Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.
Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.
Update #1: Ovarian Stimulation Techniques: Changes in ovarian stimulation techniques evolve as a better understanding of the medications and their effects on eggs and ovaries develops.
Letrozole (Femara) is increasingly being used as a mild stimulation for ovarian follicle growth and as an additional medication with gonadotropins (e.g. Follistim). In a study on the use of letrozole in preparation for IVF in breast cancer patients, a group from New York showed that breast cancer recurrence or the incidence of invasive carcinoma in the opposite breast does not appear to be increased after stimulation using letrozole and FSH for fertility preservation.
For patients with PCOS, researchers from France compared stimulation with a GnRH agonist, similar to Lupron, with oral contraceptives plus agonist. In these preliminary results, dual suppression does not provide any obvious effect in harmonizing the group of developing follicles nor in improving the quality of oocytes and embryos. This study is still ongoing in order to test these results in a larger population.
In patients that produce an excessive number of follicles in response to stimulation, ovarian hyperstimulation syndrome (OHSS) is possible. To prevent this, the fertility drugs are sometimes stopped mid-stimulation; the follicles are “coasted” – they grow without stimulation, with a lower risk of OHSS. An alternative to “coasting” is the use of Ganirelix, a GnRH antagonist, in a “salvage protocol.” Probability of live birth with the Ganirelix salvage protocol was similar to controls. High-grade embryos were more common with this regimen, in contrast to “coasting”. The miscarriage rate was slightly higher, but not statistically significant. These results suggest that the Ganirelix salvage regimen is a superior alternative to “coasting” in women at risk for OHSS.
A group in Montpelier, France is interested in gene expression in the follicle after use of fertility drugs. Using gene chips they measured gene expression in patients exposed to urinary FSH products and recombinant FSH. Significant differences were found meaning that different genes are being expressed in follicles of women receiving pure FSH (Gonal-f or Follistim) as compared to genes being expressed in follicles of women receiving urinary FSH (Repronex or Menopur)– the meaning of these changes will have to await further study.
On the other hand, a long debate about the effectiveness of urinary and recombinant FSH products is a bit closer to resolution. A meta-analysis from a group in Egypt examined pregnancy outcomes and risks in a group of previously published studies. No significant differences were found. Their conclusion was that urinary gonadotropin (hMG) is as effective as recombinant gonadotropin with regards to clinical outcomes and patient safety. Philip Chenette, MD
Update #2: PGD and Aneuploidy Screening Techniques
Preimplantation genetic diagnosis (PGD) has been one of the hallmark technologies of modern reproductive medicine. The ability to look inside a cell, beyond its visual appearance to the actual genes controlling the cell, has provided insight into the workings of the embryo and a valuable clinical tool to improve fertility care.
The most common use of PGD is to count chromosomes using FISH probes. Using labels that glow under ultraviolet light, a limited number of chromosomes can be identified and counted. Missing or duplicated chromosomes are indicators of abnormalities in the embryo, a condition known as “aneuploidy.” FISH has a significant error rate, and while clinically useful, results must be interpreted with caution.
A new technique discussed at the ASRM meeting is SNP analysis. SNPs are common tags in DNA that can be measured by automated systems. Microarrays of thousands of SNPs have been prepared that provide a clear picture of the chromosome structure of a cell. Microarray-based aneuploidy screening has excellent reliability and accuracy, and holds enormous promise for identifying genetically normal embryos. This study represents the first validated method of analyzing the entire set of chromosomes in a single cell. Stay tuned for more on this exciting technology.
Array CGH uses thousands of very small DNA probes along with computer software to describe the structure of DNA in a single cell. A very sensitive test, it is fast enough to be used during an IVF treatment cycle, and far more accurate than conventional fluorescent probe (FISH) analysis. Array CGH may lead to improved IVF outcomes as embryos containing an error in any chromosome can be detected, which would allow better selection of healthy embryos.
PGD has proven useful for the treatment of recurrent miscarriage. In an analysis of 279 patients with recurrent miscarriage (women who had previously experienced 3-5 miscarriages), researchers in New Jersey found an improved miscarriage rate of 19.5% after PGD versus their 40.9% expected rate. Philip Chenette, MD
ASRM Update #3: Egg Freezing
Oocyte cryopreservation is the storage of the female gamete, the egg, prior to fertilization. Preservation of fertility for single women that must undergo cancer therapy or surgery, or that must delay or choose to delay childbearing, and donated oocyte banking are all applications of oocyte cryopreservation. The need for this technology is clear, but reports of success with oocyte cryopreservation have been limited.
Highly successful oocyte cryopreservation is now attainable. New studies are showing pregnancy rates with oocyte cryopreservation that are equal to traditional IVF techniques.
The key to this technology is oocyte vitrification – an ultrarapid cryopreservation technique. Researchers from Atlanta described their experience with vitrification. Out of 11 patients with transfers, nine conceived, with an implantation rate of 65%.
Pregnancies after oocyte cryopreservation have developed normally. An Italian study of 105 children born after oocyte cryopreservation showed no problems. A Chicago study of the genetics of oocytes, embryos, and children born after oocyte cryopreservation was reassuring. No increase rates of aneuploidy or malformations were reported, and normal development was found in post-natal follow-up.
These results are similar to those we have previously reported from our own research at Pacific Fertility Center (see December 2007 Fertility Flash). Oocytes are now cryopreserved with high success rates. Oocyte cryopreservation technology has matured, and we look forward to providing these techniques for our patients. Philip Chenette, MD
Update #4: Acupuncture
The published study of German Paulus (1) reported improved pregnancy rates with a one-time acupuncture treatment pre-and-post embryo transfer. This sparked great interest for providers of fertility treatment, in both the conventional and Chinese medicine (TMC) communities (see Fertility Flash March, 2004). A few years later, a study from Denmark (2) reported improved pregnancy rates in patients receiving pre-and-post transfer acupuncture, but no improvement if there were two post-transfer treatments. In both of these studies, there were no sham acupuncture (i.e. simulated but not real acupuncture) treatment controls.
Smith (3) and colleagues in Australia did compare acupuncture versus sham acupuncture (but did not include a no-treatment control group), using 3 treatment sessions: ovarian stimulation day 9, pre and post embryo transfer. There was no difference found in these different study groups. Interestingly, subjects in the sham control group were more likely to report relaxation as a side effect of acupuncture. Some studies indicate that sham acupuncture evokes acupressure, and in this way, may trigger physiological responses.
In all the above studies, the acupuncture treatments were performed within the IVF centers (patients did not have to travel off-site). In general, there were no more than 100 patients per treatment group.
At ASRM, Dr. Craig and colleagues reported an acupuncture study conducted in Seattle, using 3 IVF clinics. The acupuncture sessions were performed off-site by 2 acupuncturists. The patients were randomized to pre- and post-transfer acupuncture vs. no treatment. The physicians were not aware if the subjects were or were not receiving treatment. A total of 97 patients were studied (about 50 patients per treatment group). Clinical pregnancy and live birth rates were as follows: 54% and 39% for the acupuncture group, and 78% and 65% for the control group. These results were statistically significant. Of all the acupuncture studies thus far published, this is the first study to suggest a possible detriment to the use of acupuncture in IVF treatment.
One of the important differences for this study versus other randomized controlled trials is that all the patients had to go to an off-site acupuncture center for their treatment. This may be an important factor when a patient has to travel to the acupuncture clinic immediately before and immediately after an embryo transfer. Perhaps this factor would increase stress levels. Another important difference for these Seattle IVF centers was that baseline pregnancy rates are much higher than the previously-studied non-US centers. The higher the baseline pregnancy rate, the more difficult it is to show a difference in treatment results— so a statistically significant result would be more credible.
Ideally, a multi-center randomized-controlled-trial should be performed where the following comparisons can be evaluated: acupuncture pre-and-post transfer, no-acupuncture control group, sham-acupuncture control group, and these 3 groups can be compared at both on-site and off-site acupuncture centers. Each study group would require at least 100 patients, so this would require about 1000 patients total.
As we have a chance to collaborate with TCM providers, and as patients are willing to participate in these large multi-center randomized clinical trials, we will gain a better understanding about whether a mix of allopathic and TCM medicine improves overall care, and which combination of treatments may be the most beneficial for our mutual patients. Isabelle Ryan, MD
(1) Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril. 2002, Apr; 77(4):721-4.
(2) Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial. Fertil Steril. 2006 May; 85(5):1341-6.
(3) Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006 May; 85(5):1352-8.
Update #5 Men and ART
The Mental Health Professional Group (MHPG) course entitled Men and ART: The Missing Voice, blended medical, psychological, ethical and legal information relating to men who participate in Assisted Reproductive Technology (ART).
The legal issues confronting single men and gay men considering the use of egg donors and gestational surrogates continue to be controversial. Adoption legislation in many states prohibits gays and lesbians from adopting. In a study reported in 2005 by Gurmankin, et. al, 44% of ART programs responded that they would not turn away gay couples seeking surrogacy with one partner’s sperm and 48% responded that they would turn them away. This is in contrast to the higher rate of acceptance of lesbian couples. In lesbian couples seeking treatment using donor insemination, 82% of ART programs agreed to treat versus 17% who refused to treat them.
Though often presented exclusively to women, men can also benefit from the use of stress reduction strategies and following a healthy life style which includes regular exercise, normal body weight, no smoking or recreational drug use and avoidance of environmental toxins. In addition, the effects of aging and cancer on sperm quality should not be overlooked when men seek reproduction assistance. (See Sperm aging: Fertility Flash Feb. 2004, Sperm Fragmentation: Fertility Flash March 2005, October 2004 Cancer and Infertility: Fertility Flash Oct. 2004).
The psychological component of this course was compelling. Approximately 50% of cases of infertility involve at least some degree of male infertility. Why is it that most infertility references are traditionally directed at women? By definition, Infertility is “…the inability of a woman to conceive after some months (12-24) without contraception, or the inability to carry a pregnancy to term.” (Institute of Medicine and National Research Council, 1989). Ancient biblical references and popular literature focus on women’s infertility – e.g. Sarah and Hannah in the bible, Sylvia Plath’s Barren Woman, Jane Smiley’s 1000 Acres. The list is long. Google hits by gender for infertility and psychology show 542,000 for men and 700,000 for women.
The cause of this discrepancy is multifaceted. There are fewer psychological studies on men simply because men have a lower study response rate than women. A variety of successful techniques have been developed to overcome male related medical issues. Additionally, most men spend less time in treatment and experience fewer invasive procedures than women. In general, it is more socially acceptable for women to express their feelings regarding infertility. The opposite is true for men whose fertility often is a taboo topic. Furthermore, some cultures protect their men from the unacceptable stigma of infertility and even falsely describe men as having “poor” coping skills.
Despite these discrepancies, men do have feelings about infertility and may need support and assistance to better cope with the diagnosis. A study by Mason MC in 1993 found that men felt guilt, shame, anger, isolation, loss and a personal sense of failure. This is not all that different from what women feel, but each individual’s coping mechanism is unique. We all, however, find ways to protect ourselves from what we perceive as painful information.
These coping skills can be divided along gender lines. There are ways that many, but certainly not all, men commonly protect themselves from the pain related to his or his partner’s infertility diagnosis. Frequently men are able to distance themselves from the feelings. They appear to have the ability to take painful information and put it in a little box that they then file away in the back of their minds. The box stays tightly shut. Other men want to problem-solve for their partner or avoid the topic completely, throwing themselves into work or hobbies. Some men become extremely optimistic to avoid or counter their partner’s pessimism.
These are different styles- not right or wrong. For many of us, particularly women, the closed box technique does not work. The box is opened often, and feelings appear to refuse to stay tucked away. When partners have different coping styles, it’s important to both learn to tolerate and support these differences. Sometimes that is easier said than done... Peggy Orlin, MFT
Peggy Orlin, MFT served as the 2006-7 Chair of ASRM’s Executive Committee of the Mental Health Professional Group (MHPG), is a member of Resolve’s National Mental Health Advisory Board. She co-teaches PFC’s Mind/[email protected] workshops. (see PacificFertilityCenter.com for more information on Dr. Domar and Mind/[email protected] Workshop.)
Isabelle Ryan, MD is recognized by prestigious medical associations for her pioneering research leading to new insight into the important clinical problem of endometriosis related infertility. At PFC she remains active in research while enjoying caring for infertile patients. Dr. Ryan has been repeatedly recognized as a “Best Doctor” in peer surveys for her expertise in the field of infertility (see www.BestDoctors.com). Dr. Ryan directs PFC’s Third Party Parenting Program and our in-house egg donor agency.
Philip E. Chenette, MD 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. As a member of the International Society for Stem Cell Research, he is working to apply the concepts of stem cell therapy to help couples have healthy children. His expertise is recognized by peers who repeatedly select him as “Best Doctor” in peer surveys.(see www.BestDoctors.com)
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