Jose Serna Fertility preservation.ppt

FERTILITY PRESERVATION 

José SERNA, MD, PhD 

Director IVI Zaragoza, Spain

Introduction 

o 

It is estimated that 1/1,000 

women between 20 and 30 survive 

cancer, frequently after gonadotoxic treatments (CT, RT,…). 

o 42% of young women after CT &RT 

develop aPOF. 30-90% 

men will have seminal changes (Blummenfeld). 

o 

o 

o 

1out 

of 52 women have amalignant 

tumour before 39 yo 

In the US there are 50,000000 new cases per year in people in their 

reproductive age. 

Each year in the US, around 4% of young women receive 

treatment with CT &RT 

with sterilizing effect.

Introduction 

o 

o 

o 

Thanks to the oncologic therapy improvement in the lasts 

decades, there is aspectacular 

increase in cure rates of some 

hematologic cancer and other solid tumours. 

Nowadays it is believed that 70% boy and girls with cancer will 

survive. 

There is aincreasing 

concern about the Quality of Life due to the 

increase in survival rates after an oncologic treatment.

Introduction 

o 

The more the survival and cure rate increase, the more the 

treatment consequences are taken into account. 

o 

Ovarian function and fertility maintenance are considered one of 

the major concerns among patients overcoming the disease. 

These facts influence in Quality of Life and Self-esteem. 

“Cancer-free but Sterile” 

Oosterhuis et al. Pediatr Blood Cancer 2008;50:85 -89.

Epidemiology 

2007 Estimated US Cancer Cases* 

Prostate 29% 

Men 

766,860 

Women 

678,060 

26% Breast 

Lung & bronchus 15% 

15% Lung & bronchus 

Colon & rectum 10% 

11%Colon & rectum 

Urinary bladder 7% 

6% Uterine corpus 

Non-Hodgkin 

4% 

lymphoma 

4% Non-Hodgkin 

lymphoma 

Melanoma of skin 4% 

4% Melanoma of skin 

Kidney 4% 

4% Thyroid 

Leukemia 3% 

3% Ovary 

Oral cavity 3% 

3% Kidney 

Pancreas 2% 

3% Leukemia 

All Other Sites 19% 

21% All Other Sites 

( Higher frequency in reproductive age) 

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. 

Source: American Cancer Society, 2007.

Epidemiology 

Lifetime Probability of Developing Cancer, by Site. 

Site 

Risk 

All sites † 1 in 3 

Breast 1 in 8 

Lung & bronchus 1 in 16 

Colon & rectum 1 in 19 

Uterine corpus 1 in 40 

Non-Hodgkin lymphoma 1 in 55 

Ovary 1 in 69 

Melanoma 1 in 73 

Pancreas 1 in 79 

Urinary bladder ‡ 1 in 87 

Uterine cervix 1 in 138 

Women, US. 

2001-2003* 

* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003. 

† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. 

‡ Includes invasive and in situ cancer cases 

Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.1.1 Statistical Research and 

Applications Branch, NCI, 2006. http://srab.cancer.gov/devcan

Epidemiology 

Five-year Relative Survival (%)* during three time 

periods by Cancer Site 

Site 1975-7777 1984-8686 1996-2002 

All sites 50 53 66 

Breast (female) 75 79 89 

Colon 51 59 65 

Leukemia 35 42 49 

Lung and bronchus 13 13 16 

Melanoma 82 86 92 

Non-Hodgkin lymphoma 48 53 63 

Ovary 37 40 45 

Pancreas 2 3 5 

Prostate 69 76 100 

Rectum 49 57 66 

Urinary bladder 73 78 82 

† 

*5-year relative survival rates based on follow up of patients through 2003. 

†Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates. 

Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, 

National Cancer Institute, 2006.

Breast Cancer 

o 

o 

o 

The more frequent tumour in reproductive age is Breast Cancer 

accounting 1/3 of the cancers in young women. 

More than 15% of Breast Cancers appears in women younger 

than 40 (approx. 8,600 

new cases/year) and 600 in younger than 

30. 

The majority of these patients will be treated with CT including 

gonadotoxic (CPA) that may generate POF and Sterility.

Gonadotoxic effect 

• Age 

• Initial state of the gonad 

• Cancer type 

• Treatment used 

- Association of various drugs 

- Combined CT % RT 

• Doses and number of cycles

Age 

Incidence of induced amenorrhoea following CT regarding woman age, in 

423 premenopausal women treated with 6 CEF cycles 

(cyclophosphamide, epirubicin y 5-fluoruracile).


initial gonad condition: 

Diseases with impact on ovarian function 

• Childhood cancer 

• Gynaecological cancer (breast, cervix) 

• Previous pelvic radiotherapy 

• Benign ovarian diseases 

• Prophylactic oophorectomy in inherited mutations 

• Autoimmune diseases (lupus, glomerulonephritis) 

• Autologous or heterologous hematopoietic precursor 

transplantation


POF Incidence cancer survivors 

Cancer type: 

- 1/6 survivor of childhood cancer present POF 

- 32% adults surviving Hodgkin 

- 44% adults surviving AML 

- 50% adults surviving Breast Cancer 

- 80% adults surviving BMT 

The type of cancer affecting more female fertility is lymphoma 

followed by breast cancer. 

The following by frequency and/or relevance are: leukaemias, 

colorectal cancer, ovary, cervix, bone and thyroid.


Chemotherapy 

Drugs: 

Not following all-or-nothing law 

• Drug type: : most toxic agents are alquilants (cyclophosphamide) 

acting in an independent cell cycle fashion 

• Accumulated dose 

• Ages: : around 40% women 40 

• CT Mechanism of Action: : few known, but granulose cells seems to 

be the main target 

• Pathology: : total absence total or very low number of follicles, 

inactive, with fibrosis and without signs of follicular maturation


Chemotherapy 

Agents: 

HIGH RISK 

INTERMEDIATE 

RISK 

LOW RISK 

Cyclophosphamide 

Chlorambucil 

Melphalan 

Mustine 

Cysplatin 

Adriamycin 

Doxorrubicin 

Methothrexate 

5-Fluoruracil 

Vincristin 

Actinomycin D 

Bleomycin


Antimetabolites 

- RT & CT induce an 

irreversible destruction of 

germ cells leading to a 

premature ovarian failure 

Alquilants 

- Moreover: gonadal 

hormones lose, 

mutagenesis in germ 

cells and/or teratogen 

effects 

CT leads to primary damage in primordial 

follicles


Radiotherapy 

- Dose received: in humans dose reducing follicular population to half is 2 Gy 

- Age 

- Irradiation field: probability of POF increases if corporal irradiation 

- May have effects on other structures 

RT doses and ovarian toxicity, according to age 

Dose 

Effect 

60 no 

60-150 

>40: possible 

250-500500 15-40: 50% sterile 

500-800 

15-40: 75% sterile 

>800 100% sterile 

Wallace, 2005

Ovarian injury assessment 

Clínica Clinical 

- Amenorrhea, irregular cycles 

Ecográfica Echography 

- Antral follicle count 

Analítica Biochemistry 

- FSH and estradiol 

- Inhibin B 

-Antimüllerian hormone (AMH)

Results 

• Even with the recovery of ovarian activity, oocyte quality 

will be suboptimal 

• Higher abortion rates 

• Higher IUGR and premature delivery rates in women who 

suffered cancer in childhood 

European Journal of Cancer 

• Systemic treatment (alquilants agents) affects ovary but 

not endometrium 

• RT has a dose-dependent effect on the ovaries, 

endometrium and HPG axis

Pregnancy after Breast Cancer 

• Breast Cancer is a hormone-sensitive tumor 

• Fear to possible recurrences during pregnancy 

• A multidisciplinary team is required to determine the optimal 

time to get pregnant and the appropriate strategies 

• The time-lapse between cancer diagnosis and pregnancy 

varies within each particular case 

• Several studies did not find increase incidence of neoplasia 

recurrence following pregnancy

Pregnancy after Breast Cancer 

Prognosis 

• Several studies did not show 

increases in mortality after pregnancy 

in patients properly treated 

• Moreover some found a decrease in 

the risk. 

• There is a slight increase in 

spontaneous abortion in patients who 

received CT compared with general 

population

Modalities for 

Fertility Preservation 

- Oophoropexy 

- Trachelectomy 

SURGERY 

- Good 

MEDICAL 

choice CT & RT 

- Protective agents 

- Embryo 

- Oocyte 

- Ovarian CRYO Tissue 

- (in vitro Maturation)

Ovarian Transposition 

(Oophoropexia) 

Objective: 

Move ovaries away from irradiation field to avoid direct exposition to 

radiotherapy 

• Laparoscopy or laparotomy 

• They can be fixed in the upper paracolic gutters or behind 

uterus 

• Gonadal protection in 60% of the cases 

• Ovarian function preservation in 83-88% 88% of the cases 

• Complications: vascular lesions, Fallopian tube infarct, cyst 

formation

GnRH agonist 

Ø FSH/LH 

Pituitary 

Pituitary 

GnRH 

agonist 

receptor 

GnRH 

-GnRH agonist may prevent 

follicles from reaching the toxic CT 

threshold by decreasing mitotic 

activity in granulose cells 

• It is not clearly established the 

benefits of GnRH agonists 

• Its use has to be restricted to 

controlled clinical assays 

Receptor down-regulation 

desensibilization 

Blumenfeld et al. Fertil Steril 2008;89:166–73

Fertility Preservation in People Treated for Cancer 

American Society of Clinical Oncology Clinical Practice Guideline 

Triage of Fertility Preservation Referrals 

Assessment of risk for infertility 

Communication with patient 

Patient at risk for treatment-induced infertility 

Patient interested in fertility preservation options 

Refer to specialist with expertise in fertility preservation method 

Eligible for proven fertility preservation method 

Male: 

Sperm cryopreservation 

Female: 

Embryo cryopreservation 

Conservative gynecologic surgery 

oophoropexy 

©American Society of Clinical Oncology 2006 

Clinical Trial of investigational 

fertility preservation technique 

Cryopreservation of testicular or 

ovarian tissue or oocytes 

Ovarian suppression 

http://www.asco.org/guidelines/fertility



- Oophoropexy 

- Trachelectomy 

SURGERY 

- Good 

MEDICAL 

choice CT & RT 

- Protective agents 

- Embryo 

- Oocyte 

- Ovarian CRYO Tissue 

- (in vitro Maturation) 

COH

Ovarian Stimulation 

Cryopreservation

Letrozole 

• Aromatase Inhibitor, 3 rd generation. 

• Highly selective 

• Decreases E 2 levels in 90% 

• Tamoxifen alternative in Breast Cancer 

• Recently used for Ovulation Induction, alone 

or with FSH 

• 5 mg/day more effective than 2,5 mg/day

Tamoxifen vs Letrozole in FIV patients with 

Breast Cancer 

E 2 

hCG 

Days 

Tamoxifen 

Tamox 5 60 mg/d 10 

7.8 ± 0.5 

Tamox-FSH 

FSH 150 IU 

Tamox 5 60 mg/d 10 

8.9 ± 0.8 

Letroz-FSH 

FSH 150 IU 

Letrozole 5 5 mg/d 10 

Letrozole 

9.1 ± 0.5 

0 4 8 12 

Cycle Days 

Oktay et al, J Clin Oncol 2005 Jul 1;23(19):4347-53.

Ovarian Stimulation Protocol 

with Letrozole 

FSH 150 UI 

MENS 

Letrozole 5 5 mg/d 10 

1 2 4 8 12 

Letrozole 

- GnRH antagonist with follicles ≥14 mm. 

- hCG when largest follicles reach 19-21 mm. 

- Day+3: E2>250 pg/ml, start Letrozole until E2

Letrozole vs agonist Long Protocol 

Table-2. Comparison of various characteristics between letrozole+FSH and control groups. 

Letrozole+FSH a 

Control b 

P-value c 

mean ± standard error 

mean ± standard error 

Age at IVF 36.1 ± 0.5 36.9 ± 0.5 0.69 

Baseline FSH 7.6 ± 0.5 4.3 ± 0.2

Letrozole vs. control groups 

P=0.05 

1 

% Maturity 

n=2 n=12 

17 

20 

21 

0 

hCG>17 mm 

hCG>18 mm 

0.53 ± 0.18 vs. 0.80 ± 0.05 

Mature/ Total Oocytes 

Fertilization 

Oktay et al, JCEM 2006 

17 

20 

21

Controversies Letrozole 

• 4.7 vs 1.8% major malformations 

• 150 NB after Letrozole vs 36.000 NB, in an NON-TERTIARY hospital 

• Laryngomalacia, craneosynostosis, sacral fusion, aortic stenosis (2), cystic 

lynphangioma, hepatocellular carcinoma. 

• Only slightly increased Chromosomal Abnormalities. 

ASRM 2005 abstract 

• 911 NB after Letrozole or Clomiphene stimulation 

• Similar malformation rates: 2,4% (L) vs 3% (CC). 

• Less incidence of hart malformation (0,2% vs 1,8%, p=0,02). 

Tulandi-Casper. Fertil Steril, June 2006. 

• 2.56% (L) vs 3.10% (CC) major malformation (p>0.05). 

Padte K et al. Serono Symposia on Regulation of Follicle Development and its Clinical Implications. May 2006.

Controversies Letrozole 

• Half-life: 48h 

- Drug out of the body before 

fertilization. 

• Absence of evidence of 

oocyte/embryo damage in mice 

• Cryopreserved embryos are not 

exposed to the drug 

Novartis: 

The drug “should not be used in 

women who may become 

pregnant, during pregnancy 

and/or while breast-feeding, 

because there is a potential risk 

of harm to the mother and the 

fetus, including risk of fetal 

malformations,”

Utilization of IVM Further Increases 

the Yield of Oocytes & Embryos in 

Letrozole Cycles 

% of cryopreserved embryo/oocytes 

14 

12 

10 

8 

6 

4 

2 

0 

Before IVM 

After IVM 

Before IVM 

After IVM 

Embryo or oocyte yield increase 44.7±11.2 % (p

Oocyte in vitro Maturation 

Pros 

-Simple and short time 

-Low cost 

-Low incidence of side-effects 

Cons 

- Less successful rates 

- Difficult uptake 

- Still experimental



Fertility Preservation Options in 

Females (cont’ d) 

• Embryo Cryopreservation 

– Requires ~2 weeks of ovarian stimulation w/daily injections of FSH from 

the onset of menses. 

– A delay of 2-6 weeks in chemotherapy initiation may be required if 

reproductive specialists do not see women early in their menstrual 

cycle. 

– This approach may be associated with high out-of-pocket costs for most 

women. 

– Long-term follow up with a larger number of patients is needed to 

evaluate the safety and efficacy of this approach. 

– For women with hormone-sensitive tumors, alternative hormonal 

stimulation approaches such as letrozole or tamoxifen have been 

developed to theoretically reduce the potential risk of estrogen 

exposure. 

http://www.asco.org/guidelines/fertility 

©American Society of Clinical Oncology 2006



Fertility Preservation Options in 

Females (cont’ d) 

• Recommendation (Embryo Cryopreservation): 

–Embryo cryopreservation is considered an 

established fertility preservation method as it has 

routinely been used for storing surplus embryos 

after in vitro fertilization for infertility treatment. 

http://www.asco.org/guidelines/fertility 

©American Society of Clinical Oncology 2006

Oocyte Vitrification 

Cryotop Method

Vitrified oocytes maintain intact their potential to reach blastocyst

Perinatal outcome from Vitrified vs. Fresh donated oocytes. 

Paired cohorts study. 

Singleton 

Vitrified 

Singleton 

Fresh 

Multiple 

vitrified 

Multiple 

Fresh 

Nº Deliveries 212 234 99 92 

Nº New born 212 234 199 183 

Nº Live birth 211 233 197 183 

Mean maternal age at delivering 40.6 ± 4.9 40.8 ± 4.8 40.8 ± 3.4 40.4 ± 4.5 

Mean gestational age (weeks) 39.0 ± 1.9 38.6 ± 1.9 36.7 ± 2.8 36.1 ± 2.2 

No. of deliveries at



• Recommendation (Oocyte Cryopreservation): 

–Cryopreservation of unfertilized oocytes is another option 

for fertility preservation particularly in patients for whom: 

•A partner is unavailable, or 

•Religious or ethical objections conflict with embryo 

freezing. 

- Embryo 

- Oocyte 

- Ovarian Tissue 


COH



CRYO 

- Embryo 

- Oocyte 

- Ovarian Tissue 


COH

Fertility Preservation and Cancer 

OOCYTE 

CRYOPRESERVATION 

OVARIAN CORTEX 


Advantages: 

-Demonstrated results 

-Success Rate similar to fresh 

oocytes 

-Established technique 

Advantages: 

-Unlimited cycles 

-Maintenance Hormone 

function 

Restrictions: 

-Limited IVF cycles 

-Does not guarantee pregnancy 

-May delay CT 

-Need ovarian stimulation 

Restrictions: 

-Isolated cases 

-Need tech optimization 

-Harboring cancer cells 

-Need surgery

Fertility Preservation in Cancer Patients 

1 st choice 

OOCYTE 


OVARIAN CORTEX 


-Women willing to conceive 

-Oncologist consultation 

and approval 

-Does not exclude ovarian 

cortex removal 

Concerns: 

-Cross-contamination 

-Girls 

-Contraindication for 

ovarian stimulation 

-Oncologist disapprove 

stimulation 

-No time for ovarian 

stimulation 

Concerns: 

-Leukaemia 

-Cross-contamination

Ovarıan Cortex Cryopreservatıon 

• Still experimental 

• Animals and Humans 

spontaneous 

pregnancies 

• Ovarian cortex is fully 

functional

Ovarian tissue cryopreservation 

Our protocol 

Ovarian cortex retrieval (generally by laparoscopy) and ulterior processing

Ovarian cortex cryopreservation 

Our protocol 

• Reimplantation over ovarian medulla when disease-free have 

been proved 

Limitations 

• Avoid massive follicle loss associated with transplantation 

isquemia: 

• Surgical approaches 

• Antiox. and angiogenic agents 

• Define biological hazard markers before reimplantation

IVI Program for Female 


Cancer diagnosis 

Ovarian tissue freezing 

Ovarian stimulation 

Egg vitrification 

3 weeks



http://www.asco.org/guidelines/fertility

“No childless women 

surviving cancer”

Jose Serna Fertility preservation.ppt

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