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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.

Week Ending FRIDAY July 3, 2009---------------------------News Archive

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.


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