308858112
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 401,2. 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 years5. 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.
2. 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 patients6.
3. Adjunctive or prophylactic oophorectomy for breast cancer and endometriosis
4. 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.
5. 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 19067, prior to our clinical trial, orthotopic transplantation of previously frozen ovarian
tissue had only been performed in animal studies8,9,10,11,12,13. 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 patient14,15. More recently, ovarian function was also restored by
autotransplantation of frozen banked ovarian tissue in a 32-year-old Lymphoma patient16.
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 fresh17 and frozen-banked parathyroid gland tissue18 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 patients19 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
2
congenital malformations or malignant neoplasm in the resulting offspring20,21. 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 rate22. 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, ovarian 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
Cancer Facts and Figures-2001, American Cancer Society, Atlanta, GA, 2001.
SEER*Stat Software, version 2.0.SEER Cancer Incidence Public-Use Database, 1973-1996,
August 1998 Submission. National Cancer Institute 1999.
3
RIES LAG, PERCY CL, BUNIN GR. In: RIES LAG, SMITH MA, GURNEY JG, LINET M,
TAMRA T, et al., eds. Cancer Incidence and Survival among Children and Adolescents: United
States SEER Program 1975-1995, National Cancer Institute, SEER program. Bethesda, MD:NIH
Pub. No. 99-4649;1999:1-15.
4
CHEN VW, WU XC, ANDREWS PA, eds. Cancer in North America, 1991-1995. Volume one:
Incidence, Sacramento, CA: North America Association of Central Cancer Registries, 1999.
5
APPERLEY JF, REDDY N. Mechanism and management of treatment-related gonadal failure
in recipients of high dose chemoradiotherapy. Blood Rev. 1995 Jun;9(2):93-116.
6
MEIROW D. Reproduction post-chemotherapy in young cancer patients. Mol Cell Endocrinol.
2000 Nov 27;169(1-2):123-31.
7
MORRIS RT. A case of heteroplastic ovarian grafting, followed by pregnancy, and the delivery
of a living child. Medical Record. 1906;69(18):697-698.
8
AUBARD Y, PIVER P, COGNI Y, FERMEAUX V, POULIN N, DRIANCOURT MA.
Orthotopic and heterotopic autografts of frozen-thawed ovarian cortex in sheep. Hum Reprod.
1999 Aug;14(8):2149-54.
2
3
9
BAIRD DT, WEBB R, CAMPBELL BK, HARKNESS LM, GOSDEN RG. Long-term ovarian
function in sheep after ovariectomy and transplantation of autografts stored at -196 C.
Endocrinology. 1999 Jan;140(1):462-71.
10
CANDY CJ, WOOD MJ, WHITTINGHAM DG. Restoration of a normal reproductive
lifespan after grafting of cryopreserved mouse ovaries. Hum Reprod. 2000 Jun;15(6):1300-4.
11
COX SL, SHAW J, JENKIN G. Transplantation of cryopreserved fetal ovarian tissue to adult
recipients in mice. J Reprod Fertil. 1996 Jul;107(2):315-22.
12
HARP R, LEIBACH J, BLACK J, KELDAHL C, KAROW A. Cryopreservation of murine
ovarian tissue. Cryobiology. 1994 Aug;31(4):336-43.
13
SHAW JM, COX SL, TROUNSON AO, JENKIN G. Evaluation of the long-term function of
cryopreserved ovarian grafts in the mouse, implications for human applications. Mol Cell
Endocrinol. 2000 Mar 30;161(1-2):103-10.
14
OKTAY K, KARLIKAYA G. Ovarian function after transplantation of frozen, banked
autologous ovarian tissue. N Engl J Med. 2000 Jun 22;342(25):1919.
15
OKTAY K, AYDIN BA, KARLIKAYA G. A technique for laparoscopic transplantation of
frozen-banked ovarian tissue. Fertil Steril. 2001 Jun;75(6):1212-6.
16
RADFORD JA, LIEBERMAN BA, BRISON DR, SMITH AR, CRITCHLOW JD, RUSSELL
SA, WATSON AJ, CLAYTON JA, HARRIS M, GOSDEN RG, SHALET SM. Orthotopic
reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for
Hodgkin's lymphoma. Lancet. 2001 Apr 14;357(9263):1172-5.
17
WELLS SA Jr, ELLIS GJ, GUNNELLS JC, SCHNEIDER AB, SHERWOOD LM.
Parathyroid autotransplantation in primary parathyroid hyperplasia. N Engl J Med. 1976 Jul
8;295(2):57-62.
18
WAGNER PK, SEESKO HG, ROTHMUND M. Replantation of cryopreserved human
parathyroid tissue. World J Surg. 1991 Nov-Dec;15(6):751-5.
19
OKTAY K, AYDIN BA, ECONOMOS K, RUCINSKI J, KAN MT, VEECK L,
ROSENWAKS Z. Restoration of ovarian function after autologous transplantation of ovarian
tissue in the forearm. Fertil Steril. 2000;74 (Suppl 3):S79.
20
HAWKINS MM. Pregnancy outcome and offspring after childhood cancer. BMJ. 1994 Oct
22;309(6961):1034.
21
SANDERS JE, HAWLEY J, LEVY W, GOOLEY T, BUCKNER CD, DEEG HJ, DONEY K,
STORB R, SULLIVAN K, WITHERSPOON R, APPELBAUM FR. Pregnancies following
high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and
bone marrow transplantation. Blood. 1996 Apr 1;87(7):3045-52.
22
MEIROW D, EPSTEIN M, LEWIS H, NUGENT D, GOSDEN RG. Administration of
cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive
performance and fetal malformations. Hum Reprod. 2001 Apr;16(4):632-7.
4