Week Ending FRIDAY July 3, 2009---------------------------News Archive / Return to News Alerts
Thawed Embryo Transfer After PGD = Same Pregnancy Rates
Transferring just one embryo at a time to a woman's womb after embryos have undergone preimplantation genetic diagnosis (PGD) and freezing at the blastocyst stage has become a real option after researchers achieved pregnancy rates that were as good as those for blastocysts that had not had a cell removed for PGD before freezing. Their results mean that it will be possible to reduce the number of multiple pregnancies after PGD and the consequent complications associated with these pregnancies.
The research was presented at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam and published online in Europe's leading reproductive medicine journal, Human Reproduction, simultaneously today (Tuesday).
Dr Yacoub Khalaf, director of the assisted conception unit at Guy's and St Thomas' Hospital, London (UK), told the conference: "To the best of our knowledge, our study is the first to provide reassurance that a strategy of elective single embryo transfer in good prognosis patients seeking PGD, backed by an efficient PGD cryopreservation service, can result in pregnancy rates that are comparable to those for non-biopsied embryos that are frozen as part of conventional fertility treatment. These results should empower fertility centres to include PGD cycles for inherited genetic disorders in their efforts to reduce the multiple pregnancy rates after various forms of assisted conception treatment. Given the increasing number of PGD cycles performed each year, the advantage of widespread application of this policy would be considerable."
Until now, fertility specialists have not applied a single embryo transfer policy to PGD for inherited genetic disorders because of concerns about how well biopsied embryos survive after freezing and thawing. "It was thought that the effect of the biopsy might reduce the embryos' tolerance to freezing. This concern was not based on any scientific evidence, only on observations of low survival rates of biopsied frozen embryos," said Dr Khalaf.
From January 2006 to July 2008 Dr Khalaf and his colleagues offered single embryo transfer together with freezing of surplus blastocysts to couples seeking PGD for single inherited genetic disorders such as cystic fibrosis. All the embryos were biopsied for the purposes of PGD on the third day after fertilisation, which is the time that they start to divide. Healthy embryos were cultured in the laboratory for a further two to three days to check that they were capable of reaching the next appropriate stage of development the blastocyst stage. At this point, 32 couples who had two or more embryos that had successfully reached the blastocyst stage were offered the option of having one transferred to the womb and the rest frozen.
The researchers compared the pregnancy outcomes from a subsequent 32 frozen-thawed PGD cycles in these couples with the pregnancy outcomes from a control group of couples where 191 cycles of conventional IVF/ICSI were carried out using embryos that were frozen and thawed before implantation, but not biopsied at any stage.
They found that the blastocyst survival rate after thawing was similar between the PGD and IVF/ICSI groups (87% versus 88% respectively). There was no significant difference in the implantation and clinical pregnancy rates (35% versus 29% and 34% versus 36% respectively). The overall ongoing pregnancy rate for all frozen cycles (PGD and IVF/ICSI) was 34%, which compares favourably with the UK national average for frozen cycles (currently 18% live birth rate per thaw).
When the same period was compared with the period before the single embryo transfer policy was introduced for PGD couples, the multiple pregnancy rate in the cycles of fresh PGD dropped from 36% to 10% with no reduction in pregnancy rates.
Dr Khalaf said: "This research suggests that responsible clinical decisions do not have to come at the expense of reducing effectiveness of treatment. You can be responsible and maintain the chances of success for your patients by good clinical judgment and using the appropriate techniques.
"For patients, this provides reassurance that a couple's chance of having a healthy child is not reduced by replacing only one blastocyst and freezing the surplus ones. Those frozen blastocysts do have a very good chance of leading to a healthy pregnancy too, and, therefore, patients will not feel pressurised to have more than one embryo replaced (with the increased risk of multiple pregnancies) in order to make use of their biopsied, unaffected embryos for which, otherwise, they might have little use. Now, these frozen blastocysts offer them the chance of an additional healthy pregnancy without having to go through the whole treatment cycle again."
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Preterm Birth & a High Incidence of Brain Malformation
New research out of Wake Forest University School of Medicine provides for the first time a solid scientific answer for the long-standing question of whether there is an association between preterm birth and brain malformations
In a study of more than 1,000 preterm infant autopsies, researchers found that there is a strong association between congenital brain defects and preterm birth, leading investigators to believe that something about the brain malformations may be causing preterm birth and providing a possible study path toward a better understanding of the problem.
The study appears in the June issue of Pediatric Research. It is the first to investigate the risk of being born preterm for infants who have a variety of congenital brain defects.
“The most important thing about this study is that to-date, it is still unknown why there are so many preterm births. This study suggests that one way to look for the causes of preterm birth is to look at those types of brain malformations that have very strong association with preterm birth, and see if there is some sort of difference between those babies and full-term babies some sort of soluble factor or an increased amount of something in the preterm babies that is not found in other babies,” said William R. Brown, Ph.D., a research associate professor of radiologic sciences and author/investigator for the study.
Funded by the National Institutes of Health, March of Dimes Birth Defects Foundation and the Pratt Family Foundation, Brown’s research on brain malformations and preterm birth grew out of a study of bleeds in the brains of babies, where researchers found that a large percentage of the babies being studied had small, unrecognized types of brain malformations that warranted further investigation.
Previous studies have shown that malformations of other parts of the body are associated with preterm birth. However, though there has been evidence suggesting brain malformations are also associated with preterm birth, it has been difficult to document such an association because brain defects can be hidden within the cranium and may remain undetected until autopsy, whereas malformations of other parts of the body can be determined through birth registries.
For his study, Brown looked at 1,168 autopsy files that contained congenital brain defects as well as information on the gestational age at birth of the subject. For comparison, Brown also looked at published files of over 7,000 infants with “significant birth defects of any kind” and more than 260,000 infants without brain defects. The control cases came from a large registry published by the Metropolitan Atlanta Congenital Defects Program.
In his review, Brown found that, in the autopsy cases with brain defects, the mean gestational age was 36.6 weeks, whereas the data showed a mean gestational age of 39.9 weeks for infants with no defects and a gestation of 38.1 weeks for infants with defects of any kind. “Preterm” birth is defined as 20 to 36 weeks gestation, while “term” birth is defined as 37 to 41 weeks. Only 9.3 percent of babies born without defects were preterm, compared to 21.5 percent of those with defects. In the autopsy cases with brain defects, the rate of preterm birth was even greater at 33.1 percent, showing the strongest association between the two.
Some types of brain defects have a stronger association with preterm birth than others, the study showed. The list itself could possibly offer some clue to the association. Among the malformations studied with the highest rates of preterm birth were hydrocephaly, an abnormal buildup of cerebrospinal fluid (CSF) in the ventricles of the brain (65.2 percent); anencephaly, a defect in the closure of the neural tube during fetal development resulting in the absence of a major portion of the brain, skull, and scalp (57.7 percent); multicystic encephalomalacia, the formation of multiple cystic cavities of various sizes in the cerebral cortex (50.5 percent); and hydranencephaly, a rare condition in which the brain's cerebral hemispheres are absent and replaced by sacs filled with cerebrospinal fluid (38.5 percent).
“There are a lot of preterm births where there are no apparent causes,” Brown said. “I speculate that brain defects or other defects not easily detected could be causing some of them and perhaps we should focus on studying coagulopathy (a tendency to excessive blood coagulation and formation of blood clots) to find what the association is between that and preterm birth.
“The placenta could be a key element,” he added. “In placental conditions such as preclampsia, which is strongly associated with preterm birth, there may be blood clots coming from the placenta, causing brain damage and malformations in the brain and then, perhaps, the malformed fetus induces its own preterm birth or perhaps the coagulopathy causes the preterm birth through some other mechanism. The next step is to look at the brain malformations that have the strongest association with preterm birth and see if it’s possible to identify the factors associated with those malformations that may be causing preterm birth. These are possible new directions to explore.”
Meanwhile, Brown endorses the use of folic acid before and during pregnancy.
“It’s not completely known how it works, but it could be impacting coagulopathy because folic acid is involved with the pathways that are also involved with coagulation,” he said.
Tamoxifen Stimulates Uterine Cell Growth & Cancer
UCSF researchers have identified a new “feed-forward” pathway linking estrogen receptors in the membrane of the uterus to a process that increases local estrogen levels and promotes cell growth.
The research is significant in helping determine why tamoxifen and other synthetic estrogens are linked to increased rates of endometriosis and uterine cancer, and identifies a pathway that could be targeted in drug therapies for those diseases, researchers say.
Findings are published in the July 1, 2009 issue of “Cancer Research,” the journal of the American Association for Cancer Research. The paper also can be found online at http://cancerres.aacrjournals.org/current.shtml.
The research found that when activated by estrogens, endometrial cells obtained from patients suffering from endometriosis or human uterine cancer cells initiate a previously unknown cascade of signals that leads to cellular replication and further estrogen production, the paper says.
The ensuing cycle leads to abnormal growth of the cells lining the uterus, or endometrium, which occurs in endometriosis and uterine cancer, according to senior author Holly A. Ingraham, PhD, a professor in the UCSF School of Medicine’s Department of Cellular and Molecular Pharmacology.
“It turns out that displaced endometrial cells, such as those used in this study, are estrogen factories,” said Ingraham, who also is affiliated with the UCSF Helen Diller Family Comprehensive Cancer Center and the UCSF Center for Reproductive Sciences. “They pump out estrogen in a feed-forward pathway, so the more estrogen they produce, the more estrogen they’re capable of producing.”
While this pathway was previously unknown, Ingraham said a June 2009 paper led by researchers at the University of New Mexico and published in the journal “Nature Chemical Biology” showed that blocking the GPR30 receptor in this pathway decreases uterine proliferation in a mouse. The two together, she said, validate what researchers now think may be a key area in addressing both uterine cancer and endometriosis.
Uterine cancer is the fourth most common cancer in women, with more than 37,000 women being diagnosed each year in the United States alone, according to data from the Centers for Disease Control.
Endometriosis, in which endometrial cells grow in areas other than the uterus, is the most common gynecological disease and affects more than 5.5 million women in North America, according to the National Institutes of Health. The disease often causes severe pain and can lead to infertility.
Working in collaboration with clinicians at Northwestern University in Chicago, the UCSF team analyzed cells from women with ectopic endometriosis. By studying those patients’ endometrial cells, the team was able to identify an unusual, circular pathway involving these cells, the transmembrane estrogen receptor GPR30 and the nuclear receptor SF-1.
The researchers propose that this pathway increases local concentrations of estrogen and, together with classic estrogen-receptor signaling, control the proliferative effects of these estrogens in promoting endometriosis and endometrial cancers.
The UCSF team used a unique chemical biology approach, making use of a tamoxifen-like compound developed in the laboratory of co-author Thomas Scanlan, PhD, who is affiliated with both the UCSF Department of Pharmaceutical Chemistry and the Department of Chemical Biology at the Oregon Health Sciences University in Portland.
“Tamoxifen and other synthetic estrogens have been known to increase the risk of uterine cancer, but until now, we didn’t know why that was on a cellular level,” Ingraham said. “We think this pathway is going to be an important one in solving that mystery.”
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PCOS: New Causes and Effects on Male Relatives
Researchers have found evidence that chronic disease in either a mother or father can create unfavourable conditions in the womb that are associated with the development of polycystic ovarian syndrome (PCOS) in daughters
In another study, researchers found that brothers of women with PCOS and insulin resistance are themselves at greater risk of developing insulin resistance or diabetes, suggesting that factors associated with the condition can be passed down to sons as well as daughters.
The two studies were presented to the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam heard today (Tuesday).
Associate Professor Michael Davies told a news briefing: "We already know from clinical studies of women with reproductive problems that foetal growth restriction is associated with the development of PCOS symptoms in daughters, and that problems during pregnancy and in the way the mother adapts to the metabolic challenge of pregnancy can indicate the future cardiovascular health of both the mother and the child. What we don't know is whether giving birth to a daughter who later develops PCOS is associated with increased, long term cardiovascular disease risk in the mother. Nor do we know whether conditions underlying chronic disease in the father increases the risk of PCOS in the daughter."
Prof Davies, co-director of the Research Centre for the Early Origins of Health and Disease at the University of Adelaide (Australia), looked at records for all female babies who were born and survived between 1973-1976 at The Queen Elizabeth Hospital in Adelaide. He and his colleagues interviewed the daughters to build up a picture of their health and any history of chronic disease in their parents. So far, 998 (63%) have responded, and Prof Davies reported preliminary data up to mid-1975 to the conference.
Sixty-two daughters (6.2% of the group) had a pre-existing diagnosis of PCOS. Mothers of these women tended to have elevated blood pressure during pregnancy. Daughters were nearly eight times as likely to have PCOS if their mothers had it, and they had a slightly higher risk if their mothers smoked during pregnancy. Mothers were 1.6 times as likely to have high blood pressure in later life if their daughters developed PCOS. If their fathers had heart disease or stroke, the daughters also had a higher risk of PCOS: double and three times the risk respectively. A history of diabetes in either parent was not significant.
Prof Davies said: "These findings suggest a new pathway for the development of PCOS. We think that factors associated with the pre-existence of cardiovascular dysfunction in the mother or the father, and which operate during pregnancy, may create adverse conditions for the foetus, which alter the metabolic profile of offspring, leading to insulin resistance and reproductive consequences, such as PCOS, for daughters. A family history of diabetes is, therefore, not essential to observe an insulin resistance-related disease in offspring."
He said it was still unclear exactly how the cardiovascular risk in the father affected the daughter. "We firstly need to consider the potential role of a common environment; for instance, that families with high levels of obesity (and therefore cardiovascular disease) will also tend to have heavy daughters who are thereby more likely to be affected by PCOS. However, the paternal effect that we saw was independent of the daughter's weight, maternal age, socioeconomic status, maternal smoking, and country of birth, which suggests either a direct genetic effect on the daughter, or an effect of paternal genetic factors that are expressed during pregnancy."
Dr Verena Mattle told the news briefing that her study was the first to show that brothers of women who had PCOS and insulin resistance were themselves more likely to develop insulin resistance or even diabetes or dyslipidaemia (a disruption in the levels of lipids (or fats) in the blood).
"Until now, it was not clear whether the male relatives of women with PCOS were at increased risk for the metabolic disorders associated with PCOS," said Dr Mattle, who is chief resident at the University Clinic of Gynecological Endocrinology and Reproduction Medicine in Innsbruck (Austria).
Dr Mattle and her colleagues conducted oral glucose tolerance tests on 15 brothers of sisters with PCOS and insulin resistance (group 1). They also performed a serum analysis to determine lipid levels. As a control, nine brothers of sisters with PCOS but without insulin resistance were included in the study (group 2).
The researchers found that in the first group eight brothers showed an insulin resistance, one was diagnosed with diabetes and six had a normal glucose tolerance test. All nine affected brothers had a body mass index (BMI) between 19-31 kg/m2 and had elevated cholesterol and triglyceride levels. The six unaffected brothers had a BMI between 23-29, and none had high levels of cholesterol or triglycerides. In the second group, no insulin resistance was diagnosed. BMI was between 18-27 and two brothers had elevated cholesterol levels. Although there was a trend towards higher BMI in the first group, Dr Mattle said there was no statistically significant difference in BMIs between the two groups.
Dr Mattle said: "These results mean that we should pay attention to the health not only of women with PCOS but also to their brothers as they seem to have an increased risk for the medical problems that make up the metabolic syndrome, such as insulin resistance, diabetes and cardiovascular disease. Our findings are also in accordance with the hypothesis that not only is PCOS is a heritable disease, but that factors associated with it, such as insulin resistance, can be passed down to the next generation of either sex."
She said that it could not be the case that the high BMI by itself could have caused the insulin resistance and diabetes in the affected brothers. "There must be a correlation between PCOS and insulin resistance because we could only find brothers with insulin resistance in the group that had sisters with PCOS and insulin resistance, but we couldn't find brothers with insulin resistance in the group that had sisters with PCOS and no insulin resistance. It is known that about 50% of women with PCOS are insulin resistant and also that lean PCOS patients are insulin resistant. The BMI of insulin-resistant and non-resistant brothers were not statistically different."
Dr Mattle and her colleagues are continuing to test brothers of women with PCOS for insulin resistance and lipid levels to collect more data from a larger group. "At this stage we would hesitate to say that a genetic inheritance is definitely playing a role in the increased risk of insulin resistance and other, related conditions in these brothers. We need to explore the possible effect of conditions in the womb and also the role of the environment. However, we think our data strongly support the view that brothers of women with PCOS and insulin resistance may have an increased risk of insulin resistance, diabetes and other, adverse metabolic conditions," she concluded.
THURSDAY July 2, 2009---------------------------News Archive / Return to News Alerts
Daily Sex Helps Reduce Sperm Damage - Improve Fertility
Daily sex (or ejaculating daily) for seven days improves men's sperm quality by reducing the amount of DNA damage, according to an Australian study presented today (Tuesday) to the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam
Until now there has been no evidence-based consensus amongst fertility specialists as to whether or not men should refrain from sex for a few days before attempting to conceive with their partner, either spontaneously or via assisted reproduction.
Dr David Greening, an obstetrician and gynaecologist with sub specialist training in reproductive endocrinology and infertility at Sydney IVF, Wollongong, Australia, said: "All that we knew was that intercourse on the day of ovulation offered the highest chance of pregnancy, but we did not know what was the best advice for the period leading up to ovulation or egg retrieval for IVF.
"I thought that frequent ejaculation might be a physiological mechanism to improve sperm DNA damage, while maintaining semen levels within the normal, fertile range."
To investigate this hypothesis, Dr Greening studied 118 men who had higher than normal sperm DNA damage as indicated by a DNA Fragmentation Index (DFI). Men who had a more than 15% of their sperm (DFI >15%) damaged were eligible for the trial. At Sydney IVF, sperm DNA damage is defined as less than 15% DFI for excellent quality sperm, 15-24% DFI for good, 25-29% DFI for fair and more than 29% DFI for poor quality; but other laboratories can have slightly different ranges.
The men were instructed to ejaculate daily for seven days, and no other treatment or lifestyle changes were suggested. Before they started, levels of DNA damage ranged between 15% and 98% DFI, with an average 34% DFI when measured after three days' abstinence. When the men's sperm was re-assessed on the seventh day, Dr Greening found that 96 men (81%) had an average 12% decrease in their sperm DNA damage, while 22 men (19%) and an average increase in damage of nearly 10%. The average for the whole group dropped to 26% DFI.
Dr Greening said: "Although the mean average was 26% which is in the 'fair' range for sperm quality, this included 18% of men whose sperm DNA damage increased as well as those whose DNA damage decreased. Amongst the men whose damage decreased, their average dropped by 12% to just under 23% DFI, which puts them in the 'good' range. Also, more men moved into the 'good' range and out of the 'poor' or 'fair' range. These changes were substantial and statistically highly significant.
"In addition, we found that although frequent ejaculation decreased semen volume and sperm concentrations, it did not compromise sperm motility and, in fact, this rose slightly but significantly.
"Further research is required to see whether the improvement in these men's sperm quality translates into better pregnancy rates, but other, previous studies have shown the relationship between sperm DNA damage and pregnancy rates.
"The optimal number of days of ejaculation might be more or less than seven days, but a week appears manageable and favourable. It seems safe to conclude that couples with relatively normal semen parameters should have sex daily for up to a week before the ovulation date. In the context of assisted reproduction, this simple treatment may assist in improving sperm quality and ultimately achieving a pregnancy. In addition, these results may mean that men play a greater role in infertility than previously suspected, and that ejaculatory frequency is important for improving sperm quality, especially as men age and during assisted reproduction cycles."
Dr Greening said he thought the reason why sperm quality improved with frequent ejaculation was because the sperm had a shorter exposure in the testicular ducts and epididymis to reactive oxygen species very small molecules, high levels of which can damage cells. "The remainder of the men who had an increase in DFI might have a different explanation for their sperm DNA damage," he concluded.
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Fewer Eggs May Mean Higher Risk for Trisomic Pregnancy
Women who have a diminished number of eggs in their ovaries, either because they are older or for some other reason such as ovarian surgery, may be more at risk of a trisomic pregnancy than women with an ovarian reserve within the normal, fertile range
Trisomic pregnancies occur when the embryo has three copies of a chromosome rather than the normal two. The most common trisomy is Down's syndrome or trisomy 21. Most foetuses with other trisomies miscarry, but if they are born alive then they have multiple abnormalities and usually die in childhood.
Dr Maaike Haadsma, a researcher in the departments of obstetrics & gynaecology and genetics at the University Medical Center Groningen (The Netherlands) presented her findings at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam on Tuesday, June 30th.
She said: "The results of my study support a relation between trisomic pregnancy and a decreased quantity of eggs available in the ovaries of women attending fertility clinics for IVF treatment. This finding is independent of the women's age. This suggests that the effect of a mother's age on the risk of trisomy may be explained by the age-related decrease in the numbers of eggs. Younger women may also be at increased risk of trisomic pregnancy if their ovarian reserve is reduced, either because of treatment affecting the ovaries such as surgery, or because of their genetic inheritance."
Dr Haadsma and her colleagues analysed data from a nationwide group of 19,840 women undergoing fertility treatment in The Netherlands from 1983-1995. They identified 28 women who had a trisomic pregnancy after IVF and matched them with a control group of women who had healthy children. They looked at three indications of ovarian reserve: 1) a history of ovarian surgery at the time of IVF treatment (such as the removal of benign ovarian cysts); 2) the number of eggs (oocytes) retrieved during the fertility treatment; 3) menopausal status at the end of the study period.
They found that a history of ovarian surgery increased the risks of trisomic pregnancy more than three-fold; if only four or fewer eggs were retrieved during treatment, this quadrupled the risk of trisomy (conventional IVF aims to retrieve between 8-10 eggs at one time); if there were signs of the menopause at the end of the study period, this increased the risk of a trisomic pregnancy more than five-fold.
"The biological mechanism behind our findings is, as yet, unclear," said Dr Haadsma. "It may be that women use their 'best' eggs first in their fertile life and leave their abnormal ones to the last. Women with fewer eggs would then be at increased risk of trisomic pregnancy. However, more convincing in my opinion, is the hypothesis that the chance that a fertilised, abnormal egg is selected for embryo transfer in IVF is increased in women with reduced ovarian reserve, simply because there are fewer eggs and thus embryos to choose from. The proportion of normal and abnormal embryos may be the same in women with normal and diminished ovarian reserve, but if you only have one or two embryos available (instead of, say, six or eight) the chance that no normal embryo is available is relatively high."
As women get older their supply of eggs decreases. In younger women, the reasons for a diminished ovarian reserve are more complex. "Next to ovarian surgery, other medical interventions, such as chemotherapy or radiotherapy, may cause a decrease in ovarian reserve. However, a woman's ovarian reserve is most likely to be mainly determined by her genes: the number of oocytes a woman is born with and the rate of depletion of her oocyte pool is believed to be heritable. This is reflected in the similar ages at menopause of mothers and daughters. However, exactly which genes are involved remains to be determined," said Dr Haadsma.
She concluded: "Since we studied a relatively small number of women, our results should be interpreted as an indication and not as proof of a relation between ovarian reserve and trisomy risk. We have to confirm our findings in a different IVF cohort first and than determine the exact extent of the increase in trisomy risk. Then the next step would be to study our hypothesis in a fertile group of women, since results from women having IVF cannot be extrapolated to the general population right away. If our findings are indeed confirmed, women with reduced ovarian reserve should be informed about their 'new' trisomy risk. It's perceivable this may influence their choices in prenatal testing."
Will IVF Work for You? The Answer May Be In Your Blood
For the first time, researchers have been able to identify genetic predictors of the potential success or failure of IVF treatment in blood
Dr. Cathy Allen, from the Rotunda Hospital, Dublin, Ireland, told the 25th annual conference of the European Society of Human Reproduction and Embryology on Wednesday 1 July, that her research would help understand why IVF works for some patients but not for others.
Previous work in this area has looked at gene profiles in such tissues as the uterine lining, but Dr. Allen and her team chose to examine the gene expression patterns in RNA extracted from peripheral (circulating) blood, an easily accessible biological sample. Blood samples were taken at eight different stages during the period around conception and the early stages of the IVF cycle. Five of these samples came from women who achieved clinical pregnancies, three from those who had implantation failure, and three from subfertile women who conceived spontaneously. Analysis showed that 128 genes showed a more than two-fold difference in expression in early clinical pregnancy compared with a non-pregnant state.
The molecular pathways that were most over-represented in this expression were concerned with angiogenesis (the growth of new blood vessels), endothelin signalling (blood vessel constriction), inflammation, oxidative stress (damage to cell structures), vascular endothelial growth factor (signalling processes in blood vessel growth), and pyruvate metabolism (the supply of energy to cells). "All these processes are important in the achievement and maintenance of pregnancy," said Dr. Allen.
"We found that the gene expression profiles in blood of patients at the time of pituitary down-regulation showed interesting patterns of gene clustering. Over 200 genes were differentially expressed in patients who went on to achieve an IVF pregnancy compared with those who did not," she said.
The researchers found that the peripheral blood gene expression 'signature' (also known as the transcriptome) before IVF was predictive of IVF outcome. This finding demonstrates the power of high-dimensional technology in biomarker discovery, and highlights the potential for developing clinically useful tools, they say.
One of the most difficult decisions for patients who have had unsuccessful IVF treatments is whether they should undergo further attempts at IVF, or if there are ways to optimise chances of success. The researchers hope that the results generated by this work will lead to the development of a test to aid in IVF decision-making. They say that their work will help to identity biomarkers that can identify events occurring at implantation, the maintenance of pregnancy and successful or unsuccessful pregnancy outcome.
"IVF technology has advanced tremendously over the past three decades, yet success after IVF remains an unpredictable outcome," said Dr. Allen. "Our work will help understand whether the implantation of embryos is influenced by the constantly changing expression of human genes."
Previous studies in the field of gene-expression have focused on single genes as opposed to genome-wide screening of all the human genes with high density DNA microarrays, as used by Dr. Allen and her team. The advent of tools like microarrays that can simultaneously probe for up to 29,000 genes has radically changed scientific approaches to this type of research. "It's like looking at how a team of players perform together rather than focusing on the individual players," said Dr. Allen.
"We intend to look further at the most significant genes we have identified as being important in this field in order to be able to understand their exact biological role in reproductive function. We hope that our work will lead to the development of a clinically useful tool to help doctors counsel their patients in the difficult decision-making involved in IVF," she said.
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Test Can Detect an Embryo's Genetic & Chromosome Defects
One-step screening for both genetic and chromosomal abnormalities has come a stage closer as scientists announced that an embryo test they have been developing has successfully screened cells taken from spare embryos that were known to have cystic fibrosis
They told a news briefing at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam on Tuesday, June 30th, that, as a result, they would be able to offer clinical trials to couples seeking fertility treatment later this year.
The researchers based in the USA and the UK have been able to prove that the technique, known as genome-wide karyomapping, was capable of not only detecting diseases caused by a specific gene mutation, in this case cystic fibrosis, but that it was also capable of detecting aneuploidy (an abnormal number of any of the 23 pairs of chromosome) at the same time. This is the first time they have been able to demonstrate that the test can work in cells taken from embryos that have already been diagnosed with the cystic fibrosis gene mutation using conventional preimplantation genetic diagnosis (PGD).
Gary Harton, PGD scientific director of the Genetics & IVF Institute in Fairfax, Virginia (USA) told a news briefing: "Karyomapping is a universal method for analysing the inheritance of genetic defects in the preimplantation embryo without any prior patient or disease specific test development, which often delays patient treatment. For the first time, the inheritance of both single gene defects and chromosomal abnormalities can be detected simultaneously at the single cell level. Unlike other methods, this is achieved entirely by analysing the DNA sequence at over 300,000 locations genome-wide in parents and appropriate family members, often children already affected by a disease, and comparing their sequence with that inherited by the embryo. This can be achieved very rapidly using current microchip technology known as microarray."
With karyomapping it is not necessary to know the exact DNA mutation that is being sought; the scientists just need to take the relevant chunk of DNA from the parent that carries the mutation somewhere along its length, and if it matches a chunk of DNA from the embryo, then they know the embryo has inherited the mutation. As karyomapping involves analysing chromosomes, it also detects the existence of aneuploidy at the same time.
"The range of applications is broad and includes single gene defects, abnormal chromosome number, structural chromosome abnormalities and HLA [human leukocyte antigen] matching in 'saviour sibling' cases," said Mr Harton.
Karyomapping was developed by Professor Alan Handyside of the London Bridge Fertility Gynaecology and Genetics Centre in London (UK), and Mr Harton has been providing samples and DNA information in order to test the method and validate it for use in the clinic.
"The hope is that clinicians will be able to test embryos for specific genetic diseases and know that, with one test, they are transferring chromosomally normal embryos. This will be a step forward from current technology that is mostly limited to choosing one test or the other," explained Prof Handyside.
Karyomapping would also be quicker and cheaper. Currently, developing a PGD test for a single gene defect can take weeks or months, as scientists have to identify the exact patient or disease-specific genetic mutation first before screening for it, which is labour-intensive and costly. By contrast, karyomapping can be carried out without such extended pre-test development; at present, it takes about three days, but Mr Harton and his colleagues believe this could be reduced to 18-24 hours.
In this most recent stage of their research they examined cells from five embryos that had been donated for medical research by a couple who had received successful fertility treatment, including PGD for cystic fibrosis. The embryos had developed to the blastocyst stage, which is about five days after fertilisation. Conventional PGD had already identified which embryos were unaffected, affected or were carriers of the disease. Karyomapping of cells from the donated embryos confirmed these diagnoses, but, in addition, it was able to identify which parent carried the affected chunk of DNA. Karyomapping also revealed two aneuploidies in two embryos, which had not been detected by the earlier PGD.
Mr Harton said: "This demonstrates that karyomapping, following genome-wide analysis of a single cell biopsied from embryos at the blastocyst stage, can provide highly accurate analysis for cystic fibrosis, combined with the detection of chromosomal aneuploidy. Now that vitrification [an improved method of embryo freezing] has improved embryo survival after thawing, it should be possible to vitrify embryos at the blastocyst stage, either before or after biopsy, and analyse the embryos for virtually any genetic disease and screen for aneuploidy of all 23 pairs of chromosomes simultaneously. This approach could make PGD by karyomapping less expensive than conventional single disease PGD because fewer embryos will be biopsied, more embryos will be chromosomally normal following growth to the blastocyst stage, and there is no need to custom develop tests for each disease or couple interested in PGD."
Prof Handyside concluded: "These tests have helped us to learn everything we can before we start to treat actual patients. I am confident that we will be offering a clinical trial to patients using karyomapping some time this year."
WEDNESDAY July 1, 2009---------------------------News Archive / Return to News Alerts
Women More Likely Than Men to Reject Unattractive Babies
Women are more likely than men to reject unattractive-looking babies, according to a study by researchers at Harvard-affiliated McLean Hospital, possibly reflecting an evolutionary-derived need for diverting limited resources towards the nurturing of healthy offspring
The findings also challenge the idea of unconditional maternal love.
"Our study shows how beauty can affect parental attitudes," said Dr. Igor Elman, senior author and Director of the Clinical Psychopathology Laboratory at McLean Hospital. "It shows women are more invested in raising healthy babies and that they are more prone to reject unattractive kids."
The paper, which will be in June 24 issue of the journal PLoS ONE, sought to determine whether aesthetic appearance affects how hard adults are willing to work in order to watch pictures of babies.
Subjects, including 13 healthy men and 14 healthy women, were shown photos of 80 infants, including 50 normal ones and 30 who had abnormal facial features, including such abnormalities such as cleft palates, skin disorders, Down's syndrome and others.
Each photo was set to remain on screen for four seconds, but subjects could extend or shorten the viewing time of each photo by pressing certain computer keys. A second part of the experiment asked the subjects to rate the attractiveness of each infant on a numerical scale.
The study found that men and women expended a similar amount of effort quantified by the number of key presses made to keep photos up on the screen to extend the viewing time of the normal babies. At the same time, the attractiveness ratings given by men for these normal babies were significantly lower than those given by the women. However, when it came to the photos of abnormal babies, women made a greater effort to avoid looking at them, compared to men. Still, the women rated abnormal faces as unattractive as did men.
The differences between men and women in motivational effort to extend or shorten the viewing time of abnormal-looking babies "may reflect an evolutionary-derived need for diversion of limited resources to the nurturance of healthy offspring," the paper concludes.
The findings question the concept of unconditional parental love, at least among women. "What our results suggest is that this is determined by facial attractiveness," said Dr. Rinah Yamamoto, first author. "Women may be more sensitized to aesthetic defects and may be more prone to reject unattractive kids. Men do not appear to be as motivated. They didn't expend the same effort."
The study noted that work with abandoned and neglected children firmly link their abnormal appearance to maltreatment by caregivers. One study, done in Israel, found that 70 percent of children abandoned by their parents had a conspicuous flaw in their appearance even though those flaws were not life-threatening nor did they affect the children's intellectual development.
"This may be to some extent because adults are unconsciously motivated to care for infants with healthy facial features, indicating fitness for survival and to exclude the least fit," the paper said.
"The abandonment and neglect data along with our findings may thus challenge the commonly held view of unconditional maternal love and acceptance of the offspring," it said. "If mother's love is not unconditional, what is the condition? The results provide indirect support for . . .the idea that babies' aesthetic appearance has a motivating influence on the adults' caretaking behavior."
The paper suggests that the findings may have clinical implications in terms of predicting potential for abuse and neglect of children.
Elman, who is also an Associate Professor of Psychiatry at Harvard Medical School, said since the study involved small numbers of subjects, it must be replicated in larger follow-up studies. Future studies will also involve brain scans of subjects in order to try and pinpoint how men's and women's brains may be functioning differently while they view the images and make their choices for extending or shortening the time they are looking at the images.
The study, which also involved researchers from the Massachusetts Institute of Technology and the University of Pennsylvania, was funded by grants from the National Institute of Drug Abuse.
McLean Hospital is the largest psychiatric facility of Harvard Medical School, an affiliate of Massachusetts General Hospital and a member of Partners HealthCare. For more information about McLean Hospital, visit www.mclean.harvard.edu.
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Fallopian Tubes Offer New Stem Cell Source
Human tissues normally discarded after surgical procedures could be a rich additional source of stem cells for regenerative medicine
New research from BioMed Central's open access Journal of Translational Medicine shows for the first time that human fallopian tubes are abundant in mesenchymal stem cells which have the potential of becoming a variety of cell types.
It has previously been shown that mesenchymal stem cells obtained from umbilical cords, dental pulp and adipose tissue, which are all biological discards, are able to differentiate into muscle, fat, bone and cartilage cell lineages; therefore, the search for sources to obtain multipotent stem cells from discarded tissues and without ethical problems is of great interest.
Tatiana Jazedje, and the research team from Human Genome Research Centre at the University of São Paulo, directed by Mayana Zatz, with the collaboration of medical doctors from the reproductive area, set out to isolate and assess the differentiation potential of mesenchymal stem cells from discarded human fallopian tubes. In the study, human fallopian tubes were obtained from hysterectomy and other gynecological procedures from fertile women in their reproductive years (range 35-53 years) who had not undergone hormonal treatment for at least three months prior to surgery.
The Brazilian team found that human fallopian tube mesenchymal stem cells could be easily isolated and expanded in vitro, and are able to differentiate into muscle, fat, cartilage and bone cell lines. The cells' chromosome complement showed no abnormalities, suggesting chromosomal stability. Jazedje comments, "In addition to providing an additional potential source for regenerative medicine, these findings might contribute to reproductive science as a whole."
Jazedje concludes, "Moreover, the use of human tissue fragments that are usually discarded in surgical procedures does not pose ethical problems."
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Stress in the Womb Can Last a Lifetime
Researchers from Imperial College London hope to raise families' awareness of the importance of reducing levels of stress and anxiety in expectant mothers. They say that reducing stress during pregnancy could help prevent thousands of children from developing emotional and behavioural problems
Visitors to the Exhibition will have the chance to play a game that shows how a mother's stress can increase the heart rate of her unborn baby. They will also be able to touch a real placenta, encased safely in plastic. The placenta is crucial for fetal development and it usually protects the unborn baby from the stress hormone cortisol. However, when the mother is stressed, the placenta becomes less protective and the mother's cortisol may have an effect on the fetus.
The Imperial researchers' work has shown that maternal stress and anxiety can alter the development of the baby's brain. This in turn can result in a greater risk of emotional problems such as anxiety or depression, behavioural problems such as Attention Deficit Hyperactivity Disorder, and being considerably slower at learning. Some studies have even suggested that it may increase the likelihood of later violent or criminal behaviour. Their findings have suggested that the effects of stress during pregnancy can last many years, including into adolescence.
Professor Vivette Glover, the lead researcher behind the exhibit from the Institute of Reproductive and Developmental Biology at Imperial College London, said: "We all know that if a mother smokes or drinks a lot of alcohol while pregnant it can affect her fetus. Our work has shown that other more subtle factors, such as her emotional state, can also have long-term effects on her child. We hope our exhibit will demonstrate in a fun way why we all need to look after expectant mothers' emotional wellbeing.
"Our research shows that stress due to the mother's relationship with her partner can be particularly damaging. We want fathers visiting our exhibit to see how they can help with the development of their child even before the birth, by helping their partner to stay happy," added Professor Glover.
The researchers say that the stress hormone cortisol may be one way in which the fetus is affected by the mother's anxiety during pregnancy. Usually the placenta protects the unborn baby from the mother's cortisol, by producing an enzyme that breaks the hormone down. When the mother is very stressed, this enzyme works less well and lets her cortisol through the placenta. By studying the amount of cortisol in the amniotic fluid, the Imperial researchers' latest study suggests that the higher the level of cortisol in the womb, the lower the toddler's cognitive development or "baby IQ" at 18 months.
Kieran O'Donnell from the Institute of Reproductive and Developmental Biology at Imperial College London said: "We are very excited to have this opportunity to talk with the public about our work. We think that by promoting awareness of this subject we may be able to benefit many families in the future."
Who Goes Abroad for Fertility Treatment and Why?
A substantial number of European patients travel to other countries for fertility treatment, both because they think that they will receive better quality care abroad and in order to undergo procedures that are banned in their home country says a study of the subject launched at the 25th annual conference of the European Society of Human Reproduction and Embryology (Monday June 29)
Study co-ordinator Dr. Françoise Shenfield, from University College Hospital, London, UK, said that this was the first hard evidence of considerable fertility patient migration within Europe. "Until now we have only had anecdotal evidence of this phenomenon", she said. "We think that our results will be of considerable value to patients, doctors, and policymakers."
During a one-month period, the ESHRE Task Force analysed data from participating clinics in six European countries: Belgium, the Czech Republic, Denmark, Slovenia, Spain and Switzerland. Clinics were asked to provide questionnaires to patients coming from abroad for treatment. The questionnaires asked about their age, country of residence, reasons for travelling to another country for treatment, which treatment they had received, whether they had received information in their own language, how they had chosen the centre they were attending, and whether they had received reimbursement from their home country's health system. 1230 forms were completed and returned.
"This may not seem to be a very high number", said Dr. Shenfield, "but it reflects only one month of events in a limited number of centres in six countries. The total number of treatment cycles per year can be estimated by extrapolating our monthly data to a year and by assuming that the centres represent no more than half of the centres in each of the countries studied. This leads to an estimate of at least 20 000 to 25 000 cross-border treatment cycles per year in these countries. It is, however, difficult to derive a number of patients from these numbers as patients receive more than one cycle to obtain a pregnancy, the mean number depending on the type of treatment."
Almost two-thirds of the patients surveyed came from four countries, with the largest number coming from Italy (31.8%), followed by Germany (14.4%), the Netherlands (12.1%) and France (8.7%). In total, people from 49 countries crossed borders for fertility treatment.
The main reason for going abroad for fertility was to avoid legal restrictions at home. 80.6% of the German patients surveyed have this as their primary reason, 71.6% of Norwegians, 70.6% of Italians, and 64.5% of French. Difficulties of access to treatment were cited more by patients from the UK (34.0%) than those from other countries.
Age also played an important part in the decision to travel for treatment. The average age across all countries was over 37.5, but German and UK patients tended to have a much higher age profile with 51.1% of Germans being aged over 40 and 63.5% of British. Civil status also varied between countries; overall 69.9% of all women were married and only 6.1% single. But 82% of Italian women were married, while 50% of French women were cohabiting (often in same sex couples), and 43.4% of Swedish women were single.
The majority of respondents were seeking assisted reproduction treatment (ART) only (73%) as opposed to 22.2% intrauterine insemination (IUI), and 4.9% both ART and IUI. These figures also varied between one country and other; there was a majority of IUI treatments for French (53.3%) and Swedish (62.3%) patients, with a majority of ART for most other countries.
Fertility treatment abroad is poorly reimbursed, says Dr. Shenfield. "Only 13.4% of the patients we surveyed received partial reimbursement, and as few as 3.8% were reimbursed totally for their treatment."
The most generous country was The Netherlands, with a partial or total reimbursement of 44.4% and 22.1% of patients. In France, patients could only be reimbursed for overseas treatment where there was a delay at home, and treatment that was illegal at home, for example for single women or homosexual couples, was not reimbursed at all.
"This was a pilot study carried out in a small number of countries, and hence has limitations", said Dr. Shenfield. "However, it confirms information already gathered by patient support groups and reported in the media. For example, Spain and the Czech Republic are popular destinations for oocyte donation; Swedes travel to Denmark for insemination, and French to Belgium.
"It has also enabled us to have concrete proof of the large numbers of Italians who cross borders to obtain treatments which were made illegal under the 2004 legislation, or because by doing so they will receive what they perceive to be better quality treatment. This may mean, for instance, the possibility of embryo freezing", she said.
In another study, Professor Guido Pennings from the University of Ghent, Ghent, Belgium, looked in more detail at the situation in his own country. 16 out of the 18 Belgian reproductive medicine centres which were licensed to handle oocytes and create embryos were surveyed on the nationality of foreign patients coming for treatment between 2000 and 2007, as well as on the type of treatment for which they came.
The researchers found that, since 2006, the flow of foreign patients into Belgium had stabilised at around 2100 patients per year, and that the majority of these were lesbian couples from France seeking sperm donation.
There appeared to be a clear correlation between legal prohibitions in patients' home countries and the numbers who travelled abroad, he said. "The changes in numbers of patients coming from a specific country for a specific treatment and changes in the law in that country are not coincidental.
"In France couples have to be heterosexual, in a stable relationship and of reproductive age in order to have access to assisted reproduction. In addition to the legal reasons, given the geographical closeness of the two countries and the fact that language difficulties are limited, it was not surprising to find French patients made up the largest percentage of those travelling to Belgium (38%). These were followed by patients from the Netherlands (29%), Italy (12%) and Germany (10%)", he said.
Professor Pennings believes that the numbers may be an underestimate. Not only did 2 out of the 18 qualifying centres not reply, but centres which only provided treatments that were less technically demanding, such as hormonal stimulation or artificial insemination, were not included. Additionally, no data were included from countries which provided fewer than five patients per year per centre.
"Although collection of data on the numbers of patients moving from one country to another is a first and important step, future research should include the experiences of patients, the difficulties they experience, the impact of such movements on the national health care systems, and the effects of, for instance, portability of insurance on the numbers", he said. "We will only be able to evaluate the phenomenon properly when we can see the full picture."
TUESDAY June 30, 2009---------------------------News Archive / Return to News Alerts
First Baby is Born After Ovarian Transplant
A new technique for transplanting the ovaries of women who have lost their fertility as a result of cancer treatment was outlined to the 25th annual conference of the European Society of Human Reproduction and Embryology today (Monday 29 June)
Dr. Pascal Piver, manager of the IVF Centre at Limoges University Hospital, Limoges, France, described a new, two-step method of ovarian transplant that has produced excellent results in women whose ovaries have been frozen because of cancer treatment. He said that his team's technique worked to restore ovarian function quickly and already one patient from his clinic had had a baby and another had become pregnant.
"On June 22, a baby girl was born to a mother who had been menopausal for two years as a result of treatment for sickle cell anaemia. After transplanting her own ovarian tissue she started ovulating in four months and became pregnant naturally six months after transplantation. Both mother and baby are doing well", he said.
Dr. Piver and colleagues set out to tackle one of the biggest problems of ovarian transplantation: the low response to stimulation caused by insufficient vascularisation of the transplanted tissue.
"In order for a woman to become pregnant, the ovaries need to be responsive to the action of hormones that cause them to release eggs each month," he explained. "If the blood supply to the ovaries is insufficient, this will not happen, even though the transplant may look as though it has been successful."
To overcome this problem they carried out a two-stage procedure, first grafting small pieces of the frozen ovarian tissue in the ovarian and peritoneal areas three days before the real transplant. The first graft encourages the growth of blood vessels and paves the way for the ovary to become fully functioning in a shorter time scale than would be possible if all the tissue were to be transplanted at the same time.
The researchers have so far utilised this technique with two patients who had been treated for cancer and had their ovaries frozen. In addition to the first patient, treated for sickle cell anaemia, the second patient had been treated for periarteritis nodosa, an inflammation of medium-sized arteries, which become swollen and damaged from attack by rogue immune cells.
"She suffered menopause for eight and a half years before transplantation," said Dr. Piver. "But after transplanting half of the frozen ovary, she recovered spontaneous ovulation in four months. Her right fallopian tube had been destroyed by the ovarian retrieval, and the function of the ovary and hence the chances of pregnancy are limited in time. Hence we decided to collect the highest number of eggs we could, and carry out an IVF procedure on this patient.
"Six months after the operation, we transferred two blastocysts. A total of 22 oocytes were retrieved and produced 16 embryos, which in turn produced seven blastocysts. Unfortunately the first time round this patient developed an ectopic pregnancy, but she is now pregnant again."
The technique was developed by Dr. Piver and his team, he told the conference. "This is the first time that a pregnancy has been obtained after a ten year gap between ovarian cryopreservation and grafting. We believe that it represents a considerable advance on the methods of ovarian transplantation used until now, not least because we are able to obtain large numbers of oocytes. We hope that it will enable more young patients who have been cured of cancer to regain their reproductive health and become pregnant with their own children," he said.