Preserving
Reproductive Options in
Oncology (Cancer) Patients
By
Bradford Kolb, M.D., F.A.C.O.G.
Board Certified, Reproductive Endocrinology and Infertility
Introduction
Over the last several decades we
have witnessed a significant increase in survival rates
for oncology patients. Due to the use of combination
chemotherapy and radiotherapy many young patients are
now living long healthy productive lives. While combination
regimens have been designed to avoid acute toxic effects,
many have resulted in unanticipated gonadal toxicity.
As such, an increasing number of cancer survivors are
now facing difficulties in having families as well as
hormonal deficiencies.
Preservation
of Reproductive Options in Men Undergoing Chemotherapy
Gonadotoxicity in males is dependent
on the stage of spermatogenesis affected. Damage to
mature sperm with sparing of the stem cells will result
in a temporary diminishment of spermatogenesis, while
damage to the stem cells will result in permanent impairment
of spermatogenesis. The simplest option in males is
cryopreservation of sperm prior to the initiation of
treatment. There is a long history that demonstrates
both the efficacy and safety of utilizing cryopreserved
sperm. The risk of transmitting a malignancy to either
his partner or to the offspring is negligible. The incidence
of abnormalities in the children in women who recover
their ovarian function after chemotherapy or to men
who father children after treatment has been reviewed
in over five hundred cases and there appears to be no
increase in still births, fetal abnormalities and spontaneous
abortion rates.
There are now a number of recent
advances that has greatly expanded options in men who
have already undergone treatment. The ability to retrieve
sperm via epididymal
or testicular aspiration is able to be performed
in the office with minimal discomfort and may result
in the retrieval of sperm in those who are presumed
to be azospermic by semen analysis. Coupled with intracytoplasmic
sperm injection, ICSI, (the injection of sperm into
the oocyte) has tremendously expanded reproductive options
in these couples. Unfortunately, preliminary evidence
suggests that the use of GnRH agonist/antagonists are
not effective in minimizing the cytotoxicity of chemotherapy
to the gonads and thus there is little that can be done
to minimize gonadotoxicity once treatment has been initiated.
Preservation
of Reproductive Options in Women Undergoing Chemotherapy
In women, many cancers directly
affect reproduction and childbearing functions thereby
causing infertility severe difficulties and distress. Unfortunately,
the preservation of fertility is much more complex in
women. First, radiation can adversely impact the uterus
by either directly compromising the endometrium or indirectly
by reducing its blood flow. Second, both radiotherapy
and chemotherapy may directly impair germ cell function.
Unlike men, women possess a finite number of germ cells
at birth and diminish with age. With cytotoxic therapy,
the rate at which primordial follicles regress is greatly
accelerated.
A variety of approaches have been
utilized in order to preserve either oocytes or ovarian
tissue. Until recently, attempts to cryopreserved unfertilized
oocytes have not yielded satisfactory results. Two approaches
have been taken in preserving unfertilized eggs. The
first utilizes immature oocytes (eggs that are extracted
prior to complete maturation). The obvious advantage
is that it allows for the extraction of multiple oocytes
at anytime during follicular maturation. Unfortunately,
at this time the technology is in its early stages of
development and is not clinically applicable. Excitingly,
the ability to preserve and utilize mature oocytes is
emerging as a viable option.
Research currently being performed
at Huntington Reproductive Center and a select number
of programs has demonstrated the feasibility of this
technology. The ability to preserve unfertilized oocytes
is significant because it allows single women to cryopreserve
their eggs without having to fertilize them first. The
down side to this technology is that it requires patients
to undergo ovulation induction prior to retrieving their
oocytes. This may result in an unacceptable delay in
the initiation of cancer therapy. More recently, several
labs have looked at the versatility of preserving ovarian
cortical stripes.
The advantage of ovarian cryopreservation
is that each biopsy allows for the preservation of thousands
of oocytes in their natural environment. While there
are only a handful of patients who have undergone this
procedure, preliminary results are promising. There
are now several cases of women who have undergone successful
transplantation of tissue with subsequent preservation
of endocrine function. Successful ovulation induction
with oocyte aspiration from ovarian tissue transplanted
under the forearm has been performed. Unfortunately,
this procedure has yet to result in a pregnancy and
the potential of transplanting microscopic nests of
tumor cells exist. Nonetheless, cryopreservation of
ovarian tissue shows promise.
Embryo
cryopreservation fortunately has been successfully
performed since 1983 and has resulted in thousands of
offspring. In more successful labs, pregnancy rates
in frozen embryo transfer cycles are similar to fresh
embryo transfers. This allows women to complete their
cancer treatment with subsequent initiation of childbearing
at a future date. Several drawbacks exist, however.
Most choosing embryo cryopreservation must undergo ovulation
induction with subsequent oocyte aspiration. This may
result in an unacceptable delay in the initiation of
treatment. Furthermore, embryo cryopreservation is not
an acceptable alternative in children and may not be
an acceptable option in single women.
In women undergoing radiotherapy
to the pelvis, the ovaries are frequently exposed
to unnecessary doses of ionizing radiation. While
the exposure may not result in premature ovarian failure,
the impact frequently results in sub optimal endocrine
function and infertility secondary to the cytotoxic
effect on the oocyte. Several strategies have been
devised to minimize damage to the ovaries. First,
in patients receiving external beam brachyotherapy,
a skilled radiation oncologist may be able to minimize
unnecessary ovarian exposure through careful positioning
and use of padding. Second, the ovaries can be transposed
out of the pelvis surgically. This can be accomplished
laparoscopically by fixing the ovary to the psoas
muscle. This can be accomplished as an outpatient
procedure with minimal discomfort to the patient and
should not delay therapy. As the uterus cannot be
spared from the effects of radiation, it is advisable
that these women have surrogate carriers when initiating
childbearing.
It has been recognized that girls
undergoing chemotherapy prior to the onset of menses
with alkylating agents have significantly improved ovarian
endocrine and reproductive function compared to those
receiving similar therapy after menarche. Pre and concomitant
treatment with GnRH analogs appears to be the most promising
approach to prevent ovarian failure induced by chemotherapy.
There is a growing body of evidence that suggests the
analogs minimize the gonadotoxic effect of chemotherapy
by inducing a temporary prepubertal state. GnRH inhibits
the process of follicular recruitment and thus inhibits
follicular maturation. Thus, it appears that GrRHa prevents
the follicles from reaching the chemo-sensitive stage
via suppression of the granulosa cells. As the agonists
take 2-3 weeks to suppress follicular recruitment, therapy
should be started prior to the initiation of chemotherapy.
It is unclear whether GnRH antagonists convey the same
protective benefit. Theoretically, one would expect
a similar protective effect. The antagonists have the
benefit of immediate suppressive effect and thus would
not require pretreatment. Interestingly, a similar gonadoprotective
effect is not seen in males.
Ethical Dilemmas
There are a number of ethical dilemmas
that must be answered while addressing this issue. While
it is beyond the scope of this paper to discuss this
in detail, I have listed a number of concerns. To whom
do we offer treatment? Do we consider harvesting and
preserving gonadal tissues in children and adolescents?
What about poor prognostic candidates? Is it acceptable
to delay or compromise treatment in order to maximize
future fertility?
Conclusions
Given the tremendous strides made
in both the fields of oncology and reproductive endocrinology,
future reproductive considerations must be addressed
in individuals undergoing cancer therapy. Embryo and
oocyte cryopreservation and potentially ovarian tissue
cryopreservation (the only alternative for prepubertal
girls) should be utilized when appropriate. Lastly,
GnRHa/chemotherapy co treatment should be offered when
patients are at risk of gonadotoxicity.
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