Within days of writing about the modern benefits of egg freezing a new study was published in JAMA based upon old data. They looked at national data from 2013 and concluded that pregnancy rates from egg donors were lower if the eggs had been frozen than if they were fresh. That was probably true back then. But technology is advancing at an exponential rate. Reproductive medicine is arguably one of the most technology dependent fields of medicine. So applying 2013 results to current decision making is flawed from the very onset. Having said that, let’s consider what this publication may be able to teach us and how we should more accurately interpret it today.

This study looked at the 2013 Annual Report of the pregnancy rates from fertility centers in the USA which were collected by the Society for Assisted Reproductive Technology. The science and experience of most centers using this technology has advanced considerably since then.  In fact, it was in late 2013 that the Practice Committee for the American Society for Reproductive Medicine published the guidelines for oocyte cryopreservation.  In their review they pointed out the fact that much of the data that they analyzed was from Europe as few clinics in the USA had published their experience with egg freezing at that time. They also clarified how the difference in techniques used to freeze/thaw the eggs had progressed rapidly resulting in dramatic improvements in success rates. As a result, the removed the “experimental label” from the procedure because of these advances. However one of their most important ultimate conclusions was that “success rates may not be generalizable, and clinic-specific success rates should be used to counsel patients whenever possible.” Despite that clearly stated recommendation, this latest research paper lumped together all of the clinic data and created the latest public misinformation campaign.

Today, many more centers have experience in freezing/thawing eggs using the most modern technique of vitrification. As a result, more patients that need donor eggs are able to benefit from the lower cost and greater convenience of frozen eggs and still enjoy the very best in success rates. Better still, many egg banks offer special guarantees so that if a specific donor’s eggs do not perform well: they will have access to replacement eggs without additional cost. So the best message for patients in need of donor eggs today is to be a wise consumer. Patients should ask their clinical very candidly about their unique experience with frozen donor eggs. I think that they will find greater reassurance in today’s science than in yesterday’s news.

For decades, “family planning” was synonymous with contraception. The Guttmacher Institute—a prominent reproductive health think tank—stated that “controlling family timing and size can be a key to unlocking opportunities for economic success, education and equality” for women. In fact, their most recent analysis concluded that effective contraception has contributed to increasing women’s earning power and narrowing the gender pay gap. Whether it’s for these reasons or not, studies have consistently demonstrated that many women are choosing to delay childbearing. The age at first birth for women is now approaching 28 year of age and the birth rate in the USA is at an all time low. As more women choose to delay (or extend) their reproductive years, it is important that more women become aware of the potential benefit of oocyte freezing. In a recent study called “Baby Budgeting” one research group described this technique of freezing/storing eggs as a “technologic bridge” from a woman’s reproductive prime to (her) preferred conception age.

Today egg freezing has made it possible for women to truly “plan their family” by storing eggs for later use. The first successful pregnancy from frozen eggs was reported in 1986. But for decades the process remained very inefficient; requiring about 100 eggs for each successful pregnancy. Therefore the procedure was considered experimental and primarily offered to women that were faced with chemotherapy, radiation or other fertility-robbing treatments used to treat serious illnesses. But with the development of more effective techniques for freezing eggs; success rates in many centers using frozen eggs is as good as it is with using fresh eggs. As a result of this improvement in pregnancy rates, the American Society of Reproductive Medicine lifted the “experimental” label from egg freezing and began supporting its use for social (rather than medical) reasons. Recently, two different studies determined that the most common reason for women to seek egg freezing as a means of protecting their fertility was the “lack of a current partner.”  That said, Facebook and Apple have made egg freezing available to their employees and many predict other companies to follow this trend as well. As more women consider this option of preserving their fertility, there are several questions that they should think about in order to create an individualized plan.

For practical reasons, the process of creating a fertility plan should be tailored to a woman’s current age, how many children she would like to have and her current ovarian reserve. Existing guidelines suggest that if a woman is in good health, less than 31 years old and with a normal ovarian reserve—she should wait and reevaluate her situation every one to three years. On the other end of the spectrum, if a woman is over 38 years of age she should consult with a board certified reproductive endocrinologist to discuss her options. So the women that are typically the most suitable candidates for egg freezing are women between 31 and 38 years of age that are seeking to delay pregnancy for at least 2 years. The “Baby Budgeting” study found these are the patients for whom the procedure is most cost-effective. A similar study found that based upon successful pregnancy rates women should ideally freeze their eggs by 35 to 37. Testing a woman’s ovarian reserve however is the critical factor in customizing these recommendations.

Ovarian reserve represents the best estimate of how fertile a woman is compared to other women of the same age. It is usually tested by means of a blood test and/or a properly timed ultrasound examination of her ovaries. Sometimes, this test reveals that a young healthy woman may have a fewer number of fertile eggs remaining than would be otherwise expected. That’s why this test is so important. It can inexpensively identify if someone should consider egg freezing prior to the 32-38 year old age range. This test is also predictive of how many eggs a woman is likely to produce in a single egg-freezing cycle. The current recommendation is that women should try to have 15 to 20 eggs available for each one or two pregnancies that she hopes to have. Many women will produce this number in a single egg-freezing cycle whereas others may need to go through the process two or three times in order to bank this many eggs. Once properly frozen, the eggs are generally considered as fertile on the day that they are thawed as they were on the day that they were frozen—effectively prolonging fertility for 10 years or longer.

Each egg frozen is estimated to have a 2 to 12% chance of producing a live birth. That’s the reason that it is recommended that women store a larger number of eggs than the number of children that she hopes to have. Doing so improves the odds of having several that are of good quality. Since a woman’s age serves as an estimate of her egg quality, online databases can provide estimates of a successful live birth based on a few simple questions. So now it is a lot easier for women that aren’t quite ready to become pregnant to create a proactive family plan that fits in with the rest of her personal and professional goals.

Here’s brief segment on Egg Freezing from Colorado & Co

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

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