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ONCOLOGIC AND MEDICAL
FERTILITY PRESERVATION IN ADULT
WOMEN
P N. Barri MD. PhD, B. Coroleu MD. PhD, M.
Devesa MD, M. Soler, G Arroyo
Service of Reproductive Medicine
Department of Obstetrics, Gynecology and Reproduction
Institut Universitari Dexeus
FERTILITY PRESERVATION IN ADULT WOMEN
1. Non-oncologic patients.
2. Oncologic patients.
3. Patients who wish to postpone their fertility for social reasons.
FERTILITY PRESERVATION IN ADULT WOMEN
1. Non-oncologic patients.
2. Oncologic patients.
3. Patients who wish to postpone their fertility for social reasons.
NON-MALIGNANT PATHOLOGIES WITH RISK OF POF
P. JADOUL et al (2010)
Human Reproduction Update 16-6, 617-630
FERTILITY PRESERVATION IN ADULT WOMEN
1. Non-oncologic patients.
2. Oncologic patients.
3. Patients who wish to postpone their fertility for social reasons.
Trends in 5-year relative survival rates for selected cancer sites and year of diagnosis: U.S. 1974-1999
0
20
40
60
80
100bra
in
bre
ast
cerv
ix
colo
n
ute
rus
hod
gkin
mel
anom
anon
-hod
gkin
ovar
y
thyr
oid
74-76
83-85
92-99
Year of
Diagnosis
5- Y
ear relative su
rviv
al rate
Cancer site
National Cancer Insitute, DCCPS
Breast Cancers 2713
>40 years 2305 (84,9%)
≤ 40 years 408 (15,1%)
36-40 yrs 362 (9,7%)
< 36 yrs 146 (5,4%)
Breast Pathology Committee Instituto Universitario Dexeus (1990-2009)
0
20
40
60
80
100
120
140
160
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
>40 <=40
0
20
40
60
80
100
120
140
160
180
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
>35 <=35
ASSESSMENT OF RISK OF SUBFERTILITY AFTER TREATMENT FOR COMMON CANCERS IN CHILDHOOD AND ADOLESCENCE
WALLACE et al 2005
Cytotoxic agents according to degree of gonadotoxicity
High risk Busulfan Chlorambucil Cyclophosphamide Dacarbazine Melphalan Nitrogen mustard Procarbazine
Intermediate risk Adriamycin (Doxorubicin) Carboplatin Cisplatin
Low/no risk Actinomycin D Bleomycin 5-Fluorouracil Methotrexate Vincristine
RADIOTHERAPY AND GONADAL DAMAGE
• < 600 cGy Low risk
• <1000 cGy Medium risk
• >1000 cGy High risk
FERTILITY AFTER CANCER
Gonadal damage is age and dose
dependent
Human Reproduction 24-4:982-990, 2009
ASSESSMENT OF OVARIAN RESERVE IN ADULT CHILDHOOD CANCER SURVIVORS USING ANTI-MÜLLERIAN HORMONE
S. Lie Fong et al.
METHODS: A total cohort of 185 survivors was compared with 42 control
subjects. The median follow-up time was 18.1 years (range 4.1- 43.2 year).
RESULTS: Median AMH concentrations in the analysed cohort were not different
from controls (median 1.7 versus 2.1 µg/l; P=0.57). However, AMH levels were lower than the 10th percentile of normal values in 27% (49/182) of our survivors. In addition, 43% (79/182) had AMH levels lower than 1.4 µg/l, a previously established cutt-off value which predicts ongoing pregnancy after assisted reproduction. There were no differences in AMH levels in subgroups classified according to disease. However, survivors treated with three or more procarbazine containing chemotherapy cycles had significantly lower AMH levels than controls (median 0.5 µg/l; P=0.004). Also survivors treated with abdominal or total body irradiation had significantly lower AMH levels than controls (median <0.1 µg/l; P<0.001).
Partridge A. et al. Fertil Steril, 2010; 94:638-44
Ovarian reserve after chemotherapy
No Mean Median Minimum Maximum P Value
AFC
Control
Survivors
20
20
11
5
10
6
1
0
34
12
.0042
AMH
Control
Survivors
20
20
1.8
0.6
1.4
0.4
0.3
<0.1
6.3
2.4
.0004
FSH
Control
Survivors
20
20
8
11.6
6.9
9.0
3,1
3.3
17.7
24.5
.02
FERTILITY PRESERVATION OPTIONS IN FEMALES STANDARD
Intervention Comment Considerations*
Embryo cryopreservation
The most established technique for fertility preservation in women
• Requires 10-14 days of ovarian stimulation from the beginning of menstrual cycle
• Outpatient surgical procedure
•Requires partner or donor sperm
•Aproximately $8,000 per cycle, $350 per year storage fees
Gonadal shielding during radiation therapy
Case series • Only possible with selected radiation fields and anatomy
• Expertise is required to ensure shielding does not increase dose delivered to the reproductive organs
Ovarian transposition (oophoropexy)
50% chance of success • Same day outpatient surgical procedure
•Transposition should be performed just before radiation therapy to prevent return of ovaries to former position
• May need repositioning or in vitro fertilization (IVF) to conceive
Trachelectomy Large case series and case reports
• Inpatient surgical procedure
• Limited to early stage cervical cancer S.J. LEE ET AL.
JOURNAL OF CLINICAL ONCOLOGY 2006, 24:2917-2931
FERTILITY PRESERVATION OPTIONS IN FEMALES INVESTIGATIONAL
Intervention Comment Considerations*
Oocyte cryopreservation
Aproximately 2% live births per thawed oocyte
• Requires 10-14 days of ovarian stimulation from the beginning of menstrual cycle
• Outpatient surgical procedure
• Aproximately $8,000 per cycle, $350/yr storage fees
Ovarian cryopreservation and transplantation
Case reports; as of 2005, two live births reported
• Not suitable when risk of ovarian involvement is high
• Same day outpatient surgical procedure
Ovarian suppression with gonadotropin releasing hormone (GnRH) analogues
Small randomized studies and case series
• Medication given before and during treatment with chemotherapy
S.J. LEE ET AL. JOURNAL OF CLINICAL ONCOLOGY 2006, 24:2917-2931
PREVENTION OF GONADAL DAMAGE
STRATEGIES FOR FERTILITY PRESERVATION
Patient’s age
Basal ovarian reserve
Type and stage of the oncologic pathology
Proposed therapeutic plan:
Chemotherapy: type, dose and duration
Radiotherapy: field, dose and duration
Surgery
Forseeable long term effets
Possibility of delaying start of chemotherapy
Possibility of receiving ovulatory agents
Social situation
Tumour biology and possibility of ovarian metastases
Strategies for preserving Fertility
1. Reducing toxicity
2. Cryopreservation
3. Fertility sparing surgery
Side effects of RT
Radiotherapy
Ovary Uterus
Damage to uterine muscles
and vascular perfusion
POF
20 Gy in < 40yrs; 6 Gy in > 40yrs
Lushbaugh CC et al, Cancer 1976
Reducing
gonadotoxicity
Pelvic RT ChemoT
GnRH-
Agonists
Less toxic
ChemoT
Ovarian
Transposition
STRATEGIES FOR FERTILTY PRESERVATION
Ovarian transposition
Objective:
To move the ovaries from the
irradiation field before starting RT
Indication:
Tumours requiring pelvic irradiation
Technique:
Laparoscopic / laparotomic
Medial
Lateral
Important:
- Preserving ovarian vascularization
- Easy access for possible future OPU
- Cryopreserving ovarian fragments
Chemoprophylaxis with GnRHa
Objective:
To protect the ovary against
chemotherapy.
Follicular atresia
E2
inhibin
FSH
Follicular recruitment
ChemoT
GnRHa Mechanism of action:
- Blocks follicular differentiation
- ovarian vascularization
PREMATURE OVARIAN FAILURE (POF) IN ONCOLOGIC PATIENTS UNDER GnRH-a OR ORAL CONTRACEPTIVES
COTREATMENT WITH CHEMOTHERAPY
BLUMENFELD and VON WOLF HUM. REPROD. UPDATE (2008)
GnRH-a Oral Contraceptives
25/225 (11.1%) 14/106 (13.2%)
105/189 (55.5%) 82/275 (29.8%)
POF
Study groups Controls
Cryopreservation Strategies
1. EMBRYO CRYOPRESERVATION
2. OOCYTE CRYOPRESERVATION
3. OVARIAN TISSUE CRYOPRESERVATION
EMBRYO FREEZING
Results according to frozen time (years)
Embryo freezing programme I.U.DEXEUS n=2547 transfers
Frozen Time Pregnancy rate/transfer 5-7 years 16/44 36.4% 7-9 years 5/16 31.3% ≥9 years 5/8 62.5% d.n.s
< 5 years 835/2479 (33.68%) > 5 years 26/68 (38.2%)
1 baby born after 14 years of cryopreservation (emb-DON)
1 baby born after 10 years of cryopreservation
INSTITUT UNIVERSITARI DEXEUS
BIRTH OF A HEALTHY BOY 4 YEARS AFTER EMBRYO CRYOPRESERVATION IN A PATIENT WITH A BILATERAL BORDERLINE OVARIAN
TUMOUR
N.S.
Slow freezing and vitrification for
embryocryopreservation in oocyte donation
Solé M. et al. ESHRE Roma, 2010
87.391.4
73.9
83.0
52.6
41.2
34.1
21.1
0
10
20
30
40
50
60
70
80
90
100
%
Survival rate Viable
embryos
Pregnancy
rate
Implantation
rate
Variables
Comparison of variables between the two groups
Vitrification group
Slow-freezing group
OOCYTE CRYOPRESERVATION
Requisites:
- Postpubertal
- No contraindication for ovarian stimulation
-Time
Advantages:
- No need for partner or for accepting donor semen
Drawbacks:
- > 10 oocytes cryopreserved
-Slow freezing: Pregnancy rate per cryopreserved oocyte: 2%
Maltaris T et al, Breast Cancer Research 2008
Schattman G.L. et al, Placenta 2008; Maltaris et al, In vivo 2009
Slow freezing for Oocyte cryopreservation
Borini et al. RBM Online 15, 2. 175-181, 2007
Vitrification and Oocyte donation
Cobo A. et al Hum Reprod 2010;
DELIVERY RATE USING CRYOPRESERVED OOCYTES IS COMPARABLE TO CONVENTIONAL IN VITRO FERTILIZATION USING FRESH OOCYTES:
POTENTIAL FERTILITY PRESERVATION FOR FEMALE CANCER PATIENTS
James A. Grifo, M.D., Ph.D., and Nicole Noyes, M.D.
DESIGN: Twenty-three oocyte cryopreservation cycles were performed. Collected oocytes were cryopreserved by either the slow or the vitrification method. 1-4 months later, a programmed cycle of thawing/warming, fertilization with intracytoplasmic sperm injection, and ET was performed, cycle and pregnancy outcomes were assessed. PATIENT(S): Twenty-two infertile women. INTERVENTION(S): Oocyte cryopreservation. RESULT(S): Oocyte survival, 2-pronuclei fertilization, and blastocyst formation rates were 92%, 79%, and 43%, respectively. Fourteen women became pregnant; one miscarried; 10 have delivered 13 viable infants, and three pregnancies are ongoing for an ongoing/delivered pregnancy rate of 57%. This result was not statistically different from cycles performed consecutively in age-matched controls using fresh, nonfrozen autologus or donor oocytes during a similar time period.
Fertility and Sterility 2009
Letrozole (5 mgrs/día)
FSH r (150 UI/día)
Antag-GnRH A
-
G
n
R
H Letrozole (5 mgrs/día)
R
OVARIAN STIMULATION IN BREAST CANCER
PATIENTS
Dexeus Protocol
Oktay et al. RBM Online, 2010; 20: 783-788
GnRH agonist trigger for women with breast cancer
OVARIAN STIMULATION FOR FREEZING OOCYTES / EMBRYOS
From current data it does not seem that in certain cancers ovarian stimulation techniques increases the risk of recurrence.
Provide that the oncologist thinks that it is possible to delay the start of oncology treatment for 15-20 days.
Treatment must be started as soon as possible. If it is not in follicular phase, antagonists can be administered and stimulation started once oestradiol levels of less than 50 pg/ml have been reached.
Administration of letrozole, 5 mg for 5 days. Administration can be extended until low oestradiol levels have been reached. It can be administered throughout the stimulation phase.
Gonadotrophins (dose 150 IU FSH) starting on the day following letrozole.
Antagonists when the follicle ≥ 14 mm. diameter
Ovulatory discharge with GnRH agonists
Post-aspiration: administer letrozole or antagonists
Oocyte IVM for fertility preservation “McGill Reproductive Centre”
Holzer H. et al., “ In Vitro Maduration of Oocytes Basic science to clinical aplication”. 2007
Indications 1. Hormone- sensitive tumours 2. Patients reluctant to ovarian stimulation. 3. No time for IVF before starting oncological
therapy
Nb of Embryos replaced 69
Nb of Pregnancies 7
Pregnancies / OPU 7/38
(18.4%)
Pregnancies / ET 7/33
(21.2%)
Implantation rate 8/69
(11.6%)
C. González-Llagostera y col. ASEBIR 2007
IVM RESULTS IU DEXEUS
IVM / IVF for fertility preservation
Ata B. et al. Best Practice&Research Clinical Obstetrics and Gynaecology , 2010; 24: 101-112
IVM improves fertility preservation in breast cancer patients
Oktay K. et al. RBM Online 2010; 20: 634-638
IVM improves fertility preservation in breast cancer patients
Oktay K. et al. RBM Online 2010; 20: 634-638
OS group IVM group P value
Patients who underwent thawing and embryo transfer
38 20
Mature (MII) oocytes retrieved 399 6
Inmature (GV) oocytes retrieved 91 290
Oocyte maturation rate after IVM ( SD)
70.3 20.0 67.3 19.3 NS
Oocytes matured in vitro 64 209
MII oocytes vitrified and thawed (mean per patient SD)
463 (12.2 5.7) 215 (10.8 5.9) NS
Oocytes survived (mean % SD) 383 (81.4 22.6) 148 (67.5 26.1) <.001
Oocytes fertilized (mean % SD) 287 (75.6 22.5) 96 (64.2 19.9) <.05
Clinical pregnancy rate per cycle started (%)
17 (44.7) 4 (20.0) NS
Live-birth rate per cycle started (%)
15 (39.5) 4 (20.0) NS
CLINICAL OUTCOME FOLLOWING VITRIFICATION OF OOCYTES OBTAINED FROM OVARIAN STIMULATION (OS) AND IN VITRO
MATURATION (IVM) CYCLES
Ri-Cheng Chian et al.Fertil. Steril (2008)
TREATMENT OUTCOME
LUTEAL PHASE IVM
n=5
FOLLICULAR PHASE IVM
n=13 P value
No. of oocytes aspirated
12.8 ± 8.4 17.3 ± 13.5 NS
Range 3-26 4-44 NS
MII oocytes after 24h. 4.0 ± 5.7 4.5 ± 3.8 NS
Total MII oocytesa 7.0 ± 7.6 9.5 ± 7.73 NS
Maturation rate, % 48.6 ± 18.3 57.8 ± 29.2 NS
Fertilization rate, %b 69.2 ± 47.4 63.2 ± 27.3 NS
Mean total oocytes and embryos cryopreservation
6.4 ± 6.6 7.8 ± 7.5 NS
MAMAN E. et al (2011)
Fertility and Sterility 95:1, 64-67
Note: Data are mean ± SD unless otherwise specified a Total MII in 48 hours b From injected oocytes only
Laparoscopy: Removal of ovarian slices
14 babies born
Fragments of cortex
Avascular
transplantation
Vascular transplantation
Whole ovary
Follicles isolation
in vitro culture in vitro culture
No transmission of tumoral cells Reduces ischemia
OVARIAN CRYOPRESERVATION
Ovarian tissue cryopreservation: Results
SELECTION OF PATIENTS BEFORE AND AFTER ANTICANCER TREATMENT FOR OVARIAN CRYOPRESERVATION
Ronit Abir
Human Reproduction Vol.23, No.4 pp. 869-877, 2008
Methods: Eighteen cancer patients before chemotherapy and 23 others after chemotherapy participated in the study. Results: High numbers of preantral follicles were detected in ovaries of patients ≤20 years. No antral follicles were detected. All the follicles were viable and not apoptotic. Deterioration in follicular quality was observed after chemotherapy, manifested mainly as an increase in abnormal granulosa cell nuclei and in oocyte vacuolization. Conclusions: This study stresses the importance of prechemotherapy ovarian cryopreservation. However, the large number of viable, non-apoptotic follicles in ovaries of younger patients (age ≤20 years) indicates that ovarian cryopreservation might be considered even after treatment in this age group.
RESTORATION OF OVARIAN FUNCTION IN ORTHOTOPICALLY TRANSPLANTED CRYOPRESERVED OVARIAN TISSUE: A PILOT
EXPERIENCE
Jacques Donnez
RBM Online-Vol 16 No 5.2008 694-704
In this study, ovarian cortex was removed by laparoscopy from five women and cryopreserved before chemotherapy. Thawed fragments were then grafted to an orthotopic site in all five women. Two of them underwent a second reimplantation. The first signs of ovarian function restoration occurred between 16 and 26 weeks after reimplantation. There were no signs of disease recurrence in any patients with malignant disease.
The risk of ovarian metastasis according to cancer types
Cancers with low risk of ovarian involvement
Wilm’s tumour
Ewing’s sarcoma
Breast cancer
Stage I-III
Infiltrative ductal histological subtype
Non-Hodgkin’s lymphoma
Hodgkin’s lymphoma
Non-genital rhabdomyosarcoma
Osteogenic sarcoma
Squamous cell carcinoma of the cervix
Cancers with moderate risk of ovarian involvement
Adenocarcinoma/adenosquamous carcinoma of the cervix
Colon cancer
Breast cancer
Stage IV
Infiltrative lobular histological subtype
Cancers with high risk of ovarian involvement
Leukaemia
Neuroblastoma
Burkitt lymphoma
M. Sonmezer and K. Oktay 2004
Human Reproduction Update, 10-3 : 251-266
SEARCHING FOR EVIDENCE OF DISEASE AND MALIGNANT CELL CONTAMINATION IN OVARIAN TISSUE STORED FROM
HEMATOLOGIC CANCER PATIENTS
Dror Meirow
Human Reproduction Vol.23, No.5 pp. 1007-1013, 2008
Methods: Fifty-eight patients with hematological malignancies were referred for the storage of ovarian tissue for fertility preservation. Investigation included preoperative imaging and histological evaluation of fresh ovarian tissue. After thawing markers to detect minimal residual disease (MRD) were used. Results: Preoperative imaging detected disease in the ovaries (two patients). Conventional histology post-tissue harvesting did not disclose malignant cells (56 patients). However, highly sensitive real-time RT-PCR was positive in one CML patient. Conclusions: Preoperative imaging prevented operations and storage of tissue with cancer. Evaluation of stored ovarian tissue for MRD using sensitive markers is essential to increase safety and to prevent reimplantation of tissue with malignant cells.
Nº % Tipo Preservación
Tejido Ovárico
Embriones Ovocitos Tejido Ovárico
+ Ovocitos
56 31
(55,3%)
8 (14,3%)
16 (28,6%)
1 (1,8%)
Oncológicas 49 87,5% 29 (59%) 8 (16%) 12 (25%)
Hematológicas
•Linfoma de Hodgkin
•Linfoma No Hodgkin
•Leucemia
10
8
1
1
20%
6 (60%)
5
1
3 (30%)
2
1
1 (10%)
1
Ginecológicas
•Ca. de Mama
•Ca. de Endometrio
•Ca. de Ovario
•Ca. Cérvix
36
23
5
7
1
74%
22 (61%)
15
2
4
1
5 (14%)
4
1
9 (25%)
4
2
3
Neurológicos
•Ependimoma
•T. Cerebral
•Astrocitoma
3
1
1
1
6% 1 (33%)
1
2 (67%)
1
1
Médica No Oncológica 5 9% 2 (40%) 2 (40%) 1 (20%)
Endometriosis
Sind. Turner
Cardiopatía Congénita
3
1
1
1
1
1
1
1
Motivos Sociales 2 3,5% 2 (100%)
Fertility Preservation Programme Institut Universitari Dexeus
Strategies for fertility preservation
1. Reducing toxicity
2. Cryopreservation
3. Conservative surgery
Fertility sparing surgery
1. Ovarian cancer :
- Borderline tumours
- Invasive carcinoma stage Ia G1
2. Endometrial cancer: stage Ia G1, treatment MPA
3. Cervical cancer: < 2 cm’s, stages Ia – Ib1,
Querleu D et al, Bull Cancer 2008
Gurgan T et al, Placenta 2008
Fujiwara H et al, Hum Rep 2009
Ri-Cheng Chian et al. (2008)
Fertility preservation strategies offered to female cancer patients
Ovarian wedge resection or
oophorectomy
Chemotherapy cannot be delayed and/or hormonal
stimulation contraindicated
Chemotherapy can be delayed and hormonal
stimulation not contraindicated
Immature oocyte retrieval
from ovarian tissue
Ovarian tissue cryopreservation
Immature oocyte retrieval
In-vitro maturation (IVM) of oocyte
Male partner available (ICSI)
Embryo cryopreservation
No male partner available
Male partner available (ICSI)
No male partner available
Oocyte vitrification
Embryo cryopreservation
Oocyte vitrification
Ovarian stimulation (OS) Mature oocyte retrieval
ADVANTAGES AND DISADVANTAGES OF DIFFERENT METHODS OF FERTILITY PRESERVATION IN FEMALES
GIDONI Y. 2008
RBMonline 16-6:792-800
Future…
OPTIONS FOR PRESERVING FERTILITY
In women:
If ovarian stimulation is possible
Embryo cryopreservation is the method with the greatest chance of success (only possible if there is a partner or they accept banked semen)
Oocyte cryopreservation has now a promising future thanks to vitrification
If ovarian stimulation is not possible, there are various techniques:
Cryopreservation of ovarian tissue and later orthotopic autotransplant
Aspiration of antral follicles and in-vitro vitrification of mature oocytes
GnRH analogues for gonadal protection, though the results published to date are not conclusive.
In cases of abdominal radiotherapy: ovarian transposition
Conservative gynaecological surgery whenever possible
Jukkala A M. et al. Fertil Steril 2010
ACCESS OF ONCOLOGIC PATIENTS TO EARLY FERTILITY PRESERVATION
Older age Early-stage cancer • Factors favoring early referrals are Family history of cancer Academic center involvement
LEE S. et al (2011) Fertil.Steril. 95:1932-6
Early 30s White • Patients seen for fertility preservation tend to be Well educated Married
BALTHAZAR et al. (2011)
Fertil. Steril. 95:1913-6
DISCUSSING FERTILITY PRESERVATION
The authors conducted open-ended qualitative interviews with 24 pediatric oncologists from 13 of the 15 children’s cancer centers in Florida.
Most of the pediatric oncologists were aware of fertility preservation, but they did not think it was their role to fully explain the options in great detail; they agreed that they needed more information in order to provide better explanations for parents.
None of the pediatric oncologists had received any formal training in discussing fertility preservation with patients and families.
About half of the pediatric oncologists said they would like to learn more about fertility preservation.
About one-quarter of the pediatric oncologists considered fertility preservation to be a high-priority topic for discussion with newly diagnosed patients and their families.
About half believed parents were either uncomfortable discussing fertility preservation, or were so focused on treatment that they did not want to consider it.
PATIENT EDUCATION AND COUNSELING 14-2008
DISCUSSING FERTILITY PRESERVATION
Most physicians felt that girls were typically interested in discussing fertility and options for preservation. Half of boys were open to the conversation and interested in sperm banking, while the other half were embarrassed by the conversation.
None of the pediatric oncologists surveyed was aware of any guidelines on fertility preservation.
ONCOFERTILITY CONSORTIUM (2007-2010) 55 centres in USA
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