Women diagnosed with cancer frequently have questions
regarding the effect of cancer therapy on their future reproductive
potential. Cancer therapies, including chemotherapy and radiation
therapy, may temporarily or permanently damage ovarian function,
thereby precluding the option of biologic motherhood. Surgery
involving the female reproductive organs can affect fertility
in various ways, depending on the particular organ involved. This
article describes the effects of cancer therapies on fertility
and explores the options currently available for preservation
of female fertility.
Surgical procedures that remove organs critical to female reproduction,
such as radical hysterectomy, bilateral oophorectomy (i.e., the
removal of both ovaries), and radical cystectomy in which the
ovaries and uterus are removed, will result in permanent infertility.
The removal of only a single ovary and its associated fallopian
tube, however, does not significantly affect fertility and allows
future pregnancy (Schilder et al., 2002). The removal of the uterus
but not the ovaries leaves the possibility of biologic motherhood
with the use of a surrogate gestational carrier—a woman
who carries the pregnancy to term for the biologic mother (Brinsden,
2003).
Infertility that arises following cancer treatment is the result
of ovarian damage. Typically, this is marked by amenorrhea, elevated
levels of folliclestimulating hormone (FSH), and low estrogen
levels (Molina, Barton, & Loprinzi, 2005). Infertility induced
by chemotherapy or radiation therapy is often referred to as ovarian
failure, and can be a subset of premature ovarian failure (POF).
The development of ovarian failure following chemotherapy or radiation
therapy is dependent on many factors, including patient age at
the time of treatment, the particular chemotherapy agent(s) used,
the location or “treatment port” of radiation, and
the total dose and duration of chemotherapy and/or radiation therapy.
Chemotherapy is the broad term used to describe
cancer treatment with any one or more of many different drugs.
Only some chemotherapeutic agents are known to result in infertility.
Not surprisingly, higher doses of the harmful agent are more likely
to result in toxic effects. Furthermore, combining different chemotherapy
agents that may induce infertility individually can potentiate
toxicity at a lower total dose. The class of drugs known as alkylating
agents has been most frequently implicated in reproductive system
compromise. Table 1 lists the chemotherapy agents known to affect
female fertility (Chabner & Longo, 2005).
Radiation therapy delivered near the ovaries may
result in permanent infertility. Radiation to the pelvis, abdomen,
or spine often includes the ovaries and uterus within the treatment
port. Damage to the uterus from radiation therapy can lead to
increased rates of miscarriage, premature labor, and low birth
weight infants (Critchley, Bath, & Wallace, 2002). Total-body
irradiation, which is sometimes used in preparation for a bone
marrow transplant, always affects the ovaries. In contrast, radiation
administered to areas above or well below the pelvis has no effect
on ovarian function. Similar to chemotherapy, sterilizing effects
of radiation treatment are dependent on dose, the fractionalization
schedule, and patient age at the time of treatment. Even with
low doses of radiation, women over 40 years of age at the time
of treatment may have permanent ovarian failure (Wallace, Thomson,
& Kelsey, 2003). Significantly higher doses are needed to
induce ovarian failure in younger women and girls. However, 37
of 38 young girls treated for an intra-abdominal tumor with moderate
doses of abdominal external radiotherapy developed ovarian failure
(Wallace, Shalet, Crowne, Morris Jones, & Gattamaneni, 1989).
Specifically, 71% exhibited primary amenorrhea and the remainder
underwent POF at a median age of 23.5 years.
Previously, it was believed that prepuberty girls
are resistant to the damage of chemotherapy and radiation therapy,
because progression to puberty with the establishment of monthly
cycles and hormone levels often occurs normally following cancer
treatment. However, studies of longer duration and follow-ups
indicate that prepubertal ovaries are as sensitive to the toxic
effects of chemotherapy and radiation therapy as the ovaries of
older women and suffer damage and depletion of healthy oocytes
(i.e., eggs; Wallace et al., 2005). The apparent difference in
toxicity is attributed to the fact that younger ovaries have significantly
larger pools of oocytes. Therefore, a similar number of oocytes
may be damaged with each course of chemotherapy regardless of
patient age, but the larger reserve of available oocytes in younger
individuals delays the onset of ovarian failure until a later
time. For example, early onset menopause has been described in
women treated with chemotherapy for leukemia during childhood
(Byrne, 1999).
Women are born with their entire lifetime supply of oocytes, numbering
approximately 1 million and experience a continuous decline in
the total number throughout their lives. By the time a girl enters
puberty, only about 25% of her total oocyte pool remains—
approximately 300,000 (Gosden, 1995). Most women begin to exhibit
a significant decrease in fertility around the age of 37. At menopause,
which occurs at an average age of 51 years, virtually no oocytes
remain. The vast majority of oocytes within each ovary are immature
and are stored within small cysts called follicles. Oocytes must
undergo growth and maturation to become functional. Throughout
a woman’s lifetime, an excessive number of follicles and
oocytes are recruited to begin the growth and maturation process.
The large majority, however, do not reach full maturity; most
undergo spontaneous involution and disappear in a process called
atresia (i.e., degeneration). Only about 300 to 500 oocytes will
reach maturity during a woman’s lifetime (University of
Michigan, 2005).
Maturation of oocytes within the follicle typically
lasts about 14 days and can be divided into two distinct periods.
During the initial period many oocytes, perhaps thousands, begin
to develop and grow. The second phase of development is marked
by gonadal hormone stimulation and selection of one dominant follicle.
The oocyte within the dominant follicle grows into a fully mature
state, relying on hormones for growth and stimulation, and becomes
capable of ovulation and fertilization. The remaining follicles
that began development undergo atresia. When the oocyte within
the dominant follicle is close to maturity the follicle bursts
and releases the oocyte, which then travels through the fallopian
tube toward the uterus. The oocyte is capable of being fertilized
for a short period—about 48 hours. If the oocyte is not
fertilized during this time it will die, and in approximately
1 week a new cycle of oocyte maturation will begin (University
of Michigan, 2005).
The unique and remarkable characteristics of the
human oocyte have made fertility preservation for women with cancer
a daunting task. The oocyte is the largest cell in the human body
and contains a significant amount of water, which makes oocytes
difficult to cryopreserve. The inability to generate new oocytes,
the need for oocytes to grow and mature over 14 days to become
fully functional, and the production of only a single mature oocyte
per month are all barriers to cryopreserving female gametes. Recent
advances in reproductive medicine make fertility preservation
a possibility for many women diagnosed with cancer. Attempts at
preserving fertility for women about to undergo cancer therapy
have been aimed at either protecting the ovary from the damaging
effects of chemotherapy or cryopreserving ovarian material for
later use.
Efforts to decrease the overall morbidity associated with cancer
therapy include the use of treatment regimens that use less toxic
agents, lower doses of agents with known toxicity, and lower doses
or elimination of radiation therapy. External lead shields provide
some protection to the ovaries from radiation and should be employed
if the shielding does not compromise the antineoplastic effects
of radiation treatment. Oophoropexy, also referred to as ovarian
transposition, moves the ovary from the path of the radiation
therapy beam into a protected area in the abdomen. Surgical transposition
of the ovaries before radiotherapy can reduce the risk of POF
and infertility, as evidenced by the persistence of premenopausal
gonadotropin levels following this procedure (Husseinzadeh, Nahhas,
Velkley, Whitney, & Mortel, 1984). Williams, Littell, and
Mendenhall (2000) found that laparoscopic oophoropexy prior to
pelvic radiation is an effective method of preserving ovarian
function in patients with Hodgkin’s disease.
Drugs that alter the function of the ovary, such
as oral contraceptive pills (OCPs) and gonadotropin-releasing
hormone (GnRH) analogues, have been tested as potentially useful
agents in preventing ovarian damage. The notion that ovarian function
could be preserved while in a quiescent state, thus rendering
the ovaries less susceptible to the damage of chemotherapy, is
attractive. OCPs were initially thought to provide such pharmacologic
protection. They exert their effect by inhibiting the development
and maturation of the monthly dominant follicle, thereby preventing
the development of a mature oocyte capable of being fertilized.
However, OCPs do not affect the early development of the hundreds
of other follicles that begin the maturation process; these follicles,
therefore, remain susceptible to damage from chemotherapy.
Another class of drugs that affects ovarian function
is the GnRH analogues, such as leuprolide and goserelin. These
drugs inhibit the release of anterior pituitary hormones (e.g.,
FSH and luteinizing hormone) that stimulate follicle maturation
and thereby return the ovary to a condition similar to the immature
prepubertal state (Blumenfeld, Avivi, Ritter, & Rowe, 1999).
Animal studies have shown direct ovarian protection and, therefore,
a potential benefit of GnRH analogues (Meirow, Assad, Dor, &
Rabinovici, 2004). Human ovarian protection with GnRH analogues
remains an area of active debate and research because results
of studies using GnRH analogues in females undergoing cancer treatment
have thus far produced inconsistent results. Although some reports
indicate a protective benefit from these agents (Somers, Marder,
Christman, Ognenovski, & McCune, 2005), many others have been
unable to show an advantage (Holzer & Tan, 2005; Revel &
Laufer, 2002). At this time, a large-scale, randomized, prospective
study using GnRH analogues is underway and should help clarify
the benefit of these agents (National Institutes of Health, 2005).
Three very different practices are used in attempts to preserve
the option of biologic motherhood for women with cancer who are
at risk of developing infertility. They include: (1) embryo cryopreservation;
(2) unfertilized oocyte cryopreservation; and (3) ovarian tissue
(i.e., immature or primordial oocyte) cryopreservation.
Embryos are fertilized oocytes that have begun initial cell divisions.
The fertilized oocyte or embryo tolerates the freezing and thawing
process extremely well. First performed successfully in 1984,
cryopreservation of embryos has led to the birth of thousands
of babies. Embryos for cryopreservation are produced in the laboratory
as part of in vitro fertilization (IVF). The IVF cycle begins
with exogenous hormonal stimulation of the ovary so that many
oocytes, rather than the typical single oocyte, are coaxed to
maturity. These mature oocytes are then removed from the ovary
via transvaginal ultrasound-guided needle aspiration and placed
in a petri dish, to which sperm is added. If fertilization takes
place, the new cells are called an embryo. Women with cancer can
then cryopreserve and store the embryos for future attempts at
pregnancy when cancer therapy is completed. Another option for
cancer patients is the transfer of the embryos to the uterus of
a surrogate if the health of the patient precludes pregnancy.
With this method, the surrogate will carry the infant to term;
however, the infant has no biological relationship to the carrier.
Before considering embryo cryopreservation, a reproductive
endocrinologist (a subspecialist in obstetrics and gynecology)
should ensure that the cancer patient is otherwise healthy and
able to tolerate high doses of hormonal stimulation. The gonadotropins
used to stimulate follicular development result in extremely high
levels of estrogen in the body. Some cancers, most notably breast
and uterine cancer, may be sensitive to estrogen. Options for
women with estrogen-sensitive tumors are described in Fertility
Considerations for Women with Breast Cancer on page 4.
Embryo cryopreservation requires several weeks to
complete, which could delay the onset of cancer treatment. In
addition, a male partner is needed as a source of sperm to fertilize
the oocytes. Both male and female partners share ownership of
the resulting embryo, so disposition of the embryos created in
the event of divorce or termination of the relationship should
be discussed. Donor sperm may be used if the patient does not
have a male partner; however, this may be less desirable, especially
if a partner later enters the patient’s life. The creation
of embryos and their storage may present ethical and moral concerns
to patients, and consideration of the fate of the embryos, especially
if the patient succumbs to cancer, should be discussed before
proceeding. Finally, the procedure may cost in excess of $10,000
and often is not covered by third party payers, although financial
assistance programs such as Fertile Hope’s Sharing Hope
program may lower some costs.
Success rates for IVF are difficult to estimate.
Rates vary significantly and depend on the age of the woman as
well as other factors, such as the IVF facility itself. Frozen
embryos have a slightly lower survival and implantation rate than
fresh embryos. In general, about 80% of frozen embryos survive
with a live birth occurring approximately 30% of the time (Aytoz
et al., 1999).
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