A New Hope for Male Fertility After Cancer Treatment

Written by RACHEL MABE

An experimental procedure that regenerates sperm could ensure that men are able to have kids following chemotherapy.

When Branden Lischner was 18, he got testicular cancer. Between surgery and radiation, which can cause infertility, he saved a sperm sample. But he was so removed from the idea of fatherhood that he soon stopped paying for his banked sperm. Then, in 2013, shortly after he got married, his cancer came back. Lischner only wanted to worry about the surgery to remove his second testicle, but his urologist pushed him to take the time to store sperm.

Lischner saved three samples. On the way into the operating room, the urologist asked if maybe he’d try once more. By then, the insistence was annoying. But four years later, Lischner and his wife credit the doctor with giving them the family they didn’t know they wanted.

On average, men produce between 200 and 500 million sperm per ejaculate, although only a fraction of them reach the uterus. Lischner had only 13 sperm to work with. Joseph Sanfilippo, the director of reproductive endocrinology and infertility at Magee Women’s Hospital in Pittsburgh, estimates Lischner’s wife had about a one in 100,000 chance of getting pregnant. It really shouldn’t have worked. But it did.

While the Lischners got extremely lucky, researchers are now working on a new treatment that could help men like Lischner who didn’t save a sample before radiation, or even prepubescent boys who develop cancer and have no sperm to save. This experimental technique takes a sample of testicular tissue and turns sperm precursor cells into actual sperm cells. Put back in the testes, these sperm multiply, repairing normal sperm production. This holds the promise of allowing men who lose fertility through cancer treatment to have biological children not just in a lab, but the old-fashioned way.

* * *

Dylan Hanlon was diagnosed with Ewing’s sarcoma when he was 9. At first, the news overwhelmed his mother, Christine Hanlon. A busy lawyer and single mom near Tampa, Florida, she put his care entirely in the hands of his doctors. But after the treatment succeeded in preventing Dylan’s cancer from spreading, she started researching its short- and long-term effects. Furious that none of the doctors had mentioned a high risk of infertility, she did more research, and learned of Magee-Women’s Hospital’s experimental procedure.

Hanlon was worried it was too late for Dylan after 12 weeks of chemo. Kyle Orwig, the head of the Fertility-Preservation Program at Magee, told her there was still a good chance Dylan had some spermatogonial stem cells. They’d do the procedure and check, and if they weren’t there, they wouldn’t save the sample.

Pioneered at the University of Pennsylvania School of Veterinary Medicine, spermatogonial stem-cell transplantation, as the procedure is called, was successfully performed on mice in 1994. Sperm are continuously created in adult men by turning spermatogonial stem cells into sperm. Prepubescent boys already have the stem cells, too; they just lack the ability to turn them into sperm. The technique collects a sample of stem cells, freezes it, and returns it to the testes. Although sperm precursor cells are damaged by radiation and chemotherapy, other cells in the testes seem to function normally after therapy. So putting the healthy, undamaged stem cells into the testis environment recreates the normal situation and promotes the nurturing of spermatogonial stem cells until they become actual sperm.

The procedure has since been done on rats, pigs, goats, sheep, and in 2012, nonhuman primates. Now, some fertility specialists are freezing testicular samples in the expectation of imminent human trials. At Magee Fertility-Preservation Program, doctors started freezing testicular samples in 2011. Although the exact amount of time these tissues can be frozen is uncertain, Orwig says there is “evidence in mice that stem cells can be thawed and transplanted to regenerate spermatogenesis after 14 years of storage.” Frozen eggs and sperm have been used to produce babies after decades of storage.

After consulting with Orwig, Hanlon talked to Dylan—alert and intelligent, it seemed to her, beyond his nine years. Dylan hated the chemo; he screamed and cried every time they tried to access his portal. He said more than once, “I don’t care if I die, just make them stop.” But he was enthusiastic about the experimental idea, according to Hanlon. “So I’d be a guinea pig?” he joked. She laughed and said yes.

Dylan’s doctors in Florida were not excited about the idea. Oncologists are concerned with saving the lives of their patients, and generally don’t want time and resources diverted from cancer treatment. If there isn’t a living patient, then fertility won’t ever be an issue. But Orwig contends that it was the right choice if Dylan was to have any chance of becoming a biological father one day.

* * *

Orwig sees it as his mission to disabuse doctors of the idea that thinking about fertility has to be a burden. Recently, he stood in front of a hospital conference room full of oncologists working within the University of Pittsburgh Medical Center health-care company system at their quarterly meeting, and explained a gap in care: His team estimates that they could do 1,119 fertility procedures a year, but they expect to do only 144 this year. Harvesting tissue need not delay treatment, he maintains; it can be scheduled to coincide with treatment-related procedures. And oncologists need not help patients decide whether or not to participate. They could merely present the option, give the Fertility-Preservation Program’s hotline number, and step back.

Orwig and his team give patients the option of saving a whole testicle or 20 percent of testicular tissue. The benefit of a whole testicle is that the team has more to work with, but the effects are more obvious. Taking 20 percent only appears as an indentation. In either case, the team keeps a quarter of each sample for future research.

What are the chances a successful procedure for restoring fertility will be available by the time Dylan, who’s now 16, is ready to have children? Sanfilippo and Orwig insist they’d never suggest the procedure to patients if they didn’t foresee progress. Orwig uses egg freezing as a comparable example: In 2011, it was experimental. Now it’s a standard of care. With childhood-cancer survival rates up to 85 percent, they see it as their responsibility to advance treatment.

Orwig also considers it his duty to educate doctors and to push men to think about infertility more generally. According to him, although a roughly equal number of men and women struggle with infertility—about 12 percent—fewer men think about fertility preservation. Their doctors talk less about it, too. Female fertility preservation is more complicated and costs more, both in the moment and in long-term storage fees.

Word is slowly spreading. In July, Donald and Jacqueline Renk took their son Paxton, not quite 2 years old, to the ER because he hadn’t urinated in 24 hours, and a tumor was found in his bladder. When they later sat with Paxton on a hospital bed waiting for his chemo—which his doctors are using to shrink the tumor because it’s too big to be removed—they told his doctor that fertility was the last thing on their minds. The doctor mentioned the procedure, but they were doubtful. He advised them to think about whether it might be worthwhile for Paxton to have the option in the future.

And Paxton has a future for his parents to consider. His cancer is predicted to be gone within a year. The oldest of Donald and Jacqueline’s four other children asked, “So he won’t be able to adopt kids?” When they said he would, he replied, “Well, then what’s the big deal?” Donald and Jacqueline loved that this is how their children think. And they decided that if Paxton might have the opportunity to have a biological child in the future and it wouldn’t delay his treatment, then there was really no reason not to do it. At the very least, they reasoned, his sample could help others.

View original article – https://www.theatlantic.com/health/archive/2017/10/male-fertility-cancer/542790/

What you should say to somebody who has miscarried – and what you shouldn’t

Written by 

I was saved by a friend who didn’t offer explanations for the loss of my baby or try to ‘fix’ things but listened, and knew that ‘I’m sorry’ was all I needed to hear.

“At least you know you can get pregnant,” said my doctor friend when I told her I’d had a miscarriage, 12 weeks into my first pregnancy, and following a painful struggle with infertility. “There was probably something wrong with the baby,” said one relative. “Just think of all the fun you’ll have trying again,” said another.

After my second miscarriage – a rare form of ectopic pregnancy – the focus was on the fact I was already a mother. “At least you’ve already got a child,” well-meaning friends told me, as did the surgeon who delivered the news that the pregnancy – and subsequent surgery – had left me infertile.

Not only did these insensitive comments hurt. They also made me feel diminished, as if I had no right grieving for a baby that never existed. As if I were greedy to want another child when I already had one.

Perhaps it’s because it can be uncomfortable discussing “female” things such as bleeding and cramps. Or maybe it’s because people don’t associate early miscarriage (generally defined as a loss that occurs before the 20th week of pregnancy) with a “real” baby. Whatever the reason, when you experience miscarriage you quickly discover that even the nicest people can say the most insensitive things.

 Almost every woman I know who has experienced miscarriage has a story about something inappropriate someone said following her loss.

After losing twins, one friend was told it was for the best “as she wouldn’t have been able to cope anyway”. Another endured speculation about whether her migraines were to blame, as “stress [caused by migraines] can kill babies in the womb”. “At least it was nice and early” offered little comfort to the colleague who lost babies six and seven weeks into her pregnancies.

But while words can wound, saying nothing can be just as bad.

I’m generally a positive person but both times I miscarried, I experienced extreme hopelessness. One minute I was imagining holding my baby in my arms, reading her a bedtime story or helping her take her first steps. The next I was in this dark, shadowy place, where I couldn’t see anything to live for. I thought I would never be able to stop crying. The worst thing was the crushing loneliness: the phone stayed silent – most people were too afraid to call.

When a friend or loved one loses a baby, the worst thing you can do is stay away. Picking up the phone or calling round to their home – even when you don’t know what to say – takes guts, but is better than doing nothing at all. Offering to cook, babysit, run errands – or any other practical help – can be enough to show you care.

Acknowledge the loss by asking when the baby was due to be born. If she doesn’t want to share she’ll say so. But steer clear of meaningless platitudes such as “everything happens for a reason” or “you can try again” (she can’t – that baby is gone for ever – and that was the baby she wanted). Anything that starts with “at least” will sound like you’re trying to minimise the loss – so don’t go there.

Do remember that everyone experiences grief and loss differently. I left a party in tears last year after someone made a point of telling me they’d miscarried twins and it hadn’t really bothered them. The conversation that followed was so painful – even 10 years after my last miscarriage – it took my breath away. So you had a miscarriage yourself and got over it in a few days. That’s great, but it doesn’t mean everyone else should do.

In fact a 2011 study found that the depression and anxiety experienced by many women after a miscarriage can continue for years, even after the birth of a healthy child.

Remember, also, that miscarriage hurts dads too, but they are often so busy looking after their partner that their grief goes unacknowledged. A simple hug or “how are you doing?” can go a long way.

I was saved by a wise friend who didn’t try to offer explanations, “fix” things or tell me about her friend/sister/aunt who miscarried umpteen times but went on to have a healthy baby. Who was brave enough to turn up on my doorstep with a hug and box of chocolates and just listen. Who understood that “I’m sorry” was all I needed to hear. That alone was priceless.

Janet Murray is a writer, speaker and fundraiser for miscarriage awareness. She is running the 2018 London Marathon raise money for the Ectopic Pregnancy Trust

View original article – https://www.theguardian.com/commentisfree/2017/oct/12/what-to-say-somebody-miscarried-loss-baby

Are men forgotten in miscarriage?

Written by Catherine Burns

One in four couples who discover they are pregnant have a miscarriage, but men are often forgotten both in terms of emotional support and as the potential cause. But researchers are working on a treatment which focuses on how their health could affect pregnancy.

James Barnett and his partner endured seven miscarriages before successfully having a son, Samuel, who is now nine months old. Despite their ordeal he says he only cried in front of his wife once.

At their 12-week scan the couple found the baby had no heartbeat and were sent home with drugs to induce the miscarriage. Within a few hours of agony on their bed, Joanna delivered the baby.

“She passed it to me and I looked at it and that really was the first time it hit home that this was a baby,” he told the Victoria Derbyshire programme.

“I was so upset, the potential this baby could have had, what it could have been, what it could have achieved. And I broke down, just to see it in front of you, just what it could have been.”

Supportive figure

Men say they can find themselves overlooked in terms of the emotional impact of miscarriage.

Gareth Watkins, whose wife Jo had three miscarriages before their two-year-old daughter Jessica, said he found explaining how he felt to others was the hardest thing.

“I’d make an excuse to go out to the shops just so I have ten minutes were I could compose myself, even crying sometimes, just out there on my own just trying to work through it. Just so you can go back into the house, try and be that supportive figure for your partner who’s obviously in bits with what’s gone on,” he said.

And despite the fact that one in 100 couples will have three or more miscarriages, some men say the emotional support available from medical professionals is “next to nothing” unless you are able to pay for it.

Al Ferguson has three children, but has experienced six miscarriages. He said very little support is offered to couples afterwards: “There’s no follow-up appointment. [It would help] even if there was just one appointment or something which the GPs could do, to ask ‘how’s it going?'”

Prof Lesley Regan, president of the Royal College of Obstetricians and Gynaecologists says the lack of care for men comes down to resources.

“Offering counselling and bereavement counselling often in this cash-strapped NHS that we’re working in at the moment, is difficult, and it’s maybe the one thing that’s considered, for example in the clinic I’m running, to be non-essential,” she said.

“I would have to prioritise the investigative tests I’m doing and try and encourage the couple to find the support and the counselling from other sources, from family, from friends.”

‘Incredibly optimistic’

Often miscarriage is caused by problems with chromosomes, but one of hardest things for parents is not knowing why it has gone wrong.

But last year the UK’s first national research centre dedicated to understanding miscarriage opened at Birmingham Women’s Hospital. It is funded by Tommy’s baby charity, in partnership with the University of Birmingham, the University of Warwick and Imperial College London.

One of the researchers is Dr Jackson Kirkman-Brown, who said around half of miscarriages currently have no explanation. But they think a lot may be due to the male’s sperm.

“Until now, everybody has thought, after the man has got the lady pregnant, that’s the end of his role. And if she loses the child, that’s something that’s wrong with her. Our research is really starting to turn that on its head. Now we think around half the time we can’t find an answer about miscarriage, it may be down to sperm DNA,” he said.

The researchers have developed a dietary supplement which they hope to be able to give to those men to correct the problem in how they make sperm.

“If we get the trial data to support this supplement working, we’d aim to have it out there on the market within a very few years to treat these problems,” Dr Kirkman-Brown said.

‘Incredibly optimistic’

“We’re incredibly optimistic about this research, and excited to push through to the next stage. We estimate that tens of thousands of miscarriages each year in the UK may be down to a male factor so we hope if we could correct that, perhaps 10,000 babies more a year would be born that otherwise would have had a miscarriage.”

Simon Webb and his wife Kate experienced three miscarriages while having their two sons. Simon said the development sounded amazing, but he remains cautious.

“You listen to the news and you hear of it all time, ‘they’ve found a cure for this, they’ve found a cure for that’. When they actually find that cure, then you can start really believing,” he said.

“I would like to have another child. I’d find it hard, but going through the experience and actually having a child, gives me that hope.”

Watch the Victoria Derbyshire programme on weekdays between 09:00 and 11:00 on BBC Two and the BBC News channel.

View original article – http://www.bbc.co.uk/news/health-41525610

Women with Endometriosis at Higher Risk of Multiple Surgeries, Ovarian Cancer, Study Shows

Fathers pass on four times as many new genetic mutations as mothers – study

Written by , Science editor

Faults in male DNA are a driver for rare childhood diseases, research suggests, with men passing on one new mutation for every eight months of age.

Children inherit four times as many new mutations from their fathers than their mothers, according to research that suggests faults in the men’s DNA are a driver for rare childhood diseases.

Researchers studied 14,000 Icelanders and found that men passed on one new mutation for every eight months of age, compared with women who passed on a new mutation for every three years of age.

The figures mean that a child born to 30-year-old parents would, on average, inherit 11 new mutations from the mother, but 45 from the father.

Kari Stefansson, a researcher at the Icelandic genetics company, deCODE, which led the study, said that while new mutations led to variation in the human genome, which is necessary for evolution to happen, “they are also believed to be responsible for the majority of cases of rare diseases in childhood.”

Scientists know from previous research that children born to older fathers have a greater risk of developing certain disorders, including intellectual disabilities, autism and schizophrenia. New mutations are a likely factor, given that more genes are active in the brain than in any other organ in the body.

Children inherit new mutations when they build up in the father’s sperm and the mother’s eggs. Men pass on more mutations than women because they make sperm throughout their lives, using a process that is not perfect at copying DNA. And so, as the man ages, his sperm accumulate more and more mutations. Women pass on fewer mutations because they tend to be born with their full complement of eggs.

In the study published in Nature, the researchers analysed the DNA of 1,500 Icelanders and their parents and, for 225 people, at least one of their children. They found that new mutations from mothers increased by 0.37 per year of age, a quarter of the rate found in men. While the vast majority of new mutations are thought to be harmless, occasionally they can disrupt the workings of genes that are important for good health.

The scientists also found that in some parts of the genome, new mutations were overwhelmingly passed on from mothers. In one section of chromosome 8, for example, the researchers found 50 times more mutations from the mother than in any other part of the genome. The scientists speculate that the cluster of mutations reveals an ancient Achilles heel in the genome: a region where the chromosome can easily break in two, but can be patched up, leaving mutations as a genetic scar.

“It seems that when a chromosome breaks in an egg, it can sometimes be repaired, avoiding a chromosomal catastrophe but leaving a scar of small mutations,” said Martin Taylor, a geneticist at the University of Edinburgh.

Allan Pacey, professor of andrology at Sheffield University, said: “We have known for many years that the risk of having a child with a medical condition of genetic origin increases noticeably with the father’s age at conception. It is for this reason that there is a recommended upper age limit for sperm donors, currently 40 years in the UK. Put simply, the genetic quality of sperm from younger men, in terms of new mutations, is generally much better than that of older men.”

View original article – https://www.theguardian.com/science/2017/sep/20/fathers-pass-on-four-times-as-many-new-genetic-mutations-as-mothers-study?CMP=Share_iOSApp_Other 

DNA editing in human embryos reveals role of fertility ‘master gene’

Written by , Science correspondent

In a first for the UK, genome editing has been used to understand embryo development, and could help uncover the causes of recurrent miscarriages.

Scientists in Britain have revealed the role of a fertility “master gene” in one of the world’s first demonstrations of DNA editing in human embryos.

The study, which marks a first for the UK, could help uncover the cause of recurrent miscarriages and lead to more effective fertility treatments. It also raises ethical questions about the prospect of controversial gene editing techniques being used clinically to correct defects in, or even enhance, human embryos in the future.

Kathy Niakan, who led the work at the Francis Crick Institute in London, said: “Our research is the first time that genome editing has been used to understand the role of a gene in early embryonic development. This knowledge can be used to improve IVF treatment and improve our understanding of how some pregnancies fail.”

Niakan’s team is the first in Britain to have edited the DNA of human embryos, with just a handful of such experiments having been performed in China and the US. These focused on how editing might be used to prevent inherited diseases being passed from one generation to the next.

The latest work switches the spotlight to the basic biological sequence that plays out as a fertilised egg turns into a ball of cells, known as a blastocyst, during the first seven days of development. Only when an embryo successfully reaches the blastocyst stage does it stand any chance of implanting in the womb.

Using 41 human embryos donated by couples with a surplus after IVF treatment, the scientists applied the gene-editing tool Crispr/Cas9 to make precise cuts in DNA and deactivate a gene called OCT4, which was believed to be important in the earliest stages of development. The study, published in Nature, showed this gene is critical for the embryo to make the transition from a uniform blob of cells to a blastocyst, which comprises three cell types that will go on to be the embryo, the placenta and the yolk sac.

Under a microscope, the edited embryos started by dividing and expanding normally, but then underwent repeated cycles of expansion and collapse without ever progressing to the next stage.

Scientists believe that lower than normal OCT4 activity could be why embryos fail to implant successfully, leading to miscarriage. Treating this would not necessarily require gene editing – it might be possible to coax more activity from the gene by changing the way embryos are cultured in the IVF process, for instance.

Kay Elder, study co-author from the Bourn Hall fertility clinic in Cambridge said that the technique could help improve IVF success rates, which remain frustratingly low. “Many embryos arrest in culture, or fail to continue developing after implantation,” she said. “This research will significantly help treatment for infertile couples, by helping us to identify the factors that are essential for ensuring that human embryos can develop into healthy babies.”

The failures of fertility treatments could be down, in part, to a reliance on mouse studies, which until now have been seen as the best way to work out the role of genes during embryonic development – and why things sometimes go wrong. The latest work highlights the shortcomings with this approach, showing that the OCT4 gene appears to play a different role in early human embryos than in mice.

“This is in a way unexpected, because of the dogma that the earliest stages of development are common for all mammalian and even some non-mammalian species,” said Dusko Ilic, reader in stem cell science at King’s College London. “The study is another proof that the findings from experimental animal models cannot be always extrapolated to humans.”

The latest work comes as an increasing number of researchers are applying the powerful genome editing procedure called Crispr-Cas9. The technique was invented only four years ago, but is already revolutionising biomedical research. It allows scientists to make precise edits to the genome – snipping through strands of DNA to deactivate genes and potentially correcting genetic flaws.

The technique could hold huge clinical potential, but it is also controversial because it involves altering the “germline”, meaning that any changes would be passed down to future generations.

Karen Yeung, professor of law at Kings College London, said: “The work demonstrates the invaluable role played by the Human Fertilisation and Embryology Authority in the British context in monitoring and ensuring that limits of responsible research on human embryos are respected, in order to maintain public trust in research of this kind.”

View original article – https://www.theguardian.com/science/2017/sep/20/dna-editing-in-human-embryos-reveals-role-of-fertility-master-gene?CMP=Share_iOSApp_Other