The 16th Annual In Vitro Fertilization and Embryo Transfer Comprehensive Update, July 2003, directed by Dr. Meldrum in conjunction with the Office of Continuing Medical Education, UCLA School of Medicine each year since 1987, attracted over 200 participants from the U.S. and around the world most of whom have been actively involved in IVF. Over the years Dr. Meldrum has gathered a renowned group of faculty who are excellent speakers, each of whom assume the responsibility for being right up to date on their assigned topics. Most U.S. IVF programs make a point of having one of their team attend at least every couple of years.

MALE FACTOR

Dr. Peter N. Schlegel (Cornell University Medical Center, New York, New York) spoke on evaluation of severe male factors. In azoospermic males, testicular biopsy is not usually necessary prior to sperm retrieval, but testing for Y chromosome deletions can be helpful since sperm have not been retrieved with complete deletion of the AZF-b or AZF-a portion of the Y chromosome. Men with sperm counts less than 5-10 million per ml should have a karyotype. The female partner of men with bilateral congenital absence of the vas deferens should be tested for cystic fibrosis mutations, since one can assume that the male is a carrier and available panels may not include all CF mutations that might be present in these men.

Dr. Agarwal (Cleveland Clinic) spoke on analysis of sperm chromatin and its relationship to male fertility and IVF outcome. Newer tests such as the sperm chromatin structure assay (SCSA) have shown that a high level of fragmentation of sperm DNA correlates with lower fertility and IVF success. The SCSA does not correlate with sperm morphology. Other studies have shown correlations of DNA fragmentation with increased oxidation products. It is therefore likely that antioxidants such as are available in nutritional supplements for men (e. g. FertilityBlend for Men) may have benefits in improved sperm DNA integrity. Sperm preparation methods may also be important. For example, Puresperm increases DNA integrity 450%.

Dr. Gianpiero Palermo (Cornell Medical College, New York, New York) spoke on ICSI, particularly with respect to whether it increases abnormalities. There have been reports of increased chromosomal abnormalities in ICSI offspring, most of which may be due to abnormalities in men with very abnormal sperm. Otherwise, the rates of congenital abnormalities and development have been the same as non-ICSI patients.

Dr. Schlegel spoke on sperm retrieval techniques. Their percentages of sperm retrieval in non-obstructive azoospermia have been 70% for XXY, 81% in hypospermatogenesis, 47% with maturation arrest, 25-30% with Sertoli-cell only, and 50% with prior chemotherapy. Only 33% have viable sperm after thaw. In men with sperm in the ejaculate found only with high speed centrifugation have lower pregnancy rates. Testicular retrieval of sperm may yield an improved outcome for these men.

IMPROVING IVF SUCCESS

Dr. Palermo spoke on their research in mice on nuclear transfer. They have been able to transfer immature nuclei from oocytes with induced cytoplasmic defects into donor oocytes whose nuclei have been removed, resulting in reconstituted oocytes, which are able to mature, to fertilize with ICSI, and to have normal embryo development. Limited studies were done in humans, although embryo development was sub optimal. Studies have also been done using somatic nuclei. This research is still quite preliminary. Progress will require demonstrating normal fetal development in animal models and improved culture techniques for maturation of immature oocytes in humans, but it remains a possibility in the future that such techniques could be a means to providing young cytoplasm for improved development of nuclei from older women.

Dr. William Schoolcraft (Colorado Center for Reproductive Medicine, Englewood, Colorado) spoke on the use of assisted hatching (AH). Although the literature has been mixed, the overall bulk of evidence shows improved outcomes with AH. It is highly technique dependent, which probably explains why not all IVF programs have seen improved success with AH. This was shown in one study reporting no benefit in which there were multiple clear deficiencies in technique.

Dr. Richard Scott (Reproductive Medicine Associates of New Jersey, West Orange, New Jersey) spoke on immunologic testing before IVF. His extensive review clearly showed that there is no benefit of testing for antibodies to phospholipids or thyroid or testing for natural killer cells or immunophenotype in women before IVF, including those with failure to become pregnant in prior IVF cycles.

Dr. Dominique de Ziegler (Hopital de Nyon, Nyon, Switzerland) spoke on uterine morphology, blood flow and contractions, which all influence implantation. His elegant presentation illustrated that the uterine factor remains an area with the most potential for improvement of IVF results.

Dr. Bill Yee (Reproductive Partners Medical Group, Southern California) spoke on treatment of the hydrosalpinx before IVF. Both salpingectomy and tubal interruption have resulted in normal IVF success. Rarely the enlarged tubes after tubal interruption can cause pelvic pain. There is a clear consensus that an ultrasound-demonstrable hydrosalpinx should be removed before IVF. A hydrosalpinx which is not visible on multiple transvaginal ultrasound scans may not interfere with IVF outcome, particularly if an endometrial biopsy shows normal integrin.

Dr. Gabriel Garzo (Reproductive Partners Medical Group, La Jolla, California) spoke on the luteal phase and transfer technique. Supplementation with both progesterone and estradiol enhances IVF success. Oral progesterone is not effective. Embryo transfer success is maximized by doing a trial or mock transfer, dilating the cervix if necessary, thorough cleaning of the cervix prior to transfer and by using ultrasound guidance.

Dr. Joseph Gambone (UCLA School of Medicine, Los Angeles, California) spoke on pregnancy outcomes following IVF. Although many studies have shown no differences between IVF and normal pregnancies in abnormalities, recent publications have suggested as much as a two-fold difference. This could represent publication bias or a statistical outlier. With so many studies showing no difference, it is likely that any increase is very small. There have been reports of increased prematurity or small for dates. A very recent report of these same associations with ovarian stimulation for intrauterine insemination suggests that these differences may be due to ovarian stimulation or infertility rather than to IVF. A small increase of placenta previa has been reported. This may be due to the variable placement of embryos with embryo transfer and could be reduced by ultrasound guidance. There have been reports of rare imprinting disorders being associated with IVF. Investigations are ongoing to determine whether these disorders are associated with any particular culture conditions or manipulations. It is important to keep perspective. Relative to the 2-3% chance of a major abnormality with any pregnancy, any possible increase related to IVF is probably a fraction of a % and may be related to infertility rather than the procedure. This issue continues to be subject to extensive scrutiny by our profession.

RPMG-TWENTY YEARS AND 4,000 IVF AND GIFT BABIES LATER, FERTILITY DOCTORS STILL GET KICK OUT OF BRINGING JOY TO INFERTILE COUPLES

It has been 20 years now since Dr. David Meldrum and Dr. Bill Yee of Reproductive Partners Medical Group (RPMG) led this country’s pioneering efforts into the exciting and uncharted world of in vitro fertilization.

Dr. Meldrum was a faculty member at UCLA and Dr. Yee at USC in the 1980s before deciding later to join forces in ultimately forming RPMG, one of the country’s leading fertility centers. Dr. Yee opened one of the first private practice infertility programs in the country, and also performed the country’s first frozen embryo transfer, resulting in a successful pregnancy and delivery. Dr. Meldrum performed the first ultrasound-guided egg retrieval resulting in a successful pregnancy and introduced IVF to a group of visiting Chinese physicians interested in duplicating the program in their country. He helped launch China’s first IVF program.

Over the course of their distinguished careers, the two fertility specialists have been involved in the conception and birth of more than 4,000 babies from assisted reproductive technology (ART), not to mention countless others in which they performed conventional fertility treatments and surgery that resulted in pregnancies and births.

Describing their work over the past 20 years as “challenging” and “fulfilling,” both doctors entered the field for different reasons. Dr. Meldrum was working in general infertility and surgery at UCLA when he became convinced that IVF was a far better approach than surgery. He and his wife were experiencing fertility issues of their own at the time, and despite the fact that he was on the ground floor of breakthrough IVF research; his wife became pregnant as a result of ovarian stimulation through the use of Perganol. She later delivered quadruplets, who are now 28.

Dr. Yee discovered his life’s work purely by luck, he says. As a senior OB/GYN resident in 1982, he was unaware that USC even had an IVF program. Dr. Yee was merely investigating the delay of a surgery when he was asked if he would assist with an egg retrieval procedure, which then was performed surgically using a method called laparoscopy. When the eggs were removed and he later examined them under a microscope, he immediately became excited by what he saw. “I fell in love with the human egg,” Yee said. “It was an incredible sight to behold.”

Over the years, both doctors have witnessed significant changes in the techniques that have been instrumental in the rapid growth, popularity and success of IVF in just two decades. Once the exclusive domain of university medical schools up until the 1980s, IVF programs later moved into the private practice realm, which opened up and exposed the new procedure to many more doctors and patients. Technological advancements in egg retrieval, embryo freezing, ICSI, and egg donation, plus continuing societal pressures on women to conceive by a certain age, have kept IVF at the forefront of infertility solutions and have contributed greatly to its increased acceptance and success worldwide.

Even after 20 years, Drs. Meldrum and Yee still find themselves enthusiastic over the evolution of IVF and the tremendous strides it has made, and continues to make. “Just when you think everything about IVF has been discovered, you hear about some new procedure or technique or technology that gets you excited and you want to learn about,” Dr. Meldrum said. He cites an example of a recent study indicating that biopsies performed on the lining of the uterus in the cycle before IVF takes place actually produced improved pregnancy success rates. The study suggested the body’s healing reaction to the biopsy allowed embryos to attach more effectively to the uterine lining and flourish, resulting in more pregnancies in the study group. “A fortuitous observation,” Dr. Meldrum said.

Besides the new procedures and technological advancements that keep them on the cutting edge of fertility and excited about their work, the doctors agree that the real rewards come in the form of patient gratification. When couples return to RPMG’s annual Parent’s Day celebrations with their children or the doctors are invited to attend birthday parties for IVF children because they are considered part of the family, their pride swells. “I just received a graduation picture from my first successful IVF case, a young woman who is now 19 and living in Colorado,” Dr. Meldrum said. “That’s when all this really hits home and is extremely rewarding.”

Dr. Yee truly enjoys the thread of humor contained in remarks he often hears from joking fathers who introduce him to others as “the guy who got my wife pregnant.” “We all laugh about it, but it’s very nice that they consider you such an important part of their families,” Dr. Yee said.

The doctors are also in agreement about the reasons behind the tremendous success rate of RPMG. The group’s success is the result of the combined knowledge, experience, commitment and dedication of the staff, and its team approach to each case. It’s also the result of proven leadership and outstanding administrative and technical support. But in the end, success is ultimately in the hands of the couple, and fate.

“We do our jobs by bringing sperm and egg together,” Dr. Yee said. “After that, it’s up to Mother Nature to do her part.”

STIMULATION PROTOCOLS

Dr. David Meldrum (Reproductive Partners Medical Group, Southern California) spoke on standard stimulation regimens.  The majority of programs use a combined oral contraceptive (OC)/ gonadotropin releasing hormone (GnRH0 agonist (usually Lupron) regimen that allows flexibility without the menopausal symptoms accompanying extended use of Lupron.  With this regimen, it is customary to use some LH activity as part of the stimulation either in the form of human menopausal gonadotropins (hMG) or a small dose of human chorionic gonadotropin (hCG).  Dr. Meldrum has suggested using 20 or 30 units per day based on a study he did with one of the UCLA fellows showing the ability of “mini-hCG” to replenish the levels of LH activity in women who are suppressed.  This very simple protocol avoids the use of hMG which requires intramuscular injection or causes significant reactions in some women when given subcutaneously.

Dr. William Schoolcraft (Colorado Center for Reproductive Medicine, Englewood, Colorado) spoke on the use of pure follicle stimulating hormone (FSH) versus hMG.  Reduced outcomes have been associated with very low luteinizing hormone (LH) levels.  Under certain circumstances such as full dose Lupron, O.C./Lupron and antagonist, use of a combination of FSH and hMG may improve overall results.

Dr. Francois Olivennes (Hospital A. Beclere, Clamart, France) spoke on GnRH antagonists which simplify ovarian stimulation.  Although overall experience has shown about a 20% lower pregnancy rate with antagonist, experienced centers appear to be getting results equivalent to GnRH agonists.  It is important to maintain or even increase the gonadotropin dose when the antagonist is begun, since endogenous gonadotropins fall.  Use of pretreatment with an oral contraceptive will allow flexibility.  Administering some LH activity will prevent a reduced outcome for women whose LH levels markedly fall.  Starting the antagonist at 14 mm will prevent prolonged administration and limit any possible adverse effects on the endometrium.

Dr. Richard Scott (Reproductive Medicine Associates of New Jersey, West Orange, New Jersey) spoke on reserve testing and stimulation of the poor responder.  He emphasized the value of the basal follicle count in predicting outcome in addition to day 3 FSH and the clomiphene challenge test.  When the resting follicle count is less than 4, all outcomes are markedly reduced.  The two most common regimens for poor responders are “mini-dose Lupron” and Antagon (GnRH agonist). In his experience, the GnRH antagonist appears to yield results equal to the mini-Lupron flare.

SELECTION OF PROCEDURE

Dr. Bill Yee (Reproductive Partners Medical Group, Southern California) spoke on the GIFT procedure (gamete intrafallopian transfer), emphasizing its role in particular circumstances.  GIFT has been particularly successful with donor sperm, probably because of a more consistent fertilization than with infertile husbands sperm.  When embryo transfer continues to be difficult in spite of cervical dilation and ultrasound-guided transfer and the male factor is fairly normal, GIFT may be an excellent choice.  Finally, the trend has been toward higher results with GIFT for women over age 42, although no well-controlled study has been done comparing IVF and GIFT in this age group.

Dr. Gabriel Garzo (Reproductive Partners Medical Group, La Jolla, California) spoke on gestational surrogacy and mainly emphasized the complexity of this process and that surrogate agencies vary considerably in quality.  Patients should be referred to physicians who do surrogacy and are familiar with agencies that do this well, rather than to choose the agency from the Internet or other promotional materials. It is one of the most complex ART procedures but can be very gratifying for patients, surrogates and medical staff.

Dr. Joseph Gambone (UCLA School of Medicine, Los Angeles, California) discussed uterine factors and ART. Generally polyps and submucous myomas should be removed before ART. Specifically, the data on fibroids and IVF clearly shows reduced outcome with submucosal fibroids distorting the cavity.  The data on intramural (in the wall) fibroids not distorting the uterine cavity are mixed. Clearly the chance of an intramural fibroid preventing pregnancy or causing miscarriage will be greater if the fibroid is large or very close to the cavity. The data on polyps is scant since they are generally removed.  The consensus is that all except very small polyps (e.g. less than 5 mm) should be removed before IVF.

LABORATORY TECHNIQUES

Dr. Kwang-Yul Cha (Pochon CHA University, Seoul, Korea) reviewed the subject of human oocyte (egg) and ovarian tissue freezing.  Egg freezing is now successful enough to offer to women before having chemotherapy or radiation.  In some cases a woman might choose to store her oocytes to maintain her fertility options.

Dr. David K. Gardner (Colorado Center for Reproductive Medicine, Englewood, Colorado) spoke on holistic approach to IVF, emphasizing the importance of ovarian stimulation, testing of all laboratory materials contacting the gametes and embryos, culture media, laboratory factors such as the ratio of the number of incubators to the number of cases and embryo transfer technique.

Lucinda Veeck, MLT, DSc (hon)  (Cornell University Medical Center, New York, New York) discussed the aspects of embryo morphology which have consistently been associated with implantation.  The most important are early cleavage to the two-cell, even 8 cell embryos, lack of multinucleated blastomeres and absent or minimal fragmentation.

All in all, the meeting was a great success.  This conference is unique in the world in having such a large number of speakers who are leaders in the field each indicating the methods associated with optimal results at each step in this complex process.  The U.S. has become a clear leader in IVF success in the world.  There is little doubt that this conference and its excellent faculty have played a significant role in that regard.

Next issue of Reproductive Times will feature Part 2 of the Highlights of the 16th Annual In Vitro Fertilization and Embryo Transfer-A Comprehensive Update-2003 including sections on male factor and improving IVF success.

Reproductive Partners Now Offering Telephone Consultations

Because of the overwhelming response to our website, two years ago we introduced Reproductive Partners Worldwide (RPWW). The purpose of RPWW is to make the programs and facilities of Reproductive Partners available to couples throughout the United States and around the globe.

Now, in conjunction with RPWW, we are offering telephone consultations to couples that do not live in Southern California and need a formal second opinion or would like to explore the possibility of coming to a Reproductive Partners facility for treatment.

Prospective patients need to understand that a telephone consultation has its limitations and is not as valuable as a face-to-face meeting in which we are able to perform a physical examination and ultrasound, if necessary. However a review of the previous medical records and a discussion of relevant issues will provide far more information and direction than visiting web sites or posting on a bulletin board.

To make an appointment with one of the RPMG doctors offering telephone consultations, call the appropriate office to make arrangements:

Our interactive bulletin board and e-mail communications show that there are unmet needs for couples in many parts of the U. S. as well as in the rest of the world. Until now we have tried to meet some of the educational needs through our website and books. In addition to consultations and telephone consultations, we can now also make IVF cycles more accessible for couples from other locations.

The key to success of this effort is good communication. By utilizing modern communication technology such as e-mail, faxes and the Internet, we will be able to share information with a couple’s physician close to home.  That will minimize the time required for the couple to be present in one of Reproductive Partners’ nationally recognized centers in Southern California.

Travel arrangements can be made through the patient’s travel agent or a special travel consultant to take advantage of specially priced accommodations. An IVF cycle would require the female partner to be near one of our facilities from seven to ten days, while the male partner would have to be present for one to two days at the time of egg retrieval.

Although telephone consultations are now available, we feel it would be best that the couple have an in-person consultation in order that we may meet face-to-face and perform the pre-cycle semen analysis, semen culture and trial transfer at the time of the initial consultation. The remainder of the pre-cycle testing can be done close to one’s home. We will work with the couple’s physician to perform these vital tests. If a couple chooses, we can offer a telephone consultation and arrange to have the semen analysis, culture and trial transfer done in the couple’s home city.

We will instruct the patient’s local physician in monitoring the initial portion of the preparation and stimulation phase and request the female partner arrive at a Reproductive Partners facility starting with the sixth day of stimulation. She should plan to stay until the completion of two days of bed rest following the transfer.

To make an appointment for a consultation, semen analysis, trial transfer and other precycle testing please call one of the offices for the doctor you wish.

To make travel arrangements, call your travel agent or contact our special travel consultant for special discount fares and accommodations:

Sue Lorman
Carlson Wagonlit Travel
2509 Pacific Coast Highway
Torrance, California 90505
Phone: (310) 325-7162
Fax: (310) 534-3686
E-Mail: yourpartnerintravel@worldnet.att.net

The 15th Annual In Vitro Fertilization and Embryo Transfer Comprehensive Update, July 14-17 2002 was again a huge success with well over 200 attendees from around the U.S. and the world.  Reproductive Partners’ Dr. David Meldrum has directed this postgraduate course in conjunction with the Office of Continuing Medical Education, UCLA School of Medicine each year since 1987.  The course owes its success to the large number of top-quality speakers, each an authority in his or her particular field.  Most IVF programs in the U.S. make a point of having someone attend at least every couple of years.  Since each year some applications are turned away, the conference is limited to those actively working in the field.

MALE FACTOR

Dr. Peter N. Schlegel (Cornell University Medical Center, New York, New York) outlined the clinically relevant evaluation of the infertile male.  Men with non-obstructive azoospermia (absent sperm) or severe oligospermia (very low [<5 million/ml] sperm counts) should have a karyotype.  Men with congenital absence of the vas or unexplained epididymal obstruction should have cystic fibrosis testing on the female partner, since not all mutations in such males are identifiable.  Men with non-obstructive azoospermia should have Y chromosome deletion testing.  AZF b and a deletions are associated with a very low chance of sperm retrieval.

He reviewed the published literature on malformation rates after IVF or ICSI.  A large amount of available data suggests no increase of abnormalities with these techniques except about a 0.6% increase of sex chromosome anomalies.  Most of these are probably due to an increased rate of sex chromosome anomalies in men with very low sperm counts.  There may be a very small increase due to ICSI.  However, since these anomalies are not severe, it is unclear whether ICSI alone should be an indication for prenatal genetic screening.

Dr. Gianpiero Palermo (Cornell Medical College, New York, New York) reviewed results of over 6000 ICSI cases from Cornell.  There was no observed increase of anomalies, including sex chromosome anomalies with ICSI compared to regular IVF and follow-up of children at 3 years has been normal.  A higher incidence of chromosome anomalies has been observed with “rescue ICSI.”  It appears to be best to perform ICSI whenever reduced fertilization is a concern, and to not perform ICSI after fertilization has failed.

Dr. Peter Schlegel (Cornell University Medical Center, New York, New York) spoke on sperm retrieval techniques.  Testes biopsy is generally done with obstructive azoospermia (OA) to confirm normal sperm production.  It is not necessary in non-obstructive azoospermia (NOA) since it is poorly predictive of finding sperm with microdisection.  In OA, sperm can be retrieved by percutaneous epididymal sperm aspiration (PESA) or percutaneous testes biopsy.  Microsurgical epididymal sperm aspiration (MESA) has the advantage of providing sufficient sperm for multiple IVF attempts.  For NOA, microdisection is able to find isolated functional tubules, allowing minimal removal of tissue and preservation of the vascular supply of the testes.  AZFa or AZFb Y-chromosome  microdeletions are associated with a very low chance of sperm retrieval in men with NOA.  Sperm retrieval attempts should be separated by at least 6 months in NOA to allow full recovery of testicular function.  In NOA, frozen testicular sperm often do not survive freezing/thawing.  Repeat TESE even in the most experienced hands only achieves sperm retrieval in 80% of men with successful retrieval previously.  Men with prior chemotherapy or irradiation have about a 45% sperm retrieval rate.  One should wait at least one year before TESE/ICSI.

PREIMPLANTATION GENETIC DIAGNOSIS

Dr. Mark Hughes (Wayne State University School of Medicine, Detroit, Michigan) spoke on preimplantation genetic diagnosis (PGD).  Many single gene defects can now be screened for using PGD.  Because of the very exacting work involved, it makes sense to have a limited number of large laboratories around the country that can do the analysis and provide the results in time for morula or blastocyst transfer.

Dr. William Schoolcraft (Colorado Center for Reproductive Medicine, Englewood, Colorado) spoke on “A Clinician’s Perspective” regarding preimplantation genetic diagnosis (PGD).  One of the main areas of controversy has been the role of aneuploidy (abnormal chromosomes) testing in improving implantation and reducing miscarriage, for example, in older women.  In very experienced hands, testing of a blastomere (single cell from an embryo) for numerical abnormalities of multiple chromosomes has increased pregnancy and reduced miscarriage.  There are about 10% of embryos where the result is not definitive and in 10-20%, an abnormal cell may be obtained from a normal embryo.  Until wider experience has shown clear benefits this technique should be considered experimental.

IMPROVING IVF RESULTS

Dr. Richard Scott (Reproductive Medicine Associates of New Jersey, West Orange, New Jersey) spoke on immunologic testing before IVF.  The current consensus is that there is no apparent value to testing for antiphospholipid antibodies, antithyroid antibodies, or natural killer cells before IVF.  There is no demonstrated benefit of treatment with intravenous immunoglobulin or leukocyte immunization therapy (LIT).  The FDA has indicated that LIT is experimental and requires FDA approval of any protocol.

Dr. Dominique de Ziegler (Hopital de Nyon, Nyon, Switzerland) spoke on uterine factors in implantation.  Out of this complex and elegant presentation, the work on the association of excessive uterine contractions with reduced cycle outcome perhaps deserves the most attention.  A reduction of uterine contractions could be the principle mechanism whereby optimal transfer technique improves implantation.

Dr. Bill Yee (Reproductive Partners Medical Group, Southern California) spoke on the negative effect of a hydrosalpinx on IVF outcome.  Clearly the presence of a hydrosalpinx reduces IVF success by about 50% and salpingectomy or a tubal interruption procedure raises success to normal.  There may be a minor negative effect of salpingectomy on ovarian response.  It is not clear whether surgery is helpful in women without an ultrasound visible hydrosalpinx.  There are conflicting data on whether drainage of a hydrosalpinx can improve IVF outcome.

Dr. Gabriel Garzo (Reproductive Partners Medical Group, La Jolla, California) spoke on the luteal phase and transfer technique.  Luteal phase support is advised for GnRH agonist and antagonist cycles.  There is some recent support for the use of luteal phase estrogen.  Ultrasound-guided transfer has been shown to improve the pregnancy rate in multiple randomized studies, although one can criticize the control groups regarding the use of a mock transfer, use of optimal transfer technique and whether a full bladder technique was used.  Empirically once the UTZ-guided technique is adopted, it is difficult not to become convinced of its value.

Dr. Joseph Gambone (UCLA School of Medicine, Los Angeles, California) spoke on fertility drugs and ovarian cancer.  The most recent studies have been very reassuring in not showing a significant impact of fertility drugs; although clearly, having not delivered a baby and infertility both increase ovarian cancer risk.

All in all, the meeting was a great success.  This conference is unique in the world in having such a large number of speakers who are leaders in the field each indicating the methods associated with optimal results at each step in this complex process.  The U.S. has become a clear leader in IVF success in the world.  There is little doubt that this conference and its excellent faculty have played a significant role in that regard.

STIMULATION PROTOCOLS

Dr. Meldrum (Reproductive Partners Medical Group, Southern California) began the meeting with a review of standard ovarian stimulation regimens.  The long GnRH agonist regimen using Lupron is the most common method of ovarian stimulation, yielding more eggs, reduced cancellation, and a higher pregnancy rate.  It is very commonly combined with an oral contraceptive (OC) lead-in, to avoid cysts and to minimize menopausal symptoms prior to the rise of estrogen.  Dr. Meldrum emphasized that with some regimens, particular involving OC, the levels of LH can be excessively suppressed.  Addition of human menopausal gonadotropins to the FSH can improve cycle outcomes.

Dr. Francois Olivennes (Hospital A. Beclere, Clamart, France) spoke about the new GnRH antagonists.  These agents can be given for a very short duration late in ovarian stimulation thus reducing the number of injections.  The ovarian response is lower and the rate of ovarian hyperstimulation is correspondingly reduced.  Their value hinges on whether success rates are equivalent to GnRH agonists and whether the approximately 20% lower success rate is related to a direct effect on the uterine lining or to other factors such as lower LH levels or simply that these regimens require more experience on the part of physicians.  By avoiding ovarian suppression, GnRH antagonists may prove to be ideal for poor responders.  Early in the reported studies there was not an appreciation of the differences in the ovarian response.   Estradiol levels rise more quickly, causing some clinicians to reduce the gonadotropin dose.  The marked reduction of endogenous gonadotropins when the antagonist is begun dictates that the exogenous dose should generally be maintained.

Dr. William Schoolcraft (Colorado Center for Reproductive Medicine, Englewood, Colorado) discussed the role of LH in ovarian stimulation in more detail, again emphasizing that for certain regimens, the addition of LH will improve outcomes.  Recombinant pure FSH has generally been a great advance, but LH is also probably important to full developmental competence of the eggs.  Currently this is supplied by using hMG.  In the future, recombinant LH or a very small daily dose of hCG may be a more consistent way of supplying LH actively.

Dr. Richard Scott (Reproductive Medicine Associates of New Jersey, West Orange, New Jersey) spoke on reserve testing and stimulation of the poor responder.  He emphasized the value of the basal follicle count in predicting outcome in addition to day 3 FSH and the clomiphene challenge test.  When the resting follicle count is less than 4, all outcomes are markedly reduced.  The two most common regimens for poor responders are “mini-dose Lupron” and Antagon (GnRH agonist).  There is no clear advantage of one versus the other with experience to date.

SELECTION OF PROCEDURE

Dr. Bill Yee (Reproductive Partners Medical Group, Southern California) spoke on the GIFT procedure (gamete intrafallopian transfer), emphasizing its role in particular circumstances.  GIFT has been particularly successful with donor sperm, probably because of a more consistent fertilization than with infertile husbands sperm.  When embryo transfer continues to be difficult in spite of cervical dilation and ultrasound-guided transfer and the male factor is fairly normal, GIFT may be an excellent choice.  Finally, the trend has been toward higher results with GIFT for women over age 42, although no well-controlled study has been done comparing IVF and GIFT in this age group.

Dr. Gabriel Garzo (Reproductive Partners Medical Group, La Jolla, California) spoke on gestational surrogacy and mainly emphasized the complexity of this process and that surrogate agencies vary considerably in quality.  Patients should be referred to physicians who do surrogacy and are familiar with agencies that do this well, rather than to choose the agency from the Internet or other promotional materials.

Dr. Joseph Gambone (UCLA School of Medicine, Los Angeles, California) discussed uterine factors.  The data on fibroids and IVF clearly shows reduced outcome with submucosal fibroids distorting the cavity.  There are reports finding and not finding a reduced outcome with intramural (in the uterine wall) fibroids.  It would seem prudent to consider removal of large intramural fibroids particularly since this may also reduce miscarriage. The data on polyps is scant since they are generally removed.  The consensus is that all except very small polyps (e.g. less than 5 mm) should be removed before IVF.

LABORATORY TECHNIQUES

Dr. Kwang-Yul Cha (Pochon CHA University, Seoul, Korea) reviewed the subject of human egg and ovarian tissue freezing.  There have been fewer than 50 pregnancies worldwide with freezing of human eggs.  The latest results by Dr. Cha’s group in 34 cycles showed that 69% of eggs survived freezing, 72% of those fertilized, and of 28 women undergoing transfer of an average of 4.5 embryos, the delivery rate was 25% (21% of cycles).  The low implantation rate (6% per embryo) shows the low efficiency of this technique.  The results do confirm that it is a reasonable method for cancer patients prior to chemotherapy or radiation.  Work on ovarian tissue freezing is much more preliminary with no reported pregnancies as yet.

Dr. Mike Wilson (Reproductive Resource Center, Overland Park, Kansas) spoke about results in a program that has done 5-day (blastocyst) culture in all IVF patients.  Pregnancy rates improved with a reduction of the number of embryos transferred.  Unresolved issues are whether the low rate of monozygotic (identical) twinning with 5-day culture is a reason to not offer it routinely, and whether there are women whose embryos do not survive to day 5 that could have conceived with day 3 transfer.  Freezing of blastocysts has been more variable but is improving.  It is interesting that the implantation rate with transfer of embryos that did not reach the blastocyst by day 5 is not markedly reduced.  Another important question to be resolved is whether assisted hatching can help those more advanced embryos to implant.

In a debate between embryologists, Lucinda Veeck, MLT, DSc (hon)  (Cornell University Medical Center, New York, New York) reviewed the factors that can enable the selection of the best embryos for transfer on day 3.  The simplest and most reliable method aside from the morphology of day 3 embryos is identification of early cleavage to the two-cell stage.  Excellent results can be obtained with transfer of two day 3 embryos and freezing of cleavage stage embryos is well defined. Dr. David K. Gardner (Colorado Center for Reproductive Medicine, Englewood, Colorado) took the position that the best embryos can be identified on day 5, thus allowing transfer of only two embryos in all women under age 40.  Freezing results at the blastocyst stage are less consistent but are rapidly improving.

Both debaters appeared to agree that as sequential media continue to improve with consistent quality control and as blastocyst freezing continues to improve, that ultimately extended culture might become routine.

All in all, the meeting was a great success.  This conference is unique in the world in having such a large number of speakers who are leaders in the field each indicating the methods associated with optimal results at each step in this complex process.  The U.S. has become a clear leader in IVF success in the world.  There is little doubt that this conference and its excellent faculty have played a significant role in that regard.

The next issue of Reproductive Times will feature Part II of the Highlights of the 15th Annual In Vitro Fertilization and Embryo Transfer-A Comprehensive Update-2002 meeting including sections on male factor, preimplantation genetics and improving IVF success.

Because of our many years of work in IVF and our excellent results, we commonly have patients self-referred and sometimes referred by other IVF programs. Many of these couples have experienced reduced embryo quality in their previous cycles. Poor embryo quality is a problem that frequently repeats itself in each cycle, although sometimes changes can be made in the management of the ovarian stimulation and laboratory techniques that can improve embryo quality or assist the implantation of sub-optimal embryos.

Short sperm-egg incubation:

In the fallopian tube, the human egg is exposed to a very small number of sperm. In in-vitro fertilization, very high concentrations of sperm are placed around the eggs. We know that sperm release substances such as free oxygen radicals that are harmful to eggs, and that the sperm penetrate the egg within a very short time. Studies have shown improvement in embryo quality by incubating the eggs with sperm for only one or two hours, rather than overnight which has been the classic technique since IVF first began.

Culturing embryos in groups:

Embryos produce factors that help embryo growth. Studies of mouse embryos have shown that embryos grow better in smaller volumes of fluid or in groups. Although there are no definitive studies in humans, culturing embryos in groups or individually in small drops of culture medium under oil may increase the exposure of the embryo to factors that are thought to promote or improve embryo growth.

Culture of embryos under reduced oxygen:

The concentration of oxygen in the fallopian tube is equivalent to a 5% concentration rather than the 21% that is present in air. However, the most common culture condition used for IVF is room air. This is in part because the use of 5% oxygen is more complicated. In addition, until recently there has not been any proof in the human that embryo growth is improved in the presence of the lower oxygen concentration. In a study of in vitro embryo growth to the blastocyst stage, it has recently been found that there are significantly more cells in the inner cell mass (which ultimately forms the fetus) when the lower oxygen concentration is used.

We have been using this technique and have found that more three-day embryos are developed beyond the eight-cell stage than we ever saw with room air. This technique requires a special incubator that drives down the oxygen concentration by adding more nitrogen. Besides the increased expense of the new incubators, the process uses more nitrogen tanks. It also requires more incubators because of the cooling which occurs with each door opening. However, we have been convinced enough of its benefits to now use it routinely.

Co-culture:

In vivo, the embryo develops in close contact with cells lining the fallopian tube. In vitro, cells surrounding the embryo are removed to check for normal fertilization, and the embryos are cultured in contact with only culture medium and a plastic dish. Over the last several years, studies have shown that when embryos are cultured along with various types of cells, embryo morphology can be improved.

The most convenient source of cells is from the follicle. The mature egg is surrounded by tissue called cumulus. The cells making up the cumulus have been shown to have a beneficial effect on embryo morphology. With cumulus co-culture, a piece of cumulus is taken from around a mature egg and kept in culture to place with the embryos after the fertilization check. One minor drawback of cumulus co-culture is the small chance of losing an embryo which becomes adherent to the cumulus.

Fragment removal:

Embryos with poor morphology usually have varying degrees of fragmentation. These fragments are from damaged cytoplasm extruded from the cells of the embryo. Animal studies have suggested that the fragments themselves further reduce embryo viability. The fragments can be removed at the time assisted hatching is done, provided the removal itself would not damage the embryo.

Assisted Hatching:

Embryos with reduced morphology have lower metabolic activity and may not be able to thin out the shell (zona pelucida) and escape (hatch) from the zona. By making an opening in the zona with a tiny pipette and an acidic solution, the ability of the embryo to hatch, and therefore implant, is enhanced.

Cytoplasmic Transfer:

In a very selected group of women with multiple cycles of IVF with recurrent poor embryo quality, a research group in New Jersey has taken cytoplasm from donor eggs and has injected it into each infertile woman’s egg. Embryo quality was improved, and the pregnancy rate was increased compared to women with multiple failed cycles.
There has been a lot of controversy regarding possible consequences of mixing cellular material from two individuals, and an increased incidence of chromosomal abnormalities occurred in a small group of women having the procedure. We currently do not advise use of this technique outside of a very strictly controlled research protocol.

Summary:

We now recognize that the quality of a woman’s embryos varies from woman to woman almost as much as sperm quality varies among different men. Women with poor embryo quality have a reduced prognosis with IVF. The above techniques can be used to try to improve their embryo quality, and thus maximize the chance for a successful outcome.

Reproductive Partners Introduces
SUCCESS PROGRAM

At Reproductive Partners, we believe in success. Our expert physicians and staff are dedicated to using our knowledge and skills to maximize the chances of achieving the dream of having a baby. With well over fifteen years of experience, we anticipate that a couple capable of getting pregnant with IVF will have a good chance to succeed within three completed cycles of IVF. The SUCCESS  PROGRAM is based on this philosophy. It’s designed to help take advantage of that important third cycle, if it’s needed.

Reproductive Partners SUCCESS PROGRAM is really very simple. You are eligible if you do not have insurance coverage for IVF, pay the full Global Rate for each of two complete IVF cycles at Reproductive Partners, and transfer all embryos from those cycles, including frozen embryos, without achieving a viable12 week pregnancy. Your third IVF cycle at Reproductive Partners for the same category of Global Rate and procedures will be provided free for all the same procedures covered under the Global Rate in the first two cycles.

There are no age limits, no higher up-front fees, no payments for the second cycle until the first is completed, no mandatory procedures like hysteroscopy or IVIG injections and no arbitrary cancellations. If we determine that you are a candidate for and complete at least two cycles of IVF you may participate in the program. We expect our patients to succeed, and when success does not come quickly, we will go the extra mile for you.

All frozen embryos must be transferred without achieving a viable 12-week pregnancy before you will be eligible for the third cycle. If a viable 12-week pregnancy is achieved within the first two cycles, including the use of frozen embryos, couples will not be entitled to a free third cycle. If three cycles are necessary, all must be completed in an 18-month period. You have 18 months from the start of birth control pills or Lupron in the first cycle, to the start of the third cycle. All fees for each “paid” cycle must be paid in advance.

Gestational surrogacy is yet another example of how the development of the techniques of in-vitro fertilization have allowed us to help infertile couples that never expected to become parents of their own genetic child.

Gestational surrogacy can be defined as the transfer of embryos to the uterus of a woman who is willing to become pregnant for the sole purpose of helping an infertile couple become parents. The surrogate host has no genetic connection with the embryos and does not intend to be the rearing or legal mother of the child. The commissioning parents, who are, most of the time but not always, the genetic parents, will fulfill these roles. Donation of one or both gametes that created the embryos can also be involved.

Surrogacy is clearly indicated as the only possible option for infertile couples to have their own genetic child when the wife’s uterus is absent (congenitally or post-hysterectomy), non-functional (congenital malformation or post-surgical scarring) or when the wife has a medical condition that makes pregnancy life threatening. It has also been used in repeated IVF failures, particularly when the embryos are of good quality, and in habitual abortion not corrected by available treatments.

LEGAL ISSUES

The legal status of gestational surrogacy varies greatly among different states in the USA. California has “case law” (not codified law) regarding surrogacy, which is made by the courts and constitutes “The Law” in the state. In specific cases that have been presented to them, the courts have upheld the intended parent’s rights in surrogate cases, even when there is no genetic connection with the embryo.

The latest of several landmark rulings was given in the California case Buzzanca (1998). In this instance, the intended parents entered an agreement to have an anonymously donated embryo transferred to a surrogate who would carry the child. Six days prior to the birth of the child the intended father filed for divorce and claimed that, since he was not the biologic father, he was not the legal father and could not be forced to adopt. After three years of litigation the courts ruled, that the intended parents, i.e. those who had initiated the whole surrogacy process that created the child were, in fact, the legal parents of the child.

That ruling expanded the previous one given in the California case Johnson v. Calvert (1993) in which a gestational surrogate wanted to play a rearing role after the birth of the baby. The court held that the woman who intended to “bring about the birth of the child that she intended to raise as her own is the natural mother under California law”. This ruling was also explicitly applied to recipients of donated eggs who were recognized as the intended parents.

Because of this legal background, in California, intended parents can ask for a judgment by a Superior Court naming them as the legal parents of the child in the birth certificate extended at the time of delivery.

PSYCHOLOGICAL AND SOCIAL SCREENING

Relationships in surrogacy are varied. The host carrier can be a relative, friend or someone with no attachment to the commissioning couple that may or may not receive financial compensation. It can be a direct, person-to-person agreement between the couple and the surrogate, or there may be an agency that not only will find the surrogate but will also coordinate the whole process.

No matter what the circumstances are, candidates for surrogacy should undergo a psychological as well as a social evaluation. In most instances, the social evaluation is performed by the agency.

The objective of the psychological exam is to rule out any psychopathology, assess the personality of the surrogate and is best carried out by a psychologist with experience in reproductive issues. Surrogacy is, by definition, a very unusual situation and requires a very adaptable personality.

The surrogate’s motivations should also be discussed. It is crucial that financial compensation not be the main reason for her becoming a surrogate. Not only for ethical reasons, but also because in order to take care of the pregnancy appropriately (24 hours a day for nine months) she has to truly care for the couple and their baby. Pregnancy complications can arise at any moment and require major sacrifices that no amount of money can pay for. Many candidates give, as a reason for wanting to become surrogates, the opportunity to do something life affirming and important for other human beings. Candidates on Medicare should be not approved and the family has to prove financial stability prior to acceptance.

Excluding exceptional circumstances, all surrogates have given birth and parented at least one child. Only then can they give fully informed consent and predict their own behavior as they relate to the intended child. The surrogate’s pregnancy will also touch deeply her own family’s life and, therefore, she will need their support during the whole process. The evaluation, therefore, should also include her husband and children. Her expectations about her relationship with the prospective couple are also discussed as well as her beliefs on fetal reduction and multiple gestations.

The commissioning couple also needs to be assessed in their general mental health and marital stability. They need to not be overly intrusive and controlling. The couple’s capacity to trust and empathize with the surrogate is an important factor in the success of the overall process. The degree of comfort with relinquishing the baby is increased if the surrogate knows that the couple is eagerly preparing for the baby and has bonded with them. The intended parents then meet with the surrogate and her family to get to know each other and to discuss issues such as prenatal care, fetal reduction, finances, envisioned relations, etc. Only then is a legal contract signed to formalize the arrangement the way that all parties understand it.

MEDICAL SCREENING

The medical screening of the surrogate aims at making sure that there are no contraindications to pregnancy and that the physical environment of the baby will be optimal. The surrogate needs to be healthy, less than 35 years of age and have carried at least one pregnancy to term with no complications. Her reproductive system should be normal with regular menstrual cycles, no hormonal disorders and normal uterus and endometrium.
Standard protocols are used for the stimulation of the ovaries of the genetic mother and preparation of the endometrium of the surrogate. The concept is that the surrogate’s endometrium should have been thickened with estradiol 4 or 5 days prior to the expected retrieval day to accommodate for any unexpected change in the stimulation calendar. Our criteria for the number of embryos to be transferred follows the guidelines of the Society for Assisted Reproductive Technology, but the final decision belongs to the surrogate who is the person who would face the risks of a multiple pregnancy.

RESULTS

The chances of pregnancy depend mostly on the age of the genetic mother and on the overall success rates of the program with regular ART techniques. At Reproductive Partners-UCSD Regional Fertility Center in La Jolla, we have performed 25 embryo transfers to a surrogate in the last two years with embryos derived from mothers of different ages. Currently, 15 surrogates either are carrying a pregnancy or have delivered for an overall ongoing/delivered pregnancy rate per transfer of 60%.

Reproductive Partners Worldwide

Because of the limited availability of advanced techniques like surrogacy, egg donation and even high quality IVF in parts of the United States and the rest of the world, we introduced Reproductive Partners Worldwide (RPWW). The purpose of RPWW is to make the programs and facilities of Reproductive Partners available to couples throughout the United States and around the globe.

Our interactive bulletin board and e-mail communications show that there are unmet needs for couples in other areas. Until now we have tried to meet some of the educational needs through our website and books. In addition to consultations and telephone consultations, we can now also make IVF cycles egg donation and surrogacy more accessible for couples from other locations.

The key to success of this effort is good communications. By utilizing modern communications technology such as e-mail, faxes and the Internet, we will be able to share information with a couple’s physician close to home. That will minimize the time required for the couple to be present in one of Reproductive Partners’ nationally recognized centers in Los Angeles or San Diego.

Travel arrangements can be made through the patient’s travel agent or a special travel consultant to take advantage of specially priced accommodations. An IVF cycle would require female partner to be near one of our facilities from twelve to fifteen days, while the male partner would have to be present for one to two days at the time of egg retrieval.

Although telephone consultations are available, we feel it would be best that the couple have an in-person consultation in order that we may meet face-to-face and perform the pre-cycle semen analysis, semen culture and trial transfer at the time of the initial consultation. The remainder of the pre-cycle testing can be done close to one’s home. We will work with the couple’s physician to perform these vital tests. If a couple chooses we can offer a telephone consultation and arrange to have the semen analysis, culture and trial transfer done in the couple’s home city.

We will instruct the patient’s local physician in monitoring the initial portion of the preparation and stimulation phase and request the female partner arrive at a Reproductive Partners facility starting with the sixth day of stimulation. She should plan to stay until the completion of two days of bed rest following the transfer.

To receive a packet of information on the Worldwide program, call (310) 318-3010 or e-mail your address to reproduce@earthlink.net.

Our interactive bulletin board and e-mail communications show that there are unmet needs for couples in many parts of the U. S. as well as in the rest of the world. Until now we have tried to meet some of the educational needs through our website and books. In addition to consultations and telephone consultations, we can now also make IVF cycles more accessible for couples from other locations.

The key to success of this effort is good communications. By utilizing modern communications technology such as e-mail, faxes and the Internet, we will be able to share information with a couple’s physician close to home. That will minimize the time required for the couple to be present in one of Reproductive Partners’ nationally recognized centers in Los Angeles or San Diego.

Travel arrangements can be made through the patient’s travel agent or a special travel consultant to take advantage of specially priced accommodations. An IVF cycle would require female partner to be near one of our facilities from twelve to fifteen days, while the male partner would have to be present for one to two days at the time of egg retrieval.

Although telephone consultations are available, we feel it would be best that the couple have an in-person consultation in order that we may meet face-to-face and perform the pre-cycle semen analysis, semen culture and trial transfer at the time of the initial consultation. The remainder of the pre-cycle testing can be done close to one’s home. We will work with the couple’s physician to perform these vital tests. If a couple chooses, we can offer a telephone consultation and arrange to have the semen analysis, culture and trial transfer done in the couple’s home city.

We will instruct the patient’s local physician in monitoring the initial portion of the preparation and stimulation phase and request the female partner arrive at a Reproductive Partners facility starting with the sixth day of stimulation. She should plan to stay until the completion of two days of bed rest following the transfer.

ASRM 2000 Selected Abstracts
By David R. Meldrum, M. D., Reproductive Partners Medical Group, Inc., Beverly Hills and Redondo Beach, California

This summary of selected abstracts and comments from the 56th Annual Meeting of the American Society for Reproductive Medicine (October 21-26, 2000) was prepared for educational purposes only and constitutes neither an endorsement of any of the procedures discussed nor a recommendation of any particular treatment or protocol. Most of the following studies are in the experimental phase and are not yet clinically available.

Reproductive Partners, 90210

It’s actually Beverly Hills 90211. That’s where the newest office of RPMG has recently opened. “Reproductive Partners 90210″ just sounds better because of the hit TV show, “Beverly Hills 90210.” The new office is located in the heart of Beverly Hills at 150 N. Robertson, Suite 150. It will be a convenient location for not only our Beverly Hills patients, but also for Westside and Valley couples as well. Just call (310) 855-2229.

Drs. Meldrum, Yee, Rosen and Wisot will work at this new location, providing the full range of diagnostic and therapeutic fertility options such as evaluations, ovulation induction, fertility drug stimulation, inseminations and preparation for GIFT and IVF. Patients prepared at this location will have the advantage of having their GIFT or IVF done at one of RPMG’s nationally known reproductive facilities.

Introduction: A key step in the high tech Assisted Reproductive Technologies (ART) such as In Vitro Fertilization (IVF) and Gamete IntraFallopian Transfer (GIFT) is the recruitment and development of several follicles that will yield a cohort of eggs.

This process is called Controlled Ovarian Hyperstimulation (COH). The usual goal is to recruit a cohort of around 5-12 follicles that will produce a similar number of eggs. In a natural cycle, several follicles are recruited and initiate development. However, as estrogen levels increase, negative feedback occurs and the brain (anterior pituitary gland) releases less Follicle Stimulating Hormone (FSH). This causes all but the strongest follicle to cease maturation. Thus, in a natural cycle, generally only the one “dominant” follicle ovulates, releasing one egg. COH is accomplished by administering injections of gonadotropins, either FSH and Luteinizing Hormone (LH), or FSH alone. This prevents the drop in FSH levels allowing not just a single follicle, but a cohort of follicles to continue to develop. The result is the availability of several eggs for ART.

With IVF, the eggs are then taken back to the laboratory where fertilization occurs “in vitro” by adding sperm or by Intracytoplasmic Sperm Injection (ICSI). With GIFT, the eggs are combined with sperm and placed in the fallopian tube to allow fertilization in the natural location.

Unfortunately, one may undergo a cycle with the hopes of undergoing IVF, IVF with ICSI, or GIFT only to discover that a “poor response” is occurring and a sub-optimal number of follicles / eggs are developing. The purpose of this article is to address the problem of poor response to COH and outline possible solutions.

Definition: There isn’t a universally accepted definition to “poor response” or “poor responder.” Research papers studying this problem have used various definitions including those based on early follicular phase follicle stimulating hormone (FSH) levels, number of mature follicles, maximum estradiol levels, total gonadotropin dose used for stimulation, or number of mature eggs retrieved. In clinical terms, a practical definition is the inability to achieve the maturation of more than 4 follicles / eggs.

Background: Before describing strategies and their rationale for overcoming sub-optimal COH, an understanding of the usual COH protocol also known as the “Long Protocol” is needed for comparison. The “Long Protocol” involves several steps (Figures 1, 2):

The success rates of IVF and GIFT are related to many factors, but two very important factors are the age of the woman and the number of mature eggs and high quality embryos that are harvested/created. Because of these observations, many tests have been developed to attempt to assess who might be a better candidate for these procedures, i.e., who would be more likely to ripen more eggs, before starting an attempt at IVF or GIFT.

Day 3 Follicle Stimulating Hormone (FSH)

Follicle Stimulating Hormone is the hormone which travels from the pituitary gland to the ovaries to ripen eggs. Circulating levels of FSH start to rise a few days before menstruation and remain elevated for a few days after the period starts. The theory behind measuring an FSH on Day 2 or 3 of the cycle is simple. A woman of reproductive age who has the normal number of eggs remaining in her ovaries will only require a small amount of FSH to ripen those eggs and her Day 3 FSH will be low. Conversely, a woman who has fewer eggs left would require more FSH and her blood test will reflect a higher level of FSH. Estradiol, a form of estrogen made in the ovaries as a by-product of the eggs ripening, is measured at the same time to confirm that the measurement of FSH is accurate.

In 1989, Dr. Richard Scott, who was then at the Jones Institute in Virginia, published a paper in which his group observed that women who had elevated levels of FSH on Day 3 of their cycles had less of a chance of getting pregnant in comparison to women whose levels of FSH were lower. Dr. Scott grouped patients into low, medium and high levels of FSH and he observed that the pregnancy rates were 17% in the low FSH group and only 9% and 4% in the medium and high FSH groups.

This interpretation is very controversial. There are many physicians that feel that age is the primary predictor of pregnancy rate. To demonstrate this controversy, there are two larger studies that look at FSH and its affect on IVF outcome. Dr. Toner published the first study in 1991. The other study was published by Dr. Sharif in 1998. Both of these studies observed that women with higher FSH, in comparison to women with lower FSH, used more gonadotropins during stimulation, had higher cancellation rates (as many as 25% failed to ripen enough eggs to proceed), and their pregnancy rates were lower. There was, however, a major difference in the conclusions of the two papers. Toner interpreted his findings to show that increased FSH levels were more important than age in determining pregnancy outcomes. Sharif disagreed. He felt that age was the most important criterion. At Reproductive Partners it is our opinion that both age and FSH levels are of similar importance.

Dr. Bassil published an article in 1999 where he looked at women only age 39 and older with an elevated FSH on Day 3. He observed that women with elevated FSH levels who had three or more eggs retrieved had an acceptable pregnancy rate (16%) compared with women who had fewer than three growing follicles. The pregnancy rate in this group was only 6%. His conclusion was that having an adequate ovarian response is essential to give a woman her age-adjusted chance of conceiving. He demonstrated that a significant number of women with elevated FSH levels were still able to ripen enough eggs to have a worthwhile attempt at pregnancy.

One defect of Dr. Bassil’s study and many other studies is that delivery rates were not evaluated. We now know that women with an elevated FSH have a high risk of miscarriage (probably at least 50%), which results in a low rate of delivery. When Bassil’s data is evaluated in this light, the success rate in women with at least three eggs retrieved would be anticipated to be only about 8% and 3% respectively. It can be concluded from this study that there is a small but significant chance of delivery provided that least three or four follicles result from a moderate level of stimulation.

In practice, patients seldom have a single Day 3 FSH level on which to base a decision. The prognosis appears to be poor in women with multiple abnormal levels and improved when multiple normal levels are observed in other cycles.

Clomiphene Citrate Challenge Test (CCCT)

The CCCT was first described in 1987 by Dr. Navot, two years before any information had been published on the usefulness of a Day 3 FSH. The CCCT measures an FSH and estradiol drawn on Day 3 of the cycle and then again on Day 10. In between, on Days 5 through 9, 100 mg of clomiphene citrate (SeropheneR or ClomidR) are administered daily. In a normal, non-medicated, ovulatory cycle, the FSH concentration on Day 10 should be significantly lower than on Day 3. The theory behind the CCCT is that an elevated FSH on Day 10 is an abnormal finding and indicates that either an increased requirement of FSH is necessary to stimulate the remaining follicles or that the remaining follicles are just less likely to respond to FSH. There has been much discussion in the medical literature as what is considered a normal or abnormal test, but overall, the following is in general agreement. If the Day 3 FSH or estradiol is abnormal, there is no reason to do a CCCT. An increase in FSH is expected from Day 2-3 to day 10 and the upper limit of this test on Day 10 should not exceed the upper limit of normal for a Day 3 FSH.

A review of published studies on the CCCT show that as a woman gets older or if she has only one ovary she is more likely to have an abnormal CCCT. Women who smoke have an increased incidence of abnormal tests at a younger age. Women who responded poorly to gonadotropins (ripened fewer eggs than expected) have a high incidence of abnormal CCCT. Most studies agree that an abnormal CCCT indicates, just as with an elevated FSH on Day 3, that a woman will utilize more gonadotropins, produce fewer mature eggs and have a lower pregnancy rate than if her test is normal. More recent observations, however, have shown conflicting results. A significant number show that age remains the best way to determine who will get pregnant and who won’t. An abnormal CCCT may only indicate that a woman’s chances of conception are decreased because she is less likely to ripen enough eggs for her procedure.

Ultrasound

Another tool used to predict ovarian response utilizes transvaginal ultrasound to count the number of resting follicles seen early in the menstrual cycle. These resting follicles are also called antral follicles. Ovarian stimulation can only affect antral stage follicles. If enough of these are present, it might predict who would be more likely to have an adequate response to gonadotropins.

Another View

A 1999 article in Human Reproduction studied 22 previously fertile women over the age of 35 who were about to undergo a hysterectomy with removal of the ovaries. A Day 3 FSH, estradiol and CCCT were performed just prior to the procedure. The ovaries were examined and the number of eggs was estimated. The authors found no significant correlation between baseline or clomiphene stimulated FSH levels and the number of remaining follicles. They concluded that neither a Day 3 FSH or CCCT accurately reflects the true ovarian reserve, but the study was small.

Summary

The declining ability of a woman to conceive with advancing age is primarily attributed to the decline in the quality of her eggs and, only secondarily, to the decreasing number and accessibility to those eggs. A Day 3 FSH and estradiol or a clomiphene citrate challenge test can help to distinguish a subgroup of women who might ripen fewer or more eggs with gonadotropins. These tests are still extremely controversial. Individually, that is without knowing the woman’s age and her past experience with gonadotropins, these tests allow a physician and patient to determine who might require more or less gonadotropins and who overall may ripen fewer or more eggs. The amount of gonadotropins that might be required is purely of financial interest, but egg number, especially in women who are older, is very important to success rate.

The choice as to whether an attempt at ovarian stimulation should be carried out should be individualized according to all the available information. For women over age 38 with multiple abnormal FSH levels, particularly with only a few antral follicles visible on ultrasound, egg donation should be strongly considered. For a 30-year-old with a single abnormal FSH an attempt at stimulation clearly is warranted. Between these two extremes one must make a reasonable decision as to whether a trial of stimulation is reasonable. But to maximize the chance of success, a woman should have at least four to six follicles available for aspiration.

NOW SHOWING: A LIFETIME OF HOPE IN JUST ABOUT 30 DAYS

Reproductive Partners Medical Group, Inc. is pleased to announce the premiere of “A Lifetime of Hope in Just About 30 Days,” a presentation utilizing the latest flash animation technology. In a “Lifetime of Hope” you will follow a patient through an IVF cycle, including all the visual elements from the ultrasounds monitoring follicle development, to the retrieval room and then to the laboratory, observing fertilization, embryo development and transfer.

“A Lifetime of Hope” was produced by Reproductive Partners Medical Group, Inc. through an educational grant by Organon, Inc. and developed by Alan Dale Webmasters. Bookmark our home page (www.2reproduce.com), click on the “Lifetime” icon and attend the premiere of this exciting technical marvel.

GnRH agonists have been routinely used for IVF cycles since they prevent ovulation before egg retrieval, improve the ovarian response, and increase the success rate approximately two-fold over IVF cycles without use of a GnRH agonist. These benefits are produced by suppression of luteinizing hormone (LH). Leuprolide acetate (Lupron) has been the most common GnRH agonist used for IVF, although Synarel (a form given by nasal spray) has been tried with similar success. Lupron is given by injections under the skin, sometimes overlapping with an oral contraceptive, but often given starting about one week after ovulation.

For a GnRH agonist to suppress luteinizing hormone, it must first stimulate the release of gonadotropins (FSH and LH). This can complicate the IVF cycle by causing a cyst to form and by requiring extra time for LH and the estrogen level to be suppressed. Generally about 3 weeks of treatment is required but individual patients may require longer treatment.

A new medication, Antagon (a GnRH antagonist) which suppresses LH within hours is now available. Therefore, it can be used only during the latter period of egg maturation when it is important to avoid excessive LH levels and when LH could rise enough to cause release of the eggs. It is usually used for only 3 to 5 days. Injection discomfort is similar or less than Lupron. Its most important advantage is in avoiding menopausal symptoms that occur with use of GnRH agonist after suppression and before estrogen rises with ovarian stimulation. In some women these can be severe with headache, moodiness or problems with recent memory. Such side effects could be more important with certain occupations (for example lapses in memory could be very disturbing for a trial lawyer or for someone giving lectures).

Large trials in Europe and North America have compared Antagon to GnRH agonist. A slightly lower egg yield and success rate (about 5%) was noted. However, Antagon was compared to GnRH agonist protocols that have been refined for over 10 years and with which the investigators were very familiar. It actually seems remarkable that the results with Antagon came so close with a first pass at defining an optimal protocol.

I have been involved in research on GnRH analogs for almost 20 years and Reproductive Partners was involved in the North America Antagon study. Based on the results I have advised using an oral contraceptive in the preceding cycle to improve egg yield and to allow flexibility in scheduling the egg retrieval. Since the LH levels were quite low on Antagon, and low LH levels could reduce egg quality, we are recommending that women on Antagon should take 1 or 2 ampules of hMG (Pergonal, Humegon or Repronex), that contains LH. These modifications should bring the Antagon results to levels very close or equal to Lupron. At Reproductive Partners we will be involved in additional studies to examine both of these variables over the next year or two, but I would feel confident that patients who wish to use Antagon would not significantly influence their results.

The large trials described above excluded poor responders. Since poor responders can have improved results by avoiding suppression with a GnRH agonist, they may do particularly well on Antagon. We will be doing a controlled study comparing Antagon with the mini-Lupron flare, which is currently the protocol of choice for poor responders.

In summary, Antagon should provide the same benefits as the GnRH agonist with fewer injections and no menopausal side effects, thus further simplifying ovarian stimulation for IVF.

Viagra and Fertility

A poster presented at the recent conjoint meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society concluded that men taking Viagra do not need to worry about its effects on their fertility.

This study, which was performed in vitro (outside the body), involved incubating sperm with various concentrations of Viagra and a control solution. The test had to be performed in the laboratory rather than on test subjects because the length of time required to see an effect on sperm in vivo would require the test subjects to be on the drug constantly for almost three months. In this test, the authors concluded that Viagra had no effect on a normal sperm’s motility, viability or membrane integrity.

Since this study was done in the laboratory and measured limited parameters, many further studies will be needed before couples can be reassured that Viagra has no significant effects on the chromosomes of the sperm in vivo or if it may have the potential to produce birth defects.