Fertility preservation nowdays

Dr Pirtea Paul

Chef de clinique

Department of Reproductive Medicine & Fertility Preservation

Hôpital Universitaire de Geneve

0

100

200

300

400

1950 1960 1970 1980 1990 2000 2008

Incidence males

Incidence females

Mortalité males

Mortalité females

Epidemiology

Pregnancy desire

Age of first pregnancy 30 years in France

Survivors more concerned about future fertility than age and

gravidity matched women

Ruddy et al., breast 2007

30% less toxic chemotherapy to help preserve fertility even at risk

of increased cancer recurrence (breast cancers)

Pison et al., Bull Cancer.2010

Partridge et al., J Clin Oncol 2004

Fertility after cancer is a major concern

Reproductive aging

Broekmans et al., Endocrine Reviews 2009

Dramatic decline of fecundity per cycle after 35 years

50 35

Age

Primordial follicles

Ovarian function after cancer treatment

Diagnosis

of breast cancer

Before chemotherapy After chemotherapy

Gonadal toxicity of treatments

Ovarian toxicity

High risk Moderate risk Low risk Undetermined

Cyclophosphamide

Cisplatine

Methotrexate

Irinotecan

Cholarambucil Adriamycine 5-Fluorouracil Imatinib

Melphalan

Busulfan

Ifosfamide

Procarbazine

Paclitaxel Vincristine

Actinomycin D

Bleomycine

Thiotepa

Donnez et al., Hum Reprod Update 2006

Type of chemotherapy Risk of gonadotoxicity

Gonadal toxicity of treatments

Ovarian tissue fibrosis

Apoptosis of primordial and primary follicles

Vascular damage

Follicular activation: burn-out

Oktay et al., Cancer Treat Rev 2012

Blumenfeld et al., Best Pract Res Clin Obstet Gynaecol. 2012

9 ovary

Primordial follicle pool - reduced

Meirow and Gosden 1998, Oktem and Oktay 2007

Growing follicles – destroyed

Utsunomiya 2008, Bar-Joseph 2010

Stromal effect

(Meirow, 2007)

Chemotherapy effect on the ovary

Effects of chemotherapy on growing follicles

Pathology Animals Reference

Abortions

Gross malformations

Mice Meirow et al., Hum Reprod 2000

Dramatic reduced ovulation

Apoptosis

Mice Ben Aharon et al., Reprod. Biol. Endocrinol. 2010

Apoptosis

Disintegration of chromosomes

Mice Bar Joseph et al., Reprod. Toxicol.2010

Malformations

Chromosomal abnormalities

Mice Kujjo et al., Plos One 2011

Growing follicles apoptosis Mice Kalich-Philisoph et al., Science trans. Med. 2013

Reproduction post recent chemotherapy

Very low /No response post recent chemotherapy

Alarming animal studies:

Chromosomal abnormalities

Abortions

Malformations

We do not collect mature or immature eggs for fertility preservation in

patients recently exposed to chemotherapy (6 months)

Reproduction post recent chemotherapy

Clinical implications

Chung et al., Fertil. Steril. 2013

Cyclophosphamide triggers follicular activation:

ovarian reserve burn out

PBS Cy

TUNEL staining

PBS Cy

8 week mice 5 day mice

Follicular burn out

Cy induces primordial follicular loss but no apoptosis

Follicular burn out

Ratio of growing/non growing follicles with different doses of Cy

Age

Ovarian

follicular

status

Sensitivity /

chemo

Type of cancer

Chemo

regimens

Doses of

chemo

Ovarian function

after cancer treatments

Predicting ovarian function after cancer treatments remains a challenge

Fertility in breast cancer survivors

Incidence of pregnancies

8% in women < 35 years

Blakely et al., Cancer 2004

6% % in women < 40 years

Oven Ustaalioglu et al., J BUON 2011

3% % in women < 45 years

Mueller et al., Cancer 2004

173 live births in 5725 women < 45 years (3%)

Kroman et al., Lancet 1997

Lutchman Singh et al., Br J Cancer 2007

FSH

AMH

AFC Ov. vol

Premature ovarian failure after CT

• Anderson et al., JCEM 2011

All women with AMH < 1.9 ng/ml became amenorrheic

Women with ongoing menses had higher AFC

AMH can predict long-term ovarian

activity after chemotherapy

Premature ovarian failure after CT

Poor ART outcome in cancer survivors

Barton et al., Fertil Steril 2012

Premature ovarian failure after CT

Quality of life

Ovarian tissue

cryopreservation

Oocyte

cryopreservation

Embryo

cryopreservation Medical

treatments

Ferility preservation

Secondary

Antral

Preovulatory

Initial recruitment

Cyclic recruitment

FSH

Atretic

Folliculogenesis

Primordial

Ovarian physiology

Antral follicles Preovulatory follicles

Serum E2 levels

Exogenous FSH

administration

About 10 days

Controlled ovarian hyperstimulation

GnRH antagonist protocol

Exogenous FSH

4 8 1 2

GnRH antagonists 0.25 mg/d

3 5 6 7 9 10 11 12

GnRHa

GnRH antagonist protocol

Random start

Exogenous FSH

GnRH antagonists 0.25 mg/d

Spontaneous

LH surge

GnRHa

Oophorectomy

Ovarian tissue cryopreservation

Orthotopic ovarian tissue transplantation

Heterotopic ovarian tissue transplantation

Live birth rate : 23%

Ovarian tissue

cryopreservation / transplantation

Risk of micrometastasis (Leukemia, Neuroblastoma, Burkitt lymphoma, breast cancers)

Ovarian tissue transplantation

Dolmans et al, Fertil. Steril., 2013

Ovarian involvement in patients

with acute leukemia

Transplantation

not advised

Dolmans et al, Fertil. Steril., 2013

Risk of ovarian involvement

in different types of cancer

Ovarian stimulation

aromatase inhibitors

Oktay et al., J. Clin. Oncol. 2005

Exogenous FSH

GnRH antagonists

GnRHa

Letrozole 5 mg

1 2 3 4 5 6 7 8 9 10 11 12

IVM. History

1930s: in vivo and in vitro maturation of mammalian oocytes

Pincus & Enzmann, Journal of experimental Medicine, 1935

Pincus & Saunders, Ann Rec, 1939

First pregnancy after IVM of oocyte « rescued » from an IVF cycle

Veek et al., Fertil Steril 1983

First pregnancy after IVM of oocyte in an oocyte recipient

Cha et al., Fertil Steril 1991

First pregnancy after IVM of oocyte in a PCOS patient

Chian et al., Fertil Steril 1994

Rational

Avoid potentiel side effects of COH

OHSS

Weight gain

Breast tenderness

Mood swing

Cost

PCOS

Cycle d1

ICSI

10.000 UI hCG

Oocyte retrieval

d0 d1 d3

ET

Monitoring

d2

ICSI

Protocol

17-β estradiol

No controlled ovarian stimulation

No increased serum E2 levels

No time requirements

An alternative approach for fertility preservation

IVM & Fertility Preservation

In vitro maturation of oocytes

H u m a n R p r o c l u e t i o n . V o l . 2 9 , No. '2 p p . 2 7 6 - 2 7 6 . 2 0 1 4

9, 20 3 dot.10. 1093/h11nrep/det420

human

rep rod uction

Firs t p r e g n a n c y a n d ive b i r th r e s u l t i n g

f r o m c r y o p r e s e r v e d e m b r y o s o b t a i n e d

f r o m in vitro m a t u r e d o o c y t e s a f t e r

o o p o r e c t o m y in a n o v a r i a n c a n c e r

p a t i e n t

E.B. P r a s a t h 1•4• , M . L . H . C h a n 1 , W. H . W. W o n g 1 , C . J . W. · m 1 ,

M . D . T h a r m a l i n g a m 1 , M . H e n d r icks 1 • 4 • 5 , S.F. Loh •.2.,c.5 , a n d Y.N. ChiaJ..6

Oncofertility counseling

Assessment of the follicular ovarian status

AFC + Serum AMH levels

Neoadjuvant chemotherapy Adjuvant chemotherapy No chemotherapy

Urgent FP Non urgent FP Non urgent FP

IVM

±

OTC

Ovarian stimulation (Natos?)

Or

IVM if contraindication to COH

Ovarian stimulation (Natos?)

Or

Several IVM cycles ?

Strategy of FP

in cancer patients

Perspectives

Limiting the indications of gonadotoxic treatments

Limitic the treatment gonadotoxicity

Predicting post chemotherapy ovarian function

Developing fertility biomarkers and markers of the oocyte quality

Improving FP techniques

Providing an individualized Recurrence Score® result that assesses

the benefit of chemotherapy and the likelihood of breast cancer recurrence.

Limiting the indications

of gonadotoxic treamtents

Oncotype DX®

Limiting the burn out

Limiting the gonadal toxicity

of chemotherapy

Genetic polymorphisms?

… aiming to be more discriminant in the indications of FP

Predicting post chemotherapy

ovarian function

Fertility and oocyte quality markers

Improving FP techniques

Protocols of ovarian stimulation

IVM technique

Cryopreservation techniques

Ovarian tissue grafting

Detection of micrometastasis within the frozen ovarian tissue

In vitro folliculogenesis

Improving existing

techniques

Developing new

techniques

- Surgery techniques

- Vitrification

- Vascularization (VEGF,…)

- Follicle loss (S1P,..)

-Malignant cell detection

- In vitro follicle growth

-Atrificial ovary

Ovarian tissue

Donnez and Dolmans, NRE 2013

63

Artificial ovary

Follicle isolation

Seeding in the fibrous

scaffold

Follicle after seeding

and adhesion

Scaffold to graft isolated follicles

Scaffold Transplantation

to the patient

Ovary

Scaffold to graft isolated follicles

Hum.an Reproduction U pd . Vol.21, No.l pp.285-296, lO tS

:lion o n 21 ,2015 dol:10.1093/humupd/dn"NOO I

human

r ,eproduction update

Artit·ci al gametes: a systematic review

of biological progress towards clin·cal

appl·cation

Saskia Hendriks1,Eline A.F.Dancet 1• 2 ,Ans M.M.van Pelt 1,

Geer t Hamer ' , and Sjoerd Repping l :

Articles

Livebi rth after uterus transplantation