For women

Preserving fertility before cancertreatment
For young women with cancer
who wish to have children in the futureWhat is fertility?
Fertility is defined as "the ability to reproduce".
Cancer treatment may affect your reproductivefunctions, but there are many fertility preservation
options available.

Table of contents
Introduction

1

Cancer treatment and fertility preservation

3

How cancer treatment affects ovarian functions

4

Fertility preservation options

7

Pregnancy after cancer treatment

9

Family planning after cancer treatment

10

Flow chart for fertility preservation options

11

Resources12Costs for fertility preservation

12Calendar

13

Questions you should ask your oncologist

141

Introduction
Recent advances in cancer treatment have aided many in overcoming cancer. Yet,despite these advances, some treatments can affect ovarian function, which maylead to infertility. It is therefore important to understand the potential impact ofcancer treatment on reproductive health when considering one’s options for fertility
preservation.
This brochure will assist young female patients in making informed decisions about
their fertility preservation options.

Fertility Preservation Checklist
1. I understand the process and prospects of cancer treatment,
and how they may affect my fertility.
2. I understand my fertility preservation options and what theyinvolve.
3. I understand the commitment and costs of fertility preservation
as well as its potential effect on my cancer treatment.
4. After cancer treatment, pregnancy will be permitted
only if my oncologist finds the conditions fitting.
5. I should consult my oncologist and reproductive endocrinologist
about my fertility preservation options.
6. I understand that fertility preservation does not guarantee futurepregnancy.

It is important to discuss all of these points with your partner, family, and any others
who may be affected by your decision.

2

Cancer treatment and fertility preservation
Prioritizing cancer treatment over fertility preservation
Starting an appropriate cancer treatment regimen is of utmost importance.
Although fertility preservation may be an important consideration, proper cancer
treatment should be prioritized over family planning. If time allows, effort should
be made to consult with one’s partner, family, oncologist and reproductive
endocrinologist so as to make an informed decision about fertility preservation
prior to undergoing cancer treatment.

When should I start fertility preservation treatment?
You should first discuss your fertility preservation options with your oncologist
to understand both the merits and disadvantages of all preservation options. As
preservation treatments must be performed before cancer treatment can proceed, it
is sometimes necessary to adjust the treatment schedule if possible. Complications
such as bleeding or infection may occur with transvaginal oocyte retrieval andovarian sectioning.

3How cancer treatment affects
ovarian functions
The figure below shows how the normal follicular development cycle can bedamaged by chemotherapy.

Eﬀect ofchemotherapy

Corpus luteum

STARTPrimordial follicle

Corpus luteum

Damage tovessels

Eﬀect ofchemotherapy

Direct damage
OocyteOvulated
oocyteGrowing follicle

Ovulation

Granular cell
Mature oocyte
Damage to cells
Eﬀect ofchemotherapy

There are many oocytes called "primordial follicles" in the ovary. Reduction in thenumber of primordial follicles due to cancer treatment is considered to be a causeof infertility. The effects of anticancer drug treatment on ovarian function vary
among the individuals, as well as on the type and stage of cancer.

4Effect of chemotherapy and radiation therapy
The effect of chemotherapy and radiation therapy on ovarian function varies
depending on the type and amount of chemotherapeutic agent administered,and may act directly on the ovar y and its functions. Af ter agents areadministered, ovarian function is suppressed within two to three months
post-initiation, often causing a halt in menstruation. In general, the older
the individual, the higher the likelihood of total menstrual cessation. Even if
menstruation resumes, ovarian function may not necessarily be restored.
Infertility Risk Associated with
Specific Cancer Treatments and Regimens
Risk

Cancer treatment

High Risk

Cyclophosphamide
lfosfamide
Dacarbazin

Cranial irradiation
Total body irradiation (TBl)
Whole abdominal or pelvic
radiationlntermediate
Risk

Cisplatin
Carboplatin
Doxorubicin
Etoposide

Pelvic radiation

Low Risk orNo Risk

Actinomycin D
Vincristine
Methotrexate
Fluorouracil
Bleomycin

Radioactive iodine

Unknown Risk

Paclitaxel
Docetaxel
Gemcitabinelrinotecan

Effect of hormonal therapy
How hormonal therapy affects ovarian function is still unclear. As hormonal
agents used in breast cancer and uterine cancer can cause fetal malformations,contraception during treatment is necessary. Hormonal therapy for breast
cancer has a long treatment period of 5 to 10 years, so natural pregnancy may
be difficult and the risk of delivery will be higher due to aging. In addition, it has5

been reported that there is a high possibility that resumption of menstruation
is delayed or menopause is stared when hormonal therapy is continued after
chemotherapy in the treatment of breast cancer, to compared with treatment
without endocrine therapy. It also should be noted that adding hormonal
therapy to breast cancer treatment regime can delay menstruation recovery
even further or cause early menopause.

Effects of molecular targeted drugs
Although the extent of influence of molecular-targeted drugs on ovarian function
is not yet fully known, some of these drugs may affect ovarian function.

It is difficult to predict whether menstruation will resume after
chemotherapy or hormonal therapy. Even if menstruation resumes,
this does not ensure that pregnancy is possible. Because individual
differences and conditions vary, you should always consult yourreproductive endocrinologist about fertility options prior to beginning
cancer treatment.

How aging affects egg quality and ovarian function
Reproductive function decreases from ages in the 30s onward, andnatural pregnancy becomes difficult from approximately 10 years
prior to menopause. This limit is largely due to the risk of abortion,
fetal malformation, and other complications that may arise during latepregnancies. By age 40, half of a woman's eggs are chromosomallyabnormal, and a few years later that figure rises to over 90%.
In addition to age-related complications, chemotherapy may directly
damage the ovaries. This is a possibility that should also be taken into
consideration.

6

Fertility preservation options
Two fertility preservation options available to you are oocyte/embryo
cryopreservation and ovarian tissue cryopreservation.

Uterus
Fallopian tube

Stimulated ovary
Follicle

Ovarian tissue cryopreservation

Oocyte retrieval

CultureOocytes

EmbryoFertilization withsperm

Oocytes

Oocyte cryopreservation

7

EmbryoEmbryo cryopreservation

Fertility preservation options

Advantages

Disadvantages

Oocytecryopreservation

Embryocryopreservation

Ovarian tissue
cryopreservation

No requirementof partner

EstablishedmethodPregnancy rate
are higher

No time delay
No requirement ofpartner

Lower pregnancy
rate than embryo
cryopreservation
Requires ovarian
stimulation
Risk of gonadal
hormoneelevation

Requirespartner
Requiresovarianstimulation
Risk of gonadal
hormoneelevation

Experimental
methodSurgical procedure
Risk of re-seedingcancer cells

Oocytecryopreservation

Embryocryopreservation

Ovarian tissue
cryopreservation

Period2 〜 6 weeks

2 〜 6 weeks

1 〜 3 weeks

Partner

Not necessary

Necessary

Not necessary

Pregnancy
success rate

Lower pregnancy
rate than embryo
cryopreservation

HigherExperimental

Birth cases

Established but
less case thanembryo
cryopreservation

EstablishedOver 60 cases

Surgical procedure
Risk of re-seedingcancer cells

Ovarian stimulation is necessary to collect a sufficient number of eggs for
egg/embryo cryopreservation. While there are various methods of ovarian
stimulation, nearly all require that stimulation proceed for roughly 1 to 2 weeks.
In addition, with the increasing level of estrogen, and depending on the type ofcancer you will be treated for, ovarian stimulation may not be recommended.

8Pregnancy after cancer treatment
How transplantation proceeds after cancer treatment

Egg Cryopreservation
Before transplantation, frozen eggs are thawed and then microscopicallyinseminated with the partner’s sperm. Microscopic fertilization is necessary as
frozen eggs cannot be fertilized naturally. Once fertilization is confirmed, theembryo is transplanted into the patient’s uterus.

Embryo Cryopreservation
The frozen embryo is thawed and transplanted it into the uterus.

Ovarian Tissue Cryopreservation
The frozen ovarian tissue is thawed and transplanted it to the inside of the body(such as the ovary on the side not collected) by surgery. If the recovery of thefunction of the transplanted ovary is confirmed, natural pregnancy or in vitro
fertilization can be tried. However this is an experimental surgical procedure,and only limited facilities can offer this procedure in Japan.

When should I receive reproductive medical care aftercancer treatment?
If you would like to try to become pregnant after cancer treatment, youshould consult with your oncologist because the scheduling needs tobe coordinated with your cancer treatment plan.
Since the safety of pregnancy/childbir th using reproductive
medicine after cancer treatment is still unclear, you would need toconsult with your oncologist in advance.

9Family planning after cancer treatment
Ask your doctor about fertility before cancer treatment.
Natural pregnancy is possible in some cases.
Since spontaneous pregnancy may be dif ficult depending on yourpretreatment and cancer therapy, ask reproductive endocrinologist about
fertility preservation options.
It may be difficult to have a child in a situation of illness, health condition aftertreatment, original infertility and so on.
Even if you do not receive fertility preservation treatment before cancertreatment, fer tility af ter treatment may be possible, so consult yourreproductive medical doctor.
You may have to think about a lot of things and feel burdened. Please do nothold it alone and talk to the medical staff about your feelings.

For patients who undergo fertility preservation treatment
Please carry out the renewal procedure for frozen-preserved embryo/ oocytes
as necessary.
If you wish to conceive using frozen embryos or oocytes after cancer
treatment, please consult with your reproductive endocrinologist.
Please be aware that it may be difficult to transfer frozen-preserved embryos
or oocytes to other medical institutions. Also, if you receive fertility treatmentusing cryopreserved embryo (fertilized egg) , it can only be with the partner at
the time of preservation.
Using fertility preservation before cancer treatment does not guarantee futurepregnancy.

For Partner
It is important that the partner is in good general health.
In the case of death or divorce preserved embryos cannot be used.
Frozen embryos, eggs, or sperm can not be used without the consent of thepatient.

10

Flow chart for
fertility preservation options

1

Ask your oncologist, nurses, pharmacists, medical social worker orpsychologist about fertility preservation.

2

Ask your oncologist about whether your reproductive function will beaffected by your cancer treatment.

3

Select a reproductive endocrinologist.

4

Request a letter of introduction from the oncologist to the reproductiveendocrinologist.

5

The reproductive endocrinologist will explain your current fertility andpreservation options. (Your health insurance may not cover this fee.
Please contact your reproductive medical institution for details.)

6

If you opt for fertility preservation
You will undergo treatment at a reproductive medical institution.
If you select not to pursue fertility preservation prior to treatment
You may contact a reproductive endocrinologist after cancer treatment
as needed.

7

After consulting about your fertility, you are ready to start yourcancer treatment at your hospital.

11How to find reproductive medical institutions
Consult your oncologist first. Several resources are available to you.
Japan Society for Fertility Preservation（JSFP）
日本・がん生殖医療学会 https://www.j-sfp.org/Information Center for Cancer Patients
がん・情報サービス https://ganjoho.jp/public/index.html
Oncofertility for Children and Adolescents
小児・若年がんと妊娠 https://www.j-sfp.org/ped/index.html

Costs for fertility preservation
Reproductive medicine is not covered by insurance.
Be advised that you will receive this treatment at your own expense.

Standard costs
Counseling : First visit

Thousands to 10000 yen

Oocytes cryopreservation : 200,000 yen to 400,000 yen
Embryo cryopreservation : 300,000 yen to 500,000 yen
Ovarian tissue cryopreservation 600,000 yen to 800,000 yen
Sperm cryopreservation : 50,000 yen(If testicular extraction is required 400,000 yen to 500,000 yen)
Annual storage fee for cryopreservation : 200,00 yen to 600,00 yen
Micro insemination using cryopreserved sperm : 350,000yen to 400,000 yen
Infertility treatment is covered by insurance from April 2022 in Japan, while fertility
preservation for cancer patients is not covered by insurance.
The Ministry of Health, Labour and Welfare launched the "Project to promote
Fertility Preservation for Children and AYA Cancer Patients" from April 1, 2021.
You can receive some subsidies for the fertility preservation treatment. For more
information, please contact your local government.

12Calendar
Annotate as you please

Cancer treatment

Scheduled date of cancer treatment start Day/Month/YearDay

MonthYearFirst reproductive medical examination date Day/Month/YearDay

Month

Year

Schedule of fertility preservation treatment

Your fertility preservation option
Embryo freezing / Oocyte freezing / Sperm freezing / Ovarian tissue
cryopreservation / others

Data fertility preservation was performedDayMonthPresence / absence of cryopreservation

Update frequency of cryopreservation

13YearQuestions you should ask your oncologist
Reproduction medical institutes will need the following information from youroncologist.

Primary site of cancer
Stage, prognosis
Scheduled start date of cancer treatment
Treatment (Chemotherapy, Operation, Radiation
therapy)
Urgency of cancer treatment (Time needed for
fertility preservation)
The risk of infertility by cancer treatment
Contact information of oncologist forreproductive endocrinologist.

Please review the six checkpoints on page 2 after you talk with yourreproductive endocrinologist to check whether you now have full
information to make your own decision.

14Reference
1Donnez J, Dolmans MM. Fertility Preservation in Women. The New England
journal of medicine. 2017;377(17):1657-65. Epub 2017/10/27. doi: 10.1056/
NEJMra1614676.

2Johnson EK, Finlayson C, Rowell EE, Gosiengfiao Y, Pavone ME, Lockart B,
Orwig KE, Brannigan RE, Woodruff TK. Fertility Preservation for PediatricPatients: Current State and Future Possibilities. The Journal of urology.
2017;198(1):186-94. Epub 2017/02/13. doi: 10.1016/j.juro.2016.09.159.

3

Loren AW, Mangu PB, Beck LN, Brennan L, Magdalinski AJ, Partridge
AH, Quinn G, Wallace WH, Oktay K. Fertility preservation for patients withcancer: American Society of Clinical Oncology clinical practice guideline
update. Journal of clinical oncology : official journal of the American Societyof Clinical Oncology. 2013;31(19):2500-10. Epub 2013/05/30. doi: 10.1200/
jco.2013.49.2678.

4

Duncan, F. E., Brannigan, R. E. & Woodruff, T. K. (2014). Yen and Jaffe's
Reproductive Endocrinology Physiology, Pathophysiology, and ClinicalManagement, 7th Edition: Elsevier. p. 791-821 31 p

5Fertility preservation and reproduction in patients facing gonadotoxic
therapies: a committee opinion. Fertility and sterility. 2013;100(5):1224-31.
Epub 2013/10/08. doi: 10.1016/j.fertnstert.2013.08.041.

6

Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy
and radiation on female reproduction. Clinical obstetrics and gynecology.
2010;53(4):727-39. Epub 2010/11/05. doi: 10.1097/GRF.0b013e3181f96b54.

7Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, ScottRT, Jr. The nature of aneuploidy with increasing age of the female partner:
a review of 15,169 consecutive trophectoderm biopsies evaluated withcomprehensive chromosomal screening. Fertility and sterility. 2014;101(3):65663.

15

Working Panel Tasked with Compiling Evidence Regarding the Fertility of Long-Term
Survivors of Cancer during Childhood or Adolescence and with Developing aReproductive Medicine Network (Organizer: Yoko Miyoshi)This brochure was developed with the support a research grant received from theJapanese Ministry of Health, Labour and Welfare as a cancer control promotion
project (H26-016) . (Rep: Yoko Miyoshi, MD, PhD, Department of Pediatrics, Osaka
University Graduate School of Medicine)

Authors and editors
Akitani Fumi

: Department of Integrated woman's health, St Luke's international
hospital
Tomoyasu Kato : Department of Gynecology, National Cancer Center Hospital
Atsuko Kitano: Department of Breast and Medical Oncology, National Cancer
Center Hospital
Kyouko Shioda : Department of Integrated woman's health, St Luke's international
hospital
Chikako Shimizu : Department of Breast and Medical Oncology, National Cancer
Center Hospital

English version (Ver1.2 : Revised in June 2022)
Translators
Atsuko Kusuhara : Northwestern University/ Department of Obstetrics andGynecology, The Jikei University
Yoko Miyoshi: Department of Pediatrics, Osaka University Graduate School ofMedicine
We would like to thank Chikako Shimizu and Tomoyasu Kato (National CancerHospital) and Nao Suzuki (St. Marianna University) and Duniel Tucker (NorthwesternUniverstity) .

Acknowledgment
We thank Toru Kishida (STAND Up!!) and Mie Mifune (Pink Ring) for their greatcooperation.

Production cooperation: Moonfactory,Inc