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Fertility After Cancer

Several strategies are aimed at preserving reproductive function.

The projected incidence of new cancer cases in the U.S. in 2007 is almost 1,500,000; about 4% of these will occur in patients younger than 35.1,2 By 2010, as many as 1 in 250 patients will have survived childhood cancer.3 As more children and young adults survive malignancies, cancer and its treatment will continue to add to the problem of infertility.

The probability of a female developing invasive cancer from birth to age 39 is about 2%.1 More women are surviving malignancies because of improvements in cancer diagnosis and treatment, but these lifesaving technologies come at a price: Infertility is a common complication of cancer therapy in young women. Modified chemotherapy regimens and surgical techniques as well as adjunctive treatments (e.g., gonadotropin-releasing-hormone [GnRH] analogues and oral contraceptives) and newer techniques involving cryopreservation of embryos, oocytes, or ovarian strips are all aimed at preserving fertility in female cancer patients.

ALL MAJOR MODES OF CANCER TREATMENT CAN AFFECT FERTILITY

Surgery, radiation, and chemotherapy can impair reproductive function. Malignancies involving the pelvic organs often require surgical procedures that result in removal of or damage to the ovaries, uterus, or both.

Radiation causes partial or total premature ovarian failure and may negatively affect uterine receptivity to pregnancy. Patient age and radiation dose and field influence the likelihood of premature ovarian failure: Ovarian damage from radiation therapy is proportional to age at treatment and to dose.4 When treatment involves pelvic, abdominal, or inguinal fields, the ovaries are exposed to greater amounts of radiation. Scatter radiation also can cause considerable damage even if the ovaries are not included in the treatment area. Cranial radiation contributes to infertility by damaging the hypothalamic-pituitary-gonadal axis.4 Uterine damage caused by radiation is manifested as a decrease in uterine volume and increased risks for miscarriage, preterm labor, and intrauterine growth restriction.4

Chemotherapy can also impair reproductive capacity. Patient age, drug dose, and regimen all influence chemotherapy’s negative impact on reproductive function. Increasing age is associated with decreasing fertility after chemotherapy.5 Among chemotherapy drugs, alkylating agents are associated with the highest risk for ovarian failure.

Both chemotherapy and radiation can have delayed effects on the ovaries. Therefore, the presence of menses after cancer therapy does not always portend a normal reproductive lifespan. Indeed, many patients experience subsequent premature ovarian failure despite the resumption of menstrual cycles following cancer treatment. Conversely, even when amenorrhea and elevated gonadotropin levels occur subsequent to cancer therapy, ovarian function, including fertility, might return.

ALTERING EXISTING TREATMENTS TO AVERT REPRODUCTIVE DAMAGE

Modified chemotherapy regimens and surgical techniques can alleviate reproductive harm from cancer therapy. For instance, new drug regimens for Hodgkin lymphoma have comparable efficacy with less gonadotoxicity.4 Conservative surgeries for gynecologic malignancy, such as trachelectomy for cervical cancer and unilateral oophorectomy for ovarian malignancy, can help maintain fertility. Repositioning of the ovaries above the pelvic brim can decrease gonadal exposure to radiation.

Concurrent treatment with GnRH analogues may protect against the gonadotoxic effects of chemotherapy. Results of animal and human studies have supported the role of GnRH in preserving fertility. For example, administration of cyclophosphamide plus GnRH versus cyclophosphamide alone in female rhesus monkeys significantly reduced the rate and total number of follicles lost.6 In a prospective study of female lymphoma patients who received GnRH and chemotherapy compared with similar patients who received chemotherapy alone, 94% of the GnRH group versus 39% of the non-GnRH group resumed spontaneous menses within 3 to 8 months of treatment.7 Despite the apparent fertility-preserving effects of GnRH, no prospective, randomized, controlled trials have been performed to confirm this protective effect. Moreover, prepubertal females exposed to high levels of alkylating agents undergo ovarian failure despite having inherently elevated GnRH levels. Therefore, although GnRH can be offered to women facing chemotherapy, it does not guarantee preservation of their fertility.

Results of several small observational studies suggest that oral contraceptives may help to preserve ovarian function in cancer patients.8 However, as is true for GnRH agonists, no studies have provided conclusive evidence of their efficacy.

NEW TECHNIQUES FOR MAINTAINING FERTILITY IN CANCER PATIENTS

Developments for preserving fertility after cancer therapy include cryopreservation of embryos, oocytes, or ovarian strips. Embryo cryopreservation currently is the only widely available, reasonably effective option for women who need chemotherapy, radiation, or both. This technique involves ovarian stimulation and collection of oocytes followed by in vitro fertilization. The resultant embryos are frozen and stored. Survival rates per thawed embryo range from 35% to 90% with cumulative pregnancy rates greater than 60%.9 Embryo cryopreservation does have some drawbacks. A 2-to-6–week delay in cancer treatment is required to allow for ovarian stimulation and oocyte retrieval.2 Moreover, the elevated estrogen levels associated with ovarian stimulation may be contraindicated in malignancies such as breast and endometrial cancers. In these instances, natural-cycle IVF may suffice. Alternatively, in patients with breast cancer, tamoxifen or letrozole can be used to induce ovulation.2,9

Oocyte cryopreservation is appropriate for women who do not want their eggs immediately fertilized with donor sperm. This method also requires a treatment delay of 2 to 6 weeks for ovarian stimulation and exposes patients to the risks associated with ovulation induction. Oocyte cryopreservation remains largely experimental, with pregnancy rates ranging from 1% to 5% per frozen oocyte.10 Nonetheless, the American Society for Reproductive Medicine Practice Committee recommends offering oocyte cryopreservation to cancer patients facing infertility.2

Ovarian strip cryopreservation involves laparoscopic removal of several pieces of ovarian cortical tissue for frozen storage. When the patient’s cancer is in remission, the strips are reimplanted orthotopically in the pelvis or heterotopically in the subcutaneous tissue. This method avoids ovarian stimulation for oocyte retrieval and is therefore acceptable in women with hormonally responsive tumors. Moreover, primordial follicles are less susceptible to cryoinjury than are oocytes.

Ovarian strip cryopreservation, like oocyte cryopreservation, is largely experimental. Successful orthotopic transplantation of ovarian tissue has been reported in animal models and in a case involving monozygotic twins.10,11 In each of three notable cases involving women with Hodgkin or non-Hodgkin lymphoma, pregnancy was achieved after orthotopic or heterotopic grafting of their own cryopreserved ovarian tissue.12,13,14

These cases suggest that cryopreservation protects a critical element of the ovarian tissue, whether it is follicles or a signaling molecule, from the damaging effects of chemotherapy and radiation. The major concern associated with ovarian tissue cryopreservation is reintroduction of malignant tissue. Although there are no reports as yet of cancer arising from transplantation of human ovarian tissue, transmission of lymphoma has been demonstrated in mice receiving cryopreserved ovarian tissue.15

CONCLUSION

Patients who become infertile after cancer therapy have increased risk for emotional distress.2 Furthermore, many women prefer to have biologic offspring even if they have concerns about birth defects associated with chemotherapy or anxiety about their own longevity.2 Today, women facing cancer have options to preserve their fertility. A few of these options are well-studied, standard therapies, but most are still experimental. Nonetheless, patients must be informed that such opportunities exist.

— Marcy Maguire Lash, MD, and Sandra Ann Carson, MD

Dr. Lash is a senior resident in the Department of Obstetrics and Gynecology at Tufts-New England Medical Center, Boston.

Published in Journal Watch Women's Health June 28, 2007

Citation(s):

1. Jemal A et al. Cancer Statistics, 2007. CA Cancer J Clin 2007 Jan/Feb; 57:43-66.

2. Lee SJ et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006 Jun 20; 18:2917-31.

3. Bleyer WA. The impact of childhood cancer on the United States and the world. CA Cancer J Clin 1990 Nov/Dec; 40:355-67.

4. Wallace WH et al. Fertility preservation for young patients with cancer: Who is at risk and what can be offered? Lancet Oncol 2005 Apr; 6:209-18.

5. Chiarelli AM. Early menopause and infertility in females after treatment for childhood cancer diagnosed in 1964-1998 in Ontario, Canada. Am J Epidemiol 1999 Aug 1; 150:245-54.

6. Ataya K et al. Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol Reprod 1995 Feb; 52:365-72.

7. Blumenfeld Z et al. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 1996 Aug; 11:1620-6.

8. Behringer K et al. Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: A report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 2005 Oct 20; 23:7555-64.

9. Marhhom E and Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv 2007 Jan; 62:58-72.

10. Donnez J et al. Ovarian tissue cryopreservation and transplantation: A review. Hum Reprod Update 2006 Sep/Oct; 12:519-35.

11. Silber S et al. Ovarian transplantation between monozygotic twins discordant for premature ovarian failure. N Engl J Med 2005 Jul 7; 353:58-63.

12. Donnez J et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004 Oct 16; 364:1405-10.

13. Meirow D et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med 2005 Jul 21; 353:318-21.

14. Oktay K and Oktem O. Sustained endocrine function and spontaneous pregnancies after subcutaneous transplantation of cryopreserved ovarian tissue in stem cell transplant recipients. Fertil Steril 2005 Sep; 84:S68.

15. Shaw JM et al. Fresh and cryopreserved ovarian tissue samples from donors with lymphoma transmit the cancer to graft recipients. Hum Reprod 1996 Aug; 11:1668-73.

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Copyright © 2007. Massachusetts Medical Society. All rights reserved.