The need for fertility preservation Chemotherapeutic drugs according to gonadotoxicity level Fertility preservation: subject of continuous review by experts Non-oncological conditions requiring fertility preservation Delayed childbearing AVAILABLE PROCEDURES FOR FP Embryo and oocyte cryopreservation

1. Fertility preservation
guidelines in cancer patients
A review of guidelines

2. Fertility preservation is defined as the use of
available technologies to help individuals retain
their fertility or ability to procreate.
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

3. The need for fertility preservation
• Reproductive capacity may be seriously affected by:
• Age
• Genetic syndromes
• Treatments with gonadal toxicity
• Fertility preservation (FP) is a fundamental issue for
• Individuals of reproductive age (both male and female) or prepubescent
• Boys and girls whose future fertility may be compromised
Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282

4. Chemotherapeutic drugs according to gonadotoxicity level
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

5. Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282

6. Timely referral to a
fertility specialist
for informed FP
decisions becomes
essential
Need to provide
counselling about
currently available
FP options
All individuals
wishing to
preserve their
fertility
Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282

7. Fertility preservation: subject of continuous review by experts
• Several techniques for FP are nowadays well established
• Others are still considered experimental
• Reviews have been mostly focused on FP and cancer
• Need for FP in other pathologic situations is on the rise
Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282

8. Indications for
FP
Cancer
Non-oncological
Medical
Indications
Delayed
childbearing
Fertility and Sterility® Vol. 108, No. 3, September 2017 0015-0282

9. Cancer
• Fertility is affected from commonly used treatments such as
chemotherapy with alkylating agents and pelvic radiation
• Gonadal failure resulting from these treatments may affect different
aspects of reproductive health, including:
• pubertal development
• hormone production
• sexual function
• More than 80% of children and adolescents with cancer become long-
term survivors raising the interest in the long-term effects of cancer
treatment on fertility
Hum Reprod 2015;30: 2463–75.
Cancer Epidemiol Biomarkers Prev 2015;24:653–63.

10. J Clin Oncol 2013;31:2500–10.
• Spermatogonia are especially sensitive to
chemotherapy & radiotherapy
• The effect may not be permanent if the
spermatogonial stem cell (SSC) population is
not fully depleted
• Surgical pelvic interventions for malignant or
benign disease may affect the anatomy or
normal functioning of reproductive organs

11. Fertil Steril 2013;100:1224–31.
• Chemotherapy and radiotherapy may induce
premature ovarian insufficiency (POI) in women
• Ovarian damage is drug- and dose- dependent
and increases as the patient ages
• Radiotherapy may also affect the uterus, leading
to reduced vascularity, myometrium damage
(fibrosis) and hormone- dependent insufficiency
• Fertility may also be impaired by surgical
removal or damage to reproductive organs.

12. Non-oncological conditions requiring fertility preservation

13. Delayed childbearing
• Female fertility decreases gradually but significantly after age 32 years, and faster
after 37 years
• This compromises fertility when delaying childbearing
• The term ‘AGE banking’ (oocyte banking for anticipated gamete exhaustion) has
been proposed for oocyte cryopreservation in these cases
Reprod Biomed Online 2014; 28:548–51.

14. AVAILABLE PROCEDURES FOR FP
1. Embryo and oocyte cryopreservation
2. Harvesting of immature oocytes
3. Ovarian tissue cryopreservation (OTC)
4. Whole ovary preservation
5. Fertoprotective agents

15. Embryo and oocyte cryopreservation
Fertil Steril 2013;100:1224–31.
Fertil Steril 2013;99:1485–95.
• Slow freezing or vitrification: first-line FP methods
• Oocyte cryopreservation is increasingly preferred
• Mature oocyte vitrification is preferred in post- pubertal women when
gonadotoxic treatment can be delayed to allow time for controlled ovarian
stimulation (COS)

16. Harvesting of immature oocytes
.
Hum Reprod 2014;29:1925–30.
Reprod Biomed Online 2010;20:634–8.
• Pre-pubertal girls or women with aggressive or hormone-sensitive cancers
• Unable to undergo COS
• IVM improves outcomes in breast cancer patients undergoing COS for FP

17. Ovarian tissue cryopreservation (OTC)
• COS independent experimental technique
• Allows immediate cancer treatment
• Currently the only FP option in pediatric patients & in hormone-dependent
diseases
• Reimplantation of this tissue either in the pelvic cavity (orthotopic) or elsewhere
(heterotopic) has the potential of restoring fertility and ovarian hormone
secretion
• Reimplantation of frozen–thawed ovarian tissue in the pelvic cavity is usually
carried out by laparoscopy
• The surgical technique is contingent on the presence (or not) of at least one ovary
Nat Rev Endocrinol 2013;9:735–49.
J Gynecol Oncol 2016;27:e22.
Fertil Steril 2012;98:720–5.

18. Whole ovary preservation
• Prevents ischaemic damage occurring between transplantation and
revascularization
• Fertility restoration after whole ovary preservation requires
retransplantation of the whole organ accompanied by vascular
anastomoses of the blood vessels
• Natural fertility has been fully restored with this technique after slow
freezing and thawing in sheep
Curr Opin Obstet Gynecol 2005;17:333–8.
Hum Reprod 2014;29:1749–63.
Reprod Biomed Online 2014;29:722–8.

19. Whole ovary preservation
• Cryopreservation of the whole ovary is likely to be more problematic in
adult women due to:
• Increased size of their ovaries
• Difficulty of achieving adequate perfusion and penetration of the
cryoprotectant agents
Reprod Biomed Online 2014;29:722–8.

20. Fertoprotective agents
• GnRHa may protect follicles from destruction during chemotherapy
• Used since long for the prevention of ovarian damage, despite their
debatable efficacy
• Two meta-analyses have found an overall significantly reduced risk of POI
in young breast cancer patients
• This protective effect of GnRHa is less clear in other cancer patients
(ovarian) or not present at all, as in young patients with lymphoma
Hum Reprod 2007;22: 1626–33.
Cancer Treat Rev 2014; 40:675–83.
Ann Oncol 2015;26: 2408–19.
Clin Oncol 2016;34:2568–74.

21. Algorithm for the cryopreservation of testicular tissue/sperm
Martinez. Update on fertility preservation. Fertil Steril 2017.

22. RESULTS OF ART AFTER FP
Martinez. Update on fertility preservation. Fertil Steril 2017.

23. RESULTS OF ART AFTER FP
• Live birth rate (LBR) in cancer patients undergoing IVF and embryo
cryopreservation, and cumulative live birth rate (CLBR) to that achieved
with fresh embryos in non-cancer patients has been similar
• Success rates associated with oocyte vitrification are superior to slow
freezing
• The first live birth following re- grafting of ovarian tissue that had been
cryopreserved during childhood in a 13-year old girl undergoing HSCT

24. Success rates of semen cryopreservation
• Greatly increased with advances in ICSI, with pregnancy rates of up to 57%
• With ICSI, reported a LBR of 62.1% in a cohort of 272 men with cancer
• It was significantly higher than that of the comparative normospermic non-
cancer population.
J Cancer Surviv 2015;9:208–14.

25. Curr Oncol. 2015 Aug; 22(4): e294–e304.

26. Recommendations: Early access to care and barriers to referral
• After the diagnosis of cancer or other medical conditions requiring
potentially sterilizing medical or surgical treatments in a reproductive
age woman, an immediate referral to a reproductive endocrinologists
and infertility (REI) specialist is strongly suggested
• Provide patients with counseling regarding their fertility and fertility
preservation management options.
• A multidisciplinary network to facilitate referrals to professionals with
expertise in fertility preservation should be considered
Curr Oncol. 2015 Aug; 22(4): e294–e304.

27. Recommendations: Assessment of the young cancer patient
• Serum FSH, AMH levels, and/or antral follicle count (AFC) should be
performed prior to chemotherapy to assist in the selection of
gonadotropin doses and to prognosticate gonadotoxic effects of
chemotherapy.
• Follow-up serum FSH and AMH should be considered for assessing
the gonadotoxic effects of chemotherapy.
Curr Oncol. 2015 Aug; 22(4): e294–e304.

28. Recommendations on fertility preservation options
Curr Oncol. 2015 Aug; 22(4): e294–e304.
Fertility preservation option Recommendations
GnRh agonists Can be considered as a means of gonadal cytoprotection prior to
combination chemotherapy
Embryo cryopreservation Recommended method of fertility preservation
Oocyte cryopreservation Oocyte cryopreservation by vitrification is a recommended method of
fertility preservation
Controlled ovarian stimulation of
the cancer patients
Ovarian stimulation protocols utilizing GnRH antagonists should be
considered for embryo and oocyte cryopreservation
GnRH agonists are recommended for the induction of oocyte
maturation when utilizing GnRH antagonist cycles in an effort to
minimize the risk of OHSS
Use of cytoprotective agents during
ovarian stimulation in breast cancer
Patients
Aromatase inhibitors should be considered when administering
gonadotropins.
Ovarian cryopreservation and
transplantation
Investigational and should be limited to cases of oophorectomy or
other predetermined abdominal surgeries by surgeons with the
necessary experience

29. Clin Oncol 36:1994-2001

30. Fertility Preservation in Patients With Cancer
• Recommendation 1.1. Health care providers caring for adult and pediatric patients with
cancer should address the possibility of infertility as early as possible before treatment
starts.
• Recommendation 1.2. Health care providers should refer patients who express an
interest in fertility preservation (and those who are ambivalent) to reproductive
specialists.
• Recommendation 1.3. To preserve the full range of options, fertility preservation
approaches should be discussed as early as possible, before treatment starts. The
discussions should be documented in the medical record.
Clin Oncol 36:1994-2001

31. Fertility preservation options for adult MEN
Fertility preservation option Recommendation
Sperm cryopreservation Sperm cryopreservation is effective, and health care providers
should discuss sperm banking with postpubertal males receiving
cancer treatment
Hormonal gonadoprotection Hormonal therapy in men is not successful in preserving fertility. It is
not recommended.
Other methods to preserve
male fertility
Testicular tissue cryopreservation and reimplantation or grafting of
human testicular tissue, should be performed only as part of clinical
trials or approved experimental protocols.
Postchemotherapy Sperm be collected before initiation of treatment because the
quality of the sample and sperm DNA integrity may be compromised
after a single treatment
Clin Oncol 36:1994-2001

32. Fertility preservation options for adult WOMEN
Fertility preservation option Recommendation
Embryo cryopreservation Embryo cryopreservation is an established fertility preservation
method,
and it has routinely been used for storing surplus embryos after in
vitro fertilization
Cryopreservation of
unfertilized oocytes
Cryopreservation of unfertilized oocytes is an option, and may be
especially well suited to women who do not have a male partner, do
not wish to use donor sperm, or have religious or ethical objections
to embryo freezing. Oocyte cryopreservation should be performed in
centers with the necessary expertise. As of October 2012, the
American Society for Reproductive Medicine no longer deems this
procedure experimental.
Clin Oncol 36:1994-2001

33. Fertility preservation options for adult WOMEN: qualifying statement
• More flexible ovarian stimulation protocols for oocyte collection are now available
• Ooocyte harvesting for the purpose of oocyte or embryo cryopreservation is now
possible on a cycle day–independent schedule
• Of special concern in estrogen-sensitive breast and gynecologic malignancies is the
possibility that these fertility preservation interventions (eg, ovarian stimulation
regimens that increase estrogen levels) and/or subsequent pregnancy may increase the
risk of cancer recurrence
• Aromatase inhibitor–based stimulation protocols are now well established and may
ameliorate this concern
Clin Oncol 36:1994-2001

34. Fertility preservation options for adult WOMEN
Fertility preservation
option
Recommendation
Ovarian transposition Can be offered when pelvic irradiation is performed as cancer
treatment. Because of the risk of remigration of the ovaries, this
procedure should be
performed as close to the time of radiation treatment as possible.
Conservative gynecologic
surgery
It has been suggested that radical trachelectomy (surgical removal
of the uterine cervix) should be restricted to stage IA2 to IB cervical
cancer with diameter , 2 cm and invasion , 10 mm. In the treatment
of other gynecologic malignancies, interventions to spare fertility
have generally centered on doing less radical surgery, with the intent
of sparing the reproductive organs as much as possible. Ovarian
cystectomy can be performed for early-stage ovarian cancer.
Clin Oncol 36:1994-2001

35. Fertility preservation options for adult WOMEN
Fertility preservation
option
Recommendation
Ovarian suppression
There is conflicting evidence to recommend GnRHa and other means
of ovarian suppression. When proven fertility preservation methods
such as oocyte, embryo, or ovarian tissue cryopreservation are not
feasible, and in the setting of young women with breast cancer, GnRHa
may be offered to patients. However, GnRHa should not be used in
place of proven fertility preservation methods.
Ovarian tissue
cryopreservation and
transplantation
Does not require ovarian stimulation and can be performed
immediately. Does not require sexual maturity and hence may be the
only method available in children. May also restore global ovarian
function. Further investigation is needed to confirm whether it is safe
in patients with leukemias.
Clin Oncol 36:1994-2001

36. As of the time of this publication, ovarian tissue cryopreservation
remains experimental. However, emerging data may prompt
reconsideration of this designation in the future (this technique is
already considered non-experimental in some countries, and its
experimental status is undergoing evaluation in the United States).
Clin Oncol 36:1994-2001

37. Role of healthcare providers
• All oncologic health care providers should be prepared to discuss infertility as a
potential risk of therapy. This discussion should take place as soon as possible
once a cancer diagnosis is made and can occur simultaneously with staging and
the formulation of a treatment plan.
• Encourage patients to participate in registries and clinical studies, as available, to
define further the safety and efficacy of these interventions and strategies.
• Refer patients who express an interest in fertility, as well as those who are
ambivalent or uncertain, to reproductive specialists as soon as possible.
• Refer patients to psychosocial providers when they are distressed about potential
infertility
Clin Oncol 36:1994-2001

38. Special considerations: Children
• Suggest established methods of fertility preservation (eg, semen or oocyte
cryopreservation) for postpubertal children, with patient assent and parent or
guardian consent
• For prepubertal children, the only fertility preservation options are ovarian and
testicular cryopreservation, which are investigational
Clin Oncol 36:1994-2001

39. G. Mintziori et al. / Maturitas 77 (2014) 85– 89

40. Fertility preservation in pre-pubertal boys and girls
• Pre-treatment counseling
• Long-term reproductive potential should be taken into consideration in the
construction of the therapeutic plan
• Children diagnosed with genetic conditions that impair the reproductive
function should be referred, as early as possible, to a reproductive
endocrinologist
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

41. Fertility preservation in pre-pubertal boys and girls
Fertility preservation option Recommendations
Preservation of gonadal tissue
and transplantation of germ
stem cells
Could be applied for fertility preservation in pre-pubertal boys
and girls
Testicular tissue or
spermatogonial cryopreservation
and transplantation
Still considered experimental
Ovarian tissue cryopreservation Also largely experimental, but it could be used in pre-pubertal
girls who require gonadotoxic treatment, in the absence of other
available options
Ovarian transposition Could be considered in pre-pubertal girls whose treatment plan
involves pelvic irradiation. However, this method is not always
practical.
Retrieval and subsequent
freezing of immature germ cells
Should be considered in pre-pubertal boys diagnosed with
Klinefelter syndrome
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

42. Fertility preservation in women
Fertility preservation option Recommendations
Embryo cryopreservation Well-established technology and should be applied whenever
possible. May give a satisfactory live birth rate for cancer
patients.
Cryopreservation of unfertilized
oocytes
The most suitable option for young women who wish to preserve
their fertility as it is possible to preserve oocytes of good quality,
without the need for sperm
Oocyte slow freezing It failed to be established in everyday clinical practice
Oocyte vitrification No longer an experimental procedure. A major concern is its
potential effect on the genetic material, such as increased rates
of chromosome misalignment
Ovarian tissue cryopreservation Considered to be a promising procedure for women of
reproductive age with a malignant disease, but is an option only
in specialized centers
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

43. Other experimental procedures
• Use of existing germ stem cells in the adult ovary
• Bone marrow transplantation
• Oocyte and zygote micro-manipulations, such as cytoplasmic (mitochondria),
germinal vesicle and pronuclear transfer
• Ethical matters remain to be solved
• The ovarian fragmentation – in vitro activation approach, if proved efficient and
safe, could be a valuable option
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

44. Fertility preservation in men
Fertility preservation option Recommendations
Pre-treatment counseling All males of reproductive age or younger should be thoroughly
informed before the initiation of any gonadotoxic treatment
about the possible risks
Sperm cryopreservation (sperm
banking)
Established fertility preservation method that should be always
the first-line option for men of reproductive age
Scrotal shield When the pelvis or malignancies of the proximal thigh are being
irradiated, a scrotal shield may protect the gonads
Testicular tissue cryo-
preservation
Limited use in adults, although it is the only fertility preservation
option for pre-pubertal males
Testicular tissue or
spermatogonial cryopreservation
and transplantation
Still considered experimental, with scarce information about
their efficacy and risks
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

46. Fertility preservation methods in cancer patients: Males
• Sperm banking should be planned before treatment initiation
• Semen cryopreservation with one to three samples collection is recommended
• Sperm banking can be proposed independently of patients’ age, according to
their wishes of future paternity
• There is no role for gonadal protection by any form of hormonal or
pharmacological means
Annals of Oncology 24 (Supplement 6): vi160–vi170, 2013

47. Fertility preservation methods in cancer patients: Females
• Use of GnRH analogues concomitantly with chemotherapy should not be
regarded as a reliable means of preserving fertility
• Embryo or oocyte cryopreservation is the main method to preserve female
fertility
• Ovarian stimulation should be carried out before commencing
chemotherapy
• This may result in relative delay in oncological treatment and in increased
serum estradiol levels, which could be of concern in hormone-driven
tumours like breast cancer.
Annals of Oncology 24 (Supplement 6): vi160–vi170, 2013

48. Fertility preservation methods in cancer patients: Females
• The use of gonadotropins and letrozole or tamoxifen has been shown to be
associated with adequate yield of oocytes compared with standard
stimulation regimens and is generally recommended for cancer patients
• Ovarian tissue freezing
• Chemotherapy- and radiotherapy-induced sterility can be prevented also by
freezing ovarian tissue before treatment
• It is still considered experimental, but remains a unique option for young girls
with cancer
Annals of Oncology 24 (Supplement 6): vi160–vi170, 2013

49. Conclusions
• As the number of cancer survivors is increasing, the need for fertility preservation
is emerging
• Fertility preservation should be a priority when treating children or adults of
reproductive age with agents that may have hazardous effects on the
reproductive system
• Gonadotoxicity should be kept to a minimum
G. Mintziori et al. / Maturitas 77 (2014) 85– 89

50. https://www.cosa.org.au/publications/guidelines/
Fertility preservation for Adolescents and Young Adults
(AYAs) diagnosed with cancer: Guidance for health
professionals.

51. Discuss fertility early and fully
• All AYAs with cancer requiring treatment that could compromise future fertility
must be informed of the likely risk and options to protect or preserve fertility
before treatment begins.
• Health professionals should be guided by institutional policies and protocols, if
they exist, on when and how to discuss fertility with newly diagnosed patients
• AYA patients and their families should be given written information about the
issues discussed, and offered psychosocial support
https://www.cosa.org.au/publications/guidelines/

52. Managing the fertility preservation process
• Cancer treatment teams, fertility specialists and other key stakeholders should
work together to preserve and optimise the future reproductive capacity of
young people diagnosed with cancer.
• Develop local protocols and pathways to enable clear and timely communication
between all professionals and services involved in the fertility preservation
process, and between the team and the patient and their family.
https://www.cosa.org.au/publications/guidelines/

53. Options for fertility preservation
• The most effective and established means of preserving fertility in young
people with cancer are:
• Oocyte and embryo cryopreservation where appropriate for females
• Sperm cryopreservation for males before cancer treatment starts
• Where possible, investigational procedures should be undertaken in the
context of a clinical trial.
https://www.cosa.org.au/publications/guidelines/

54. Oocyte and embryo freezing prior to chemotherapy
and/or radiotherapy
• Embryo or oocyte cryopreservation is an established procedure.
• It should be discussed with all young women about to undergo potentially
sterilising chemotherapy or pelvic radiation. It may be suitable for young
women who:
• are medically fit for the procedure
• are expected to be able to tolerate the treatment regimen
• have sufficient time before the commencement of their cancer treatment and
• are informed of the potential risks of hormonal treatment including the risks of cancer progression.
https://www.cosa.org.au/publications/guidelines/

55. Ovarian tissue freezing prior to chemotherapy
• Ovarian tissue must be tested for the presence of cancer cells or markers.
• Ovarian tissue cryopreservation is an investigational technique.
• For young women at high risk of ovarian failure, or for whom other options may
not be suitable, ovarian tissue storage may be considered.
• Patients must be counseled that the use of preserved ovarian tissue to achieve
pregnancy is not yet considered to be a routine clinical practice.
https://www.cosa.org.au/publications/guidelines/

56. Ovarian suppression with GnRH analogues during
chemotherapy
• Ideally GNRH analogues for ovarian protection should be used within the context
of a clinical trial setting.
• Where this is not possible, administration is supported provided the patient and
family are fully informed of the lack of large randomised trials addressing the
potential benefit.
https://www.cosa.org.au/publications/guidelines/

57. Cryopreservation of semen
• The only well-established method of preserving fertility in post-pubertal
adolescent and adult males.
• Must be offered to all adolescent and young adult males prior to chemotherapy
or radiotherapy that may damage the testes.
• The procedure of epididymal or testicular aspiration or biopsy attempting to
obtain sperm for cryopreservation should be offered to post-pubertal males who
have an azoospermic ejaculate or who are unable to ejaculate.
https://www.cosa.org.au/publications/guidelines/

58. Long term follow up
• Follow up after cancer treatment is essential
• All AYA cancer survivors should have access to systematic long-term follow-up of
their reproductive, endocrine and sexual health.
https://www.cosa.org.au/publications/guidelines/

59. Conclusions
• If gonadotoxic treatment has to be used, methods of fertility preservation should
be discussed, as early as possible
• Fertility preservation may also be used with adults who wish to postpone
parenthood
• Decisions always have to be taken after careful consideration of all relevant
ethical and social aspects.
G. Mintziori et al. / Maturitas 77 (2014) 85– 89