Clinical Aspects of Ovarian Transplantation

K.H. Oktay

Assistant Professor, Obstetrics and Gynecology, Reproductive Medicine, Joan and Sanford I. Weill Medical College of Cornell University, The Center for Reproductive Medicine and Infertility, New York, NY U.S.A.

Key Words
Cryopreservation, ovarian transplantation, cancer-related infertility

Introduction

In the year 2001, over 625,000 women in the United States will be afflicted with invasive cancer. It is estimated that 8%, or 50,000, of these women will be under the age of 40[1],[2]. With modern improvements in treatment regimens, which include aggressive chemo- and radiotherapy, as well as bone marrow transplantation (BMT), cure rates can exceed 90%[3]. However, the alkylating agents, which are commonly used in chemotherapy regimens, as well as ionizing radiation, induce premature ovarian failure in the majority of these patients. This is a significant consequence of cancer treatment, since patients are not only rendered infertile but will also undergo premature menopause.

While advances in assisted reproduction have enabled many infertile couples to conceive, most reproductive age cancer patients do not have the option of utilizing established assisted reproductive technologies to safeguard fertility. In nearly all cancers, with the exception of breast cancer, chemotherapy is initiated within 1-2 weeks of diagnosis. Because an ovarian stimulation cycle for oocyte retrieval typically takes longer, it is generally not feasible to freeze embryos in adult patients with a partner and oocytes in women without a partner for future use. In breast cancer patients, there is a six-week hiatus between surgery and chemotherapy, but because high estrogen levels induced by traditional ovarian stimulation protocols can have adverse effects on breast cancer, oocyte and embryo freezing are not typically offered to these patients.

Candidates for Ovarian Cryopreservation

Ovarian cryopreservation and autotransplantation was initially designed to protect and restore reproductive function in patients receiving sterilizing chemotherapy and/or radiotherapy. The current indications for ovarian cryopreservation extend beyond cancer; gonadotoxic chemotherapy is also used for the treatment of other systemic diseases. Moreover, patients that are undergoing oophorectomy for benign ovarian conditions and for prophylactic reasons may also benefit from ovarian cryopreservation. The following are the main indications for ovarian tissue cryopreservation, both in cancer and non-cancer patients:

  1. Females receiving chemo- and/or radiotherapy for treatment of cancer

Breast Cancer: Breast cancer is the most common cancer in reproductive-age women. About 15% of the estimated 182,000 cases of invasive breast cancer will occur in women less than age 45 years old2,3.Many of these patients opt for adjunctive chemotherapy and, as a result, are subjected to the risk of premature ovarian failure.

Cervical Cancer: In the United States approximately 3,000 will occur in premenopausal women2,[4]. Ovarian involvement is extremely uncommon (<1%) in invasive squamous cell cervical cancer.

Cancers of Childhood and Youth: With improved treatment regimens, including chemotherapy, radiotherapy, and BMT, the cancer survival rates have increased dramatically for children over the past forty years[5]. For all sites combined, the 5-year survival rate has increased from less than 30% to nearly 70%2. As these effective modalities are used more liberally and aggressively, more than 4,000 female children are exposed to sterilizing chemotherapy and/or radiotherapy annually.

  1. Patients undergoing Bone Marrow Transplantation (BMT)

Whereas, BMT was initially used as a treatment for patients with leukemia, it is now being increasingly utilized for a number of other cancerous and non-cancerous diseases. Prior to BMT, high doses of chemo- and/or radiotherapy are used to ablate the bone marrow. Unfortunately, this regimen results in ovarian failure in nearly all patients[6].

  1. Adjunctive or prophylactic oophorectomy for breast cancer and endometriosis
  2. Autoimmune Diseases

For those patients with severe lupus glomerulonephritis, a regimen of cyclophosphamide, a potentially sterilizing form of chemotherapy, is often initiated. Ovarian cryopreservation prior to chemotherapy would be an option for these patients.

  1. Benign ovarian tumors

Human Trials

Encouraged by the mounting evidence from animal orthotopic and heterotopic autograft studies 29,30,31,32,33,34, we have initiated an ovarian transplantation trial in humans. In the initial phase, we developed two different approaches to transplant ovarian tissue:

1)Pelvic or orthotopic, where the tissue is grafted near the infindibulopelvic ligament. In case of pelvic-orthotopic transplantation, a natural pregnancy could theoretically be achieved if the fallopian tubes are intact and if the ovarian tissue is not implanted retroperitoneally. Even though fresh ovarian transplantation has been reported as early as in 1906[7], prior to our clinical trial, orthotopic transplantation of previously frozen ovarian tissue had only been performed in animal studies[8],[9],[10],[11],[12],[13]. These animal studies have shown that the ovarian endocrine function and fertility could be restored with the orthotopic transplantation technique.With this technique, ovarian function was restored in a 29-year-old patient[14],[15]. More recently, ovarian function was also restored by autotransplantation of frozen banked ovarian tissue in a 32-year-old Lymphoma patient[16].

2)Forearm or heterotopic, where the tissue is grafted into the subcutaneous space above the brachioradialis fascia of the forearm. In this technique, patients will always require an IVF-ET procedure to conceive. The forearm transplantation technique does not require general anesthesia or abdominal surgery, and allows the ovarian tissue to be more closely monitored. If there is a need, ovarian removal will be much less complicated compared to a graft implanted in the pelvis. Moreover, the forearm has been successfully used for autografting fresh[17] and frozen-banked parathyroid gland tissue[18] for many years, and there have been several reports on the feasibility of heterotopic sites for ovarian transplantation. With this technique we restored ovarian function in 2 patients[19] and were able to percutaneously retrieve oocytes from one of them.

Safety of Cryopreservation in Patients Recently Exposed to Chemotherapy

Because most chemotherapy regimens need to be initiated soon after diagnosis, several weeks of intensive monitoring and controlled ovarian hyperstimulation may not be an option for many patients. These patients may be offered IVF for the purpose of embryo cryopreservation during a break from chemotherapy or during remission, if ovarian failure has not already occurred.

It is known that chemotherapeutic agents can cause mutations, DNA adducts and structural breaks, as well as oxidative damage in somatic and germ cells. Studies which have looked at pregnancy outcome in cancer survivors have found no significant increase in congenital malformations or malignant neoplasm in the resulting offspring[20],[21]. These studies, however, looked primarily at women who conceived years after their treatment. No human studies have specifically examined quality of oocytes and embryos immediately after chemotherapy.

In female mice exposed to cyclophosphamide, early fertilization post-chemotherapy was shown to result in a higher rate of pregnancy failure and malformation rate[22]. The damage to the oocyte was felt to be time-dependent and influenced by the stage of follicle development at the time of exposure to the chemotherapeutic agent. No data has been published regarding the safety of using human oocytes that have been recently exposed to cytotoxic treatment. Hence, until human studies are available, these patients should avoid pregnancy or IVF for at least six months after chemotherapy.

Conclusions

There have been significant scientific advances in the field of clinical ovarian cryopreservation and transplantation. Ovarian function has been reported after the first cases of orthotopic and heterotopic transplantation of ovarian cortical strips. As a heterotopic site, the forearm emerged as a suitable choice because of the simplicity of the grafting technique and the ease of subsequent monitoring.

Future studies will determine in larger number of patients whether an acceptable longevity can be achieved with both pelvic and forearm ovarian cortical transplant procedures, and whether fertility can be restored with these techniques. Research will also focus on ways to enhance the revascularization process with the goal of reducing follicle losses that take place after tissue grafting. In the meantime, oowH

oooovarian tissue cryopreservation can be recommended in carefully selected patients but should still be offered as experimental protocols. Likewise, ovarian transplantation should only be performed in centers under institutional review board guidelines.

References

1

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