Fertility treatment in the USA has always been different from most of the rest of the world. Although the first IVF pregnancy was conceived in England; the first IVF pregnancy involving ovarian stimulation  to produce more eggs occurred in Norfolk, VA in 1981. Thus began the modern trend of producing multiple embryos in order to boost the chance for a pregnancy. We’ve achieved that goal. As I wrote about several months back fertility treatments have become both safer and more successful. Yet pregnancy following IVF still has higher risks than naturally conceived pregnancies. New data now supports that lowering the number of embryos transferred per cycle may be the key to both higher pregnancy rates and lower risks. Here’s what we now know.

Multiple pregnancies—twins in particular—remain fairly common after IVF. In 2013, (the most recent year that we have outcome data available for ) most embryo transfers involved two embryos or dual embryo transfer (DET). Not surprisingly, the incidence of twins or higher order multiples nearly reached 30% of those that became pregnant. By comparison the natural incidence of twins is about 2%. One of the major factors that appear to drive this continued trend for twins over singletons is that most patients don’t have enough information available to them to make a fully informed decision of one vs. two embryos.  In fact as one recent editorial stated “it is not the fear of multiples that drives decisions about the number of embryos to transfer…but rather the fear of not conceiving at all .”

Many of the most successful programs have been urging their patients to consider single embryo transfer based upon their clinic-specific success rates. Some have even demonstrated that imposing a mandatory policy of single embryo transfer (SET) is well supported by patients in these settings . But now we have new data suggesting that patients at the typical center should also be considering SET.

A just published study  using the national database for IVF centers’ information gathered from 2006 to 2012 has provided new insights into live birth rates (LBR) from elective SET vs. DET. They demonstrated that LBR is as good as or better with two SET cycles than with one DET cycle. In fact, in some patients the LBR was up to 20% higher with an incidence of twins of around 1 to 3% (due to a single embryo splitting and forming identical twins). Other studies have also demonstrated that when two or more embryos are transferred, the excess embryos have a negative effect on the one remaining. This impact may manifest as a low birth weight, a higher risk of preterm labor or an elevated risk of miscarriage. It can even contribute as adverse neurologic effects on the embryo that survives to term; resulting in a child with cognitive or developmental impairment. The studies’ authors concluded that “success for modern IVF should be defined as a singleton pregnancy that results in a healthy singleton infant who is born at term.”

The greatest challenge toward achieving that goal remains the cost and availability of fertility services. Currently, only about a quarter of the states require insurance companies provide any coverage for fertility treatments. However, databases  demonstrate that in states where IVF is covered by insurance; fewer embryos are transferred per cycle and lower multiple gestations occur. This actually lowers the cost to insurance companies since there is universal coverage mandated for pregnancies and singleton pregnancies cost less. Therefore, the burden for the cost of multiple pregnancies tends to fall back upon the insurance companies that often opposed providing the fertility treatment as a covered benefit. Hopefully, as this information becomes more widely available we will see more patients choosing SET as the best outcome; instead of simply making a choice based upon personal financial pressures  which are becoming more a by-product of where they live .

[r1]Link to first IVF  http://www.fertstert.org/article/S0015-0282(07)02985-8/fulltext

[r2]Link to https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0




[r6] http://www.asrm.org/insurance.aspx



An important aspect of “lifestyle medicine” is helping our patients take control of the factors of their daily routine that may tip them towards a higher pregnancy rate. Toward that end, one of important determining factors of egg quality has to do with whether not the egg has been damaged prior to fertilization. So let’s consider what causes egg damage and what we can do to prevent it.

Each egg that you have has been waiting since you were an infant for the opportunity to grow and develop. During the years that the eggs remain dormant, they are very susceptible to adverse conditions. For instance, small charged particles called free radicals can damage the proteins, membranes and the DNA within the eggs. These free radicals are formed normally as a result of physiologic processes like digestion and ovulation. However, there are lifestyle situations like tobacco use or over-eating that can promote free radical formation.  Additionally, conditions like endometriosis are believed to impair fertility at least partially due to the increase in the production of free radicals. A recent review  detailed how eggs that have been damaged by free radicals have a lower capacity to produce a successful pregnancy.

Your body makes chemicals called antioxidants whose purpose is to be there to capture and neutralize free radicals when they are formed. Since free radicals only exist for an instant, it is important that these antioxidants are always around. Unfortunately, most of us don’t make enough of these little protectors. That’s why foods that contain antioxidants are believed to be so healthful. Not only can they provide us with these chemicals that we need but they can do so when they would be most useful—during digestion. There is evidence that berries of the Acai—a palm tree grown primarily in northern Brazil—may be able to tip the delicate balance in your favor and therefore protect your ovaries from damage.

Studies suggest that Acai berries may contain more antioxidants than blueberries, raspberries or any other potent natural antioxidants. Additionally, the juice contains healthy omega-3 fatty acids suggesting that this may be another means by which it may provide health benefits. To date, one on-going study suggested that women that had failed IVF due to poor egg quality; had an improved outcome after taking an Acai supplement prior to their next attempt. The two to three months prior to an egg’s release represent the time when it is most susceptible to harm. Therefore if you have a low ovarian reserve and/or a history of poor egg quality; you should consider taking an Acai Supplement. A convenient dosing schedule is 1000 mg taken twice each day. There are various supplements available or you can try consuming Acai products two to three times each day as part of a healthy diet. I find the Sambazon products (http://www.sambazon.com/products ) to be diverse and very appealing because they are organic and sustainably harvested.

[r1]Link to http://www.fertstert.org/article/S0015-0282(14)02371-1/fulltext

Earlier this year, a comprehensive review  of advanced fertility treatments demonstrated that the risk of serious complications as a result of advanced reproductive techniques (ART) was relatively low.  Still, there is always an effort to try to reduce any adverse outcomes even further. One of the rare but more serious complications associated with successful IVF treatments is the risk of developing an ectopic pregnancy; a situation that results when the embryo migrates from where it had been placed within the patient’s uterus to another site, most commonly the fallopian tube. The frequency of ectopic pregnancy in patients that conceive through IVF is between 2% and 5%. Ironically, this is higher than the 2% to 3% incidence seen with naturally conceived pregnancies. New insights suggest what may be contributing to the elevated risk associated with ART and what steps that we can take to prevent it from happening

In order to better understand why IVF has a higher risk of ectopic pregnancy, let’s consider what we now know about implantation. The process whereby an embryo successfully establishes contact with the uterine lining is actually a coordinated event that depends upon the timing of several important factors. One major factor is development. The embryo must be develop to the blastocyst stage—where it appears as a fluid filled ball with a clump of cells concentrated at one location. It then must break out of its protective coating in a process called hatching. Another important factor is the hormonal milieu. The uterine lining must be hormonally prepared for the initial contact with the hatched blastocyst; there is typically a limited time period of about 36 hours during which the conditions are ideal for attachment (the first step towards implantation) to occur. A recent analysis   compared several variables associated with different embryo transfer strategies.

For their study, they reviewed over 3,300 embryo transfers. They compared the developmental stage of the embryos as well as whether the embryo transfers were done during the same cycle as the egg retrieval (Fresh) or whether they had been cryopreserved and transferred later (Frozen). The difference between a Fresh transfer and a Frozen transfer is two-fold. Not all embryos develop at precisely the same rate. So with Fresh transfers, some embryos are more developed than others. In fact, they separated their analysis based upon whether it was 3, 5 or 6 days after the egg retrieval. In a natural cycle, an embryo typically enters the uterus 5 or 6 days after it is released from the ovaries. With Frozen embryos, they are actually preserved when they have reached a specific stage of development chosen by the IVF center. As a result most frozen embryos are at the morula stage (day 3) of development or the blastocyst stage where they are ready to hatch. Some embryos reach this preimplantation stage on the 5th day of development and others take until the 6th. If they do not make it by day 6 it is considered an unhealthy embryo. The other distinction is that Fresh transfers tend to be associated with higher than normal hormone levels as a result of the ovaries producing multiple mature eggs instead of just one or two. By contrast, the goal of a Frozen transfer is to create a hormonally balanced environment within the uterus that more closely represents what happens in a natural physiologic conception.

In order to try to differentiate both of these factors, this study compared Day 3-Fresh and Day 5-Fresh to Day 3-Frozen, Day 5-Frozen and Day 6-Frozen, The finding in this analysis was that risk of ectopic pregnancy was lowest for Day 5-Frozen embryo transfers. In fact, the calculated risk for those patients was far less than 1% suggesting that the ideal transfer strategy is to split the ART cycle to optimize the healthy pregnancy rate while minimizing the risk of ectopic pregnancy. A previous study  also found that embryos that were judged to be of poorer quality—based upon their appearance under the microscope—also pose an elevated risk of ectopic pregnancy making the embryo grade a potential third factor to consider. There have also been two other studies  that have also found that frozen embryo transfers (FET) have lower ectopic pregnancy rates than fresh embryo transfers.

Since many centers now have advanced freezing techniques to safely preserve embryos it makes sense for more patients to separate the process of ART into two parts; the first month to create the embryos and the second month to transfer them. Although this split cycle strategy lengthens the time from start to pregnancy, there is compelling evidence that for many patients it will improve their chance of having the highest pregnancy rate with the fewest possible complications and the lowest possible risk.

Link to http://jama.jamanetwork.com/article.aspx?articleid=2088842#Discussion

Link to http://www.fertstert.org/article/S0015-0282(14)02379-6/abstract

Link to http://journals.lww.com/greenjournal/Fulltext/2006/03000/Ectopic_Pregnancy_Risk_With_Assisted_Reproductive.11.aspx

Link to http://www.fertstert.org/article/S0015-0282(12)01889-4/abstract and http://www.fertstert.org/article/S0015-0282(11)00267-6/abstract

There are few topics as emotionally driven as food choices. For most of us, our dietary choices are guided mostly by our taste preferences, familiarity (think comfort foods) and convenience. In fact, much of what passes as nutritional science in the popular media is incorrect or overstated. As a result there are often widely held misconceptions and untruths about what is a “healthy food.” A classic example is soy based food products. About 4 years ago, I wrote a column  to debunk the popular (and inaccurate) belief that some of the hormone-like chemicals—called phytoestrogens—in these healthy beans could interfere with fertility. The latest research goes one step further suggesting that these foods actually boost the pregnancy rates in women undergoing advanced reproductive techniques (ART).

It’s been well established that adding soy based foods can lead to small changes in the hormone balance  of people that eat them. But for too long, people that wanted to promote unhealthy dietary choices successfully created concerns among fertility patients. Then two clinical studies came along that demonstrated women taking soy supplements during either ovulation induction  treatment or IVF cycles  had higher pregnancy rates. The problem with these studies however was that the supplements that were used boosted the level of phytoestrogens to levels that are over 10 times higher than people eating a traditional Asian diet. New research has provided more practical insights into the health benefits achieved by simply switching to easily obtained soy based foods.

This latest study  was very practical because they looked at the dietary choices in a group of 315 women that ultimately completed 520 ART cycles in 2013. Better still, they followed them prospectively to minimize the risk of obtaining biased results. They then looked at various results from their IVF cycles. They found that the eggs from women that were eating foods that contained soy had a higher fertilization rate. More specifically, they found that the clinical pregnancy rate was 11% and live birth rate was 13% when they compared women that were eating soy to age-matched women that were not. In fact, women that were consuming the most amount of soy had a nearly 80% higher chance of success. Bottom line was that soy containing foods seem to be very beneficial to women undergoing fertility treatment without making huge dietary changes.

An important step towards validating any finding is to then try to establish a theory of how the intervention may have resulted in the finding. The previous studies on soy supplements and IVF outcome suggested that the isoflavones—these are the estrogen-like chemicals in soybeans—resulted in a healthier uterine lining and thereby improved the ability of embryos to implant. They based this assumption on the fact that the ultrasound imaging of the lining appeared different. This recent study did not find any such changes. Instead, they hypothesized that the benefit are demonstrated by the fertilization rate of the eggs from the women eating soy vs. those that weren’t The fact that it was higher in the soy group suggests that eating soy may improve egg quality. Regardless of the mechanism, all of the research agrees that dietary soy is associated with higher pregnancy rate and greater chance at a live birth.

Maybe the most important aspect of clinical research is guiding and motivating patients on how and when to implement changes. Given the large number of products that now contain soy as well as the various “meat substitutes” (ie, veggie patties, soy milk, soy yogurt, soy butter) it makes sense to encourage women going through IVF to try to make some conscious changes to select these products or to eat soybeans. Another potential advantage of reducing meat, chicken and fish consumption is that plant based proteins contain far less of the unhealthy aspects of our modern diet like; hormone disrupting chemicals, pesticides and antibiotics. The end result is not only a higher chance of conceiving but also having a healthier pregnancy and giving your child the very best start possible.

[r1]Link to https://thegreeneguide.wordpress.com/?s=soy

[r2]Link to http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=906924&fulltextType=RA&fileId=S0007114500001872

[r3]Link to http://www.rbmojournal.com/article/S1472-6483(10)60465-8/abstract

[r4]Link to http://www.fertstert.org/article/S0015-0282(04)02356-8/abstract

[r5]Link to http://www.fertstert.org/article/S0015-0282(14)02529-1/abstract

It’s time to review the latest findings in Reproductive Medicine. This month there are new insights into why more boys are born in the US than girls as well as a new strategy for women undergoing fertility treatment to reduce the risk of having a child with autism. As always, I have included links to the studies for you check them out for yourself:

  • More Boys are Born than Girls; here’s why—about 51% of all of the babies born are male. This observation has been consistent for several hundred years.  A new study  has provided the most comprehensive data to explain why we don’t see an equal number of boys and girls in the delivery room. It turns out that the explanation is based upon what happens during pregnancy; not prior to fertilization as previously assumed. The researchers found that although a higher number of male are lost during the first trimester; female fetuses are more likely to miscarry later in pregnancy. The end result is that a slightly higher number of males survive until birth than females.
  • Supplementing Estrogen Does Not Improve Pregnancy Outcome—there has long been debate amongst fertility centers as to whether or not additional estrogen is beneficial to pregnancy rates. New data  shows that levels higher than the normal physiologic ones are not helpful. Other studies have suggested the extra estrogen may even boost the risk of blood pressure problems later in pregnancy. Combined these findings support the ongoing trend to create a hormonally balanced environment rather than simply adding more.
  • Genetic Testing improves Live Birth Rate in Women over 40—using pre-implantation genetic screening (PGS) to identify the healthiest embryos for transfer is an effective tool according to new information . They demonstrated a live birth rate that was three times higher using this technique then using standard IVF alone for women over 40. This means that identifying healthy embryos prior to transfer is a highly effective strategy to achieve a successful birth.
  • Single Embryo Transfer associated with Lower Risk of Autism—previous data has suggested that there may be a higher risk of Autism Spectrum Disorder (ASD) associated with advanced reproductive techniques (ART). Other studies have shown that this is more likely age related or that it might be due to the population of patients seeking fertility treatment. This new study  found that when only singleton pregnancies result following IVF; the observed risk disappears. This is another good reason to consider elective single embryo transfer (ESET).
  • Vitamin D Deficiency associated with Lower Pregnancy Rate in IVF—a comprehensive review  of 34 published trials has found that women with lower than normal vitamin D levels have less success when undergoing IVF treatment. There is not yet proof that supplementing with vitamin D reverses this trend. However, given the other health benefits and the low cost of this “sunshine hormone” it sure makes sense to consider vitamin D supplementation for women whose level is lower than normal.
  • Smoking during Pregnancy can have Lasting Effects Upon your Child—it has long been recognized that women that were smokers had lower fertility rates, higher miscarriage rates and earlier onset of menopause than nonsmokers. New information  now suggests that at least some of these negative reproductive effects can be passed on their children as well. Specifically, they found girls born to women that smoked had an earlier onset of puberty than those born to nonsmokers. Noted by the investigators was that early onset of puberty is also linked to a higher risk of certain types of cancer including breast cancer.

[r1]Link to http://www.pnas.org/content/early/2015/03/27/1416546112

[r2]Link to http://link.springer.com/article/10.1007/s10815-014-0402-1?wt_mc=alerts.TOCjournals

[r3]Link to http://link.springer.com/article/10.1007/s10815-014-0417-7?wt_mc=alerts.TOCjournals

[r4]Link to http://consumer.healthday.com/cognitive-health-information-26/autism-news-51/ivf-kids-have-higher-odds-of-autism-study-finds-697622.html

[r5]Link to http://link.springer.com/article/10.1007/s10815-014-0407-9?wt_mc=alerts.TOCjournals

[r6]Link to http://www.reuters.com/article/2015/03/19/us-womens-health-smoking-pregnancy-idUSKBN0MF29W20150319

Whenever someone asks me “what else can we do to boost our chances?” it represents one of the most exciting and challenging moments of our interaction. It’s exciting because it shows a willingness to make changes in their current diet and/or lifestyle. It’s challenging because there are no simple answers and most of the data is rather loosely supportive of the recommendations. Fortunately better studies are coming out all the time.

The January 2015 Issue of the journal Fertility & Sterility put this topic front and center. The journal opened with a commentary  that pointed out the fact that each egg–even those from fertile egg donors–has no more than a 40% chance of becoming a successful pregnancy. Therefore, we need to look beyond what we do with the sperm and eggs and also direct our attention toward what else can impact their quality. A “global medicine approach” proposes  that we look at the nutritional status, environment and lifestyle for additional answers and better outcomes. The journal went on to present three papers to bring us closer to that goal.

The first study  looked at infant birthweight and the risk–several decades later–of male factor infertility. Specifically, they were looking at the theory that some male infertility begins in the womb prior to birth. Other studies have found results suggesting this happens for women; that low birthweight may increase the risk of longer time to conception and a higher risk of diminished ovarian reserve. That prompted this research to determine if the same might be true in men. It was. They found that men that were born with a birthweight less than 2,500 gm (normal is 2,500 to 3,500 gm at term) were at a higher risk of having a low sperm count and their sperm was more likely to have damaged DNA. They also tended to be overweight or obese which is also associated with male factor infertility. So nutrition during pregnancy can have lasting implications for the children that are born.

A second article  summarized the concept of “ecofertlility;” environmental toxins that may alter fertility. The examples that they focused on were those that were most common and most easily controlled, tobacco and marijuana since there is typically a choice to use or not use these substances. The authors reviewed a variety of studies that consistently demonstrate that women that are cigarette smokers tend to take about a year longer to conceive, have a higher rate of infertility and are more likely to have a diminished ovarian reserve than nonsmokers. Men were impacted similarly. Male smokers had a higher risk of abnormal semen analysis as well as a higher rate of erectile dysfunction. The authors also presented evidence that various substances produced by tobacco smoke appear in the fluid that surrounds the eggs and then have a very toxic impact. These substances may actually result in a higher rate of failed fertilization. This may explain why smokers have about a 40% lower pregnancy rate when undergoing IVF than nonsmokers. Even with sperm injection (ICSI) directly into the egg; the rate of “fertilization failure” is about three times higher in smokers. The impact of marijuana was more difficult to quantify. In men it has been linked to a higher risk of sperm abnormalities, as well as various hormonal dysfunctions including gynecomastia (increase in breast size), low libido and problems with erectile dysfunction. There is less data on women as exposure is difficult to accurately assess and monitor and correlate with egg function since exposure now may impact an egg many months (or even years) later.

Finally, in a third paper  they reviewed the potential impact of one of the most widely studied chemicals that we’re all exposed to called bisphenol-A (BPA). This chemical was first produced in 1891. It was identified to have estrogen-like activity as far back as 1936. Unfortunately, that did not stop its production and distribution. Today it is recognized as one of the most ubiquitous hormone disrupting chemicals. About 20% of the BPA produced—nearly 3.4 million tons per year—is used to line various food containers. From there, it has clearly been shown to leech into the food that we eat and then contribute to various health problems like diabetes, obesity, heart disease, lung problems, kidney disorders as well as various reproductive problems. The data on its toxicity has been alarming enough to prompt Canada from banning its use in baby bottles (2008). More recently the European Union went a step further and banned its use entirely in 2011. Here in the US, there is just now legislation  proposed to require clear labeling on food containers that contain BPA.  The study authors went on to provide a further note of caution by providing evidence that two chemicals that have been proposed to replace it—BPS and BPF—may have similar negative effects based upon animal data. Human studies are pending. The bottom line is that we need to pay more attention to the chemicals that we use to package our food in as they may actually taint our food supply as well as reduce our health and fertility.

As a reproductive health specialist, I don’t want to alarm my patients but I also don’t want to marginalize the potential impact of our choices upon our ability to initiate a healthy pregnancy. Although walking the line between concern and unnecessarily upsetting people may be a delicate one; I do feel compelled to empower those that are willing to listen. Success is not just about what happens in the clinic—it begins at home.

[r1]Link to http://www.fertstert.org/article/S0015-0282(14)02274-2/abstract

[r2]Link to http://www.fertstert.org/article/S0015-0282(14)02383-8/abstract

[r3]Link to http://www.fertstert.org/article/S0015-0282(14)02354-1/abstract


[r5]Link to http://www.endocrine.org/membership/email-newsletters/endocrine-insider/2015/march-19-2015/endocrine-society-endorses-bpa-in-food-packaging-right-to-know-act

This week’s picks from the Greene Guide include a first reported case of sextuplets from the drug Letrozole as well as a new twist on the “nature vs. nurture debate” as it relates to naturally elevated testosterone levels in elite female athletes:

  • Oral Medication (Letrozole) and a case of Sextuplets—Ovulation induction is associated with a higher risk of multiple pregnancy than IVF treatment. That said, most patients and their providers often take for granted the relative safety of oral medications like Letrozole used to stimulate the ovaries. All that may change now that there is a documented case of sextuplets  using Letrozole 7.5 mg—a higher than normal dosage. Take home lesson, this may have been preventable if the patient had been monitored using ultrasound and blood tests.
  • Most Men with Borderline Testosterone Levels, More Likely to Experience Depression—New data on the hormone-brain connection suggests that a low testosterone level may trigger depressive symptoms. A recent presentation  demonstrated that not only were these men more likely to experience emotional symptoms but also to have problems with obesity and an inactive lifestyle. Further evidence that men quality of life is also linked to a healthy hormone balance.
  • US Fertility Rate Hits an All Time Low—The most recent government figures  show that the number of births has dropped below 63 per 1000 reproductive aged women (15-44 y.o.a). Whether or not this reflects a growing number of women experiencing infertility or is simply a result of people delaying their family due to recent economic downturns remains an active debate.  Most likely, it is a combination of both as well as other emerging factors.
  • Early Onset of Menopausal Hot Flashes May be a Risk Factor for Heart Disease—It is indisputable that those uncomfortable hot flashes experienced by women going through menopause are the result of changes in blood flow patterns. However there has long been debate on whether these symptoms are simply a nuisance to endure or a warning warranting treatment. Two new studies  suggest the latter. Given that there is now strong agreement that treatment of hot flashes is reasonable and safe this data offers new discussion points for patients and their healthcare providers.
  • Fertility Center  Courts Controversy: Offering non-FDA approved Treatment to Rejuvenate Eggs—The procedure involves removing a piece of a woman’s ovary in order to extract mitochondria—the power source—from immature eggs. These mitochondria are then added to mature eggs along with sperm during a subsequent IVF cycle. The company  that developed this procedure has not yet reported any live as a result of the procedure. It does however add an additional $25,000 to the cost of IVF.
  • Early Miscarriage; providing more options improves patient care AND lowers cost—About one out of every three pregnancies end in an early loss. In fact 25% of women will experience a miscarriage at some time in their life. A new study found  that providing patients with more options—beyond D&C or taking a wait-and-see approach—improves patient satisfaction as well as results in a cost savings of about $241 per case. Since about 1 million US women per year experience an early pregnancy loss the emotional and financial impact of this can be huge.
  • Testosterone Levels and Athletic Eligibility in Women—Since 2011/2012, the International Association of Athletics Federations (IAAF) and the International Olympic Committee (IOC) have implemented regulations that elite female athletes must have a blood testosterone level that is below the lower limit for men in order to compete. In reality, there is a vigorous debate  on whether there is reliable biological evidence to support this restriction. The opposing opinion  is that success in sport should be due exclusively due to talent and dedication rather than to any naturally occurring, potentially advantageous biology. Currently, the restriction stands and some women may be required to undergo hormone reducing treatment in order to compete.

[r1]Link to http://www.fertstert.org/article/S0015-0282(14)02356-5/abstract

[r2]Link to http://www.endocrine.org/news-room/current-press-releases/most-men-with-borderline-testosterone-levels-may-have-depression

[r3]Link to http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_01.pdf

[r4]Link to http://consumer.healthday.com/cardiovascular-health-information-20/heart-attack-news-357/early-onset-hot-flashes-may-point-to-heart-disease-rosk-in-women-697085.html


[r6]Link to http://www.ovascience.com

[r7]Link to http://www.ajog.org/article/S0002-9378(14)00908-9/abstract

[r8]Link to http://press.endocrine.org/doi/abs/10.1210/jc.2014-3206

[r9]Link to http://press.endocrine.org/doi/abs/10.1210/jc.2014-3603


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