Endometriosis was a puzzling disease when first described by pathologist Rokitansky in 1860. Though we now have a clearer understanding of some aspects of the biology of this disease, it still remains largely a mystery 150 years later.

Endometriosis affects about 5 million women in the U.S. Of women with infertility, approximately 25% are diagnosed with endometriosis. The symptoms fall into two categories: 1) pelvic pain, most significantly with menses, and 2) infertility. The definitive method to diagnose this disease is surgery. A laparoscopy is performed to obtain tissue biopsies of typical peritoneal lesions (peritoneum is the internal layer overlaying pelvic organs including the uterus, fallopian tubes and ovaries); and confirm the presence of endometrial glands in those biopsies. The American Fertility Society has created a classification scheme which grades the disease (Grade I-IV). It is important to understand that there is not necessarily a correlation between pelvic pain and the severity (or grade) of the disease. Another method for presumptively diagnosing endometriosis is with ultrasound, if the patient has endometriosis ovarian cysts (endometriomas), or with MRI if one there is endometriosis growth in the
uterine muscle layer (adenomyosis).

A diagnosis of even minimal to mild endometriosis (stage I and II) can have significant consequences on fertility success rates. A fertile 30 year old woman has about a 25% chance of pregnancy per month (fecundity rate). A patient diagnosed with minimal to mild endometriosis has about a 3% monthly fecundity rate (1, 2, 3). If surgery is performed to dissect and remove the visible endometriosis lesions, the fecundity rate improves to 6%; but this is still much lower than the 25% afforded a fertile 30 year old. If that same patient undergoes ovarian stimulation and insemination cycles, her monthly fecundity rate increases to 11% (4). If the combination of ovarian stimulation/IUI treatment is going to increase chances of pregnancy, results are usually seen within the first 3-4 treatment cycles. Undergoing additional IUI cycles is not typically beneficial, and proceeding to in-vitro fertilization (IVF) treatment would be the next step. For patients with severe endometriosis, gonadotropin/IUI therapy is of minimal assistance. Most patients with moderate to severe endometriosis (stage III and IV) will need to pursue IVF therapy (5).

IVF studies from the 80s and 90s indicate that patients with endometriosis have a slightly lower chance of achieving a pregnancy than patients with other infertility diagnoses (6). With current IVF laboratory techniques and current ovarian stimulation strategies, this difference will probably disappear—but up-to-date studies are needed as proof. When assessing if the lower pregnancy rate is because of a uterine or ovarian issue, it appears that the uterus of endometriosis patients is effective in providing a supportive environment for the embryo to attach (7). However, the oocytes (eggs) from endometriosis patients, particularly those with endometriomas, seem to have some compromised quality (8). This lower egg quality seems to lead to less healthy and effective embryos, and therefore overall lower pregnancy rates.

We clearly understand that strategies of suppressing endometriosis growth by using medications such as birth control pills, Danazol, Lupron or others, does not lead to improved pregnancy rates (9). The concept of a fertility “rebound” post-medical suppression has been proven false over-and-over again. These strategies only lose potentially precious time for the patient. Similar strategies of using medical suppression post surgical removal of endometriosis also fail to improve fecundity rates. The best approach is to move forward with an appropriate form of fertility treatment as soon as the patient desires fertility.

How to treat endometriomas has been debated, but we now have some studies to guide us. Collectively these studies indicate that patients who have undergone surgery for their endmetrioma(s) have the same IVF outcomes as those where the endometrioma(s) was left alone (10). We feel that the patient’s current clinical situation should be scrutinized carefully before recommending ovarian surgery for a patient who is seeking fertility. With surgical removal of an endometioma (ovarian cystectomy), we know that the ovary where surgery is performed will have fewer eggs and less normal ovarian tissue post surgery (11). This implies that we will have a lower chance of gathering eggs in an IVF cycle. Additionally, the patient will have a greater chance of having an elevated FSH after a cystectomy procedure, especially if she undergoes cystectomies of both ovaries (11). The risk of premature ovarian failure (POF or premature menopause) for a patient undergoing cystectomies of both ovaries for endometriomas is about 2% (12).

Historically the strategy for treating endometriosis has been to surgically remove or hormonally suppress its growth with various medications. As we better understand the biology of this disease, we can use more targeted therapies which interrupt the biochemical pathways that promote the growth of endometriosis lesions: aromatase inhibitors, estrogen and progesterone receptor blockers, angiogenesis inhibitors, etc. All of these types of medications are being studied in endometriosis patients. The future may hold some promising new medical options.

In summary, endometriosis clearly affects fecundity rates, even with minimal and mild disease. Using hormonal medications to suppress endometriosis provides no improvement in pregnancy rates, and surgical intervention provides minimal improvement. Most patients will need to pursue fertility treatment. For patients with moderate to severe disease, they most often will need to pursue IVF. For patients with endometriomas, careful consideration has to be given to all factors (age, assessment of egg quality, prior fertility treatment, etc.). The patient needs to be fully counseled prior to surgery, including risk of diminished ovarian quality (DOR) and premature menopause (POF). Patients with adenomyosis seem to have impaired implantation rates, and those with severe adenomyosis may need to consider a gestational carrier. Having a clear understanding of endometriosis as it impacts fertility, and having realistic expectations with each treatment type is most important when choosing fertility treatment options.

– Isabelle Ryan, M.D.

References

1. Jansen RP, Fertil Steril 1986; 46:141-3
2. Marcoux et al, NEJM 1997; Jul 24; 337(4):269-70
3. Parazzini, Hum Reprod 1999; 14(5):1332-4
4. Tummon et al, Fertil Streil 1997; 68(1):8-12
5. Dmowsky et al, Fertil Steril 78:750 2002
6. Barnhart et al, Fertil Steril 2002; 77:1148-1155
7. Diaz et al, Fertil Steril 2000; 74:31-34
8. Simon et al, Hum Reprod 1994; 9, 725-9
9. Hughes et al, Cochrane Database Syst Rev 2007; 3:CD000155
10. Tsoumpou et al, Fertil Steril 2009; 92, 75-87
11. Li et al, Fertil Steril 2009; 92(4):1428-35
12. Busacca et al, Obstet Gynecol 2006; (195), 4

A Reproductive Endocrinologist (REI) is a specialist in Reproductive Endocrinology and Infertility, a medical doctor with advanced training in the science of fertility and its evaluation and treatment.  An REI focuses on the hormones and mechanics of conception with advanced knowledge of sperm, eggs, male anatomy, female anatomy, and the complex interactions between pituitary and reproductive hormones.  An REI will be trained in evaluating the problems that can interfere with conception, and has in depth knowledge of the treatments for fixing these problems.

An REI starts training after medical school in a 4 or 5 year residency in obstetrics and gynecology.  Specialty training in reproduction after residency requires 2-3 years at an advanced educational and research institute.  The fellow in REI works side-by-side with experts in the field, developing clinical expertise in evaluation and treatment of fertility, and researching new areas of reproduction.  The REI will be trained in laboratory and clinical research techniques, the mechanics and hormones of fertility, and in maintaining a lifelong love of the pursuit of advancing knowledge of fertility.

After completing the fellowship, an REI is “board eligible”. To be “board certified,” an REI must publish a thesis in a peer-reviewed journal. The REI must pass an in-depth written exam and then appear before experts in the field for an oral exam to test their depth of knowledge, defend their thesis, and demonstrate reasoning in solving fertility problems.  If they pass the exams, they are then “board certified”. This certification is the highest level of achievement in the field of infertility.

All REIs certified since 1990 are required to maintain their certification every year (a few are grandfathered in).  This involves reading and evaluating peer-reviewed journal articles on current advances in the field, and a written exam every year.  New standards require demonstration of clinical knowledge and a commitment to advancing standards of clinical care, the Maintenance of Certification (MOC) process.

While there is no formal requirement, most REIs will maintain membership in national and international fertility societies, such as the Society for Reproductive Endocrinology and Infertility (SREI).  The Society for Assisted Reproduction (SART), devoted to in vitro fertilization and its variants, does not require REI certification.  The American Society for Reproductive Medicine (ASRM) is the umbrella organization supervising these specialized societies.  Most anyone with a professional interest in fertility can join ASRM, but SREI requires board certification.

At Pacific Fertility Center, we bring a complete team of specialists together to focus on your fertility situation. With extensive backgrounds as REI specialists, embryologists, nurses, marriage and family therapists and financial counselors, we develop a single, integrated solution to your medical, psychological and financial needs.

Please use our Ask the Experts resource if you have further questions.

– Philip Chenette, MD

Spring, a time for celebrating Mothers and Fathers, can be a particularly difficult time for infertility patients. Because dealing with these two holidays can be a challenge, I have some suggestions for ways to develop some good coping skills. To cope is to “develop the ability to manage in a difficult situation.”

Here are a few suggestions:

1. Give up any and all feelings of guilt for how you are feeling! There is no right or wrong way to experience Mother or Father’s Day.
2. Know your limits and stick with them. If attending a family gathering is too painful, then don’t. You can still write a caring letter to your parent letting them know how you feel about them. If you do feel comfortable attending a family gathering, then do.
3. Plan to do something that is unrelated to parenting.
4. Attend religious services if you are comfortable knowing that the focus may be on mother’s or fathers. Perhaps you can ask your religious leader to say a prayer for those who have not yet achieved parenthood or are dealing with some other sort of crisis.
5. Plan for how you will answer uninvited questions about how you are feeling. Remember, you are not required to tell them your entire “story!”
6. Communicate with your partner to let him/her know of your feelings. Even if you and your partner are feeling differently about Mother’s or Father’s Day, it may help to share. If you are single, call a friend with whom you feel safe to share your feelings.
7. If you think it might be helpful, please call the clinic and set up an appointment with me, at no charge. Our number is 415-834-3000.

– Peggy Orlin, MS, MFT

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.

On May 15th, we were fortunate to have Dr. Daoshing Ni, D.O.M, L.AC., Ph.D., a Licensed Acupuncturist in the State of California, a Diplomat of Chinese Herbology, and a 76th generation acupuncturist come to speak at PFC about the benefits of combining acupuncture and ART.

Dr. Ni spoke about some of his own research studies on acupuncture and ART and also discussed some of the issues with the current protocols that are being used today. He emphasized that the Paulus protocol is a good guideline when doing embryo transfers, and he encouraged the addition of other supportive acupuncture points. He also strongly encouraged that patients be treated with Chinese medicine for at least 3 months before their ART cycle begins. Dr. Ni also spoke about how the use of Chinese herbs contribute to improving egg quality.

This outstanding program was attended by PFC’s acupuncturists, physicians, and staff. In addition, area wide acupuncturists were invited to hear Dr. Ni’s presentation, meet one another, and share ideas.

We are excited to introduce a new website FertilityWire, http://fertilitywire.com.  This site is separate from our current website www.pacificfertilitycenter.com.

FertilityWire will provide access to a wealth of fertility information, news, and social content. Please take a moment to check out this exciting new resource. You can let us know what you think in the comments section.

Enjoy!

-Robb Mayberry, Director of Development

In January, Dr. Carolyn Givens and I attended a meeting in Hawaii organized by the American Board of Bioanalysts (ABB). This organization board certifies and licenses embryologists, andrologists, and a number of other laboratory specialists in the United States. Our meeting was under the direction of the College of Reproductive Biology, a special interest group within the ABB and for which I am the immediate past Chair.

The meeting was small and intimate, a situation always welcomed among reproductive biology professionals. The location allowed for good interaction with embryologists from Japan who have always been a great source of ideas and innovation within our specialty.

In fact, the highlight of the meeting was a series of videos shown by Dr. Yasuyuki Mio from the Mio Fertility Clinic in Yonago, Japan. He was able to take time-lapse cinematography of human embryos in culture, and as a result reported some novel observations on how oocytes fertilize and how embryos develop. The actual moment of sperm entry into the oocyte was recorded and it was possible to see that human oocytes form a fertilization cone (a membrane that helps bring the sperm into the oocyte), shortly after sperm entry. The events that follow (2nd polar body extrusion, which is the egg extruding a set of chromosomes, and pronuclear formation, alignment of the nuclei from the egg and sperm) occurred as expected, but for the first time the male and the female nuclei could be distinguished from each other.

After fertilization, the embryos were seen to change dramatically as they developed. In particular, they appeared more disorganized and untidy immediately after a cell division event and more symmetrical and organized several hours later. This discovery has implications for those embryos that sometimes may appear poorly. It suggests that they may look better later in the day when they are clear of the cell division process. Another important observation regarding blastocysts, is that those that develop 2 inner cell masses (ICM: the precursor cells of the fetus) do so in a predictable way. At PFC, we avoid using embryos with two ICMs whenever possible, as they are likely to lead to the formation of identical twins. A normal embryo should have only a single ICM. Currently, it is possible that one of the ICMs may be small enough to avoid detection. The observation was made that the fine cellular bridges within the embryo cavity appear to correlate to the presence of an extra ICM.

Another notable presentation was that of Dr. Tetsunori Mukaida, of Hiroshima HART Clinic, on sperm morphology. He demonstrated that observing sperm under ultra-high magnification can show structural defects that are not always visible when using standard microscopes. While magnifying sperm thousands of times has its difficulties, Dr. Mukaida reported that sperm with subtle physical defects have a much lower chance of making an embryo that can become a baby. Sperm that are close to perfect in size, shape and structure are difficult to find in any sperm sample and it can take hours just to find a few ideal sperm. However, the extra effort may be worthwhile, especially in patients that have had a previous IVF cycle where the embryos did not develop well or implant after transfer. PFC is currently looking into this technology and we will report more details in a future issue of Fertility Flash.

Attending meetings like this and keeping up with the latest developments in our field is an important part of the culture at PFC. We share the load of traveling to educational events and are always excited to bring home ideas and thoughts to share with our colleagues. PFC is committed to implementing the latest technology and innovations to maximize pregnancy rates for our patients. We will continue to stay updated with all of the research and development in our specialty.

Both Dr. Givens and Dr. Conaghan contributed to this article.

	Joe Conaghan, Ph.D., HCLD is PFC’s laboratory director. Dr. Conaghan is internationally recognized for his work on improving embryo culture conditions. His interests include developing programs for the treatment of severe male factor infertility; diagnosis of genetic disease in embryos; and improved embryo culture. See more posts
	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. See more posts

Stress is no stranger to most of our lives. The everyday, chronic strain of a demanding job, driving in traffic, dealing with relationships, taking care of the chores of life, all leave us feeling “stressed out.” “Does stress cause infertility?” No matter what the answer to the question, it is important to look at ourselves and determine just how stressed we are. We need to then take steps to attempt to reduce the stress. One undisputable fact is that it makes good sense to reduce our stress to the lowest levels possible. At the very least, you will feel better!

To provide you with the opportunity to assess your fertility stress, we have added a Stress Test domar© to our website at www.pacificfertilitycenter.com. Click on “for patients” then “support” then “infertility stress test.” The test is brief and it generates a stress level score with comments. You can take it as frequently as you would like.

The goal of stress reduction is to reach what Harvard physician, Herbert Benson calls the “relaxation response.” It’s like stress running backwards. We can calm our racing minds. We can soften our tense bodies. The relaxation response leads to a series of changes that take place in the body and mind as you calm down. Your heart rate, muscle tension, breathing rate, and oxygen consumption fall below resting levels. Your brain wave patterns become slower. There are many ways to elicit the relaxation response. The goal is to find the one that works for you, meaning that it reduces your stress and you will take the time to practice it!

One way to learn about all of these techniques is to participate in our Mind/Body class. We discuss and practice each of the following methods; progressive muscle relaxation, breathing techniques, yoga, visualization, mindfulness meditation, and journaling. It is a wonderful day where you get to meet others going through treatment, learn some new skills, eat some excellent food and de-stress.

In addition to learning specific techniques to reduce stress, it may also be helpful to consider the following suggestions:

-Give up any and all feelings of guilt for how you are feeling. There is no right or wrong way to experience infertility. Your feelings may run the gamut from indifference to intense anger and despair and everywhere in between.

-Choose the gatherings you attend carefully. If being around children or babies upsets you, gracefully decline invitations to events where they are likely to be present. Know your limits and stick with them.

-Continue to get moderate amounts of exercise. Eat healthy and get plenty of rest. You will feel better if you treat your body with care.

-Communicate with your partner to let him/her know of your feelings. Even if you and your partner are feeling differently it may help to share. If you are single, call a friend with whom you feel safe to share your feelings.

-Meet and talk with others who are experiencing similar feelings. Finding that you are not alone helps.

We offer these stress reduction workshops every quarter. There is no charge for PFC patients to attend. Join us!

Participants in a workgroup.	Practicing micromanipulation

On November 8 th and 9 th, 2008, PFC held a training course for embryologists interested in learning the techniques associated with Preimplantation Genetic Diagnosis (PGD).

The course was organized in conjunction with the Genetics and IVF Institute (GIVF) of Fairfax, Virginia and was originally scheduled to run on the Sunday only. However, due to the overwhelmingly positive response to attend the course, PFC decided to offer the course on Saturday as well. Forty seven individuals heard excellent lectures over the 2 day period.

Dr Dagan Wells from Oxford, UK and Dr Alan Thornhill from London, UK, gave talks on current and future technologies for genetic testing on embryos. Participants were then divided into 4 working groups that spent the rest of the day rotating between activities. The activities included embryo biopsy training, cell fixation training, media and solution making and PGD troubleshooting. Lauri Black, MS, CGC, a Certified Genetic Counselor at California Pacific Medical Center and Mary Sands of GIVF gave talks on genetic counseling. The course also allowed embryologists from all over the world to view the new state of the art laboratory at PFC.

Joe Conaghan, PhD, HCLD

Pacific Fertility Center launched it’s Educational Series on July 31 st with a presentation on the “Disclosure of Use of Sperm or Egg Donors.” The speaker was Dr. Bob Nachtigall, a local Reproductive Endocrinologist, who has done much research and published numerous papers on various fertility related issues. Dr. Nachtigall addressed the difficult decisions couples face, who attempt conception with donor sperm or donor eggs. These include when to abandon medical treatment using their own gametes, whether to conceive with donor gametes over other options such as adoption, and decisions related to the selection of a donor. Yet the final decision, whether to disclose to their children the circumstances of their conception, is one of the most challenging.

He and his team, conducted research which was based on interviews with 254 parents of children conceived with donor sperm or eggs, they found that 95% of study couples came to a united disclosure after discussions that reflected a wide range of contexts and influences that included: the sociopolitical environment of the community; the couples’ friendships and support network; counseling and professional opinion; religious and cultural background; extended and immediate family structure and relationships; the child’s appearance; and the couple’s individual personal and ethical beliefs. For those couples who decided to tell their young children about their use of a donor, no parent expressed regret or reported a negative outcome after having initiated disclosure.

Dr. Nachtigall will be returning to PFC, to present his findings from a research study he did on “Frozen Embryos.” The annual number of IVF procedures performed in the U.S. has increased from less than 2,500 in 1985 to over 120,000 today. Yet the rapid growth and availability of this advanced reproductive technology has had an unforeseen consequence – the accumulation of an estimated 500,000 frozen embryos that represent the unused “leftovers” of past IVF cycles.

His presentation will address the question of what to do with frozen embryos, which is complicated by the variety and disparity of their potential uses and fates: (1) they can be used by the couple in further attempts to conceive; (2) they can be “donated” to other infertile couples who wish to have a child; (3) they can be used in stem cell research; (4) they can be destroyed; (5) they can be stored indefinitely. Dr. Nachtigall and his team interviewed over 100 couples (many of whom were PFC patients) who had undergone IVF. The team found that ambivalence, uncertainty and most significantly, feelings of deep connection to a couple’s own embryos are several factors that cause difficulty in reaching a disposition decision.

The presentation on “Frozen Embryos” has not been scheduled at this time. However, please watch for dates and times in upcoming issues of Fertility Flash.

PFC Educational Series 2008

The PFC Educational Series are presentations held the last Thursday of each month from 4:00 till 5:30 p.m. in the PFC Education Center located at 55 Francisco Street, Suite 500. The presentations address various topics, which are open to PFC staff, as well as members of the medical community. The PFC physicians found offering programs of this nature would be an ideal way to increase knowledge regarding different topics. In addition, this is a great opportunity to “reach out” to other local physicians and their staff, by offering educational resources, that they otherwise may not have access. The presentations are offered at no charge and the topics will be published in the Fertility Flash, as well as on the website www.pacificfertilitycenter.com. If you are interested in attending this presentation, please contact our Development Department directly at 415-249-3656.