Most women are aware that their fertility declines more rapidly than other—often more visible—signs of aging. In fact, the ovaries have very unique properties. They begin a prolonged hibernation-like state from infancy until the start of puberty. During this ten to fourteen year period, the ovaries remain inactive; producing neither hormones nor mature eggs. However, there are still biological signs of aging taking place within the resting ovary but at a much slower pace than after the menstrual cycles begin. Then throughout the reproductive years a group of eggs is lost each month. In some women—depending on their diet and lifestyle—eggs may be lost at a faster pace. This happens for instance in women that use tobacco products. As I’ve written about previously, the blood test for the hormone AntiMullerian Hormone (AMH) is considered by most fertility specialists today to be the most reliable assessment of a woman’s ovarian reserve (the approximate number of immature eggs that she has available at any given time). Now there are also new ways to actually measure how we age physiologically as well.

One study recently demonstrated that people do age at variable rates. They quantified the aging process by measuring various physiologic and genetic markers over a 12 year period in 954 individuals beginning at age 26. They correlated their findings with each test subject’s appearance and their quality of life. They found that those that appeared to be aging faster also had measureable changes in their physiology, cognition and physical complaints consistent with their appearance. The researchers also analyzed their DNA. Their analysis supported that some individuals were aging faster than others and that diet and lifestyle seemed to be a major influence on the rate of aging. In fact, some people seemed to age 3 years for each 1 year that passed on the calendar while others didn’t seem to be aging at all during the 12 years of the project. So taking steps to improve your health and wellness may in fact slow your rate of aging. However, there are still some changes taking place that can’t be delayed indefinitely.

In most species, females are able to conceive throughout their natural lifespan. Humans are unique from most other mammals in that women typically live about half of their life after their fertility has ceased. It has also been reported that women that conceive later in life tend to live longer. Efforts to look at the genetic relationship have found that there are 17 genetic markers that explain about 30% of the occurrence of premature ovarian failure. That means that most ovarian aging is related to other factors including damage to the egg’s DNA (telomere length) that naturally occurs over time. There are also changes that occur in the egg’s power house, the mitochondria. Each egg has 20,000 to 800,000 of these important power units. Each mitochondrion has its own small strand of DNA. We inherit all of our mitochondria from our mother. As women age, the DNA of mitochondria within the eggs becomes damaged. This damage cannot be repaired. As a result, the mitochondria are intimately linked to egg quality. They not only impact the chance that an egg will fertilize and grow successfully but also the health of the child that results. There are also other ways that delaying pregnancy may influence the child’s health but in a more positive way. There is considerable evidence that children born to older mothers may have more positive cognitive and behavioral outcomes.

There is a growing trend for women to delay childbearing. Doing so is associated with higher socioeconomic status, increased educational achievement, higher income level and smaller family size. It may be due to any or all of these reasons or it may be due to greater readiness for pregnancy or more that children of older mothers tend to fair better when it comes to cognitive and behavioral measures. Others feel that it may due to a more mature mother-child interaction. Whatever the reason the benefits are present without any elevated risks in psychiatric problems.  So even though cause and effect cannot be established in the available studies, advanced maternal age seems to have a protective effect upon the psychological and cognitive development of children. Now there is also evidence that carrying a pregnancy may in turn have healthy implications on the aging of the mother as well.

A new series of investigations is finding that a healthy pregnancy may slow aging process. In animal studies, it has been a consistent finding that pregnancy has a rejuvenating effect upon mother through a process called parabiosis (connecting the circulation between the young and the old). In humans, studies have found measureable benefits including improved liver functioning, improved reparative abilities within the central nervous system and protective effects upon the heart following a healthy pregnancy. There is also data suggesting that unhealthy pregnancies can identify women at risk of age-related conditions like diabetes, stroke and heart disease—possibly identifying those at risk so that preventive measures can be initiated. So it seems that healthy women have a longer opportunity to conceive and that when women in their later years get pregnant that they remain healthier longer.

In summary, the links between fertility and healthy aging are far more complicated than previously believed. We can reassure women that taking steps during their younger years to live a healthy lifestyle should optimize their opportunities for pregnancy. We can not only track a woman’s fertility status through ovarian reserve testing but now we can also freeze/store eggs to extend their reproductive years. Then, by taking steps to optimize a women’s health during pregnancy, women may both have a healthier child as well as slow their own aging.

Let’s take a few moments to review some of the latest findings in reproductive medicine. This month there is another first in reproductive medicine as well as new evidence that hormone problems may be passed to spouses. Check out the following:

Ovarian Stimulation for IVF does not increase the risk of cancer: The largest review of the data available provides more reassuring news to women undergoing advanced reproductive treatment. Included in their review was the information obtained from nearly 180,000 women that had undergone IVF therapy. They found that there was no increased risk of ovarian cancer, endometrial cancer, cervical cancer or breast cancer. Although a few isolated studies raised concerns in the past; this new information should further reassure patients and egg donors of that ovarian stimulation will not create future health risks.

First successful birth after woman receives her own ovarian tissue frozen during her childhood: In a new report, it has been proven that ovarian tissue from a child can be removed, frozen and replaced later in her life to restore lost fertility. Previously there have been about 3 dozen cases of women freezing ovarian tissue prior to receiving life-saving chemotherapy. However this was the first report a 14 year old having her fertility preserved through removing an ovary prior to the onset puberty and before receiving chemotherapy. Now at age 27—and two years after a piece of her ovary was transplanted back into her body—she conceived and delivered a healthy child naturally. This proof-of-concept should make fertility preservation a more tangible option for children faced with the need for chemotherapy.

Diet and lifestyle impact embryo quality: A research group recently looked at the quality of 2659 embryos produced by 269 patients. They had data on the diet and some of the social habits of the women that were undergoing treatment as well. They found that eating fruit, vegetables and fish was associated with higher embryo quality. By contrast consumption of red meat, smoking and alcohol reduced the chances that an embryo would develop to the blastocyst stage—the last stage before it hatches. They also found that women that consumed red meat have a lower chance for implantation as well. This is only one study so patients shouldn’t feel compelled to make dramatic dietary changes. However, it should encourage women trying to conceive to pay greater attention to their diet and lifestyle.

Fathers at risk of diabetes after their partners experience Gestational Diabetes: As we continue to seek to prevent new cases of diabetes, an emerging risk factor may be having a partner with a history of gestational diabetes. A study from Canada followed nearly 72,000 male partners after the delivery of their child. They found that the risk of developing diabetes was 33% higher following a pregnancy complicated by gestational diabetes vs. normal controls. The authors theorized that this increased risk may be likely due to shared diet/lifestyle as well as ethnocultural risks. If confirmed however it could provide support that counseling the entire family to prevent later risk may be in order.

Sunshine boosts IVF success: Many studies have looked at seasonal variations on pregnancy rates and tried to explain their fluctuations. But a new study from Belgium has taken their analysis a step further. They looked at a group of almost 11,500 women undergoing IVF at the same center between 2007 and 2013. They then analyzed what the weather was like the month prior to their cycle. Although they did not find a clear seasonal pattern; they did find that women exposed to more sunlight the month prior to their IVF cycle had a higher pregnancy rate. This boost in success translated to about a one third higher chance of conceiving. The authors theorized that the boost might be related to higher melatonin and vitamin D production. The strongest correlation was actually with live birth rate.

Men with low-normal testosterone levels have high rate of depressive symptoms: There has been a recent trend to check testosterone levels in men; most likely due to media attention and advertising. This prompted a group of researchers to study whether or not there was a higher rate of depression and/or depressive symptoms in people requesting such testing. They screened 200 men with an average age of 48 (range 20 to 77) with a validated symptom questionnaire. They found 56% screened positive. In fact, the risk that a man experienced depressive symptoms seemed highest for the younger men with low-normal testosterone levels. Follow up studies are needed to determine if testosterone replacement—instead of traditional antidepressants—would relieve these symptoms.

Robert Greene, MD, is a reproductive endocrinologist with Conceptions Reproductive Associates in Denver.

I wanted to thank all of those that follow this blog for your continued support and guidance. Some of you are aware of the fact that I have been changing positions over the last several months. I appreciate very much the patience that you’ve extended to me during this time period. The terms of my leaving my former position required that I remain discrete. As a result, I was not allowed to notify you of my planned departure or assist you in your transition. I apologize to you for that. It was not my choice nor was it how I would have preferred to depart. I want to now welcome you to contact me so that I can provide you with the support and guidance that you so deserve on your pathway to parenthood. Let me please explain further so that everyone understands why I am so very excited to now be a member of the Conceptions Reproductive Associates team!

Our specialty is very success driven. My efforts have always been to bring the latest and greatest techniques to patients in each and every community that I’ve lived in. When I’ve been unable to do so, I’ve chosen to move to where I was able to confidently offer women the most comprehensive range to treatment options available. With my current relocation to Denver, CO I’m pleased to say that I’m done moving. Although not every patient needs the most high tech assistance, I’m finally at a location that is able to do it all. The result is a center with one of the highest pregnancy rates documented as well as one of the lowest miscarriage rate. That is what the technology has to offer. However, on the flipside we are also able to offer basic supportive care as well as everything else in between. Bottom line is that I couldn’t feel any better about the group that I am now working with.

For those of you that have been readers of this blog and have not been patients of mine, please forgive this post if it seems self promotional. I decided to write this post in response to the many emails that I have received wondering where I was and how they could reach me. To anyone interested, I would welcome the opportunity to meet with you in person, over the phone or on the internet for a consultation. Rest assured that if you choose to come to Denver we will offer you the same hospitality and success that the patients in this area have enjoyed for so long now. You might even like it so much that you too might choose to stay!

In gratitude to all,

~Robert

Robert Greene, MD, FACOG

Conceptions Reproductive Associates of Colorado

Finding at least one high quality egg is the most important factor in achieving a successful pregnancy. In previous blog posts, I have outlined various strategies to achieve that goal. But what about women whose ovaries do not respond well to standard ovarian stimulation protocols? For them treatment can sometimes seem frustrating or even futile. New data supports that “ovarian priming” may help women with diminished ovarian reserve (DOR) achieve that goal even if they have a history of poor response to IVF treatment.

The common theme of Advanced Reproductive Treatments (ART) is to produce a group of mature healthy eggs in order to create at least one or more healthy embryos. In 2011 a large consensus  meeting agreed upon the definition of a ‘poor response’ to ovarian stimulation and described it as three or fewer oocytes recovered with a conventional IVF protocol. Pregnancies do occur when even one egg is recovered. However, success rates are markedly lower in patients with DOR. The goal of creating this definition was to encourage research on how we can better serve women with this biological challenge.

The most common reason for DOR is a simple depletion in the number of eggs secondary to aging. However new information now suggests that the quality of the remaining eggs is also impacting their ability to respond to the hormonal signals and thus limiting the ability of the ovaries to produce multiple follicles. The goal of preparing or “priming” the potential population of eggs prior to IVF is to optimize the ability of the ovaries to respond prior to starting the hormonal stimulation. Several strategies for priming have been used for the last several years with much debate about which (if any) is best. The FOLLPRIM study  was designed to compare them in patients with an established history of DOR.

The FOLLPRIM study was a randomized prospective study intended to minimize the risk of bias based upon protocol selection. Patients that had failed an IVF attempt were randomly assigned to one of three priming protocols prior to their next IVF attempt. They were either given estradiol (to simulate the cycle of young fertile women), an oral contraceptive (to synchronize follicle development) or testosterone (which serves as a precursor to estradiol as well as to help promote the earlier stages of egg development). The patients then repeated their IVF cycle with a comparison of number of eggs recovered after priming compared to their initial response without priming. The results were very encouraging.

They found that all three strategies increased the number of mature eggs that were recovered through IVF compared to the unprimed cycle. In fact, they averaged two to three more eggs per patient. Although it was uncertain which priming protocol had the highest pregnancy rate, the data suggested that the testosterone priming might be the best. Further research will be needed to determine if this is true. In fact, another technique (not tested in this study) to boost testosterone levels is to give women the supplement DHEA for one to three months prior to IVF. Many centers have adopted this strategy as well.

What’s most important about this research is that women with DOR are being given choices rather than simply discouraged or re-directed to egg donors. Ovarian priming prior to IVF is one option that should be considered. Combined with other tools like anti-oxidants and CoQ10, more women are overcoming this biological challenge of DOR and having healthy babies.

[r1]Link to http://humrep.oxfordjournals.org/content/26/7/1616.full.pdf+html

[r2]Link to http://www.pubfacts.com/detail/25955224/Antral-follicle-priming-FOLLPRIM-prior-to-ICSI-in-previously-diagnosed-low-responders-A-randomized-c

Recently I was interviewed for a piece on the EndocrineWeb. Here is a link for anyone interested: http://www.endocrineweb.com/infertility-insulin-resistance-5-tips-your-odds-getting-pregnant?page=1

One of the most difficult subjects to discuss—especially for those treating or experiencing infertility—is miscarriage. Yet not talking about it often leads to unnecessary guilt, exacerbated shame and all too often to treatments of questionable value. So let’s review some of the most recent findings about this challenging topic in order to foster better communication and improved outcomes.

Miscarriage occurs in at least one out of every five pregnancies. Most of these miscarriages—estimated to be 60% to 80% depending on the woman’s age—are due to a genetic abnormality in the developing fetus. Yet a recent national survey  demonstrated that both men and women in the USA believe that miscarriage is rare; occurring in fewer than 6% of pregnancies. Even worse, the same respondents felt that lifting heavy objects and stressful events were among the most common causes of pregnancy loss. Maybe this false sense of responsibility explains why feelings of guilt and shame are so frequently reported by patients following a miscarriage. So let’s set the record straight by reviewing what the science has taught us.

For a successful pregnancy to occur there are three critical factors. First, there must be a healthy, genetically competent embryo. Then the embryo must arrive into the woman’s uterus during the hormonally synchronized window of time to support implantation. Finally the blood flow to the implantation site and woman’s immunologic functions must foster the growth of the pregnancy along with providing continued hormonal support. So let’s consider what interventions we can take to assist women with recurrent pregnancy loss (REPL)—defined as at least two pregnancy losses—to improve their chance of delivering a healthy baby.

In general, REPL is fairly uncommon and occurs in less than 5% of women. However, it is becomes increasingly more frequent after the age of 35 due to the increased likelihood of producing genetically abnormal embryos associated with aging. Comprehensive chromosomal screening (CCS) involves performing a biopsy on developing embryos created through IVF. These biopsies can then be tested for missing or extra copies of all 24 (including X & Y) chromosomes in each embryo—the most common cause of miscarriage. Several studies have demonstrated that doing so can reduce the risk of miscarriage substantially. In fact, one recent study  performed on women with REPL demonstrated that selecting and transferring only genetically competent embryos reduced the subsequent miscarriage rate to around 7%; making it three to five times less common than women that did not undergo this important test. So taking steps to insure that a pregnancy is started with an apparently healthy embryo is an effective strategy but some argue that it is too costly. Given that about half of the women with REPL are never given a diagnosis explaining why their pregnancy loss occurred; the insight gained from CCS might be considered invaluable. In fact, the lack of this diagnostic information likely fuels many of the other—often unnecessary—treatments offered to prevent subsequent miscarriage.

It has long been theorized that decreased blood flow and inflammation were major contributors to pregnancy failure and that low dose aspirin would help correct these problems. Unfortunately a randomized study  involving over 1200 women with REPL demonstrated that using low-dose aspirin (started before conception) was no better than placebo in reducing the risk of subsequent miscarriage. Given that low-dose aspirin is inexpensive; many may continue to use it anyway on the outside chance that it may help some individuals with REPL even though it is clearly not a major preventative measure for most women. However, other more expensive and risky treatments are often suggested as well.

Since immunologic problems have long been theorized to contribute to recurrent pregnancy loss, treatment with intravenous immunoglobulin (IVIG) has been proposed for nearly two decades to modulate the immune response. In truth this expensive and potentially hazardous treatment has failed to show benefit in multiple studies. Nonetheless, it has recently been put to the test yet again. This time the study was a larger prospective, randomized trial  where both the patients and their providers were blinded as to whether they were receiving the actual treatment or a placebo. The group studied included 82 patients that had each experienced four or more miscarriages in previous attempts at conception. Unfortunately, the live birth rate was no different between the treatment group and the placebo group. This is yet another study demonstrating that immunologic therapy is not likely to help most REPL patients.

Another strategy to reduce inflammation and improve blood flow as well as boosting health in general is to look at the patient’s diet and lifestyle. Obesity is associated with an increase in miscarriage risk as well as a higher risk of nearly every pregnancy related complication. Recently the Nurse’s Health Study II —a prospective monitoring of over 17,000 women that had conceived over 25,000 pregnancies provided some helpful insight. They found that pre-pregnancy weight gain and obesity were associated with a higher risk of miscarriage. So helping overweight or obese women with REPL to lose weight prior to pregnancy may be one of the best ways to help them have a baby as well as a healthier life.

Sharing the latest research on miscarriage is critical. Not only can it reassure and empower women but also help them avoid further heartache. It can also help prevent them from making emotionally based decisions to pursue treatments that may even cause further harm as well as financial hardship.

[r1]Link to http://journals.lww.com/greenjournal/Pages/currenttoc.aspx

[r2]Link to http://www.fertstert.org/article/S0015-0282(15)00134-X/abstract

[r3]Link to http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60157-4/abstract

[r4]Link to http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13192/abstract

[r5]Link to http://journals.lww.com/greenjournal/Abstract/2014/10000/Prepregnancy_and_Early_Adulthood_Body_Mass_Index.3.aspx

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

[r3]http://www.ajog.org/article/S0002-9378(15)00248-3/abstract

[r4]http://www.fertstert.org/article/S0015-0282(11)02256-4/fulltext

[r5]http://www.ajog.org/article/S0002-9378(15)00127-1/abstract

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

[r7]http://www.fertstert.org/article/S0015-0282(10)00983-0/abstract

[r8]http://familybuilding.resolve.org/fertility-scorecard

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