This past summer, I had the opportunity to travel to Amsterdam, Holland for the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). Though largely attended by Europeans, this scientific meeting draws physicians, embryologists and scientists from around the world to discuss their research, attend courses and lectures, and discuss the latest topics in our field. Although I don’t think this year’s meeting was as quite as good as last year’s ESHRE in Barcelona, there
were still some good learning opportunities. Here are some of the highlights of the meeting:
"From Gamete to Heartbeat: The Missing Link"
This was a post-graduate course offered in conjunction with the meeting. The course covered sperm and egg evaluation,
expression of genes in the early embryo and in the endometrium (uterine lining) and some of the latest research into basic embryo implantation
mechanisms.
One of the interesting talks was on gene expression in the early embryo. We have come to believe that the differences in pregnancy rates between younger and older women is mainly due to an increase in the number of abnormal chromosomes in
embryos from women as they age (such as increased risk for Down Syndrome).
However, this only explains part of the differences in successful pregnancy in younger compared to older mothers. New research into expression of proteins from embryonic genes is showing that in both chromosomally normal and abnormal embryos, there are differences in the number and types of genes encoding proteins in younger and older women. This suggests that it is not just changes in the number of chromosomes but subtler differences in the way individual genes are being expressed that affect the developmental competence of their embryos. Determining which genes and proteins are involved, and what the mechanisms are for regulating the expression of these genes in early embryos, will be an area of focused research in the coming years.
“Hyaluronic Acid (HA) favors selection of spermatozoa with intact DNA and normal nucleus, resulting in improvement of embryo quality” (Bologna, Italy)
This presentation (Parmegiani, et al.) looked at the percentage of sperm showing DNA fragmentation based on several methods of sperm preparation for IVF-ICSI (in vitro fertilization with intracellular sperm injection). They compared sperm in the fresh specimen 30 minutes after ejaculation, sperm that had been processed with a standard “swim-up” technique, and sperm that were placed in PVP (polyvinyl propylene), a substance used to slow sperm down so they can be picked up from a culture dish just prior to injection into the eggs. Lastly, they looked at sperm that had been placed into dishes that contain a ring of hyaluronic acid at the bottom of the dish, a substance to which some sperm will automatically bind. They looked at the percentage of sperm showing total or partial fragmentation of the DNA with each of these steps in the sperm preparation process. In the freshly ejaculated sperm, the DNA fragmentation was 16.5% of tested sperm. In the “swim-up” sperm prep, 11% were fragmented and in the PVP-exposed sperm, it was also 11%. Sperm that had bound to hyaluronic acid showed the least amount of fragmentation, at 5.3%.
These findings suggest that using HA binding to select sperm for sperm injection may result in fewer abnormalities in embryos, and possibly higher pregnancy rates. PFC is currently investigating HA binding on our own to see if it is something we would wish to routinely incorporate into IVF. The downside (like everything else!) is that HA plates are expensive.
Stress and Fertility – an enlightening symposium
Jacky Boivin, PhD., a researcher from Cardiff University in Wales, presented some very interesting data about the stresses of infertility treatment. She discussed a new study from Alice Domar’s group in Boston that surveyed why women/couples discontinued IVF treatment before achieving pregnancy (Fertility and Sterility, in press 2009). In this study, 132 women who had insurance coverage for IVF were surveyed. The two main reasons given for dropping out of treatment were the toll that infertility took on the couples’ relationship and being too anxious or depressed to continue. Among the less common reasons for dropping out were medication-related issues (such as difficulty with injections) and feeling the need for a female doctor. Dr. Boivin also discussed results from her own study that was published in the journal Human Reproduction in 2008. In that study, she developed a copingstratagem for women awaiting results of their treatment (i.e. the time between embryo transfer and first beta hCG). It is known that this is a most anxious time for women and the stress of waiting can become overwhelming. She utilized something called the “positive reappraisal coping intervention” card, or “PRCI” card. This is a small printed card that a patient can carry around in his or her pocket and it is meant to be read 2 times per day, every day during the 9-11 days between embryo transfer and first pregnancy test. The card has several little sayings such as: “During this experience I will try …to do something that makes me feel positive” and “During this experience I feel that….I’m energized or I’m creative.” This is a way of programming thoughts towards the positive and away from the negative. She and her colleagues were able to show that patient felt less stressed and felt that the PRCI was helpful during this period.
Currently, at PFC, we have begun a task force to look into ways to better incorporate counseling and tools for stress management for our patients. Please also see the Patient Odyssey in this newsletter. Support groups are a wonderful way to diffuse stress and feel more positive.
Corifollitropin: a modification of Follistim to allow a once-a-week injection.
As most people know, the medication we most commonly use for fertility treatment, Follistim, is pure human FSH, manufactured using recombinant DNA technology. The company that makes Follistim, Schering Plough, is working towards FDA approval of a modified version of Follistim, called Corifollitropin, that will make the drug very long-acting.
For those interested in the details; Corifollitropin is the recombinant FSH molecule + 22 C-terminal peptides from betahCG. It does not bind to the LH receptor. This modification lengthens the half-life of Follistim from 22-34 hours to 60-74 hours for Corifollitropin. The recommended regimen will be one dose per week, starting at baseline, then switch to daily recombinant FSH after that. After injection, peak levels are reached in 2 days then they slowly level. It may be possible to only take one injection per week!
A symposium at ESHRE presented information from the ENGAGE trial with data from 14 European and 5 Asian IVF centers, using women with body mass indices (BMIs) between 18 and 32 (generally less than 60 kg -132 lb). The patients were randomized to receive either Corifollitropin or conventional daily recombinant FSH for oocyte recruitment. The number of days of stimulation was the same in both groups (9). The number of eggs retrieved was significantly higher in the Corifollitropin group (13.3) vs. the FSH group (10.6). The rates of ovarian hyperstimulation syndrome were the same in both groups (about 3%). The pregnancy rates were 25% in the Corifollitropin group and 34% in the FSH group, a difference that did not quite reach statistical significance.
Data were also presented on a second study of Corifollitropin from the U.S. and Europe, comparing two doses of the drug. In the study, 100 mcg/dose was given to women less than or equal to 60 kg and women greater than 60 kg were dosed at 150 mcg. Over 1500 patients were included in this large trial. In this study, the average number of eggs recovered was 13.7 for the Corifollitropin group and 12.5 for the Follistim group. The mature egg and fertilization rates were the same. The percentage of good quality embryos was the same.
The clinical pregnancy rate in the Cori group was 38.9% and was 38.1% in the Follistim group. These rates were statistically the same. We expect that Corifollitropin will likely be available in the U.S. in 2010 or 2011.
—Carolyn Givens, M.D.
Carolyn Givens, M.D. was the first in San Francisco to successfully initiate a pregnancy using intracytoplasmic sperm injection (ICSI). She currently co-directs the Bay Area Pre-Implantation Genetic Diagnosis Program (PGD) and is director of PFC’s PGD program.
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My husband and I have been riding the infertility roller coaster for almost 3 years now. The ups and downs have included invasive diagnostic testing, four failed intrauterine inseminations (IUIs) and most recently an unsuccessful in-vitro fertilization (IVF) attempt. Each wave of excitement over the hope brought on by the next treatment cycle would come crashing back down with the negative news. While I am confident I am receiving the best possible medical care with the team at PFC and am keeping “hope frozen in time” with my frozen embryos, it can still be a hard road to travel.
Considering my first attempt at IVF failed, you would think I would be at the lowest point of my journey towards parenthood. But, amazingly, I am not. I am sharing my story to tell you how I survived the ups and downs and was able to feel more grounded and
Lisa Wickham.
This is what saved me: A powerful combination of group support and mind/body techniques.
My PFC acupuncturist (seeing tears stream down my face) recommended a Mind/Body class to help ease my obvious difficulty in coping with the emotional stress I was under. This was huge. This was the first step I would take in reclaiming my 0ormer self. What are Mind/ Body techniques? They are tools including deep breathing, meditation, guided imagery, progressive muscle relaxation, cognitive reframing, light yoga, tai chi and journaling exercises. My first thought was, “Will this be too ‘new age-y’ for me?” I could barely comprehend the fact that I was doing acupuncture regularly, let alone meditate.
The great thing about Mind/Body is that it is a tool box, so you pick what works for you. I never really did learn to meditate, but the regular use of relaxation CDs for deep breathing, muscle relaxation and guided imagery has given me profound peace of mind. Cognitive reframing (learning to recognize destructive thoughts and “reframe” them) was also powerful for me. I used to hear a tape playing in my head over and over, “I’ll never get pregnant, I’ll never get pregnant”. I learned to challenge the truth of that statement and rethink how it made me feel. A 10-week Mind/Body course I took was a key turning point. PFC offers a one-day workshop that offers an introduction to Mind/Body and is free for patients.
The other key component to my peace of mind has been meeting others who “get it”. It’s hard to explain to someone not experiencing infertility themselves just how this takes over your life. Well-meaning family and friends try to understand, but they truly cannot. Only my best friend, who also experienced difficulty in trying to conceive “got it”. That is, until I did my first IUI. Having to explain washed sperm to her and describe what it’s like to have your legs in stirrups as the washed sperm is
inserted into you was beyond depressing. I knew I needed to meet others going through similar situations.
Lisa and Jonathan Wickham.
I attended my first Open Path group support meeting last year and had no idea what to expect. I only knew I needed to at least talk to someone else who knew what an IUI was. Open Path (fertilityandadoption.com) is a Bay Area organization that provides regular group support. There I met two amazing women and we are now a larger group of women who meet regularly and support each other over email, coffee and even cocktails in between cycling. We are a Sisterhood of Infertility. We all have different stories whether doing IUIs, IVF, using donor eggs, considering a gestational carrier or considering adoption. We have different personalities, some are quiet, some are loud, some blog their innermost thoughts to the online world (google “Stirrup Queens”), some are “closeted” with their infertility secret to all but a few. But our common thread is infertility. We all wear the red, pomegranate string around our wrists as a reminder that we are not alone (you can google “infertility’s common thread” to read more about this). We support each other when we are down and we celebrate our victories (small and large) together. While most of us could not find it in ourselves to feel happiness for friends we had known all our lives that got pregnant, we were able to give loud cheers of joy when one our IF Sisters did. This was healing beyond words. And this gives us hope.
I’ve heard the statistics about Mind/Body and group support increasing pregnancy success odds, but, for me, even more important than getting pregnant, was the peace of mind that came.
My hope is that my story can, in some way, help bring peace of mind to someone else as they navigate their own path. You are not alone. You do not have to do this alone. And there are concrete ways you can make yourself feel significantly better while undergoing treatment.
Try these resources for more information:
— Lisa Wickham, Current PFC Patient, San Francisco, CA
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Microarray Preimplantation Diagnosis (MA-PGD) created much excitement and interest at three recent meetings attended by Dr. Schriock; Pacific Coast Reproductive Society, The Midwest Reproductive Symposium, and the IVF Comprehensive Update.
PGD is a technique used to diagnosis genetic disorders by performing a biopsy of the embryo on day 3 or 5. PGD can diagnose single gene or chromosomal defects. PFC has been doing embryo biopsy for over 10 years. During this time the major method of diagnosing chromosomal disorders has been fluorescent in situ hybridization, FISH. FISH uses a fluorescent color to label individual chromosomes. This technique lacks accuracy and is now seldom used to screen embryos for the presence of missing or extra chromosomes. (refer to Fertility Flash Vol. 5 Issue 2). This technique, however, is still valid for identifying the gender of the embryo. MA-PGD uses a new technology, Single Nucleotide Polymorphisms (SNPs). SNPs are single bases, the building blocks of DNA, which can be in a different sequence in different individuals. Six to ten million SNPs have been characterized. This is the technology used in DNA fingerprinting in criminal or forensic work. Compared to FISH, where only one color marker identifies the chromosome, SNPs havethousands of markers per chromosome.
FISH can only identify 8-12 of the 24 unique chromosomes; MA-PGD will identify all 24 chromosomes, similar to amniocentesis. Identifying both single gene defects and chromosome abnormalities from one embryo cell was not possible with the older techniques, but can be done with MA-PGD. MA-PGD will identify whether the abnormal chromosome came from the mother or father. If from the mother, it will determine if the error was in meiosis I or II, or mitosis. In other words, it can identify in which stage of early cell division the genetic error occurred. Using MA-PGD, it may be possible to determine which embryo produced the baby when more than one embryo is transferred. The most important advance, however, will be the accuracy of the result. New research using MA-PGD shows that FISH is inaccurate over 40% of the time. MA-PGD appears to be nearly 100% accurate in diagnosing abnormal embryos.
This new technology is also helping to answer scientific questions. 50 – 70% of embryos with one missing or extra chromosome still develop to a healthy-looking day 5 blastocyst. This helps explain why beautiful blastocysts do not always turn into healthy pregnancies. MA-PGD will also raise new questions: Only 55% of chromosomally normal embryos turn into successful pregnancies in 30-year-olds, only 25% in 40-year-olds. Why do these embryos with a normal number of chromosomes fail? There is more to the embryo than chromosomes and more research is needed to determine what factors allow an embryo to develop into a healthy baby. Current areas of investigation include RNA production (transcriptomics), protein production (proteomics), and metabolic by products (metabolomics).
We will continue to update readers on PFC’s experience with MA-PGD in future Fertility Flash issues.
— Eldon Schriock, M.D.
Eldon Schriock, M.D. has been at the forefront of A.R.T. since 1981 and was a member of the medical team that performed the first IVF treatment in Northern California. In addition, Dr. Schriock is keenly attuned to the psychological repercussions of those undergoing A.R.T. treatments.
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Imagine a website that allows you to search for the very latest information on fertility. Well, it’s here and it’s called fertilitywire.com.
PFC is proud to present fertilitywire.com as a completely unique website that offers real-time and fresh information on fertility and infertility related topics. It’s a resource for people engaged in the process of becoming pregnant through fertility treatments or people studying this field who want to explore it.
And, it’s a unique resource in that it’s powered by a type of search called “browsing or universal search,” which is how we’re able to pull together all of the content for any given search term you see. You are able to see, in one place, the latest fertility related news, blogs, tweets, videos, images, articles and books.
We are excited by the positive feedback we have been receiving about fertilitywire.com. Here is one testimonial that sums up the experience very well:
"This website has a friendly approachable tone. It also covers so much, by the time I was done navigating, fertility issues seemed not intimidating but manageable and that there is a world that one
could enter, (your center) and not be a stranger. At the same time, it seems like there is hope; if not here and now--it is being developed right around the corner."
— Michael Lynn, PFC Patient
Visit fertilitywire.com. We hope you find everything you are searching for!
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Ovarian reserve is an expression of the number and quality of eggs available for conception. As a parameter for predicting pregnancy, ovarian reserve testing is often part of a fertility evaluation. Such testing requires specific measurement, and clinical judgment to interpret the results.
Egg numbers are at a maximum before birth, at around 20 weeks gestation. After birth, there is a progressive decline in the number of eggs from roughly one million at birth to 300,000 at puberty. Through the reproductive years the remaining eggs are lost, with the rate accelerating around the mid-30s, resulting in few eggs left at menopause, around age 50-52. The number of eggs available for reproduction at a certain age is the ovarian reserve, which is the target of the diagnostic tests described here.
Age is the most accurate predictor of egg health, but within age groups, there is considerable variation in the number of eggs remaining for reproduction. Age alone as a predictor of ovarian reserve is not sufficient, since, for individuals, fertility may be better or worse than the average for that age. Extreme examples of this variability include the teenager in menopause and the 59 year-old that delivered a natural pregnancy in 1997. This variability in pregnancy rates within an age group is present in all reproductive age groups.
To predict an individual woman’s fertility rate, in addition to her age, both clinical and laboratory methods are available to evaluate ovarian reserve. The best tests are direct measures of the ovary, such as the Antral Follicle Count (AFC) and Anti-mullerian Hormone (AMH) level; indirect measures, such as clinical history and levels of pituitary hormones, are common tools for prediction of ovarian reserve.
The simplest method of predicting fertility rates is clinical history, of both the individual and her closely related family. The number of months spent attempting to conceive predicts fertility. A
couple that has been trying for some time will naturally have a lower fertility rate than a woman that has not had unprotected intercourse. Response to ovarian stimulation can also be used as a marker, as it is fairly consistent between cycles. Family history, i.e., the fertility of the woman’s mother or sisters reflected in age at menopause and age at conception are useful predictors. Such factors from clinical history can help define the risk of a problem with ovarian reserve.
Ultrasound is a useful tool for predicting ovarian reserve, as in measuring the Antral Follicle Count (AFC). Antral follicles are the smaller follicles, visible on ultrasound, between 2 and 10 mm, that are lost as a woman ages. In younger women, the AFC is 10-20, declining by 5% per year through age 37, and then accelerating to a loss of 10% per year thereafter. Women show a fairly consistent AFC loss rate of one follicle every two years.
AFC predicts the response to ovarian stimulation at least as well as blood tests, but its ability to predict pregnancy outcomes is limited, particularly when low. A woman with a higher AFC will show a better response to fertility drug treatments. A high AFC seems to predict pregnancy rates, but data remains limited, as there are no prospective studies published. A low AFC seems to be a less accurate predictor
of ovarian reserve, particularly in older age groups. AFC may help predict outcomes, but should not be used to exclude patients from treatment.
Anti-mullerian hormone (AMH) is a blood test that directly measures ovarian reserve. Produced directly by early stage ovarian follicles, high levels (over 1.0) are favorable, while low levels (less than 1.0) indicate decreased ovarian reserve. AMH may be the best measure of the menopausal transition and ovarian age. It may also be useful in predicting ovarian hyperstimulation syndrome, the effects of chemotherapy, and in determining the treatment of PCOS.
AMH seems a superior predictor of ovarian response compared to other markers, including age, and day 3 FSH and estradiol. It offers similar predictive value compared to AFC. AMH can be drawn at any time in the menstrual cycle, and is not affected by hormonal therapy, including oral contraceptives.
AMH still requires further study. The range of normal variation is still being determined, and the true predictive value of the test requires a great deal more analysis. The specific range of reliability and predictive value by age is yet to be established.
Cycle day three FSH and estradiol, and, to a lesser extent, the clomiphene challenge test, remain viable tests for estimating ovarian reserve. These tests are established as predictors of response to ovarian stimulation. Prediction of pregnancy rates is more difficult. Recent studies concentrating on the predictive value of these tests have shown that they cannot be used to determine which patients cannot conceive, but are useful for screening and counseling.
All in all, these tests are only rough predictors of ovarian reserve. They are moderately good predictors of ovarian response to stimulation, and relatively poor predictors of pregnancy outcome. In a particular patient, the tests can be used to counsel about potential response to ovulation induction, but it remains difficult to predict pregnancy outcome based on the test results.
The ultimate test of ovarian reserve is response to treatment and whether a pregnancy results from that treatment. Stay tuned as we evaluate further research to establish the validity of ovarian reserve testing methods.
— Philip Chenette, M.D.
Philip Chenette, M.D. has spent over a decade specializing in the treatment of patients with complex infertility diagnoses, especially in women with decreased ovarian reserve and women over 40.
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