Preservation of Fertility | iii
Table of Contents
1 Preservation of Fertility in Women 1
Who needs preservation of fertility 1
Effects of cancer treatment on future fertility 2
Ovarian function after exposure to chemotherapy & radiotherapy 3
Methods used for preservation of fertility 3
Genetic Perspective 7
Coordination of treatment and preservation of fertility 8
Real Cases 9
Pregnancy after breast cancer 9
2 Preservation of Fertility in Men 11
Who needs to consider preservation of fertility 11
Methods used for preservation of fertility 12
1 Preservation of Fertility in Women
Fertility is a key aspect for quality of life a. In 2009 about 700,000 women will be di-
for cancer patients of childbearing age. Preservation agnosed with cancer, about 10% of them under the
of fertility is defined as the application of medi- age of 45. Breast cancer is the most common cancer
cal, surgical and laboratory procedures to preserve affecting women.
the potential of genetic parenthood in adults and
children at risk of sterility before the end of natural
reproductive lifespan (Gosden 2009). Decrease or
loss of fertility can take place due to exposure to
medication (chemotherapy), radiation or surgery
(e.g. Removal of the ovaries). The American Cancer
Society estimates that cancer affects one in each 3
women living in the United States. Modern cancer
treatment commonly involve exposure to chemo-
therapy and sometimes pelvic radiation.
Cancer and its treatment though is not the only
situation that affect fertility. Fertility can also be
diminished by bone marrow transplantation and
treatment of kidney disease usually due to lupus.
If you are a women or a man living in the United
Proportion of cancer by site in women. (From American Cancer
States and recently diagnosed with cancer or
another condition that threatens your future ability
to mother or father children, this bulletin is writen
Each year bout 15,000 women will be diagnosed
with you in mind. The odds are you will beat your
with breast cancer before 45year
disease and survive for many years to come. Consid-
ering fertility-sparing before starting disease treat- Women can also be diagnosed with leukemias, lym-
ment may greatly enhance your ability to conceive a phomas, cancer of the colon, uterus, ovary, skin or
biological child after cure. thyroid gland. Treatment of all these cancers is as-
sociated with long term effects during the survivor-
Who needs to consider preser- ship period including decline in fertility. The effects
of cancer treatment go beyond the harm caused by
vation of Fertility? the method of treatment itself to the time spent in
treatment and time needed for follow up. This delay
2 | Preservation of Fertility
means women will probably attempt pregnancy
several years later than they intended.
b. Women undergoing bone marrow trans- Effects of Cancer Treatment
plantation for treatment of cancer, anemias (e.g.
Sickle cell disease) and other diseases. The use of on Ovarian Function
chemotherapy and radiation prior to transplantation
In general the younger the woman, the more
is usually associated with fertility loss in the vast
oocytes she harbors in the ovary and the higher
majority of patients.
the likelihood that some oocytes will remain in the
c. Some women develop breast or ovarian ovary after treatment.
cancers due to abnormality in breast cancer gene
A. Chemotherapy and the Ovary. The use of
(BRCA1 & 2). Reducing the risk of future cancer
chemotherapy can lead to fast loss of oocytes (eggs).
may require removal of both ovaries with loss of
Oocytes carry the genetic material that women pass
to their children after fertilization by a sperm. The
d. Women diagnosed with connective tissue effect of these agents is variable depending on the
disease (Systemic lupus, rheumatoid arthritis...) or drug, dose, frequency of administration, and age of
autoimmune disease may have severe disease af- the woman at the time of treatment. Cyclophosph-
fecting their organs (e.g. Kidney). Chemotherapy is amide is the most harmful agent for future fertility.
sometimes used to suppress their immunity which
These medication appear to cause loss of eggs
may lead to fertility decline. Moreover, the antibod-
through damage of its DNA and inducing sponta-
ies generated by the disease process may directly
neous demise of the egg. There is no proven method
affect ovarian function.
that can prevent this loss.
e. Individuals exposed to accelerated loss
B. Pelvic Radiation and the Ovary. Expo-
of eggs due to genetic disease (e.g. Mosaic Turner
sure of the ovary to radiation can damage the eggs
syndrome) can also benefit from preservation of
and the remaining tissue of the ovary. The amount
of radiation that leads to complete loss of ovar-
f. Fertility extension. Women delaying preg- ian function is dependent on the age. A dose of
nancy for career or social reasons (no male partner 1500cGy will sterilize the majority of women at age
at this time) can consider freezing their eggs or 30. Smaller doses will sterilize older women.
embryos (using donor sperm). This option was not
C. Time factor. Cancer treatment usually re-
studied in large population studies.
quires several months. For some cancers (e.g. Breast
cancer) medical treatment (tamoxifen) is required
for 2 to 5 years after surgery and chemotherapy. For
Cancer treatment (chemotherapy, radiation and others oncologists recommend a period of observa-
bone marrow transplantation) will not only dimin- tion for 1 to 2 years. This will a woman’s plan to
ish fertility by accelerating loss of oocytes but also start a family to a later age when fewer oocytes
by delaying attempts to become pregnant for years remain in the ovary.
Actually the effect of cancer treatment on the ovary
appears to be similar. Continuous loss of eggs from
Women | 3
the ovary takes place in all women. Cancer treat-
ment accelerates this loss so that the number of eggs
in the ovary would correspond to older age. Women exposed to chemotherapy exhibit a much
lesser response to medications that stimulate egg
D. Pelvic Radiation and the Uterus. Expo-
production in the ovary than women presenting
sure of the uterus to radiation increases the risk of
before exposure to chemotherapy, hence the impor-
miscarriage, preterm labor and abnormal pregnancy
tance of considering preservation of fertility early
after cancer diagnosis.
Evaluation of Ovarian Func-
Methods used for Fertility
tion after Cancer Treatment
Although many think that resumption of men-
struation after cancer treatment indicates that the Methods used to preserve fertility in women are
woman retains the ability to conceive, this is not generally divided into three categories:
true. Some women have regular menses with near
Modification of cancer treatment plan to reduce damage
exhaustion of the eggs in the ovaries. Thus, men-
to the ovaries and uterus:
struation is not a reliable indicator of the ability to
conceive. 1. Preserving one ovary in women affected with
early ovarian cancer.
The function of the ovary before after cancer treat-
ment can be evaluated using hormone tests and 2. Preservation of the body of the uterus with
ultrasound. removal of the cervix in early cervical cancer.
♦ Cycle day 2 or 3 FSH (normal is less than 3. Use of progesterone treatment instead of re-
12mIU/mL) moval of the uterus in endometrial cancer.
♦ Inhibin Protection of the ovaries from the damage caused by
♦ Antimullerian hormone (AMH). This is a new
and promising marker and appear to be more 1 Ovarian transposition is a surgical procedure to
accurate than the other markers. move the ovaries upwards, away from radiation field
before pelvic radiation. Results are variable as some
♦ Vaginal ultrasound to evaluate the number of
scattered radiation still reaches the ovaries.
small follicles visible in the ovary.
2. Protection of the ovaries from the effect of
Although these markers are more accurate than
chemotherapy. GnRH agonists are a group of
menstrual history, normal markers after treatment
medications that suppress the master gland in the
does not mean that ovarian function is completely
brain, preventing the release of the hormones that
preserved after exposure to treatment.
stimulate development of follicles in the ovaries.
Although suggested, there is no proof that they
actually protect the ovaries and improve the chance
of pregnancy after the use of chemotherapy.
4 | Preservation of Fertility
special attention. The use of fertility medication is
usually associated with considerable rise in estrogen
levels. One potential risk of estrogen rise, though
Low Temperature Storage of Embryos, Oocytes or Ovarian not proven, is increase in activity of cancer cells.
Tissue: This is addressed during stimulation by adding a
a. Embryo Freezing. This is considered the medicine (letrozole) that blocks the enzyme that
standard method for preservation of fertility. Its makes estrogen in the ovaries, so that stimulation
suitable for women with a male partner or ac- with gonadotropins can progress without increase in
cepting the use of donor sperm and when cancer estrogen. When the follicles (the bag that contain
treatment does not need to be started immediately. the eggs) reach adequate size, final maturation is
This method entails stimulation of the ovary with triggered using another hormone, hCG. This is fol-
medications and frequent monitoring of response lowed by egg harvest.
using ultrasound and blood work. This stimulation The safety of this method for stimulation of the ovary
usually requires 12 to 14 days. The eggs are then was studied. We compared women presenting for
removed from the ovary by an outpatient procedure ovarian stimulation after the diagnosis of breast
under sedation. Egg retrieval requires passing a cancer with women diagnosed with breast cancer and
needle through the vagina into the ovary. Eggs are declined ovarian stimulation. The follow up period was
then fertilized in the lab and the resulting embryos approximately 2 years. There was no increase in breast
are frozen 2 to 6 days later and stored for later use. cancer recurrence between both groups (Azim et al ,
Cancer treatment can start immediately after egg Journal of Clinical Oncology 2008). Although further
retrieval. After cure, women can request to use their follow up is required, results so far are reassuring that
embryos, that are placed back into the uterus after this method is probably safe.
simple preparation of the lining of the uterus. The
transfer of two embryos into the uterus yields a
pregnancy rate of about 30%.
Women diagnosed with an estrogen sensitive
tumors (e.g. Breast cancer, uterine cancer) require
Women | 5
egg at thawing. The egg is placed in a solution that
prevents damage caused by ice crystals (cryopro-
Protocol for stimulation of the ovaries in women diagnosed with tectant) and then stored in liquid nitrogen at -170.
breast or endometrial cancer.
Embryo freezing is the standard method for preser-
vation of fertility in women with male partner (or
using a donor sperm) and when cancer treatment
does not need to be started immediately.
For women not diagnosed with estrogen sensitive Three oocytes frozen in a small film of fluid.
cancer (e.g. Lymphoma) or those at risk for decline
of fertility due to non-cancer conditions, standard
methods for ovarian stimulation are used. The
ultimate success of this option is dependant on the
number and quality of embryos produced which is
related to woman’s age and ovarian function at the
time of stimulation. Cancer diagnosis in itself does
not appear to affect success provided stimulation is
started before cancer treatment.
After cure some women transfer the embryos to
their own uterus or to a gestational carrier.
b. Oocyte Cryopreservation (egg freezing). It
is considered for women with no male partner and
declining the use of donor sperm. It requires stimu-
lation of the ovaries and egg harvest as described Mature oocyte.
The human egg is unique. Its the largest cell in the The success rate for egg freezing based in all pub-
body with high water contents. The membrane sur- lished reports in the world are given below.
rounding the cell is not very permeable. Moreover, In general 2/3 of eggs frozen using slow freezing
its the only cell in the body where chromosomes are method survive compared to about 90% of oocytes
spread on flimsy structure called the spindle, rather frozen by vitrification method. After thaw, the eggs
than being enclosed inside the nucleus of the cell. need to be fertilized using intracytoplasmic sperm
The egg requires special expertise to freeze. Two injection (ICSI). About 70 to 90% fertilization rate
techniques are used; slow freezing or vitrification is expected. Embryos are cultured to day 3 stage or
(rapid freezing). The newer vitrification method has blastocysts before transfer. Each thawed egg yield
the advantage of avoiding the formation of ice crys- about 2-3% pregnancy rate after slow freezing and
tals inside the egg and yields better survival of the about 8 to 10% when vitrification was used. Transfer
6 | Preservation of Fertility
The only caveat to vitrification is that this method c. Ovarian Tissue Freezing. This is an ex-
has not been around long enough to ascertain its perimental method for preservation of fertility. In
safety. this method one ovary is removed, processed and
frozen. After cure, the ovary is transplanted back in
the pelvis (orthotopic) or under the skin (hetero-
topic). Processing of the ovary means that the outer
2-3mm (this is the part that contains the eggs-the
cortex) is shelled out and cut into thin strips. So far
the ovary cannot be frozen as a whole organ because
its too thick for cryoprotectants (the substance that
protects the tissue from damage caused by freez-
ing) to diffuse into it before freezing. Removal of
the ovary is performed using laparoscopy (minimal
access surgery) or at the time of surgery for other
indication. The inner part of the ovary (does not
contain eggs) is sent for tissue examination to make
sure it does not contain any malignant cells.
Since ovarian harvest can be accomplished in 1 to
2 hours, this method is used when there is no time
to complete ovarian stimulation (2 to 3 weeks) or
Cleavage stage (day 3) embryo. when stimulation of the ovary is not possible as
in girls before puberty. Because of the experimental
nature of the procedure, its offered to women with very
high risk for ovarian failure after treatment.
The main risk for transplantation is transferring
cancer cells in the graft leading to recurrence of can-
cer. Although possible, no such case was reported
Worldwide, several hundred women froze their
ovaries. So far much smaller number came back for
transplantation. There were eight babies born after
transplantation. (Belgium 1, Israel 1, Spain 1, Den-
mark 5) All the ovaries resulting in live births were
transplanted in the pelvis.
Vitrification is a very promising method for egg
Blastocyst stage (day 5-6) embryo. freezing. It yields outcome comparable to embryo
Women | 7
of two to three embryos can yield a pregnancy rate similar to that obtained after embryo thawing.
Oocyte cryopreservation; World Experience
Slow freezing Vitrification
(38 studies) (EG 2.7M+DMSO 2.1M+sucrose 0.5M)
Oocytes thawed 11937 1346
Oocytes survived 7610 (63.8%) 1233 (91.6%)
Oocytes injected with a sperm 6871 1123
Oocytes fertilized 5029 (73.2%) 964 (91%)
Clinical Pregnancy per oocyte thawed 275 (2.3%) 157 (8.8%)
Miscarriage rate 21.8% 16.8%
Amr Azim, MD, FACOG
d. In Vitro Maturation of Oocytes. In this method a very short ovarian stimulation for 3 to 5 days
is performed followed by retrieval of immature eggs. Eggs are then matured in the lab, fertilized and the
resulting embryos are frozen for later use. The efficiency of this method is lower than retrieving fully mature
oocytes. About 50% of follicles punctured yield an egg. Approximately 70% of the eggs reach maturity in
the lab and about 70% of those fertilize with ICSI. This method is suitable for women demonstrating high
response to stimulation to fertility medication.
Genetic susceptibility to cancer is now recognized for a number of malignancies. The most famous is breast
cancer susceptibility genes BRCA1 &2. Women diagnosed with cancer that associated with mutation of
one of the known genes are at risk for passing this gene to her future children. If a woman is a carrier of
one of these known genes, the effort to preserve her fertility can be combined with testing of oocytes or
embryos to prevent the transmission of the gene to her children. Pre-implantation genetic diagnosis (PGD)
is a techniques where one or few cells from an embryo can be analyzed for specific genetic information.
The majority of cancer susceptibility genes can be detected in the embryo, so that affected embryos can be
excluded from transfer back to the uterus. Not all women though accept screening or embryo testing.
8 | Preservation of Fertility
Some Genetic syndromes with increased susceptibility to cancer
Women | 9
Questions to Questions Things to do
Oncologist *Type of cancer Ask for a
*Treatment plan Obtain
1. Surgery records;
Women interested in preservation of fertility 2. Chemo- Surgery
should be counseled about the availability of therapy records
genetic screening pertaining to their cancer and if 3. Bone mar- Pathology
row transplant records
carriers about PGD to avoid transmission to future 4. Radiothera- Other tests;
children. py ER, PR,
5. Hormonal BRCA
*Is Preservation cal tests
of fertility suit-
able for me?
Coordination of Cancer Treat- Reproduc- *How is cancer and Blood work;
ment and Preservation of
tive cancer treat- FSH,
ment expected to estradiol,
Endocrinol- impact future my AMH
Fertility *What are the suit-
able options for
Multiple studies in the US surveying patients or fertility?
oncologists found that discussion and referral for Embryo freezing eral tests
preservation of fertility takes place in less than 50% Oocyte freezing for IVF
of patients. Referral was more likely when patients Ovarian tissue freez- and tissue
inquire about fertility issues. Others Referral for
This underlines the importance of educating women Combination counsel-
about fertility issues and the diagnosis of cancer *Is it safe?
and other allied diseases. Empowering women to *What to do with the fertility
ask questions appears to one of the most important frozen embryos, eggs tion plan
initial steps to receive appropriate information about or tissue after cure oncologist
and possibly pursue preservation of fertility. *What is the success
rate for my op-
Collecting information and coordination of care
between providers concerned with cancer treatment
Psychologist How to deal with Make an ap-
and those that deal with preservation of fertil- stresses of treat- pointment
ity can be a demanding task, especially at difficult
and busy times. The table below aims at organizing Support Help with referral E.g. fertile-
your thoughts and collecting information about the group hope.org
Help with medica-
feasibility of preservation of fertility after diagnosis, tions livestrong.org
before making a decision to pursue these options youngsurvival.
or to bypass them and proceed directly to disease lbbc.org
Women | 10
Real Cases Colon Cancer
A 34 year old presented with her husband after a
recent diagnosis of colon cancer. Her planned treat-
Breast Cancer ment was chemotherapy, pelvic radiation followed
1. A 28 year old Caucasian system analyst present- by surgery. She wanted to preserve the ability to
ed with her partner shortly after the diagnosis of have biological children.
duct carcinoma of the breast. The tumor was stage II She was counseled that
after lumpectomy and axillary lymph node sampling 1. Chemotherapy used for colon cancer has mild or
and was estrogen receptor positive. Her treatment no long term effects on future ovarian function
plan per her oncologist was 4 cycles of cyclophos- 2. Pelvic radiation at the planned dose, however will
phamide, adriamycin and taxol followed five years of very likely result is complete cessation of ovarian
She was counseled to the effect of chemotherapy on 3. Pelvic irradiation will likely damage the tissue of
ovarian function. The risk for ovarian failure is about the uterus so that pregnancy would not be safe.
30%. Time factor also should be considered (she She was offered a combined approach to preserve
will be 35 by the time she could attempt pregnancy). her fertility
The possibility of underlying genetic factor was also 1. Ovarian stimulation and egg retrieval and embryo
discussed and breast cancer gene testing was offered freezing
(she turns out to be BRCA1 and 2 negative). 2. Laparoscopic surgery to move one ovary upwards
As she had a steady partner, she was offered ovar- away from radiation field
ian stimulation using letrozole and gonadotropins 3. Harvest of the other ovary during the same sur-
followed by oocyte retrieval and embryo cryopreser- gery and freezing it for later transplantation.
vation. The risks and benefits of this approach was
discussed in details. She accepted this option and so She accepted only ovary stimulation and embryo
did her oncologist. After retrieval, 6 blastocysts were freezing. This was performed after consulting with
frozen within 18 days. She completed cancer treat- her oncologist and 20 blastocysts were frozen.
ment and her period stopped after chemotherapy After radiation, her menses stopped.
and did resume yet. She came back with her to use the embryos. One
embryo was transferred to the uterus of her sister
2. A 37 year old mathematician presented shortly resulting in pregnancy and delivery of healthy baby.
after the diagnosis of stage I, estrogen receptor
positive breast cancer. She does not have a partner.
The size of the tumor was small that her oncologist
did not recommend chemotherapy. She, however,
Pregnancy after Breast Cancer
Is it safe to get pregnant after treatment for breast
recommended 5 years of tamoxifen. cancer? It is the general consensus that pregnancy
This delay in attempting pregnancy (she would be after treatment and a follow up period of 6 months
42 at the end of treatment) and because she de- to two years is not associated with increase in the
clined the use of donor sperm, she was offered egg odds for breast cancer recurrence. Most oncologists
freezing. With the approval of her oncologist, she advise their patients to wait for a variable period
underwent two cycles of egg freezing and 10 eggs after treatment before attempting pregnancy. Recent
were cryopreserved after each cycle by vitrification. evidence from multiple studies including a large
She is in good health so far. Danish study indicated that there is no evidence
11 | Preservation of Fertility Women | 11
that pregnancy after breast cancer diagnosis in-
creases the risk of poorer outcome.
Remember that the use of a gestational carrier is
always an option for women that do not want to or
cannot get pregnant in their own uterus.
The vast majority of young cancer survivors view
themselves as potential parents. Inquiring about
survivorship issues including fertility increases
the odds that you will referred for counseling and
subsequently become informed about your options.
1. Azim et al. Safety of Fertility Preservation by
Ovarian Stimulation With Letrozole and Gonado-
tropins in Patients With Breast Cancer: A Prospec-
tive Controlled Study. Journal of Clinical Oncology
2. Gook & Edgar. Human oocyte cryopreservation.
Human Reproduction 2007,13(6):591-605.
3. Lee et al. American Society of Clinical Oncology
Recommendations on Fertility Preservation in
Cancer Patients. Journal of Clinical Oncology 2006.
12 | Preservation of Fertility
of Fertility in
Like women, men are also diagnosed with diseases
that directly or by virtue of their treatments impair
future fertility. Recognition of these diseases enables
timely counseling and effort to preserve male germ
cells. This is specially important since the interven-
tion to preserve future fertility in men is easier and Sperm count sometimes recover to a variable extent
less invasive compared to women. 50–70% of men years after cancer treatment. This depends on the
diagnosed with cancer wanted children in the future. type of cancer and treatment used. For example
Only 24% of young cancer patients banked sperm, 90% of men diagnosed with Hodgkin’s lymphoma,
including 37% of childless men. The most com- treated with MOPP chemotherapy regimen, do not
mon reason for failing to bank sperm was a lack of have any sperm in the ejaculate after one year.
information. b. Bone marrow transplantation for cancer of
nonmalignant diseases usually require prior irradia-
Who needs to consider preser- tion and chemotherapy. This is associated with high
risk (85%) of complete failure of sperm production.
vation of Fertility? c. Connective tissue / autoimmune diseases
a. The American Cancer Society estimates as lupus and rheumatoid arthritis requiring treat-
that 760,000 men will be diagnosed with cancer in ment with chemotherapy.
2009. Cancer itself (before treatment) is known to
be associated with less sperm production in men. d. Genetic abnormalities associated with
This is specially the case in Hodgkin’s lymphoma, rapid loss of male germ cells e.g. Kleinefelter syn-
testicular cancer, leukemias and colon cancer. drome, Y chromosome microdeletion (AZFc).
Cancer treatment (chemotherapy and radiation) also
significantly impair sperm production. The effect
of chemotherapy depends on age, drug used, dose
and duration. Cyclophosphamide appears to be the
most harmful agent. Radiation also impairs sperm
production especially at doses of 1200cGy or more.
men | 13
Methods used for Fertility modern reproductive medicine can handle the
majority of compromised specimens yielding excel-
Preservation lent pregnancy rates, similar to those of fresh sperm.
b. Testicular Sperm Extraction
Methods used to preserve fertility in men are gener-
(TESE). This surgical procedure retrieves sperm
ally divided into two categories:
from inside the testes if no sperm was found in the
Protection of the testes from damage caused by cancer ejaculate. If this procedure is used before cancer
treatment: treatment, sperm are retrieved in over 50% of cases.
Sperm or testicular biopsies are frozen for later use.
1. Shielding the testes from radiation field.
ICSI is used for fertilization. In case of testicular
2. Protection of the testes from the effect of chemo-
cancer, sperm retrieval can be performed at the same
therapy. GnRH agonists are a group of medications
time of surgery for cancer.
that suppress the master gland in the brain, pre-
venting the release of the hormones that stimulate c. Testicular Tissue or Germ
sperm production in the testes. Although suggested, Cell Freezing. This is an experimental technique.
there is no proof that they actually increase the odds Immature germ cells or testicular pieces are frozen
for pregnancy after the use of chemotherapy. for later transplantation. No pregnancy was achieved
There is no effective protective medication using this method so far.
available for use in humans.
In conclusion, fertility-sparing strategy is readily
Low Temperature Storage of Sperm and Testicular Tissue: available to the majority of men at risk for dimin-
a Sperm Cryopreservation. ished fertility through sperm cryopreservation. Men
This is the standard method for preservation of interested in fathering children in the future should
fertility in men. A sperm sample is obtained by be counseled about this option.
masturbation and frozen for later use. If feasible
multiple samples are obtained. In the future sperm
sample are used for intrauterine insemination or
IVF / intracytoplasmic sperm injection (ICSI).
Banking sperm was found to offer not only a chance
to father children in the future but also encourage-
ment and improved morale during disease treat-
ment especially if it was initiated by the patient own
Lack of information and counseling is the most
important reason why men diagnosed with cancer
do not bank thier sperm.
Although freezing may reduce the quality of sperm
especially if it was not optimal before freezing,
NYCIVF, 400 East 56 Street. New York, NY 10022 ¤ 800•853•7595 www.nycivf.org, preservationoffertility.rg
Personal & Innovative Fertility Care