Progress has been steady at the Center this week. From last Sunday up until this coming Saturday we will do 13 egg retrievals, 14 fresh embryo transfers, 6 frozen embryo transfers and one hysteroscopy. It looks to be a fairly typical week.

Last Saturday I attended an investigators’ meeting, along with our lab director, Dr. Joe Conaghan, for a new clinical research study that we may be undertaking with Gene Security Network (GSN). GSN is one of the pre-implantation genetic diagnosis/screening (PGD/PGS) laboratories with which we work. I really can’t discuss the details of the study at this time, as we have signed a standard non-disclosure agreement with GSN, but this will be a big study to investigate how useful PGS will be to the average IVF patient.

This leads me to the topic of today’s blog: clinical research. Although PFC is not an academic institution, we are still interested in research because this is how the field of reproductive medicine advances. In fact, since there are so many private IVF clinics, much of the research on IVF is currently being done in the private sector. We would not have the field of assisted reproduction today if it were not for clinical research and for the thousands of patients who have participated in this research to this point. I’d like our readers to know that participation in research is not taken lightly by anyone conducting the studies. As investigators, we all have to be trained in the ethical conduct of research, to make sure the risks of participation are minimized and that there is potential benefit to patients from participation. Our number one goal is still to get our patients a healthy pregnancy. We will not compromise that goal for the sake of a clinical study. The study protocols are carefully reviewed by an independent Institutional Review Board (IRB), tasked with ensuring there is no harm or undue coercion to participants. In most good studies, the design of the study includes a “control arm” and the patients who are randomized into this arm receive current standard treatment. The patients randomized to the “treatment arm” receive the treatment under investigation. It is very important that the patients in the treatment arm should be expected to be at least as successful, if not more so, than the patients in the control arm.

This year, PFC is participating in at least 4 clinical studies. Some, like our acupuncture study, are designed by PFC and are only being done at our facility. Some, like the GSN study, are being designed by the company and will be done at multiple IVF centers, then GSN will pool the data.  If you are interested, please let us know. I will be posting more details very soon to our PFC website.

UPDATE: Research web page is live

UPDATE: This study is currently on hold while we attend to some administrative details. Please check back to this blog often, as we will keep our readers updated.  You may also call the New Patient Coordinators at 415 834-3095 for more information.

PREVIOUSLY: Pacific Fertility Center is pleased to announce that as of October 1st we are enrolling patients into a groundbreaking research study to determine the value of combining acupuncture with IVF. Traditional

Chinese medicine has been practiced in throughout Asia for thousands of years:in the last decade, the west has been following suit.

There have been sufficient peer reviewed studies to warrant a clinical trial in which there are predictable parameters of patient involvement. One of the first studies involving acupuncture and IVF was published by Paulus et al in the journal Fertility Sterility in 2002. The Paulus study reported the influence of acupuncture on the pregnancy rate in patients who undergo assisted reproductive therapy. Clinical pregnancies were documented at 42.5% of patients in the acupuncture/IVF group, whereas pregnancy rates were 26.3% in the control group, using IVF alone. In this study, the acupuncture was performed before and after embryo transfer only.

How does acupuncture affect fertility? A review article in Alternative Therapies (Anderson 2007) suggested four possible mechanisms by which acupuncture could improve the outcome of IVF: modulatingneuroendocrine factors; increasing blood flow to the uterus and ovaries; modulating cytokines; and reducing stress, anxiety, and depression.

By the end of the year we will have started a new and very exciting research project in our lab. We have partnered with a company called Incept Biosystems (www.inceptbio.com) to do a clinical trial of a new embryo culture system called microfluidics.

The traditional culture dish with medium droplets under oil as described by Brinster, R.L., 1963, Exp. Cell Res., Vol. 32

This involves culturing embryos in very small volumes of culture media inside a chip specifically designed for this purpose. Tiny pumps regulate the flow of culture medium in and out of the chip without causing the embryos to move around.

The traditional vessel for embryo culture is the petri dish, where small droplets of culture medium are overlain with a highly purified mineral oil. The culture medium, regulated in much the same way as pharmaceuticals, is one of the most highly tested and expensive components of the IVF laboratory operation. We typically make droplets of medium that are in the 50-200µl size range, and the oocytes or embryos are placed in the droplets for 24-48 hours at a time. This is a static culture system where nutrients are depleted by the developing embryos and waste products (e.g. ammonia from amino acid breakdown) accumulate over time. The droplets are large enough to make sure that the supply of nutrients is more than adequate and that waste is diluted to the point of not harming the embryo in any way. The embryos are changed into fresh medium at least every 48 hours.

This system for embryo culture has been in use since human IVF began in the late 1970′s and early 1980′s. It was actually developed in the early 1960′s by a pioneer of mouse embryo culture, Dr Ralph Brinster, at the University of Pennsylvania. Some early human embryologists cultured embryos in small test tubes without the mineral oil, but nowadays, despite the age of this technique, it is very unusual to find a facility that does not use the droplets under oil method. After 45 years, perhaps it is time for a change?

A microfluidic system for embryo culture has been in development for over 5 years at the University of Michigan in Ann Arbor. Professor Gary Smith combined the talents of his graduate students in physiology with those of engineering students and came up with a device that has had outstanding results with growing mouse embryos. Professor Smith is no stranger to IVF, as he was the director of the University’s IVF Laboratory for many years and he was instrumental in designing and testing the vitrification system that we now use to preserve oocytes and embryos. He solicited venture capital to start Incept Biosystems with the intent to bring microfluidics into human IVF labs. Incept Biosystems were onsite at PFC during the last week of October to train our embryologists on the use of the system. We did several trials with mouse embryos to achieve proficiency with the system and then we will actively recruit patients to enroll in a clinical trial using the system.

The clinical trials are being run at 3 centers in the US. In addition to PFC, patients will participate at the Fertility Center of San Antonio and at Southeastern Fertility Center in Charleston, South Carolina.

A schematic of a microfluidic embryo culture device with fresh medium in blue and spent medium in red. The embryo is contained at the base of the chamber, where the blue medium ends.

Patients that are asked to participate will have to consent to the study, where their embryos will be divided into 2 groups for culture in the microfluidic device and in the traditional petri dish. The culture media will be the same for all the embryos, but half will be in a replenishing media current (microfluidics) and half will be in our traditional static culture.

Microfluidics has had impressive results with mouse embryos where it significantly increased rates of development and implantation over those for embryos grown in static culture. Cell numbers for the microfluidic embryos were almost twice as high as for traditional culture (110 vs. 65), and pregnancy rates from transferred embryos were increased by 22%. Incept Biosystems have tested the new technology extensively and have been able to obtain surplus IVF embryos donated for research for human trials. There are some nice videos on their website that showcase the equipment and procedure, and detail the mouse embryo results. Professor Smith presented the results and won the prize paper at the 2008 American Society for Reproductive Medicine (ASRM) meeting (Smith et al., 2008, Fertility and Sterility, Vol 90, pages S1-S2), and these results will soon be published in a peer reviewed journal.

We will be asking for participants to join the study, beginning in November and continuing for 2-3 months. This is a short study requiring enrollment of only 20 patients, but a larger study is planned for next year subject to favorable outcomes here. If you are interested in the study and would like more information, please ask your physician at your next visit.

Pacific Fertility Center is pleased to announce the launch of our in-house mind-body medicine program. We are offering on-site acupuncture and mind-body groups to further support your treatment choices.

Over the years, Pacific Fertility Center (PFC) patients have elected to receive acupuncture treatment in combination with IVF and other fertility treatments. These treatments have been provided at outside facilities. We now offer acupuncture on-site, to minimize the stress of visiting numerous providers during your treatment cycle. We recognize that family building choices are diverse and want to support you throughout your important, personal decisions on your journey to parenthood.

This new service offers the expertise of acupuncturists who specialize in reproductive care. Our acupuncture team will work in close communication with the physicians of PFC. The result is a program that supports you with safe and convenient treatment. This exceptional new team is comprised of four licensed acupuncturists (LAc) who hold Masters of Science degrees in Traditional Chinese Medicine from accredited schools in California.

The medical team at Pacific Fertility Center is proud to provide this new service. While current studies do not show improved pregnancy rates with the combination of IVF and acupuncture treatment, we look forward to collaborative research studies to clarify these important questions. Together, we are launching exciting research projects that will investigate the scope and effectiveness of combined acupuncture and assisted reproductive technologies. Fertility Flash will provide readers with more information as the research program develops.

We hope you will enjoy getting to know the acupuncturists and take advantage of these new treatment options.

Pacific Fertility Center continues to offer the Mind/Body@PFC Workshop. At the workshop, our experienced, Alice Domar-taught instructors help patients learn healthy, positive ways to relax and decrease the symptoms of stress during their fertility treatments.

It is our hope that these offered services will provide a more comprehensive approach to your journey through fertility treatment with us at PFC.

Learn more about the acupuncture program at PFC

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 #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 articles on: Sperm Aging: Fertility Flash Feb. 2004, Sperm Fragmentation: Fertility Flash March 2005, 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

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 #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

References:

(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.

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.

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

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 #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

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

In late October of this year, our first patient who underwent embryo transfer with embryos created from vitrified and warmed donor oocytes has successfully delivered. The baby was born at term and appears to be perfectly healthy.

Three other pregnancies are ongoing and are expected to deliver in 2008. We congratulate our new parents and the parents-to-be who have participated in this ground breaking program.

PFC has ended enrollment of patients into this program, but expects to continue research efforts with respect to oocyte vitrification.