Fertility Issues
Chemotherapy
Radiation
Preventive Strategies
Procreative Alternatives
Adjuvant radiation therapy and/or chemotherapy introduce higher risks of
infertility in the treatment of cancer. Sterility from these therapies may be
temporary or permanent. The occurrence of this toxicity is related to a number
of factors including the individual’s gender, age at the time of treatment,
type of therapeutic agent, radiation field, total dose, single versus multiple agents, and
length of time since treatment.
When treatment-related or disease-related dysfunction is a possibility, every effort should be made to provide adequate information and education on reproduction and fertility. Conveying such information can be complicated, especially in younger pediatric cancer patients. Children may be too young to comprehend the implications of treatment on fertility. Additionally, in some instances, parents may decide to shelter children from such discussions.[1] Existing literature suggests that only about half of men and women of child-bearing age receive the information they need from their health care providers about cancer-related infertility at the time of diagnosis and treatment planning.[2] This lack of information is one of the most common reasons men give for failing to bank sperm.[2] To address this issue, a computerized interactive educational tool for patients, families, and physicians called Banking on Fatherhood after Cancer is under development and will be viewable on CD-ROM or over the Internet.[2]
Chemotherapy
With regard to chemotherapy, the extent of damage to a patient's fertility depends on the agent administered, the doses received, and the patient's age at the time of treatment. Age is an important factor, and the
possibility of gonadal recovery improves with the length of time off
chemotherapy. The germinal epithelium of the adult testis is more susceptible
to damage than that of the prepubertal testis.[3] The evidence to date
(largely from adjuvant studies) suggests that patients older than 35 to 40
years are most susceptible to the ovarian effects of chemotherapy. The
ovaries of younger women can tolerate greater doses.[4] Predicting the outcome
for any individual patient is difficult, as the course of ovarian functioning
following chemotherapy is variable.[3] Relative risk of ovarian failure and
testicular damage from cytotoxic agents has been studied, and the alkylating
agents have subsequently been shown to be damaging to fertility.
The following agents have been shown to be gonadotoxic: busulfan,
melphalan, cyclophosphamide, nitrosoureas, cisplatin, chlorambucil, mustine,
carmustine, lomustine, cytarabine, ifosfamide, and procarbazine.[3,5-8] In addition to these alkylating agents, vinblastine, cytarabine, cisplatinum, and procarbazine have also been reported to be gonadotoxic in male and female patients.[9] Chemotherapy regimens for the treatment of non-Hodgkin lymphoma are generally
less gonadotoxic than those used for Hodgkin lymphoma.[3] The effects of
chemotherapy on testicular function have also been widely studied in patients
with testicular cancer. One review reported that more than half of the patients with testicular germ cell cancer showed impaired spermatogenesis
before undergoing cytotoxic treatment. Permanent infertility is ultimately
defined by dose of cisplatin in these patients. At doses lower than 400 mg/m2,
long-term effects on endocrine function and sperm production are unlikely to
occur. Higher doses would be expected to cause long-term endocrine-gonadal
dysfunction.[10]
Although chemotherapy causes ovarian damage, there appears to be no risk of toxicity to future offspring of women treated with these agents before pregnancy.[9]
Radiation
When the testes are exposed to radiation, sperm count begins to decrease and,
depending on the dosage, temporary or permanent sterility may result.[4]
Men who receive radiation to the abdominal or pelvic region may still regain
partial or full sperm production depending on the amount of injury to the
testes. Unlike the germinal epithelium, Leydig cell function may be more prone
to damage from irradiation in prepubertal life than in adulthood.[3] Testicular radiation with doses higher than 20 Gy is associated with Leydig cell dysfunction in prepubertal boys, while Leydig cell function is usually preserved with doses of as much as 30 Gy in sexually mature males.[11] Exposing
the testes to ionizing radiation at a dose lower than 6 Gy causes disturbances of
spermatogenesis and altered spermatocytes with recovery periods dependent on
dose;[4] doses higher than 6 Gy cause permanent infertility by killing off all stem
cells.[12] For patients with testicular germ cell cancer, using modern
radiation techniques (radiation doses to the para-aortic field <30 Gy) and
testis shielding providing testis scatter radiation (<30 Gy), radiation-induced
impairment of fertility is very unlikely.[10] Sperm counts are typically lowest at 4 to 6 months posttreatment; return to pretreatment levels usually occurs in 10 to 24 months, with longer periods required for recovery after higher doses.[9] Total-body irradiation (TBI) as a conditioning regimen for stem cell transplantation causes permanent gonadal failure in approximately 80% of men.[13] For men, gonadal toxicity can be
evidenced by the following three measurements: testicular biopsy, serum hormone
assays (levels), and semen analysis. When male infertility is the result of
abnormal hormone production, the use of hormone manipulation may lead to the
return of sperm production.[14]
For women, a dose of 5 Gy to 20 Gy administered to the ovary is sufficient to
completely impair gonadal function regardless of the patient’s age; a dose of
30 Gy provokes premature menopause in 60% of women younger than 26 years.[15] Women who are older than 40 years when undergoing treatment have a smaller pool of remaining oocytes and require only 5 to 6 Gy to produce permanent ovarian failure. TBI, as when used before stem cell transplantation, is associated with more than 90% permanent gonadal failure in women overall and an incidence of pregnancy less than 3%.[9] The outlook for recovery of ovarian function before puberty is more favorable, particularly if radiation is delivered in several fractions.[13] Measurement of gonadal toxicity in women is more difficult to assess
due to the relative inaccessibility of the ovary to biopsy (which would require
laparoscopy). Therefore, menstrual and reproductive history, measurements of
serum hormone levels, and clinical evidence of ovarian function are the
criteria most commonly used to determine ovarian failure. Several authors
provide reviews of gonadal dysfunction in patients receiving chemotherapy [14]
and the effect of cancer therapy on gonadal function.[4]
Preventive Strategies
For women, studies [16] have shown that movement of the ovaries out of the
field of radiation (ovariopexy), either laterally, toward the iliac crest, or
behind the uterus may help preserve fertility when high doses of radiation
therapy are being applied. By relocating the ovaries laterally it is possible
to shield them during radiation of the para-aortic and femoral lymph nodes.[4]
Pelvic radiation, however, still provokes an irradiation of the ovary of 5% to 10%, even if transposed outside the irradiation area.[15] Similar prevention
strategies are available for men. When possible, lead shields are used to
protect the testes.[4]
Procreative Alternatives
When feasible and relative to the necessity of treatment, oncology
professionals should discuss reproductive cell and tissue banking with
patients, referring to a reproductive endocrinologist before chemotherapy
and/or radiation. Men can store sperm from semen ejaculate, epididymal
aspirate, testicular aspirate, and testicular biopsy.[17-20] Women can store
ovarian tissue, ovarian follicles, and embryos.[21,22] In oocyte
cryopreservation, which is still experimental,[23] reproductive cells/tissue
are cryopreserved for future use in artificial insemination for patients who
wish to protect their reproductive capacity. One published case report describes a live birth after in vitro fertilization of thawed cryopreserved ovarian cortical tissue into the ovaries of a 28-year-old woman who experienced ovarian failure secondary to high-dose chemotherapy for non-Hodgkin lymphoma.[24] For this case, ovarian tissue (containing many primordial follicles) was harvested after administration of a second-line conventional therapy regimen and before treatment with high-dose chemotherapy. Freezing oocytes has also had some success but with significant limitations and only a small number of reported pregnancies. Overall current survival rates for the freeze-thaw process range from 15% to 43%, with approximately 45% fertilization rates but only 1% to 2% clinical pregnancy rates.[25] Reviews [15,25,26] of indications for
cryopreservation of ovarian tissue and current reproductive-assisted
technologies are available.
These options may not be appropriate for all patients. Counseling is an
important part of the decision-making process for patients. Thinking through
these decisions at a time when patients are struggling with issues of life and
potential death are often difficult. Patients need to consider costs, stress,
time, emotions, and potential inclusion of another individual in the pregnancy
process (i.e., a surrogate). For many patients, the financial costs associated
with in vitro fertilization and subsequent embryo cryopreservation is cost
prohibitive. Consideration also needs to be given to the current rate of
failure for in vitro fertilization procedures and the potential adverse effect
of malignancy on sperm parameters.[23] A retrospective analysis, with a
limited sample size, reported that the oocytes from patients with malignant
disorders were of a poorer quality and exhibited a significantly impaired
fertilization rate compared with age-matched controls.[23] Importantly, data on
the outcome of pregnancies in cancer survivors [27] have not shown any increase in genetically mediated
birth defects, birth-weight effects, and sex ratios. Based on the evidence
thus far, individuals treated with cytotoxic chemotherapy who remain fertile
are not at an increased risk of having children with genetic abnormalities.[3]
For all patients who wish to be parents and who have permanent infertility,
adoption should be presented as a choice.
Men who are treated with sterilizing chemotherapy may have semen cryopreserved, yet utilization remains low.[28] In a 15-year study of 776 men with a variety of malignancies, the cumulative rate of using the cryopreserved semen for assisted conception was less than 10% up to 8 years. Younger age at cryopreservation and a diagnosis of testicular cancer were associated with lower utilization.[29] Despite poor postthawing sperm survival rates, intracytoplasmic sperm injection (ICSI) offers the possibility of a pregnancy even if only a single motile sperm is present after thawing.[30] Cryopreservation of sperm should be recommended even to oncological patients younger than 15 years (provided these patients can produce a semen sample), as overall success rates (defined as the observation of at least a single motile sperm after the thawing procedure) have been found to be similar to those observed in adults.[31] For men who experience retrograde ejaculation after treatment and remain
fertile, it is often possible to retrieve live sperm cells. An infertility
specialist can retrieve sperm cells from the testicles and from urine. Testis
sperm extraction incorporates the removal of testicular parenchyma with
processing and isolation of individual sperm cells. This allows for ICSI in azoospermic men. In a retrospective
study, 15 of 23 men who were azoospermic after receiving chemotherapy had
retrievable testis sperm leading to successful fertilization. Pregnancies occurred in 31% of cycles. Future research is needed to address whether the offspring produced after ICSI techniques are at increased risk of genetic or congenital malformation.[32] Medication can
sometimes be used to stimulate the remaining nerves around the prostate and
seminal vesicles to convert a retrograde ejaculation to an antegrade
ejaculation. In the United States, ephedrine sulfate is most often used; in
Europe, imipramine has also been used. Pharmacologic agents can also be used
to induce an ejaculation (i.e., intrathecal neostigmine or subcutaneous
physostigmine). When medication does not work, several other techniques are
available and may be recommended, including vibratory stimulation,
electroejaculation, direct aspiration of fluid from the vas deferens, perineal
needle stimulation, and hypogastric-nerve stimulation. Further review of these
treatments and information regarding treatment of infertility and assisted reproductive technology is available.[12,33]
Fertility outcomes after therapy of common cancer types (breast cancer, leukemia and lymphoma, cervical cancer, ovarian cancer, endometrial cancer, and testicular cancer) are available in a published review.[9]
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