Volume 3, Issue 2, Pages 78-82 (October 2005)

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ABSTRACT

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Preserving fertility after cancer: What are our options?

Fertility options appropriate for cancer survivors depend on the patient's age, disease site and stage, and treatment protocol. Conservative surgery, ovariopexy during pelvic irradiation, in vitro fertilization, and cryopreservation can preserve reproductive function without compromising survival.

Article Outline

• Abstract

• Preserving female fertility

• Ovarian cancer

• Cervical cancer

• Breast cancer

• Preserving male fertility

• Radiotherapy

• Chemotherapy

• Orchiectomy

• Moving forward

• References

• Copyright

Key Points

▪Chemotherapy-induced gonadal dysfunction in women can include follicular destruction, ovarian fibrosis, premature ovarian failure, and reduced levels of estrogen and progesterone.

▪More than 50% of women younger than 35 years resume menstruation after completing chemotherapy: after age 35, reduced ovarian reserve increases the risk of amenorrhea.

▪Fertility-sparing surgery can be performed in women with ovarian borderline tumors, malignant ovarian germ cell tumors, or early-stage cervical cancer without compromising overall survival.

▪In vitro fertilization and embryo cryopreservation after ovarian stimulation with tamoxifen may offer breast cancer patients an option for preserving fertility.

▪In men, sperm cryopreservation and hormonal substitution are options for preserving fertility and managing androgen deprivation after orchiectomy.

Advances in the diagnosis and management of adult and childhood cancers have significantly improved the life expectancy of cancer patients. Approximately 1 in 1,000 adults today is a cancer survivor,1 and overall survival rates for patients with pediatric cancers exceed 75%. This marked improvement in long-term prognosis has generated increased interest in quality-of-life issues among cancer survivors, including preservation of fertility potential. Conservative treatment of early-stage and borderline tumors is crucial for patients desiring future fertility. In this review, we will discuss the impact of cancer and its treatment on female and male fertility and explore the current options available for preserving reproductive function.1

Preserving female fertility

Clinical considerations: Options for fertility-sparing surgery (FSS) include cystectomy, unilateral salpingo-oophorectomy, and unilateral salpingo-oophorectomy plus contralateral cystectomy. Preservation of the uterus in women considering ovarian cryopreservation or future oocyte donation is also considered a form of FSS (Table 1). When assessing conservative surgery options for gynecologic malignancies, clinicians should consider:2

•How are oncologic and reproductive outcomes affected by FSS?

•Does ovulation induction affect reproductive or oncologic outcomes following FSS?

•Does chemotherapy affect reproductive and endocrine physiology?

•Does the rate of fetal anomalies increase with these treatment modalities?

TABLE 1.

Options for preserving fertility in cancer patients

Fertility-sparing surgery

Ovarian cancer

Cystectomy

Unilateral salpingo-oophorectomy

Unilateral salpingo-oophorectomy + contralateral cystectomy

Uterine preservation (with ovarian cryopreservation or oocyte donation)

Cervical cancer

Radical vaginal trachelectomy + laparoscopic lymphadenectomy

Testicular cancer

Unilateral orchiectomy

Organ-sparing surgery guided by frozen section analysis

Ovarian protection

Ovarian transpositioning (ovariopexy) before pelvic irradiation

Cryopreservation

IVF and embryo cryopreservation*

Oocyte retrieval and cryopreservation (after ovarian stimulation)*

Ovarian tissue cryopreservation

Sperm cryopreservation

IVF, in vitro fertilization.

Ovarian stimulation is relatively contraindicated in patients with breast cancer:ovarian stimulation with tamoxifen and/or letrozole may be considered for these patients.

Chemotherapy can induce a wide array of gonadal dysfunction in cancer patients.3, 4 Follicular destruction, ovarian fibrosis, premature ovarian failure, and reduced levels of estrogen and progesterone can all contribute to the risk of decreased fertility in women. The effects of various chemotherapeutic agents on female fertility are summarized in Table 2.

TABLE 2.

Gonadal effects of selected chemotherapeutic agents on female fertility40, 41, 42, 43


Cell cycle–nonspecific
Agents	Mechanism of action	Direct gonadal and reproductive effects
*Alkylating*	• Prevent cell division by cross-linking DNA	• Result in direct ovarian suppression, reflected in elevated FSH and LH levels, and suppressed estrogen levels
Busulfan
Chlorambucil	• *Cyclophosphamide also inhibits DNA synthesis	• Reduce number of oocytes (follicular depletion)
Cyclophosphamide*		• Cause ovarian stromal fibrosis
Ifosfamide		• Impair follicular maturation
Melphalan		• Associated with general ovarian dysfunction
		• *Cyclophosphamide is strongly associated with amenorrhea
Cell cycle–specific
Agents	Mechanism of action	Direct gonadal and reproductive effects
*Antibiotics*	• Bind DNA to prevent transcription	• ‡Doxorubicin is the most strongly toxic to gonadal function
Bleomycin†	• †Bleomycin causes scission of DNA	(the other agents listed are gonadotoxic to a lesser degree)
Dactinomycin
Doxorubicin‡
*Antimetabolites*	• Inhibit metabolic processes essential for DNA and/or RNA synthesis	• Associated with amenorrhea, decreased libido, and ovarian dysfunction
Cytarabine
5-Fluorouracil
Methotrexate
*Plant alkaloids*		• Are toxic to ovaries
Etoposide		• Associated with general ovarian dysfunction
Vinblastine
Vincristine
Vinorelbine
*Taxanes*	• Arrest cell in metaphase by binding microtubular protein used in mitotic spindle formation	• Effects on human fertility are not well described
Docetaxel	• §Paclitaxel initiates apoptosis	• Rodent studies demonstrate damage to healthy oocytes, with depletion of primordial follicular reserve
Paclitaxel§

FSH, follicle-stimulating hormone; LH, luteinizing hormone.

Age is of paramount importance in assessing the future fertility capabilities of a cancer patient. More than 50% of women younger than 35 years will resume menstruation after completing chemotherapy. This may be attributable to the greater follicular reserve and resistance of the ovaries in this population. After age 35, reduced ovarian reserve increases the risk of amenorrhea after chemotherapy. However, irregular menstrual cycles or amenorrhea after chemotherapy does not necessarily confer permanent sterility.4

Ovarian cancer

Ovarian cancer is the second most common gynecologic malignancy. Ovarian tumor diagnosis in reproductive-age women has increased as a result of improvements in diagnostic methods and patients' compliance with recommendations for annual gynecologic examinations. A significant number of invasive epithelial tumors and borderline epithelial tumors are diagnosed in patients younger than 40.5 Approximately 80% of malignant ovarian germ cell tumors are diagnosed in women younger than 30.6

Five-year survival rates of 62% to 85% have been reported for patients with early-stage invasive epithelial ovarian cancers; survival rates for those with stage IA ovarian cancers range as high as 95%.7, 8 One study that compared recurrence rates in women with well-differentiated epithelial ovarian tumors who underwent FSS or radical surgery showed no statistically significant difference.9 Another comparison of FSS and radical surgery for early epithelial ovarian cancer concluded that FSS can be performed for stage I disease regardless of histologic type and grade.10

Ovarian borderline or low malignant potential (LMP) tumors are associated with 5-year survival rates of 95%.11 Although the recurrence rate of borderline tumors appears to be higher after FSS than after radical surgery, conservative management does not appear to affect overall survival and offers the potential for spontaneous pregnancy. In a recent study in France, 14 of 44 women treated conservatively for LMP tumors achieved 17 pregnancies, 15 of which were spontaneous.12 Another study reported excellent reproductive potential among 56 patients receiving FSS, including 40 normal term pregnancies, 6 terminations, and 9 miscarriages.9

Malignant ovarian germ cell tumors are usually unilateral, and equal cure rates have been reported with bilateral and unilateral salpingo-oophorectomy.13 Postoperative chemotherapy (bleomycin, etoposide, and cisplatin) achieves cure rates ranging from 75% to 95% depending on the disease stage.14 Amenorrhea rates as high as 61.7% during chemotherapy have been reported, but normal menstrual cycles resume in 91.5% of the affected women after completion of therapy.13 However, the effects of adjuvant postoperative chemotherapy in women with ovarian cancer vary depending on the regimen, cumulative drug dose, duration of therapy, and patient age.2

Cervical cancer

In the United States, approximately 12,000 new cases of cervical cancer are diagnosed yearly. The distribution of disease is generally bimodal, with the first peak occurring in women between the ages of 35 and 39.15 The second peak occurs between ages 60 and 64.

Preinvasive disease may be treated with conization, loop electrosurgical excision procedure, or cryosurgery. Early-stage disease has historically been treated with radical hysterectomy or radiotherapy, achieving 5-year survival rates of 80% to 90%.16 An alternative to radical hysterectomy is radical vaginal trachelectomy followed by laparoscopic lymphadenectomy.17 This procedure allows women with early cervical cancer the option of retaining their fertility.18

More advanced stages of cervical cancer are treated with radiotherapy or combined chemotherapy and radiotherapy.16 Doses of radiotherapy ranging from 3.2 to 20 Gy induce complete menopause.19 Ovarian transpositioning (ovariopexy), either by laparotomy or laparoscopy, with uterine conservation may be used to maintain ovarian function and preserve fertility in women requiring pelvic irradiation.20, 21 A study assessing fertility outcomes after ovarian transpositioning reported preservation of ovarian function in 100% of the 37 women evaluated; 12 patients had 18 pregnancies, 16 of which were spontaneously achieved.20 No fetal morphologic anomalies were observed.

Breast cancer

Each year in the United States, 180,000 new cases of breast cancer are diagnosed, 25% of them in premenopausal women—15% in women younger than 45 years.22 Preserving fertility in breast cancer survivors presents several challenges. Chemotherapy-induced ovarian failure is potentially reversible. However, delaying pregnancy for at least 5 years during the course of treatment is usually recommended, allowing additional age-related diminishing of ovarian reserves to occur. An established method of fertility preservation for patients awaiting cancer therapy is ovarian stimulation and oocyte aspiration for in vitro fertilization (IVF) and embryo cryopreservation. However, ovarian stimulation is contraindicated for breast cancer patients because estrogens can cause cancer cell proliferation and dissemination.23

IVF and embryo cryopreservation after ovarian stimulation with tamoxifen may offer breast cancer patients a safe option for preserving fertility.24 Generally, this approach would be taken after a remission, when a cancer-free state is diagnosed. Tamoxifen, an antiestrogenic, nonsteroidal compound, currently is the drug of choice for breast cancer treatment and prophylaxis.24, 25 In one study, 2 of 6 breast cancer patients conceived using the tamoxifen IVF protocol.24 More recently, the same authors found that a combination of low-dose follicle-stimulating hormone with either tamoxifen or letrozole produced higher embryo yields than did the tamoxifen-IVF approach alone.26

Preserving male fertility

Male infertility of testicular origin results from a failure of the testicles to produce viable sperm.27, 28 This can be caused by cancer or its treatment. Certain malignancies (eg, Hodgkin's disease, testicular cancer, and extragonadal germ cell cancer) are associated with abnormal testicular function. Abnormalities in sperm count, sperm motility, and sperm morphology have been reported in men with Hodgkin's disease, as has histologic evidence of seminiferous tubular epithelium.29, 30

Radiotherapy

The testes are one of the most radiosensitive tissues. Radiotherapy-induced testicular damage is dose-dependent.31 Even small doses of radiation may damage the germinal epithelium, resulting in changes to the spermatogonia; the risk of permanent infertility begins at fractionated doses of 2 Gy. At doses of 4 to 6 Gy, the numbers of spermatozoa are significantly decreased, resulting in damage to the spermatids. Leydig cells are more resistant to damage from radiotherapy than is the germinal epithelium; at fractionated doses above 2 Gy, serum levels of luteinizing hormone show only transient elevations, and serum levels of testosterone remain normal.32 The risk of Leydig cell toxicity increases significantly with high-dose (30 Gy) testicular radiation; prepubertal boys are affected to a greater degree than men.33

Complete recovery of sperm concentration and germinal cell numbers requires 9 to 18 months after small doses of radiation and approximately 30 months after moderate doses. At least 5 years is needed for recovery from large doses of radiation.31 The threshold for permanent testicular damage may be as low as 1.2 Gy. Low doses of radiation may be key to improved recovery rates for spermatogenesis. Testicular radiation doses lower than 0.2 Gy have no significant effect on follicle-stimulating hormone levels or sperm counts.34

Chemotherapy

The gonadotoxic effects of chemotherapy are greatest on the cells of the germinal testicular epithelium, which have high mitotic and meiotic indices.35 Agents that damage the stem cells are most likely to cause prolonged azoospermia or permanent infertility.35 Alkylating agents are among the most gonadotoxic agents in men and carry the greatest risk of inducing permanent sterility. Cyclophosphamide causes permanent infertility at doses above 7.5 g/m2.36 Mechlorethamine and melphalan also demonstrate significant gonadotoxic effects in men.37, 38

Orchiectomy

Testicular tumors occur in approximately 6 to 8 men per 100,000. Orchiectomy is associated with androgen deprivation and infertility. The long-term survival rate for patients with malignant germ cell tumors approaches 100%, making quality-of-life issues such as fertility preservation particularly important.

Sperm cryopreservation and hormonal substitution are options for preserving fertility and combating androgen deprivation when the testes must be removed. Differentiating benign from malignant testicular lesions is impossible by ultrasonography or magnetic resonance imaging. To avoid unnecessary testis removal, organ-sparing surgery guided by frozen-section analysis may be an option for preserving fertility and maintaining physiologic endocrine function.39 However, this approach is suitable only for patients with benign masses or completely resectable malignant tumors.

Moving forward

Advances in fertility preservation have given cancer survivors hope for maintaining reproductive function. Ongoing research promises to continue this trend. Cryopreservation of ovarian and testicular tissue is an area of current research. Oocyte cryopreservation protocols are being used today, and ways of optimizing these techniques are also being studied. As health care providers, it is our obligation to present our cancer patients with the fertility options now available to them.

References

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a Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, Los Angeles, Medical Center, Los Angeles, California

Department of Obstetrics and Gynecology, UCLA Medical Center, Los Angeles, CA 90095

1 See also “Preserving reproductive function in women with cancer,” Sexuality, Reproduction & Menopause, December 2004.

PII: S1546-2501(05)00039-3

doi:10.1016/j.sram.2005.09.004

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