Infertility eNews, Spring 2014
Exploring the Feasibility of Uterine Transplantation
Infertility is a major issue for thousands of women. For those with uterine factor infertility caused by a congenitally absent or removed uterus, traditional assisted-reproduction technologies may not be feasible. Although adoption and surrogacy provide opportunities for parenthood, both options pose logistical challenges and may not be acceptable due to personal, cultural or legal reasons.
Gynecologists, researchers and transplant surgeons are pursuing uterine transplantation as a potential method for helping women with uterine factor infertility start or build their families.
Cleveland Clinic Florida transplant surgeon Andreas Tzakis, MD, is collaborating with one of the leading teams, which is conducting human clinical trials at the University of Gothenburg, Sweden. Dr. Tzakis, Tommaso Falcone, MD, Chairman of Cleveland Clinic’s Department of Obstetrics and Gynecology, and Cleveland Clinic Florida gynecologist Stephen Zimberg, MD, have observed the surgery and met with patients.
Entering little-known territory
In the past 20 years at least 11 uterine transplant attempts have been made outside the United States. The initial effort took place in Saudi Arabia in 2000. The recipient experienced two menstrual cycles post-transplant, but a vascular occlusion and necrosis prompted the organ’s removal after 99 days. The second uterine transplant, performed in Turkey in 2011, resulted in a brief clinical pregnancy 18 months later. The recipient miscarried after five weeks; the cause remains undetermined.
The University of Gothenburg team performed the world’s third and fourth uterine transplants in September 2012, using two donors who provided organs to their respective daughters. The Swedish team subsequently has done an additional seven uterine transplants, for a total of nine.
“Within the next year, we will know if these women can conceive and bear normal children,” Dr. Tzakis says.
The Swedish group is proceeding carefully after lengthy experimentation with small animals and baboons. For several years, Dr. Tzakis himself has been conducting research on swine as well as baboons. Although differences in physiology and reproductive anatomy make translating animal experience to human subjects difficult, the surgeons felt they had enough scientific evidence to proceed with clinical trials.
An intriguing concept
Uterine transplantation represents a distinct departure from conventional models of transplantation. Unlike a liver or heart, the uterus is not a vital organ. In this respect, uterine transplantation is similar to hand, leg and face transplants, which are life-enhancing but not life-prolonging.
Yet uterine transplantation differs from these in one salient way: It is intended to be temporary. Because its benefit ceases after childbearing, the graft will be removed or allowed to be rejected after the child or children are born. This eliminates the need for lifelong immune suppression and associated medical problems.
Uterine transplantation raises many ethical issues. As an experimental process, its outcomes must undergo scientific scrutiny to ensure the safety of the transplant recipients as well as the children born of the process.
“Uterine transplantation could be an exciting option and very important for a couple who faces uterine factor infertility, yet much research remains to be done,” says Ruth Farrell, MD, a Cleveland Clinic ob/gyn and fellowship-trained bioethicist. “Researchers must not only examine the transplant procedure, but also determine outcomes during and after the pregnancy.
Institutional review boards and bioethicists will have to work with researchers and physicians to ensure that adequate protections are in place both during and after the investigational phases of the procedure. Important topics, such as research on pregnant women, will be a part of these discussions.”
The issue of the temporary transplant also presents new challenges, and must be an important part of these deliberations.
“Typically, other transplanted organs are not removed unless they are dysfunctional,” she says. “The notion of removing the uterus after childbearing raises issues such as, What additional risks would a woman be exposed to from the hysterectomy procedure? What if she wants more children? There may be many reasons why a woman may elect not to undergo additional surgery to have the uterus removed. These must be carefully considered by a transplant candidate and her healthcare team prior to initiating the procedure,” she adds.
Other hurdles to overcome
Ethical issues aside, there are many other hurdles in the path to making uterine transplantation a viable option.
One is procedural. How would candidates be screened and chosen, and donors be identified, selected and protected in the short and long term?
Another issue is technical. Currently, removing a healthy uterus intact poses a surgical challenge. “The uterus must be taken out with care, because it must have sufficient vasculature to be reconnected. This process needs to be simplified,” says Dr. Tzakis. He and Dr. Zimberg intend to study new techniques for uterine removal.
Uterine transplantation is likely to be expensive, giving it little chance of being covered by private insurers. Moreover, at a time when healthcare expenditures are being scrutinized, Dr. Farrell wonders whether Cleveland Clinic — or anyone else — could justify underwriting such an expensive procedure, when the funds could be used for primary and preventive healthcare needs.
An extensive analysis of the pros and cons of the procedure would be needed before uterine transplantation would be offered at Cleveland Clinic.
Dr. Tzakis remains optimistic.
“If we can overcome the hurdles, we should be able to help these women bear their own children,” he says.
Dr. Tzakis is a transplant surgeon in the Department of General Surgery at Cleveland Clinic and Cleveland Clinic Florida. He can be reached at 216.445.4793 or firstname.lastname@example.org.
Ovulation Induction Agents in Women with PCOS Provides Effective Treatment
By Rebecca Flyckt, MD
Ovulation disorders represent 20 percent of female infertility. These patients typically describe unpredictable bleeding patterns and/or cycle intervals greater than 35 days. These reports usually signal underlying oligoovulation, defined as irregular or infrequent ovulation, or, less commonly, anovulation, defined as the absence of ovulation. The majority of patients with ovulation disorders will ultimately be diagnosed as having polycystic ovarian syndrome (PCOS) – the presence of at least two of the following signs and symptoms:
- Oligoovulation or anovulation
- Clinical evidence of elevated androgens
- Polycystic-appearing ovaries on ultrasound
Fortunately, ovulatory dysfunction is amenable to treatment and remains one of the more correctable causes of infertility. The majority (up to 85 percent) of patients will ovulate in response to oral medications, such as antiestrogens (clomiphene citrate/Clomid) or aromatase inhibitors (letrozole/Femara), and up to 40 percent of these patients will conceive.
In the initial treatment of ovulatory disorders due to PCOS, clomiphene citrate is an FDA-approved oral medication with few side effects and documented efficacy over many decades of use. Doses larger than 50 milligrams daily for a five-day course are often not needed, and the lowest dose required to achieve ovulation is preferred. Unnecessary increases in the dose carry the risk of thinning the endometrial lining and altering cervical mucous adversely. Common side effects include hot flashes, abdominal discomfort and breast tenderness. The risk of multiple pregnancy (twins or higher) is about 9 percent. In contrast to controlled ovarian hyperstimulation, the risk of ovarian hyperstimulation syndrome with oral agents is minimal. Most prescribers limit clomiphene use to four to six months due to decreased efficacy as well as the concern for ovarian neoplasms with less than 12 months exposure.
An alternative agent
In the past decade, the use of letrozole as an alternative agent for ovulation induction has risen. In contrast to clomiphene, it is not FDA approved for ovulation. Letrozole is, however, free of adverse antiestrogenic effects on the endometrium and cervical mucous and appears to have similar efficacy to clomiphene. Side effects of letrozole are very rare at doses of 2.5 to 5 milligrams daily for five days, but can include hot flashes, nausea and headaches. The concern with aromatase inhibitors relates to an early report of possible fetal toxicity/malformations; this risk has not been substantiated by any subsequent publications on the topic.
In the past, metformin was used liberally in oligoovulatory PCOS patients. In more recent large trials, the use of metformin in patients with PCOS did not appear to increase the live birth rate when administered with clomiphene citrate or as a single agent. Metformin is generally not used in our practice unless there is documented abnormal glucose tolerance test, hemoglobin A1C or fasting glucose.
In summary, oral agents such as clomiphene and letrozole are relatively inexpensive, easy to administer, and effective in treating fertility due to PCOS and ovulatory dysfunction. For refractory cases, fertility specialists can assist with more advanced techniques, such as injected gonadotropins, laparoscopic ovarian drilling and in vitro fertilization to achieve ovulation and pregnancy in these patients.
Dr. Flyckt is an associate staff member in Cleveland Clinic’s Department of Obstetrics and Gynecology. She can be reached at 216.839.3100 or email@example.com.
Robotic Tubal Reversal Reduces Pain, Recovery Time
By Julierut Tantibhedhyangkul, MD
Surgical (tubal) sterilization is the second most common contraceptive method used by women of reproductive age in the United States. The percentage of women who choose to have their fallopian tubes surgically cut, sealed or tied is only slightly less than the percentage who opt to take the contraceptive pill.
But what are the options if a woman who has undergone a tubal ligation has a change of heart, relationship status or circumstance that prompts her to want more children?
For those women, the choices are in vitro fertilization (IVF) or surgical reversal of the sterilization.
After tubal reversal surgery, a woman does not need additional medical visits while trying to conceive, unlike IVF. Tubal reversal also avoids the concerns that some women have about using assisted reproductive technology. And the procedure is more affordable than IVF, especially for women who want to have more than one child.
Tubal reversal is done by removing the abdominal scar tissue from the original sterilization procedure, then re-attaching the fallopian tubes using sutures. Various surgical approaches are available for tubal sterilization reversal.
Traditionally, the procedure has been performed by laparotomy or minilaparotomy. The procedure can also be done laparoscopically. However, that technique is much more challenging than the open surgery.
Cleveland Clinic’s Fertility Center has introduced and pioneered robot-assisted tubal anastomosis to overcome some of those challenges. The first published report of robot-assisted tubal ligation reversal was by Cleveland Clinic gynecologists 15 years ago. The robot-assisted procedure and minilaparotomy are equally effective at achieving tubal reversal. The decision of which procedure to perform is based on an individual patient’s case.
Details of Procedure
Robot-assisted tubal anastomosis is accomplished with four or five small incisions, each less than a centimeter in length. Laparoscope instruments placed inside the patient through these incisions provide clear visualization of the area, while allowing the surgeon to manipulate needles and sutures to re-connect the fallopian tubes.
The robot provides a 3-D view of the anastomosis sites with a high level of magnification. With the assistance of the robot, the surgeon has better control of the instruments, with a greater degree of freedom than in the traditional laparoscopy. Thus, the surgeon can perform this complex procedure with more precision.
Because of the minimal incision size, post-operative pain and recovery time are reduced. Patients typically are released the same day as the surgery and are able to return to work after several days – significantly sooner than with traditional open surgery, according to Cleveland Clinic research.
Whether a patient becomes pregnant after tubal reversal depends on several factors. They include the patient’s age, the method of original sterilization, the length of remaining fallopian tube available for reanastomosis, and any concurrent infertility issues.
Dr. Tantibhedhyangkul is a staff member of Cleveland Clinic’s Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology and Infertility. She can be reached at firstname.lastname@example.org or 216.839.3150.
Cleveland Clinic Offers Fertility Services Nearby
Cleveland Clinic fertility experts provide the full range of leading-edge services for the diagnosis and treatment of infertility, including in vitro fertilization.
Patients are seen in a caring environment, where the major emphasis not only is on technological excellence, but on accessibility, personal attention and emotional support. Our fertility specialists work closely with patients to achieve pregnancy, and collaborate with a patient’s current physician throughout that pregnancy to ensure coordinated care.
For maximum convenience, we have six locations throughout Northeast Ohio:
Beachwood Family Health And Surgery Center
26900 Cedar Road, Suite 220 South
Beachwood, Oh 44122
Cleveland Clinic Main Campus
9500 Euclid Ave. / A81
Cleveland, Oh 44195
Richard E. Jacobs Health Center (Avon)
33100 Cleveland Clinic Blvd.
Avon, Oh 44011
Solon Family Health Center
29800 Bainbridge Road, 2nd Floor
Solon, Oh 44139
Strongsville Family Health And Surgery Center
16761 Southpark Center, 1st Floor
Strongsville, Oh 44136
Twinsburg Family Health And Surgery Center
8701 Darrow Road
Twinsburg, Oh 44087
CME Activity: Ethical Dilemmas in the Practice of Obstetrics, Gynecology & Reproductive Medicine
Presented by Cleveland Clinic’s Ob/Gyn & Women’s Health Institute
Medical professionals can discuss leading ethical issues and challenges in obstetrics and gynecology, maternal-fetal medicine, and reproductive endocrinology during a daylong activity on April 23, 2014, at Cleveland Clinic’s main campus.
“Ethical Dilemmas in the Practice of Obstetrics, Gynecology & Reproductive Medicine,” presented by Cleveland Clinic’s Ob/Gyn & Women’s Health Institute, will take place from 7:30 a.m. – 4 p.m.
Topics include maternal-fetal interventions, conscientious objection, periviability, advances in prenatal testing, uterine transplantation, oocyte cryopreservation, gestational surrogacy, and the clinical translation of innovative and experimental procedures into patient care.
The CME activity’s director is Ruth Farrell, MD, MA, of Cleveland Clinic’s Center for Ethics, Humanities and Spiritual Care. Co-directors are Tommaso Falcone, MD, Chair of Cleveland Clinic’s Ob/Gyn & Women’s Health Institute, and Amanda Kalan, MD, an associate staff member in Cleveland Clinic’s Department of Obstetrics and Gynecology specializing in maternal-fetal medicine.
The activity has been approved for AMA PRA Category 1 Credit™.
To register, go to clevelandclinic.org/obgyn. For more information, contact Danielle Berry at email@example.com or 216.445.2358.