident, frozen it and a year later shipped it to a fertility clinic in the USA, where sex selection was used to produce a male grandchild (see BioNews 967).
The article itself is peculiar in several ways, not least in the fact that it claims that the 2014 case 'may be the first instance of posthumous sperm extraction'. Yet some paragraphs later, it details the case of Diane Blood, who famously fought the law and won, on the issue of whether sperm harvested from her dead husband Stephen could be used to enable her to conceive. (Sperm was 'harvested' from Stephen Blood both while he was dying, and after he was dead.)
So the case described by the Mail on Sunday reporter is not unique. In fact, it resembles many other such incidents that have emerged since Diane Blood's pioneering battle. There has been a succession of dead or dying men, whose bodies have been 'harvested' without their consent in order for others to make use of the seeds thus obtained.
I do not propose to give copious details of each separate occurrence here: they are very similar. In each case a man unexpectedly falls critically ill. One or more loved ones – spouses/parents, request sperm-harvesting, which is duly carried out by doctors in contravention of UK law. This case may look different in some respects: the dead man's parents wanted to choose the sex of their grandchild, which would also be illegal in the UK, but is permitted in many other jurisdictions. However, as long as it remains the case that sperm can be exported for use abroad, it is not surprising that people should seek to use it in ways that are legally acceptable in those countries. The key issue I want to focus on here is the common feature in all these cases: the harvesting of sperm without consent. What happens afterwards is a secondary issue.
Does consent matter? After Stephen Blood's sperm was harvested, many people thought it did matter. The case was described as 'unique' and something that could never happen again. Part of the reason for this is not just the significance that people attach to sperm, but because of the importance that English law places on a person's right to determine what happens to their body. Not just while they are alive, but throughout the period during which they are dying and even after they are dead.
There are two methods for 'harvesting' sperm. Both are highly invasive. The method used in Stephen Blood's case was electro-ejaculation. An electric probe is inserted into the dead or dying man's rectum. A current is applied in rhythmic waves at increasing voltage until ejaculation occurs, usually into the bladder. A catheter is inserted through the urethra into the bladder to retrieve the sperm. This method is more common among patients who are brain dead but whose respiratory and circulatory functions are being sustained.
The other method is more common in use among men who are not being ventilated. It involves cutting into the testicles. The technique is described in one paper as follows: '… surgical bilateral resection in bloc of the proximal part of vas deferens, testicle and epididymis. At the laboratory, by milking the epididymis and vas deferens, the extracted fluid was collected…'.
Of course many men might view these procedures as being an acceptable means of allowing their loved one(s) to create children. But equally, many might not. In the context of organ donation, we expect that people will make judgments about what happens to their body – and that these judgments should be respected as far as possible.
When we are faced with reproductive material, a different standard seems to apply. The issue is complicated because – as I have argued elsewhere  – the person whose testimony is given as to the dead or dying man's probable willingness to undergo sperm harvesting is usually the very person whose interests are most entangled with the outcome.
To put this another way, the parents or spouses who want to harvest their loved one's sperm are asked whether this is what the dead man would have wanted. Of course their perception is coloured by their own desire. They stand to benefit from the procedure. Thus, while consent from loved ones is sometimes used as a proxy for organ donation, it does not follow that the same standard should apply to reproductive tissue harvesting when the prospective beneficiary is also the one giving proxy consent. This is straightforwardly a conflict of interest and should be recognised as such.
So why does this continue to happen? The Human Fertilisation and Embryology Act was drawn up so as to focus on the acceptability of storing sperm and using it in treatment. Both require the consent of the person from whom it was obtained. Yet the 'harvesting' itself is not explicitly included in the Act.
Of course that does not mean that gamete harvesting is simply unregulated. Rather, it is assumed to fall under the more general law that protects people from undergoing unwarranted medical procedures or physical assault. But this law is clearly not functioning as it should do to prevent the harvesting of reproductive tissue from dead and dying people.
Diane Blood's legal victory has paved the way for subsequent infringements of men's bodily integrity. Because, despite the fact that her husband's sperm was harvested without his consent, she was permitted to take it abroad and use it for treatment. It is clear that other people quite reasonably expect to do the same thing. Until the law is tightened up and/or prosecutions are brought for gamete harvesting without consent, the bodies of dead and dying men are vulnerable to exploitation.
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8 October 2018 - by Bethany Muller
Scientists have discovered alterations in the sperm cell DNA of adult men who had been abused as children.
Men who had experienced childhood abuse carried epigenetic markers – which alter gene expression – that appeared to be linked to their early-life trauma.
'We can look at our study as one small piece in the huge overall puzzle of how intergeneration trauma works,' said study author Nicole Gladish, a PhD candidate at the University of British Columbia in Canada. 'It is certainly possible that epigenetic changes in sperm cells play a role in the physical and mental health of the next generation, but we don't know for sure.'
The study, carried out at the University of British Columbia and Harvard University in Cambridge, Massachusetts, looked at methylation patterns in sperm from 34 men, who were classed as having been exposed to childhood abuse or not.
Differences in DNA methylation between the two groups were found in 12 regions of the genome. These regions play roles in the brain, regulation of body weight and the immune system.
DNA methylation is a common type of epigenetic tag. Epigenetics alter the packaging of nuclear information, altering the way genes are accessed and expressed. Methylation in particular is often described as having a 'dimming' effect, leading to the down-regulation of genes.
'When the sperm meets the egg, there is a massive amount of genetic reshuffling, and most of the methylation is at least temporarily erased,' Dr Andrea Roberts, lead author of the publication, noted. 'But finding a molecular signature in sperm brings us at least a step closer to determining whether child abuse might affect the health of the victim's offspring.'
The researchers also suggest that DNA methylation in sperm has the potential to be used as a biomarker as evidence of whether abuse had happened in a criminal justice case. Professor Michael Kobor, a medical geneticist at the University of British Columbia, and also a study author said: 'It's conceivable that the correlations we found between methylation and child abuse might provide a percentage probability that abuse had occurred.'
Environment-induced epigenetic changes have been shown to be passed on to offspring in animals. However, the impact of psychosocial stress on human sperm and eggs is not well understood.
Next the researchers plan to investigate whether these epigenetic changes would persist in the children of men who had experienced abuse. Larger-scale studies could help to find out whether the effect of childhood abuse could be passed on further down the generations.
The research was published in Translational Psychiatry.
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Men are not getting adequate care for infertility
8 October 2018 - by Professor Sheena Lewis
There has been much media interest in male infertility care this year, but two major issues have stood out. The first is the inadequacy of care for the man, from incomplete diagnosis to non-information about his treatment choices. The second is the use of a vulnerable woman to undergo invasive fertility treatment in order to treat a third party – her male partner. This is unparalleled in other branches of medicine.
There are clear reasons why this situation has come about. There are also clear motivations for why we must act to change it, both at an individual and a societal level. To understand more, let's explore some contributing factors.
Mind the gap
The advent of intracytoplasmic sperm injection (ICSI), where a sperm cell is injected directly into the egg cell, was a quantum leap in short-term clinical success. But it has led to a lethargy in progressing our evidence-based diagnosis of male infertility. We must make it a research priority to plug these knowledge gaps.
In their recent focused issue of Translational Andrology and Urology, Dr James Hotaling of the University of Utah and Dr Ranjith Ramasamy of the University of Miami suggest that 'we need to identify what issues need to be solved to bring male infertility care to the same level of diagnosis and treatment as female infertility'.
Inadequate diagnosis
Conventional semen analysis is routinely used in male fertility diagnoses. But it is widely reported that there is little association between semen parameters and male infertility diagnosis. It also has little relationship with IVF outcomes and no relationship with ICSI outcomes.
Further, around 30 percent of couples are given a diagnosis of unexplained infertility. These couples are often referred for ICSI, rather than using some of the tests shown to identify defects such as sperm DNA damage that are present in the majority of these men. If there is no diagnosis, there can be no direct solution. This leads to expensive, invasive, prolonged and often unsuccessful cycles of treatment. Since ICSI now accounts for a significant proportion of fertility treatments across Europe, we particularly need a test to predict which patients will benefit from it.
Inequality of care
Fertility treatment is primarily focused on women. This is to be expected since the speciality is run by gynaecologists and obstetricians whose training is in female, not male, reproduction. However, this can lead to men feeling ignored and emasculated by the whole fertility journey. There are even examples of doctors telling the female partners the devasting result of azoospermia, rather than telling her male partner to whom the results relate.
The woman is also affected by inequality of care. In up to 30 percent of ICSI cycles, the woman has no detectable reproductive anomalies, yet she undergoes this invasive form of treatment to treat a dysfunction in her partner. She consents to this procedure willingly as usually she is told there is no other way to conceive the child they yearn for.
Inadequate treatment options
In all branches of medicine except reproductive technology, interventions are to treat the patient's symptoms. In our speciality, ICSI is used to bypass the problem of male symptoms. Since treatment is unsuccessful for so many couples, would it not seem prudent to suggest interventions to improve the quality of sperm before treatment?
There are simple ways to do this. Doctors must take a detailed clinical history of the patient, examine him and know which medications he is taking. He may be on drugs as seemingly innocuous as drug treatments for hair loss, which can lower his sperm count. His semen also needs more than the 'first step' semen analysis. Semen should be cultured to detect infections that can be treated with antibiotics. Specialised tests for oxidative stress and sperm DNA quality should be done to find out if he needs antioxidant supplementation. Using supplements as a panacea without a clinical indication can damage his health and his sperm.
Since men have a turnover in sperm every few months, lifestyle changes can bring about rapid improvements. Simple changes in diet, weight loss and reduction or cessation of smoking, anabolic steroid use and recreational drug use can improve sperm health. These low-cost and effective interventions are too often ignored.
Static success rates
IVF success rates have remained at their modest level of less than 30 percent live birth rate for many years now. Improvements have been among the couples who can be treated for an underlying condition. For example, we can now treat men with obstructive azoospermia with testicular sperm. Single women can use donor sperm and gay couples can use surrogacy. But the actual IVF success rate per couple has remained disappointingly low.
Given that the numbers of couples seeking fertility investigations are increasing by eight to nine percent a year across Europe, it is imperative that success rates are improved. How is this most likely to occur? I would suggest it will be through advancements in male investigations leading to more accurate male diagnosis, complemented by therapy pre-ART.
Impact on offspring
We have, as yet, little evidence of the health of people conceived by ICSI as they reach middle-age. However, we already know that young men conceived by ICSI inherit poor semen quality and possibly infertility from their fathers. A recent small study suggested that IVF children have a six times higher risk of hypertension than children conceived naturally (see BioNews 966).
Using aging and smoking as paradigms for poor sperm quality, there are reports – such as one I authored – that ART is linked to increases in childhood cancers and psychiatric disease in offspring. Does this not create a further moral imperative to improve sperm quality as much as possible before ART?
An indicator of male health
Poor semen quality, as assessed by semen analysis, has been highlighted as a significant predictor for cardiovascular risk, late-onset cancers and shortened life expectancy. This may lead to its use as an inexpensive, non-invasive biomarker of late-onset disease. If we had a better test for sperm quality, this could prove useful in this application too.
One mechanism for change
So, what can we do about these shortcomings in our speciality? Perhaps we can follow the Australian example of forming a national 'centre without walls' funded by government to raise awareness of male reproductive health disorders and their associations with chronic disease. Andrology Australia provides a range of activities to educate men and improve their reproductive health of males through community and professional education. Perhaps it's time that we in the UK followed suit.
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A story sent to Mensfe
Why do some men feel so underrepresented in the world of fertility ?
When I say under represented I do not mean they are not there………. In spirit, but their role, and often their presence is often overlooked and/or undervalued.
Within fertility issues, it is clear from (my) experience that the drive is far more intense from the female. both initially as well as the endurance to undergo multiple rounds of treatment. It is usually the male who will contemplate or breach the concept of “giving up” first.
Why is this? Maybe it is the pure evolutionary bio-psychological drive that such a short period of a woman’s life is the window of opportunity to give life. This itself evokes an intensity hard for some males to imagine.
Also often males may have already had children in previous relationships and the drive to spread the gene is less powerful as a result of this…… but I feel that one of the main issues that culminates in my exclusion is historically encultured values in the role of men and women.
Man the provider, man who goes and prepares to lay down his life for his homeland in war. Man the strong one and all this evolving into an unhealthy patriarchal society where any display of emotion is often still considered a weakness for men.
So all this manifests itself in the consultation room in the hospitals and in the counselling room.
As a man my role is to fix, protect and supply.
In that fertility center, I am in a position where I can not fix this problem, there are experts who have taken that control and expertise out of my hands……… I am redundant, pushed out.
My partner is unhappy and the situation is that whatever I do I can not alleviate her pain, I am frustrated and as a man I get angry and turn that in on myself
What I can do is research, I find myself gathering prodigious amounts of data from the internet, but it is futile.
So I run away, away from the shame of not fulfilling my role for my partner,   and you just do not see me.
The problem is historic and societal, the solution needs to be shaped by modern thinking and practice.
High level conferences need to recognise the need to acknowledge the plight of men struggling to come to terms with the changing expectations of a modern world.
The implications and impact of fertility crosses the gender boundary and men need to have a space to be heard.
Can you imagine any other scenario where one group was excised? where a black groups experience was relayed by an all-white panel, where the elderly’s experience of care was spoken about by young people…… 
It just deepens the division and further drives men away when they are ignored, and not represented by the leaders in such important fields as fertility.
It is without doubt that the process of addressing fertility in the medical environment, the period of pregnancy, and of course the raising of children in a mutually respecting and supportive home will be better served with a couple working together. …In a world where the male feels included and important, and where he has had a stake all through the process.
Sadly, for many reasons that is not the world of fertility and there are few so enlightened practitioners like …… who recognize this truth.

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12 February 2018

By Professor Robin Lovell-Badge
Appeared in BioNews 937

The problem of fertility preservation for girls and women undergoing cancer treatments has been a subject of research for many decades. The recent study by McLaughlin and colleagues from Professor Evelyn Telfer's lab at the University of Edinburgh, UK, is aimed at finding a solution to this problem, with the claim that they have produced mature human egg cells in the lab for the first time (see this week's BioNews story).

Egg cells or oocytes begin their development in the ovary as a small cell contained within a single layer of granulosa cells, together making up a 'primordial follicle'. For these to develop to a stage when they can be fertilised requires a period of growth of the oocyte (from 15 to about 100 micrometres) and development of a multi-layered and complex follicle, which after puberty usually takes a minimum of about four weeks. This is then followed by a phase referred to as maturation when the fully-grown oocyte completes the first meiotic cell division (MI) and divides asymmetrically to give a large MII oocyte and a very small first polar body, which usually dies within a day and does not contribute to any subsequent development of an embryo.

In vitro maturation (IVM) to go from a fully-grown to an MII oocyte is already a fairly common procedure (although still formally an experimental one), sometimes for cancer patients, but also for other cases where standard IVF procedures are difficult, such as polycystic ovary syndrome (PCOS). The use of this technique has led to many hundreds of apparently healthy babies. Therefore, for women who have fully grown and/or mature oocytes (eggs), it is now possible to freeze these, thaw them and carry out IVF. It is also possible to freeze pieces of ovary and then to thaw and graft these back to the ovary (or a nearby site) after cancer treatment. Care has to be taken with the latter approach, however, in case the ovary tissue contains some cancer cells, which is likely if the cancer is, for example, a leukaemia or there has been metastasis.

For prepubertal girls, however, they will not have any fully-grown oocytes; indeed they will almost all be at the primordial follicle stage. This McLaughlin et al. paper claims to have developed a method for growing and maturing these all the way through to oocytes that might be capable of being fertilised (metaphase II, or MII). Despite considerable effort form several labs, this had been done previously only in the mouse, with the first demonstration some 20 years ago, and with substantial improvements made in following years.

Nevertheless, several of the steps had already been achieved with human material, notably going from primordial follicles to secondary (multi-laminar) follicles and from secondary follicles to MII oocytes, so the novel aspect of this current work is to have joined these into one continuous process.

However, there are several problems. It was really quite inefficient, with perhaps 385 early follicles (of which about 80 percent were primordial) giving 87 secondary follicles suitable for the second stage culture method. Of these, 54 developed a typical fluid-filled cavity suggesting that they were progressing normally, but of these, only 32 gave fully grown oocytes. These were then transferred to typical IVM conditions. However, only nine gave rise eventually to mature fully-grown MII oocytes.

Critically, the pieces of ovarian tissue that the authors began with were not from prepubertal girls, but were biopsies from adult women, which clearly contained some follicles that had already begun to develop. The authors can't be certain that the ones that did make it to fully-grown MII oocytes actually arose from primordial follicles; they could have developed from later stage 'primary follicles' or even some of the already growing secondary oocytes present in the original tissue. The timing from beginning to end was also relatively fast compared with what is thought to happen in vivo, which could suggest that the mature oocytes were indeed not coming from primordial follicles. If they did originate from primordial follicles, their development may have been too fast, then this might lead to abnormal oocytes.

The characterisation of the oocytes obtained was rather minimal, but it was very obvious that they were not quite right. Usually, when the fully-grown oocyte divides to give rise to an MII oocyte, this is a very asymmetric cell division producing the large oocyte and a very small 'first polar body'. The latter contains a nucleus, but has too little cytoplasm to support its survival for long. However, the 'polar bodies' associated with the MII oocytes in this paper were very large. (The first meiotic cell division had not been sufficiently asymmetric.) In addition to suggesting that the oocytes had not developed normally, these large polar bodies could probably survive for longer and may even be capable of being fertilised.

If both the oocyte and the polar body are fertilised (by separate sperm) this can lead to the development of a mosaic individual, composed of cells with two distinct genotypes. ICSI (intracytoplasmic sperm injection) could be used to fertilise just the larger cell, but this will be smaller than normal, and it would be necessary to know that it wasn't deficient in some way. The large 'polar body' might also interfere with development of any embryo.

Moreover, although the authors showed evidence for a spindle (the cellular structure on which the MII chromosomes line up, moving to opposite ends of the cell when it divides in two), they did not check to see if there were any problems with the chromosome and their subsequent segregation. They did not see if the oocytes could be fertilised, which would have required an HFEA (Human Fertilisation and Embryology Authority) licence, or ask what would happen if they were activated. All the final IVM steps have been done before to yield normal fertilisable eggs that have given children, so the fact that the oocytes in this study were abnormal suggests that there were problems with the steps that were used to promote the early in vitro growth.

Finally, for clarification, this work is not describing the development of mature oocytes all the way from pluripotent stem cells in vitro. It is beginning with small oocytes that are already enclosed in follicles that have been obtained from adult ovaries. In this respect it is also not clear whether the methods will be of use for the purpose of allowing fertility preservation from stored ovarian tissue obtained from prepubertal girls prior to cancer treatments, which is one of the main justifications for the research. The follicles in prepubertal ovaries will be at an early stage, not yet primed for growth, and perhaps quite different from those in an adult.
The authors were aware of the limitations of their work and gave balanced comments. But the media interest seems to have been egged-on by an over-enthusiastic press release from the University of Edinburgh. This was not very responsible given the topic and the desperate need for workable solutions. A more balanced judgement might be that the paper indicates that it should be achievable, but don't count your chickens before they have hatched.

Started by mensfe_admin - Last post by mensfe_admin
30 years of declining male sperm count - some professional views - however there are others !
Well - that may come as a shock -  but there is always a HOWEVER - please read on

So are we anywhere nearer to finding an explanation for why are so many more men today are suffering from reproductive problems?
"It's most likely a reflection of the fact that many environmental and lifestyle changes over the past 50 years are inherently detrimental to sperm production," says Professor Richard Sharpe, fertility research expert at the Medical Research Council. "It may be that different factors come together to have a combined effect." A number of studies point to a connection between early development in the womb and male reproductive problems in later life, especially low sperm counts. For example, men whose pregnant mothers were exposed to high levels of toxic dioxins as a result of the 1976 industrial accident in Seveso, Italy have been found to have lower-than-average sperm counts. But men exposed to dioxins in adulthood showed no such effect. Another study found women who ate large amounts of beef during pregnancy, a diet rich in potentially damaging chemicals called polycyclic aromatic hydrocarbons (PAHs), had sons with relatively low sperm counts. But eating beef as an adult man shows no similar impact.
Meanwhile, studies of migrants between Sweden and Finland, showed that a man's lifetime risk of testicular cancer tends to follow the country he was born in rather than the country where he was brought up. It was his mother's
So are we anywhere nearer to finding an explanation for why are so many more men today are suffering from reproductive problems?
"It's most likely a reflection of the fact that many environmental and lifestyle changes over the past 50 years are inherently detrimental to sperm production," says Professor Richard Sharpe, fertility research expert at the Medical Research Council. "It may be that different factors come together to have a combined effect." A number of studies point to a connection between early development in the womb and male reproductive problems in later life, especially low sperm counts. For example, men whose pregnant mothers were exposed to high levels of toxic dioxins as a result of the 1976 industrial accident in Seveso, Italy have been found to have lower-than-average sperm counts. But men exposed to dioxins in adulthood showed no such effect. Another study found women who ate large amounts of beef during pregnancy, a diet rich in potentially damaging chemicals called polycyclic aromatic hydrocarbons (PAHs), had sons with relatively low sperm counts. But eating beef as an adult man shows no similar impact.
Meanwhile, studies of migrants between Sweden and Finland, showed that a man's lifetime risk of testicular cancer tends to follow the country he was born in rather than the country where he was brought up. It was his mother's environment when she was pregnant with him, rather than his own as a boy or as an adolescent, that seems to have largely determined a man's risk of testicular cancer.
One of the strongest pieces of evidence in support of this idea comes from studies of people who smoke. A man who smokes typically reduces his sperm count by a modest 15 per cent or so, which is probably reversible if he quits. However, a man whose mother smoked during pregnancy has a fairly dramatic decrease in sperm counts of up to 40 per cent – which also tends to be irreversible.
Professor Sharpe said such findings can be explained by understanding how the first cells of the testes form. Sertoli cells, which in the adult act as guardians for the development of sperm cells, are the very first cells to form from a "genital ridge" of the human male foetus. The number of sperm that can be produced in an adult man is critically dependent on the number of Sertoli cells that develop in his foetus, so anything that interferes with the formation of Sertoli cells in a mother's womb will affect sperm production many years later. "Maternal-lifestyle factors in pregnancy can have quite substantial effects on sperm counts in sons in adulthood, and the most logical mechanism by which this could occur is via reducing the number of Sertoli cells," Professor Sharpe says.
But the key question now is to identify the relevant lifestyle and environmental factors.
This is proving tricky. Obesity, for instance, is a growing problem and it has been linked with reproductive problems in both men and women. One study has also indicated that overweight pregnant women tend to produce sons with poor semen quality. But is it being fat that is the cause, or the environmental chemicals stored in fat?
There has been a lot of interest in chemicals in the environment, especially those that can either mimic female sex hormones – oestrogenic chemicals – or block male sex hormones, specifically testosterone which plays a critical role in stimulating the development of Sertoli cells in the womb. So far, the Seveso study provides the clearest link between human foetal development, low sperm counts and prenatal exposure to an environmental chemical. But the dioxin concentrations from this industrial accident were exceptionally high.
It is more difficult trying to establish a similar, significant link between male reproductive problems and exposure to low concentrations of the many other environmental chemicals that may have weak oestrogenic or androgen-blocking properties, including substances as wide-ranging as pesticides, traffic fumes, plastics and even soya beans. Professor Sharpe says that much of the evidence to date is weak or non-existent.
"Public concern about the adverse effects of environmental chemicals on spermatogenesis in adult men are, in general, not supported by the available data for humans. Where adverse effects of environmental chemicals have been shown, they are usually in an occupational setting rather than applying to the general population," he says.
So although scientists are closing in on the critical window of foetal development in the womb that determines a man's fertility status in later life, they are still not sure about what it is that could be affecting this change in his reproductive status. But one thing is clear, it is his mother who almost certainly holds the key

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