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Fertility preservation in women: exploring clinical dilemmas

Dahhan, T.

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Citation for published version (APA):Dahhan, T. (2016). Fertility preservation in women: exploring clinical dilemmas.

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FERTILITY PRESERVATION IN WOMEN:

EXPLORING CLINICAL DILEMMAS

FERTILITY

PRESER

VATIO

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N SABRA DAHHAN

FERTILITY PRESERVATION IN WOMEN:

EXPLORING CLINICAL DILEMMAS

SABRA DAHHAN

Fertility preservation in women: exploring clinical dilemmas

PhD-thesis, University of Amsterdam, The Netherlands

© 2016 Taghride Dahhan

All rights reserved. No parts of this publication may be reproduced in any form

without permission of the author.

The printing of this thesis was supported by: Stichting gynaecologische endocri-

nologie en kunstmatige voortplanting, Amsterdam

Cover: Sabra Dahhan

-BZ�PVU��#FćMà�,BSBIBO�BOE�%FOJ[�,BSBNBO

Printed by: Gilde Print Drukkerijen

ISBN: 978-94-6233-211-9

Academisch proefschrift

ter verkrijging van de graad van doctor aan

de Universiteit van Amsterdam

PQ�HF[BH�WBO�EF�3FDUPS�.BHOJmDVT

prof. dr. D.C. van den Boom

ten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Aula der Universiteit

op vrijdag 12 februari 2016, te 13:00 uur

door

Taghride Dahhan

geboren te Amsterdam

FERTILITY PRESERVATION IN WOMEN: EXPLORING CLINICAL DILEMMAS

Promotiecommissie

Promotores:

Copromotores:

Overige leden:

Faculteit der Geneeskunde

Prof. Dr. F van der Veen Prof. Dr. S.C. Linn

Universiteit van Amsterdam Universiteit van Utrecht

%S��.��(PEEJKO Dr. E.A.F. Dancet

Universiteit van Amsterdam Universiteit van Amsterdam

Prof. Dr. C.B. Lambalk Vrije Universiteit Amsterdam1SPG��%S��4��3FQQJOH Universiteit van Amsterdam1SPG��%S��"�.��4UJHHFMCPVU Universiteit LeidenDr. D. Stoop Vrije Universiteit Brussel%S��.�1��WBO�EFO�5PM Vrije Universiteit Amsterdam

Voor mijn ouders

Contents

Chapter 1 General introduction and outline of the thesis 10

Chapter 2 Fertility preservation: a challenge for IVF-clinics 28

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#BMLFOFOEF �'��WBO�EFS�7FFO �&�"�'��%BODFU �.��(PEEJKO

Eur J Obstet Gynecol Reprod Biol 2015; 194:78-84.

Chapter 3 A prospective case series of women with estrogen receptor- 50

positive breast cancer: levels of tamoxifen metabolites in

controlled ovarian stimulation with high-dose tamoxifen

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Human Reproduction 2013; 28:953-9.

Chapter 4 Tamoxifen or letrozole versus standard methods for women 68

with estrogen-receptor positive breast cancer undergoing

oocyte or embryo cryopreservation in assisted reproduction

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.��(PEEJKO�

Cochrane Database Systematic Reviews 2013; 11:CD010240.

Chapter 5 Stimulation of the ovaries in women with breast cancer 94

undergoing fertility preservation: alternative versus standard

stimulation protocols; the study protocol of the STIM-trial

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Submitted

Chapter 6 The experiences of women with breast cancer who undergo 108

fertility preservation

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Submitted

Chapter 7 Reproductive choices and outcomes after freezing oocytes 128

for medical reasons: a follow up study

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Human Reproduction 2014; 29:1925-30.

Chapter 8 General discussion 144

Chapter 9 Summary 154

Chapter 10 Samenvatting 164

Appendices

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List of publications 180

Portfolio 182

Dankwoord 186

Curriculum Vitae 190

C H A P T E R 1General introduction

CHAPTER 1

10

Discovery of chemotherapy

Curing cancer by chemotherapy is marked as one of the greatest achievements in mod-

FSO�NFEJDJOF��5IF�mSTU�DIFNPUIFSBQFVUJD�BHFOU�UP�CF�EJTDPWFSFE�XBT�OJUSPHFO�NVT-

UBSE��5IJT�EJTDPWFSZ�IBE�JUT��VHMZ��CFHJOOJOHT�JO�8PSME�8BS�*�XIFO�JU�XBT�PCTFSWFE�

that soldiers who were gassed with mustard gas had destroyed cell-lines in their bone

NBSSPX�,SVNCIBBS�BOE�,SVNCIBBS ��

%VSJOH�UIF�4FDPOE�8PSME�8BS �XJUI�DIFNJDBM�XBSGBSF�MBZJOH�PO�UIF�MVSF �BO�FYUFOTJWF�

search for information on the effects of war gases was undertaken – mustard gas in

particular, because this war gas could circumvent protection by chemical masks. A US

nFFU �TFDSFUMZ�DPOUBJOJOH�B�TIJQNFOU�PG�NVTUBSE�HBT �XBT�TVOL�BGUFS�B�(FSNBO�SBJE�JO�

#BSJ�JO��DBVTJOH�BDDJEFOUBM�TQJMM�PG�UIF��UPOT�PG�NVTUBSE�HBT�PO�CPBSE��.FEJDBM�

reports showed low white blood cells counts in the blood of the sailors after the at-

UBDL�"MFYBOEFS ��5IF�EFTUSVDUJWF�FGGFDUT�PG�NVTUBSE�HBT�PO�CMPPE�DFMMT �BMSFBEZ�

PCTFSWFE�JO�8PSME�8BS�*�XFSF�UIFSFCZ�DPOmSNFE�

"T�QBSU�PG� UIF�64�NJMJUBSZ� SFTFBSDI�QSPHSBN� JO�� 8JOUFSOJU[ �XIP�IBE� TUVEJFE�

NVTUBSE�HBT�JO�8PSME�8BS�* �BTLFE�UXP�QSPNJOFOU�:BMF�QIBSNBDPMPHJTUT �(JMNBO�BOE�

(PPENBO �UP�XPSL�UPHFUIFS�JO�DBSSZJOH�PVU�FYQFSJNFOUT�UP�mOE�PVU�XIFUIFS�OJUSPHFO�

mustard might also halt malignant proliferation of white blood cells that occur in pa-

UJFOUT�XJUI�MFVLFNJB�PS�MZNQIPNB��5IJT�SFTFBSDI�QSPHSBN�XBT�DMBTTJmFE�BT�AUPQ�TFDSFU��

because of the secrecy associated with war gas programs so results were not published

until 1946. Findings included marked regressions of lymphoid tumor in mice treated

with nitrogen mustard and were so convincing that thoracic surgeon Lindskog ad-

ministered nitroHFO�NVTUBSE�UP�B�QBUJFOU�XJUI�OPOo)PEHLJO�T� MZNQIPNB �SFTVMUJOH�

in marked regression of disease (Gilman 1946; Goodman et al., 1946; Gilman Science

��"GUFS� UIFTF�QVCMJDBUJPOT � TFWFSBM� SFMBUFE�BMLZMBUJOH�BHFOUT � TVDI�BT�CVTVMQIBO�

BOE�DZDMPQIPTQIBNJEF�XFSF�TZOUIFTJ[FE�BOE�UFTUFE��

Discovery of gonadotoxic side effects of chemotherapy

Busulphan, an alkyl sulfonate drug that acts as a bifunctional alkylating agent in the

TBNF�NBOOFS�BT�OJUSPHFO�NVTUBSE�EPFT �XBT�mSTU�EFTDSJCFE�BT�B�QPUFOUJBMMZ�FGGFDUJWF�

USFBUNFOU�GPS�DISPOJD�NZFMPJE�MFVLFNJB�JO��)BEEPX�BOE�5JNNJT ��"MTP�JO�

1953, Bollag, a clinician in Switserland, observed that menses ceased in a 42-year old

woman after treatment with busulphan. To further investigate this observation, he

performed histological examination in ovaries of rats treated with busulphan, which

GENERAL INTRODUCTION

11

SFWFBMFE�BUSPQIJD�PWBSJFT�#PMMBH ��#BTFE�PO�UIFTF�mOEJOHT �UIF�$[FDIPTMPWBLJBO�

researcher Belohorsky performed histological examination of the ovary of a 32-year

old woman whose menses ceased after treatment with busulphan, which showed de-

pletion of follicles (Belohorsky et al� ��

Discovery of combination chemotherapy and its long-term side effects on the men-

strual cycle

Cyclophosphamide, also a nitrogen mustard alkylating agent, was approved by the

64�'PPE�BOE�%SVH�"ENJOJTUSBUJPO�'%"�JO��&NBEJ �+POFT�et al. ��JO�BO�FSB�

full of skepticism surrounding the clinical usefulness of chemotherapy because of

its harsh side effects and low effectivity in improving survival (Zubrod et al� ��/FWFSUIFMFTT � UIF�XFBMUIZ� QIJMBOUISPQJTU�.BSZ�-BTLFS�XBT� JNQSFTTFE� CZ� UIF� EBUB�

on chemotherapy in childhood leukemia, and had been urging the US Congress to

provide funds to set up a cancer research program. She played an important role

in the foundation of the National Service Center Cancer Chemotherapy in 1955, a

semi-political program that gave rise to a multibillion-dollar cancer pharmaceutical

industry.

One of the greatest achievements of the program was the discovery that series of a

cyclically administered combination of nitrogen mustard with vincristine, procar-

CBNB[BQJOF �BOE�QSFEOJTPOF�.011�DIFNPUIFSBQZ�GPS�)PEHLJO�T�EJTFBTF�SFTVMUFE�

in remission rates of up to 80 % (Devita et al� ��5IJT�MFE�UP�UIF�CBTJD�DPODFQU�UIBU�

chemotherapy could cure cancer.

Clinicians began to use combination chemotherapy in advanced breast cancer in the

MBUF��T �BOE�UIF�$.'�QSPHSBN�DZDMPQIPTQIBNJEF �NFUIPUSFYBUF�BOE��nVPSBDJM�

showed an impressive overall response rate of over 50% (Canellos et al� ��&O-

UIVTJBTN�GPS�DMJOJDBM�VTF�PG�$.'�XBT�GVSUIFS�FODPVSBHFE�CZ�QPTJUJWF�SFTVMUT�PG�#PO-

OBEPOOB�T�$.'�TUVEZ�JO�UIF�/FX�&OHMBOE�+PVSOBM�PG�.FEJDJOF�JO��#POBEPOOB�

et al. �� QVCMJTIFE�POF�ZFBS�BGUFS�UIF�BOOPVODFNFOU�UIBU�CPUI�UIF�XJGF�PG�UIF�

QSFTJEFOU�PG�UIF�6OJUFE�4UBUFT �#FUUZ�'PSE �BOE�UIF�XJGF�PG�UIF�WJDF�QSFTJEFOU �)BQQZ�

3PDLFGFMMFS �XFSF�EJBHOPTFE�XJUI�CSFBTU�DBODFS��

#POOBEPOOB�T�TUVEZ�BMTP�SFQPSUFE�UIBU�IBMG�PG�UIF�QSFNFOPQBVTBM�XPNFO�JO�UIFJS�

study ceased menstruating during chemotherapy and they remarked that long-term

TJEF�FGGFDUT�TIPVME�CF�UBLFO�JOUP�BDDPVOU�XIFO�BENJOJTUFSJOH�$.'�SFHJNFOT��5IJT�

XBT� JO� MJOF�XJUI�mOEJOHT�GSPN�POF�ZFBS�FBSMJFS�UIBU��PVU�PG�UIF��XPNFO�XIP�

had received cyclophosphamide for non-malignant disease (glomerulonephritis and

CHAPTER 1

12

SIFVNBUPJE�BSUISJUJT�IBE�TZNQUPNT�PG�PWBSJBO�GBJMVSF�BOE�UIBU�PWBSJBO�CJPQTJFT�JO�

six of tIFN�TIPXFE�BCTFODF�PG�QSJNPSEJBM�GPMMJDMFT�8BSOF�et al. ��4FWFSBM� BVUIPST� BU� UIBU� UJNF�FNQIBTJ[FE� UIF�OFFE� UP� JOGPSN�XPNFO�PO� UIF� SJTL�PG�

QSFNBUVSF�PWBSJBO�JOTVGmDJFODZ�BT�BO�BEWFSTF�PVUDPNF�PG�SFHJNFOT�DPOUBJOJOH�DZDMP-

phosphamide (Chapman et al. ��8BSOF�et al. �� CVU�XBZT�UP�QSFTFSWF�GFSUJMJUZ�

were remote at that time.

Discovery of freezing oocytes

*O�� 8IJUUJOHIBN�QVCMJTIFE� B� HSPVOE�CSBLJOH�QBQFS� JO�XIJDI�IF� TIPXFE� UIBU�

NJDF�PPDZUFT�DPVME�CF�GSP[FO �UIBXFE�BOE�GFSUJMJ[FE�8IJUUJOHIBN ��0OF�EFD-

BEF�MBUFS �UIF�XPSME�DBNF�UP�IFBS�PG�UIF�mSTU�POHPJOH�IVNBO�oUXJO��QSFHOBODZ�BGUFS�

DSZPQSFTFSWBUJPO�PG�PPDZUFT�$IFO ��8IJUUJOHIBN�OPS�$IFO�NFOUJPOFE�UIF�BQ-

plicability of this technique for women at risk of sterility because of radio- and/or

chemotherapy in their key papers.

*U�XBT�7BO�6FN�FU�BM��XIP �XIFO�SFQPSUJOH�PO�UIF�TFDPOE�MJWF�CJSUI�GPMMPXJOH�GSFF[-

JOH� PG� PPDZUFT� JO� �� XSPUF� UIBU� ADSZPQSFTFSWBUJPO� PG� PPDZUFT�NJHIU� JNQSPWF� UIF�

prospects of fertility in young women scheduled to be treated by chemotherapy or

SBEJPUIFSBQZ�GPS�DBODFS��WBO�6FN�et al� ��5IJT�TUVEZ�XBT�UIF�mSTU�UP�NFOUJPO�UIF�

DPODFQU�PG�GFSUJMJUZ�QSFTFSWBUJPO�GPS�XPNFO�XJUI�DBODFS��.FBOXIJMF �UIF�TUSVHHMF�UP�

overcome cryobiological problems to make cryopreservation of oocytes a clinically ap-

plicable procedure for women with cancer was ongoing.

5IF�mSTU�IVSEMF�CFDBNF�NBOJGFTU�BU�UIF�JODFQUJPO�PG�PPDZUF�GSFF[JOH �XIFO�UIF�NJDF�

PPDZUFT� �GSP[FO�XJUI�EJNFUIZMTVMQIPYJEF�%.40�BOE�TUPSFE�VOEFS�MJRVJE�OJUSPHFO�

BU�o��¡$ �TIPXFE�MPXFS�GFSUJMJ[BUJPO�SBUFT�UIBO�UIPTF�PG�GSFTI�PPDZUFT�8IJUUJOHIBN �

��.FNCSBOF�EBNBHF�DBVTFE�CZ�GSFF[JOH�BOE�UIBXJOH�XBT�TVHHFTUFE�BT�B�QPTTJCMF�

FYQMBOBUJPO��*U�XBT�MBUFS�DPOmSNFE�UIBU�GSFF[JOH�JOEVDFE�IBSEFOJOH�PG�UIF�[POB�QFMV-

DJEB �XIJDI�FYQMBJOFE�MPX�GFSUJMJ[BUJPO�SBUFT�$BSSPMM�et al� ��+PIOTPO�et al., 1988;

Vincent et al� ��/PU�POMZ�UIF�[POB�QFMMVDJEB �CVU�BMTP�UIF�NFJPUJD�TQJOEMF�JOTJEF�UIF�PPDZUF�XBT�UBSHFU-

ed by cooling injury (Pickering et al., 1990; Sathananthan et al� ��"MTP �JODSFBTFE�

QPMZQMPJEZ�XBT� GPVOE�XIFO� GSP[FO�UIBXFE� PPDZUFT�XFSF� GFSUJMJ[FE� #PVRVFU� et al., 1992; Carroll et al., 1989; Glenister et al� ��(JWFO�UIF�MPX�TVDDFTT�SBUFT�BDIJFWFE�CZ�NBUVSF�PPDZUF�GSFF[JOH �UIF�QPUFOUJBM�CFOFmUT�

PG�JNNBUVSF�PPDZUF�GSFF[JOH�XFSF�FYQMPSFE �CVU�UIJT�UFDIOJRVF�XBT�TPPO�BCBOEPOFE�BT�

WFSZ�MPX�OVNCFST�PG�GFSUJMJ[FE�PPDZUFT�SFBDIFE�EFWFMPQNFOUBM�TUBHFT�WJBCMF�GPS�FNCSZP�


13

transfer (Son et al� ��.BOEFMCBVN�et al. ��5IFTF�EJTBQQPJOUJOH�SFTVMUT�GPSDFE�

SFTFBSDI�HSPVQT�UP�SF�JOWFTUJHBUF�UIF�QSPCMFNT�FODPVOUFSFE�JO�NBUVSF�PPDZUF�GSFF[JOH��

By the mid-1990s, Gook et al. booked success in overcoming the problem of hardened

[POBF�CZ�QFSGPSNJOH�*$4*�JO�TMPX�GSP[FO�NFUBQIBTF�**�PPDZUFT�VTJOH�� QSPQBOFEJPM�

130)�BT�B�DSZPQSPUFDUBOU� (PPL�et al� � ��1PSDV�FU�BM�� GPMMPXFE�UIJT�BQQSPBDI�

BOE�XFSF�UIF�mSTU��BGUFS�B�IJBUVT�PG�BMNPTU��ZFBST��UP�SFQPSU�PO�B�IVNBO�MJWF�CJSUI�

BGUFS�QFSGPSNJOH�*$4*�PO�GSP[FO�UIBXFE�PPDZUFT�1PSDV �'BCCSJ et al� ��'PS�UIJT�live birth, 12 oocytes had to be thawed, of which only 4 survived the thawing process

�� -PX�TVSWJWBM�SBUFT�BGUFS�UIBXJOH�SFNBJOFE�UIF�NBKPS�QSPCMFN�BT�JMMVTUSBUFE�CZ�

the fact that the same research group obtained only six live births out of more than 700

oocytes thawed (Porcu et al� ��$PNQBSBCMF�EJTBQQPJOUJOH�SFTVMUT�XFSF�SFQPSUFE�CZ�

Tucker et al., who had to thaw almost 400 oocytes to achieve one live birth (Tucker et al� ��%FTQJUF�BMM�UIFTF�PCTUBDMFT �-FUVS�,POJSTI�FU�BM��XFSF�UIF�mSTU�UP�SFQPSU�UP�IBWF�DSZPQSF-

TFSWFE�PPDZUFT�GPS�B�XPNBO�XJUI�DBODFS�-FUVS�,POJSTDI�et al� ��*O�UIFJS�DPIPSU�PG�

��XPNFO�XJUI�DBODFS ��XPNFO�GSP[F�FNCSZPT�BOE�POF�XPNBO�GSP[F�PPDZUFT�CFDBVTF�

she had no male partner. The authors fail to mention what type of cancer she had, what

UZQF�PG�GSFF[JOH�QSPUPDPM�UIFZ�VTFE�BOE�XIBU�UIF�GPMMPX�VQ�XBT��

So, clinicians had no options other than to either watch how women started cancer

treatment that would leave them sterile, or to offer them cryopreservation of oocytes

XJUI�JUT�MPX�FGmDJFODZ��

Towards clinical applicability of freezing oocytes

5IF�OFFE�UP�FTUBCMJTI�BO�FGGFDUJWF�QSPUPDPM�GPS�GSFF[JOH�PPDZUFT�XBT�OPU�POMZ�QSFTTJOH�

because of women with cancer who had to undergo fertility-threatening treatment,

CVU�BMTP�CFDBVTF�PG�UIF�DPOUSPWFSTJFT�BCPVU�GSP[FO�FNCSZP�T �JODMVEJOH�FUIJDBM�BOE�MF-

gal issues (Bankowski et al. ��3PCFSUTPO ��,VMFTIPWB�FU�BM��FYQMPSFE�VMUSBSB-

QJE�DPPMJOH�PG�PPDZUFT �B�UFDIOJRVF�DBMMFE�AWJUSJmDBUJPO��*O�UIJT�QSPDFEVSF �GPSNBUJPO�

of intracellular ice is avoided and the damaging effects of osmosis that occur during

DPPMJOH�BOE�UIBXJOH�BSF�EJNJOJTIFE��"�UPUBM�PG��PPDZUFT�XFSF�WJUSJmFE�JO�GPVS�XPN-

FO�XIP�BHSFFE�UP�IBWF�UIFJS�TVSQMVT�PPDZUFT�WJUSJmFE�JOTUFBE�PG�UIFJS�FNCSZPT��0VU�

PG�UIFTF��PPDZUFT ��TVSWJWFE�UIBXJOH�BGUFS�WJUSJmDBUJPO��BOE�BGUFS�*$4*�mWF�

QSPOVDMFBS�[ZHPUFT�XFSF�PCUBJOFE��5ISFF�FNCSZPT�XFSF�USBOTGFSSFE�JO�UISFF�XPNFO �

resulting in POF�MJWF�CJSUI�,VMFTIPWB�et al. ��#Z�� SFTFBSDIFST�JO�+BQBO�SFQPSUFE�SFNBSLBCMF�IJHI�TVSWJWBM��BOE�GFSUJMJ[BUJPO�SBUFT�

CHAPTER 1

14

PG�WJUSJmFE�PPDZUFT�PG�VQ�UP��VTJOH�UIF�TP�DBMMFE� A$SZPUPQ��NFUIPE��*O�UIF�$SZP-

UPQ�NFUIPE �PPDZUFT�BSF�XBTIFE�JO�WJUSJmDBUJPO�TPMVUJPO�BGUFS�FRVJMJCSBUJPO��5IFO�UIFZ�

BSF�QJDLFE�VQ�JOEJWJEVBMMZ�JO�BO�FYUSFNFMZ�TNBMM�WPMVNF�PG�WJUSJmDBUJPO�TPMVUJPO�BOE�

QMBDFE�PO�UPQ�PG�B�QPMZQSPQZMFOF�TUSJQ�DSZPUPQ �XIJDI�JT�BUUBDIFE�UP�B�QMBTUJD�IBOEMF��

As soon as the oocyte is placed on top of the cryotop, the oocyte is plunged into liquid

OJUSPHFO�,VXBZBNB�et al. ��5IF�UFDIOJRVF�SFTVMUFE�JO�IJHI�TVSWJWBM�BOE�GFSUJMJ[B-

UJPO�SBUFT�BGUFS�UIBXJOH�BOE�XBT�TVHHFTUFE�UP�SFTPMWF�UIF�MPOH�MBTUJOH�FGmDJFODZ�QSPC-

MFNT�PG�GSFF[JOH�IVNBO�PPDZUFT�,BUBZBNB�et al. ��4JODF�UIFO �DPOTJTUFOUMZ�IJHI�

TVSWJWBM�SBUFT�IBWF�CFFO�SFQPSUFE�GPMMPXJOH�WJUSJmDBUJPO�PG�NFUB�QIBTF�**�PPDZUFT�BOE�

UIF�BWBJMBCMF�FWJEFODF�TVHHFTUT�UIBU�WJUSJmDBUJPO�JT�DVSSFOUMZ�UIF�NFUIPE�PG�DIPJDF�GPS�

cryopreservation of meta-phase II oocytes (Glujovsky et al.,��Now that there were fertility preserving options for women with cancer who did not

IBWF�UIF�PQUJPO�PS�XJTI�UP�QSFTFSWF�FNCSZP�T �UIF�"NFSJDBO�4PDJFUZ�GPS�$MJOJDBM�0ODPM-

PHZ�"4$0�JTTVFE�GFSUJMJUZ�QSFTFSWBUJPO�HVJEFMJOFT�GPS�IFBMUI�DBSF�QSPWJEFST�JO�DBODFS�

in 2006 (Lee et al. ��5IFTF�HVJEFMJOFT�NFOUJPOFE�UIF�OFFE�UP�EJTDVTT�GFSUJMJUZ�SFMBU-

ed side effects of cancer treatment and referral to centers where fertility preservation

can be performed.

In conclusion from then till now

-PPLJOH�CBDL�JO�UJNF �XIFO�64�QSFTJEFOU�/JYPO�EFDMBSFE�AUIF�XBS�PO�DBODFS��JO��

one could not have envisioned that 35 years later, due to increased survival after cancer

treatment, the focus would shift towards the quality of life for cancer survivors.

8JUI�SFHBSE�UP�UIF�IJTUPSJD�DPMMJTJPO�PG�SFQSPEVDUJPO�BOE�DBODFS�TVSWJWBM �POF�NJHIU�

OPUJDF�UIBU�UIF�DPODFQU�PG�GSFF[JOH�PPDZUFT�BT�B�NFBOT�UP�QSFTFSWF�GFSUJMJUZ�GPS�XPNFO�

with cancer was not designed beforehand, but somehow emerged naturally after the

UFDIOJDBM�ESBXCBDLT�PG�GSFF[JOH�PPDZUFT�XFSF�PWFSDPNF��*O�UIF�TBNF�GBTIJPO �PUIFS�

JOEJDBUJPOT�GPS�GSFF[JOH�PPDZUFT�BSPTF �TVDI�BT�B�SJTL�PG�QSFNBUVSF�PWBSJBO�JOTVGmDJFODZ�

10*�CFDBVTF�PG�HFOFUJD�QSFEJTQPTJUJPO�PS�PWBSJBO�TVSHFSZ �PS�UIF�XJTI�UP�EFGFS�NPUI-

FSIPPE�GPS�PUIFS�TP�DBMMFE�AOPO�NFEJDBM��SFBTPOT�

Towards the future

"4$0�T�SFDPHOJUJPO�JO��UIBU�GFSUJMJUZ�QSFTFSWBUJPO�JT�BO�JOUFHSBM�QBSU�PG�UIF�DBSF�GPS�

young patients with cancer can be considered a milestone in the evolution of cancer

USFBUNFOU��*O��UIF�"NFSJDBO�4PDJFUZ�GPS�3FQSPEVDUJWF�.FEJDJOF�"43.�SFNPWFE�


15

UIF�FYQFSJNFOUBM�DPOOPUBUJPO�PG� GSFF[JOH�PPDZUFT� 1GFJGFS�et al.,� ��5IJT�PQFOFE�

the gate for clinics to offer this procedure to any woman at risk for therapy- or dis-

ease-induced POI and for women wishing to defer motherhood for other reasons. As

a consequence, we now need studies that investigate the clinical implications of the

procedure.

Background of this thesis

Cryopreservation of oocytes became available in 2006 in the Netherlands, and was

UIFO�POMZ�QFSGPSNFE�JO�UIF�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF�PG�UIF�"DBEFNJD�.FE-

ical Centre in Amsterdam. Until 2010 cryopreservation of oocytes was only applied

GPS�XPNFO�XIPTF�QBSUOFS�IBE�JOTVGmDJFOU�TQFSN�BU�UIF�EBZ�PG�PWVN�QJDL�BOE�TQPSBE-

ically for women with cancFS�XIP�IBE�UP�VOEFSHP�HPOBEPUPYJD�UIFSBQZ�EF�.FMLFS�et al� ��#Z��UIF�UFDIOJRVF�CFDBNF�BMTP�BWBJMBCMF�GPS�B�OFX�TVCTFU�PG�QBUJFOUT �

namely women who have to defer motherhood at a time that their fertility is likely to

be at threat. This can be due to planned gonadotoxic therapy, ovarian surgery, genetic

predisposition for POI or because of age-related decline of fertility or anticipated

gamete exhaustion (Pfeifer et al.,� ��#FEPTDIJ� BOE�0LUBZ � ��)PNCVSH� et al., 2009, Stoop et al.,��5IF� JOUSPEVDUJPO� PG� OPO�FMFDUJWF� GSFF[JOH� PPDZUFT� PS� FNCSZPT� IBT� CSPVHIU� BMPOH�

OFX�DMJOJDBM�EJMFNNBT��8IFSFBT�EBJMZ�DMJOJDBM�*7'�QSBDUJDF�JT�NBSLFE�BT�FMFDUJWF�DBSF �

GSFF[JOH�PPDZUFT�SFRVJSFT�DMJOJDBM�QBUIXBZT�GPS�BDVUF�DBSF��2VBMJUZ�NBOBHFNFOU�QSP-

jects on how to set-up a program for fertility preservation were lacking, but strongly

needed by 2011 as that year is marked by the event of political permission in the Neth-

FSMBOET�GPS�GSFF[JOH�PPDZUFT�GPS�OPO�NFEJDBM�SFBTPOT�BOE�UIFSFCZ�PQFOFE�UIF�HBUF�GPS�

B�QPUFOUJBMMZ�MBSHF�JOnVY�PG�XPNFO�PQUJOH�GPS�DSZPQSFTFSWBUJPO�PG�PPDZUFT��4P �XF�TFU�

up a quality management project to establish and evaluate our fertility preservation-

QSPHSBN� CZ�NFBOT� PG� A4USFOHIUT �8FBLOFTTFT � 0QQPSUVOJUJFT� BOE� 5ISFBUT�� 4805�

analysis over a time-period of two years.

8F�FYQFDUFE�XPNFO�XJUI�CSFBTU�DBODFS�UP�CF�UIF�MBSHFTU�HSPVQ�PG�XPNFO�XIP�PQU�

for cryopreservation of oocytes in the acute setting, because breast cancer is the most

DPNNPO�NBMJHOBODZ�JO�ZPVOH�XPNFO�+FNBM�et al. �� BOE�JU�T�USFBUNFOU�BGGFDUT�

fertility in multiple ways. First, breast cancer occurring at reproductive age often

requires cyclophosphamide containing chemotherapy regimens, which has gonado-

toxic side effects (Bines et al. ��.FJSPX�BOE�/VHFOU ��4VLVNWBOJDI�et al.,

CHAPTER 1

16

��4FDPOE �UIF�NFEJDBMMZ�BEWJTFE�EFMBZ�PG�QSFHOBODZ�VOUJM�UXP�ZFBST�BGUFS�EJBH-

OPTJT�(XZO�BOE�5IFSJBVMU ��*TBBDT ��3$0( ��JODSFBTFT�UIF�DIBODFT�PG�

age-related decline of fertility, and a 5-to 10 year delay during endocrine therapy in

DBTF�PG�IPSNPOF�TFOTJUJWF�CSFBTU�DBODFS�GVSUIFS�BNQMJmFT�UIJT�#BSUIFMNFT�BOE�(BUF-

ley, 2004; Braems et al. ��5IJSE ��UP��PG�ZPVOH�XPNFO�XJUI�CSFBTU�DBODFS�BSF�

BGGFDUFE�CZ�B�#3$"��NVUBUJPO�XJUI�B�TVCTFRVFOU�JODSFBTFE�SJTL�PG�PWBSJBO�DBODFS�

(Begg et al. �� GPS�XIJDI�XPNFO�NBZ�DIPPTF�UP�QSPQIZMBDUJDBMMZ�VOEFSHP�CJMBUFSBM�

salpingo-ovariectomy. Therefore, we aimed to answer research questions particularly

relevant for women with breast cancer.

At the time we started our studies, few studies were at hand that dealt with the issue

of controlled ovarian stimulation in women for whom high estrogen exposure could

be potentially harmful, as growth of breast tumours can be stimulated by estrogens

,FZ�et al. ��:BHFS�BOE�%BWJETPO ��&MJBTTFO�et al. ��4PNF�TUVEJFT�NFO-

UJPOFE�UIF�QPUFOUJBM�CFOFmDJBM�FGGFDU�PG�BEEJOH�MFUSP[PMF��BO�BSPNBUBTF�JOIJCJUPS��UP�

controlled ovarian stimulation as this would lead to decreased peak estradiol levels

(Oktay et al., 2005; Oktay et al. ��3FEEZ�BOE�0LUBZ �� XIJMF�PUIFST�SFQPSU�UIBU�

BEEJUJPOBM� MFUSP[PMF�IBT� DPVOUFSBDUJOH�FGGFDUT�PO�PPDZUF�ZJFME� 3FWFMMJ� et al. � ��"EEJOH� UBNPYJGFO�XBT� TVHHFTUFE� UP� CF� CFOFmDJBM � BT� UIJT� BQQSPBDI� TFFNFE� OPU� UP�

compromise oocyte-yield in a small patient series (Oktay et al. ��5BNPYJGFO�JT�

a complex drug that undergoes extensive biotransformation to eventually become

BDUJWF�BT�B�TFMFDUJWF�FTUSPHFO�SFDFQUPS�NPEVMBUPS��8IFO�UBNPYJGFO�JT�VTFE�JO�UIF�BE-

KVWBOU� UIFSBQFVUJD� TFUUJOH� PG� CSFBTU� DBODFS� GPS� QPTU�NFOPQBV[BM�XPNFO � AFGmDBDZ��

PG� UBNPYJGFO�DBO�CF�FYQSFTTFE�XIFO� JU�T�NPTU�BDUJWF�NFUBCPMJUF�FOEPYJGFO�SFBDIFT�

B�UISFTIPME�JO�QMBTNB�PG��OH�NM�.BEMFOTLZ�et al., 2011; Borges et al. ��+JO�et al., ��"T�JU�XBT�VOLOPXO�IPX�FGmDBDZ�PG�UBNPYJGFO�DBO�CF�FYQSFTTFE�JO�ZPVOH�XPN-

en with breast cancer undergoing ovarian stimulation, we performed a pilot study to

FMVDJEBUF�IPX�UBNPYJGFO�ACFIBWFT��JO�UIF�TFUUJOH�PG�JU�CFJOH�BO�BEEJUJPOBM�BHFOU�EVS-

ing controlled ovarian stimulation.

"EKVTUFE� TUJNVMBUJPO�QSPUPDPMT� XJUI� BEEJUJPOBM� UBNPYJGFO� PS� MFUSP[PMF� IBE� GPVOE�

UIFJS�XBZ�JOUP�EBJMZ�DMJOJDBM�QSBDUJDF�CBTFE�PO�TUVEJFT�XJUI�NFUIPEPMPHJD�nBXT�UIBU�

DPODMVEFE�UIBU�UBNPYJGFO�BOE�MFUSP[PMF�DBO�TFSWF�B�AQSPUFDUJWF��SPMF�JO�XPNFO�XJUI�

breast cancer. In view of this, we thus evaluated these stimulation-protocols in terms

PG�TBGFUZ�BOE�FGmDJFODZ��'JSTU �XF�DPOEVDUFE�B�TZTUFNBUJD�SFWJFX�PG�MJUFSBUVSF�PG�UIFTF�

TUJNVMBUJPO�QSPUPDPMT�JO�UFSNT�PG�TBGFUZ��4VCTFRVFOUMZ �XF�BJNFE�UP�mMM�UIF�LOPXMFEHF�

HBQ�PG�XIBU�TUJNVMBUJPO�QSPUPDPM�XJUI�PS�XJUIPVU�BEEJUJPOBM�UBNPYJGFO�PS�MFUSP[PMF�

TFSWFT�XPNFO�XJUI�CSFBTU�DBODFS�CFTU�JO�UFSNT�PG�PPDZUF�ZJFME��8F�DPOEVDUFE�B�SBO-


17

domised-controlled trial in which controlled ovarian stimulation plus tamoxifen and

DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�QMVT�MFUSP[PMF�XBT�DPNQBSFE�XJUI�TUBOEBSE�DPOUSPMMFE�

ovarian stimulation in terms of the number of oocytes retrieved at follicle aspiration.

*O�BEEJUJPO�JU�XBT�VOLOPXO�XIBU�JTTVFT�BSF�SFMFWBOU�GPS�UIF�XPNFO�UIFNTFMWFT��8F�

therefore aimed to answer the question how women experienced the procedure of

GSFF[JOH�PPDZUFT�PS�FNCSZP�T�XIJMF�CFJOH�SFDFOUMZ�EJBHOPTFE�XJUI�CSFBTU�DBODFS�CZ�B�

qualitative study using phenomenological methodology.

By 2013, the question arose what reproductive choices were made after women had

previously cryopreserved their oocytes for medical reasons. A follow-up study was

performed, in which we collected data on demographics, outcomes of ovarian stimu-

lation, fertility-threatening treatments, menstrual cycle changes, pregnancy attempts

BOE�PVUDPNFT�PG�UIFTF�BUUFNQUT �BOE�XPNFO�T�JOUFOEFE�QMBOT�GPS�UIFJS�DSZPQSFTFSWFE�

oocytes.

Outline of this thesis

In Chapter 2 we describe a quality-management project that took place between 2011

BOE��JO�XIJDI�XF�QSFTFOU�IPX�PVS�$FOUFS�GPS�3FQSPEVDUJWF�.FEJDJOF�PSHBOJ[FE�

GFSUJMJUZ�QSFTFSWBUJPO�DBSF�CZ�NFBOT�PG�B�A4USFOHUIT �8FBLOFTTFT �0QQPSUVOJUJFT�BOE�

5ISFBUT��4805�BOBMZTJT�

In Chapter 3 we report a prospective case-series in which we assessed tamoxifen and

UBNPYJGFO�NFUBCPMJUF�MFWFMT�FOEPYJGFO�CZ�UBLJOH�CMPPETBNQMFT�PG�GPVS�XPNFO�XJUI�

estrogen receptor-positive breast cancer who underwent controlled ovarian stimula-

UJPO�XJUI�BEEJUJPOBM�UBNPYJGFO��NH�QFS�EBZ�GPS�DSZPQSFTFSWBUJPO�PG�PPDZUFT�

In Chapter 4 we present a systematic review which aimed to assess the effects of

BEEJOH�UBNPYJGFO�PS�MFUSP[PMF�UP�TUBOEBSE�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�QSPUPDPMT�

on the breast cancer free interval in young women with estrogen receptor-positive

breast cancer who banked oocytes or embryos.

In Chapter 5�XF�QSFTFOU� UIF� TUVEZ�QSPUPDPM�PG� UIF�45*.�USJBM� USJBM� SFHJTUFS�OVN-

CFS��/53��i4UJNVMBUJPO�PG�UIF�PWBSJFT�JO�XPNFO�XJUI�CSFBTU�DBODFS�VOEFSHPJOH�

fertility preservation: alternative versus standard stimulation protocols”. This is a

NVMUJDFOUSF�SBOEPNJTFE�PQFO�MBCFM�DPOUSPMMFE�USJBM��8F�DPNQBSFE�$04�BMPOF�XJUI�

CHAPTER 1

18

$04�QMVT�UBNPYJGFO��NH�XJUI�$04�QMVT�MFUSP[PMF��NH��1SJNBSZ�PVUDPNF�JT�UIF�

number of oocytes retrieved at follicle aspiration. Secondary outcomes are number of

mature oocytes retrieved, number of oocytes or embryos banked and peak E2 levels

during COS.

In Chapter 6 we present a qualitative phenomenological study investigating the lived

experience of women undergoing fertility preservation while being newly diagnosed

with breast cancer.

In Chapter 7 we report a follow-up study on the reproductive choices and outcomes

of 68 women after cryopreservation of their oocytes for medical reasons.

In Chapter 8�XF�QSPWJEF�B�HFOFSBM�EJTDVTTJPO�PG�UIF�mOEJOHT�PG�UIJT�UIFTJT�BOE�QSPWJEF�

suggestions for future research.

In Chapter 9 we provide a summary of the data presented in this thesis.


19

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UJPO��$PDISBOF�%BUBCBTF�4ZTU�3FW��$%��

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�t +PIOTPO�.) �1JDLFSJOH�4+�BOE�(FPSHF�."��5IF�JOnVFODF�PG�DPPMJOH�PO�UIF�QSPQFS-

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WJUSJmDBUJPO�PG�B�TNBMM�OVNCFS�PG�IVNBO�PPDZUFT��DBTF�SFQPSU��)VN�3FQSPE��

14: 3077-3079.

�t ,VXBZBNB�. �7BKUB�( �,BUP�0�BOE�-FJCP�41��)JHIMZ�FGmDJFOU�WJUSJmDBUJPO�NFUIPE�

GPS�DSZPQSFTFSWBUJPO�PG�IVNBO�PPDZUFT��3FQSPE�#JPNFE�0OMJOF��

�t -FF�4+ �4DIPWFS�-3 �1BSUSJEHF�") �1BUSJ[JP�1 �8BMMBDF�8)�FU�BM��"NFSJDBO�4PDJFUZ�

of Clinical Oncology recommendations on fertility preservation in cancer patients.

+�$MJO�0ODPM��

�t -FUVS�,POJSTDI�) �'FSOBOEF[�) �(VJT�' �"OESF�#�BOE�'SZENBO�3��0ODPMPHJD�BQQMJ-

cation of oocyte donation. Contracept Fertil Sex 1994; 22: 263-270.

�t .BEMFOTLZ�- �/BUBSBKBO�- �5DIV�4 �1V�. �.PSUJNFS�+�FU�BM��5BNPYJGFO�NFUBCPMJUF�

DPODFOUSBUJPOT �$:1�%�� HFOPUZQF � BOE� CSFBTU� DBODFS� PVUDPNFT��$MJO�1IBSNBDPM�

Ther 2011; 89: 718-725.


23

�t .BOEFMCBVN�+ �+VODB�". �1MBDIPU�. �"MOPU�.0 �4BMBU�#BSPVY�+�FU�BM��$SZPQSFTFSWB-

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breast cancer patients: a prospective controlled comparison of ovarian stimulation

XJUI�UBNPYJGFO�BOE�MFUSP[PMF�GPS�FNCSZP�DSZPQSFTFSWBUJPO��+�$MJO�0ODPM��

4347-4353.

�t 0LUBZ� , � 5VSLDVPHMV� *� BOE� 3PESJHVF[�8BMMCFSH� ,"�� (O3)� BHPOJTU� USJHHFS� GPS�

women with breast cancer undergoing fertility preservation by aromatase inhibi-

UPS�'4)�TUJNVMBUJPO��3FQSPE�#JPNFE�0OMJOF��

�t 1GFJGFS�4 �(PMECFSH�+ �.D$MVSF�3 �-PCP�3 �5IPNBT�.�FU�BM��1SBDUJDF�$PNNJUUFFT�PG�

"NFSJDBO� 4PDJFUZ� GPS� 3FQSPEVDUJWF�.FEJDJOF�� 4PDJFUZ� GPS� "TTJTUFE� 3FQSPEVDUJWF�

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�t 1JDLFSJOH�4+ �#SBVEF�13 �+PIOTPO�.) �$BOU�"�BOE�$VSSJF�+��5SBOTJFOU�DPPMJOH�UP�

room temperature can cause irreversible disruption of the meiotic spindle in the

human oocyte. Fertil Steril 1990; 54: 102-108.

�t 1PSDV�& �'BCCSJ�3 �4FSBDDIJPMJ�3 �$JPUUJ�1. �.BHSJOJ�0�FU�BM��#JSUI�PG�B�IFBMUIZ�GF-

male after intracytoplasmic sperm injection of cryopreserved human oocytes. Fertil

Steril 1997; 68: 724-726.

�t 1PSDV�& �'BCCSJ�3 �4FSBDDIJPMJ�3 �$JPUUJ�1. �1FUSBDDIJ�4�FU�BM��#JSUI�PG�TJY�IFBMUIZ�DIJM-

ESFO�BGUFS�JOUSBDZUPQMBTNJD�TQFSN�JOKFDUJPO�PG�DSZPQSFTFSWFE�IVNBO�PPDZUFT��)V-

NBO�3FQSPEVDUJPO��

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�t 3FEEZ�+�BOE�0LUBZ�,��0WBSJBO�TUJNVMBUJPO�BOE�GFSUJMJUZ�QSFTFSWBUJPO�XJUI�UIF�VTF�PG�

aromatase inhibitors in women with breast cancer. Fertil Steril 2012; 98: 1363-1369.

CHAPTER 1

24

�t 3FWFMMJ�" �1PSDV�& �-FWJ�4FUUJ�1& �%FMMF�1- �.FSMP�%'��*T�MFUSP[PMF�OFFEFE�GPS�DPO-

trolled ovarian stimulation in patients with estrogen receptor-positive breast can-

cer? Gynecol Endocrinol 2013; 29: 993-996.

�t 3PCFSUTPO�+"��&UIJDBM�BOE�MFHBM�JTTVFT�JO�DSZPQSFTFSWBUJPO�PG�IVNBO�FNCSZPT��'FSUJM�

Steril 1987; 47: 371-381.

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ing-thawing on the in vitro developmental capacity of human immature oocytes.

Fertil Steril 1996; 66: 995-999.

�t 4UPPQ�% �WBO�EFS�7FFO�' �%FOFZFS�. �/FLLFCSPFDL�+ �5PVSOBZF�)��0PDZUF�CBOLJOH�

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time course of bleeding after long-term amenorrhea after breast cancer treatment: a

prospective study. Cancer 2010; 116: 3102-3111.

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BUFE�XJUI�B�SFEVDUJPO�JO�UIF�OVNCFS�PG�DPSUJDBM�HSBOVMFT�QSFTFOU��+�3FQSPE�'FSUJM�

1990; 89: 253-259.

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25

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1974; 78: 395-402.

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�t :BHFS�+%�BOE�%BWJETPO�/&��&TUSPHFO�DBSDJOPHFOFTJT�JO�CSFBTU�DBODFS��/�&OHM�+�.FE�

2006; 354: 270-282.

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$IFNPUIFS��3FQ��

26

CHAPTER X

27

XXXXXXX

CHAPTER 2Fertility preservation:

a challenge for ivf-clinics

T. Dahhan

'��.PM(�(��,FOUFS

&�.�&��#BMLFOFOEF"�"��EF�.FMLFSF. van der Veen

E.A.F. Dancet

.��(PEEJKO

&VS�+�0CTUFU�(ZOFDPM�3FQSPE�#JPM��

CHAPTER 2

28

Abstract

Objective

Acute fertility preservation for women is an interdisciplinary treatment that requires

adequate information provision and early referral. This quality management pro-

ject aimed to improve fertility preservation care by using a practical tool: Strengths,

8FBLOFTTFT �0QQPSUVOJUJFT�BOE�5ISFBUT�4805�BOBMZTJT�

Study design

5IJT�RVBMJUZ�NBOBHFNFOU�QSPKFDU�XBT�FYFDVUFE�CFUXFFO�.BZ��BOE�+VMZ��5IJT�

QSPKFDU�IBT�CFFO�FYFDVUFE� JO�B�VOJWFSTJUZ�BGmMJBUFE�*7'�DMJOJD� JO�DPPQFSBUJPO�XJUI�

UXP�PODPMPHJDBM�TJUFT�BOE�VTFE�B�GPVS�TUFQ�TUSBUFHZ��NPOJUPSJOH�CBTFMJOF�SFGFSSBM�

QSPDFTT � �� FYQMPSJOH� CBTFMJOF� GFSUJMJUZ� QSFTFSWBUJPO� QSPHSBN� CZ� 4USFOHUIT �8FBL-

OFTTFT �0QQPSUVOJUJFT�BOE�5ISFBUT��4805�BOBMZTJT ��TFUUJOH�VQ�B�OFX�GFSUJMJUZ�QSFT-

FSWBUJPO�QSPHSBN�BOE��FWBMVBUJOH�UIF�OFX�GFSUJMJUZ�QSFTFSWBUJPO�QSPHSBN�CZ�NFBOT�

PG�4805�BOBMZTJT�

Results

During the three-months monitoring period, fertility preservation was requested for

a total of 126 women. The mean age of the women was 33.8 years old (range 1–42 years

PME��.PTU�SFRVFTUT�DBNF�GSPN�XPNFO�XIP�XBOUFE�UP�DSZPQSFTFSWF�PPDZUFT�CFDBVTF�

PG�BHF�SFMBUFE�EFDMJOF�PG�GFSUJMJUZ�O��.PTU�SFRVFTUT�GPS�BDVUF�GFSUJMJUZ�QSFT-

FSWBUJPO�DPODFSOFE�XPNFO�XJUI�CSFBTU�DBODFS�O��*OGPSNBUJPO�MFBnFUT�BOE�

pre-consultation questionnaires for women and referring health care professionals

JNQSPWFE�UIF�RVBMJUZ�PG�mSTU�GFSUJMJUZ�QSFTFSWBUJPO�DPOTVMUBUJPO�BT�FWBMVBUFE�CZ�mOBM�

4805�BOBMZTJT��$PMMBCPSBUJPO�XJUI�PODPMPHJDBM�DFOUSFT�BOE�JOGPSNBUJPO�BCPVU�GFS-

tility preservation for health care professionals improved the referral process.

Conclusions

4805�BOBMZTJT�QSPWFE�VTFGVM�GPS�TFUUJOH�VQ�B�OFX�GFSUJMJUZ�QSFTFSWBUJPO�QSPHSBN�BOE�

can be recommended as a tool to improve the management and organisation of new

types of reproductive care.

FERTILITY PRESERVATION: A CHALLENGE FOR IVF-CLINICS

29

Introduction

'FSUJMJUZ� QSFTFSWBUJPO� '1� IBT� FNFSHFE� BT� B� OFX� EJTDJQMJOF� XJUIJO� SFQSPEVDUJWF�

medicine and aims to increase chances for future parenthood in case of fertility

threatening circumstances. These circumstances may be planned gonadotoxic ther-

apy or ovarian surgery, genetic disease that may lead to premature ovarian insuf-

mDJFODZ �PS�BHF�SFMBUFE�EFDMJOF�PG�GFSUJMJUZ�[1, 2]. Although major developments have

taken place in cryopreserving and transplanting ovarian tissue [3, 4], ovarian stim-

ulation followed by cryopreservation of oocytes or embryos is currently the only

non-experimental FP technique for women [5]. The dominant clinical pathway in

*7'�DMJOJDT�JT�FMFDUJWF�*7'�*$4* �DPOTJTUJOH�PG�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�$04 �

follicle aspiration and fresh embryo-transfer after in vitro fertilisation, which may

take 2–6 weeks, depending on the type of stimulation protocol [6, 7]. In contrast,

COS followed by follicle aspiration and cryopreservation of oocytes or embryos is

an acute treatment modality if women have cancer. IVF-clinics have therefore been

challenged to organise reproductive care within a short period of time, as women

often have to start cancer treatment soon after diagnosis.

Patient surveys have reported that only half of the cancer survivors recalled having

discussed possible infertility as a consequence of their cancer treatment with their

oncology team [8-10]. Also, a recent study estimated that only half of young women

diagnosed with cancer receive information about fertility preservation before their

cancer treatment [11]. This poses another challenge for IVF clinics, because the time-

consuming process of informing patients about FP needs to be organised within

the already restricted time available before women start their cancer treatment. It

has been shown that adequate information provision about fertility preservation

prior to cancer treatment increases quality of life on the long run [12]. It is also

known that knowledge about FP and adequate time to ask questions results in less

EFDJTJPOBM�DPOnJDU�BCPVU�XIFUIFS�PS�OPU�UP�QVSTVF�XJUI�'1�[12-15]. Therefore, a basic

requirement for a FP-program is time for information provision. Early referral can

help to increase time for information provision and decision-making [16]. Barriers

GPS�FBSMZ�SFGFSSBM�IBWF�CFFO�JEFOUJmFE�TVDI�BT�MBDL�PG�LOPXMFEHF�BCPVU�SJTLT�PG�JO-

EVDJOH�QSFNBUVSF�PWBSJBO�JOTVGmDJFODZ�CZ�TQFDJmD�USFBUNFOUT � MBDL�PG�LOPXMFEHF�

about available FP options, and lack of time [15-19]. Informing oncologists about FP

can also be seen as a basic requirement for a FP-program so that the knowledge gap

that is responsible for no or late FP referral can be overcome. In addition, it could

be helpful to increase awareness among the general public about FP, so that women

CHAPTER 2

30

themselves can address FP when their oncologists fail to do so [20]. Other require-

ments for a FP-program are guidance and support of women by doctors and nursing

staff [21] and [22]. Although literature suggests these basic requirements for a well-

functioning FP-program, no studies thus far have described how IVF-clinics have

set up an FP-program. In view of this, the aim of this study was to provide insight

in how an IVF-clinic has organised itself to manage FP-care. To do so, we used a

QSBDUJDBM�UPPM��4USFOHUIT �8FBLOFTTFT �0QQPSUVOJUJFT�BOE�5ISFBUT�4805�BOBMZTJT��

4805�BOBMZTJT�IBT�CFFO�VTFE�FYUFOTJWFMZ�JO�CVTJOFTT�TFUUJOHT�UP�VODPWFS�OFX�PVU-

looks and identify problems that would impede progress.

Materials and methods

5IJT�RVBMJUZ�NBOBHFNFOU�QSPKFDU�XBT�BTTFTTFE�CZ� UIF�*OTUJUVUJPOBM�3FWJFX�#PBSE�

*3#�PG�UIF�"DBEFNJD�.FEJDBM�$FOUSF�"NTUFSEBN�QSPKFDU�OP�8��@��5IF�*3#�

TUBUFE�CZ�MFUUFS�UIBU�UIF�TUVEZ�XBT�OPU�TVCKFDU�UP�UIF�%VUDI�i.FEJDBM�3FTFBSDI�*O-

WPMWJOH�)VNBO�4VCKFDUT�"DUw �NFBOJOH� UIBU� OP� GVSUIFS� BQQSPWBM�XBT�OFFEFE�CF-

cause the project would not subject patients to investigations or treatment.

5IF� JOJUJBUJPO� PG� UIF� RVBMJUZ� NBOBHFNFOU� QSPKFDU� OBNFE� A0QUJNJTJOH� '1�DBSF��

took place in February 2011. The Centre for Gyneacological Oncology Amsterdam

$(0" �XIJDI�QSPWJEFT�DBSF�BU�UIF�"DBEFNJD�.FEJDBM�$FOUSF�".$�BOE�UIF�"O-

UPOJ�WBO�-FFVXFOIPFL�IPTQJUBM�"W- �CFDBNF�QSPKFDU�QBSUOFS��5IF�QSPKFDU�VTFE�B�

GPVS�TUFQ�TUSBUFHZ��.POJUPSJOH�CBTFMJOF�SFGFSSBM�QSPDFTT ��&YQMPSJOH�UIF�CBTFMJOF�

FP-program, 3.Setting up a new FP-program, 4.Evaluating the new FP-program.

Step 1: Monitoring baseline referral process

'SPN�.BZ��VOUJM�+VMZ��BMM�IFBMUI�DBSF�QSPWJEFST�GSPN�UIF�DFOUSF�GPS�SFQSP-

EVDUJWF�NFEJDJOF�PG�UIF�".$�XFSF�BTLFE�UP�mMM�PVU�B�OPUJmDBUJPO�GPSN�PODF�UIFZ�

received a request for fertility preservation from either a patient or a health care

professional. Disregarding whether women requesting FP did eventually pursue

XJUI�'1�PS�OPU �UIF�GPSN�SFDPSEFE�UIF�PSJHJO�J�F��XIP�SFGFSSFE�UIF�QBUJFOU �UIF�JO-

dication of the request and suggestions to improve organisational handling of that

TQFDJmD�JODPNJOH�SFRVFTU��%BUB�XFSF�DPMMFDUFE�VTJOH�4144�WFSTJPO��


31

Step 2. Exploring the baseline FP-program

8JUI� SFHBSE� UP� UIF� NPOJUPSJOH� QFSJPE� PG� JODPNJOH� BDVUF� SFRVFTUT � B� A4USFOHUIT �

8FBLOFTTFT �0QQPSUVOJUJFT�BOE�5ISFBUT��4805�BOBMZTJT�XBT�DIPTFO�BT�B�UPPM�GPS�

FYQMPSJOH� UIF� UIFO�FYJTUJOH�'1�DBSF� iCBTFMJOF�'1�QSPHSBNw�BOE�XBZT� UP� JNQSPWF�

UIBU�'1�DBSF��4805�BOBMZTJT�JT�B�GSFRVFOUMZ�VTFE�NBSLFUJOH�BOE�CVTJOFTT�UPPM�GPS�

BTTFTTJOH� GBDUPST� UIBU�NBZ� JOnVFODF� CVTJOFTT� QFSGPSNBODF� [23]. Attributes of the

organisation that were helpful to achieve the objective – improving FP care– were

EFmOFE�BT�TUSFOHUIT��BUUSJCVUFT�DPOTJEFSFE�EFUSJNFOUBM�GPS�PVS�QVSQPTF�XFSF�EFmOFE�

as weaknesses. Additionally, external conditions considered as helpful to achieve the

PCKFDUJWF�XFSF�EFmOFE�BT�PQQPSUVOJUJFT��&YUFSOBM�DPOEJUJPOT�UIBU�DPVME�CF�EFUSJNFO-

UBM�UP�UIF�PCKFDUJWF�XFSF�EFmOFE�BT�UISFBUT�

5IF�BOBMZTJT�XBT�QFSGPSNFE�CZ�BO�FYQFSU�UFBN��UXP�HZOBFDPMPHJTUT�.(�BOE�'. �

UIF�IFBE�PG�UIF�DFOUSF�GPS�SFQSPEVDUJWF�NFEJDJOF�'7 �B�GFSUJMJUZ�EPDUPS�1I%�TUVEFOU�

5%�

Step 3: Setting up a new FP-program

#BTFE�PO�UIF�EBUB�GSPN�UIF�CBTFMJOF�SFGFSSBM�QSPDFTT�BOE�UIF�SFTVMUT�PG�UIF�4805�

analysis a FP-program was set up for women referred for acute cryopreservation of

oocytes or embryos within the centre for reproductive medicine.

Step 4: Evaluating the new FP-program

To evaluate the progress and remaining challenges of the acute FP clinical pathway

UXP�ZFBST�BGUFS�JUT�TFU�VQ �B�mOBM�FWBMVBUJWF�4805�BOBMZTJT�XBT�DPOEVDUFE�JO�+VMZ�

��5IJT�4805�BOBMZTJT�XBT�QFSGPSNFE�EVSJOH�B�TUSVDUVSFE�CSBJOTUPSN�TFTTJPO��

Participants were selected from the various professional reproductive specialists in-

volved in acute FP, including: one gynaecologist specialised in reproductive endocri-

OPMPHZ�BOE�JOGFSUJMJUZ �POF�*7'�EPDUPS �POF�GFSUJMJUZ�OVSTF �POF�QIZTJDJBO�T�BTTJTUBOU �

one embryologist and one laboratory technician. The session was moderated by an

FYQFSJFODFE�RVBMJUBUJWF�SFTFBSDIFS�&%�BOE�PCTFSWFE�CZ�B�TFDPOE�SFTFBSDIFS�5%��

The moderator ensured that during the brain-storm session participants kept focus

on mentioning strengths, weaknesses, opportunities and threats of acute FP only.

5IJT�XBZ�JU�XBT�FOTVSFE�UIBU�UIF�4805�BOBMZTJT�XPVME�FWFOUVBMMZ�POMZ�SFWFBM� JT-

sues relevant for FP in the acute setting. The session took place at a neutral location

CHAPTER 2

32

outside the fertility clinic to minimise the effect of collegial hierarchy on group

dynamics. Aspects brought up by the participants during the structured brainstorm

TFTTJPO�XFSF�XSJUUFO�JO�B�RVBESBOU�TUBOEBSEJTFE�4805�UFNQMBUF�PO�B�XIJUF�CPBSE��

The position of aspects that were brought up by the group was based on group agree-

NFOU��"U�UIF�FOE�PG�UIF�TFTTJPO �UIF�NPEFSBUPS�DPNQBSFE�UIF�mOEJOHT�XJUI�UIPTF�PG�

UIF�CBTFMJOF�4805�BOBMZTJT�BOE�BTLFE�UP�EJTDVTT�BTQFDUT�UIBU�IBE�DIBOHFE�RVBESBOU�

PS� UIBU�IBE�OPU�CFFO�CSPVHIU�VQ� JO� UIF�mOBM�4805�BOBMZTJT��5IJT� MFE� UP� UIF� BE-

dition of new aspects based on group agreement. The session was audio-recorded

and transcribed verbatim to allow in-depth analysis by checking whether all aspects

brought up during the brainstorm session had been recorded on the white board by

the moderator.

Results

Monitoring baseline referral process

Information about fertility preservation was requested for a total of 126 women

and girls during the three months monitoring period. All indications for requesting

FP are shown in Table 1. The mean age of the women was 33.8 years old (range 1–42

ZFBST�PME��.PTU� SFRVFTUT�DBNF�GSPN�XPNFO�XIP�XBOUFE� UP�DSZPQSFTFSWF�PPDZUFT�

CFDBVTF�PG�BHF�SFMBUFE�EFDMJOF�PG�GFSUJMJUZ�O��.PTU�SFRVFTUT�GPS�BDVUF�'1�

DPODFSOFE�XPNFO�XJUI�CSFBTU�DBODFS�O��5ISFF�NPUIFST�SFRVFTUFE�DSZP-

QSFTFSWBUJPO�PG� UIFJS� PPDZUFT� GPS� EPOBUJPO� UP� UIFJS� ZPVOH�EBVHIUFST�XJUI�.PTBJD�

Turner syndrome.


33

Table 1��*ODPNJOH�SFRVFTUT�GPS�GFSUJMJUZ�QSFTFSWBUJPO�CFUXFFO�.BZ��BOE�+VMZ��

3FBTPO�GPS�SFRVFTUJOH�DSZPQSFTFSWBUJPO�PPDZUFT

Acute reasons

��$IFNPUIFSBQIZ�GPS�CSFBTU�DBODFS� � � � � ��

��*0'�BGUFS�DIFNPUIFSBQZ�JO�UIF�QBTU� � � � � ��

��3BEJPUIFSBQZ�GPS�CSBJO�UVNPVS�XJUI�SJTU�PG�JNQBJSJOH� � � ��

pituitary gland function

Future ovarian surgery 2

��*0'�OPU�PUIFSXJTF�TQFDJmFE� � � � � � �

Chemotherapy for chronic lymphoid leukaemia 1

��3BEJPUIFSBQZ�GPS�HZOBFDPMPHJDBM�DBODFS� � � � � �

Non-acute reasons

Age-related decline of fertility 90

��3FRVFTU�GPS�PPDZUFEPOBUJPO�NPUIFS�UP�EBVHIUFS�XJUI� � � �

��.PTBJD�5VSOFS�TZOESPNF

��.PTBJD�5VSOFS�TZOESPNF� � � � � � �

��.3,�TZOESPNF�TJOHMF�BOE�XJTI�UP�QSFTFSWF�PPDZUFT� � � �

for future surrogate pregnancy

PCOS 1

Total 126

IOF, imminent ovarian failure; MRK, Mayer-Rokitansky-Küster; PCOS, polycystic

ovarian syndrome.

Exploring baseline FP-program

5IF�mSTU�4805�BOBMZTJT�PG��JOEJDBUFE�UIF�OFFE�UP�TFU�VQ�BO�'1�QSPHSBN�BT�BDVUF�

cryopreservation of oocytes or embryos was not regarded common reproductive prac-

UJDF�JO��TFF�5BCMF��.PSF�TQFDJmDBMMZ �MPHJTUJDT�PG�BDVUF�DBSF�XFSF�OPU�ZFU�JODPS-

QPSBUFE�JOUP�EBJMZ�QSBDUJDF�BOE�EFMBZT�JO�QMBOOJOH�B�mSTU�DPOTVMU�XFSF�DPNNPO��5IF�

delays were not due to lack of motivation of staff but rather due to the absence of

digital or paper information about FP.

CHAPTER 2

34

Table 2:�4805�BOBMZTFT�GPS�JNQSPWJOH�NBOBHFNFOU�GFSUJMJUZ�QSFTFSWBUJPO�JO��BOE��

Strengths Weaknesses

Strengths in 2011 as well as 2013Good laboratory capacity for urgent gamete

GSFF[JOH

Good access because of acceptance of self-

referrals

Acute FP requests are dealt with swiftly

.PUJWBUFE�QFSTPOOFM�

New strengths in 2013'1�RVFTUJPOOBJSFT� BOE� JOGPSNBUJPO� MFBnFUT�

available

$IFDLMJTU�EVSJOH�mSTU�'1�DPOTVMUBUJPO�'1�IBT�

become more common care

0ODPMPHJD�DFOUFST�BSF�AUFBN�QMBZFST��JO�'1�

Weaknesses 2011 but resolved in 20131BUJFOUT�XFSF�JOGPSNFE�JOTVGmDJFOUMZ�BU�UJNF�

PG�UIF�mSTU�DPOTVMUBUJPO

.FEJDBM� JOGPSNBUJPO�PG�'1�QBUJFOU�XBT�OPU�

DPNQMFUF�BU�UIF�UJNF�PG�UIF�mSTU�'1�DPOTVMUB-

tion and contact details of referring doctors

were often not at hand

6OTUSVDUVSFE�mSTU�'1�DPOTVMUBUJPO�

Weaknesses from 2011 remaining in 2013No adequate follow-up of patients

New weaknesses in 2013*OTVGmDJFOU� UJNF� GPS� BEFRVBUF� QBUJFOU� TVQ-

port

FP patients are discussed several times with

different doctors in our clinic.

FP-care unavailable in the evenings/week-

ends.


35

Opportunities Threats

Opportunities from 2011 that had been taken up by 2013To structure a multidisciplinary approach

To inform women with acute FP indication

QSJPS�UP�UIFJS�mSTU�WJTJU�UP�UIF�DFOUSF�GPS�SFQSP-

ductive medicine

To inform doctors prescribing fertility threat-

ening treatment about FP

5P� PSHBOJ[F� NFFUJOHT� UP� FYDIBOHF� JOGPSNB-

tion among involved specialisms in FP

To incorporate oncological centres as team

members for FP

New opportunities in 2013Increasing FP knowledge amongst general

public

Developing FP guidelines

%FWFMPQJOH�SFGFSSBM�nPX�DIBSU�GPS�PODPMPHJTUT

Availability of more FP techniques in more

centres nationwide

Threats from 2011 that had been taken up by 2013.PSF�DPOTFOTVT�BCPVU�XIJDI�NFEJDBM�EPDUPS�

is in charge of the patient during FP (refer-

SJOH� EPDUPS� PS� SFQSPEVDUJWF� TQFDJBMJTU� EVF�

to increased cooperation between IVF clinic

and oncology site

Threats from 2011 remaining in 2013Time shortage for FP because of overlap of

oncological treatment trajectory; especially

in case of neo-adjuvant treatment

Low number of referrals considering the

amount of patients with cancer

New threats in 2013Political climate of limiting health care costs

FP = fertility preservation

AvL = Antoni van Leeuwenhoek hospital

CHAPTER 2

36

Setting up a new FP-program

5IF�OFX�'1�QSPHSBN�XBT�TFU�VQ�BGUFS�UIF�CBTFMJOF�4805�PG��'PVS�HFOFSBM�NFBT-

VSFT�XFSF�UBLFO�UP�PWFSDPNF�XFBLOFTTFT�BOE�UISFBUT�PG�UIF�CBTFMJOF�4805�PG��

and to use the opportunities mentioned.

Firstly, information about FP for patients was developed. Detailed information about

FP became available on the website of the centre for reproductive medicine and via

B�MJOL�PO�UIF�XFCTJUF�PG�UIF�PODPMPHJDBM�DFOUSF�"W-��"O�'1�JOGPSNBUJPO�MFBnFU�XBT�

TFOU� SPVUJOFMZ� UP�XPNFO�XIP�DPOUBDUFE� UIF�QIZTJDJBO�T�BTTJTUBOU�PG� UIF�DFOUSF� GPS�

reproductive medicine by telephone with a FP request.

Secondly, several measures were taken to inform potential referring physicians. A let-

ter was sent to all general practitioners working within the region of the Academic

.FEJDBM�$FOUSF�UP�BTL�TQFDJmD�BUUFOUJPO�GPS�QBUJFOUT�XJUI�BO�JOEJDBUJPO�GPS�'1��%F-

tailed information about FP became available on the internal website for profession-

BMT�XPSLJOH�JO�UIF�".$��*OGPSNBUJPO�TFTTJPOT�BCPVU�'1�XFSF�PSHBOJTFE�GPS�TVSHFPOT �

SBEJPUIFSBQJTUT �PODPMPHJTUT�BOE�OVSTFT�XIP�XPSL�JO�UIF�mFME�PG�CSFBTU�DBODFS �TJODF�

breast cancer is the most prevalent malignancy among women of reproductive age.

"MPOHTJEF� UIJT�RVBMJUZ�NBOBHFNFOU�QSPKFDU � KVTU� BGUFS� UIF�CBTFMJOF�4805�BOBMZTJT�

in 2011, the Dutch national guideline for breast cancer was revised and information

about the need to discuss FP option was added (http://www.oncoline.nl/breastcan-

DFS�

5IJSEMZ �TFWFSBM�PSHBOJTBUJPOBM�UPPMT�XFSF�EFWFMPQFE�UP�SFEVDF�UJNF�PG�mSTU�DPOTVMUB-

UJPO��8PNFO�XFSF�BTLFE�UP�mMM�PVU�B�QSF�DPOTVMUBUJPO�'1�RVFTUJPOOBJSF�BOE�CSJOH�JU�

BMPOH�BU�mSTU�WJTJU�UP�UIF�DFOUSF�TP�UIBU�BMM�SFRVJSFE�JOGPSNBUJPO�F�H��GSPN�SFGFSSJOH�

QIZTJDJBOT�XPVME�CF�BWBJMBCMF�BU�UIF�UJNF�PG�mSTU�DPOTVMUBUJPO�

-BTUMZ �B�DIFDLMJTU�GPS�UIF�mSTU�DPOTVMUBUJPO�XBT�EFWFMPQFE �UP�NBLF�TVSF�UIBU�BMM�QIZ-

TJDJBOT�BU�UIF�DFOUSF�GPS�SFQSPEVDUJWF�NFEJDJOF�DPVME�QFSGPSN�UIF�mSTU�DPOTVMUBUJPO�

BOE�XPVME�DPWFS�BMM�SFMFWBOU�'1�JUFNT�TFF�"QQFOEJY��5IF�OFX�'1�QSPHSBN�JT�JM-

lustrated in Fig. 1.


37

Figure 1: New FP-program in detail.

Collects information from patient on:

t�$BODFS�EJBHOPTJT

t�1MBOOFE�GFSUJMJUZ�UISFBUFOJOH�USFBUNFOU

t�$POUBDU�EFUBJMT�SFGFSSJOH�EPDUPS

t�.FOTUSVBM�DZDMF�EBZ

t�6TF�PG�PSBM�DPOUSBDFQUJWF�

Fertility doctor collects information

from patient:

t�(PFT�UISPVHI�mMMFE�RVFTUJPOOBJSF�BOE�

agreements with patient

t�8PSLT�XJUI�'1�JOGPSNBUJPO�DIFDLMJTU

Fertility doctor collects information

for referring doctor:

t�$IBOHFT�PG�USFBUNFOU�JOEVDFE�JOGFSUJMJUZ

t�5JNF�BWBJMBCMF�GPS�'1

Team discussion with staff-members of IVF-clinic

t�$POTFOTVT�PO�JOEJDBUJPO�GPS�'1

t�$POTFOTVT�PO�UJNF�GSBNF�GPS�'1

t�$POTFOTVT�PO�UZQF�PG�'1�J�F��PWBSJBO�UJTTVF�GSFF[JOH�XIFO�OP�UJNF�GPS�GSFF[JOH�PPDZUFT�

PS�FNCSZPT

Fertility doctor discusses results of team-discussion on the same day

Patient receives time to decide whether or not to pursue with FP

'1�ATUBSU�USFBUNFOU��DPOTVMUBUJPO�CZ�GFSUJMJUZ�EPDUPS�JT�QMBOOFE��IPVST�MBUFS�

t� *OGPSNFE� DPOTFOU�QSPDFEVSF�PO� *7'� JODMVEJOH� SJTLT � DPNQMJDBUJPOT� BOE� DIBODFT�PG�

success are discussed with patient

t�4UBSUJOH�EBUF�'1�JT�TFU�XJUI�QBUJFOU

t�1BUJFOU�SFDFJWFT�NFEJDBUJPO�UP�TUBSU�'1�USFBUNFOU

Sends information to patient:

t� 2VFTUJPOOBJSF� PO� HFOFSBM� SFQSPEVDUJWF�

health

t�*OGPSNBUJPO�MFBnFU�BCPVU�'1

t�*OGPSNBUJPO�MFBnFU�BCPVU�*7'�*$4*

%PDUPST�T�BTTJTUBOU

Plans FP intake with fertility

doctor within 2 days

FP consultation by fertility doctor

Incoming request for FP by email,

telephone or fax

CHAPTER 2

38

Evaluating the new FP-program

5IF�GBDUPST�JEFOUJmFE�CZ�UIF�4805�BOBMZTFT�PG��BOE��BSF�TIPXO�JO�5BCMF��

"MM�GPVS�TUSFOHUIT�JEFOUJmFE�JO��XFSF�TUJMM�SFMFWBOU�JO�� OBNFMZ��HPPE�MBCPSB-

tory capacity for cryopreservation of oocytes or embryos, acceptance of self-referrals,

swift dealing with acute requests, and motivated staff in the IVF-clinic. Compared to

2011, four new strengths had emerged that all resulted directly from the quality man-

BHFNFOU�QSPKFDU��'PS�FYBNQMF �UIF�OFJHICPVSJOH�PODPMPHJDBM�DFOUSF�"W-�XBT�OPX�B�

AUFBN�QMBZFS��TJODF�DPNNVOJDBUJPO�EVSJOH�UIF�SFGFSSBM�QSPDFTT�IBE�NVDI�JNQSPWFE�

"MM�XFBLOFTTFT�JEFOUJmFE�CZ�UIF�CBTFMJOF�4805�BOBMZTJT�PG��IBE�CFFO�UBLFO�VQ�

and developed into strengths by 2013 except for adequate follow-up after FP that was

TUJMM�MBDLJOH��5IF�4805�BOBMZTJT�TIPXFE�UIBU�OFX�XFBLOFTTFT�IBE�FNFSHFE�CZ��

TVDI�BT�JOTVGmDJFOU�UJNF�GPS�BEFRVBUF�QBUJFOU�TVQQPSU�BOE�TPNFUJNFT�QBUJFOUT�XFSF�

discussed several times with different doctors in our clinic. Also, the fact that acute

FP could not be organised in the evenings and weekends was mentioned as a weak-

ness as weekend delay could impede starting FP on the ideal menstrual cycle day if

XPNFO�XFSF�UP�TUBSU�DBODFS�USFBUNFOU�TPPO��"MM�PQQPSUVOJUJFT�JEFOUJmFE�CZ�UIF�CBTF-

MJOF�4805�BOBMZTJT�PG��IBE�CFFO�UBLFO�VQ�BOE�XFSF�OP�MPOHFS�PQQPSUVOJUJFT�JO�

��0G�BMM�UISFBUT�JEFOUJmFE�JO�� UXP�XFSF�TUJMM�QSFTFOU�JO��OBNFMZ�UIF�TIPSU�

time span available for FP and the relatively small number of women referred for FP

in relation to the number of women about to receive gonadotoxic treatment. All op-

QPSUVOJUJFT�JEFOUJmFE�CZ�UIF�CBTFMJOF�4805�BOBMZTJT�PG��IBE�CFFO�UBLFO�VQ�BOE�

XFSF�OP�MPOHFS�PQQPSUVOJUJFT�JO��0G�BMM�UISFBUT�JEFOUJmFE�JO�� UXP�XFSF�TUJMM�

present in 2013 namely the short time span available for FP and the relatively small

number of women referred for FP in relation to the number of women receiving

fertility-threatening therapy.

#Z�� UIF�4805�BOBMZTJT�TIPXFE�UIBU�OFX�PQQPSUVOJUJFT�IBE�FNFSHFE��(FOFSBU-

ing more common knowledge about FP among the general public was seen as a future

task, as well as developing FP guidelines to make FP-care more evidence based and

uniform. Flow-charts for oncologists should be developed and to save travel time for

patients, the availability of FP in more centres nationwide was considered required.

5IF�QPMJUJDBM�DMJNBUF�PG�MJNJUJOH�IFBMUI�DBSF�DPTUT�XBT�JEFOUJmFE�BT�B�OFX�UISFBU�JO�

2013 because this could imply that the current reimbursement of FP costs in the

Netherlands could be stopped.


39

Comments

This quality management project describes the logistic steps that have led to incorpo-

SBUJPO�PG�BDVUF�'1�JOUP�HFOFSBM�SFQSPEVDUJWF�DBSF��8F�FWBMVBUFE�UIF�IBOEMJOH�BOE�PS-

ganising of acute FP requests in our centre in 2011 and found that the logistics for ef-

mDJFOU�'1�DBSF�XFSF�OPU�ZFU�FTUBCMJTIFE�BGUFS�FYQMPSJOH�UIF�TJUVBUJPO�JO��CZ�NFBOT�

PG�4805�BOBMZTJT��5IF�TUBSUJOH�QPJOU�PG�UIJT�RVBMJUZ�NBOBHFNFOU�QSPKFDU�XBT�FYQMPS-

ing how incoming requests for FP were managed logistically, disregarding whether

the request came from a woman eventually undergoing FP or from a woman declin-

JOH�'1�BGUFS�DPOTVMUBUJPO��#Z�NFBOT�PG�4805�BOBMZTJT �XF�UIFO�FYQMPSFE�UIF�FYJTUJOH�

CBTFMJOF�'1�QSPHSBN�JO��UP�FWFOUVBMMZ�TFU�VQ�B�OFX�'1�QSPHSBN�JO��5IF�

analysis showed that it was deemed important to develop information for patients and

doctors who prescribe fertility threatening treatment to facilitate good time manage-

NFOU�BU�UJNF�PG�mSTU�'1�DPOTVMUBUJPO��"�OFX�'1�QSPHSBN�XBT�TFU�VQ�BT�B�SFTVMU�PG�UIJT�

FWBMVBUJPO �MFBEJOH�UP�TFWFSBM�FBTZ�BDDFTTJCMF�TPVSDFT�PG�JOGPSNBUJPO�BCPVU�'1��8IFO�

we evaluated the organisation of FP two years after the set-up of the FP-program by

B�mOBM�4805�BOBMZTJT �XF�GPVOE�UIBU�OFX�TUSFOHUIT�FNFSHFE�BT�B�SFTVMU�PG�JNQSPWFE�

information provision for patients and surrounding oncology centres. Also, FP consul-

tation was improved by introducing a FP-questionnaire for patients and a checklist for

doctors to use during consultation. Our new FP-program can be used as an example

for other IVF-clinics on how to manage acute FP care and can offer insight in how to

VTF�4805�BOBMZTJT�BT�B�QSBDUJDBM�UPPM�UP�JNQSPWF�PS�TUBSU�'1�DBSF�

5IJT�JT�UIF�mSTU�UJNF�UIBU�UIF�FWPMVUJPO�PG�PSHBOJTJOH�BDVUF�DSZPQSFTFSWBUJPO�PG�PPDZUFT�

IBT�CFFO�GPMMPXFE�PWFS�UJNF�XJUIJO�BO�*7'�DMJOJD��"MTP �UIJT�JT�UIF�mSTU�UJNF�BO�FWBMV-

BUJPO�PG�PSHBOJTJOH�'1�GPS�XPNFO�IBT�CFFO�EFTDSJCFE�CZ�NFBOT�PG�4805�BOBMZTJT��

Although this quality management project was undertaken to improve acute FP, the

new FP-program also covers elective FP. The majority of women requesting FP during

UIF�UISFF�NPOUI�NPOJUPSJOH�QFSJPE�JO�.BZ��XFSF�XPNFO�XJUI�BHF�SFMBUFE�EFDMJOF�

of fertility. This could have been a temporary phenomenon as oocyte cryopreservation

received a lot of media-attention in the Netherlands in April 2011 when women with

age-related decline of fertility were allowed to cryopreserve oocytes. The lack of met-

ric tools to evaluate the effectiveness of FP-programs that involve oncological centres

IBT�CFFO�QPJOUFE�PVU�CZ�TUVEJFT�SFWJFXJOH�POHPJOH�'1�QSPHSBNT�TVDI�BT�'FSUJMF�)PQF�

[22]��#FDBVTF�'1�JT�B�SFMBUJWFMZ�OFX�UZQF�PG�DBSF�XJUIJO�UIF�mFME�PG�SFQSPEVDUJWF�NFEJ-

DJOF �4805�BOBMZTJT�JT�B�EFTJHOBUFE�NFUIPE�UP�SFWFBM�GBDUPST�UIBU�IBWF�BO�JOnVFODF�PO�

management and organisation.

CHAPTER 2

40

A primary limitation of the study is that benchmarking for quality was not possible

since this quality management project was conducted in one IVF-clinic only. In addi-

UJPO �BMUIPVHI�XF� JODMVEFE�QSPGFTTJPOBMT� GSPN�EJGGFSFOU�SFQSPEVDUJWF�mFMET �RVBMJUZ�

XBT�OPU�BTTFTTFE�GSPN�UIF�QBUJFOU�T�QFSTQFDUJWF �XIJDI�DBO�CF�SFHBSEFE�BT�B�NJTTJOH�

EFUFSNJOBOU�JO�PVS�4805�BOBMZTJT�JO�UFSNT�PG�NJTTJOH�FYUFSOBM�DPOEJUJPOT��'VSUIFS-

more, the methods used in this project could not quantitatively examine the effec-

UJWFOFTT�PG�OFX�'1�QSPHSBN�JO�UFSNT�PG�SFGFSSBM�SBUFT �BOE�QBUJFOUT��BOE�IFBMUI�DBSF�

professionals satisfaction. In agreement with literature, most acute FP requests came

from women with breast cancer [24-25]��8PNFO�XJUI�CSFBTU�DBODFS�NBZ�DPOTUJUVUF�UIF�

largest FP population because of their high risk on therapy-induced infertility and the

increase in breast cancer incidence among young women [26]. Integration of informa-

tion provision of FP and referral into patient care was lacking in high quality cancer

centres [27]. Cooperation with oncological centres can stimulate timely referral and

IFMQ�UP�PWFSDPNF�EJGmDVMUJFT�JO�PSHBOJTJOH�'1�[28]. This is in is in accordance with our

mOEJOH�UIBU�UIF�DPMMBCPSBUJPO�XJUI�UXP�PODPMPHJDBM�TJUFT�IBT�CFFO�FWBMVBUFE�BT�B�GBDUPS�

UIBU�JNQSPWFE�UIF�SFGFSSBM�QSPDFTT��,OPXMFEHF�BOE�JOGPSNBUJPO�EFmDJUT�BU�UIF�MFWFM�PG�

patients and health-care professionals are barriers for effectively organising FP-care

[29]. Implementing paper and digital information for patients and health-care profes-

TJPOBMT�IBT�CFFO�FWBMVBUFE�BT�JNQPSUBOU�CZ�4805�BOBMZTJT�JO�UIJT�TUVEZ�BOE�DBO�CF�

DPOTJEFSFE�BT�B�TJHOJmDBOU�mSTU�TUFQ�JO�PWFSDPNJOH�HBQT�JO�LOPXMFEHF��%FTQJUF�FGGPSUT�

to ease access to information about FP for patients and oncologists by international

OFUXPSLT�TVDI�BT�*4'1�BOE�UIF�A0ODPGFSUJMJUZ�$POTPSUJVN� �UIF�JNQPSUBODF�PG�PGGFSJOH�

FP in an early stage to patients whose fertility is at threat is not yet resounded to its

full potential [30]. Furthermore, with regard to follow-up of patients, registration of

'1�JOEJDBUJPOT �USFBUNFOUT�BOE�PVUDPNFT�JT�XBSSBOUFE�TP�UIBU�UIF�TBGFUZ�BOE�FGmDBDZ�

of FP can be measured over time.

In conclusion, because the nature of acute FP is different from conventional elective

reproductive assisted techniques, the set-up of a separate FP-program was required

JO�PVS�*7'�DMJOJD�UP�NFFU�UIF�OFFET�GPS�BDVUF�'1��4805�BOBMZTJT�QSPWFE�VTFGVM�GPS�

setting up this program and can be recommended as a tool to gain insight in organisa-

tional process of new types of reproductive care. The scope of FP is rapidly broaden-

ing which will subsequently lead to subdivision in FP populations and FP options.

'VUVSF�TUVEJFT�XJMM�OFFE�UP�FWBMVBUF�UIF�TQFDJmD�DIBMMFOHFT�JO�PSHBOJTJOH�PQUJNBM�DBSF�

for men, pre-pubertal boys and girls. Also, further studies are needed to quantitatively

examine the effect of information strategies so that all patients with an indication for

FP are adequately referred to IVF-clinics.


41

$POnJDU�PG�JOUFSFTUT

/P�DPOnJDU�PG�JOUFSFTU�

Funding

5IJT�TUVEZ�XBT�GVOEFE�CZ�GPVOEBUJPO�A/VUT0ISB��BOE�A7JSUVUJT�0QVT��

Acknowledgements

8F�XPVME�MJLF�UP�UIBOL�BMM�QBSUJDJQBOUT�PG�UIF�TUSVDUVSFE�CSBJOTUPSN�TFTTJPO�

CHAPTER 2

42

Appendix 1

Checklist for oocyte cryopreservation

Date:

Fertility doctor:

3FGFSSJOH�EPDUPS��

Discussed with patient:

0PDZUF�DSZPQSFTFSWBUJPO�JO�UIF�/FUIFSMBOET�JT�SFHBSEFE�BT�iNPOJUPSFE�JOUSPEVDUJPO�

of new technique”

'PMMPX�VQ�DIJMESFO�VOUJMM�UIF�BHF�PG�mWF�ZFBST

IVF treatment precedes cryopreservation of oocytes (risks: bleeding, infection, ovar-

JBO�IZQFS�TUJNVMBUJPO�TZOESPNF

5SFBUNFOU�EPFT�OPU�HVBSBOUFF�IBWJOH�B�GVUVSF�DIJME�

Estimated number of oocytes needed for live birth is 20-30

Future use of cryopreserved oocytes for pregnancy will be preceded by medical and

moral judgment of IVF-clinic staff

$PTUT�PG�USFBUNFOU��WJUSJmDBUJPO�LJU�QMVT�ZFBSMZ�TUPSBHF�DPTUT�

Ovum pick up is performed until the age of 40 years

Embryo transfer untill the age of 45 years

Check whether patient received:

A(FOFSBM�QBUJFOU�JOGPSNBUJPO�MFBnFU�*7'�*$4*��

A1BUJFOU�JOGPSNBUJPO�MFBnFU�GSFF[JOH�PPDZUFT��PS�A1BUJFOU�JOGPSNBUJPO�MFBnFU�GSFF[JOH�

FNCSZPT�


43

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UFS�DBODFS��B�QJMPU�TVSWFZ�PG�TVSWJWPST��BUUJUVEFT�BOE�FYQFSJFODFT �$BODFS ��

697–709.

9. .�.��(BSWFMJOL �.�.��5FS�,VJMF �3�.��#BLLFS�FU�BM� �8PNFO�T�FYQFSJFODFT�XJUI�

information provision and deciding about fertility preservation in the Neth-

FSMBOET�� ATBUJTGBDUJPO� JO� HFOFSBM� CVU� VONFU� OFFET� �)FBMUI�&YQFDU� �� IUUQ��

dx.doi.org/10.1111/hex 12068.

CHAPTER 2

44

10. -�"��-PVXF �.�.��5FS�,VJMF �$�(��)JMEFST�FU�BM� �0ODPMPHJTUT��QSBDUJDF�BOE�BUUJ-

tudes regarding fertility preservation in female cancer patients: a pilot study in

UIF�/FUIFSMBOET �+�1TZDIPTPN�0CTUFU�(ZOBFDPM �� o��

11. .��%F�7PT � +�� 4NJU[� BOE�5�,��8PPESVGG �'FSUJMJUZ�QSFTFSWBUJPO� JO�XPNFO�XJUI�

cancer, Lancet, 2014, 4, 1302–1310.

12. +�.��-FUPVSOFBV �&�&��&CCFM �1�1��,BU[�FU�BM� �1SFUSFBUNFOU�GFSUJMJUZ�DPVOTFMJOH�BOE�

fertility preservation improve quality of life in reproductive age women with

cancer, Cancer, 2012, 118, 1710–1717.

13. .�.��(BSWFMJOL �.�.��5FS�,VJMF �-�"��-PVXF �$�(��)JMEFST�BOE�"�.��4UJHHFMCPVU �

A Delphi consensus study among patients and clinicians in the Netherlands on

the procedure of informing young breast cancer patients about fertility preserva-

tion, Acta Oncol, 2012, 51, 1062–1069.

14. 7�-�� 1FEEJF �.�"�� 1PSUFS � 3�� #BSCPVS� FU� BM� � 'BDUPST� BGGFDUJOH� EFDJTJPO�NBLJOH�

BCPVU� GFSUJMJUZ� QSFTFSWBUJPO� BGUFS� DBODFS� EJBHOPTJT�� B� RVBMJUBUJWF� TUVEZ � #+0( �

2012, 119, 1049–1057.

15. L. Bastings, Ö. Baysal, C.C. Beerendonk et al., Deciding about fertility preserva-

UJPO�BGUFS�TQFDJBMJTU�DPVOTFMMJOH �)VN�3FQSPE �� o��

16. 4��-FF �4��0[LBWVLDV �&��)FZUFOT �'��.PZ�BOE�,��0LUBZ �7BMVF�PG�FBSMZ�SFGFSSBM�UP�

GFSUJMJUZ�QSFTFSWBUJPO�JO�ZPVOH�XPNFO�XJUI�CSFBTU�DBODFS �+�$MJO�0ODPM ��

4683–4686.

17. &�+��'PSNBO �$�,��"OEFST�BOE�.�"��#FIFSB �"�OBUJPOXJEF�TVSWFZ�PG�PODPMPHJTUT�

regarding treatment-related infertility and fertility preservation in female cancer

patients, Fertil Steril, 2010, 94, 1652–1656.

18. (�1��2VJOO �4�5��7BEBQBSBNQJM �+�)��-FF�FU�BM� �1IZTJDJBO�SFGFSSBM�GPS�GFSUJMJUZ�QSFT-

FSWBUJPO�JO�PODPMPHZ�QBUJFOUT��B�OBUJPOBM�TUVEZ�PG�QSBDUJDF�CFIBWJPST �+�$MJO�0O-

col, 2009, 27, 5952–5957.


45

19. 4��7BEBQBSBNQJM �(��2VJOO �-��,JOH �$��8JMTPO�BOE�.��/JFEFS �#BSSJFST�UP�GFSUJMJUZ�

preservation among pediatric oncologists, Patient Educ Couns, 2008, 72, 402–410.

20. "�)��1BSUSJEHF �4��(FMCFS �+��1FQQFSDPSO�FU�BM� �8FC�CBTFE�TVSWFZ�PG�GFSUJMJUZ�JTTVFT�

JO�ZPVOH�XPNFO�XJUI�CSFBTU�DBODFS �+�$MJO�0ODPM �� o��

21. +��4DPUU�5SBJOFS �5IF�SPMF�PG�B�QBUJFOU�OBWJHBUPS�JO�GFSUJMJUZ�QSFTFSWBUJPO �$BODFS�

5SFBU�3FT �� o��

22. +�%��3FJOFDLF �+�'��,FMWJO �4�3��"SWFZ�FU�BM� �*NQMFNFOUJOH�B�TZTUFNBUJD�BQQSPBDI�

UP�NFFUJOH�QBUJFOUT��DBODFS�BOE�GFSUJMJUZ�OFFET��B�SFWJFX�PG�UIF�'FSUJMF�)PQF�$FO-

USFT�0G�&YDFMMFODF�QSPHSBN �+�0ODPM�1SBDU�� o��

23. .�.��)FMNT� BOE� +��/JYPO �&YQMPSJOH�4805�BOBMZTJT� o�XIFSF� BSF�XF�OPX �"�

SFWJFX�PG� BDBEFNJD� SFTFBSDI� GSPN� UIF� MBTU�EFDBEF � +�� 4USBUFH��.BOBHF� � ��

215–251.

24. +�"��(BSDJB�7FMBTDP �+��%PNJOHP �"��$PCP �.��.BSUJOF[ �-��$BSNPOB�BOE�"��1FMMJD-

FS �'JWF�ZFBST��FYQFSJFODF�VTJOH�PPDZUF�WJUSJmDBUJPO�UP�QSFTFSWF�GFSUJMJUZ�GPS�NFEJ-

cal and nonmedical indications, Fertil Steril, 2013, 7, 1994–1999.

25. "��+FNBM �3��4JFHFM �+��9V�BOE�&��8BSE �$BODFS�TUBUJTUJDT �$"�$BODFS�+�$MJO ��

60, 277–300.

26. .��)JDLFZ �.��1FBUF �$�.��4BVOEFST�BOE�.��'SJFEMBOEFS �#SFBTU�DBODFS�JO�ZPVOH�

XPNFO�BOE�JUT�JNQBDU�PO�SFQSPEVDUJWF�GVODUJPO �)VN�3FQSPE�6QEBUF ��

323–339.

27. .�-��$MBZNBO �.�.��)BSQFS �(�1��2VJOO �+��3FJOFDLF�BOE�4��4IBI �0ODPGFSUJMJUZ�

SFTPVSDFT�BU�/$*�EFTJHOBUFE�DPNQSFIFOTJWF�DBODFS�DFOUSFT �+�/BUM�$PNQS�$BODFS�

Netw, 2013, 11, 1504–1509.

28. (�1��2VJOO �4�5��7BEBQBSBNQJM �$�,��(XFEF � +�%��3FJOFDLF �5�.��.BTPO�BOE�$��

Silva, Developing a referral system for fertility preservation among patients with

OFXMZ�EJBHOPTFE�DBODFS �+�/BUM�$PNQS�$BODFS�/FUX �� o��

CHAPTER 2

46

29. .�� 1FBUF � #�� .FJTFS � .�� 'SJFEMBOEFS� FU� BM� � *U�T� OPX� PS� OFWFS�� GFSUJMJUZ�SFMBUFE�

knowledge decision-making preferences and treatment intentions in young

women with breast cancer-- – an Australian fertility decision aid collaborative

HSPVQ�TUVEZ �+�$MJO�0ODPM �� o��

30. ,�&��8BJNFZ �'�&��%VODBO �)�*��4V�FU�BM� �'VUVSF�EJSFDUJPOT�JO�PODPGFSUJMJUZ�BOE�

fertility preservation: a report from the 2011 Oncofertility Consortium Confer-

FODF �+�"EPMFTD�:PVOH�"EVMU�0ODPM �� o��

48

CHAPTER X

49

XXXXXXX

CHAPTER 3A prospective case series of

women with estrogen receptor-positive breast cancer: Levels of tamoxifen metabolites

in controlled ovarian stimulation with high-dose

tamoxifen

&�.�&��#BMLFOFOEFT. Dahhan

S.C. Linn

/�(��+BHFS+�)��#FJKOFO.��(PEEJKO

)VNBO�3FQSPEVDUJPO��

CHAPTER 3

50

Abstract

$POUSPMMFE�PWBSJBO�TUJNVMBUJPO�$04�JO�XPNFO�XJUI�FTUSPHFO�SFDFQUPS�&3�QPTJUJWF�

breast cancer is potentially harmful because of the increase in serum estrogen levels.

During COS for cryopreservation of oocytes or embryos, these women may receive high

EPTFT�PG�UBNPYJGFO��NH�UP�NPEVMBUF�UIF�&3�BOE�QSFWFOU�FYUSB�HSPXUI�PG�FTUSPHFO�

SFTQPOTJWF�UVNPVST�EVSJOH�$04��)PXFWFS �JU�JT�VOLOPXO�XIFUIFS�BEFRVBUF�TFSVN�DPO-

centrations of endoxifen, the most important metabolite of tamoxifen, can be reached.

The aim of this study is to evaluate whether the tamoxifen dose used in a tamoxifen–

$04�DPNCJOFE�TDIFEVMF�GPS�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�DBODFS�JT�IJHI�FOPVHI�UP�

reach endoxifen levels that are considered therapeutically effective to inhibit breast

DBODFS�HSPXUI��5IF�GPVS�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�DBODFS�XIP�VOEFSXFOU�$04�

GPS�DSZPQSFTFSWBUJPO�PG�PPDZUFT�XFSF�QSPTQFDUJWFMZ�TUVEJFE�BU� UIF�"DBEFNJD�.FEJDBM�

Centre, Amsterdam, the Netherlands. Throughout COS, blood samples were collected

and tamoxifen and endoxifen levels were determined by a validated high-performance

MJRVJE� DISPNBUPHSBQIZ� UBOEFN�NBTT� TQFDUSPNFUSZ� BTTBZ��5IF� GPVS�XPNFO�XJUI�&3�

QPTJUJWF�CSFBTU�DBODFS�VOEFSXFOU�B�UPUBM�PG�mWF�$04�DZDMFT �XIJMF�BEEJUJPOBMMZ�VTJOH�

tamoxifen 60 mg daily. The tamoxifen and endoxifen levels showed a large variability

between the women, with endoxifen levels during the whole period of ovarian stimu-

MBUJPO�WBSZJOH�CFUXFFO��BOE��OH�NM��5IF�BWFSBHF�OVNCFS�PG�WJUSJmFE�PPDZUFT�

XBT��o��5IFSBQFVUJDBMMZ�FGGFDUJWF�FOEPYJGFO�TFSVN�MFWFMT�DBO�CF�SFBDIFE�XIFO�

tamoxifen is used to counteract estrogen levels during COS for fertility preservation,

but not in all women. Large variations of tamoxifen and endoxifen levels between the

women were observed.

Introduction

Breast cancer is the most common neoplasm found in women of reproductive age

(Bray et al. ��.PTU�ZPVOH�CSFBTU�DBODFS�QBUJFOUT�XJUI�B�GVUVSF�XJTI�UP�IBWF�DIJM-

dren require lifesaving treatment with toxic side-effects on ovarian function. Cyclo-

phosphamide, an alkylating agent commonly used in breast cancer, has known gonado-

UPYJD�FGGFDUT�UIBU�DBO�MFBE�UP�TVCGFSUJMJUZ�4PONF[FS�BOE�0LUBZ ��)VMWBU�BOE�+FSVTT �

��3PESJHVF[�8BMMCFSH�BOE�0LUBZ ��$SZPQSFTFSWBUJPO�PG�PPDZUFT�PS�FNCSZPT�JT�

a fertility preservation technique which can improve chances of offspring after breast

DBODFS�USFBUNFOU��$POUSPMMFE�PWBSJBO�TUJNVMBUJPO�$04�JT�SFRVJSFE�JO�PSEFS�UP�IBSWFTU�B�

A PROSPECTIVE CASE SERIES OF WOMEN WITH ESTROGEN RECEPTOR-POSITIVE BREAST CANCER

51

TVGmDJFOU�OVNCFS�PG�PPDZUFT�GPS�FJUIFS�EJSFDU�DSZPQSFTFSWBUJPO�PS�GFSUJMJ[BUJPO�GPMMPXFE�

by embryo cryopreservation. For a period of at least 2 weeks, women undergo treatment

XJUI�IJHI�EPTFT�PG�GPMMJDMF�TUJNVMBUJOH�IPSNPOF�'4)�GPS�NVMUJGPMMJDVMBS�HSPXUI �BOE�

DPODVSSFOU�PWBSJBO�TVQQSFTTJPO�CZ�EPXO�SFHVMBUJPO�XJUI�(O3)�BOBMPHVFT��*O�SFTQPOTF�

to daily gonadotrophin injections, women undergoing COS have a 2–3-fold higher peak

FTUSBEJPM�&��MFWFM�XIFO�DPNQBSFE�XJUI�MFWFMT�PG�UIF�OPSNBM�NFOTUSVBM�DZDMF�#BSCJFSJ �

��4USBVTT�BOE�-FTTFZ ��5IF�UIFPSFUJDBM�SJTL�PG�QSPNPUJOH�CSFBTU�DBODFS�HSPXUI�

CZ�$04�JO�UIF�DBTF�PG�FTUSPHFO�SFDFQUPS�&3�QPTJUJWF�CSFBTU�DBODFS�IBT�MFE�UP�UIF�VTF�

of adjusted COS protocols with the additional use of therapy regimens that can coun-

UFSBDU�UIF�SBJTFE�JBUSPHFOJD�FTUSPHFO�MFWFMT��5IJT�DBO�CF�BDIJFWFE�CZ�FJUIFS�CMPDLJOH�&3T�

by tamoxifen or by diminishing estrogen peak serum concentrations using aromatase-

JOIJCJUPST�"*�T��)PXFWFS �JU�SFNBJOT�VOLOPXO�XIJDI�$04�QSPUPDPM�TIPVME�CF�DIPTFO�

JO�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�DBODFS �UP�NJOJNJ[F�UIF�SJTL�PG�BEWFSTFMZ�JOnVFOD-

ing the breast cancer outcome. Current literature does not supply evidence on which

stimulation protocol is superior in terms of safety and IVF outcomes. One prospective

study (Oktay et al. ��DPNQBSFE�UISFF�BEKVTUFE�TUJNVMBUJPO�QSPUPDPMT�JO��XPNFO�

with breast cancer. The women received tamoxifen alone, COS with tamoxifen or COS

XJUI�MFUSP[PMF��$04�XJUI�UBNPYJGFO�SFTVMUFE�JO�TUBUJTUJDBMMZ�TJHOJmDBOU�IJHIFS�QFBL�&��

MFWFMT��QH�NM�DPNQBSFE�XJUI�MFUSP[PMF�BOE�$04�&��QFBL�MFWFMT��QH�

NM�CVU�UIFSF�XFSF�OP�EJGGFSFODFT�JO�CSFBTU�DBODFS�PVUDPNF�BGUFS��NPOUIT�GPMMPX�VQ�

Tamoxifen is a non-steroidal anti-estrogen triphenylethylene derivative which, after

PSBM� BENJOJTUSBUJPO �NFUBCPMJ[FT� B�P�� UP�N-desmethyltamoxifen, 4-hydroxytamoxifen

and endoxifen. These active metabolites, of which endoxifen is the most potent me-

UBCPMJUF �TFMFDUJWFMZ�NPEVMBUF�UIF�&3�BOE�TVQQSFTT�CSFBTU�HSPXUI��)PXFWFS �UIF�UIFSB-

QFVUJDBM�FGmDBDZ�J�F��UIF�QSPUFDUJWF�FGGFDU�PG�CMPDLJOH�UIF�FGGFDU�PG�SBJTFE�FTUSPHFO�MFWFMT�

EVSJOH�$04�BOE�PQUJNBM�UIFSBQFVUJD�EPTF�PG�UBNPYJGFO�GPS�XPNFO�XJUI�&3�QPTJUJWF�

breast cancer undergoing undergoing COS for oocyte- or embryo-cryopreservation is

unclear. Since the terminal half life (time required to decrease the serum concentration

XJUI��PG�UIF�TUFBEZ�TUBUF�DPODFOUSBUJPO�PG�UBNPYJGFO�JT��XFFLT �BOE�TUFBEZ�TUBUF�

concentrations are reached by only 2 months of administration, we wondered whether

the higher tamoxifen dose used during COS would lead to adequate tamoxifen and,

more importantly, endoxifen serum concentrations, since the most important tamox-

ifen metabolite is endoxifen. The aim of this study therefore was to evaluate wheth-

er the tamoxifen dose used in a tamoxifen-COS combined schedule for women with

&3�QPTJUJWF�CSFBTU�DBODFS�JT�IJHI�FOPVHI�UP�SFBDI�FOEPYJGFO�MFWFMT�UIBU�BSF�DPOTJEFSFE�

therapeutically effective to inhibit breast cancer growth.

CHAPTER 3

52

Materials and Methods

8PNFO�PG�SFQSPEVDUJWF�BHF��o��ZFBS�PME�XIP�TVGGFSFE�GSPN�&3�QPTJUJWF�CSFBTU�

cancer were eligible for inclusion if chemotherapy was indicated but not yet start-

FE��5IFZ�XFSF�SFGFSSFE�UP�UIF�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF�PG�UIF�"DBEFNJD�

.FEJDBM�$FOUSF�CZ�UIFJS�PODPMPHJTUT �OVSTF�QSBDUJUJPOFST�PS�XFSF�TFMG�SFGFSSBMT �BOE�

SFDSVJUFE�EVSJOH�UIF�mSTU�DPOTVMUBUJPO�GPS�GFSUJMJUZ�QSFTFSWBUJPO��8PNFO�XFSF�FY-

DMVEFE�CBTFE�PO�QPPS�NFEJDBM�DPOEJUJPO�PS�UIF�VTF�PG�NFEJDBUJPO�UIBU�NJHIU�JOnV-

FODF�UBNPYJGFO�NFUBCPMJTN�F�H��nVPYFUJOF�PS�JG�UIFZ�XFSF�VOXJMMJOH�PS�VOBCMF�UP�

sign the informed consent form.

5IF�TUVEZ�QFSJPE�XBT�GSPN�"QSJM��VOUJM�.BZ��8PNFO�VOEFSXFOU�EPXO�

SFHVMBUJPO�XJUI�B�(O3)�BHPOJTU� JO�B� MPOH�QSPUPDPM�XJUI�B�NJEMVUFBM� TUBSU�XIFO�

UJNF�BMMPXFE�GPS�JU��$04�XBT�TUBSUFE�PO�DZDMF�EBZ��XJUI�SFDPNCJOBOU�'4)�S'4)�

JO�EBJMZ�EPTFT�SBOHJOH�GSPN��UP��*6�EFQFOEJOH�PO�UIF�XPNBO�T�BHF�BOE�UIF�BO-

tral follicle count. In the case of time restraint, a short protocol with a simultane-

PVT�TUBSU�UP�(O3)�B�BOE�S'4)�XBT�DPNNFODFE�CFUXFFO�DZDMF�EBZ��BOE��5SBOT-

WBHJOBM� VMUSBTPVOE�NPOJUPSJOH� BOE�NFBTVSFNFOUT� PG� MVUFJOJ[JOH� IPSNPOF� -)�

BOE�&��XFSF� SPVUJOFMZ�QFSGPSNFE�EVSJOH�PWBSJBO� TUJNVMBUJPO��3PVUJOF�IPSNPOF�

MFWFMT�XFSF�BTTFTTFE�XJUI�SBEJPJNNVOPBTTBZ�3*" �%1$ �-PT�"OHFMFT �$" �64"�GPS�

E2, and electrochemiluminescence immunoassay (ECLIA, Cobas E immunoassay

BOBMZTFS �*OEJBOBQPMJT �*/ �64"�GPS�-)�NFBTVSFNFOU��'PMMJDVMBS�NBUVSBUJPO�XBT�

induced by 10 000 IU human chorioOJD�HPOBEPUSPQIJO�IPSNPOF�I$(�1SFHOZM®�

when the majority of follicles reached 18–20 mm diameter as shown by transvagi-

nal ultrasound. Transvaginal ultrasound guided follicle aspiration was performed

��I�MBUFS��0PDZUFT�XFSF�DSZPQSFTFSWFE�BU�UIF�NFUBQIBTF�**�TUBHF�CZ�WJUSJmDBUJPO�

8PNFO�XFSF�QSFTDSJCFE�UIF�VTF�BEEJUJPOBM�UBNPYJGFO��NH ��PSBM�UBCMFUT�PG��

NH�UBLFO�JO�POF�EBJMZ�EPTF�CFUXFFO��BOE��1.��%FQFOEJOH�PO�IPX�NVDI�

time there was available to perform COS, women were prescribed to start tamox-

JGFO�BT�TPPO�BT�UIFZ�TUBSUFE�(O3)�BOBMPHVFT�PS�'4)��8PNFO�SFDFJWFE�B�EJBSZ�UP�

register the exact time of tamoxifen intake.

The levels of endoxifen and tamoxifen were analysed in serum samples acquired

during routine blood testing during COS and on the day of ovum pick up. All se-

SVN�HFM�UVCFT�XFSF�DPEFE�BOE�BOPOZNJ[FE��5IF�TFSVN�TBNQMFT�XFSF�DPMMFDUFE�JO�

TFSVN�HFM�UVCFT�BOE�TUPSFE�BU�¦��¡$�VOUJM�UJNF�PG�BOBMZTJT�

"O�BTTBZ�GPS�UIF�EFUFSNJOBUJPO�PG�UBNPYJGFO��o��OH�NM�BOE�FOEPYJGFO��o��

OH�NM�GSPN�5FVOJTTFO�et al. ��XBT�VTFE�XJUI�TMJHIU�NPEJmDBUJPOT��%FUFDUJPO�


53

was QFSGPSNFE�PO�B�USJQMF�RVBESVQPMF�.4�.4�EFUFDUPS�XJUI�BO�FMFDUSPTQSBZ�JPOJ-

[BUJPO�TPVSDF�"1*�� "#�4DJFY �'PTUFS�$JUZ �64"�PQFSBUJOH�JO�UIF�QPTJUJWF�JPO�

mode. Data with regard to baseline clinical characteristics, the COS-cycles and

PVUDPNFT� JO� UFSNT� PG� OVNCFS� PG� PPDZUFT� SFUSJFWFE� BOE� WJUSJmFE�XFSF� DPMMFDUFE��

Graphs were made with SPSS version 19. The study protocol was approved by the

*OTUJUVUJPOBM�3FWJFX�#PBSE�PG�UIF�"DBEFNJD�.FEJDBM�$FOUSF �"NTUFSEBN�BOE�BMM�

women gave written informed consent before starting COS.

Results

"�UPUBM�PG� GPVS�FMJHJCMF�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU� DBODFS�XFSF� JODMVEFE� JO�

this prospective case series. They all opted for oocyte cryopreservation prior to

chemotherapy: three women before starting docetaxel, adriamycine and cyclo-

QIPTQIBNJEF�5"$�DZDMFT �BOE�POF�XPNBO�CFGPSF�5"$�BOE�WJODSJTUJOF �FQJSVCJDJO�

BOE�DZDMPQIPTQIBNJEF�7&$�DZDMFT��#BTFMJOF�DIBSBDUFSJTUJDT�BSF�QSFTFOUFE�JO�5B-

CMF�*��5IF�NFBO�BHF�PG�UIF�XPNFO�XBT��ZFBST� SBOHF��o��ZFBST��%BUB�XJUI�

regard to the type of COS per cycle are presented in Table II. One woman under-

went a long stimulation protocol and two underwent short stimulation protocols,

and one woman underwent two long stimulation protocols. The average number

PG�WJUSJmFE�PPDZUFT�XBT��SBOHF��o��

CHAPTER 3

54

Table I: #BTFMJOF�DMJOJDBM�DIBSBDUFSJTUJDT�PG�GPVS�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�DBODFS�

Baseline clinical characteristics

Age at start COS

.BSJUBM�TUBUVT

Previous pregnancies

#.*�LH�N�

)JTUPMPHJDBM�mOEJOHT�breast

tumour

#MPPNo3JDIBSETPO�HSBEF

)PSNPOF�SFDFQUPS�

status

Interventions before

start COS

Interventions after

start COS

Type of chemotherapy

AFC

Serum E2 at start COS ONPM�M

Case 1

27

.BSSJFE

0

22.2

IDC

2

&3� �13� �

)FS�/FV¦

BCS

35��$5

6 × TAC

14

0.2

Case 2

24

Single

0

21.7

IDC

3

&3� �13� �

)FS�/FV¦

#$4��35

35��$5

6 × TAC

19

0.6

Case 3

28

.BSSJFE

1 LB

18.3

IDC

Unknown

&3� �13� �

)FS�/FV¦

#.

"/%��35

��$5

6 × TAC

13

<0.1

Case 4

27

.BMF�QBSUOFS

0

22.6

IDC

2

&3� �13� �

)FS�/FV¦

BCS

.9��$5

�9�7&$��9�5"$

9

1.5

"'$ �BOUSBM�GPMMJDMF�DPVOU��"/% �BYJMMBSZ�OPEF�EJTTFDUJPO��#$4 �CSFBTU�DPOTFSWJOH�TVSHFSZ��#. �CJMBUFSBM�

NBTUFDUPNZ��)FS�/FV �)FS�OFV�TUBUVT��*%$ �JOWBTJWF�EVDUBM�DBSDJOPNB��-# �MJWF�CJSUI��.9 �NBTUFDUPNZ��

5"$ �EPDFUBYFM �BESJBNZDJOF�BOE�DZDMPQIPTQIBNJEF��35 �SBEJPUIFSBQZ��$5 �DIFNPUIFSBQZ


55

Table II: Characteristics of four women undergoing COS cycles for purpose of oocyte

WJUSJmDBUJPO�

Case 4

Long

protocol

8

225

1800

5

5.0

6

5

5

None

Characteristics of COS cycles

Stimulation protocol

'4)�EBZT

%PTBHF�PG�S'4)�EBZ�*6

5PUBM�EPTBHF�PG�S'4)�DZDMF�*6

Number of follicles 18-20mm

at time of hCG injection

4FSVN�&��ONPM�NM�BU�UJNF

of hCG injection

Number of oocytes retrieved

Number of oocytes metaphase II

/VNCFS�PG�PPDZUFT�WJUSJmFE

Complications COS/ovum

pick up

Case 1

Short

protocol

12

100/150a

1500

10

8.6

14

12

12

None

Case 2

Short

protocol

12

100

1200

12

12.1

19

14

14

None

Case 3-1

Long

protocol

11

200

2200

12

9.9

15

13

13

None

Case 3-2

Long

protocol

11

200

2200

8

9.3

13

10

10

None

aThe dosage was increased on stimulation day 7.

COS, controlled ovarian stimulation.

The tamoxifen and endoxifen levels showed a great variability between the women.

Serum E2 levels increased during COS in all women and showed a normal pattern,

XJUI�OP�NBKPS�EJGGFSFODFT�CFUXFFO�UIF�XPNFO�'JH��

CHAPTER 3

56

Figure 1

4FSVN�FTUSBEJPM�MFWFMT�EVSJOH�$04��5��JT�EBZ��PG�'4)�BENJOJTUSBUJPO��%BTIFT�SFQSFTFOU�EBZ�PG�CMPPE�

TBNQMJOH�BOE�NFBTVSFNFOUT�PG�&��MFWFMT��5IF�mOBM�&��NFBTVSFNFOUT�XFSF�CFGPSF�PWVN�QJDL�VQ�

The endoxifen levels during the whole period of COS varied between 3.96 and 41.0

ng/ml. At the time of ovum pick up a large inter-individual variability in serum ta-

moxifen and endoxifen levels between the women was demonstrated (range 5.9–44.5

ng/ml; Figs 2 and 3��*ODSFBTF�JO�FOEPYJGFO�MFWFMT�PCTFSWFE�JO�SFMBUJPO�UP�EVSBUJPO�PG�

tamoxifen use (Fig. 4�

00.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

11.0

12.0

13.0

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Stimulation period with FSH

Case number

1233 second cycle41233 second cycle4

Oes

trad

iol (

nmol

/l)


57

Figure 2

4FSVN�FOEPYJGFO�MFWFMT�EVSJOH�$04��5��JT�EBZ��PG�'4)�BENJOJTUSBUJPO��"MM�XPNFO�TUBSUFE��NH�UBNPY-

JGFO�UPHFUIFS�XJUI�'4)�PO�TUJNVMBUJPO�EBZ��8PNBO��TUBSUFE��NH�UBNPYJGFO�JO�UIF�MVUFBM�QIBTF�DZDMF�

EBZ��DPNCJOFE�XJUI�(O3I�B�%FDBQFQUZM¥��-BTU�FOEPYJGFO�NFBTVSFNFOUT�XFSF�QFSGPSNFE�BU�UIF�EBZ�

of ovum pick up.

00.0

10.0

20.0

30.0

40.0

50.0

60.0

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Case number


End

oxif

en (n

g/m

l)

15


CHAPTER 3

58

Figure 3

4FSVN�UBNPYJGFO�MFWFMT�EVSJOH�$04��5��JT�EBZ��PG�'4)�BENJOJTUSBUJPO��$BTF�OVNCFS��TUBSUFE��NH�

UBNPYJGFO�PO�DZDMF�EBZ�� UPHFUIFS�XJUI�UIF�JOJUJBUJPO�PG�(O3I�B�%FDBQFQUZM®��"MM�PUIFS�DBTFT�TUBSUFE��

NH�UBNPYJGFO�UPHFUIFS�XJUI�'4)�PO�TUJNVMBUJPO�EBZ��-BTU�FOEPYJGFO�NFBTVSFNFOUT�XFSF�QFSGPSNFE�BU�

the day of ovum pick up.

00.0

50.0

100.0

150.0

200.0

250.0

300.0

350.0

400.0

450.0

500.0

550.0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15


Tam

oxif

en (n

g/m

l)

Case number



59

Figure 4

4FSVN�FOEPYJGFO�MFWFMT�BOE�EBZT�PG�UBNPYJGFO�VTF��5��JT�EBZ��PG�'4)�BENJOJTUSBUJPO��$BTF�OVNCFS��

had restarted tamoxifen after withdrawal of 18 days.

All patients were pleased with their decision to undergo oocyte cryopreservation.

There were no complications during COS or ovum pick up for all four women in this

study.

Patient descriptions

Case 1

A 27-year-old nulligravid woman presented with a left breast mass suggestive of ma-

MJHOBODZ� BGUFS� WJTVBMJ[BUJPO�CZ�VMUSBTPVOE� BOE�NBNNPHSBQIZ��$PSF�OFFEMF� CJPQTZ�

TIPXFE� BO� &3�QPTJUJWF� CSFBTU� DBSDJOPNB�� #SFBTU�DPOTFSWJOH� TVSHFSZ� BOE� TFOUJOFM�

OPEF�QSPDFEVSF�XFSF�QFSGPSNFE �OP�BYJMMBSZ�NFUBTUBTFT�XFSF� GPVOE��3BEJPUIFSBQZ �

200.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

50.0

55.0

4 6 8 10 12 14 16 18 20 22 24 26 28

Days of Tamoxifen use

End

oxif

en (n

g/m

l)

Case number


30

CHAPTER 3

60

chemotherapy and subsequent possible future loss of fertility were discussed. She

married shortly after being diagnosed with breast cancer. The woman referred herself

for a fertility preservation consultation and was seen on menstruation cycle day 1, 2

XFFLT�QPTU�PQFSBUJWFMZ��"�TIPSU�QSPUPDPM�PG�$04�TJNVMUBOFPVT�TUBSU�PG�S'4)�BOE�(O-

3)�B�XBT�TUBSUFE�BT�XFMM�BT�BEEJUJPOBM�UBNPYJGFO��NH�QFS�EBZ��5IF�XPNBO�EJE�OPU�

opt for another COS cycle. Chemotherapy was started 51 days after oocyte retrieval.

Case 2

A 24-year-old nulligravid woman palpated a large lump in her right breast for which

a mammography and ultrasound of the breast and right axillary node was performed.

Lumpectomy was planned 1 week later, followed by radiotherapy and chemotherapy.

)JTUPMPHJDBM�mOEJOHT�SFWFBMFE�BO�&3�QPTJUJWF�JOWBTJWF�EVDUBM�CSFBTU�DBSDJOPNB�XJUI�

one axillary metastasis. The surgeon referred her to our centre, where she was seen

2 days post-operatively, to discuss options for fertility preservation. She had no male

QBSUOFS�BU�UIF�UJNF�PG�EJBHOPTJT��)FS�mSTU�DZDMF�PG�$04�XBT�B�MPOH�QSPUPDPM�PG�$04�

with tamoxifen. During this COS cycle, no extra blood samples were drawn as this

cycle took place before the start of the current study.

She stopped using tamoxifen after ovum pick up and restarted 16 days later, with the

initiation of her second COS cycle. As it was a late decision to start a second COS

cycle, a short stimulation protocol and tamoxifen was started on cycle day 5. The

woman reported misuse of tamoxifen in her diary and had used 30 mg in the luteal

QIBTF�QSFDFEJOH�UIF�TUBSU�PG�S'4)��0O�TUJNVMBUJPO�EBZ�� UIF�EPTBHF�XBT�DPSSFDUFE�

UP��NH�UBNPYJGFO�EBJMZ��3BEJPUIFSBQZ�XBT�DPOUJOVFE�VOUJM��XFFLT�BGUFS�mSTU�PWVN�

pick up. Chemotherapy was initiated 54 days after the second oocyte retrieval.

Case 3

A 28-year-old woman, who gave birth to a child in 2010, palpated a lump in her left

breast for which a mammography and ultrasound were performed. Core biopsy showed

BO�&3�QPTJUJWF�JOWBTJWF�EVDUBM�CSFBTU�DBSDJOPNB��#JMBUFSBM�NBTUFDUPNZ�XBT�QMBOOFE �

followed by gonadotoxic chemotherapy. The patient asked for a referral to our centre,

for information about fertility preservation techniques. This married woman had a

strong wish to vitrify oocytes because of her wish for autonomy in the course of fertil-

ity preservation. A long COS protocol with tamoxifen was started. After ovum pick up

��PPDZUFT�XFSF�SFUSJFWFE�BOE��NFUBQIBTF�**�PPDZUFT�XFSF�WJUSJmFE�


61

4IF�PQUFE�GPS�B�TFDPOE�$04�DZDMF�GPS�PPDZUF�WJUSJmDBUJPO �XIJDI�DPNNFODFE�BGUFS�

surgical removal of axillary nodes. Tamoxifen was stopped after the last ovum pick

up, for a period of 16 days. A long COS protocol with 60 mg tamoxifen was started

on menstrual cycle day 5 after surgery. Seven days after her second ovum pick up she

started with chemotherapy.

Case 4

A 27-year-old nulligravid woman palpated a small lump in the right breast. Visuali-

[BUJPO�CZ�VMUSBTPVOE�BOE�NBNNPHSBQIZ�XBT�QFSGPSNFE��XFFLT�MBUFS�BOE�TIPXFE�

NBMJHOBOU�GFBUVSFT��)JTUPMPHJDBM�mOEJOHT�SFWFBMFE�BO�&3�QPTJUJWF�JOWBTJWF�EVDUBM�DBS-

cinoma with no metastasis in axillary nodes. She was advised to undergo mastectomy,

followed by chemotherapy.

She was referred to our centre by her surgeon, and had had a male partner for 10

years. A long COS protocol with 60 mg tamoxifen was started. This woman started

UBNPYJGFO� JO� UIF� MVUFBM�QIBTF� DZDMF�EBZ�� UPHFUIFS�XJUI� UIF� JOJUJBUJPO�PG�(O3I�

agonist. On cycle day 5 of the next cycle, transvaginal ultrasound showed two cysts

JO�UIF�SJHIU�PWBSZ��(O3)�BHPOJTU�XBT�DPOUJOVFE�BOE�PO�DZDMF�EBZ��CJMBUFSBM�USBOT-

WBHJOBM�DZTU�QVODUJPO�XBT�QFSGPSNFE�BOE�DZUPMPHZ�TIPXFE�OP�NBMJHOBODZ��3FD'4)�

was started in the evening of cycle day 15. Seven days after ovum pick up the woman

started chemotherapy.

Discussion

8F�BTTFTTFE�UBNPYJGFO�BOE�UBNPYJGFO�NFUBCPMJUF�MFWFMT�JO�GPVS�XPNFO�XJUI�&3�QPT-

itive breast cancer who cryopreserved oocytes. Serum E2 levels increased during COS

in all women, with no major differences between the women. The average number

PG�WJUSJmFE�PPDZUFT�XBT��SBOHF��o��"�MBSHF�JOUFS�JOEJWJEVBM�WBSJBCJMJUZ�JO�TFSVN�

tamoxifen and endoxifen levels between the women at time of ovum pick up (range

��o��OH�NM�XBT�GPVOE��0G�OPUF �UISFF�PVU�PG�GPVS�XPNFO�BDIJFWFE�FOEPYJGFO�MFW-

FMT�DPOTJEFSFE�BEFRVBUF�GPS�&3�JOIJCJUJPO��OH�NM��.BEMFOTLZ�et al. ��Consistent with studies assessing pharmacokinetic effects of tamoxifen in the adju-

vant setting, we found a large variability in analysed endoxifen serum levels between

XPNFO��(FOPUZQF�WBSJBUJPO �JO�QBSUJDVMBS�UIF�$:1�%��HFOPUZQF �IBT�CFFO�GPVOE�UP�

be partly responsible for the large interpatient variability in endoxifen-levels (Borg-

CHAPTER 3

62

es et al. ��4JODF�POMZ�B�NJOPS�GSBDUJPO�PG�UIF�WBSJBUJPO�JO�FOEPYJGFO�MFWFMT�DBO�CF�

explained by genotyping, analysis of endoxifen concentrations is more appropriate

when assessing the pharmacokinetics of tamoxifen. Several studies support the idea

that the therapeutic effect of tamoxifen in the adjuvant setting can be demonstrated

XIFO�TFSVN�FOEPYJGFO�MFWFMT�SFBDI�B�DFSUBJO�UISFTIPME�+JO�et al., 2005; Borges et al., ��.BEMFOTLZ�et al. ��#FDBVTF�UIF�XPNFO�JO�PVS�TUVEZ�SFDFJWFE�IJHI�EPTFT�

of tamoxifen during COS, the cut-off points of endoxifen levels described in current

literature may be different from the cut-off point applicable for women in our study.

The pharmacokinetic action and biotransformation of tamoxifen when used during

COS is unknown. By handing out a diary in which women reported the time and

BNPVOU�PG�UBNPYJGFO�JOUBLF �XF�NJOJNJ[FE�DIBODFT�PG�JOBDDVSBUF�EPTF�SFMBUFE�mOE-

ings due to misuse of tamoxifen.

The long half life of tamoxifen might explain the observation that a prior cycle with

tamoxifen, with discontinuation and restart before a next COS cycle (as in case num-

CFS��DPOUSJCVUFT�UP�IJHIFS�MFWFMT�PG�UBNPYJGFO�BOE�FOEPYJGFO�

Our study has certain limitations. Because of the small case series, the interpretation

PG�UIF�SFTVMUT�JT�EJGmDVMU��4PNF�XPNFO�VOEFSXFOU�B�TIPSU�$04�QSPUPDPM�EVF�UP�UJNF�

restraints. This may have contributed to different outcomes in terms of serum tamox-

JGFO�BOE�FOEPYJGFO�MFWFMT�BOE�UIF�OVNCFS�PG�WJUSJmFE�PPDZUFT�

0VS�DFOUSF�VTFT�UBNPYJGFO�BT�BO�BEEJUJPOBM�BHFOU�UP�$04�JO�XPNFO�XJUI�&3�QPTJUJWF�

breast cancer. Another option to prevent the potentially harmful effect of high E2 lev-

FMT�JT�MFUSP[PMF�"*��-FUSP[PMF�MPXFST�FTUSPHFO�MFWFMT�EVSJOH�$04�0LUBZ�et al. ��*U�IBT�CFFO�GPVOE�UP�TVQQSFTT�UPUBM�CPEZ�BSPNBUJ[BUJPO�CZ��JO�QPTU�NFOPQBVTBM�

women (Dowsett et al. ��5IFSFGPSF �EVSJOH�$04 �UIF�BEEJUJPOBM�VTF�PG�MFUSP[PMF�

to reduce peak E2 levels may be considered an alternative regimen to counteract the

temporarily increased estrogen levels (Oktay et al. ��*O�UIF�BCTFODF�PG�MBSHF�SBO-

EPNJ[FE� DPOUSPMMFE� USJBMT� FWBMVBUJOH� UIF� TBGFUZ�PG� BEKVTUFE�$04�QSPUPDPMT�VTFE� JO�

XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�DBODFS � JOTJHIU� JOUP�UIF�QIBSNBDPLJOFUJD�BDUJPO�PG�

UIFTF�QSPUPDPMT�JT�JNQPSUBOU��0O�UIF�CBTJT�PG�UIFTF�mSTU�SFTVMUT �XF�DBO�DPODMVEF�UIBU�

therapeutically effective endoxifen serum levels, as when tamoxifen is used in the

adjuvant setting, can be reached when tamoxifen is used to counteract estrogen levels

during COS for fertility preservation. It is unknown whether the large interpatient

WBSJBUJPO�PG�PVS�TUVEZ�DPVME�JOnVFODF�UIF�QPUFOUJBM�BEWFSTF�FGGFDU�PG�UBNPYJGFO�QSP-

tected COS on breast cancer outcome. A large prospective cohort study with a larger

group of women is warranted.


63

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�t #BSCJFSJ�3-��'FNBMF�JOGFSUJMJUZ�DIBQUFS�� mHVSF��*O��4USBVTT�+' �#BSCJFSJ�

3- �FEJUPST��:FO�BOE�+BGGF�T�3FQSPEVDUJWF�&OEPDSJOPMPHZ��1IZTJPMPHZ �1BUIPQIZTJ-

PMPHZ�BOE�$MJOJDBM�.BOBHFNFOU��&MTFWJFS��Q��

�t #PSHFT� 4 �%FTUB�; � -J� - � 4LBBS�5$ �8BSE�#" �/HVZFO�" � +JO�: � 4UPSOJPMP�". �

/JLPMPGG�%. �8V�-�FU�BM��2VBOUJUBUJWF�FGGFDU�PG�$:1�%��HFOPUZQF�BOE�JOIJCJ-

UPST� PO� UBNPYJGFO� NFUBCPMJTN�� JNQMJDBUJPO� GPS� PQUJNJ[BUJPO� PG� CSFBTU� DBODFS�

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�t #PSHFT�4 �%FTUB�; �+JO�: �'BPV[J�" �3PCBSHF�+% �1IJMJQT�4 �/HVZFO�" �4UFBSOT�7 �

)BZFT�% �3BF�+.�FU�BM��$PNQPTJUF�GVODUJPOBM�HFOFUJD�BOE�DPNFEJDBUJPO�$:1�%��

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UJFOUT��+�$MJO�1IBSNBDPM��

�t #SBZ�' �3FO�+4 �.BTVZFS�& �'FSMBZ�+��&TUJNBUFT�PG�HMPCBM�DBODFS�QSFWBMFODF�GPS��

TJUFT�JO�UIF�BEVMU�QPQVMBUJPO�JO��*OU�+�$BODFS��

�t %PXTFUU�. �+POFT�" �+PIOTUPO�43 �+BDPCT�4 �5SVOFU�1 �4NJUI�*&��*O�WJWP�NFBT-

VSFNFOU�PG� BSPNBUBTF� JOIJCJUJPO�CZ� MFUSP[PMF� $(4�� JO�QPTUNFOPQBVTBM�

QBUJFOUT�XJUI�CSFBTU�DBODFS��$MJO�$BODFS�3FT��

�t )VMWBU�.$ �+FSVTT�+4��.BJOUBJOJOH�GFSUJMJUZ�JO�ZPVOH�XPNFO�XJUI�CSFBTU�DBODFS��

Curr Treat Options Oncol 2009; 10:308-317.

�t +JO�: �%FTUB�; �4UFBSOT�7 �8BSE�# �)P�) �-FF�,) �4LBBS�5 �4UPSOJPMP�". �-J�- �

"SBCB�"�FU�BM��$:1�%��HFOPUZQF �BOUJEFQSFTTBOU�VTF �BOE�UBNPYJGFO�NFUBCPMJTN�

EVSJOH�BEKVWBOU�CSFBTU�DBODFS�USFBUNFOU��+�/BUM�$BODFS�*OTU��

�t .BEMFOTLZ�- �/BUBSBKBO�- �5DIV�4 �1V�. �.PSUJNFS�+ �'MBUU�48 �/JLPMPGG�%. �

)JMMNBO�( �'POUFDIB�.3 �-BXSFODF�)+�FU�BM��5BNPYJGFO�NFUBCPMJUF�DPODFOUSB-

UJPOT �$:1�%��HFOPUZQF �BOE�CSFBTU�DBODFS�PVUDPNFT��$MJO�1IBSNBDPM�5IFS��

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CHAPTER 3

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duces estrogen and gonadotropin exposure in women with breast cancer under-

HPJOH�PWBSJBO�TUJNVMBUJPO�CFGPSF�DIFNPUIFSBQZ��+�$MJO�&OEPDSJOPM�.FUBC��

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QSPEVDUJWF�USBDU�DIBQUFS�� mHVSF��*O��4USBVTT�+' �#BSCJFSJ�3- �FEJUPST��:FO�

BOE�+BGGF�T�3FQSPEVDUJWF�&OEPDSJOPMPHZ��1IZTJPMPHZ �1BUIPQIZTJPMPHZ�BOE�$MJOJ-

DBM�.BOBHFNFOU��&MTFWJFS��Q��

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NPYJGFO�BOE�JUT�mWF�NBJO�QIBTF�*�NFUBCPMJUFT�JO�IVNBO�TFSVN�VTJOH�MJRVJE�DISP-

NBUPHSBQIZ�DPVQMFE�XJUI� UBOEFN�NBTT� TQFDUSPNFUSZ�� +�$ISPNBUPHS�#�"OBMZU�

Technol Biomed Life Sci 2011; 879:1677-1685.

66

CHAPTER X

67

XXXXXXX

CHAPTER 4Tamoxifen or letrozole versus standard methods for women

with estrogen-receptor positive breast cancer undergoing oo-

cyte or embryo cryopreservation in assisted reproduction.

T. Dahhan

&�.�&��#BMLFOFOEFS.C. Linn

.��WBO�8FMZ

.��(PEEJKO

Cochrane Database of Systematic Reviews, 2013; 11:CD010240.

CHAPTER 4

68

Abstract

Background

Cryopreservation of oocytes or embryos preceded by controlled ovarian stimulation

$04�DBO�JODSFBTF�UIF�DIBODF�PG�GVUVSF�QSFHOBODZ�JO�XPNFO�XJUI�CSFBTU�DBODFS�XIP�

SJTL�UIFSBQZ�JOEVDFE�PWBSJBO�GBJMVSF��*O�XPNFO�XJUI�FTUSPHFO�SFDFQUPS�&3�QPTJUJWF�

CSFBTU�DBODFS �BMUFSOBUJWF�$04�QSPUPDPMT�XJUI�UBNPYJGFO�PS�MFUSP[PMF�BSF�CFJOH�VTFE�

to theoretically inhibit breast cancer growth during COS.

Objectives

5P�BTTFTT�UIF�FGGFDUT�PG�UBNPYJGFO�PS�MFUSP[PMF �JO�BEEJUJPO�UP�TUBOEBSE$04�QSPUPDPMT �

PO�UIF�CSFBTU�DBODFS�GSFF�JOUFSWBM�JO�QSFNFOPQBVTBM�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�

cancer who undergo COS for embryo or oocyte cryopreservation.

Search methods

8F�TFBSDIFE�UIF�0WJE�$PDISBOF�$FOUSBM�3FHJTUFS�PG�$POUSPMMFE�5SJBMT�$&/53"- �

0WJE�.&%-*/& �0WJE�&.#"4& �0WJE�1TZD*/'0 �BOE�&#4$0IPTU�$*/")-��8F�

applied no limitations in year of publication or language. In addition, we searched

trial registers for ongoing and registered trials, conference abstracts, and sources of

HSFZ�MJUFSBUVSF��5IF�TFBSDI�XBT�DPOEVDUFE�JO�+BOVBSZ��

Selection criteria

3BOEPNJTFE�USJBMT�DPNQBSJOH�EJGGFSFOU�$04�QSPUPDPMT�JO�XPNFO�XJUI�CSFBTU�DBODFS�

were eligible for inclusion.

Data collection and analysis

Two review authors independently scanned the titles, abstracts, or both sections ac-

cording to Cochrane guidelines. If data to include were provided, data extraction

would have been independently performed by two review authors by using forms

designed according to Cochrane guidelines.

TAMOXIFEN OR LETROZOLE VERSUS STANDARD METHODS FOR WOMEN WITH ESTROGEN-RECEPTOR POSITIVE BREAST CANCER UNDERGOING

OOCYTE OR EMBRYO CRYOPRESERVATION IN ASSISTED REPRODUCTION

69

Main results

No randomised controlled trials were found that met the inclusion criteria.

Authors’ conclusions

$04�TDIFEVMFT�XJUI�UIF�BEEJUJPOBM�VTF�PG�UBNPYJGFO�PS�MFUSP[PMF�BSF�DPNNPOMZ�DIP-

TFO�BT�BO�BMUFSOBUJWF�SFHJNFO�JO�ZPVOH�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU�DBODFS�XIP�

undergo COS for oocyte or embryo cryopreservation. No randomised controlled tri-

als support the idea that these alternative COS schedules are superior to standard

COS.

Background

Description of the condition

8PSMEXJEF �BSPVOE��NJMMJPO�XPNFO�BSF�EJBHOPTFE�XJUI�CSFBTU�DBODFS�BOOVBMMZ�

(-0#0$"/� �� *O� �� OFX� DBTFT�XFSF� FYQFDUFE� UP� CF� SFQPSUFE� JO�

XPNFO�PG�SFQSPEVDUJWF�BHF�JO�UIF�64�"$4��"EKVWBOU�TZTUFNJD�CSFBTU�DBODFS�

USFBUNFOU�NBZ�IBWF�B�OFHBUJWF�JNQBDU�PO�GFSUJMJUZ��8PNFO�XJUI�FTUSPHFO�SFDFQUPS�

&3�QPTJUJWF�CSFBTU�DBODFS�VTVBMMZ�VOEFSHP�BEKVWBOU�IPSNPOBM�USFBUNFOU�GPS�mWF�

years, during which time pregnancy is contraindicated. The ovarian reserve at the

age by which conception is considered to be safe for these women might be insuf-

mDJFOU�GPS�DIBODFT�PG�OBUVSBM�DPODFQUJPO��5IF�"NFSJDBO�4PDJFUZ�PG�$MJOJDBM�0ODPM-

ogy recommends addressing options to preserve fertility for young women early in

UIF�CSFBTU�DBODFS�USBKFDUPSZ�-FF��

Description of the intervention

Cryopreservation of oocytes or embryos is a fertility-preserving technique that re-

RVJSFT� PWBSJBO� TUJNVMBUJPO� BOE� TIPVME� CF� QFSGPSNFE�CFGPSF� OFPBEKVWBOU� DIFN-

PUIFSBQZ� JT� QSPWJEFE�� 4UBOEBSE� DPOUSPMMFE� PWBSJBO� TUJNVMBUJPO� $04� QSPUPDPMT�

JODMVEF�IJHI�EPTFT�PG� GPMMJDMF�TUJNVMBUJOH�IPSNPOF� '4) �XIJDI�DBVTF� JODSFBTFE�

FTUSPHFO� FTUSBEJPM� MFWFMT � BOE�DPODVSSFOU�QJUVJUBSZ� TVQQSFTTJPO�CZ�EPXO�SFHVMB-

UJPO�PG�B�XPNBO�T�FOEPHFOPVT�'4)�BOE�MVUFJOJ[JOH�IPSNPOF�-)�QSPEVDUJPO�XJUI�

CHAPTER 4

70

HPOBEPUSPQJO�SFMFBTJOH�IPSNPOF�(O3)�BOBMPHVFT�PS�BOUBHPOJTUT��$04�QSFDFEFT�

retrieval of oocytes that can be used for direct cryopreservation or in vitro fertilisa-

UJPO�*7'�GPMMPXFE�CZ�DSZPQSFTFSWBUJPO�PG�FNCSZPT��&TUSPHFO�MFWFMT�SJTF�ESBTUJDBMMZ�

EVSJOH�$04��'PS�XPNFO�XJUI�&3�QPTJUJWF�CSFBTU� DBODFS � FMFWBUFE�FTUSPHFO� MFWFMT�

may theoretically induce growth of tumour cells. To avoid a potentially harmful

impact of COS on breast cancer outcome, women may receive an additional poten-

UJBMMZ�QSPUFDUJWF�FOEPDSJOF�BHFOU�UBNPYJGFO�PS�MFUSP[PMF�EVSJOH�$04�0LUBZ��

0LUBZ��B��0LUBZ��5BNPYJGFO�JT�BO�PSBMMZ�BENJOJTUFSFE�OPO�TUFSPJEBM�BOUJ�

estrogen triphenylethylene derivative with suppressive effects on breast cancer

HSPXUI�+PSEBO��5IF�ESVH�JT�FGGFDUJWF�BT�BEKVWBOU�USFBU�NFOU�JO�&3�QPTJUJWF�

CSFBTU�DBODFS�$MBSLF��-FUSP[PMF�JT�B�UIJSE�HFOFSBUJPO�BSPNBUBTF�JOIJCJUPS�"* �

which systemically prevents the synthesis of estrogen from androgens by competi-

UJWF � SFWFSTJCMF�CJOEJOH�PG� UIF�FO[ZNF�BSPNBUBTF�$:1��6TF�PG� UIJSE�HFOFSBUJPO�

AIs has long been restricted to postmenopausal women because preclinical studies

have indicated that aromatase inhibition can lead to an increase in gonadotropin

MFWFMT�BOE�NVMUJGPMMJDVMBS�HSPXUI�4IFUUZ��)PXFWFS �XJUI�DPODVSSFOU�TVQQSFT-

sion of ovarian estrogen synthesis, third-generation AIs can now be used safely in

premenopausal women for the purpose of providing adjuvant endocrine therapy

(PFM��8IFO�DPODVSSFOU�'4)�JT�HJWFO�UP�TUJNVMBUF�GPMMJDMF�HSPXUI �BT�JO�UIF�

case of COS, the co-administration of an AI attenuates estrogen levels to normal

premenopausal preovulatory peak concentrations.

How the intervention might work

"GUFS�PSBM�BENJOJTUSBUJPO�PG�UBNPYJGFO �NFUBCPMJUFT�BSF�GPSNFE�XJUI�IJHI�BGmOJUZ�

GPS�UIF�&3�UIBU �CZ�DPNQFUJUJWF�CJOEJOH �QSFWFOU�FTUSPHFOT�GSPN�CJOEJOH�BOE�BDUJ-

WBUJOH�UIF�&3�+PSEBO��5IF�FGmDBDZ�PG�UBNPYJGFO�JO�QSFWFOUJOH�CSFBTU�DBODFS�

HSPXUI�EVSJOH�$04�JT�VOLOPXO��-FUSP[PMF�EFDSFBTFT�UIF�QFBL�FTUSBEJPM�&��MFWFM�

EVSJOH�$04�0LUBZ��0LUBZ��B��#FDBVTF�UIF�NBJO�BDUJPO�PG�"*T�JO�UIF�BE-

juvant setting is considered to come from decreasing estrogen levels to less than

��QH�N-�CZ�CMPDLJOH�UIF�BSPNBUBTF�FO[ZNF�UIBU�GBDJMJUBUFT�UIF�DPOWFSTJPO�GSPN�

androgens into estrogens, it is unclear how E2 levels of ~380 pg/mL, measured dur-

JOH�$04�XJUI�MFUSP[PMF �DPVME�QSFWFOU�CSFBTU�DBODFS�HSPXUI��8IFUIFS�UIF�BEEJUJPO�

PG�UBNPYJGFO�PS�MFUSP[PMF�UP�TUBOEBSE�$04�EJNJOJTIFT�UIF�SJTL�PG�TVCTFRVFOU�CSFBTU�

DBODFS�SFDVSSFODF�JO�DPNQBSJTPO�XJUI�TUBOEBSE�$04�BMPOF�JO�XPNFO�XJUI�&3�QPTJ-

tive breast cancer remains unknown. In addition, although indications suggest that



71

B�IJHIFS�OVNCFS�PG�PPDZUFT�PS�FNCSZPT�BSF�SFUSJFWFE�XJUI�UIF�BEEJUJPO�PG�MFUSP[PMF�

UP�TUBOEBSE�$04�XIFO�DPNQBSFE�XJUI�UBNPYJGFO�0LUBZ�� UIF�QBSUJDJQBOU�TF-

SJFT�BSF�UPP�TNBMM�UP�BMMPX�BOZ�EFmOJUJWF�DPODMVTJPOT�UP�CF�ESBXO�

Why it is important to do this review

:PVOH�XPNFO�XJUI� CSFBTU� DBODFS� IBWF� SFQPSUFE�NBKPS� GFSUJMJUZ� SFMBUFE� DPODFSOT�

before and during breast cancer treatment and have stressed the need for more in-

GPSNBUJPO�PO�GFSUJMJUZ�QSFTFSWBUJPO�1BSUSJEHF��1BSUSJEHF��1SFNFOPQBVTBM�

&3�QPTJUJWF�CSFBTU�DBODFS�QBUJFOUT�XIP�SJTL�UIFSBQZ�JOEVDFE�JNQBJSNFOU�PG�PWBSJBO�

function rely on fertility-preserving techniques with minimal effects on breast can-

cer growth and unknown effects on the breast cancer free interval. Given that most

young breast cancer patients who opt for fertility preservation in current clinical

practice will undergo ovarian stimulation with an approximately two-week period

of iatrogenic high levels of estrogens, reproductive gynaecologists and oncologists

GBDF�TJHOJmDBOU�NBOBHFNFOU�DIBMMFOHFT�UP�BEFRVBUFMZ�JOGPSN�QBUJFOUT�BCPVU�$04��

Objectives

5P�BTTFTT�UIF�FGGFDUT�PG�UBNPYJGFO�PS�MFUSP[PMF �JO�BEEJUJPO�UP�TUBOEBSE�DPOUSPMMFE�

PWBSJBO�TUJNVMBUJPO�$04�QSPUPDPMT �PO�UIF�CSFBTU�DBODFS�GSFF�JOUFSWBM�JO�QSFNFOP-

pausal women with breast cancer who undergo COS for embryo or oocyte cryo-

preservation.

Methods

Criteria for considering studies for this review

Types of studies

3BOEPNJTFE�USJBMT�DPNQBSJOH�EJGGFSFOU�$04�QSPUPDPMT�JO�XPNFO�XJUI�CSFBTU�DBODFS�

were eligible for inclusion.

CHAPTER 4

72

Types of participants

8PNFO�CFUXFFO�UIF�BHFT�PG��BOE��ZFBST�EJBHOPTFE�XJUI�&3�QPTJUJWF�CSFBTU�DBO-

cer and undergoing COS were eligible for inclusion. For women older than 42 years

of age, cryopreservation of oocytes or embryos is no longer considered to be of use

because of the natural fertility decline.

Types of interventions

5IF�JOUFSWFOUJPO�PG�JOUFSFTU�XBT�$04�XJUI�UIF�VTF�PG�'4)�BMPOF �XIJDI�XBT�DPOTJE-

ered to be the control intervention. Comparison was made with COS protocols that

JODMVEFE�UIF�BEEJUJPOBM�VTF�PG�PSBM�UBNPYJGFO�PS�MFUSP[PMF�

Types of outcome measures

Primary outcomes

t�4BGFUZ�PG�$04 �EFmOFE�BT�SFDVSSFODF�GSFF� JOUFSWBM� 3'*�PG�CSFBTU�DBODFS� UIF�UJNF�

between breast cancer diagnosis and breast cancer recurrence; locoregional recurrence,

EJTUBOU�NFUBTUBTJT �PS�EFBUI�GSPN�CSFBTU�DBODFS �XIJDIFWFS�PDDVST�mSTU�)VEJT��

Secondary outcomes

t�$04�PVUDPNF �EFmOFE�BT�UIF�OVNCFS�PG�PPDZUFT�PS�FNCSZPT�SFUSJFWFE�BOE�DSZPQSF-

served after COS.

t�1FBL�FTUSBEJPM�MFWFMT�EVSJOH�$04 �EFmOFE�BT�UIF�MFWFM�PG�FTUSBEJPM�PO�UIF�EBZ�PG�IVNBO�

DIPSJPOJD�HPOBEPUSPQJO�I$(�JOKFDUJPO�

t�-JWF�CJSUI�SBUF�

t�"OZ�BEWFSTF�FWFOUT�

4FBSDI�NFUIPET�GPS�JEFOUJmDBUJPO�PG�TUVEJFT

5IF�$PDISBOF�.FOTUSVBM�%JTPSEFST�BOE�4VCGFSUJMJUZ�(SPVQ�.%4(�5SJBMT�4FBSDI�$P�

PSEJOBUPS�54$�XBT�DPOTVMUFE�SFHBSEJOH�EFWFMPQNFOU�PG�UIF�TFBSDI�TUSBUFHZ�JO�.&%-

-*/& �$&/53"- �&.#"4&�BOE�1TZD*/'0��5IF�54$�GPS�UIF�$PDISBOF�#SFBTU�$BODFS�

(SPVQ�XBT�DPOTVMUFE�SFHBSEJOH�TFBSDIJOH�PG�UIF�#SFBTU�$BODFS�4QFDJBMJTFE�3FHJTUFS�TFF�

"QQFOEJY��/P�MBOHVBHF�SFTUSJDUJPOT�XFSF�BQQMJFE�UP�BOZ�PG�UIF�TFBSDIFT�



73

Electronic searches

8F�TFBSDIFE�UIF�GPMMPXJOH�CJCMJPHSBQIJD�EBUBCBTF�TPVSDFT�GSPN�UIFJS�JODFQUJPO�UP�0D-

tober 2013:

t�0WJE�$PDISBOF�$FOUSBM�3FHJTUFS�PG�$POUSPMMFE�5SJBMT�$&/53"-�OPU�MJNJUFE�CZ�ZFBS�

PG�QVCMJDBUJPO�PS�MBOHVBHF�TFF�"QQFOEJY��

t�0WJE�.&%-*/&�OPU�MJNJUFE�CZ�ZFBS�PG�QVCMJDBUJPO�PS�MBOHVBHF�TFF�"QQFOEJY��

t�0WJE�&.#"4&�OPU�MJNJUFE�CZ�ZFBS�PG�QVCMJDBUJPO�PS�MBOHVBHF�TFF�"QQFOEJY��

t�0WJE�1TZD*/'0�OPU�MJNJUFE�CZ�ZFBS�PG�QVCMJDBUJPO�PS�MBOHVBHF�TFF�"QQFOEJY��BOE

t�&#4$0IPTU�$*/")-�OPU�MJNJUFE�CZ�ZFBS�PG�QVCMJDBUJPO�PS�MBOHVBHF�

TFF�"QQFOEJY��

Both indexed and free text terms were used in the search strategies. In identifying ran-

EPNJTFE�USJBMT �UIF�.&%-*/&�TFBSDI�XBT�DPNCJOFE�XJUI�UIF�$PDISBOF�IJHIMZ�TFOTJUJWF�

search strategy, which appears in the Cochrane Handbook for Systematic Reviews of Inter-ventions 7FSTJPO�� $IBQUFS�� 5IF�&.#"4&�TFBSDI�XBT�DPNCJOFE�XJUI�USJBM�

mMUFST�EFWFMPQFE�CZ� UIF�4DPUUJTI� *OUFSDPMMFHJBUF�(VJEFMJOFT�/FUXPSL� 4*(/� www.

TJHO�BD�VL�NFUIPEPMPHZ�mMUFST�IUNM�SBOEPN�

Searching other resources

Conference proceedings from 2000 to 2012: International Federation of Fertility So-

DJFUJFT�*''4 �"NFSJDBO�4PDJFUZ�GPS�3FQSPEVDUJWF�.FEJDJOF�"43. �#SJUJTI�'FSUJMJUZ�

4PDJFUZ�#'4 �&VSPQFBO�4PDJFUZ�GPS�)VNBO�3FQSPEVDUJPO�BOE�&NCSZPMPHZ�&4)3&�

BOE�*OUFSOBUJPOBM�4PDJFUZ�GPS�'FSUJMJUZ�1SFTFSWBUJPO�*4'1�XFSF�TFBSDIFE��'VSUIFSNPSF �

hand searches were performed of the proceedings of the annual meetings of the Ameri-

DBO�4PDJFUZ�PG�$MJOJDBM�0ODPMPHZ��UP��BOE�UIF�4BO�"OUPOJP�#SFBTU�$BODFS�

4ZNQPTJVN��UP��$POGFSFODF�BCTUSBDUT�XFSF�TFBSDIFE�PO�UIF�8FC�PG�,OPXM-

edge (http://wokinfo.com/�� 5SJBM� SFHJTUFST� XFSF� TFBSDIFE� GPS� POHPJOH� BOE� SFDFOUMZ�

completed trials:

t��$MJOJDBM5SJBMT�HPW� �B�TFSWJDF�PG�UIF�64�/BUJPOBM�*OTUJUVUFT�PG�)FBMUI�IUUQ��DMJOJDBM-

USJBMT�HPW�DU��IPNF��BOE

t�8PSME�)FBMUI�0SHBOJ[BUJPO��*OUFSOBUJPOBM�5SJBMT�3FHJTUSZ�1MBUGPSN�TFBSDI�QPSUBM��0QFO�

4*(-&�EBUBCBTF�XBT�TFBSDIFE�GPS�&VSPQFBO�HSFZ�MJUFSBUVSF�IUUQ��PQFOTJHMF�JOJTU�GS��

CHAPTER 4

74

Data collection and analysis

Selection of studies

As has been mentioned, eligibility criteria for including trials were applied by two re-

WJFX�BVUIPST�5%�BOE�&# �XIP�JOEFQFOEFOUMZ�TDBOOFE�UIF�UJUMFT �UIF�BCTUSBDUT�PS�CPUI�

sections. All potentially relevant articles that were likely to meet the inclusion criteria

were investigated in full text. No studies were found that met the inclusion criteria.

8IFO�UIJT�SFWJFX�JT�VQEBUFE�BOE�SBOEPNJTFE�DPOUSPMMFE�USJBMT�BSF�BWBJMBCMF�UIBU�NFFU�

our inclusion criteria, two review authors will independently investigate full text arti-

cles for compliance with the inclusion criteria and will select eligible studies according

to Cochrane guidelines. Differences and disagreements will be resolved by consensus or

by discussion with a third review author.

Data extraction and management

8F�QMBOOFE�UIBU�UXP�SFWJFX�BVUIPST�XPVME�FYUSBDU�BMM�EBUB�CZ�VTJOH�GPSNT�EFTJHOFE�JO�

accordance with Cochrane guidelines. Any disagreements would be resolved by discus-

TJPO�XJUI�UIF�TFOJPS�SFWJFX�BVUIPST�.( �.W8�BOE�4-�BOE�CZ�DPOTFOTVT��%BUB�XPVME�

be collected from each study that met the inclusion criteria. If studies failed to provide

information on time of follow-up, type of COS protocol, dosage of tamoxifen or letro-

[PMF �JOUFOUJPO�UP�USFBU�QPQVMBUJPO�TJ[F �IPSNPOF�SFDFQUPS�TUBUVT �PWBSJBO�SFTQPOTF�BOE�

breast cancer outcome, original data would be sought from the principal author.

Assessment of risk of bias in included studies

8F�QMBOOFE�UIBU�BMM�JODMVEFE�TUVEJFT�XPVME�CF�SBOEPNJTFE�USJBMT��5IF�NFUIPEPMPHJ-

cal quality of the included randomised trials would be assessed and reported by using

UIF�DSJUFSJB�TQFDJmFE�JO�UIF�Cochrane Handbook for Systematic Reviews of Interventions )JHHJOT��5XP�SFWJFX�BVUIPST�5%�BOE�&#�XPVME�JOEFQFOEFOUMZ�BTTFTT�UIF�SJTL�

PG�CJBT�PG�FBDI�JODMVEFE�TUVEZ��3JTL�PG�CJBT�BTTFTTNFOU�XPVME�DPNQSJTF�B�EFTDSJQUJPO�

BOE�B�KVEHNFOU�GPS�FBDI�FOUSZ�JO�B��3JTL�PG�CJBT��UBCMF �XIFSF�FBDI�FOUSZ�XPVME�BE-

ESFTT�B�TQFDJmD�GFBUVSF�PG�UIF�TUVEZ��5IF�NFUIPEPMPHJDBM�GFBUVSFT�UP�CF�BTTFTTFE�XPVME�

JODMVEF� �� TFRVFODF�HFOFSBUJPO � �� BMMPDBUJPO� TFRVFODF�DPODFBMNFOU � ��CMJOEJOH �

��JODPNQMFUF�PVUDPNF�EBUB ��TFMFDUJWF�PVUDPNF�SFQPSUJOH�BOE��PUIFS�QPUFOUJBM�

sources of bias.



75

Measures of treatment effect

8F�QMBOOFE�UIBU�PSEJOBM� TDBMFT� TVDI�BT� SFDVSSFODF�GSFF� JOUFSWBM�BOE�QFBL�FTUSBEJPM�

MFWFMT�EVSJOH�$04�XPVME�CF� USFBUFE�BT� DPOUJOVPVT�PVUDPNFT��.FBOT�BOE� TUBOEBSE�

EFWJBUJPOT�4%T�XPVME�CF�BCTUSBDUFE �DBMDVMBUFE�PS�SFRVFTUFE��'PS�DPOUJOVPVT�PVU-

DPNFT �NFBO�EJGGFSFODFT�.%T�XPVME�CF�QSFTFOUFE��"MM�CJOBSZ�PVUDPNFT�XPVME�CF�

TVNNBSJTFE�CZ�VTJOH�UIF�PEET�SBUJP�03�XJUI��DPOmEFODF�JOUFSWBM�$*��*G�EBUB�

XFSF�TLFXFE��¨�4%��NFBO�JT�HSFBUFS�UIBO�UIF�IJHIFTU�PS�MPXFTU�WBMVF �XF�XPVME�

log-transform the mean and SD within each group and then would make the com-

parison across groups. SDs would thus be allowed to differ in the two groups with a

5BZMPS�TFSJFT�BQQSPYJNBUJPO�PG�UIF�TUBOEBSE�FSSPS�4&�)JHHJOT��

Unit of analysis issues

8F�QMBOOFE�UIBU�BMM�PVUDPNFT�XPVME�CF�FYQSFTTFE�QFS�XPNBO�SBOEPNMZ�BTTJHOFE�

Dealing with missing data

8F�QMBOOFE�UIBU �JG�XF�XPVME�mOE�JOTVGmDJFOU�JOGPSNBUJPO�JO�UIF�QVCMJTIFE�SFQPSU�

PG�B�TUVEZ �XF�XPVME�BUUFNQU�UP�DPOUBDU�UIF�BVUIPST�GPS�DMBSJmDBUJPO��*G�NJTTJOH�EBUB�

CFDBNF�BWBJMBCMF �UIFTF�XPVME�CF�JODMVEFE�JO�UIF�BOBMZTJT��8F�BOUJDJQBUFE�UIBU�USJBMT�

conducted over 10 years ago might not have data on live birth rates of study partici-

QBOUT��8F�QMBOOFE�UIBU�EBUB�FYUSBDUFE�GSPN�UIF�USJBMT�XPVME�CF�BOBMZTFE�PO�BO�JOUFO-

UJPO�UP�USFBU�CBTJT��8IFSF�SBOEPNJ[FE�DBTFT�XFSF�NJTTJOH�GSPN�PVUDPNF�BTTFTTNFOU �

XF�XPVME�mSTU�DPOUBDU�UIF�BVUIPST�GPS�BEEJUJPOBM�EBUB��*G�GVSUIFS�EBUB�XFSF�OPU�BWBJM-

able, we would assume that the missing participants had failed to achieve pregnancy.

Assessment of heterogeneity

8F�QMBOOFE� UIBU� UIF� QSFTFODF� PG� BOZ� TUBUJTUJDBM� IFUFSPHFOFJUZ� PG� USFBUNFOU� FGGFDU�

among trials would be determined using the I2�TUBUJTUJD��8F�QMBOOFE�UP�BEPQU�UIF�GPM-

lowing broad interpretation: 0% to 40%, might not be important; 30% to 60%, may rep-

resent moderate heterogeneity; 50%to 90%, may represent substantial heterogeneity;

BOE��UP�� DPOTJEFSBCMF�IFUFSPHFOFJUZ�QSFTFOU�)JHHJOT��)JHHJOT��

CHAPTER 4

76

Assessment of reporting biases

8F�QMBOOFE�UIBU�UP�FWBMVBUF�FYUFSOBM�SFQPSUJOH�CJBT � GVOOFM�QMPUT�GPS�QSJNBSZ�PVU-

DPNFT�BOE�GPS�UIF�DMJOJDBM�QSFHOBODZ�SBUF�XPVME�CF�QSFTFOUFE � JG�TVGmDJFOU�TUVEJFT�

XFSF�JEFOUJmFE��*G�FWJEFODF�PG�TNBMM�TUVEZ�FGGFDUT�XBT�GPVOE �QVCMJDBUJPO�CJBT�XPVME�

CF�DPOTJEFSFE�BT�POMZ�POF�PG�B�OVNCFS�PG�QPTTJCMF�FYQMBOBUJPOT��8F�XPVME�BMTP�JOGPS-

mally compare the results for live birth rates between those studies that reported live

birth rates and those that did not.

Data synthesis

*G�USJBMT�XFSF�TVGmDJFOUMZ�TJNJMBS �3FWJFX�.BOBHFS�TPGUXBSF�XPVME�CF�VTFE�UP�QFSGPSN�

NFUB�BOBMZTFT�VTJOH�B�mYFE�FGGFDU�NPEFM��3FTVMUT�GPS�DPOUJOVPVT�PVUDPNFT�XPVME�CF�

DPNCJOFE�VTJOH�.%�BOE��$*��'PS�CJOBSZ�PVUDPNFT �UIF�1FUP�BQQSPBDI�XPVME�CF�

applied.

Subgroup analysis and investigation of heterogeneity

8F�QMBOOFE�UIBU�JG�NPEFSBUF�IFUFSPHFOFJUZ�*2 *��FYJTUFE�XJUIJO�TUSBUB �JU�XPVME�

be explored informally by using the clinical and design details recorded in the table

�$IBSBDUFSJTUJDT�PG�JODMVEFE�TUVEJFT��)FUFSPHFOFJUZ�CFUXFFO�TUSBUB�XPVME�CF�BOUJDJ-

pated, and possible reasons would be discussed.

Sensitivity analysis

8F�QMBOOFE�UIBU�JG�EBUB�GSPN�NPSF�UIBO�GPVS�TUVEJFT�XFSF�BWBJMBCMF �TFOTJUJWJUZ�BOBMZ-

TFT�XPVME�CF�QFSGPSNFE��8F�XPVME�BTTFTT�UIF�JOnVFODF�PG�SJTL�PG�CJBT�PO�FGGFDU�TJ[F�

by removing trials deemed to be at high risk. Studies with high risk of bias would

JODMVEF�UIPTF�UIBU�XFSF�OPU�EPOF�CZ�VTJOH�BO�JOUFOUJPO�UP�USFBU�*55�BQQSPBDI�BOE�

those that had inadequate concealment of allocation. Analyses would be repeated by

using a random-effects model to explore whether different conclusions were reached.

Sensitivity analyses would be reported for the primary outcome only.



77

0WFSBMM�RVBMJUZ�PG�UIF�CPEZ�PG�FWJEFODF��4VNNBSZ�PG�mOEJOHT��UBCMF

8F�QMBOOFE�UIBU�B� A4VNNBSZ�PG�mOEJOHT��UBCMF�XPVME�CF�HFOFSBUFE�CZ�VTJOH�(3"-

%&130�TPGUXBSF��5IJT�UBCMF�XPVME�FWBMVBUF�UIF�PWFSBMM�RVBMJUZ�PG�UIF�CPEZ�PG�FWJ-

EFODF�GPS�UIF�NBJO�SFWJFX�PVUDPNFT�VTJOH�(3"%&�DSJUFSJB�TUVEZ�MJNJUBUJPOT �UIBU�

JT �SJTL�PG�CJBT��DPOTJTUFODZ�PG�FGGFDU��JNQSFDJTJPO��JOEJSFDUOFTT��BOE�QVCMJDBUJPO�CJBT��

+VEHNFOUT�BCPVU�FWJEFODF�RVBMJUZ�IJHI �NPEFSBUF�PS�MPX�XPVME�CF�KVTUJmFE �EPDV-

mented and incorporated into the report of results for each outcome.

Results

Description of studies

No randomised controlled trials comparing different COS protocols in women with

breast cancer were found.

Results of the search

Two review authors independently screened 262 titles and abstracts that were identi-

mFE�CZ�UIF�DPOEVDUFE�FMFDUSPOJD�TFBSDIFT�BOE�CZ�TDSFFOFE�DPOGFSFODF�QSPDFFEJOHT �

abstracts, sources of grey literature and trial registers. No randomised controlled tri-

BMT�XFSF�JEFOUJmFE�'JHVSF��

CHAPTER 4

78

Figure 1: 4UVEZ�nPX�EJBHSBN

198 of records

JEFOUJmFE�UISPVHI�

database searching

262 of records

screened

7 of full-text

articles assessed

for eligibility

No studies included in

qualitive synthesis

255 of records excluded

7 of full-text articles ex-

cluded, because they did

not meet inclusion criteria

64 of additional

SFDPSET�JEFOUJmFE

through other sources

Included studies

No studies met our inclusion criteria.

Excluded studies

In total, seven studies were excluded after the full text of the article had been read,

because the studies did not meet our inclusion criteria. In particular, one study was

FYDMVEFE�GSPN�UIF�SFWJFX�CFDBVTF� JU�XBT�OPU� SBOEPNJTFE� 0LUBZ��5IJT� TUVEZ�

DPNQBSFE�EJGGFSFOU�$04�QSPUPDPMT� JO�XIJDI�QSPUPDPMT�XJUI�SFD'4)�UBNPYJGFO � UB-

NPYJGFO�BMPOF�BOE�SFD'4)�MFUSP[PMF�XFSF�DPNQBSFE�JO��XPNFO�XJUI�CSFBTU�DBODFS�

VOEFSHPJOH�$04�GPS�DSZPQSFTFSWBUJPO�PG�FNCSZPT�0LUBZ��"�UPUBM�PG��XPNFO�

XIP�VOEFSXFOU��TUJNVMBUJPO�DZDMFT�XJUI�UBNPYJGFO�BMPOF��NH�E�PS�SFD'4)�UB-

NPYJGFO��NH�E�PS�SFD'4)�MFUSP[PMF��NH�E�XFSF�DPNQBSFE�XJUI�B�DPOUSPM�HSPVQ�

of 31 women with breast cancer who did not opt for fertility preservation. Compared

with women who received tamoxifen alone, women who received the combination

SFD'4)�UBNPYJGFO�PS� SFD'4)�MFUSP[PMF �IBE�B�HSFBUFS�OVNCFS�PG� GPMMJDMFT��1FBL�&��

MFWFMT�JO�UIF�SFD'4)�MFUSP[PMF�HSPVQ�XFSF�TJHOJmDBOUMZ�MPXFS�UIBO�JO�UIF�HSPVQ�SF-



79

DFJWJOH�UBNPYJGFO�BMPOF�PS�SFD'4)�UBNPYJGFO��"GUFS��EBZT�SBOHF��UP��

EBZT�PG�GPMMPX�VQ �DBODFS�SFDVSSFODF�SBUF�XBT�TJNJMBS�CFUXFFO�XPNFO�VOEFSHPJOH�

COS and women who served as a control group (three of 29 vs three of 31 women,

SFTQFDUJWFMZ��IB[BSE�SBUJP ��$*��UP��

Risk of bias in included studies

Not applicable.

Effects of interventions

Not applicable.

Discussion

Summary of main results

No randomised controlled trials were found that compared COS protocols with ad-

EJUJPOBM�UBNPYJGFO�PS�MFUSP[PMF�WFSTVT�TUBOEBSE�$04�QSPUPDPMT�JO�XPNFO�XJUI�CSFBTU�

cancer. Cryopreservation of oocytes or embryos is a common form of fertility pres-

ervation in women with breast cancer who risk therapy-induced ovarian failure. No

evidence indicates that standard COS promotes breast cancer growth in the setting

of fertility preservation before adjuvant treatment. Nevertheless, alternative COS

QSPUPDPMT�XJUI� UBNPYJGFO�PS� MFUSP[PMF�BSF�CFJOH�VTFE�PO� UIF�CBTJT�PG� UIF� JEFB� UIBU�

standard COS promotes breast cancer growth. Given the lack of evidence to support

UIJT�JEFB �UIF�VTF�PG�$04�QSPUPDPMT�UIBU�JODMVEF�UBNPYJGFO�PS�MFUSP[PMF�TIPVME�CF�SF-

stricted to the setting of randomised controlled trials.

Author’s conclusions

Implications for practice

No available evidence supports the idea that women with breast cancer should un-

EFSHP�$04�XJUI� UIF� BEEJUJPO� PG� UBNPYJGFO� PS� MFUSP[PMF�� 5IFSFGPSF � TUBOEBSE�$04�

CHAPTER 4

80

SFNBJOT�UIF�mSTU�DIPJDF�SFHJNFO�GPS�XPNFO�XJUI�CSFBTU�DBODFS�XIP�XJTI�UP�VOEFSHP�

COS for cryopreservation of oocytes or embryos.

Implications for research

3FHBSEJOH�UIF�DVSSFOU�MBDL�PG�SBOEPNJTFE�DPOUSPMMFE�USJBMT�DPNQBSJOH�TUBOEBSE�$04�

QSPUPDPMT�XJUI�BMUFSOBUJWF�$04�QSPUPDPMT �XIJDI�JODMVEF�UBNPYJGFO�PS�MFUSP[PMF �XF�

TUSFTT�UIF�OFFE�GPS�B�SBOEPNJ[FE�DPOUSPMMFE�USJBM��5BNPYJGFO�PS�MFUSP[PMF�TIPVME�CF�

given in addition to COS only in the setting of a randomised controlled trial under-

taken to compare the effects on the breast cancer free interval of standard versus

alternative COS protocols.

Acknowledgements

8F�XBOU�UP�UIBOL�.BSJBO�4IPXFMM�BOE�UIF�FEJUPSJBM�TUBGG�PG�UIF�$PDISBOF�.FOTUSVBM�

%JTPSEFST�BOE�4VCGFSUJMJUZ�(SPVQ�GPS�UIFJS�BTTJTUBODF�BOE�TVQQPSU �3PC�4DIPMUFO�PG�

the Dutch Cochrane Center for his help during the process of title registration and

Fergus Tai of the Cochrane Breast Cancer Group for his search.



81

Appendix 1. Cochrane Breast Cancer Group search strategy

Details of the search strategies used by the Cochrane Breast Cancer Group Specialised

3FHJTUFS�GPS�UIF�JEFOUJmDBUJPO�PG�TUVEJFT�BOE�UIF�QSPDFEVSF�VTFE�UP�DPEF�SFGFSFODFT�

BSF�PVUMJOFE�JO�UIF�(SPVQ�T�NPEVMF�XXX�NSX�JOUFSTDJFODF�XJMFZ�DPN�DPDISBOF�DMB-

CPVU�BSUJDMFT�#3&"45$"�GSBNF�IUNM��8F�FYUSBDUFE�USJBMT�DPEFE�XJUI�UIF�LFZ�XPSET�

ACSFBTU� DBODFS� � AFOEPUIFSBQZ� � AMFUSP[PMF� � ABSPNBUBTF� JOIJCJUPS� � A'BNBSB� � AUBNPYJGFO�

DJUSBUF� �AUBNPYJGFO� �A/PMWBEFY� �A*TUVCVM� �A7BMPEFY� �AFNCSZP�USBOTGFS� �AGFSUJMJTBUJPO�JO�

WJUSP� �ATQFSN�JOKFDUJPO� �APWBSJBO�TUJNVMBUJPO� �AWJUSP�GFSUJMJTBUJPO� �AWJUSP�GFSUJMJ[BUJPO� �

AJWJ�FU� � AJWG� � AJDTJ� � AJOUSBDZUPQMBTNJD� TQFSN� JOKFDUJPO� � ACMBTUPDZTU� USBOTGFS� � ABTTJTUFE�

SFQSPEVDUJPO� � APWVMBUJPO� JOEVDUJPO� � ATVQFSPWVMBUJPO� � APWBSJBO� IZQFSTUJNVMB� � ADPI� �

ADSZPQSFTFSWBUJPO� � ASFQSPEVDUJWF� QSPDFTT� � ASFQSPEVDUJWF� QSPDFEVSF� � ADPT� � AGFSUJMJUZ�

QSFTFSWBUJPO� �AWJUSJmDBUJPO� �ADSZPQSFTFSWBUJPO� �APPDZUF� �AFNCSZP� �APWBSJBO�JOEVDUJPO� �

BOE�APWBSJBO�IZQFSTUJNVMBUJPO��GPS�DPOTJEFSBUJPO��5IJT�TFBSDI�XBT�SVO�PO��+VMZ��

On October 25 the search was updated using the following terms:

$#$(�43�i5BNPYJGFO�WT�-FUSP[PMF�SNEw��i5BNPYJGFO�WT�-FUSP[PMF�SNYw�i$#$(�43�

4FBSDI�3FTVMUT��UYUw��SFDPSET�SFUSJFWFE�

CHAPTER 4

82

Appendix 2. CENTRAL search strategy

5IJT�TFBSDI�XBT�SVO�PO��.BZ�� BOE�VQEBUFE�UP��0DUPCFS��

��FYQ�FNCSZP�USBOTGFS��PS�FYQ�GFSUJMJ[BUJPO�JO�WJUSP��PS�FYQ�TQFSN�JOKFDUJPOT �JOUSBDZ-

UPQMBTNJD��

��FNCSZP�USBOTGFS��UX��

��WJUSP�GFSUJMJ BUJPO�UX��

��JWG�FU�UX��

��JWG�UX��

��JDTJ�UX��

��JOUSBDZUPQMBTNJD�TQFSN�JOKFDUJPO��UX��

��CMBTUPDZTU�BEK��USBOTGFS��UX��

��PWVMBUJPO�JOEVD��UX��

��PWBSJ��BEK��TUJNVMBU��UX��

��TVQFSPWVMBU��UX��

��$0)�UX��

��PWBSJ��BEK��JOEVDUJPO�UX��

��FYQ�GFSUJMJUZ�QSFTFSWBUJPO��PS�FYQ�PWVMBUJPO�JOEVDUJPO��PS�FYQ�TVQFSPWVMBUJPO��

��$04�UX��

��GFSUJMJUZ�QSFTFSW��UX��

��FYQ�$SZPQSFTFSWBUJPO��

��FYQ�7JUSJmDBUJPO��

��$SZPQSFTFSWBUJPO�BEK��PPDZUF��UX��

��$SZPQSFTFSWBUJPO�BEK��FNCSZP��UX��

��PWBSJ��BEK��IZQFSTUJNVMBUJ��UX��

��PS��

��5BNPYJGFO�UX��

��5BNPYJGFO��

��/PMWBEFY�UX��

��*TUVCBM�UX��

��7BMPEFY�UX��

��PS��

��-FUSP[PMF�UX��

��'FNBSB�UX��

��FYQ�"SPNBUBTF�*OIJCJUPST��

��PS��

��BOE��BOE��



83

Appendix 3. MEDLINE search strategy



UPQMBTNJD��


��WJUSP�GFSUJMJ BUJPO�UX��









��$0)�UX��


14 exp fertility preservation/ or exp ovulation induction/ or exp superovulation/

��

��$04�UX��


��FYQ�$SZPQSFTFSWBUJPO��

��FYQ�7JUSJmDBUJPO��




��PS��


��5BNPYJGFO��




��PS��



��FYQ�"SPNBUBTF�*OIJCJUPST��

CHAPTER 4

84

��"SPNBUBTF�*OIJCJUPS��UX��

��PS��


��SBOEPNJ[FE�DPOUSPMMFE�USJBM�QU��

��DPOUSPMMFE�DMJOJDBM�USJBM�QU��

��SBOEPNJ[FE�BC��

��QMBDFCP�UX��

��DMJOJDBM�USJBMT�BT�UPQJD�TI��

��SBOEPNMZ�BC��

��USJBM�UJ��

��DSPTTPWFS�PS�DSPTT�PWFS�PS�DSPTT�PWFS�UX��

��PS��

��BOJNBMT�OPU�IVNBOT�BOE�BOJNBMT�TI��

��OPU��

��BOE��



85

Appendix 4. EMBASE search strategy



UPQMBTNJD��


��WJUSP�GFSUJMJTBUJPO�PS�WJUSP�GFSUJMJ[BUJPO�UX��






��BTTJTUFE�SFQSPEVDU��UX��




��PWBSJBO�IZQFSTUJNVMBUJPO�UX��

��$0)�UX��


��FYQ�PWVMBUJPO�JOEVDUJPO��

��FYQ�DSZPQSFTFSWBUJPO��

��FYQ�SFQSPEVDUJWF�QSPDFEVSFT��

��FYQ�TVQFSPWVMBUJPO��

��$04�UX��


��FYQ�WJUSJmDBUJPO��




��PS��

��FYQ�UBNPYJGFO�DJUSBUF��PS�FYQ�UBNPYJGFO��





��PS��

CHAPTER 4

86

��FYQ�MFUSP[PMF��PS�BSPNBUBTF�JOIJCJUPS��



��BSPNBUBTF�JOIJCJUPS��UX��

��PS��


��$MJOJDBM�5SJBM��

��3BOEPNJ[FE�$POUSPMMFE�5SJBM��

��FYQ�SBOEPNJ[BUJPO��

��4JOHMF�#MJOE�1SPDFEVSF��

��%PVCMF�#MJOE�1SPDFEVSF��

��$SPTTPWFS�1SPDFEVSF��

��1MBDFCP��

��3BOEPNJ FE�DPOUSPMMFE�USJBM��UX��

��3DU�UX��

��SBOEPN�BMMPDBUJPO�UX��

��SBOEPNMZ�BMMPDBUFE�UX��

��BMMPDBUFE�SBOEPNMZ�UX��

��BMMPDBUFE�BEK��SBOEPN�UX��

��4JOHMF�CMJOE��UX��

��%PVCMF�CMJOE��UX��

��USFCMF�PS�USJQMF�BEK�CMJOE��UX��

��QMBDFCP��UX��

��QSPTQFDUJWF�TUVEZ��

��PS��

��DBTF�TUVEZ��

��DBTF�SFQPSU�UX��

��BCTUSBDU�SFQPSU��PS�MFUUFS��

��PS��

��OPU��

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87

Appendix 5. PsycINFO search strategy


��FYQ�SFQSPEVDUJWF�UFDIOPMPHZ��

��JO�WJUSP�GFSUJMJ BUJPO�UX��


��JWG�PS�FU�UX��




��BTTJTUFE�SFQSPEVDU��UX��



��PWBSJBO�IZQFSTUJNVMBUJPO�UX��

��$0)�UX��



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��$04�UX��





��PS��





��PS��



��"SPNBUBTF�*OIJCJUPS��UX��

��PS��


CHAPTER 4

88

Appendix 6. CINAHL search strategy

This search was run on 16 October 2013.

S5 AND S10 13

� 4��03�4��03�4��

4�� 59�GSFF[��

4�� i7JUSJmDBUJPOw� � � � � � � � ��

4�� .)�i$SZPQSFTFSWBUJPO�w�03�i$SZPQSFTFSWBUJPOw� � � � ��

4�� ..�i'FSUJMJUZw�03�iGFSUJMJUZw03�i..�i'FSUJMJUZ�1SFTFSWBUJPOw��

S5 S1 AND S4 644

4�� 4��03�4��

4�� ..�i"SPNBUBTF�*OIJCJUPSTw�03�i"SPNBUBTF�*OIJCJUPSTw��

4�� i-FUSP[PMFw� � � � � � � � ��

4�� .)�i5BNPYJGFO�w�03�i5BNPYJGFO� � � � � � ��



89

References

References of excluded full-text articles

�% "[JN�"" �$PTUBOUJOJ�'FSSBOEP�. �0LUBZ�,��4BGFUZ�PG�GFSUJMJUZ�QSFTFSWBUJPO�CZ�PWBS-

JBO�TUJNVMBUJPO�XJUI�MFUSP[PMF�BOE�HPOBEPUSPQJOT�JO�QBUJFOUT�XJUI�CSFBTU�DBODFS��B�

prospective controlled study. Journal of Clinical Oncology 2008; 26:2630–5.

�% ,PWBDT�1 �.BUZBT�4 �6OHBS�-��1SFTFSWBUJPO�PG�GFSUJMJUZ�JO�SFQSPEVDUJWF�BHF�XPNFO�XJUI�

the diagnosis of cancer. European Journal of Gynaecological Oncology 2008; 29:425–34.

�% .BSIIPN�& �$PIFO�*��'FSUJMJUZ�QSFTFSWBUJPO�PQUJPOT�GPS�XPNFO�XJUI�NBMJHOBODJFT��

Obstetrical & Gynecological Survey 2007; 62:58–72.

�% .JUXBMMZ�.'��'FSUJMJUZ�QSFTFSWBUJPO�BOE�NJOJNJ[JOH�SFQSPEVDUJWF�EBNBHF�JO�DBO-

cer survivors. Expert Review of Anticancer Therapy 2007; 7:989–1001.

�% 0LUBZ�, �#VZVL�& �-JCFSUFMMB�/ �"LBS�. �3PTFOXBLT�;��'FSUJMJUZ�QSFTFSWBUJPO�JO�

breast cancer patients: a prospective controlled comparison of ovarian stimulation

XJUI�UBNPYJGFO�BOE�MFUSP[PMF�GPS�FNCSZP�DSZPQSFTFSWBUJPO��Journal of Clinical On-cology 2005; 23:4347–53.

�% 1BSUSJEHF�") �3VEEZ�,+��'FSUJMJUZ�BOE�BEKVWBOU�USFBUNFOU�JO�ZPVOH�XPNFO�XJUI�

breast cancer. Breast (Edinburgh, Scotland) 2007; 16:175–81.

�% 4PONF[FS�. �0LUBZ�,��'FSUJMJUZ�QSFTFSWBUJPO�JO�ZPVOH�XPNFO�VOEFSHPJOH�CSFBTU�

cancer therapy. The Oncologist 2006; 11:422–34.

Additional references

�% $MBSLF�.+��5BNPYJGFO�GPS�FBSMZ�CSFBTU�DBODFS��Cochrane Database of Systematic Re-views 2008: CD000486.

�% (PFM�4 �4IBSNB�3 �)BNJMUPO�" �#FJUI�+��-)3)�BHPOJTUT�GPS�BEKVWBOU�UIFSBQZ�PG�FBS-

ly breast cancer in premenopausal women. Cochrane Database of Systematic Reviews 2009:CD004562.

CHAPTER 4

90

�% )JHHJOT�+1 �5IPNQTPO�4(��2VBOUJGZJOH�IFUFSPHFOFJUZ�JO�B�NFUB�BOBMZTJT��Statis-tics in Medicine 2002; 21:1539–58.

�% )JHHJOT�+1 �8IJUF�*3 �"O[VSFT�$BCSFSB�+��.FUB�BOBMZTJT�PG�TLFXFE�EBUB��DPNCJO-

ing results reported on log-transformed or raw scales. Statistics in Medicine 2008;

27:6072–92.

�% )JHHJOT� +15 �(SFFO�4��Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011.

�% )VEJT�$" �#BSMPX�8& �$PTUBOUJOP�+1 �(SBZ�3+ �1SJUDIBSE�,* �$IBQNBO�+"�FU�BM��

1SPQPTBM�GPS�TUBOEBSEJ[FE�EFmOJUJPOT�GPS�FGmDBDZ�FOE�QPJOUT�JO�BEKVWBOU�CSFBTU�

cancer trials: the STEEP system. Journal of Clinical Oncology 2007; 25:2127–32.

�% +PSEBO�7$��5BNPYJGFO��B�NPTU�VOMJLFMZ�QJPOFFSJOH�NFEJDJOF��Nature Reviews. Drug Discovery 2003; 2: 205–13.

�% +PSEBO�7$��/FX�JOTJHIUT� JOUP�UIF�NFUBCPMJTN�PG� UBNPYJGFO�BOE� JUT� SPMF� JO� UIF�

treatment and prevention of breast cancer. Steroids 2007; 72:829–42.

�% -FF�4+ �4DIPWFS�-3 �1BSUSJEHF�") �1BUSJ[JP�1 �8BMMBDF�8) �)BHFSUZ�,�FU�BM��"NFS-

ican Society of Clinical Oncology recommendations on fertility preservation in

cancer patients. Journal of Clinical Oncology 2006; 24:2917–31.

�% 0LUBZ�, �#VZVL�& �-JCFSUFMMB�/ �"LBS�. �3PTFOXBLT�;��'FSUJMJUZ�QSFTFSWBUJPO�JO�

breast cancer patients: a prospective controlled comparison of ovarian stimula-

UJPO�XJUI�UBNPYJGFO�BOE�MFUSP[PMF�GPS�FNCSZP�DSZPQSFTFSWBUJPO��Journal of Clinical Oncology ��o��

�% 0LUBZ�,)��0QUJPOT�GPS�QSFTFSWBUJPO�PG�GFSUJMJUZ�JO�XPNFO��The New England Jour-nal of Medicine 2005a; 353:1418-20.

�% 0LUBZ�, �)PVSWJU[�" �4BIJO�( �0LUFN�0 �4BGSP�# �$JM�"�FU�BM��-FUSP[PMF�SFEVDFT�

estrogen and gonadotropin exposure in women with breast cancer undergoing

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91

�% 1BSUSJEHF�") �3VEEZ�,+��'FSUJMJUZ�BOE�BEKVWBOU�USFBUNFOU�JO�ZPVOH�XPNFO�XJUI�

breast cancer. Breast 2007; 16:S175–81.

�% 1BSUSJEHF�")��'FSUJMJUZ�QSFTFSWBUJPO��B�WJUBM�TVSWJWPSTIJQ�JTTVF�GPS�ZPVOH�XPNFO�

with breast cancer. Journal of Clinical Oncology 2008; 26:2612–3.

�% 4IFUUZ�( �,SJTIOBNVSUIZ�) �,SJTIOBNVSUIZ�)/ �#IBUOBHBS�4 �.PVEHBM�3/��&G-

fect of estrogen deprivation on the reproductive physiology of male and female

primates. The Journal of Steroid Biochemistry and Molecular Biology 1997; 61:157–66.

92

CHAPTER X

93

XXXXXXX

CHAPTER 5Stimulation of the ovaries in

women with breast cancer un-dergoing fertility preservation:

alternative versus standard stimulation protocols; the

study protocol of the stim-trial

T. Dahhan

&�.�&��#BMLFOFOEF

$�$�.��#FFSFOEPOL

,��'MFJTDIFS

D. Stoop

"�.�&��#PT

C.B. Lambalk

3��4DIBUT

3�+�5��WBO�(PMEF

+��4DIJQQFS

+�4�&��-BWFO�

L.A. Louwe

"��)PFL

A.E.P. Cantineau

+�.�+��4NFFOL

3��/FWFEJUB

:��,PQFJLB

F. van der Veen

.��WBO�8FMZ

S.C. Linn

.��(PEEJKO

Submitted

CHAPTER 5

94

Abstract

Background: Chemotherapy for breast cancer may have a negative impact on repro-

ductive function due to gonadotoxic damage. Fertility preservation via banking of

PPDZUFT� PS� FNCSZPT� BGUFS� DPOUSPMMFE� PWBSJBO� TUJNVMBUJPO�XJUI� '4)� $04� DBO� JO-

DSFBTF�UIF�MJLFMJIPPE�PG�B�GVUVSF�TVDDFTTGVM�QSFHOBODZ��*U�IBT�CFFO�IZQPUIFTJ[FE�UIBU�

elevated serum estrogen levels during COS may induce breast tumour growth. This

has led to the use of alternative COS protocols with addition of tamoxifen or letro-

[PMF��5IF�FGGFDUJWFOFTT�PG�UIFTF�$04�QSPUPDPMT�JO�UFSNT�PG�PPDZUF�ZJFME�JT�VOLOPXO��

.FUIPET�EFTJHO��3BOEPNJ[FE�PQFO�MBCFM� USJBM� DPNQBSJOH�$04�QMVT� UBNPYJGFO�BOE�

$04�QMVT� MFUSP[PMF�XJUI�TUBOEBSE�$04�JO� UIF�DPVSTF�PG� GFSUJMJUZ�QSFTFSWBUJPO��5IF�

study population consists of women with breast cancer who opt for banking of oo-

cytes or embryos, aged 18 – 43 years at randomisation. Primary outcome is the number

of oocytes retrieved at follicle aspiration. Secondary outcomes arenumber of mature

oocytes retrieved, number of oocytes or embryos banked and peak E2 levels during

COS.

Discussion: Concerning the lack of evidence on what stimulation protocol should be

used in women with breast cancer and the growing demand for fertility preservation,

there is an urgent need to undertake this study. By performing this study, we will be

able to closely monitor the effects of various COS protocols in women with breast

cancer and pave the way for long term follow up on the safety of this procedure in

terms of breast cancer prognosis.

5SJBM�3FHJTUSBUJPO��/53��

,FZXPSET�� PWBSJBO� TUJNVMBUJPO � CSFBTU� DBODFS � GFSUJMJUZ� QSFTFSWBUJPO � FTUSBEJPM � PP-

cytes, cryopreservation, embryos, recurrence, survival.

STIMULATION OF THE OVARIES IN WOMEN WITH BREAST CANCER UNDERGOING FERTILITY PRESERVATION: ALTERNATIVE VERSUS STANDARD

STIMULATION PROTOCOLS; THE STUDY PROTOCOL OF THE STIM-TRIAL

95

Background

#SFBTU�DBODFS�JT�UIF�NPTU�DPNNPO�NBMJHOBODZ�JO�XPNFO�PG�SFQSPEVDUJWF�BHF�<�>��.PTU�

young women with breast cancer are advised to undergo chemotherapy, which can

be lifesaving, but negatively impacts ovarian reserve [2-6]. The American Society for

Clinical Oncology recommends that fertility preservation is discussed early in the tra-

jectory of breast cancer treatment [7]. To bank oocytes or embryos, women have to

VOEFSHP�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�$04�CZ�GPMMJDMF�TUJNVMBUJOH�IPSNPOF�'4)�

to obtain multifollicular growth, and by concurrent pituitary down regulation with

(O3)�BOUBHPOJTUT�PS�(O3)�BHPOJTUT�UP�QSFWFOU�B�QSFNBUVSF�-)�TVSHF��$VSSFOU� MJU-

FSBUVSF� GBWPVST�$04�XJUI�(O3)��BOUBHPOJTUT�XJUI�B�(O3)�BHPOJTU�PWVMBUJPO�USJH-

HFS�UP�NJOJNJ[F�UIF�SJTL�PG�PWBSJBO�IZQFS�TUJNVMBUJPO�TZOESPNF�0)44�<��>��%VS-

ing COS, peak estradiol levels can reach a 2-3 fold increase compared to physiological

peri-ovulatory levels [11, 12]. Earlier research showed an association between estrogen

exposure and the initiation and promotion of breast cancer [13]. To counterbalance

FTUSPHFO�FYQPTVSF�JO�CSFBTU�UJTTVF �BEEJOH�UBNPYJGFO�PS�MFUSP[PMF�UP�$04�QSPUPDPMT�IBT�

been suggested. Current clinical practice for fertility preservation therefore varies from

standard COS without any anti-estrogenic agents, to adjusted stimulation protocols

BEEJOH�UBNPYJGFO�PS�MFUSP[PMF�UP�$04�<��>��

Tamoxifen is a non-steroidal selective estrogen receptor modulator, which has an anti-

FTUSPHFOJD�FGGFDU�PO�CSFBTU�UJTTVF��-FUSP[PMF�JT�BO�BSPNBUBTF�JOIJCJUPS�UIBU�TZTUFNJDBMMZ�

prevents the synthesis of estrogen from androgens by competitive reversible binding of

UIF�DZUPDISPNF�1��FO[ZNF�BSPNBUBTF��5IF�BTTVNQUJPO�UIBU�UBNPYJGFO�BOE�MFUSP[PMF�

serve a protective role in women with breast cancer undergoing COS is based on data

that show an improved prognosis for women with estrogen-receptor positive breast

DBODFS�XIP�VTF�UBNPYJGFO�PS�MFUSP[PMF�BT�MPOH�UFSN�BEKVWBOU�UIFSBQZ�<��>��

A Cochrane review aiming to compare safety and effectiveness outcomes of tamoxifen

PS�MFUSP[PMF�JO�BEEJUJPO�UP�TUBOEBSE�TUJNVMBUJPO�QSPUPDPMT�JO�XPNFO�XJUI�&3�QPTJUJWF�

breast cancer found no randomised controlled trials [20]. One non-randomised prospec-

UJWF�TUVEZ�DPNQBSFE�PPDZUF�ZJFME�GPS�XPNFO�VTJOH�UBNPYJGFO�BMPOF�O��XJUI�XPNFO�

VTJOH�'4)�DPNCJOFE�XJUI� UBNPYJGFO� O��XJUI�XPNFO�VTJOH�'4)�DPNCJOFE�XJUI�

MFUSP[PMF�O��<��>��5IF�MFUSP[PMF�'4)�BOE�UBNPYJGFO�'4)�QSPUPDPM�IBE�B�TUBUJTUJDBMMZ�

TJHOJmDBOU�IJHIFS�OVNCFS�PG�PPDZUFT�DPNQBSFE�UP�UIF�UBNPYJGFO�BMPOF�QSPUPDPM��

BOE��BOE��PPDZUFT� SFTQFDUJWFMZ��5IF�EJGGFSFODF� JO�OVNCFS�PG�PPDZUFT� SFUSJFWFE�

CFUXFFO�UIF�MFUSP[PMF�'4)�BOE�UBNPYJGFO�'4)�XBT�OPU�TUBUJTUJDBMMZ�TJHOJmDBOU��'PMMPX�

VQ��ZFBST�PO�UIF�TBGFUZ�PG�$04�JO�XPNFO�XJUI�CSFBTU�DBODFS�TIPXFE�TJNJMBS�SFDVS-

CHAPTER 5

96

rence rates as compared to women with breast cancer who did not undergo COS [16, 21,

��>��)PXFWFS �UIFTF�TUVEJFT�DPOTJTUFE�PG�B�TNBMM�TBNQMF�TJ[F�BOE�XFSF�OPO�SBOEPNJ[FE��

*U�UIVT�SFNBJOT�VOLOPXO�XIFUIFS�BEKVTUFE�$04�QSPUPDPMT�XJUI�UBNPYJGFO�BOE�MFUSP[PM�

-suggested to serve a protective role by preventing breast cancer growth during COS

-are just as effective in terms of oocyte yield as COS without these agents.

In view of this lack of knowledge, the aim of the current study is to evaluate the effec-

UJWFOFTT�PG�$04�XJUI�UBNPYJGFO�PS�MFUSP[PMF�DPNQBSFE�UP�TUBOEBSE�$04�PO�UIF�OVNCFS�

of oocytes retrieved in women with breast cancer undergoing COS to bank oocytes or

embryos.

Methods/Design

Ethical considerations

5IJT�TUVEZ�IBT�CFFO�BQQSPWFE�CZ�UIF�*OTUJUVUJPOBM�3FWJFX�#PBSE�*3#�PG�UIF�"DB-

EFNJD�.FEJDBM�$FOUFS�JO�"NTUFSEBN�.&$��@��BOE�CZ�UIF�CPBSE�PG�EJSFDUPST�

of all participating centres. This study is designed and will be conducted using the

HVJEFMJOFT�GPS�HPPE�DMJOJDBM�QSBDUJDF�($1�BT�XFMM�BT�UIF�%FDMBSBUJPO�PG�)FMTJOLJ��

Study design

This study is a multicentre randomised open-label trial in the Netherlands and Bel-

HJVN��8PNFO� BSF� BMMPDBUFE� UP� POF� PG� UIF� UISFF� USFBUNFOU� HSPVQT�� $04�UBNPYJGFO �

$04��MFUSP[PMF�PS�$04�BMPOF �mHVSF��3FDSVJUNFOU�PG�XPNFO�TUBSUFE�JO�+BOVBSZ��

Participants

To be eligible to participate in this study, women must meet all of the following in-

DMVTJPO�DSJUFSJB��BHF��o��ZFBST��DPOmSNFE�CSFBTU�DBODFS�QPTJUJWF�FTUSPHFO�SFDFQUPS�

&3�TUBUVT �OFHBUJWF�&3�TUBUVT�PS�VOLOPXO�&3�TUBUVT��DBOEJEBUF�GPS�DSZPQSFTFSWB-

tion of oocytes or embryos (as approved by referring breast cancer specialists and the

GFSUJMJUZ�DMJOJDT�UIF�XPNFO�BSF�SFGFSSFE�UP��8PNFO�BSF�FYDMVEFE�JG�UIFSF�JT�B�DPOUSBJO-

dication to use study medication, or if women use medication that opposes the effect

PG�TUVEZ�NFEJDBUJPO�J�F��QBSPYFUJOF��*O�XPNFO�GVMmMMJOH�UIF�JODMVTJPO�DSJUFSJB �XSJU-

UFO�JOGPSNFE�DPOTFOU�JT�PCUBJOFE�CFGPSF�SBOEPNJTBUJPO��8PNFO�BSF�SBOEPNJTFE�UP�



97

FJUIFS�VOEFSHPJOH�$04�XJUI�UBNPYJGFO�HSPVQ��PS�MFUSP[PMF�HSPVQ��PS�$04�BMPOF�

HSPVQ��8PNFO�JO�BMM�TUVEZ�HSPVQT�SFDFJWF�TUBOEBSE�DBSF�DPODFSOJOH�$04��

Randomisation

8PNFO�BSF�SBOEPNJTFE�PO�MJOF�WJB�B�XFC�CBTFE�GBDJMJUZ�JO�B��SBUJP��5IFZ�BSF�TUSBU-

JmFE�GPS�PSBM�BOUJDPODFQUJPO�VTF�BU�TUBSU�$04 �GPS�QPTJUJWF�FTUSPHFO�SFDFQUPS�TUBUVT�

and positive lymph nodes. The allocated treatment, i.e. group 1, group 2, or group 3,

appears directly online and an automatic email with allocation code is sent to the data

manager.

Figure 1: 4UVEZ�EFTJHO�45*.�USJBM

3��SBOEPNJ[BUJPO�

S'4)��SFDPNCJOBOU�GPMMJDMF�TUJNVMBUJOH�IPSNPOF� � 016��PWVN�QJDL�VQ

��CMPPE�TBNQMF�GPS�"OUJ�.àMMFSJBO�IPSNPOF�� ?��CMPPE�TBNQMF�GPS�QFBL�&��

Tamoxifen 60 mg

Letrozole 5 mg

Letrozole 5 mg

rFSH

Group 1

Group 2

Group 3

rFSH

rFSH

GnRH-antagonist

GnRH-antagonist

GnRH-antagonist

* Cycle day 2

* Cycle day 2

* Cycle day 2

%BZ��PG�S'4)

%BZ��PG�S'4)Day 3 of

-FUSP[PMF

%BZ��PG�S'4)

ˆ

ˆ

ˆ

R

(O3)�BHPOJTU

(O3)�BHPOJTU

(O3)�BHPOJTU

OPU

OPU

restart for 3 days

OPU

CHAPTER 5

98

Outcome measures

Primary outcome is the mean number of oocytes retrieved at follicle aspiration,

EFmOFE�BT�DVNVMVT�PPDZUF�DPNQMFYFT��4FDPOEBSZ�PVUDPNFT�BSF�UIF�OVNCFS�PG�NB-

UVSF�NFUBQIBTF�**�PPDZUFT �OVNCFS�PG�PPDZUFT�PS�FNCSZPT�CBOLFE �QFBL�&��MFWFMT �

EFmOFE�BT�TFSVN�&��MFWFM�NFBTVSFE�PO�UIF�EBZ�PG�PWVMBUJPO�USJHHFS��

Other study parameters

Baseline characteristics are collected including age, ethnicity, education, body

NBTT�JOEFY� #.* �NFEJDBUJPO � DVSSFOU� TNPLFS �NFOTUSVBM� DZDMF � 1$04 � QSFWJPVT�

pregnancies, past history of subfertility, contraceptive use, and history of ovarian or

tubal surgery, family history of premature menopause. Parameters regarding breast

DBODFS��#3$"�TUBUVT �TUBHF�BOE�IJTUPMPHZ �IPSNPOF�SFDFQUPS�TUBUVT �BOE�USFBUNFOU�

including dose, type, number of cycles of chemotherapy are registered. COS related

parameters including follicular or luteal start of COS, antral follicle count, dura-

UJPO�PG�TUJNVMBUJPO �UPUBM�EPTF�PG�'4)�BOE�OVNCFS�PG�DBODFMMFE�DZDMFT�BSF�DPMMFDUFE��

5IJT�EBUB�XJMM�CF�QSFTFOUFE�EFTDSJQUJWFMZ�BT�NFBOT�XJUI�4%�BT�QSPQPSUJPO��EF-

QFOEJOH�PO� UIF� WBSJBCMF��"GUFS�mOJTIJOH� UIF� TUVEZ�XF�XJMM� DPMMFDU�EBUB� SFHBSEJOH�

long term outcomes, see appendix 1.

Sample size

8F�FTUJNBUF�UIF�NFBO�OVNCFS�PG�PPDZUFT�SFUSJFWFE�UP�CF��JO�UIF�DPOUSPM�HSPVQ�

<�� >��#BTFE�PO�UIF�BWBJMBCMF�MJUFSBUVSF�XF�FTUJNBUF�UIF�TUBOEBSE�EFWJBUJPO�4%�

to be 6 [23]. Based on previous studies we assume that tamoxifen will result in 4

PPDZUFT�NPSF�BOE�MFUSP[PMF�XJMM�SFTVMU�JO��PPDZUFT�MFTT�<�� >��5P�QSPWF�B�UXP�TJEFE�

difference of 4 oocytes with an alpha of 5% and a power of 90%, we need to include

48 women in each group. To compensate for 10% lost to follow-up we aim to enroll

��XPNFO�JO�FBDI�HSPVQ �J�F��XPNFO�JO�UPUBM��5IJT�TBNQMF�TJ[F�JT�TVGmDJFOU�UP�

DPNQBSF�CPUI�UBNPYJGFO�BOE�MFUSP[PMF�XJUI�DPOUSPM�USFBUNFOU�BT�XFMM�BT�XJUI�FBDI�

other.



99

Study procedures

Group 1 - COS-tamoxifen:

8PNFO�SFDFJWF� UBNPYJGFO� UBCMFUT�XJUI�B�EPTF�PG��NJMMJHSBNT��NH�QFS�EBZ�

PSBMMZ � TUBSUJOH�BT�TPPO�BT�UIFZ�TUBSU�XJUI��*6�S'4)�PO�DZDMF�EBZ��8PNFO�BSF�

QSFTDSJCFE�UP�VTF�UBNPYJGFO�CFUXFFO��BOE��1.��5BNPYJGFO�JT�EJTDPOUJOVFE�

PO�UIF�EBZ�PG�(O3)B�BENJOJTUSBUJPO��

Group 2 – COS-letrozole:

8PNFO�SFDFJWF�MFUSP[PMF�UBCMFUT�XJUI�B�EPTF�PG��NH��NH�QFS�EBZ�PSBMMZ �TUBSUJOH�

PO�DZDMF�EBZ��5IFO �PO�DZDMF�EBZ��EBZ��PG�MFUSP[PMF�UIFZ�TUBSU�XJUI��*6�S'4)��

8PNFO�BSF�QSFTDSJCFE�UP�VTF�MFUSP[PMF�CFUXFFO��BOE��1.��-FUSP[PMF�JT�EJT-

DPOUJOVFE�PO�UIF�EBZ�PG�(O3)�B�BENJOJTUSBUJPO��8PNFO�SFTUBSU�MFUSP[PMF��NH�QFS�

EBZ�BU�UIF�EBZ�PG�016�UP�QSFWFOU�B�SFCPVOE�JODSFBTF�JO�&��MFWFMT �BOE�TUPQ�BGUFS��

days.

Group 3 – standard COS:

On cycle day 2, or the second day of interruption of the contraceptive pill, 225 IU/day

S'4)�1VSFHPO®; Organon, Oss, the Netherlands or Gonal-F®��.FSDL�4FSPOP �4XJU-

TFSMBOE�JT�VTFE�BT�HPOBEPUSPQIJO��0O�EBZ��PG�S'4) �B�(O3)�BOUBHPOJTU� 0SHBMV-

USBO�� NH��0SHBOPO �0TT � UIF�/FUIFSMBOET�PS�$FUSPUJEF�� NH �.FSDL�4FSPOP �

4XJUTFSMBOE�JT�BENJOJTUFSFE�UP�QSFWFOU�QSFNBUVSF�-)�TVSHF��(POBEPUSPQJOT�TIPVME�

BMXBZT�CF�BENJOJTUFSFE�JO�UIF�FWFOJOH�CFUXFFO��IST�BOE��IST��8IFO�POF�

GPMMJDMF�PS�NPSF�SFBDIFT��NN �PPDZUF�NBUVSBUJPO�JT�USJHHFSFE�CZ�(O3)B�%FDB-

peptyl® �� NH��'FSSJOH�#7 �)PPGEEPSQ�PS�5SJQUPGFN ® �� NH��(PPEMJGF�#7�-FMZTUBE��

(POBEPUSPQIJOT�S�'4)�BSF�EJTDPOUJOVFE�PO�UIF�EBZ�PG�UIF�(O3)B�USJHHFS��(O3)�

BOUBHPOJTUT�BSF�DPOUJOVFE�VOUJM�UIF�EBZ�PG�UIF�(O3)B�USJHHFS��5IF�(O3)�BOUBHPOJTU�

JOKFDUJPO�OFFET�UP�CF�HJWFO�CFGPSF�UIF�(O3)B�USJHHFS�JOKFDUJPO��0PDZUF�SFUSJFWBM�JT�

QFSGPSNFE��IPVST�BGUFS�PWVMBUJPO�USJHHFS��0PDZUFT�BSF�GSP[FO�JO�NFUBQIBTF�**�PS�

GFSUJMJ[FE�CZ�*$4*�XJUI�TVCTFRVFOU�FNCSZP�CBOLJOH��

CHAPTER 5

100

Luteal start of stimulation

8IFO�UIF�BCPWFNFOUJPOFE�$04�QSPUPDPMT�DBOOPU�CF�QFSGPSNFE�EVF�UP�FYUSFNF�UJNF�

pressing circumstances, women are allowed to start COS in the luteal phase.

Data analysis

"OBMZTJT�XJMM�CF�PO�*55�JOUFOUJPO�UP�USFBU�CBTJT �J�F��BMM�XPNFO�UIBU�XFSF�SBOEPNJTFE�

XJMM�CF�JODMVEFE�JO�UIF�BOBMZTJT��8F�EP�OPU�FYQFDU�MPTT�UP�GPMMPX�VQ�XJUIJO�UIJT�QPQV-

lation. Number of oocytes retrieved will be presented as means and SD. Differences

in number of oocytes between the groups will be presented as mean differences with

�� DPOmEFODF� JOUFSWBMT� BOE�XJMM� CF� DPNQBSFE�VTJOH�"/07"��5IF� TFDPOEBSZ�QB-

SBNFUFST�DPODFSOJOH�PWBSJBO�SFTQPOTF�J�F��OVNCFS�PG�NBUVSF�NFUBQIBTF�**�PPDZUFT �

number of oocytes or embryos banked, peak E2 levels will be presented as mean dif-

GFSFODFT�XJUI��DPOmEFODF�JOUFSWBMT�BOE�XJMM�CF�DPNQBSFE�VTJOH�"/07"��%JGGFS-

ences in number of cancelled cycles will be expressed as a relative risk with 95% con-

mEFODF�JOUFSWBM��#BTFMJOF�DIBSBDUFSJTUJDT�XJMM�CF�QSFTFOUFE�JO�EFTDSJQUJWFMZ�BT�NFBOT�

XJUI�4%�PG�BT�QSPQPSUJPO��EFQFOEJOH�PO�UIF�WBSJBCMF��"�CMJOEFE�JOUFSJN�BOBMZTJT�

PO�TBGFUZ�IBT�CFFO�QFSGPSNFE�CZ�B�%BUB�4BGFUZ�.POJUPSJOH�CPBSE �CZ�UIF�UJNF��PG�

UIF�TBNQMF�TJ[F�XBT�JODMVEFE�BOE�UIFZ�DPODMVEFE�UIBU�UIF�TUVEZ�XBT�TBGF�FOPVHI�UP�

advise continuation of the study.

Discussion

In view of the lack of evidence on what stimulation protocol should be used in wom-

en with breast cancer and the growing demand for fertility preservation, there is an

urgent need to undertake this study. By performing this study, we will be able to

closely monitor the effects of various COS protocols in women with breast cancer

and pave the way for long term follow up on the safety of this procedure in terms

of breast cancer prognosis. The trial runs under the auspices of the Consortium for

)FBMUIDBSF�&WBMVBUJPO�BOE�3FTFBSDI�PG�UIF�4PDJFUZ�GPS�0CTUFUSJDT�BOE�(ZOBFDPMPHZ�

/70(�$POTPSUJVN�� 5IF� TUVEZ� TUBSUFE� JODMVEJOH�XPNFO� JO� +BOVBSZ� ��"U�

present there are seven participating centers in the Netherlands and one center in

#FMHJVN�6OJWFSTJUZ�)PTQJUBM�PG�#SVTTFMT��*O�UIF�/FUIFSMBOET�UISFF�PUIFS�DFOUFST�BSF�

QSFQBSJOH�TUBSU�PG�SFDSVJUNFOU��.BBTUSJDIU�.FEJDBM�$FOUFS ��-FJEFO�.FEJDBM�$FOUFS�



101

BOE�.FEJDBM�$FOUFS�(SPOJOHFO��*O�UIF�6, �(VZ�T�)PTQJUBM�JO�-POEPO�JT�QSFQBSJOH�

start of recruitment of women. Currently 58 women have been included. The study

is still open for additional centres who can recruit women for the study, for which

the corresponding author can be contacted. By promotional campaigns among gy-

naecologists and oncologists, together with the participation of multiple centres, we

IPQF�UP�mOJTI�SFDSVJUNFOU�BGUFS��ZFBST��

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

8F�XPVME� MJLF� UP� UIBOL� UIF� A1JOL�3JCCPO�'PVOEBUJPO�� GPS� UIFJS�mOBODJBM� TVQQPSU�

GPS�UIJT�TUVEZ�QSPKFDU�OVNCFS��80��$��8F�BMTP�XPVME�MJLF�UP�UIBOL�UIF�

SFTFBSDI�OVSTFT�5�4�EF�7SJFT�BOE�.�"�"LFS�GPS�UIFJS�XPSL�JO�EBUBNBOBHFNFOU�GPS�UIF�

study.

Author’s contributions

5% �$$.# �,' �%4 �".&# �$#- �34 �4$- �'WE7 �.W8 �BOE�.(�EFTJHOFE�UIF�USJBM�

QSPUPDPM�BOE�BQQMJFE�GPS� UIF�SFTFBSDI�HSBOU��5%�ESBGUFE� UIJT�NBOVTDSJQU��&.&#�JT�

responsible for the logistical aspects of the trial. All authors are responsible for inclu-

sion of the eligible women.

"MM�BVUIPST�DP�BVUIPSFE�UIF�NBOVTDSJQU�BOE�BQQSPWFE�UIF�mOBM�WFSTJPO��

CHAPTER 5

102

Appendix 1: Long term secondary outcomes

Long term outcomes data will be collected for future research purposes. This data is

not part of this study.

Data regarding oocyte and embryo banking:

�% uptake of oocytes or embryos

�% pregnancy rates

�% miscarriage rates

�% ongoing pregnancy rates

�% maternal outcomes

�% neonatal outcomes

�% congenital malformations

Data regarding breast cancer outcomes:

�% 5 and 10 years survival

�% 5 and 10 years breast cancer free interval

5IJT�EBUB�XJMM�CF�PCUBJOFE�CZ�QFSNJTTJPO�PG�UIF�/BUJPOBM�$BODFS�3FHJTUSZ



103

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FEO��&EJUFE�CZ�+FSPNF�'��4USBVTT�***�. �1I% �BOE�3PCFSU�-��#BSCJFSJ �.%�4BVOEFST �

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��4USBVTT�+' �-FTTFZ�#"��5IF�4USVDUVSF �'VODUJPO �BOE�&WBMVBUJPO�PG�UIF�'FNBMF�3FQSP-

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365:1687-1717.

��#VSTUFJO�)+ �1SFTUSVE�"" �4FJEFOGFME�+ �"OEFSTPO�) �#VDIIPM[�5" �%BWJETPO�/& �

(FMNPO�,& �(JPSEBOP�4) �)VEJT�$" �.BMJO�+�FU�BM��"NFSJDBO�4PDJFUZ�PG�$MJOJDBM�0O-

cology clinical practice guideline: update on adjuvant endocrine therapy for women

XJUI�IPSNPOF�SFDFQUPS�QPTJUJWF�CSFBTU�DBODFS��+�$MJO�0ODPM��

��%BWJFT�$ �1BO�) �(PEXJO�+ �(SBZ�3 �"SSJBHBEB�3 �3BJOB�7 �"CSBIBN�. �.FEFJSPT�

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ifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive

breast cancer: ATLAS, a randomised trial. Lancet 2013, 381:805-816.



105

��%BIIBO�5 �#BMLFOFOEF�& �WBO�8. �-JOO�4 �(PEEJKO�.��5BNPYJGFO�PS�MFUSP[PMF�WFS-

sus standard methods for women with estrogen-receptor positive breast cancer under-

going oocyte or embryo cryopreservation in assisted reproduction. Cochrane Database

4ZTU�3FW�� $%��

��.FJSPX�% �3BBOBOJ�) �.BNBO�& �1BMVDI�4IJNPO�4 �4IBQJSB�. �$PIFO�: �,VDIVL�

* �)PVSWJU[�" �-FWSPO�+ �.P[FS�.FOEFM�.�FU�BM��5BNPYJGFO�DP�BENJOJTUSBUJPO�EVSJOH�

DPOUSPMMFE�PWBSJBO�IZQFSTUJNVMBUJPO�GPS�JO�WJUSP�GFSUJMJ[BUJPO�JO�CSFBTU�DBODFS�QBUJFOUT�

increases the safety of fertility-preservation treatment strategies. Fertil Steril 2014,

102:488-495.e483.

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PNJ[FE�DMJOJDBM�USJBM��)VN�3FQSPE��

106

CHAPTER X

107

XXXXXXX

CHAPTER 6The experiences of women with

breast cancer who undergo fertility preservation

T. Dahhan

F. van der Veen

"�.�&��#PT.��(PEEJKO

E.A.F. Dancet

Submitted

CHAPTER 6

108

Abstract

Study question:�)PX�EP�XPNFO�FYQFSJFODF�PPDZUF�PS�FNCSZP�CBOLJOH�XIFO�UIFZ�

have just been diagnosed with breast cancer?

Summary answer: The sudden identity as an infertility patient as well as a cancer

patient was challenging and fertility preservation was burdensome. Even so, the vast

majority of women experienced fertility preservation as a welcome way to take action

when just confronted with having breast cancer.

What is known already:�8PNFO�XJUI�DBODFS�DBO�CBOL�PPDZUFT�PS�FNCSZPT�CZ�*7'�

treatment, prior to gonadotoxic treatment. Being newly diagnosed with cancer and

VOEFSHPJOH�*7'�BSF�NBKPS�MJGF�FWFOUT�LOPXO�UP�DBVTF�TUSFTT��)PX�XPNFO�FYQFSJFODF�

going through these two events simultaneously has not yet been investigated.

Study design, size, duration:�8F�VTFE� B�QIFOPNFOPMPHJDBM� BQQSPBDI� UP� TUVEZ� UIF�

lived experience of being diagnosed with breast cancer and banking oocytes or em-

CSZPT��5XFOUZ�POF�XPNFO�XFSF� JOUFSWJFXFE�CFUXFFO�.BSDI�BOE�+VMZ�� XIJDI�

XBT�TVGmDJFOU�UP�SFBDI�EBUB�TBUVSBUJPO��

Participants/materials, setting, methods:�8PNFO�XJUI� CSFBTU� DBODFS�XIP� CBOLFE�

oocytes or embryos 1-15 months earlier in two university based fertility clinics were

FMJHJCMF� GPS� JODMVTJPO�� 8F� DPOEVDUFE� JO�EFQUI � GBDF�UP�GBDF� JOUFSWJFXT � HVJEFE� CZ�

open-ended questions and a topic list.

Main results and the role of chance: The 21 interviewed women had a mean age

PG� �� ZFBST�� 5IFZ� CBOLFE� PPDZUFT� O�� FNCSZPT� O�� PS� TUPQQFE� CFGPSF� GPMMJDMF�

BTQJSBUJPO�O��'JGUFFO�XPNFO�IBE�UJNF�GPS�POMZ�POF�DZDMF�PG�CBOLJOH�PPDZUFT�PS�

embryos. Fertility preservation was experienced as a burden, mainly because of time

pressure and the fear for complications that could result in a delay for chemotherapy.

Through fertility preservation women experienced a new identity as a fertility pa-

UJFOU �XIJDI�XBT�TPNFUJNFT�SFQPSUFE�BT�EJGmDVMU�CFDBVTF�CFJOH�EJGGFSFOU�GSPN�SFHVMBS�

GFSUJMJUZ�QBUJFOUT�GVSUIFS�FNQIBTJ[FE�XPNFO�T�VOQMFBTBOU�JEFOUJUZ�BT�B�CSFBTU�DBODFS�

QBUJFOU��0O�UIF�PUIFS�IBOE �XPNFO�GFMU�SFMJFWFE�UP�TFF�ASFHVMBS��JOGFSUJMJUZ�QBUJFOUT�JO�

UIF�GFSUJMJUZ�DMJOJD�CFDBVTF�UIJT�NBEF�UIFN�SFBMJ[F�UIBU�UIFZ�XFSF�OPU�UIF�POMZ�POFT�

TUSVHHMJOH�UP�IBWF�B�GVUVSF�XJUI�DIJMESFO��8PNFO�BMTP�EFTDSJCFE�DPQJOH�XJUI�CSFBTU�

THE EXPERIENCES OF WOMEN WITH BREAST CANCER WHO UNDERGO FERTILITY PRESERVATION

109

cancer through fertility preservation as it allowed them to take action in a time when

they were not yet able to start with cancer treatment. Their diagnosis had induced a

TUSPOH�TVSWJWBM�NPEF�BOE�BO�FBHFSOFTT�UP�ABDU��BOE�UP�QVTI�FNPUJPOT�BTJEF��'PS�UIFTF�

XPNFO �GFSUJMJUZ�QSFTFSWBUJPO�XBT�UIF�ATUBSU��BOE�UIFSFGPSF�BO�JOUFHSBUFE�QBSU�PG�UIFJS�

breast cancer trajectory.

Limitations, reasons for caution: One researcher coded the interviews but discussing

all phases of the analysis with a second researcher increased the dependability of the

analysis.

8JEFS�JNQMJDBUJPOT�PG�UIF�mOEJOHT� This study provides in-depth insight in the expe-

riences of women with breast cancer undergoing fertility preservation. This insight

can be used to increase clinicians understanding, empathy and psychosocial care for

these women. Future studies are necessary to investigate ways to incorporate these

mOEJOHT�JOUP�SPVUJOF�QTZDIPTPDJBM�DBSF �BOE�UP�NFBTVSF�JUT�FGGFDU�PO�XPNFO�T�XFMMCF-

ing or even treatment outcome.

Study funding/competing interest(s): No funding, no competing interests.

Introduction

One in 46 women under the age of 39 are diagnosed with invasive cancer (Siegel et al� ��#SFBTU�DBODFS�JT�UIF�NPTU�DPNNPO�NBMJHOBODZ�JO�XPNFO�PG�SFQSPEVDUJWF�

BHF�BOE�SFRVJSFT�NBOBHFNFOU�UIBU�NBZ�UISFBUFO�UIFJS�GFSUJMJUZ�JO�UISFF�XBZT�)JDL-

ey et al., 2009; Siegel et al� ��'JSTU �CSFBTU�DBODFS�PGUFO�SFRVJSFT�DIFNPUIFSBQZ�

regimens containing cyclophosphamide, which has gonadotoxic side-effects (Bines

et al� ��.FJSPX�BOE�/VHFOU ��4VLVNWBOJDI�et al� ��4FDPOE �XPNFO�

are frequently advised to delay pregnancy for two years because of the risk of recur-

rence, which may lead to age-related fertility decline (Gwyn and Theriault, 2000;

*TBBDT ��3$0( ��*O�XPNFO�XJUI�IPSNPOF�TFOTJUJWF�CSFBTU�DBODFS�USFBUFE�

with adjuvant tamoxifen therapy, this risk is even higher because they are advised

to delay childbearing for as long as they are using tamoxifen, which is usually for

BU�MFBTU�mWF�ZFBST�#BSUIFMNFT�BOE�(BUFMFZ ��#SBFNT�et al� ��5IJSE �ZPVOH�

XPNFO�XJUI�CSFBTU�DBODFS�XIP�BSF�BGGFDUFE�CZ�B�#3$"��NVUBUJPO�NBZ�DPOTJEFS�

bilateral salpingo-ovariectomy to prevent ovarian cancer (Begg et al� ��

CHAPTER 6

110

To deal with these threats to their fertility, women currently have the option to

CBOL� PPDZUFT� PS� FNCSZPT� 3VEJDL� et al� � �� 4OZEFS� BOE�5BUF � ��0PDZUF� PS�

embryo banking is done as soon as possible after the diagnosis has been made and

DPOTJTUT�PG�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�$04 �GPMMJDMF�BTQJSBUJPO�BOE�DSZPQSFTFS-

vation of oocytes or embryos.

It is known that IVF treatment causes distress to subfertile women (Verhaak et al� ��#SPE�BOE�'FOOFNB ��8PNFO�XJUI�DBODFS�NBZ�BEEJUJPOBMMZ�GFBS�UIBU�

COS will decrease their chances of survival as it increases oestrogen levels, even

when used in combination with tamoxifen (Balkenende et al� ��"MUIPVHI�UIFSF�

are studies on the perspectives of breast cancer survivors on childbearing, the ex-

perience of going through FP has not been studied (Goncalves et al., 2013; Dow,

1994; Connell et al., 2006; Lee et al� �� 5IJT�MBDL�PG�LOPXMFEHF�NBZ�OPU�CF�UP�

UIF�CFOFmU�PG�PVS�QBUJFOUT �BT�JOTJHIU�JOUP�XPNFO�T�FYQFSJFODFT�BOE�OFFET�EVSJOH�

treatment is necessary to provide appropriate psychosocial care during infertility

treatment. Psychosocial care by all fertility staff members is a prerequisite for high-

RVBMJUZ�GFSUJMJUZ�DBSF �BT�SFDFOUMZ�TUBUFE�CZ�&4)3&�(BNFJSP�et al� ��5IJT�TUVEZ�

therefore aimed to explore how women experience oocyte or embryo banking when

they have just been diagnosed with breast cancer.

Methods

"�QIFOPNFOPMPHJDBM�EFTJHO�XBT�DIPTFO�BT�QIFOPNFOPMPHZ�JT�B�TQFDJmD�RVBMJUBUJWF�

research methodology devoted to exploring and understanding experiences (Giorgi,

��1PMLJOIPSOF��

Ethical approval

5IF�*OTUJUVUJPOBM�3FWJFX�#PBSET�PG�UIF�"DBEFNJD�.FEJDBM�$FOUSF�".$�"NTUFS-

EBN�BOE�PG�UIF�6OJWFSTJUZ�.FEJDBM�$FOUSF�6USFDIU�6.$6�BQQSBJTFE�UIF�QSPUPDPM�

PG�UIJT�TUVEZ�8��@��BOE�BGmSNFE�UIBU�XPNFO�QBSUJDJQBUJOH�JO�UIJT�

study would not be subjected to any risks. Therefore, no further review was re-

RVJSFE�BDDPSEJOH�UP�UIF�%VUDI�i.FEJDBM�3FTFBSDI�*OWPMWJOH�)VNBO�4VCKFDUT�"DUw��

Participating women did give written informed consent prior to participation.


111

Recruitment of women

All women aged between 18 and 43 years old with newly diagnosed breast cancer who

CBOLFE�UIFJS�PPDZUFT�PS�FNCSZPT� JO�UIF�$FOUSFT�GPS�3FQSPEVDUJWF�.FEJDJOF�PG�UIF�

".$�PS�UIF�6.$6�CFUXFFO�+BOVBSZ��BOE�+VMZ��XFSF�FMJHJCMF�GPS�JODMVTJPO��

5IF�XPNFO�SFDFJWFE�B�MFUUFS�CZ�QPTUBM�NBJM�JOGPSNJOH�UIFN�BCPVU�UIF�BJN �UIF�DPOm-

EFOUJBM�OBUVSF�PG�UIF�TUVEZ�BOE�UIF�DPOUBDU�EFUBJMT�PG�UIF�SFTFBSDIFS��8PNFO�XIP�EJE�

not contact the researcher themselves received a telephone call two weeks later. The

ten women who had banked their oocytes or embryos most recently were contacted

mSTU��"OPUIFS�FJHIUFFO�XPNFO�XFSF�DPOUBDUFE�JO�UIF�TFDPOE�SPVOE�PG�SFDSVJUNFOU��

3FDSVJUNFOU�TUPQQFE�XIFO�B�TFOTF�PG�DMPTVSF�XBT�BUUBJOFE�CFDBVTF�OFX�EBUB�EJE�OPU�

yield new insights, meaning that data saturation was achieved.

Data-collection

After obtaining written informed consent, data on demographics i.e. age, education,

ethnicity, relationship status, on medical background i.e. date of breast cancer diag-

nosis, type of tumour and cancer treatment, and on the number of oocytes or embryos

retrieved, were collected with the aid of a questionnaire. Interviews were conducted

CZ�5%�O��BOE�&%�O��5%�JT�B�GFNBMF�1I%�TUVEFOU�BOE�B�GFSUJMJUZ�EPDUPS��&%�JT�B�

female post-doctoral research fellow experienced with qualitative research and a mid-

XJGF�TQFDJBMJ[FE�JO�GFSUJMJUZ�QSPCMFNT��%FQFOEJOH�PO�UIF�XPNFO�T�QSFGFSFODF �JOUFS-

WJFXT�UPPL�QMBDF�BU�UIFJS�IPNF�O�� BU�UIFJS�GFSUJMJUZ�DMJOJD�O��PS�JO�B�DBGF�O��

The face-to-face in-depth interviews, which lasted 45-90 minutes, were guided by

PQFO�FOEFE�RVFTUJPOT�F�H��A)PX�EJE�ZPV�FYQFSJFODF�IBWJOH�CSFBTU�DBODFS�XIJMF�GSFF[-

JOH�PPDZUFT�PS�FNCSZPT ��BOE�QSPCJOH�RVFTUJPOT�EFSJWFE�GSPN�B�UPQJD�MJTU�CBTFE�PO�

literature review. The sequence of questions and how they were formulated depend-

FE�PO�UIF�JOUFSWJFX �SFTVMUJOH�JO�JO�EFQUI�JOUFSWJFXT�8FJTT ��1SJPS�UP�UIF�mSTU�

JOUFSWJFX �5%�IBE�XSJUUFO�EPXO�IFS�QSFDPODFJWFE�CFMJFGT�BCPVU�XPNFO�T�FYQFSJFODF�

XJUI�GFSUJMJUZ�QSFTFSWBUJPO�JO�B�SFnFDUJWF�KPVSOBM�BOE�EJTDVTTFE�UIFTF�XJUI�&%��%VSJOH�

the study TD and ED were aware of their own beliefs, and their role as a co-partici-

QBOU�JO�UIF�JO�EFQUI�DPOWFSTBUJPO�BOE�BT�BOBMZTFST�-PnBOE�BOE�-PnBOE ��%VS-

JOH�UIF�JOUFSWJFXT �mFME�OPUFT�PG�JNQPSUBOU�OPO�WFSCBM�DPNNVOJDBUJPO�XFSF�UBLFO��

The interviews were audiotaped and transcribed verbatim, as this guarantees that the

UFYU�DPOTJTUT�PG�UIF�BDUVBM�JEJPN�VTFE�CZ�UIF�QBSUJDJQBOUT�8FTUFS ��

CHAPTER 6

112

Data-analysis

5IF�USBOTDSJCFE� JOUFSWJFXT �FBDI� JEFOUJmFE�CZ�B�OVNCFS�UP�TBGFHVBSE�DPOmEFOUJBMJUZ �

XFSF�SFBE�NVMUJQMF�UJNFT�UP�HFU�B�TFOTF�PG�UIF�XIPMF�JOUFSWJFX��.FBOJOHGVM�UFYU�GSBH-

NFOUT �XIJDI�BOTXFSFE�UIF�SFTFBSDI�RVFTUJPO�PO�XPNFO�T� MJWFE�FYQFSJFODF �XFSF�FY-

USBDUFE�BOE�MBCFMFE�XJUI�B�DPEF�J�F��B�TIPSU�EFTDSJQUJPO�TVNNBSJTJOH�UIF�UFYU�GSBHNFOUT��

"GUFS�DPEJOH�BMM�USBOTDSJCFE�JOUFSWJFXT �B�ADPEJOH�USFF��XBT�GPSNFE �NFBOJOH�UIBU�DPEFT�

were clustered in case they showed resemblance, or further subdivided. Once the coding-

tree was formed, the interviews were read as a whole again to check for meaningful units

of text which could be added to the existing codes or which required adding a new code

UP�UIF�DPEJOH�USFF�%PXMJOH ��'JOBMMZ �XF�DPVOUFE�IPX�NBOZ�XPNFO�BEESFTTFE�B�

particular code.

0OF�SFTFBSDIFS�5%�DPOEVDUFE�UIF�DPEJOH�QSPDFTT�BOE�EJTDVTTFE�UIF�DPEFT�BOE�UIFJS�

NFBOJOHGVM�VOJUT�PG�UFYU�XJUI�B�TFDPOE�SFTFBSDIFS�&%�UP�JODSFBTF�UIF�USVTUXPSUIJOFTT�

of the data-analysis. Discrepancies were discussed until consensus was met. Data-col-

lection and analysis alternated so that emerging new ideas from early data could lead to

SFWJTJOH�BOE�BEKVTUJOH�UIF�JOUFSWJFX�UPQJD�MJTU�.BZFT�BOE�1PQF ��8F�VTFE�UIF�TPGU-

XBSF�QSPHSBN�GPS�RVBMJUBUJWF�EBUB�BOBMZTJT�.BY�2VBMJUBUJWF�%BUB�"OBMZTJT�.BY�2VBMJUB-

UJWF�%BUB�"OBMZTJT �WFSTJPO��*O�SFQPSUJOH�UIF�EBUB �XF�VTFE�UIF�DPOTPMJEBUFE�DSJUFSJB�

GPS�SFQPSUJOH�RVBMJUBUJWF�SFTFBSDI�$03&2 �XIJDI�JT�DPNQBSBCMF�UP�UIF�$POTPMJEBUFE�

4UBOEBSET�PG�3FQPSUJOH�5SJBMT�$0/4035�5POH�et al� ��.PIFS�et al. ��

Results

The participating women

In total, we invited twenty-eight women of whom twenty-one women consented to

QBSUJDJQBUF��8PNFO�XIP�EFDMJOFE�XFSF�PO�IPMJEBZT�EVSJOH�UIF�JOUFSWJFX�QFSJPE�O��

DPOTJEFSFE�DBODFS�B�ADMPTFE�DIBQUFS��UIBU�UIFZ�EJE�OPU�XBOU�UP�UBML�BCPVU�O��PS�XFSF�JO-

UFSWJFXFE�CVU�SFGVTFE�SFDPSEJOH�O��%BUB�TBUVSBUJPO�XBT�BDIJFWFE�BGUFS��JOUFSWJFXT�

BOE�DPOmSNFE�CZ�UIF�MBTU�UISFF�JOUFSWJFXT�

At the time of the interview, FP had taken place on average 7.9 months previously.

The characteristics of the 21 participating women are presented in table I. The women

IBE�B�NFBO�BHF�PG��ZFBST��.PTU�XPNFO�XFSF�%VUDI�BOE�IBE�B�6OJWFSTJUZ�DPMMFHF�EF-

gree. Eighteen women had a stable relationship with a male partner during their FP, for


113

two women their relationship ended during FP and one woman was single during FP. At

the time of diagnosis six women were trying to conceive and four other women already

had children.

Fourteen of the 21 women had hormone-sensitive breast cancer and nine women had

had surgery just before FP. Of the 21 interviewed women, 15 banked oocytes (15 oo-

DZUFT�PO�BWFSBHF�QFS�XPNBO�BOE��XPNFO�CBOLFE�FNCSZPT��FNCSZPT�PO�BWFSBHF�QFS�

XPNBO��0OF�XPNBO�EFDJEFE�OPU�UP�QSPDFFE�XJUI�GPMMJDMF�BTQJSBUJPO�BGUFS�$04��'JGUFFO�

women had time for only one cycle of FP.

Table I: Demographic characteristics, relationship status and medical characteristics of the 21 partici-

pating women with breast cancer who banked oocytes or embryos

FP: fertility preservation

"HF�JO�ZFBST�NFBO �SBOHF

&EVDBUJPOBM�MFWFM�O

University University college High school education/BUJPOBMJUZ�O

Dutch Other4UBCMF�SFMBUJPOTIJQ�EVSJOH�'1�O

4JOHMF�EVSJOH�'1�/

Relationship ended during FP (n)8BT�BUUFNQUJOH�QSFHOBODZ�KVTU�CFGPSF�CSFBTU�DBODFS�EJBHOPTJT�O

)BE�DIJMESFO�BU�UJNF�PG�CSFBTU�DBODFS�EJBHOPTJT�O

)BE�B�IPSNPOF�SFDFQUPS�QPTJUJWF�CSFBTU�UVNPS�O

)BE�UVNPVS�TVSHJDBMMZ�SFNPWFE�QSJPS�UP�'1

Number of women banking oocytes

#BOLFE��PPDZUFT�O

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Stopped before follicle aspiration

/VNCFS�PG�PPDZUFT�CBOLFE�QFS�XPNBO�NFBO �SBOHF�

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$PVME�OPU�VOEFSHP�NPSF�UIBO�POF�DZDMF�PG�'1�O

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CHAPTER 6

114

The lived experiences

"OBMZTJT�PG�UIF��JOUFSWJFXT�SFWFBMFE�UISFF�NBJO�FYQFSJFODFT��5IF�CVSEFO�PG�'1�

��"�OFX�JEFOUJUZ�BT�B�GFSUJMJUZ�QBUJFOU ��$PQJOH�XJUI�CSFBTU�DBODFS�UISPVHI�'1��%F-

tailed codes for each of these three main experiences, are presented in table II.

The burden of FP

5XFMWF�XPNFO�SFQPSUFE�UP�FYQFSJFODF�UJNF�QSFTTVSF�EVSJOH�'1�BT�UIFZ�GFMU�UIFZ�IBE�AB�

POF�BOE�POMZ�DIBODF��UP�QSPEVDF�FOPVHI�PPDZUFT�CFDBVTF�PG�UIF�OFFE�UP�TUBSU�DIFNP-

therapy in time. Ten women described their fear for complications of FP -such as

ovarian hyper stimulation syndrome- because they were worried about the time need-

ed to recover from these complications. Seven women said that they experienced dif-

mDVMUJFT�JO�EJTUJOHVJTIJOH�XIFUIFS�UIFZ�GFMU�TUSFTTFE�BT�B�SFTVMU�PG�UIF�TJEF�FGGFDUT�PG�

hormonal medication for COS or as a result of having to deal with breast cancer. Six

women explained that simultaneously undergoing treatment trajectories for breast

cancer and FP resulted in discomfort as both treatments required revealing private

body parts. Four women reported having to travel between hospitals for undergoing

FP and for their breast cancer as a burden. Besides the threats induced by having

breast cancer, women said that they felt unsure about the effectiveness and safety

PG�UIF�QSPDFEVSFT�SFRVJSFE�GPS�'1��.PSF�TQFDJmDBMMZ �GPVS�XPNFO�SFQPSUFE�XPSSJFT�

about safety with regard to hormone-induced tumor growth during COS and three

women about effectiveness in terms of future chances of pregnancy.

A new identity as fertility patient

Sixteen women reported to feel like an outsider in comparison to the women they

TBX�JO�UIF�XBJUJOH�SPPN�PG�UIF�GFSUJMJUZ�DMJOJDT �CFDBVTF�oVOMJLF�ASFHVMBS��GFSUJMJUZ�QB-

tients- they were not actively trying to have a child at time of their visits to the fertil-

JUZ�DMJOJD��#FJOH�EJGGFSFOU�GSPN�SFHVMBS�GFSUJMJUZ�QBUJFOUT�GVSUIFS�FNQIBTJ[FE�XPNFO�T�

unpleasant identity as a breast cancer patient. On the other hand, three women felt

SFMJFWFE�UP�TFF� ASFHVMBS�� JOGFSUJMJUZ�QBUJFOUT� JO� UIF� GFSUJMJUZ�DMJOJD�CFDBVTF� UIJT�NBEF�

UIFN�SFBMJ[F�UIBU�UIFZ�XFSF�OPU�UIF�POMZ�POFT�TUSVHHMJOH�UP�IBWF�B�GVUVSF�XJUI�DIJM-

dren. Seven women reported that the medical advice to delay pregnancy for a long

QFSJPE�PG�BU�MFBTU�UXP�ZFBST �GVSUIFS�DPOmSNFE�UIFJS�JEFOUJUZ�PG�BO�JOGFSUJMJUZ�QBUJFOU �

as they understood that this could result in age-related subfertility. Eight women said


115

UIBU�UIFJS�JNNJOFOU�JOGFSUJMJUZ�BMTP�KFPQBSEJ[FE�UIFJS�QBSUOFS�T�JEFBM�GBNJMZ�QMBOOJOH��

'JWF�XPNFO�FYQMBJOFE�UIBU�JU�XBT�EJGmDVMU�UP�TFU�BTJEF�UIFJS�B�QSJPSJ�PCKFDUJPOT�BHBJOTU�

BTTJTUFE�SFQSPEVDUJPO�BT�UIFZ�XFSF�OPX�AGPSDFE��UP�SFMZ�PO�*7'�CFDBVTF�PG�CSFBTU�DBO-

cer. Five women kept their FP a secret for family, friends and/or colleagues, as they

feared being judged for taking actions leading to procreation.

Coping with breast cancer by undergoing FP

Sixteen women were happy to be able to undergo FP as it allowed them to take action

in a time when they were not yet able to start with cancer treatment. Their diagno-

TJT�IBE� JOEVDFE�B� TUSPOH�TVSWJWBM�NPEF�BOE�BO�FBHFSOFTT� UP� ABDU�� BOE� UP�QVTI�FNP-

UJPOT�BTJEF��'PS�UIFTF�XPNFO�'1�XBT�UIF�ATUBSU��BOE�UIFSFGPSF�BO�JOUFHSBUFE�QBSU�PG�

their breast cancer trajectory. After follicle aspiration these sixteen women reported

UIBU� UIFZ�GFMU� MJLF�UIFZ�IBE�mOJTIFE�POF�DIBQUFS�PG� UIFJS�CSFBTU�DBODFS�FYQFSJFODF��

Eleven women reported that FP gave the strength to start breast cancer treatment.

In contrast, two women who could only bank few oocytes or embryos said that FP

NBEF�TUBSUJOH�DIFNPUIFSBQZ�EJGmDVMU��4FWFO�XPNFO�SFQPSUFE�GFFMJOH�SFMJFWFE�CZ�TFF-

ing their follicles grow as this made them feel that their body was functioning well

– a welcome contrast to having breast cancer. FP was even experienced romantic by

seven women, as they felt FP was about having a future with children, together with

their partner. This increased commitment in their relationship. Four women said that

by undergoing FP they felt that they invested their ability to have a future, in which

they survive breast cancer and become a mother.

CHAPTER 6

116

Table II: The coding tree presenting codes, number of women sharing experience relevant to each code

and an exemplifying interview quote

Stress as only one cycle of FP

could be performed to make

it in time before starting

chemotherapy

Fearful of having complica-

tions of FP

%JGmDVMUZ� EJTUJOHVJTIJOH�

emotional side effects medi-

cation for FP from stress due

to breast cancer

Discomfort in undergoing

treatment for breast cancer

and for FP in terms of intimacy

Travelling between hospitals

12

10

7

6

4

A*�XBT�WFSZ�OFSWPVT�CFDBVTF�FWFSZ�

time [I injected myself] I thought:

iEJE�*�EP�JU�SJHIU w�:PV�LOPX �TP�

much depends on this, and you

can only do it right one time. It

NBEF�NF�GFFM�WFSZ�JOTFDVSF��

A*�XBT�BGSBJE�PG�DPNQMJDBUJPOT�PG�

FP treatment that would disable

me from starting my chemo on

UJNF��

A8IFO�*�GFMU�FNPUJPOBM �*�UIPVHIU�

iAJT�UIJT�CFDBVTF�PG�UIJT�*7'�NFEJ-

cation or do I feel emotional be-

cause of everything I have to go

UISPVHI�BU�UIJT�NPNFOU w�

A%VSJOH� POF� USFBUNFOU� ZPV� BSF�

half naked from the top and

during the other treatment you

are half naked from the bottom.

5IBU�T� WFSZ� VOQMFBTBOU� UP� HP�

UISPVHI��

A5SBWFMMJOH� CFUXFFO� IPTQJUBMT�

back and forth, shopping for a

XJH �JU�XBT�B�IFDUJD�UJNF��

The burden of FP

Exemplifying interview quotes

Number of women reporting this experience

The lived experience of undergoing FP while having breast cancer


117

Stress on safety of FP due to

possible hormone-induced tu-

mor growth

Insecurity about effective-

ness of FP

Disappointment of having

low number of banked oo-

cytes or embryos made start-

JOH�DIFNPUIFSBQZ�EJGmDVMU�

Feeling like an outsider with

regard to regular IVF-patients

$POTFRVFODFT� PO� QBSUOFS�T�

family planning

4

3

2

16

8

A*�XBT� TDBSFE� BCPVU�IPX�FWFSZ-

thing would interact hormon-

BMMZ��

A'JSTU� ZPV�IFBS� ZPVS� EPDUPS� TBZ�

AXF�BSF�HPJOH�UP�TBGFHVBSE�ZPVS�

GFSUJMJUZ��BOE�UIFO�ZPV�IFBS�iCVU�

there are no guarantees”. I found

UIBU�WFSZ�EJTUVSCJOH��

A8F� IBE� POMZ� B� GFX� FNCSZPT��

I was very sad because of that.

7FSZ �WFSZ�TBE��

A:PV�TFF�BMM�UIPTF�DPVQMFT�<JO�UIF�

IVF clinic] and I felt different

GSPN� UIFN�� *� UIPVHIU� i(VFTT�

XIZ� *�N� IFSF�� #SFBTU� DBODFS�w��

.BZCF� *� XBT� B� CJU� KFBMPVT� PG�

UIFN �*�E�SBUIFS�CF�UIFSF�JO�UIFJS�

TJUVBUJPO��

A#FGPSF�CSFBTU�DBODFS�IF�IBE�UIJT�

romantic idea of waiting for the

right time and then starting a

family. Now, due to my breast

cancer, having children became

something related to disease and

to chances. Now, his romantic

idea of having children was also

EFTUSVDUFE��

A new identity as a fertility patient

CHAPTER 6

118

Preoccupied with possible

age-related subfertility due to

medical advice to delay preg-

nancy for a long period

Secrecy about undergoing FP

Not wanting to belong to the

group of regular fertility pa-

tients due to a priori objec-

tions against assisted repro-

duction

Seeing other fertility patients

in the waiting room offered

relief

FP allowed taking action

while having lost control due

to BC diagnosis

7

5

5

3

16

A5IF� NPTU� JNQPSUBOU� RVFTUJPO�

for me at that time was; how

long do I have to wait before at-

UFNQUJOH�QSFHOBODZ �

A"MNPTU�OP�POF�LOFX�*�XBT�EP-

ing this [banking oocytes]. I

thought they would judge me

GPS�VOEFSHPJOH�UIJT�USFBUNFOU��

A#FGPSF�<CSFBTU�DBODFS>�*�UIPVHIU�

if it happens the natural way

UIBU�T� mOF � CVU� *� BN� OPU� HPJOH�

through all these procedures

because I urgently want to have

children. And now, I am stuck

UP� UIFTF�QSPDFEVSFT�� *� SFBMJ[FE�

that all of a sudden I am part of

this group of people who rely on

*7'�UP�IBWF�DIJMESFO��

A*�XBT�TVSQSJTFE�IPX�CVTZ�JU�XBT�

in the waiting room. That com-

forted me somehow. I thought,

I may have breast cancer but

there are plenty of people with

other reasons why having chil-

ESFO�NBZ�CF�EJGmDVMU��

A*� DPVME� BMSFBEZ� TUBSU� XJUI�

something. I had a goal I could

XPSL� IBSE� GPS�� .Z� FNPUJPOT�

were blocked. I felt like I had

TXJUDIFE�NZ�TVSWJWBM�NPEF�PO��

Coping with breast cancer through FP


119

)BWJOH� PPDZUFT� PS� FNCSZPT�

banked gave strength to start

chemotherapy

FP called attention to well-

functioning part of body

FP offered romantic relief in

stressful period

FP as a means to invest in a

future as breast cancer survi-

vor

11

7

7

4

A8IFO� *� HPU� UIBU� DBMM� PG� UIF�

number of oocytes retrieved I

GFMU�FNQPXFSFE��*�UIPVHIU�iUIJT�

JT�XIBU�ZPV�BSF�mHIUJOH�GPS �UIJT�

is why you had your breast re-

moved, this is what will make

you strong enough to handle

DIFNPw��

A:PV� BQQSFDJBUF� UIF� UIJOHT� UIBU�

function well, and because

ZPV�SF� JO� UIF�NJEEMF� PG� QFPQMF�

having problems with some-

thing you do not have a problem

with at that moment [at time of

FP] I was fertile because I had

not yet underwent chemothera-

QZ��5IBU�GFFMT�WFSZ�HPPE��

A.F� BOE� NZ� IVTCBOE� NBEF� B�

picture during ovum-pick up.

8F�XBOUFE�UP�DBQUVSF�UIBU�NP-

ment as a memory for our future

DIJMESFO��

A<5ISPVHI�'1>�*�XBT�XPSLJOH�PO�

NZ� GVUVSF� BOE� UIF� JEFB� iJU� <NZ�

MJGF>� EPFTO�U� IBWF� UP� FOEw� DBNF�

up in my mind. I [thought I] had

a very positive future perspec-

tive, otherwise they [the oncolo-

HJTUT�BOE�UIF�'1�UFBN>�XPVMEO�U�

IBWF�PGGFSFE�NF�UIJT�QSPDFEVSF��

FP= fertility preservation

CHAPTER 6

120

Discussion

This study provides in-depth insight in the experiences of women newly diagnosed

with breast cancer, who banked oocytes or embryos. Being an infertility patient as

well as a cancer patient was challenging and FP was burdensome. Even so, the vast

majority of women experienced fertility preservation as a welcome way to take ac-

UJPO�XIFO�KVTU�DPOGSPOUFE�XJUI�IBWJOH�CSFBTU�DBODFS��5IJT�JT�UIF�mSTU�TUVEZ�JO�XIJDI�

women with breast cancer were interviewed on how they experienced FP. Through

the chosen phenomenological methodology, personal experiences of women were

IFBSE�BOE�BOBMZ[FE�BT�B�mSTU�TUFQ�UP�VOSBWFM�UIF�QFSTQFDUJWFT�PG�XPNFO�XJUI�CSFBTU�

cancer on banking their oocytes of embryos.

�8F� VTFE� UIF� DPOTPMJEBUFE� DSJUFSJB� GPS� SFQPSUJOH� RVBMJUBUJWF� SFTFBSDI� $03&2 �

XIJDI� JT� DPNQBSBCMF� UP� UIF� $POTPMJEBUFE� 4UBOEBSET� PG� 3FQPSUJOH� 5SJBMT� $0/-

4035�5POH�et al� ��.PIFS�et al� ��8F�BMTP�SFQPSUFE�PO�UIF�OVNCFS�PG�

women mentioning a certain experience to enhance readability of this qualitative

TUVEZ �CVU�OPU�UP�DSFBUF�BOZ�BEEJUJPOBM�WBMJEJUZ�PS�USBOTGFSBCJMJUZ�PG�PVS�mOEJOHT�

Interviewing women after, rather than during FP, might have induced recall bias.

8F�OFWFSUIFMFTT�EFDJEFE�UP�JOUFSWJFX�UIF�XPNFO�BGUFS�'1 �CFDBVTF�XPNFO�BSF�JO�

a state of shock immediately after hearing their diagnosis, which might mask their

BCJMJUZ� UP� SFnFDU�PO� UIFJS� FYQFSJFODFT� 5BZMPS � ��-BOENBSL� et al� � ��8FJT-

NBO�BOE�8PSEFO ��0VS�mOEJOHT�TVHHFTU�UIBU�SFDBMM�CJBT�XBT�MJNJUFE�BT�XPNFO�

who underwent FP less than two months prior to the interview reported similar

experiences as women for whom FP had taken place more than two months earlier

o�B�SBOEPNMZ�DIPTFO�UJNF�GSBNF�UIBU�TFFNFE�BQQSPQSJBUF�UP�EFmOF�B�NPSF�SFDFOU�

treatment. Another limitation of this study was that only one researcher coded the

interviews, but discussing all phases of the analysis with a second researcher until

consensus was reached, increased dependability of the analysis.

This study shows that women experience FP as a means to cope with breast cancer

by taking action and as part of their breast cancer treatment trajectory, rather than

as a separate treatment for which they had to compromise. This contradicts previ-

ous reports that women consider fertility concerns secondary to the importance of

survival (Gorman et al., 2011; Lee et al� ��4USJWJOH�GPS�TVSWJWBM�TIPVME�UIVT�OPU�

discourage doctors to initiate emergency FP. Also, the advice of the American Soci-

FUZ�PG�$MJOJDBM�0ODPMPHZ�UIBU�'1�TIPVME�CF�DPOTJEFSFE�BO�JOUFHSBM�QBSU�PG�XPNFO�T�

breast-cancer treatment trajectory is now underpinned by our study results, show-

ing that FP can provide women an essential focus in a horrid time where they have


121

just been diagnosed with breast cancer (Loren et al� ��5IF�ATVSWJWBM�NPEF��XIJDI�JOEVDFE�BO�FBHFSOFTT�UP�BDU�BOE�B�UFOEFODZ�UP�QVTI�FNP-

tions aside is in line with previous studies reporting that women with newly diag-

nosed breast cancer use hope and looking forward as a coping-strategy and banking

oocytes or embryos is therefore not necessarily an additional burden but generates

hope (Taylor, 2000; Landmark et al� ��The worries about injecting hormones while having a hormone-sensitive tumor,

DPOmSNT�UIBU�UIF�MBDL�PG�FWJEFODF�PO�TBGFUZ�PG�$04�JO�UFSNT�PG�UIF�QSPHOPTJT�PG�

CSFBTU� DBODFS� JO�XPNFO�XJUI� IPSNPOF�TFOTJUJWF�CSFBTU� DBODFS�QSFTFOUT� B�NBKPS�

clinical problem (Dahhan et al� ��8PNFO�XFSF�BMTP�PDDVQJFE�XJUI�UIF�UISFBU�UP�UIFJS�GFSUJMJUZ�EVF�UP�UIF�BEWJDF�UP�

delay pregnancy for at least two years. This suggests that women with breast cancer

also consider themselves at risk for age-related subfertility, an item that can easily

CF�PWFSMPPLFE�CZ�DMJOJDJBOT�EVF�UP�UIF�EJDIPUPNJ[BUJPO�PG�JOEJDBUJPOT�GPS�GFSUJMJUZ�

preservation into medical and non-medical reasons.

Although women with breast cancer undergo COS and follicle aspiration just like

ASFHVMBS��GFSUJMJUZ�QBUJFOUT �UIFZ�BSF�EFBMJOH�XJUI�EJGGFSFOU�FNPUJPOT��3FHVMBS�GFSUJM-

ity patients have reported stress and anxiety during their treatment as a result of

their insecurity on whether they will get pregnant, the treatment burden of having

to inject medication and the interference of treatment with their daily life (Verhaak

et al� ��#SPE�BOE�'FOOFNB��8PNFO�XJUI�CSFBTU�DBODFS�FYQFSJFODFE�UIFJS�

COS and follicle aspiration as a way to help them deal with breast cancer since it

reassured them that their body was still functioning well.

In conclusion, our data on the experiences of women with breast cancer undergo-

ing FP can be used to increase clinicians understanding, empathy and psychosocial

care for these women. Future studies are necessary to investigate ways to incor-

QPSBUF�UIFTF�mOEJOHT�JOUP�SPVUJOF�QTZDIPTPDJBM�DBSF �BOE�UP�NFBTVSF�JUT�FGGFDU�PO�

XPNFO�T�XFMMCFJOH�PS�FWFO�USFBUNFOU�PVUDPNF��

CHAPTER 6

122

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Lancet 2014; 4:1302-10.

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126

CHAPTER X

127

XXXXXXX

CHAPTER 7Reproductive choices and

outcomes after freezing oocytes for medical reasons:

a follow-up study

T. Dahhan

E.A.F. Dancet

%�7��.JFEFNBF. van der Veen

.��(PEEJKO

Human Reproduction, 2014; 29:1925 –1930.

CHAPTER 7

128

Abstract

Study question:�8IBU�SFQSPEVDUJWF�DIPJDFT�EP�XPNFO�NBLF�BGUFS�UIFZ�IBWF�DSZPQSF-

served oocytes for medical reasons?

Summary answer��8PNFO�XIP�IBE� DSZPQSFTFSWFE�PPDZUFT� GPS�NFEJDBM� SFBTPOT� BOE�

tried to become pregnant, either attempted natural conception or resorted to assisted

reproduction with fresh oocytes.

What is known already:�8PNFO�DPOGSPOUFE�XJUI�B�SJTL�PG�QSFNBUVSF�PWBSJBO�JOTVG-

mDJFODZ �EVF�UP�HPOBEPUPYJD�UIFSBQZ �PWBSJBO�TVSHFSZ�PS�HFOFUJD�QSFEJTQPTJUJPO �IBWF�BO�

JOEJDBUJPO�UP�DSZPQSFTFSWF�PPDZUFT��.BOZ�PG�UIFTF�XPNFO�XJMM�SFUBJO�PWBSJBO�GVODUJPO �

thus will retain the possibility of natural conception. The added value of cryopreserved

oocytes to reproductive outcomes is unknown as there is a lack of follow-up of women

who have cryopreserved oocytes for medical reasons.

Study design, size, duration: This follow-up study included a cohort of 85 women who

cryopreserved their oocytes for medical reasons between 2009 and 2012.

Participants/materials, setting, methods:�.FEJDBM� EBUB� GSPN�XPNFO�XIP� DSZPQSF-

TFSWFE�UIFJS�PPDZUFT�BU�UIF�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF�JO�UIF�"DBEFNJD�.FEJDBM�

Centre in Amsterdam were extracted and self-report questionnaires were disseminated.

The collected data considered demographics, outcomes of ovarian stimulation, fertili-

ty-threatening treatments, menstrual cycle changes, pregnancy attempts and outcomes

and intended plans for the cryopreserved oocytes.

Main results and the role of chance: A total of 68 women, followed up for an average

��NPOUIT �SFUVSOFE�UIF�RVFTUJPOOBJSF�SFTQPOTF�SBUF��/POF�PG�UIF�XPNFO�IBE�

used her cryopreserved oocytes although 16 women had tried to conceive. Of these

XPNFO �FJHIU�XFSF�USZJOH�UP�DPODFJWF�OBUVSBMMZ �mWF�IBE�DPODFJWFE�OBUVSBMMZ�XJUIJO�

2 months and three had conceived with assisted reproduction not requiring cryopre-

served oocytes (two women with conventional IVF because of tubal pathology and en-

EPNFUSJPTJT�BOE�POF�XPNBO�XJUI�*6*�CFDBVTF�PG�QPMZDZTUJD�PWBSZ�TZOESPNF��5ISFF�PVU�

of the eight pregnancies had resulted in live births, two resulted in miscarriages and

UISFF�XFSF�POHPJOH��.PTU�XPNFO��JOUFOEFE�UP�DPODFJWF�XJUI�UIFJS�DSZPQSFTFSWFE�

oocytes as a last resource option.

REPRODUCTIVE CHOICES AND OUTCOMES AFTER FREEZING OOCYTES FOR MEDICAL REASONS: A FOLLOW UP STUDY

129

Limitations, reasons for caution:�5SBOTGFSBCJMJUZ�PG�PVS�mOEJOHT�JT�DIBMMFOHFE�CZ�UIF�

small sample but positively affected by our high response rate. As the time span be-

tween cryopreservation of oocytes and follow-up was short, follow-up of the cohort

should be repeated in 2 years.

8JEFS�JNQMJDBUJPOT�PG�UIF�mOEJOHT� After a mean follow-up of 2 years, none of the

XPNFO�XJUI�B�NFEJDBM�SFBTPO�UP�DSZPQSFTFSWF�PPDZUFT�IBE�VTFE�IFS�PPDZUFT��8PNFO�

who were trying to conceive during follow-up were doing so without using their

stored oocytes. It is unclear whether starting assisted reproduction while having cry-

PQSFTFSWFE�PPDZUFT�JT�UIF�NPTU�BQQSPQSJBUF�DMJOJDBM�EFDJTJPO��0VS�mOEJOHT�FNQIBTJ[F�

the relevance of taking the chances of natural conception into account in counselling

women about cryopreservation of oocytes.

Study funding/competing interest(s): This study was not externally funded. There

BSF�OP�DPOnJDUT�PG�JOUFSFTU�UP�EFDMBSF�

Introduction

8PNFO� DPOGSPOUFE�XJUI� B� SJTL�PG�QSFNBUVSF�PWBSJBO� JOTVGmDJFODZ� 10*� EVF� UP�

gonadotoxic therapy, ovarian surgery or genetic predisposition have a medical rea-

TPO�UP�VOEFSHP�GFSUJMJUZ�QSFTFSWBUJPO�'1�#FEPTDIJ�BOE�0LUBZ ��

Cryopreservation of embryos has long been the only option to preserve fertility,

but it is slowly being overtaken by cryopreservation of oocytes since this technique

BMMPXT�GPS�SFQSPEVDUJWF�BVUPOPNZ�BOE�IBT�TJNJMBS�QSFHOBODZ�SBUFT�,VXBZBNB�et al� ��(SJGP�BOE�/PZFT ��3JFO[J�et al� ��5IF�FGmDBDZ�PG�UIJT�UFDIOJRVF�

and the reassuring data on the health of babies conceived with cryopreserved oo-

cytes (Noyes et al� � �� MFE� UP� UIF� SFNPWBM� PG� UIF� FYQFSJNFOUBM� DPOOPUBUJPO�PG�

DSZPQSFTFSWBUJPO� PG� PPDZUFT� CZ� UIF�"NFSJDBO� 4PDJFUZ� PG� 3FQSPEVDUJWF�.FEJDJOF�

(Loren et al� � ��/FWFSUIFMFTT � UIF� UJNFMZ�OFFE� UP�FWBMVBUF� UIF�BEEFE�WBMVF�PG�

OFXMZ�JOUSPEVDFE�UFDIOJRVFT�CZ�NFBOT�PG�GPMMPX�VQ�IBT�CFFO�BDLOPXMFEHFE�)BSQ-

er et al� ��The likeliness of chemotherapy to induce POI depends on the dose, agent, number

of cycles of chemotherapy and age of the patient (Bines et al� ��.FJSPX ��

#VSTUFJO�BOE�8JOFS ��.FJSPX�et al� ��"�SFDFOU�GPMMPX�VQ�TUVEZ�PO�GFSUJM-

ity in women who cryopreserved ovarian tissue because of planned gonadotoxic

CHAPTER 7

130

chemotherapy, revealed that the majority retained ovarian function with an overall

risk of POI of 22% after a mean follow-up of 58 months (Schmidt et al� ��1SFH-

nancy rates of 65% are described in childhood cancer survivors (Nielsen et al� �� even when trying to conceive naturally for longer than 1 year (Barton et al� ��%BUB�PO�UIF�SJTLT�PG�10*�JO�XPNFO�XJUI�.PTBJD�5VSOFS�4ZOESPNF�BSF�CBTFE�PO�B�

limited number of studies indicating loss of ovarian reserve in women with karyo-

UZQFT�BTTPDJBUFE�XJUI�QPPS�GFSUJMJUZ�QSPHOPTJT�TVDI�BT�9R�EFMFUJPOT�BOE��90�CVU�

natural conceptions rates are rarely mentioned in literature (Tarani et al., 1998;

Sybert, 2002; Purushothaman et al� � ��8PNFO�XJUI� B�NPUIFS�XJUI� B�IJTUPSZ�

of POI are at risk for developing POI themselves, but natural conception rates are

VOLOPXO�#FOU[FO�et al� ��Considering the increased awareness about FP, a result of the tremendous efforts

PG� PSHBOJ[BUJPOT� MJLF� UIF�"NFSJDBO� 4PDJFUZ� GPS�$MJOJDBM�0ODPMPHZ � 'FSUJMF�)PQF �

the International Society for Fertility Preservation, the Oncofertility Consortium

BOE�MPDBM�JOJUJBUJWFT�J�F��UIF�%VUDI/FUXPSL�GPS�'1 �JU�JT�MJLFMZ�UIBU�XF�XJMM�FOUFS�

an era in which many women have anticipated their risk of POI and cryopreserved

their oocytes. Since many of these women will retain ovarian function, chances

of natural conception will be present while cryopreserved oocytes are stored. The

added value of cryopreserved oocytes to reproductive outcomes is unknown in

these women, as there is a lack of a comprehensive follow-up of women who have

DSZPQSFTFSWFE�PPDZUFT�GPS�NFEJDBM�SFBTPOT�BOE�JOTJHIU�JOUP�XPNFO�T�JOUFOUJPOT�GPS�

their cryopreserved oocytes is lacking. This study therefore aimed to examine the

reproductive choices and outcomes of women who have cryopreserved their oo-

cytes for medical reasons.

Methods

Ethical approval

5IJT� GPMMPX�VQ� TUVEZ� XBT� DPOEVDUFE� JO� "VHVTU� �� 5IF� *OTUJUVUJPOBM� 3FWJFX�

#PBSE�PG�UIF�"DBEFNJD�.FEJDBM�$FOUSF�".$�"NTUFSEBN�QSPKFDU�OP�8��@��

TUBUFE�UIBU�UIF�TUVEZ�XBT�OPU�TVCKFDU�UP�UIF�%VUDI�A.FEJDBM�3FTFBSDI�*OWPMWJOH�)V-

NBO�4VCKFDUT�"DU� �NFBOJOH�UIBU�OP�GVSUIFS�BQQSPWBM�XBT�SFRVJSFE�


131

Study population

"�DPIPSU�PG��XPNFO �XIP�IBE�DSZPQSFTFSWFE�PPDZUFT�CFUXFFO�+BOVBSZ��BOE�%F-

DFNCFS�� CFDBVTF�PG�NFEJDBM�SFBTPOT �BU�UIF�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF�PG�

UIF�".$�JO�"NTUFSEBN�XBT�FMJHJCMF�GPS�GPMMPX�VQ�

Data collection

.FEJDBM� EBUB� PO� UIF� JOEJDBUJPO� GPS� DSZPQSFTFSWBUJPO� PG� PPDZUFT � PWBSJBO� TUJNVMB-

UJPO� BOE� UIF� SFTVMUT� PG� PPDZUF� DSZPQSFTFSWBUJPO�XFSF� FYUSBDUFE� GSPN�NFEJDBM� mMFT��

A paper–pencil questionnaire was developed and consecutively pilot tested. The

RVFTUJPOOBJSF� mOBMMZ� DPWFSFE� mWF� UPQJDT�� FTUBCMJTIFE� NFEJDBM� EJBHOPTJT� BOE� GFS-

tility-threatening treatment received, menstrual cycle changes and use of con-

USBDFQUJPO � BUUFNQUT� UP� DPODFJWF� BOE� JOUFOEFE� QMBO� GPS� SFTJEVBM� DSZPQSFTFSWFE�

oocytes. All 14 questions had a multiple choice response scale but for each, the

QPTTJCJMJUZ� UP� BEE� FYQMBOBUJPOT� XBT� QSPWJEFE� TFF� 4VQQMFNFOUBSZ� EBUB � 'JMF� ��

6Q� UP� EBUF� DPOUBDU� JOGPSNBUJPO� J�F�� QPTUBM� BEESFTTFT� PG� UIF� FOUJSF� DP-

IPSU� PG� XPNFO� XBT� SFUSJFWFE� GSPN� UIF� DFOUSBM� IPTQJUBM� SFHJTUFS� PG� UIF� ".$�

The questionnaire was coded and sent by mail in August 2013 accompanied by an in-

vitation and information letter and possibility to declare no interest in participation.

Three weeks later, non-responders were reminded by mail and again by telephone af-

ter another 3 weeks.

Data-analysis

%BUB�XFSF�FOUFSFE�BOE�BOBMZ[FE�VTJOH�4144�TUBUJTUJDT��%FTDSJQUJWF�TUBUJTUJDT�XFSF�

computed to describe demographics, indications for oocyte cryopreservation, repro-

duction after oocyte cryopreservation, menstrual cycle changes and intended use of

SFTJEVBM�DSZPQSFTFSWFE�PPDZUFT�

CHAPTER 7

132

Results

Respondents

5IF�nPXDIBSU�PG�UIF�SFDSVJUNFOU�PG�UIF�TUVEZ�DPIPSU�JT�TIPXO�JO�'JH��1. A total of 85

questionnaires were sent, and 68 women completed the questionnaire and returned

JU�CZ�QPTU��%FNPHSBQIJDT�PG�UIFTF�XPNFO�BSF�TIPXO�JO�5BCMF�I. The mean age

BU� UJNF�PG�PPDZUF� SFUSJFWBM� GPS� DSZPQSFTFSWBUJPO�XBT�� ZFBST� SBOHF��o��ZFBST�

BOE�POMZ�UXP�XPNFO��IBE�DIJMESFO�BU�UIF�UJNF�PG�DSZPQSFTFSWBUJPO�PG�PPDZUFT��

5IF�NBKPSJUZ��PG�UIF�XPNFO�XFSF�IJHIMZ�FEVDBUFE��8PNFO�XFOU�UISPVHI�POF�

O�� UXP�O�� UISFF�O��PS�GPVS�DPOTFDVUJWF�DZDMFT�O��

��5ISFF�XPNFO��DSZPQSFTFSWFE�PPDZUFT�JO�� XPNFO��JO��

XPNFO��JO��BOE��XPNFO��JO��5IF�NFBO�UJNF�UP�GPMMPX�VQ�XBT�

��NPOUIT�SBOHF��o��NPOUIT�

Figure I: Flowchart study cohort of women who cryopreserved oocytes for medical reasons

from 2009 to 2012.

Eligible for study n=85

3FUVSOFE�

questionnaire n=68

Non-responders n=17

t�%JE�OPU�XBOU�UP�QBSUJDJQBUF�O=3

t�$PVME�OPU�mOE�UJNF�UP�QBSUJDJQBUF�O=9

t�6OSFBDIBCMF�CZ�QIPOF�O=5


133

Table I: Demographics of 68 women who cryopreserved oocytes for medical reasons from 2009

to 2012.

#.* �CPEZ�NBTT�JOEFY�

Indications for cryopreservation of oocytes

"U�UIF�UJNF�PG�GPMMPX�VQ ��XPNFO��SFQPSUFE�IBWJOH�VOEFSHPOF�UIFSBQZ�XIJDI�

contained cyclophosphamide. Other fertility-threatening treatments were chemother-

BQZ�DPOTJTUJOH�PG�EPYPSVCJDJO �CMFPNZDJO �WJOCMBTUJOF�BOE�EBSDBSCBDJOF� "#7%� O��

� �DIFNPUIFSBQFVUJD�QSFQBSBUJPO�GPS�CPOF�NBSSPX�USBOTQMBOUBUJPO�O�� FOEPDSJOF�

UIFSBQZ�POMZ�O�� NFUIPUSFYBUF�O��BOE�CJMBUFSBM�TBMQJOHP�PPQIPSFDUPNZ�#40�

CFDBVTF�PG�B�#3$"��HFOF�NVUBUJPO�O��

0VU�PG�UIF��XPNFO�XJUI�CSFBTU�DBODFS ��XPNFO��XFSF�VOEFSHPJOH�BEEJUJPOBM�

endocrine therapy because of hormone-sensitive breast cancer at time of follow-up,

which made conception ill advised (11 women were using tamoxifen; 9 women were us-

JOH�UBNPYJGFO�BOE�(O3)�BOBMPHVFT ��XPNFO�XFSF�VTJOH�(O3)�BOBMPHVFT�BOE��XPN-

BO�EJE�OPU�SFNFNCFS�UIF�OBNF�PG�IFS�FOEPDSJOF�CSFBTU�DBODFS�USFBUNFOU��0OF�PG�UIFTF�

women however was trying to conceive after a wash out period to clear the tamoxifen.

Demographic characteristic

.FBO�BHF�BU�UJNF�PG�PPDZUF�SFUSJFWBM

Previous children

)JHIFS�QSPGFTTJPOBM�TDIPPM�PS�VOJWFSTJUZ

Dutch origin

#.*�LH�N2

Non-smokers

3FHVMBS�DZDMF�

8PNFO�VOEFSHPJOH�POF�DZDMF�

8PNFO�VOEFSHPJOH�UXP�DZDMFT

8PNFO�VOEFSHPJOH�UISFF�DZDMFT�

8PNFO�VOEFSHPJOH�GPVS�DZDMFT��

.FBO�OVNCFS�PG�DSZPQSFTFSWFE�PPDZUFT�QFS�XPNBO�

.FBO�OVNCFS�PG�DZDMFT�QFS�XPNBO��

.FBO�UJNF�PG�GPMMPX�VQ

Mean (range)

��ZFBST��o��

��o��

��o��

��o��

25.3 months

�o��

N (%)

��

��

��

��

��

��

��

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��

CHAPTER 7

134

Reproduction after cryopreserving oocytes

Out of the 68 women, 16 women had tried to conceive after cryopreservation

of oocytes; eight women were trying to conceive naturally at time of follow-up

PG� XIPN� POF� XPNBO� XBT� VTJOH� EPOPS� JOTFNJOBUJPO� BOE� FJHIU� XPNFO� IBE� BM-

ready became pregnant without using their cryopreserved oocytes. Of the eight

XPNFO�XIP�IBE�BMSFBEZ�CFDBNF�QSFHOBOU �mWF�DPODFJWFE�OBUVSBMMZ�BOE�BMM�XJUIJO�

UIF�mSTU��NPOUIT�PG� USZJOH��5IFTF�mWF�QSFHOBODJFT�SFTVMUFE� JO�POF� MJWF�CJSUI � UXP�

miscarriages and two ongoing pregnancies (at gestational ages of respectively 8.5

BOE� �� XFFLT�� 5IF� UISFF� PUIFS� XPNFO� CFDBNF� QSFHOBOU� XJUI� BTTJTUFE� SFQSPEVD-

UJWF� UFDIOJRVFT� UXP�VTJOH� DPOWFOUJPOBM� *7'� BOE� POF� VTJOH� *6*�� 5IF� SFBTPOT� GPS�

starting conventional IVF after cryopreservation of oocytes were bilateral tubal

pathology in one woman who had undergone unilateral ovariectomy and endome-

triosis in the other woman. Both women had live births after conventional IVF.

IUI with ovarian stimulation was performed in a woman with a family history of

POI and polycystic ovarian syndrome, which became apparent after cryopreser-

vation of oocytes. This woman reported a pregnancy at 9 weeks gestational age.

Of the remaining 52 women who were not trying to conceive, 22 were using endo-

crine therapy for breast cancer which made conception ill-advised, two women had a

contraindication for pregnancy due to unstable auto-immune disease and 14 women

EJE�OPU�IBWF�B�NBMF�QBSUOFS��*O�UPUBM ��XPNFO��XFSF�OPU�USZJOH�UP�DPODFJWF�

despite having a male partner and being medically allowed a pregnancy.

Menstrual cycle changes

2VFTUJPOT�BCPVU�DIBOHFT�JO�NFOTUSVBM�DZDMF�DPVME�CF�BOTXFSFE�CZ��XPNFO�BT�UIFZ�

did not use any medication that could mask their menstrual cycle (i.e. oral contracep-

UJPO��"MM��XPNFO�SFUBJOFE�UIFJS�NFOTUSVBM�DZDMF�BU�UJNF�PG�GPMMPX�VQ��0OF�XPNBO�

XJUI�.PTBJD�5VSOFS�TZOESPNF�SFQPSUFE�IBWJOH�OPUJDFE�B�DIBOHF�GSPN�B�SFHVMBS�DZDMF�

��o��EBZT�UP�BO�JSSFHVMBS�DZDMF�PG��o��EBZT�BGUFS�B�GPMMPX�VQ�PG��NPOUIT�

Intended use of cryopreserved oocytes

The majority of the responding women (n ��SFQPSUFE�UIBU�UIFZ�XPVME�VTF�

UIFJS� DSZPQSFTFSWFE�PPDZUFT� JG� UIFZ�IBE�EJGmDVMUJFT� DPODFJWJOH�OBUVSBMMZ��"EEJUJPO-

BMMZ ��XPNFO��IBE�OP�TQFDJmD�QMBO�XJUI�UIFJS�DSZPQSFTFSWFE�PPDZUFT�BOE�POF�


135

XPNBO�XBOUFE�UP�EPOBUF�IFS�DSZPQSFTFSWFE�PPDZUFT�UP�SFTFBSDI��8IFO�BTLFE�UIFJS�

intentions in case of residual cryopreserved oocytes, some women reported not to

IBWF�B�QMBO�JO�NJOE�� XIFSFBT�PUIFST�QMBOOFE�UP�EPOBUF�UIFJS�SFTJEVBM�PPDZUFT�JO�

UIF�GVUVSF�UP�SFTFBSDI�� FJUIFS�UP�SFTFBSDI�PS�PUIFS�XPNFO�� PS�POMZ�UP�PUIFS�

XPNFO�� XIFSFBT�PUIFST�XPVME�XJTI�UP�EFTUSPZ�UIFJS�SFTJEVBM�DSZPQSFTFSWFE�PP-

DZUFT��PS�EJE�OPU�BOTXFS�UIJT�RVFTUJPO��

Discussion

Cryopreservation of oocytes is becoming mainstream for women opting for FP be-

cause this technique does not require a male partner and is no longer considered ex-

perimental (Loren et al� ��5IJT�GPMMPX�VQ�TUVEZ�GPVOE�UIBU�BGUFS�B�NFBO�GPMMPX�VQ�

of 25.3 months, women who had cryopreserved oocytes for medical reasons and tried

to become pregnant, had attempted natural conception or resorted to assisted repro-

duction techniques with fresh oocytes for various reasons. So far, none of the cryopre-

TFSWFE�PPDZUFT�IBE�CFFO�VTFE��)BMG�PG�UIF�XPNFO�BUUFNQUJOH�UP�DPODFJWF�CFDBNF�QSFH-

OBOU �NPTUMZ�CZ�OBUVSBM�DPODFQUJPO��5IJT�JT�UIF�mSTU�GPMMPX�VQ�TUVEZ�JO�XPNFO�XIP�

have cryopreserved oocytes for medical reasons, to report all reproductive outcomes,

including outcomes resulting from the choice not to use cryopreserved oocytes.

None of the women in our study reported clinical symptoms indicating an onset of

NFOPQBVTF�EFmOFE�BT�BO�BCTFODF�PG�NFOTUSVBM�DZDMF�GPS�MPOHFS�UIBO�POF�ZFBS�XJUIPVU�

VTJOH�IPSNPOBM�DPOUSBDFQUJPO�PS�FOEPDSJOF�UIFSBQZ�GPS�CSFBTU�DBODFS��*U�XBT�JNQPT-

sible to detect symptoms of impaired ovarian function for the total study cohort, since

most women in this study used hormonal therapy masking their menstrual cycle.

Our study found that 50% of the women cryopreserving oocytes for medical reasons

did so because of breast cancer. The relatively large proportion of women with breast

cancer opting for FP in our study was also found in a large retrospective cohort of 475

oncological patients, in which the majority of women cryopreserving oocytes were di-

agnosed with breast cancer (Garcia-Velasco et al� ��#SFBTU�DBODFS�JT�UIF�NPTU�DPN-

mon malignancy of women of reproductive age and its management usually includes

gonadotoxic chemotherapy regimens with cyclophosphamide. In case of hormone-

sensitive breast cancer, prolonged endocrine treatment with tamoxifen or aromatase-

inhibitors for 5 years is recommended after chemotherapy (Davies et al� ��8PNFO�

are frequently advised by their oncologists to postpone motherhood during therapy

with tamoxifen because of possible teratogenicity (Barthelmes and Gateley, 2004;

CHAPTER 7

136

Braems et al� ��*O�DBTF�XPNFO�EP�PQU�GPS�B�QSFHOBODZ�EVSJOH�UBNPYJGFO�VTF �TVDI�

as one woman in our cohort, a wash out period of at least 2 months is advised (Braems

et al� ��.PSFPWFS �BT�XBT�UIF�DBTF�JO�POF�XPNBO�PG�PVS�DPIPSU �XPNFO�XIP�DBSSZ�B�

#3$"��HFOF�NVUBUJPO�NBZ�IBWF�UP�QSPQIZMBDUJDBMMZ�VOEFSHP�#40�CFGPSF�UIFZ�IBWF�

had a chance to conceive. Therefore, the fertility of women with breast cancer is at an

even greater threat.

As reported in this study, women who have cryopreserved oocytes in the past may not

rely on their cryopreserved oocytes in the future due to maintenance of natural chanc-

es of conception. This is in accordance with data from women who had cryopreserved

oocytes for age-related decline of fertility, where <1% of women who achieved a preg-

OBODZ�BGUFS�DSZPQSFTFSWBUJPO�PG�PPDZUFT�NBEF�VTF�PG�IFS�DSZPQSFTFSWFE�PPDZUFT�)PEFT�

8FSU[�et al� ��"EEJUJPOBMMZ �POF�TUVEZ�SFQPSUFE�UIBU�JO��XPNFO�XIP�DSZPQSF-

served ovarian tissue because of gonadotoxic treatment, 46 women became pregnant

BGUFS�USFBUNFOU�� PG�XIPN��XPNFO��DPODFJWFE�OBUVSBMMZ�4DINJEU�et al., ��5IJT�JT�B�IJHIFS�QSPQPSUJPO�UIBO�UIBU�GPVOE�JO�PVS�TUVEZ��5IF�EJGGFSFODF�NJHIU�

be explained by a longer follow-up time in this study compared with our study (mean

PG��WFSTVT��NPOUIT�BOE�UIF�SFMBUJWFMZ�IJHI�OVNCFS�PG�XPNFO�XJUI�CSFBTU�DBO-

cer in our study, who were still undergoing additional endocrine therapy at time of

GPMMPX�VQ �EJTBCMJOH� UIFN� GSPN�DPODFJWJOH�� *U� JT� EJGmDVMU� UP�EFmOF� UIF� BQQSPQSJBUF�

timespan after which to start follow-up. Our relatively short time to follow-up (mean

PG��NPOUIT�SFTVMUT�JO�UIF�OFFE�UP�SFQFBU�UIJT�TUVEZ�JO��ZFBST��0O�UIF�PUIFS�IBOE �

UIF�OFFE�GPS�UJNFMZ�DSJUJDBM�SFnFDUJPO�PO�OFXMZ�JOUSPEVDFE�UFDIOJRVFT�)BSQFS�et al., ��BOE�UIF�mOEJOH�JO�PVS�TUVEZ �UIBU�IBMG�PG�UIF�XPNFO�XIP�XFSF�BMSFBEZ�USZJOH�UP�

conceive did not need to rely on their cryopreserved oocytes, demonstrates the timeli-

ness of our study.

Of the 52 women who were not trying to conceive, only 14 women had a male part-

ner and had no medical contraindication to pregnancy. Although this study did not

thoroughly question motivations for not conceiving, fears about pregnancy-related

risks after surviving cancer may contribute to postponing motherhood (Schover, 2005;

Gonçalves et al� ��5SBOTGFSBCJMJUZ�PG�PVS�mOEJOHT�JT�DIBMMFOHFE�CZ�UIF�TNBMM�TBNQMF�TJ[F�CVU�QPTJUJWFMZ�

JOnVFODFE�CZ�PVS�IJHI� SFTQPOTF� SBUF��"OPUIFS� MJNJUBUJPO�PG�PVS� TUVEZ�XBT� UIBU�BT-

TFTTNFOU�PG�PWBSJBO�GVODUJPO�J�F��CMPPE�TBNQMJOH�PS�USBOTWBHJOBM�VMUSBTPVOE�XBT�OPU�

included in the study design. Therefore, the decisions of women (and their advising

QIZTJDJBOT�PO�XIFO�BOE�IPX�UP�TUBSU�USZJOH�UP�DPODFJWF�XBT�OPU�JOnVFODFE�CZ�LOPXM-

edge about ovarian reserve. It is likely that having undergone fertility-threatening


137

USFBUNFOU�JOnVFODFE�EFDJTJPOT�PO�UIF�UJNJOH�PG�BUUFNQUJOH�DPODFQUJPO�

In our study population, 75% of women were highly educated (higher professional

TDIPPM� PS� VOJWFSTJUZ �XIFSFBT� POMZ� ��PG� UIF� HFOFSBM�%VUDI�QPQVMBUJPO� JT� IJHIMZ�

educated. The overrepresentation of highly educated women opting for cryopreserva-

tion of oocytes is also found in other cohorts of women cryopreserving oocytes (Stoop et al� ��)PEFT�8FSU[�et al� ��"�QPTTJCMF�FYQMBOBUJPO�JT�UIBU�IJHIMZ�FEVDBUFE�

XPNFO�BSF�QSPOF�UP�EFMBZ�NPUIFSIPPE�)FDL�et al� ��BOE�NBZ�CF�NPSF�BTTFSUJWF�

in asking about possible fertility related risks of medical treatments and subsequent

options to preserve fertility. Data available to gain insight into the pregnancy chances

for this study population are based on comparisons of pregnancy rates of fresh oocytes

by conventional IVF with cryopreserved and thawed oocytes, showing no superior-

ity of fresh oocytes over cryopreserved oocytes (Cobo et al� ��3JFO[J�et al� ��Our study showed that two women with a pregnancy wish after cryopreservation of

oocytes relied on fresh conventional IVF. It is debatable whether conventional IVF/

ICSI indications justify the use of conventional IVF in women who have already un-

dergone IVF for cryopreservation of oocytes, which in this respect can be regarded

BT� BO� AVOmOJTIFE� *7'�� USFBUNFOU��'SPN�B�QSBHNBUJD� BOE�DPTU�FGGFDUJWFOFTT�QPJOU�PG�

WJFX �POF�NJHIU�PQU�GPS�VTJOH�DSZPQSFTFSWFE�PPDZUFT�mSTU�CFGPSF�JOJUJBUJOH�B�OFX�GSFTI�

IVF cycle. On the other hand, from the perspective of age-related fertility decline, one

NJHIU�DIPPTF�UP�VOEFSHP�DPOWFOUJPOBM�GSFTI�*7'�mSTU�CFGPSF�VTJOH�UIF�DSZPQSFTFSWFE�

oocytes. This implies that the rationale for cryopreserving oocytes has then changed

from a medical reason into a non-medical reason, which may be an ethical dilemma.

In conclusion, this study found that after a mean follow-up of 2 years, none of the

women with a medical reason to cryopreserve oocytes had used any of these oocytes,

and all women attempting to conceive after cryopreservation of oocytes were doing

so without the use of the stored oocytes. There is a need to develop tailored prog-

OPTUJD�BOE�QSFEJDUJPO�NPEFMT�UP�QFSTPOBMJ[F�DIBODFT�PG�PCUBJOJOH�B�QSFHOBODZ�XJUI�

or without use cryopreserved oocytes. It may be too soon to predict these chances

because cryopreservation of oocytes has been introduced only recently and rates at

XIJDI�UIFTF�PDDZUFT�BSF�VTFE�BSF�JOIFSFOUMZ�MPX��5IF�SFTVMUT�PG�UIJT�TUVEZ�FNQIBTJ[F�

the importance of taking the chances of obtaining a pregnancy without use of cryo-

QSFTFSWFE�PPDZUFT�F�H��CZ�OBUVSBM�DPODFQUJPO�JOUP�BDDPVOU�XIFO�DPVOTFMMJOH�XPNFO�

on live birth rates after cryopreserving oocytes and when designing new studies that

evaluate pregnancy rates in the setting of oocyte cryopreservation.

CHAPTER 7

138

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5BZMPS�$ �8BOH�:$�FU�BM��3FMFWBODF�PG�CSFBTU�DBODFS�IPSNPOF�SFDFQUPST�BOE�PUIFS�

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�% (BSDJB�7FMBTDP�+" �%PNJOHP�+ �$PCP�" �.BSUJOF[�. �$BSNPOB�- �1FMMJDFS�"��'JWF�

ZFBST��FYQFSJFODF�VTJOH�PPDZUF�WJUSJmDBUJPO�UP�QSFTFSWF�GFSUJMJUZ�GPS�NFEJDBM�BOE�

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CSFBTU�DBODFS�TVSWJWPST��B�TZTUFNBUJD�SFWJFX��)VN�3FQSPE�6QEBUF��

�% (SJGP�+" �/PZFT�/��%FMJWFSZ�SBUF�VTJOH�DSZPQSFTFSWFE�PPDZUFT�JT�DPNQBSBCMF�UP�

DPOWFOUJPOBM�JO�WJUSP�GFSUJMJ[BUJPO�VTJOH�GSFTI�PPDZUFT��QPUFOUJBM�GFSUJMJUZ�QSFTFS-

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�% )FDL�,& �4DIPFOEPSG�,$ �7FOUVSB�4+ �,JFMZ�+-��%FMBZFE�DIJMECFBSJOH�CZ�FEVDB-

UJPO�MFWFM�JO�UIF�6OJUFE�4UBUFT ��o��.BUFSO�$IJME�)FBMUI�+��

�% )PEFT�8FSU[�# �%SVDLFONJMMFS�4 �4NJUI�. �/PZFT�/��8IBU�EP�SFQSPEVDUJWF�BHF�

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�% -PSFO� "8 � .BOHV� 1# � #FDL� -/ � #SFOOBO� - � .BHEBMJOTLJ� "+ � 1BSUSJEHF� ") �

2VJOO�( �8BMMBDF�8) �0LUBZ�,��'FSUJMJUZ�QSFTFSWBUJPO�GPS�QBUJFOUT�XJUI�DBODFS��

"NFSJDBO�4PDJFUZ�PG�$MJOJDBM�0ODPMPHZ�DMJOJDBM�QSBDUJDF�HVJEFMJOF�VQEBUF��+�$MJO�

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CHAPTER 7

140140

�% /JFMTFO�4/ �"OEFSTFO�"/ �4DINJEU�,5 �3FDIOJU[FS�$ �4DINJFHFMPX�, �#FOU[FO�

+( �-BSTFO�&$��"��ZFBS�GPMMPX�VQ�PG�SFQSPEVDUJWF�GVODUJPO�JO�XPNFO�USFBUFE�GPS�

DIJMEIPPE�DBODFS��3FQSPE�#JPNFE�0OMJOF��

�% Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no

BQQBSFOU�JODSFBTF�JO�DPOHFOJUBM�BOPNBMJFT��3FQSPE�#JPNFE�0OMJOF��

�% 1VSVTIPUIBNBO�3 � -B[BSFWB�0 �0LUBZ�, � 5FO� 4��.BSLFST� PG� PWBSJBO� SFTFSWF� JO�

ZPVOH�HJSMT�XJUI�5VSOFS�T�TZOESPNF��'FSUJM�4UFSJM��

�% 3JFO[J�- �$PCP�" �1BGGPOJ�" �4DBSEVFMMJ�$ �$BQBMCP�" �7BKUB�( �3FNPIJ�+ �3BHOJ�( �

6CBMEJ�'.��$POTJTUFOU�BOE�QSFEJDUBCMF�EFMJWFSZ�SBUFT�BGUFS�PPDZUF�WJUSJmDBUJPO��

BO� PCTFSWBUJPOBM� MPOHJUVEJOBM� DPIPSU� NVMUJDFOUSJD� TUVEZ�� )VN� 3FQSPE� ��

6:1606-1612.

�% 3JFO[J�- �3PNBOP�4 �"MCSJDDJ�- �.BHHJVMMJ�3 �$BQBMCP�" �#BSPOJ�& �$PMBNBSJB�4 �

4BQJFO[B�' �6CBMEJ�'��&NCSZP�EFWFMPQNFOU�PG�GSFTI�AWFSTVT��WJUSJmFE�NFUBQIBTF�**�

PPDZUFT�BGUFS�*$4*��B�QSPTQFDUJWF�SBOEPNJ[FE�TJCMJOH�PPDZUF�TUVEZ��)VN�3FQSPE�

2010; 1:66-73.

�% 4DIPWFS�-3��.PUJWBUJPO�GPS�QBSFOUIPPE�BGUFS�DBODFS��B�SFWJFX��+�/BUM�$BODFS�*OTU�

.POPHS��

�% 4DINJEU�,5 �/ZCPF�"" �(SFWF�5 �&SOTU�& �-PGU�" �:EJOH�"$��'FSUJMJUZ�JO�DBODFS�QB-

UJFOUT�BGUFS�DSZPQSFTFSWBUJPO�PG�POF�PWBSZ��3FQSPE�#JPNFE�0OMJOF��

�% 4UPPQ�% �/FLLFCSPFDL�+ �%FWSPFZ�1��"�TVSWFZ�PO�UIF�JOUFOUJPOT�BOE�BUUJUVEFT�UP-

wards oocyte cryopreservation for non-medical reasons among women of repro-

EVDUJWF�BHF��)VN�3FQSPE��

�% 4ZCFSU�71��1IFOPUZQJD�FGGFDUT�PG�NPTBJDJTN�GPS�B�� 999�DFMM�MJOF�JO�5VSOFS�TZO-

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�% 5BSBOJ�- �-BNQBSJFMMP�4 �3BHVTP�( �$PMMPSJEJ�' �1VDBSFMMJ�* �1BTRVJOP�". �#SVOJ�

-"��1SFHOBODZ�JO�QBUJFOUT�XJUI�5VSOFS�T�TZOESPNF��TJY�OFX�DBTFT�BOE�SFWJFX�PG�

literature. Gynecol Endocrinol 1998; 2:83-87.

142

CHAPTER X

143

XXXXXXX

CHAPTER 8General discussion

CHAPTER 8

144

The Greek myth of Daedalus and Icarus tells the story of a father and son who are

imprisoned on the isle of Crete. Daedalus, a resourceful genius, invents a tool that

would enable release from captivity: two wings of feathers, held together with wax by

XIJDI�IJT�TPO �*DBSVT �JT�JOTUSVDUFE�UP�nZ��i%PO�U�nZ�UPP�MPX �PS�UPP�IJHI w�IF�UFMMT�IJT�

TPO�iLFFQ�B�NJEEMF�SBOHF �BOE�EP�OPU�TIPX�PGGw��8JUI�UIFTF�SFNBSLT�*DBSVT �JOJUJBMMZ �

nJFT�XJUI�DBVUJPO��#VU�TPPO �IF�XPOEFST�XIBU�IF�DBO�EP�XJUI�UIJT�TQMFOEJE�UPZ �XIBU�

MJNJUT�UIFSF�BSF�UP�IJT�GBUIFS�T�JOWFOUJPO��*U�JT�FYDJUJOH �XPOEFSGVM�GVO �CVU�IF�EPFT�OPU�

notice the wax of his wings is melting and feathers are falling out.” Tragically, Icarus

EJFT�BGUFS�GBMMJOH�JOUP�UIF�TFB�+POFT��

In analogy with this myth, excitement about being able to cryopreserve oocytes after

a long time of research and development warrants thoughtfulness on its clinical ap-

plication.

According to the principles of evidence-based medicine, proper clinical care requires

information on safety and effectiveness acquired after careful evaluation research.

)PXFWFS � FWBMVBUJPO� SFTFBSDI� JT� MBSHFMZ� MBDLJOH� BT� JMMVTUSBUFE� CZ� DIBQUFS� GPVS � JO�

XIJDI�XF� GPVOE�OP� SBOEPNJ[FE�DPOUSPMMFE� USJBMT� BGUFS�B� TZTUFNJD� MJUFSBUVSF� TFBSDI�

PO�UIF�UPQJD�PG�TBGFUZ�BOE�FGmDBDZ�PG�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�JO�XPNFO�XJUI�

CSFBTU� DBODFS��5IF� SFBTPO� UIBU�FWBMVBUJPO� SFTFBSDI� JT� MBDLJOH� JO� UIJT�mFME�DPVME�CF�

related to idiosyncratic nature of fertility preservation: there is a - potentially large

- time-gap between the moment of cryopreservation and the moment of thawing.

'FSUJMJUZ�QSFTFSWBUJPO�JT�UIFSFGPSF�POMZ�UIF�mSTU�IBMG�PG�B�QSPDFEVSF �PG�XIJDI�UIF�TFD-

POE�IBMG��UIBXJOH��EPFT�OPU�OFDFTTBSJMZ�IBWF�UP�UBLF�QMBDF��)PX�UP�EFmOF�UIF�TUVEZ�

QPQVMBUJPO �UIF�JOUFSWFOUJPOT�BOE�UIF�PVUDPNF�NFBTVSFT�JO�SFTFBSDI�JO�UIF�mFME�PG�

fertility preservation therefore deserves further thought.

%FmOJOH�UIF�TUVEZ�QPQVMBUJPO�

Identifying the study population for fertility preservation is challenging as all wom-

en are subject to the physiological characteristic of age-related decline of fertility and

UIFSFGPSF�DBO�CFOFmU�GSPN�GFSUJMJUZ�QSFTFSWBUJPO� 'BEEZ�et al. ��$VSSFOU�DMJOJ-

cal practice uses the subdivision between medical and non-medical indications for

GFSUJMJUZ�QSFTFSWBUJPO��8F�IBWF�TIPXO�JO�DIBQUFS�TJY�UIBU�XPNFO�XJUI�CSFBTU�DBODFS�

ESFBEFE�IBWJOH�UP�EFMBZ�QSFHOBODZ�GPS�UXP�UP�mWF�ZFBST�EVF�UIFJS�CSFBTU�DBODFS�USFBU-

ment, as they were aware of their age-related risk for sub- or infertility. Aborting the

UFSN�ATPDJBM��PS�AOPO�NFEJDBM��JOEJDBUJPOT�JO�EJTDVTTJPOT�PO�OPNFODMBUVSF�GPS�PPDZUF�

cryopreservation would acknowledge the overlap of medical and non-medical indica-

GENERAL DISCUSSION

145

tions (Stoop et al. ��.BSUJO��5IJT�DMBTTJD�EJTUJODUJPO�CFUXFFO�XPNFO�XIP�

IBWF� B�NFEJDBM� SJTL� GBDUPS� GPS� QSFNBUVSF� PWBSJBO� JOTVGmDJFODZ� 10*� PS�XIP�IBWF�

B�AOPO�NFEJDBM��SJTL�GBDUPS�GPS�JOGFSUJMJUZ�JT�RVFTUJPOBCMF��1SFNBUVSF�PWBSJBO�JOTVGm-

DJFODZ�JT�B�SJHJE�UFSN�UIBU�JT�CBTFE�PO�B�CJPMPHJDBM�QFSDFQUJPO�PG�PWBSJBO�AGBJMVSF��UIBU�

PDDVST�CFGPSF�UIF�BHF�PG��ZFBST��5IJT�DPODFQU�EJTSFHBSET�XPNFO�T�TPDJBM�BOE�SFMB-

tional context in which women are not always in the right circumstances to conceive

CFGPSF�UIF�BHF�PG��J�F��EVF�UP�MBDL�PG�NBMF�QBSUOFS �NBLJOH�UIFN�BU�SJTL�GPS�PWBSJBO�

JOTVGmDJFODZ�CZ�UIF�UJNF�UIFZ�BSF�BCMF�UP�DPODFJWF��5IFTF��XPNFO�NBZ�XFMM�GFFM�BU�

SJTL�GPS�AQSFNBUVSF��PWBSJBO�JOTVGmDJFODZ �BT�QSFNBUVSF�JO�UIJT�DPOUFYU�NFBOT�ACFGPSF�

CFJOH�JO�UIF�SJHIU�DJSDVNTUBODFT�UP�DPODFJWF��

"OPUIFS�JTTVF�UP�DPOTJEFS�JT�IPX�UP�JEFOUJGZ�QBUJFOUT�QPUFOUJBMMZ�CFOFmUUJOH�GSPN�B�

risk-reducing therapy, since fertility preservation does not treat a disease, but targets

the eventuality of a disease, namely infertility. In that sense, fertility preservation can

CF�TJEFE�XJUI�PUIFS�ASJTL�SFEVDUJWF��PS�AQSFWFOUJWF��NFEJDBM�UIFSBQJFT�TVDI�BT�DIPMFT-

terol reducing drugs for persons at risk of heart disease or prophylactic antibiotics

in persons at risk of infection. For women seeking fertility preservation, there are

QSFTFOUMZ� OP� FWJEFODF�� PS� DPOTFOTVT� CBTFE� DVU�PGG� MFWFMT� BU� IBOE��2VBOUJGZJOH� UIF�

SJTL�PO�QSFNBUVSF�PWBSJBO�JOTVGmFODZ�GPS�XIJDI�GFSUJMJUZ�QSFTFSWBUJPO�JT�QFSGPSNFE�

JT�UIVT�OFDFTTBSZ��4UBOEBSEJ[FE�PWBSJBO�SFTFSWF�UFTUJOH�QSJPS�UP�GFSUJMJUZ�QSFTFSWBUJPO�

and at several moments within the time-gap inherent to fertility preservation may

CF�PG�IFMQ��5IJT�MPOHJUVEJOBM�GPMMPX�VQ�PG�PWBSJBO�SFTFSWF�UFTUJOH�JT�UIF�mSTU�TUFQ�UP-

XBSET�QSFEJDUJOH�XIP�XJMM�PS�XJMM�OPU�CFOFmU�GSPN�GFSUJMJUZ�QSFTFSWBUJPO��3FDFOUMZ �

"OUJ�.àMMFSJBO�)PSNPOF�".)�IBT�CFFO�QSPWFE�UP�CF�B�NBSLFS�GPS�PWBSJBO�SFTFSWF�

(Broer et al. � ��".)�IBT�BMTP�CFFO�NFOUJPOFE� UP�CF�B�NBSLFS� GPS� UIF� MFWFM�PG�

gonadotoxicity in young women with cancer (Fabbri et al., 2014; Broughman et al., �� 'VSUIFSNPSF � QSF�USFBUNFOU�".)�IBT�CFFO�EFNPOTUSBUFE� UP� DPSSFMBUF�XJUI�

QPTU�DIFNPUIFSBQZ�".)�MFWFM�%JMMPO�et al.,��5IF�QBSBEJHN�PG�BTTFTTJOH�PWBS-

ian reserve prior to a time-gap in which women are not reproducing has also been

NFOUJPOFE� JO�XPNFO� TUBSUJOH�PSBM� DPOUSBDFQUJPO� ,VTIOJS� et al� � ��$PMMFDUJOH�

this information can help setting up evaluation research in terms of effectiveness of

treatment and classify risk-categories.

8IFUIFS�UIF�CFOFmUT�PG�GFSUJMJUZ�QSFTFSWBUJPO�JO�UFSNT�PG�FGGFDUJWFOFTT�PVUCBMBODF�

the costs, remains unknown. Prediction models have been proposed, that use decision

BOBMZTJT�UP�FTUJNBUF�DPTU�FGGFDUJWFOFTT�PG�PPDZUF�DSZPQSFTFSWBUJPO�GPS� AOPO�NFEJDBM��

SFBTPOT��)PXFWFS�DPIPSU�TUVEJFT�XJUI�UIF�BJN�UP�BTTFTT�DPTU�FGGFDUJWFOFTT�BSF�OPU�ZFU�

performed, because only few women have returned to use their banked oocytes - as

CHAPTER 8

146

BMTP�JOEJDBUFE�CZ�DIBQUFS��)JSTDIGFME�$ZUSPO�et al., 2012; Loendersloot et al.,��.PSF�SFTFBSDI�JT�UIVT�OFFEFE�UP�FWBMVBUF�UIF�DPTU�FGGFDUJWFOFTT�PG�PPDZUF�CBOLJOH�GPS�

TP�DBMMFE�AOPO�NFEJDBM�SFBTPOT��

8JUI�UIF�MPVE�DBMM�UIBU�GFSUJMJUZ�QSFTFSWBUJPO�TIPVME�CF�JOUFHSBUFE�JOUP�UIF�SFHVMBS�

USFBUNFOU�USBKFDUPSZ�GPS�DBODFS�8BMMBDF ��8BJNFZ�et al. ��,POH�et al. �� this integration may imply that in the future fertility preservation will not only take

place prior to cancer treatment but also after cancer treatment. As cancer therapy is

often multifaceted, one might argue that women who have high chances on relapse of

EJTFBTF�DBO�CFOFmU�GSPN�NVMUJQMF�GFSUJMJUZ�QSFTFSWBUJPO�USBKFDUPSJFT�FWFO�XIFO�UIFTF�

are interrupted by chemotherapy. Future cancer guidelines should take this into ac-

count when mentioning timing of performing fertility preservation.

%FmOJOH�UIF�JOUFSWFOUJPO

Fertility preservation consists of several techniques that have a common goal but dif-

fer completely in their execution and consequences. For example, cryopreservation

PG�PWBSJBO�UJTTVF�BGUFS�NJOJNBM�JOWBTJWF�TVSHFSZ�BJNT�UP�ATUPSF��B�MBSHF�QBSU�PG�PWBSJBO�

reserve that would otherwise serve a physiological role, whereas by cryopreservation

PG�PPDZUFT�POF�BJNT�UP�ATUPSF��B�GSBDUJPO�PG�PWBSJBO�SFTFSWF�UIBU�XPVME�CF�MPTU�JO�UJNF�

anyway. After reimplantation of thawed ovarian tissue, conception can theoretically

CF� JOTUJHBUFE�CZ� UIF� JO� TJUV� OPO�USBOTQMBOUFE�PWBSZ��5IPSPVHI�NPOJUPSJOH�PG� UIF�

ovaries is thus required when effectiveness of this procedure is to be evaluated.

Clinics differ in their policy of who should be offered cryopreservation of ovarian

UJTTVF�� TPNF� DMJOJDT� SFTFSWF� UIJT� PQUJPO� GPS�XPNFO�XJUI� B� QSFEFmOFE� IJHI� SJTL� PG�

chemotherapy-induced menopause, while others offer the procedure to any woman

opting for it, even in absence of malignant disease. Some clinics offer a combination

of several fertility preserving techniques, resulting in a future in which women will

have a combination of various reproductive materials stored i.e. cryopreserved ovar-

JBO� UJTTVF� ÈOE� PPDZUFT� NBUVSF� PS� JNNBUVSF� PS� FNCSZPT��)FODF � USBDJOH� CBDL� UIF�

origin of conception in case of an achieved pregnancy after thawing and using mul-

UJQMF�UFDIOJRVFT�XJMM�CF�B�EJGmDVMU�UBTL�XIFO�UIPSPVHI�NPOJUPSJOH�JT�MBDLJOH��3FHJT-

tering patients undergoing fertility preservation and performing long-term follow

VQ�JT�UIFSFGPSF�OFDFTTBSZ��5IF�JOJUJBUJWF�PG�&4)3&�UP�TFU�VQ�JOUFSOBUJPOBM�SFHJTUSJFT�

for fertility preservation is encouraging and can provide essential information for

evaluation research. To tackle the problem of confounding in evaluation research in

fertility preservation, the registry should incorporate frequent moments of follow-up

GENERAL DISCUSSION

147

similar to how the national cancer registry in the Netherlands operates.

Considering the issue on safety of fertility preservation in women with breast cancer,

connecting these two registries on a patient-level could provide relevant informa-

UJPO��5IF�MPOH�UFSN�GPMMPX�VQ�PG�UIF�45*.�USJBM�QSFTFOUFE�JO�DIBQUFS�� JOUFOET�UP�

use this approach. Although this seems a simple solution, a great change in mind-set

is required to reach this goal which entails the concept of fertility preservation not

ending with cryopreservation but starting with cryopreservation, as is also expressed

CZ�PUIFS�BVUIPST�2VJOO�BOE�7BEBQBSBNQJM ��

%FmOJOH�UIF�PVUDPNF�NFBTVSFT

8PNFO�XIP�VOEFSXFOU�GFSUJMJUZ�QSFTFSWBUJPO�EJGGFS�GSPN�TVCGFSUJMF�QBUJFOUT�BT�UIFZ�

carry an unknown risk to become subfertile after fertility preservation, but after fer-

tility preservation can appear to be fully capable of conceiving naturally, as has been

TIPXO�JO�DIBQUFS��*U�IBT�SFDFOUMZ�CFFO�QSPQPTFE�UIBU�UIF�EJDIPUPNJ[BUJPO�CFUXFFO�

GFSUJMJUZ� BOE� TVCGFSUJMJUZ� JT� nBXFE� BT� �EFTQJUF� MBDL� PG� DPODFQUJPO�XJUIJO� POF� ZFBS��

NBOZ�ATVCGFSUJMF��DPVQMFT�BSF�BCMF�UP�DPODFJWF�OBUVSBMMZ�CVU�POMZ�UBLF�MPOHFS�UP�EP�TP�

.D-FSOPO�et al.,��4VCGFSUJMJUZ�UIFSFGPSF�SFQSFTFOUT�B�QSPHOPTJT�SBUIFS�UIBO�BO�

absolute diagnosis, and this prognosis should also be taken into account when design-

ing research assessing the effect of fertility preservation.

In chapter seven we found that out of the 68 women that banked their oocytes for

NFEJDBM�SFBTPOT ��XFSF�USZJOH�UP�DPODFJWF�OBUVSBMMZ�BOE��XPNFO��SFQPSUFE�

to have intentions of using cryopreserved oocytes only if natural conception failed.

Several studies indicated that chances of natural conception are often retained after

chemotherapy (Barton et al., 2013; Nielsen et al., 2013; Schmidt et al. � ��8JUI�

SFHBSE�UP�SFUBJOJOH�QBSU�PG�UIF�OBUVSBM�SFQSPEVDUJWF�QPUFOUJBM�BGUFS�GFSUJMJUZ�QSFTFS-

vation, one must think about how to value the issue of leftover stored oocytes when

women complete family planning after natural conception or decide not to have

children at all. Are leftover stored oocytes in this case a negative outcome, because

women underwent a costly and risky treatment that in it self did not lead to pregnan-

cy? Or is this a positive outcome if fertility preservation is considered an insurance

against future sterility, thereby legitimating obtaining a surplus of oocytes? Apart

from autologous use, leftover stored oocytes from women with cancer can serve lim-

ited other purposes as scrutiny is warranted when oocytes of women with -poten-

tially hereditary- cancer are to be used for heterologous donation. This implies that

leftover stored oocytes can only be used for laboratory science or will be wasted. So

CHAPTER 8

148

far, the issue of leftover stored oocytes is paid little attention as fertility preservation

JT�PGUFO�QFSGPSNFE�XJUIPVU�DPOTJEFSJOH�MPOH�UFSN�JNQMJDBUJPOT��2VBMJUBUJWF�SFTFBSDI�

can provide relevant insight in how women approach these questions. This insight

can lead to a more general concept of the meaning of surplus gametes for women and

may reveal what plans women have for these surplus gametes. This way clinicians can

CF�CFUUFS�QSFQBSFE�GPS�GVUVSF�DMJOJDBM�EJMFNNB�T�

Clinical implications

8JUI�UIJT�JO�NJOE �XF�NVTU�UBLF�PVS�SFTQPOTJCJMJUZ�XIFO�DPVOTFMJOH�QBUJFOUT�JO�BO�

FSB�WBDBOU�PG�FWJEFODF�CBTFE�JOGPSNBUJPO�BCPVU�GFSUJMJUZ�QSFTFSWBUJPO��8IFO�XF�GVM-

ly acknowledge that we are currently only offering fertility preservation to women

because no one knows what reproductive future lies ahead of them, and when we

encourage our patients to participate in evaluation research, we can look forward

to a future in which women will be able to make an honest decision that will not

leave them disillusioned when the future turns out to be different from what they

expected.

GENERAL DISCUSSION

149

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PWBSJBO�SFTFSWF�UFTUJOH�BOE�JUT�QPUFOUJBM�DMJOJDBM�JNQMJDBUJPOT��)VN�3FQSPE�6Q-

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�% #SPVHIBN� .' � $SPGUPO� 1. � +PIOTPO� + � &WBOT� / � "OEFSTPO� 3"� FU� BM�� "OUJ�

.VMMFSJBO� IPSNPOF� JT� B�NBSLFS� PG� HPOBEPUPYJDJUZ� JO� QSF�� BOE� QPTU� QVCFSUBM�

HJSMT�USFBUFE�GPS�DBODFS��B�QSPTQFDUJWF�TUVEZ��+�$MJO�&OEPDSJOPM�.FUBC��

2059–2067.

�% %BIIBO�5 �%BODFU�&" �.JFEFNB�%7 �WBO�EFS�7FFO�'�BOE�(PEEJKO�.��3FQSPEVD-

UJWF�DIPJDFT�BOE�PVUDPNFT�BGUFS�GSFF[JOH�PPDZUFT�GPS�NFEJDBM�SFBTPOT��B�GPMMPX�

VQ�TUVEZ��)VN�3FQSPE��

�% %JMMPO�,& �%BNNFM�.% �1SFXJUU�. �(JOTCFSH�+1 �8BMLFS�%�FU�BM��1SFUSFBUNFOU�

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�% 'BCCSJ�3 �.BDDJPDDB�. �.FMPUUJ�$ �1BTRVJOFMMJ�( �7JDFOUJ�3�FU�BM��"OUJ�.VMMFSJ-

an hormone as an ovarian reserve marker in young cancer women who undergo

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�% )JSTIGFME�$ZUSPO�+& �(SPCNBO�8" �.JMBE�.1��'FSUJMJUZ�QSFTFSWBUJPO�GPS�TPDJBM�

indications: a cost-based decision analysis. Fertil Steril 2012; 97:665-70.

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150

�% 'BEEZ�.+ �(PTEFO�3( �(PVHFPO�" �3JDIBSETPO�4+�BOE�/FMTPO�+'��"DDFMFSBUFE�

disappearance of ovarian follicles in mid-life: implications for forecasting men-

PQBVTF��)VN�3FQSPE��

�% ,POH�#: �4LPSZ�3.�BOE�8PPESVGG�5,��$SFBUJOH�B�DPOUJOVVN�PG�DBSF��JOUFHSBU-

ing obstetricians and gynecologists in the care of young cancer patients. Clin

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�% ,VTIOJS�7" �#BSBE�%)�BOE�(MFJDIFS�/��0WBSJBO�SFTFSWF�TDSFFOJOH�QSJPS�UP�DPO-

USBDFQUJPO �3FQSPE�#JPNFE�0OMJOF��

�% -PFOEFSTMPPU�-- �.PPMFOBBS�-. �.PM�#8 �3FQQJOH�4 �WBO�EFS�7FFO�' �(PEEJKO�

.��&YQBOEJOH�SFQSPEVDUJWF�MJGFTQBO��B�DPTU�FGGFDUJWFOFTT�TUVEZ�PO�PPDZUF�GSFF[-

JOH��)VN�3FQSPE��

�% .BSUJO� -+�� "OUJDJQBUJOH� JOGFSUJMJUZ�� &HH� 'SFF[JOH � (FOFUJD� 1SFTFSWBUJPO � BOE�

3JTL��(FOEFS��4PDJFUZ��

�% .D-FSOPO�%+ �UF�7FMEF�&3 �4UFZFSCFSH�&8 �.PM�#8 �#IBUUBDIBSZB�4��$MJOJDBM�

QSFEJDUJPO�NPEFMT�UP�JOGPSN�JOEJWJEVBMJ[FE�EFDJTJPO�NBLJOH�JO�TVCGFSUJMF�DPV-

QMFT��B�TUSBUJmFE�NFEJDJOF�BQQSPBDI��)VN�3FQSPE��

�% /JFMTFO�4/ �"OEFSTFO�"/ �4DINJEU�,5 �3FDIOJU[FS�$ �4DINJFHFMPX�,�FU�BM��"�

10-year follow up of reproductive function in women treated for childhood

DBODFS��3FQSPE�#JPNFE�0OMJOF��

�% 1GFJGFS�4 �(PMECFSH�+ �-PCP�3 �1JTBSTLB�. �5IPNBT�.�FU�BM��0WBSJBO�UJTTVF�DSZP-

preservation: a committee opinion. Fertil Steril 2014; 101: 1237-43.

�% 2VJOO�(1�BOE�7BEBQBSBNQJM�45��.PSF�SFTFBSDI �NPSF�SFTQPOTJCJMJUZ��UIF�FYQBO-

TJPO�PG�EVUZ�UP�XBSO�JO�DBODFS�QBUJFOUT�DPOTJEFSJOH�GFSUJMJUZ�QSFTFSWBUJPO��"N�+�

Obstet Gynecol 2013; 209: 98-102.

�% 4DINJEU�,5 �/ZCPF�"" �(SFWF�5 �&SOTU�& �-PGU�"�FU�BM��'FSUJMJUZ�JO�DBODFS�QB-

UJFOUT�BGUFS�DSZPQSFTFSWBUJPO�PG�POF�PWBSZ��3FQSPE�#JPNFE�0OMJOF��

279.

GENERAL DISCUSSION

151

�% 4UPPQ�% �WBO�EFS�7FFO�' �%FOFZFS�. �/FLLFCSPFDL�+�BOE�5PVSOBZF�)��0PDZUF�

CBOLJOH�GPS�BOUJDJQBUFE�HBNFUF�FYIBVTUJPO�"(&�JT�B�QSFWFOUJWF�JOUFSWFOUJPO �

OFJUIFS�TPDJBM�OPS�OPONFEJDBM��3FQSPE�#JPNFE�0OMJOF��

�% 8BJNFZ�,& �%VODBO�'& �4V�)* �4NJUI�, �8BMMBDI�)�FU�BM��'VUVSF�%JSFDUJPOT�JO�

0ODPGFSUJMJUZ�BOE�'FSUJMJUZ�1SFTFSWBUJPO��"�3FQPSU�GSPN�UIF��0ODPGFSUJMJUZ�

$POTPSUJVN�$POGFSFODF��+�"EPMFTD�:PVOH�"EVMU�0ODPM��

�% 8BMMBDF�8)��0ODPGFSUJMJUZ�BOE�QSFTFSWBUJPO�PG�SFQSPEVDUJWF�DBQBDJUZ�JO�DIJM-

dren and young adults. Cancer 2011; 117: 2301-2310.

152

CHAPTER X

153

XXXXXXX

CHAPTER 9Summary

CHAPTER 9

154

5IJT�UIFTJT�FYQMPSFT�DMJOJDBM�EJMFNNBT�PG�GFSUJMJUZ�QSFTFSWBUJPO �DPOmOFE�UP�UIF�CBOL-

ing of oocytes or embryos.

In chapter 1 we provide a general introduction of this thesis and describe the objec-

tives of this thesis.

In chapter 2 we describe a quality management project, which aimed to provide in-

TJHIU� JO�IPX�PVS�DFOUFS�GPS�SFQSPEVDUJWF�NFEJDJOF�*7'�PSHBOJ[FE� JUTFMG� UP�NBOBHF�

fertility preservation-care. The dominant clinical pathway in IVF clinics is elective

IVF/ICSI, consisting of controlled ovarian stimulation, follicle aspiration and fresh

embryo-transfer, which may take 2–6 weeks. If women have cancer and have to start

their cancer treatment soon, controlled ovarian stimulation followed by cryopreser-

vation of oocytes or embryos has become an acute treatment modality. IVF-clinics

have therefore been challenged to organise reproductive care within a short period

of time.

0VS�TUVEZ�JT�UIF�mSTU�UP�EFTDSJCF�IPX�BO�*7'�DMJOJD�IBT�TFU�VQ�B�GFSUJMJUZ�QSFTFSWBUJPO�

QSPHSBN��5P�EP�TP �XF�VTFE�B�QSBDUJDBM� UPPM��4USFOHUIT �8FBLOFTTFT �0QQPSUVOJUJFT�

BOE�5ISFBUT�4805�BOBMZTJT��4805�BOBMZTJT�IBT�CFFO�VTFE�FYUFOTJWFMZ�JO�CVTJOFTT�

settings to uncover new outlooks and to identify problems that would impede pro-

HSFTT��5IF�QSPKFDU�VTFE�B�GPVS�TUFQ�TUSBUFHZ��mSTU�XF�NPOJUPSFE�UIF�CBTFMJOF�SFGFSSBM�

QSPDFTT�EVSJOH�UISFF�NPOUIT��8F�EJE�TP�CZ�BTLJOH�BMM�IFBMUI�DBSF�QSPWJEFST�GSPN�UIF�

DFOUFS� GPS� SFQSPEVDUJWF�NFEJDJOF�PG� UIF�".$�UP�mMM� PVU� B�OPUJmDBUJPO� GPSN�PODF�

they received a request for fertility preservation from either a patient or a health

DBSF�QSPGFTTJPOBM��3FHBSEMFTT�PG�XIFUIFS�XPNFO�SFRVFTUJOH�GFSUJMJUZ�QSFTFSWBUJPO�EJE�

eventually pursue with fertility preservation or not, the form recorded the origin i.e.

who referred the patient, the indication of the request and suggestions to improve

PSHBOJTBUJPOBM�IBOEMJOH�PG�UIBU�TQFDJmD�JODPNJOH�SFRVFTU�

After this monitoring period, the second step of the project was performed. This con-

TJTUFE�PG� B� 4805�BOBMZTJT � QFSGPSNFE�CZ� BO� FYQFSU�UFBN �XIJDI� BJNFE� UP� FYQMPSF�

UIF�UIFO�FYJTUJOH�GFSUJMJUZ�QSFTFSWBUJPO��DBSF�J�F��UIF�iCBTFMJOF�GFSUJMJUZ�QSFTFSWBUJPO�

program” and ways to improve that fertility preservation care. The third-step of the

project consisted of setting up a new fertility preservation-program within the center

for reproductive medicine for women referred for acute cryopreservation of oocytes

or embryos.

8F�TFU�VQ�UIF�OFX�GFSUJMJUZ�QSFTFSWBUJPO�QSPHSBN�CBTFE�PO�UIF�EBUB�GSPN�UIF�UISFF�

months monitoring period of the baseline referral process and the results of the

SUMMARY

155

4805�BOBMZTJT��5IFO � UXP�ZFBST�BGUFS� UIF�TFU�VQ�PG� UIJT� GFSUJMJUZ�QSFTFSWBUJPO�QSP-

gram, we performed the last step of this quality management project consisting of the

FWBMVBUJPO�PG�UIF�QSPHSBN�CZ�B�mOBM�4805�BOBMZTJT �QFSGPSNFE�EVSJOH�B�TUSVDUVSFE�

brainstorm session. The three-months monitoring period showed that a total of 126

XPNFO�SFRVFTUFE�GFSUJMJUZ�QSFTFSWBUJPO �PG�XIJDI��XPNFO��XJTIFE�UP�DSZPQSF-

TFSWF�PPDZUFT�CFDBVTF�PG�BHF�SFMBUFE�EFDMJOF�PG�GFSUJMJUZ��5XFOUZ�FJHIU��XPNFO�

SFRVFTUFE�GFSUJMJUZ�QSFTFSWBUJPO�GPS�BDVUF�SFBTPOT �PG�XIJDI��XPNFO�EJE�TP�

CFDBVTF�PG�CSFBTU�DBODFS��5IF�4805�BOBMZTJT�PG�UIF�CBTFMJOF�GFSUJMJUZ�QSFTFSWBUJPO�

program revealed that logistics of acute fertility preservation care were not yet in-

DPSQPSBUFE�JOUP�EBJMZ�QSBDUJDF�BOE�EFMBZT�JO�QMBOOJOH�B�mSTU�DPOTVMU�XFSF�DPNNPO��

5IF�OFX�GFSUJMJUZ�QSFTFSWBUJPO�QSPHSBN�TFU�VQ�BGUFS�UIJT�4805�BOBMZTJT� UPPL�GPVS�

general measures. Firstly, information about fertility preservation for patients was

EFWFMPQFE�BOE�XBT�TQSFBE�UISPVHI�MFBnFUT�BOE�UIF�JOUFSOFU��4FDPOEMZ �QPUFOUJBM�SFGFS-

ring physicians were informed by letters, our website and by information sessions.

Thirdly, organisational tools such as a pre-consultation fertility preservation-ques-

UJPOOBJSF�XFSF�EFWFMPQFE�UP�SFEVDF�UJNF�PG�mSTU�DPOTVMUBUJPO��-BTUMZ �B�DIFDLMJTU�GPS�

UIF�mSTU�DPOTVMUBUJPO�XBT�EFWFMPQFE�UIBU�DPWFST�SFMFWBOU�GFSUJMJUZ�QSFTFSWBUJPO�JUFNT��

8IFO�XF�FWBMVBUFE�UIF�PSHBOJTBUJPO�PG�GFSUJMJUZ�QSFTFSWBUJPO�UXP�ZFBST�BGUFS�UIF�TFU�

VQ�PG� UIF�OFX� GFSUJMJUZ�QSFTFSWBUJPO�QSPHSBN�CZ� B�mOBM�4805�BOBMZTJT �XF� GPVOE�

that consultation was less time-consuming by introducing a pre-consultation fertil-

ity preservation-questionnaire for patients and a checklist for doctors to use during

DPOTVMUBUJPO��8F�DPODMVEF�UIBU�PVS�OFX�GFSUJMJUZ�QSFTFSWBUJPO�QSPHSBN�DBO�CF�VTFE�BT�

an example for other IVF-clinics on how to manage acute fertility preservation care

BOE�DBO�PGGFS�JOTJHIU�JO�IPX�UP�VTF�4805�BOBMZTJT�BT�B�QSBDUJDBM�UPPM�UP�JNQSPWF�PS�

start fertility preservation care.

In chapter 3 we report a prospective case-series in which we assessed tamoxifen and

UBNPYJGFO�NFUBCPMJUF�MFWFMT�FOEPYJGFO�JO�GPVS�XPNFO�XJUI�FTUSPHFO�SFDFQUPS�&3�

positive breast cancer who cryopreserved oocytes. All women in this study received

IJHI�EPTFT�PG�UBNPYJGFO��NH�QFS�EBZ�UP�NPEVMBUF�UIF�&3�PG�UIF�CSFBTU�UVNPVS�

and therefore hypothetically prevent extra tumour growth during controlled ovarian

stimulation. The aim of this study was to assess whether endoxifen levels considered

IJHI�FOPVHI�GPS�&3�JOIJCJUJPO��OH�NM�DPVME�CF�SFBDIFE��5ISPVHIPVU�DPOUSPMMFE�

PWBSJBO�TUJNVMBUJPO �CMPPE�TBNQMFT�XFSF�DPMMFDUFE�BOE�TFSVN�MFWFMT�PG�FTUSBEJPM�&� �

UBNPYJGFO�BOE�FOEPYJGFO�EFUFSNJOFE��5IF�BWFSBHF�OVNCFS�PG�WJUSJmFE�PPDZUFT�XBT��

SBOHF��o��5IFSF�XBT�B�MBSHF�JOUFS�JOEJWJEVBM�WBSJBCJMJUZ�JO�TFSVN�FOEPYJGFO�MFWFMT�

CHAPTER 9

156

CFUXFFO� UIF�XPNFO� BU� UJNF�PG� GPMMJDMF� BTQJSBUJPO� SBOHF� ��o��OH�NM��0G�OPUF �

UISFF�PVU�PG�GPVS�XPNFO�BDIJFWFE�FOEPYJGFO�MFWFMT�DPOTJEFSFE�IJHI�FOPVHI�GPS�&3�

JOIJCJUJPO��OH�NM��"MUIPVHI�JU�JT�VOLOPXO�XIBU�UIF�DMJOJDBM�SFMFWBODF�JT�PG�IJHI�

endoxifen levels for this particular group of women, we can conclude that, when

dosages of tamoxifen are used like the ones commonly used in the adjuvant setting,

endoxifen serum levels similar to those in the adjuvant setting can be reached in the

setting of controlled ovarian stimulation for fertility preservation. To further explore

BOE�VOEFSTUBOE�UIF�NFDIBOJTN�PG�IPX�UBNPYJGFO�NFUBCPMJ[FT�JO�UIF�TFUUJOH�PG�DPO-

trolled ovarian stimulation a prospective study in a larger group of women is war-

ranted.

In chapter 4 we present a systematic review which aimed to assess the effects of add-

JOH�UBNPYJGFO�PS�MFUSP[PMF�UP�TUBOEBSE�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�QSPUPDPMT�PO�

the breast cancer free interval in young women with estrogen receptor positive breast

cancer who banked oocytes or embryos. Alternative controlled ovarian stimulation

QSPUPDPMT�XJUI�UBNPYJGFO�PS�MFUSP[PMF�BSF�CFJOH�VTFE�CBTFE�PO�UIF�JEFB�UIBU�TUBOEBSE�

DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�QSPNPUFT�CSFBTU�DBODFS�HSPXUI��8F�TFBSDIFE�GPS�SBO-

domised trials comparing controlled ovarian stimulation protocols with additional

UBNPYJGFO�PS�MFUSP[PMF�JO�XPNFO�XJUI�CSFBTU�DBODFS��

Two review authors independently screened 262 titles and abstracts that were identi-

mFE�CZ�UIF�DPOEVDUFE�TFBSDIFT�CVU�OP�SBOEPNJTFE�DPOUSPMMFE�USJBMT�XFSF�JEFOUJmFE��

"MUIPVHI�OP�SBOEPNJ[FE�DPOUSPMMFE�USJBMT�XFSF�GPVOE �XF�JEFOUJmFE�POF�QSPTQFDUJWF�

cohort study that compared three controlled ovarian stimulation protocols: recombi-

OBOU�GPMMJDVMBS�TUJNVMBUJOH�IPSNPOF�SFD'4)�XJUI�FYUSB�UBNPYJGFO��NH�QFS�EBZ �

B�QSPUPDPM�VTJOH�POMZ�UBNPYJGFO�BT�PWBSJBO�TUJNVMBOU��NH�QFS�EBZ�BOE�B�QSPUPDPM�

VTJOH�SFD'4)�XJUI� MFUSP[PMF� ��NH�QFS�EBZ��5IFTF�QSPUPDPMT�XFSF�DPNQBSFE� JO��

women with breast cancer who were banking embryos. A total of 29 women who

underwent 33 cycles were compared with a control group of 31 women with breast

cancer who did not undergo fertility preservation. Compared with women who re-

DFJWFE� UBNPYJGFO� BMPOF �XPNFO�XIP� SFDFJWFE� UIF� DPNCJOBUJPO� SFD'4)�UBNPYJGFO�

PS�SFD'4)�MFUSP[PMF �IBE�B�HSFBUFS�OVNCFS�PG�GPMMJDMFT��1FBL�&��MFWFMT�JO�UIF�SFD'4)�

MFUSP[PMF�HSPVQ�XFSF�TJHOJmDBOUMZ�MPXFS�UIBO�JO�UIF�HSPVQ�SFDFJWJOH�UBNPYJGFO�BMPOF�

PS�SFD'4)�UBNPYJGFO��"GUFS�BO�BWFSBHF�PG��EBZT�SBOHF��UP��EBZT�PG�

follow-up for all women including controls, the cancer recurrence rate was similar

between women undergoing controlled ovarian stimulation and the women who did

OPU�VOEFSHP�GFSUJMJUZ�QSFTFSWBUJPO�UIF�DPOUSPM�HSPVQ�UISFF�PG��WFSTVT�UISFF�PG��

SUMMARY

157

XPNFO �SFTQFDUJWFMZ��IB[BSE�SBUJP ��$*��UP��5IVT �UIF�POMZ�TUVEZ�UIBU�

DPNQBSFE�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�QSPUPDPMT�JODMVEJOH�UBNPYJGFO�PS�MFUSP[PMF�

used a non randomised approach in which small groups of women were compared

without power-calculation and the control group consisted of women who did not

undergo fertilitypreservation, in stead of women receiving controlled ovarian stimu-

MBUJPO�XJUIPVU�BEEJUJPOBM�MFUSP[PMF�PS�UBNPYJGFO��*O�BEEJUJPO �UIF�TUVEZ�GBJMFE�UP�QSP-

vide long-term follow for women undergoing controlled ovarian stimulation with

UBNPYJGFO�PS� MFUSP[PMF��'PS� UIJT� TZTUFNBUJD�SFWJFX �XF�DPODMVEFE�UIBU� UIFSF�BSF�OP�

SBOEPNJTFE�DPOUSPMMFE�USJBMT�DPNQBSJOH�QSPUPDPMT�XJUI�FYUSB�UBNPYJGFO�PS�MFUSP[PMF��

Given this lack of evidence, we suggest that controlled ovarian stimulation protocols

UIBU�JODMVEF�UBNPYJGFO�PS�MFUSP[PMF�TIPVME�CF�SFTUSJDUFE�UP�UIF�TFUUJOH�PG randomised

controlled trials.

In chapter 5�XF�QSFTFOU�UIF�TUVEZ�QSPUPDPM�PG�UIF�45*.�USJBM�USJBM�SFHJTUFS�OVNCFS��

/53��i4UJNVMBUJPO�PG�UIF�PWBSJFT�JO�XPNFO�XJUI�CSFBTU�DBODFS�VOEFSHPJOH�GFS-

tility preservation: alternative versus standard stimulation protocols”. To counter-

balance estrogen exposure in breast tissue, it has been suggested to add tamoxifen

PS� MFUSP[PMF� UP� DPOUSPMMFE� PWBSJBO� TUJNVMBUJPO� QSPUPDPMT�� $VSSFOU� DMJOJDBM� QSBDUJDF�

for fertility preservation therefore varies from standard controlled ovarian stimula-

tion without any anti-estrogenic agents, to adjusted stimulation protocols adding

UBNPYJGFO� PS� MFUSP[PMF� UP� DPOUSPMMFE� PWBSJBO� TUJNVMBUJPO��5IF� BTTVNQUJPO� UIBU� UB-

NPYJGFO�BOE�MFUSP[PMF�TFSWF�B�QSPUFDUJWF�SPMF�JO�XPNFO�XJUI�CSFBTU�DBODFS�VOEFSHP-

JOH�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�JT�CBTFE�PO�B�HFOFSBMJ[BUJPO�PG�EBUB�UIBU�TIPX�BO�

improved prognosis for women with estrogen-receptor positive breast cancer who

VTF�UBNPYJGFO�PS�MFUSP[PMF�BT�MPOH�UFSN�BEKVWBOU�UIFSBQZ��'PMMPX�VQ��ZFBST�PO�

the safety of controlled ovarian stimulation in women with breast cancer showed

similar recurrence rates as compared to women with breast cancer who did not

undergo fertility preservation. Although these studies consisted of a small sample

TJ[F�CFUXFFO��BOE��XPNFO�BOE�EJE�OPU�DPNQBSF�EJGGFSFOU�DPOUSPMMFE�PWBSJBO�

stimulation protocols with each other but only with controls who had not received

controlled ovarian stimulation, it seems that thus far controlled ovarian stimulation

XJUI�FYUSB�UBNPYJGFO�PS�MFUSP[PMF�IBT�OP�IBSNGVM�FGGFDU�PO�MPOH�UFSN�PVUDPNFT�GPS�

XPNFO�XJUI�CSFBTU�DBODFS��)PXFWFS �B�MBSHFS�DPIPSU�TUVEZ�JT�OFDFTTBSZ�UP�DPNQBSF�

the effects of different controlled ovarian stimulation protocols (with and without

FYUSB�UBNPYJGFO�PS�MFUSP[PMF��#FTJEFT�TBGFUZ �JOTJHIU�JOUP�XIBU�TUJNVMBUJPO�QSPUPDPM�

is most effective in terms of oocyte yield is also necessary. One study comparing a

CHAPTER 9

158

standard controlled ovarian stimulation protocol with a controlled ovarian stimula-

UJPO�QSPUPDPM�XJUI�FYUSB�MFUSP[PMF�TIPXFE�B�TJHOJmDBOUMZ�MPXFS�ZJFME�PG�PPDZUFT�GPS�

cryopreservation as compared to a standard controlled stimulation protocol (6,6 ± 3,5

WFSTVT�� Q�� "OPUIFS�TUVEZ�DPNQBSFE�UISFF�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�

QSPUPDPMT��SFDPNCJOBOU�GPMMJDVMBS�TUJNVMBUJOH�IPSNPOF�SFD'4)�XJUI�FYUSB�UBNPY-

JGFO��NH�QFS�EBZ �B�QSPUPDPM�VTJOH�POMZ�UBNPYJGFO�BT�PWBSJBO�TUJNVMBOU��NH�QFS�

EBZ�BOE�B�QSPUPDPM�VTJOH�SFD'4)�XJUI�MFUSP[PMF��NH�QFS�EBZ��5IJT�TUVEZ�GPVOE�UIBU�

XPNFO�XIP�SFDFJWFE�UIF�QSPUPDPM�DPOUBJOJOH�SFD'4)�BOE�UBNPYJGFO�PS�MFUSP[PMF�IBE�

a higher number of mature oocytes as compared with the women receiving a proto-

DPM�XJUI�UBNPYJGFO�POMZ��WFSTVT��BOE�� SFTQFDUJWFMZ��1��

��#FDBVTF�UIF�RVJOUFTTFODF�PG�GFSUJMJUZ�QSFTFSWBUJPO�JT�UP�ZJFME�B�IJHI�OVNCFS�PG�

mature oocytes, as a possible proxy for future chances of conception, it is warranted

to know which stimulation protocol suits women with breast cancer best in terms

PG�PPDZUF�ZJFME��#Z�DPOEVDUJOH�UIF�45*.�USJBM�XF�BJN�UP�FWBMVBUF�UIF�FGGFDUJWFOFTT�

PG�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�XJUI�UBNPYJGFO�PS�MFUSP[PMF�DPNQBSFE�UP�TUBOEBSE�

controlled ovarian stimulation on the number of oocytes retrieved in women with

breast cancer undergoing controlled ovarian stimulation to bank oocytes or embryos.

.FBOXIJMF �XF�BJN�UP�DPMMFDU�EBUB�PO�UIF�TBGFUZ�PG�DPOUSPMMFE�PWBSJBO�TUJNVMBUJPO�

CZ�DPOEVDUJOH�MPOH�UFSN�GPMMPX�VQ�PG�UIF�XPNFO�FOSPMMFE��5IF�45*.�USJBM�JT�B�NVM-

ticenter open-label randomised controlled trial. The study population consists of

women with breast cancer who opt for banking of oocytes or embryos, aged 18 – 43

years at randomisation. Primary outcome is the number of oocytes retrieved at fol-

licle aspiration. Secondary outcomes are the number of mature oocytes retrieved, the

number of oocytes or embryos banked and peak E2 levels during controlled ovarian

stimulation. To prove a two-sided difference of 4 oocytes with an alpha of 5% and a

power of 90%, we need to include 48 women in each group. To compensate for 10%

lost to follow-up we aim to enroll 53 women in each group, i.e. 159 women in total.

5IJT�TBNQMF�TJ[F�JT�TVGmDJFOU�UP�DPNQBSF�CPUI�UBNPYJGFO�BOE�MFUSP[PMF�XJUI�DPOUSPM�

USFBUNFOU�BT�XFMM�BT�XJUI�FBDI�PUIFS��5IF�TUVEZ�TUBSUFE�JODMVEJOH�XPNFO�JO�+BOVBSZ�

2014. Currently 58 women are included.

In chapter 6 we present a qualitative study that aimed to explore how women experi-

ence oocyte or embryo banking when they have just been diagnosed with breast can-

cer. Although there are studies on the perspectives of breast cancer survivors on child-

bearing, and decision-making for or against fertility preservation, the experience of

going through fertility preservation has not been studied. This lack of knowledge

SUMMARY

159

NBZ�OPU�CF�UP�UIF�CFOFmU�PG�PVS�QBUJFOUT �BT�JOTJHIU�JOUP�XPNFO�T�FYQFSJFODFT�BOE�

needs during treatment is necessary to provide appropriate psychosocial care during

infertility treatment. Psychosocial care by all fertility staff members is a prerequisite

GPS�IJHI�RVBMJUZ�GFSUJMJUZ�DBSF �BT�SFDFOUMZ�TUBUFE�CZ�UIF�&VSPQFBO�4PDJFUZ�PG�)VNBO�

3FQSPEVDUJWF�BOE�&NCSZPMPHZ�&4)3&��5IJT�TUVEZ�UIFSFGPSF�BJNFE�UP�FYQMPSF�IPX�

women experience oocyte or embryo banking when they have just been diagnosed

with breast cancer. A phenomenological design was chosen as phenomenology is a

TQFDJmD�RVBMJUBUJWF� SFTFBSDI�NFUIPEPMPHZ�EFWPUFE� UP� FYQMPSJOH� BOE�VOEFSTUBOEJOH�

experiences. All women aged between 18 and 43 years with newly diagnosed breast

DBODFS�XIP�CBOLFE�UIFJS�PPDZUFT�PS�FNCSZPT�JO�UIF�$FOUSFT�GPS�3FQSPEVDUJWF�.FEJ-

DJOF�PG�UIF�"DBEFNJD�.FEJDBM�$FOUFS�PS�UIF�6OJWFSTJUZ�.FEJDBM�$FOUFS�6USFDIU�CF-

UXFFO�+BOVBSZ��BOE�+VMZ��XFSF�FMJHJCMF�GPS�JODMVTJPO��"GUFS�PCUBJOJOH�XSJUUFO�

informed consent, we collected data on demographics and on medical background

with the aid of a questionnaire. Then, we conducted face-to-face in-depth inter-

views, which lasted 45-90 minutes. In total, we invited twenty-eight women of whom

twenty-one women consented to participate. The 21 interviewed women had a mean

BHF�PG��ZFBST��5IFZ�CBOLFE�PPDZUFT�O�� FNCSZPT�O��PS�TUPQQFE�CFGPSF�GPMMJDMF�

BTQJSBUJPO�O��'JGUFFO�XPNFO�IBE�UJNF�GPS�POMZ�POF�DZDMF�PG�CBOLJOH�PPDZUFT�PS�

embryos. Fertility preservation was experienced as a burden, mainly because of time

pressure and the fear for complications that could result in a delay for chemotherapy.

Through fertility preservation women experienced a new identity as a fertility pa-

UJFOU �XIJDI�XBT�TPNFUJNFT�SFQPSUFE�BT�EJGmDVMU�CFDBVTF�CFJOH�EJGGFSFOU�GSPN�SFHVMBS�

GFSUJMJUZ�QBUJFOUT�GVSUIFS�FNQIBTJ[FE�XPNFO�T�VOQMFBTBOU�JEFOUJUZ�BT�B�CSFBTU�DBODFS�

QBUJFOU��0O�UIF�PUIFS�IBOE �XPNFO�GFMU�SFMJFWFE�UP�TFF�ASFHVMBS��JOGFSUJMJUZ�QBUJFOUT�JO�

UIF�GFSUJMJUZ�DMJOJD�CFDBVTF�UIJT�NBEF�UIFN�SFBMJ[F�UIBU�UIFZ�XFSF�OPU�UIF�POMZ�POFT�

TUSVHHMJOH�UP�IBWF�B�GVUVSF�XJUI�DIJMESFO��8PNFO�BMTP�EFTDSJCFE�DPQJOH�XJUI�CSFBTU�

cancer through fertility preservation as it allowed them to take action in a time when

they were not yet able to start with cancer treatment. Their diagnosis had induced a

TUSPOH�TVSWJWBM�NPEF�BOE�BO�FBHFSOFTT�UP�ABDU��BOE�UP�QVTI�FNPUJPOT�BTJEF��'PS�UIFTF�

XPNFO �GFSUJMJUZ�QSFTFSWBUJPO�XBT�UIF�ATUBSU��BOE�UIFSFGPSF�BO�JOUFHSBUFE�QBSU�PG�UIFJS�

breast cancer trajectory. In conclusion, this study provides in-depth insight in the

experiences of women with breast cancer undergoing fertility preservation. This

insight can be used to increase clinicians understanding, empathy and psychosocial

care for these women. Future studies are necessary to investigate ways to incorporate

UIFTF�mOEJOHT�JOUP�SPVUJOF�QTZDIPTPDJBM�DBSF �BOE�UP�NFBTVSF�JUT�FGGFDU�PO�XPNFO�T�

wellbeing or even treatment outcome.

CHAPTER 9

160

In chapter 7 we present a follow-up study on the reproductive choices women make

after they have cryopreserved oocytes for medical reasons. There have been efforts to

JODSFBTF� BXBSFOFTT� BCPVU� GFSUJMJUZ�QSFTFSWBUJPO �CZ�PSHBOJ[BUJPOT� MJLF� UIF�"NFSJDBO�

4PDJFUZ� GPS�$MJOJDBM�0ODPMPHZ � 'FSUJMF�)PQF � UIF� *OUFSOBUJPOBM� 4PDJFUZ� GPS�'FSUJMJUZ�

Preservation, the Oncofertility Consortium and local initiatives i.e. the Dutch Net-

work for fertility preservation. It may be that more women know of their risk of pre-

NBUVSF�PWBSJBO�JOTVGmDJFODZ�BOE�NBZ�XJTI�UP�GSFF[F�UIFJS�PPDZUFT��4JODF�JU�JT�LOPXO�

that many of these women will retain ovarian function, chances of natural conception

will be present while their oocytes are banked. The added value of banked oocytes

to reproductive outcomes is unknown in these women, as there is a lack of a com-

prehensive follow-up of women who have banked oocytes for medical reasons. This

follow up study included a cohort of 85 women who banked their oocytes for medical

SFBTPOT�CFUXFFO��BOE��JO�UIF�"DBEFNJD�.FEJDBM�$FOUFS�JO�"NTUFSEBN��8F�

FYUSBDUFE�NFEJDBM�EBUB�GSPN�NFEJDBM�mMFT�BOE�EJTTFNJOBUFE�TFMG�SFQPSU�RVFTUJPOOBJSFT��

The collected data consisted of demographics, outcomes of ovarian stimulation, type

of fertility-threatening treatments, changes in the menstrual cycle, attempts to be-

come pregnant and the outcomes of a possible pregnancy attempt, and intended plans

for future use of banked oocytes. A total of 68 women, followed up for an average 25.3

NPOUIT �SFUVSOFE�UIF�RVFTUJPOOBJSF�SFTQPOTF�SBUF��/POF�PG�UIF�XPNFO�IBE�VTFE�

her cryopreserved oocytes. Sixteen women had tried to conceive. Of these 16 women,

FJHIU�XFSF�USZJOH�UP�DPODFJWF�OBUVSBMMZ �mWF�IBE�DPODFJWFE�OBUVSBMMZ�XJUIJO��NPOUIT�

and three had conceived with medically assisted reproduction not requiring cryopre-

served oocytes; two women with conventional IVF because of tubal pathology and

endometriosis and one woman with IUI because of polycystic ovary syndrome. Three

out of the eight pregnancies had resulted in live births, two resulted in miscarriages

BOE�UISFF�XFSF�POHPJOH��.PTU�XPNFO��JOUFOEFE�UP�DPODFJWF�OBUVSBMMZ�BOE�POMZ�

wished to use their cryopreserved oocytes as a last resource option. The results of our

TUVEZ�FNQIBTJ[F�UIF�JNQPSUBODF�PG�UBLJOH�UIF�DIBODFT�PG�HFUUJOH�QSFHOBOU�XJUIPVU�

use of cryopreserved oocytes e.g. by natural conception into account when counseling

women on live birth rates after cryopreserving oocytes and when designing new stud-

ies that evaluate pregnancy rates in the setting of oocyte cryopreservation.

In chapter 8�XF�EJTDVTT�UIF�mOEJOHT�PG�UIJT�UIFTJT�BOE�SFnFDU�PO�UIF�DMJOJDBM� JNQMJ-

DBUJPOT�PG�PVS� TUVEJFT��8F�EFTDSJCF� UIF�OFDFTTJUZ� UP�EFTJHO�BOE�QFSGPSN�FWBMVBUJPO�

SFTFBSDI�XJUIJO�UIF�mFME�PG�GFSUJMJUZ�QSFTFSWBUJPO�BOE�XF�SFnFDU�PO�SFTFBSDI�JEFBT�UIBU�

incorporate long-term follow up to reach this goal.

162

CHAPTER X

163

XXXXXXX

CHAPTER 10Samenvatting

CHAPTER 10

164

*O�EJU�QSPFGTDISJGU�POEFS[PFLFO�XJK�EF�LMJOJTDIF�EJMFNNB�T�WBO�GFSUJMJUFJUTQSFTFSWBUJF �

UPFHFTQJUTU�PQ�IFU�JOWSJF[FO�WBO�FJDFMMFO�PG�FNCSZP�T�

In hoofdstuk 1 verschaffen wij een algemene inleiding van dit proefschrift en be-

schrijven wij de doelstellingen van dit proefschrift.

In hoofdstuk 2 CFTDISJKWFO�XJK�FFO�LXBMJUFJUTNBOBHFNFOU�QSPKFDU�EBU�JT�PQHF[FU�NFU�

IFU�EPFM�PN�JO[JDIU�UF�WFSTDIBGGFO�PWFS�IPF�POT�DFOUSVN�WPPS�WPPSUQMBOUJOHTHFOFFT-

LVOEF�GFSUJMJUFJUTQSFTFSWBUJF�IFFGU�PQHF[FU��)FU�PWFSIFFSTFOEF�LMJOJTDIF�[PSHQBE�JO�

FFO�*7'�LMJOJFL�JT�FMFDUJFWF�*7'�*$4* �CFTUBBOEF�VJU�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMB-

UJF �GPMMJLFMBTQJSBUJF�FO�WFSTF�FNCSZPUSBOTGFS��%F[F�*7'�*$4*�CFIBOEFMJOH�LBO�UXFF�

UPU�[FT�XFLFO�EVSFO��7PPS�WSPVXFO�EJF�LBOLFS�IFCCFO�FO�PQ�LPSUF�UFSNJKO�NFU�IVO�

behandeling moeten starten, kan een dergelijke IVF behandeling een spoedeisend

LBSBLUFS�IFCCFO��*7'�LMJOJFLFO�[JKO�EBO�PPL�HFEXPOHFO�PN�EF[F�[PSH�CJOOFO�FFO�

BG[JFOCBSF�UJKE�WPPS�EF[F�WSPVXFO�UF�PSHBOJTFSFO��%JU�JT�EF�FFSTUF�TUVEJF�EJF�CFTDISJKGU�

IPF�FFO�*7'�LMJOJFL�FFO�GFSUJMJUFJUTQSFTFSWBUJF�QSPHSBNNB�IFFGU�PQHF[FU��%JU�IFCCFO�

XJK�HFEBBO�EPPS�FFO�QSBLUJTDIF�NFUIPEF�UPF�UF�QBTTFO �EF��i4USFOHUIT �8FBLOFTTFT �

0QQPSUVOJUJFT�BOE�5ISFBUTw� 4805�BOBMZTF��4805�BOBMZTF� JT� FFO�WFFM�HFCSVJLUF�

NFUIPEF�CJOOFO�IFU�CFESJKGTMFWFO�PN�OJFVXF�JEFFÑO�UF�POUSBGFMFO�FO�QSPCMFNFO�UF�

JEFOUJmDFSFO�EJF�WPPSUHBOH�IJOEFSFO��

)FU�QSPKFDU�IBOUFFSEF�FFO�WJFS�TUBQQFO�QMBO��BMMFSFFSTU�NPOJUPSEFO�XF�IFU�WFSXJKT-

QSPDFT�HFEVSFOEF�ESJF�NBBOEFO��8F�WSPFHFO�BMMF�[PSHWFSMFOFST�WBO�IFU�DFOUSVN�WPPS�

WPPSUQMBOUJOHTHFOFFTLVOEF�WBO�IFU�"DBEFNJTDI�.FEJTDI�$FOUSVN�PN�FFO�NFMEJOHT-

GPSNVMJFS�JO�UF�WVMMFO�[PESB�[JK�FFO�WFS[PFL�CJOOFOLSFHFO�WPPS�GFSUJMJUFJUTQSFTFSWBUJF�

WBO�FFO�QBUJÑOU�PG�BOEFSF�[PSHWFSMFOFS��0Q�EJU�GPSNVMJFS�XFSE�EF�WFSXJK[FS�HFOPUFFSE �

de indicatie voor fertiliteitspreservatie en werden suggesties genoteerd hoe dit speci-

mFLF�WFS[PFL�PSHBOJTBUPSJTDI�CFUFS�IBE�LVOOFO�XPSEFO�BGHFIBOEFME��%JU�GPSNVMJFS�

XFSE�JOHFWVME�POHFBDIU�PG�WSPVXFO�NFU�FFO�WFS[PFL�UPU�GFSUJMJUFJUTQSFTFSWBUJF�PPL�

daadwerkelijk doorgingen voor fertiliteitspreservatie of niet.

/B�EF[F�QFSJPEF�WBO�NPOJUPSFO �WPFSEFO�XJK�EF�UXFFEF�TUBQ�VJU�WBO�IFU�QSPKFDU��EF�

4805�BOBMZTF��%F[F�XFSE�VJUHFWPFSE�EPPS�FFO�UFBN�WBO�FYQFSUT�FO�IBE�BMT�EPFM�PN�

het reeds bestaande fertiliteitspreservatie-programma in kaart te brengen en manie-

SFO�UF�POEFS[PFLFO�PN�EJU�QSPHSBNNB�UF�WFSCFUFSFO��%BBSOB�WPFSEFO�XF�EF�EFSEF�

TUBQ�WBO�IFU�QSPKFDU�VJU��IFU�PQ[FUUFO�WBO�FFO�OJFVX�GFSUJMJUFJUTQSFTFSWBUJF�QSPHSBN-

NB� WPPS� WSPVXFO�NFU� FFO� BDVVU� WFS[PFL� UPU� GFSUJMJUFJUTQSFTFSWBUJF� JOWSJF[FO� WBO�

FJDFMMFO�PG�FNCSZP�T� JO�PO[F�LMJOJFL��8F�IFCCFO�EJU�OJFVXF� GFSUJMJUFJUTQSFTFSWBUJF�

SAMENVATTING

165

QSPHSBNNB�PQHF[FU�BBO�EF�IBOE�WBO�EBUB�EJF�XFSE�WFS[BNFME�EPPS�TUBQ��WBO�QSPKFDU�

IFU� ESJF�NBBOEFO� MBOH�NPOJUPSFO� WBO�EF� JOLPNFOEF� WFS[PFLFO� FO�EF� SFTVMUBUFO�

WBO�EF� ACBTJT��4805�BOBMZTF��5XFF�KBBS�OBEBU�XF�EJU�OJFVXF�GFSUJMJUFJUTQSPHSBNNB�

IBEEFO�PQHF[FU � WPFSEFO�XF�EF� MBBUTUF� TUBQ�VJU� WBO�IFU�QSPKFDU�� IFU� FWBMVFSFO� WBO�

POT�CFTUBBOEF� GFSUJMJUFJUTQSFTFSWBUJFQSPHSBNNB�NFU�CFIVMQ�WBO�FFO� MBBUTUF�4805�

BOBMZTF��%F[F�4805�BOBMZTF�XFSE�VJUHFWPFSE�UJKEFOT�FFO�HFTUSVDUVSFFSEF�CSBJOTUPSN�

TFTTJF��5JKEFOT�EF�ESJF�NBBOEFO�EVSFOEF�OVMNFUJOH �NFMEEFO��WSPVXFO�[JDI�BBO�

NFU�IFU�WFS[PFL�UPU�GFSUJMJUFJUTQSFTFSWBUJF��%F�NFFTUF�WFS[PFLFO�LXBNFO�WBO�WSPV-

XFO�EJF�IVO�FJDFMMFO�XJMEFO�MBUFO�JOWSJF[FO�WBOXFHF�MFFGUJKETHFCPOEFO�BGOBNF�WBO�

EF�WSVDIUCBBSIFJE�O��"DIUFOUXJOUJH�WSPVXFO��WFS[PDIUFO�GFSUJMJUFJUT-

QSFTFSWBUJF� WBOXFHF� FFO� BDVUF� SFEFO �XBBSWBO�� WBOXFHF� � CPSTULBOLFS��%F�

FFSTUF� ACBTJT�� 4805� BOBMZTF � UPPOEF� BBO� EBU� IFU� GFSUJMJUFJUTQSFTFSWBUJF� QSPHSBNNB�

van destijds niet volledig uitgerust was om de logistieke problemen van acute ferti-

liteitspreservatie te ondervangen. Zo trad er bijvoorbeeld vaak vertraging op bij het

QMBOOFO�WBO�FFSTUF�DPOTVMU��)FU�OJFVXF�GFSUJMJUFJUTQSFTFSWBUJF�QSPHSBNNB�EBU�OB�EF[F�

4805�BOBMZTF�XFSE�PQHF[FU �CFTUPOE�VJU�WJFS�TUBQQFO��"MMFSFFSTU�XFSE�FS�JOGPSNBUJF�

PWFS�GFSUJMJUFJUTQSFTFSWBUJF�POUXJLLFME�WPPS�QBUJÑOUFO�FO�WFSTQSFJE�BMT�GPMEFS�FO�PQ�

IFU�JOUFSOFU�HF[FU��5FO�UXFFEF�XFSEFO�QPUFOUJÑMF�WFSXJK[FST�HFÕOGPSNFFSE�EPPS�FFO�

OJFVXTCSJFG �PO[F�XFCTJUF�FO�UJKEFOT�JOGPSNBUJFCJKFFOLPNTUFO��5FO�EFSEF�XFSEFO�FS�

NJEEFMFO�POUXJLLFME�PN�EF�[PSH�FGmDJÑOUFS�UF�NBLFO �[PBMT�FFO�WSBHFOMJKTU�EJF�QB-

UJÑOUFO�LVOOFO� JOWVMMFO�WPPSBGHBBOEF�BBO�IVO�FFSTUF� DPOTVMU��&O�BMT� MBBUTUF�XFSE�

FS�FFO�DIFDLMJTU�WPPS�BSUTFO�POUXJLLFME�NFU�EBBSJO�BMMF� JUFNT�EJF�SFMFWBOU�[JKO�PN�

UF�CFTQSFLFO�UJKEFOT�IFU�FFSTUF�DPOTVMU �[PEBU�EJU�DPOTVMU�NJOEFS�UJKE�LPTU��5PFO�EJU�

OJFVXF�GFSUJMJUFJUTQSFTFSWBUJF�QSPHSBNNB�UXFF�KBBS�OB�EF�PQCPVX�XFSE�HFÑWBMVFFSE�

NFU�EF�MBBUTUF�4805�BOBMZTF �DPODMVEFFSEFO�XF�EBU�IFU�DPOTVMU�NJOEFS�UJKESPWFOE�

XBT�EBOL[JK�EF�WSBHFOMJKTU�FO�EF�DIFDLMJTU��4BNFOHFWBU�DPODMVEFSFO�XJK�EBU�4805�

analyse kan worden aanbevolen als praktische methode om het management en de

PSHBOJTBUJF�WBO�[PSH�PNUSFOU�GFSUJMJUFJUTQSFTFSWBUJF�UF�WFSCFUFSFO�

In hoofdstuk 3 geven wij een prospectieve studie weer waarbij we tamoxifen metabo-

MJFU�FOEPYJGFO�TQJFHFMT�NFFUUFO�CJK�WJFS�WSPVXFO�NFU�IPSNPPOHFWPFMJHF�CPSTULBOLFS�

EJF�IVO�FJDFMMFO�MJFUFO�JOWSJF[FO��"MMF�WSPVXFO�JO�EF[F�TUVEJF�LSFHFO�FFO�IPHF�EPTJT�

UBNPYJGFO��NH�QFS�EBH�PN�EF�PFTUSPHFFO�SFDFQUPS�WBO�EF�CPSTUUVNPS�UF�NPEVMF-

ren. Daardoor werd hypothetisch getracht extra tumor groei tijdens gecontroleerde

PWBSJÑMF�TUJNVMBUJF�UF�WPPSLPNFO��)FU�EPFM�WBO�EF[F�TUVEJF�XBT�PN�UF�POEFS[PFLFO�

of er endoxifen spiegels konden worden bereikt die geacht worden hoog genoeg te

CHAPTER 10

166

[JKO�WPPS�IFU�CMPLLFSFO�WBO�PFTUSPHFFO�SFDFQUPS��OH�NM��(FEVSFOEF�EF�HFDPOUSP-

MFFSEF�PWBSJÑMF�TUJNVMBUJF�XFSE�CMPFE�BGHFOPNFO�CJK�EF�WSPVXFO��*O�IFU�CMPFE�XFSEFO�

EF�XBBSEFO�PFTUSBEJPM�&�� UBNPYJGFO�FO�FOEPYJGFO�HFNFUFO��)FU�HFNJEEFME�BBOUBM�

FJDFMMFO�EBU�XFSE�JOHFWSPSFO�XBT��TQSFJEJOH��5VTTFO�EF�WSPVXFO�CFTUPOEFO�

grote verschillen in de endoxifen spiegels ten tijde van follikel aspiratie (spreiding

��OH�OM��%SJF�WBO�EF�WJFS�WSPVXFO�CFSFJLUFO�FOEPYJGFO�TQJFHFMT�EJF�IPPH�HF-

OPFH�XPSEFO�HFBDIU�WPPS�PFTUSPHFFO�SFDFQUPS�CMPLLBEF��OH�NM��"M�JT�EF�LMJOJTDIF�

SFMFWBOUJF�WBO�IPHF�FOEPYJGFO�TQJFHFMT�CJK�EF[F�TQFDJmFLF�HSPFQ�WSPVXFO�POCFLFOE �

LVOOFO�XF�XFM� DPODMVEFSFO�EBU�XBOOFFS� UBNPYJGFO� �JO� EF[FMGEF�IPHF� EPTFSJOHFO�

BMT�JO�EF�BEKVWBOUF�TFUUJOH��XPSEU�HFCSVJLU�BMT�UPFWPFHJOH�PQ�HFDPOUSPMFFSEF�PWBSJÑMF�

TUJNVMBUJF �FOEPYJGFO�TQJFHFMT�LVOOFO�XPSEFO�CFSFJLU�EJF�OBHFOPFH�FWFO�IPPH�[JKO�

als in de adjuvante setting. Om meer te begrijpen van hoe tamoxifen metaboliseert in

EF�TFUUJOH�WBO�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�JT�FFO�QSPTQFDUJFWF�TUVEJF�NFU�NFFS�

WSPVXFO�OPPE[BLFMJKL��

In hoofdstuk 4 QSFTFOUFSFO�XF�FFO�TZTUFNBUJTDI�MJUFSBUVVSPWFS[JDIU�EBU�BMT�EPFM�IBE�

EF�UPFHFWPFHEF�XBBSEF�WBO�UBNPYJGFO�PG�MFUSP[PM�BBO�TUBOEBBSE�HFDPOUSPMFFSEF�PWB-

SJÑMF� TUJNVMBUJF� UF�POEFS[PFLFO�PQ�IFU�CPSTULBOLFS� WSJKF� JOUFSWBM� CJK� WSPVXFO�NFU�

IPSNPPOHFWPFMJHF� CPSTULBOLFS� EJF� FJDFMMFO� PG� FNCSZP�T� JOWSJF[FO�� 4UJNVMBUJF� QSP-

UPDPMMFO�NFU� UPFHFWPFHEF� UBNPYJGFO�FO� MFUSP[PM�XPSEFO� UPFHFQBTU�PQ�CBTJT�WBO�EF�

HFEBDIUF�EBU�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�[POEFS�EF[F�NJEEFMFO�EF�HSPFJ�WBO�

CPSTULBOLFS�[PV�LVOOFO�EPFO�BBOXBLLFSFO��8JK�[PDIUFO�OBBS�HFSBOEPNJTFFSEF�TUV-

EJFT�EJF�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�QSPUPDPMMFO�NFU�FYUSB�UBNPYJGFO�WFSHFMF-

LFO�NFU�QSPUPDPMMFO�XBBSBBO�MFUSP[PM�XBT�UPFHFWPFHE �CJK�WSPVXFO�NFU�CPSTULBOLFS��

&S�XFSEFO��UJUFMT�FO� ABCTUSBDUT��HFWPOEFO�EPPS�EF�[PFLTUSBUFHJF�FO�EF[F�XFSEFO�

EPPS� UXFF� BVUFVST � PQ� POBGIBOLFMJKLF�XJK[F � HFMF[FO� FO� HFDPOUSPMFFSE�� &S�XFSEFO�

geen gerandomiseerde studies gevonden. Al werden er geen gerandomiseerde stu-

dies gevonden, er werd wel een prospectieve cohort studie gevonden die drie ovari-

ele stimulatie protocollen met elkaar vergeleek: recombinant folliculair stimulerend

IPSNPPO�SFD'4)�NFU�FYUSB�UBNPYJGFO��NH�QFS�EBH �FFO�QSPUPDPM�XBBSCJK�BMMFFO�

UBNPYJGFO� BMT� PWBSJÑMF� TUJNVMFSJOH�XFSE� HFCSVJLU� ��NH�QFS�EBH� FO� FFO�QSPUPDPM�

XBBSCJK�SFD'4)�NFU�FYUSB�MFUSP[PM��NH�QFS�EBH�XFSE�HFCSVJLU��%F[F�QSPUPDPMMFO�

werden met elkaar vergeleken in een groep van 60 vrouwen met borstkanker die ei-

DFMMFO�PG�FNCSZP�T�MJFUFO�JOWSJF[FO��*O�UPUBBM�XFSEFO�FS��WSPVXFO �EJF��DZDMJ�GFS-

tiliteitspreservatie ondergingen, vergeleken met een controle groep van 31 vrouwen

die geen fertiliteitspreservatie onderging.

SAMENVATTING

167

Vergeleken met de vrouwen die alleen tamoxifen hadden gekregen, hadden de vrou-

XFO�EJF�SFD'4)�NFU�FYUSB�UBNPYJGFO�PG�FYUSB�MFUSP[PM�HFLSFHFO�FFO�IPHFS�BBOUBM�GPM-

MJLFMT��)FU�QJFL�FTUSBEJPM�HFIBMUF� JO�EF�SFD'4)�MFUSP[PM�HSPFQ�XBT�TJHOJmDBOU� MBHFS�

EBO�JO�EF�HSPFQ�EJF�TMFDIUT�UBNPYJGFO�POUWJOHFO�PG�SFD'4)�NFU�FYUSB�UBNPYJGFO��/B�

FFO�HFNJEEFMEF�GPMMPX�VQ�WBO��EBHFO�TQSFJEJOH��UPU��EBHFO�WPPS�BMMF�

vrouwen inclusief de controle groep, was de snelheid van terugkeer van de borstkan-

LFS�WBO�WSPVXFO�EJF�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�IBEEFO�POEFSHBBO�IFU[FMGEF�

BMT�EJF�WBO�WSPVXFO�EJF�IFU�OJFU�IBEEFO�POEFSHBBO�EF�DPOUSPMF�HSPFQ�SFTQFDUJFWF-

MJKL�ESJF�WBO�EF��WSPVXFO �WFSTVT�ESJF�WBO�EF��WSPVXFO �IB[BSE�SBUJP ��$*�

��UPU��%F�FOJHF�TUVEJF�EVT�EJF�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�QSPUPDPMMFO�

NFU�FYUSB�UBNPYJGFO�PG�MFUSP[PM�NFU�FMLBBS�IFFGU�WFSHFMFLFO �NBBLUF�HFCSVJL�WBO�FFO�

niet-gerandomiseerde aanpak waarbij een kleine groep vrouwen met elkaar werden

WFSHFMJKLFO�[POEFS�QPXFS�CFSFLFOJOH��%BBSCJK�CFTUPOE�EF�DPOUSPMF�HSPFQ�VJU�WSPV-

wen die geen fertiliteitspreservatie hadden ondergaan, in plaats van uit vrouwen die

HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�[POEFS�FYUSB�UBNPYJGFO�PG�MFUSP[PM�IBEEFO�POEFS-

gaan. Bovendien verschaft de studie geen lange termijn follow-up van de vrouwen

EJF�HFDPOUSPMFFSEF�TUJNVMBUJF�NFU�FYUSB�UBNPYJGFO�PG�MFUSP[PM�IFCCFO�POEFSHBBO��8JK�

DPODMVEFSFO� JO� EJU� TZTUFNBUJTDIF� MJUFSBUVVSPWFS[JDIU� EBU� FS� HFFO� HFSBOEPNJTFFSEF�

TUVEJFT� [JKO� WFSSJDIU� EJF� HFDPOUSPMFFSEF� PWBSJÑMF� TUJNVMBUJF� QSPUPDPMMFO� NFU� FYUSB�

UBNPYJGFO� WFSHFMJKLFO�NFU� FYUSB� MFUSP[PM��(F[JFO� EJU� HFCSFL� BBO�XFUFOTDIBQQFMJKL�

CFXJKT �DPODMVEFSFO�XJK�EBU�IFU�HFCSVJL�WBO�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�QSP-

UPDPMMFO�NFU�FYUSB�UBNPYJGFO�FO�MFUSP[PM�BMMFFO�[JKO�QMBBUT�IFFGU�CJOOFO�FFO�HFSBOEP-

miseerde studie.

In hoofdstuk 5�QSFTFOUFSFO�XJK�IFU�TUVEJFQSPUPDPM�WBO�EF�45*.�USJBM�USJBM�SFHJTUSB-

UJF�OVNNFS��/53��i4UJNVMBUJF�WBO�EF�PWBSJB�CJK�WSPVXFO�NFU�CPSTULBOLFS�EJF�

fertiliteitspreservatie ondergaan: alternatieve versus standaard stimulatie protocol-

MFO�w�5BNPYJGFO�PG�MFUSP[PM�[PVEFO�NPHFMJKL �[P�TVHHFSFFSU�NFO �UPFHFWPFHE�LVOOFO�

XPSEFO�BBO�HFDPOUSPMFFSE��PWBSJÑMF�TUJNVMBUJF�QSPUPDPMMFO�PN�[P�FFO�UFHFOXJDIU�UF�

CJFEFO�UFHFO�PFTUSPHFOFO �EJF�NPHFMJKL�TDIBEFMJKL�LVOOFO�[JKO�WPPS�EF�CPSTUUVNPS��

%F�IVJEJHF�LMJOJTDIF�QSBLUJKL�WBSJFFSU�WBO�TUBOEBBSE�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMB-

UJF�QSPUPDPMMFO�[POEFS�UBNPYJGFO�PG�MFUSP[PM �UPU�BBOHFQBTUF�HFDPOUSPMFFSEF�PWBSJÑMF�

TUJNVMBUJF�QSPUPDPMMFO�NFU�FYUSB�UBNPYJGFO�PG�MFUSP[PM��%F�BBOOBNF�EBU�UBNPYJGFO�FO�

MFUSP[PM�FO�CFTDIFSNFOEF�SPM�[PVEFO�TQFMFO�WPPS�WSPVXFO�NFU�CPSTULBOLFS�EJF�HF-

DPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�POEFSHBBO �JT�HFCBTFFSE�PQ�FFO�WFS[BNFMJOH�WBO�HF-

gevens die aantonen dat vrouwen met oestrogeen-receptor positieve borstkanker die

CHAPTER 10

168

UBNPYJGFO�PG�MFUSP[PM�BMT�MBOHF�UFSNJKO�CFIBOEFMJOH�LSJKHFO�JO�EF�BEKVWBOUF�TFUUJOH�

FFO�CFUFSF�QSPHOPTF�IFCCFO��'PMMPX�VQ�HFHFWFOT��UPU��KBBS�PWFS�EF�WFJMJHIFJE�WBO�

HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�CJK�WSPVXFO�NFU�CPSTULBOLFS�UPPOEF�HFMJKLF�LBO-

sen voor terugkeer van de tumor tussen vrouwen met borstkanker die gecontroleerde

PWBSJÑMF�TUJNVMBUJF�IBEEFO�POEFSHBBO�WFSHFMFLFO�NFU�WSPVXFO�NFU�CPSTULBOLFS�EJF�

EBU�OJFU�IBEEFO�POEFSHBBO��0OEBOLT�EBU�EF[F�TUVEJFT�TMFDIUT�FFO�LMFJOF�POEFS[PFLT-

QPQVMBUJF�IBEEFO�UVTTFO�EF��FO��WSPVXFO�FO�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�

protocollen niet met elkaar, maar slechts met een controle groep vergeleken die geen

HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�IBE�POEFSHBBO �MJKLU�IFU�EBU�UPU�OV�UPF�HFDPOUSP-

MFFSEF�PWBSJÑMF�TUJNVMBUJF�QSPUPDPMMFO�NFU�FYUSB�UBNPYJGFO�PG�MFUSP[PM�HFFO�TDIBEF-

lijke effecten geeft op de lange termijn uitkomsten voor vrouwen met borstkanker.

&S�JT�FDIUFS�FFO�HSPUFSF�DPIPSU�TUVEJF�JT�OPEJH�PN�EF�FGGFDUFO�WBO�EF[F�WFSTDIJMMFOEF�

HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�QSPUPDPMMFO�NFU�FMLBBS�UF�WFSHFMJKLFO�NFU�FO�[PO-

EFS�FYUSB�UBNPYJGFO�PG�MFUSP[PM��/BBTU�JO[JDIUFO�PWFS�EF�WFJMJHIFJE �JT�IFU�PPL�OPEJH�

PN�JO[JDIUFO�UF�WFSLSJKHFO�PWFS�XFML�TUJNVMBUJFQSPUPDPM�OV�IFU�NFFTU�FGGFDUJFG�JT�BMT�

het gaat om het aantal verkregen eicellen. Een studie die een standaard gecontroleerd

ovarieel stimulatie protocol vergeleek met een gecontroleerd ovarieel stimulatie pro-

UPDPM�NFU�FYUSB�MFUSP[PM �UPPOEF�BBO�EBU�FS�TJHOJmDBOU�NJOEFS�FJDFMMFO�XFSEFO�WFSLSF-

HFO�WPPS�DSZPQSFTFSWBUJF�JO�EF�HSPFQ�EJF�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�NFU�FYUSB�

MFUSP[PM�IBE�POEFSHBBO�� WFSTVT�� Q��

&FO� BOEFSF� TUVEJF� WFSHFMFFL� ESJF� WFSTDIJMMFOEF� HFDPOUSPMFFSEF� PWBSJÑMF� TUJNVMBUJF�

QSPUPDPMMFO�NFU�FMLBBS��SFDPNCJOBOU�GPMMJDVMBJS�TUJNVMFSFOE�IPSNPPO�SFD'4)�NFU�

FYUSB�UBNPYJGFO��NH�QFS�EBH �FFO�QSPUPDPM�XBBSCJK�BMMFFO�UBNPYJGFO�BMT�PWBSJÑMF�

TUJNVMFSJOH�XFSE�HFCSVJLU��NH�QFS�EBH�FO�FFO�QSPUPDPM�XBBSCJK�SFD'4)�NFU�FYUSB�

MFUSP[PM��NH�QFS�EBH�XFSE�HFCSVJLU��7FSHFMFLFO�NFU�EF�WSPVXFO�EJF�BMMFFO�UBNPYJ-

GFO�IBEEFO�HFLSFHFO �IBEEFO�EF�WSPVXFO�EJF�SFD'4)�NFU�FYUSB�UBNPYJGFO�PG�FYUSB�

MFUSP[PM�HFLSFHFO�FFO�IPHFS�BBOUBM�GPMMJLFMT��WFSTVT��FO��

SFTQFDUJFWFMJKL��1��

8BBS�IFU�JO�EF�LFSO�PN�HBBU�CJK�GFSUJMJUFJUTQSFTFSWBUJF �JT�IFU�WFSLSJKHFO�WBO�FFO�[P�

hoog mogelijk aantal van rijpe eicellen als mogelijke proxy voor een toekomstige kans

PQ�DPODFQUJF��)FU�JT�EBBSPN�OPPE[BLFMJKL�PN�UF�XFUFO�XFML�TUJNVMBUJF�QSPUPDPM�CJK�

WSPVXFO�NFU�CPSTULBOLFS�IFU�CFTUF�JT�JO�UFSNFO�WBO�FJDFMPQCSFOHTU��8JK�WPFSFO�EF�

45*.�USJBM�VJU�NFU�BMT�EPFM�EF�FGGFDUJWJUFJU�JO�UFSNFO�WBO�FJDFMPQCSFOHTU�UF�FWBMV-

FSFO�WBO�HFDPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�QSPUPDPMMFO�NFU�PG�[POEFS�UBNPYJGFO�PG�

MFUSP[PM�CJK�WSPVXFO�NFU�CPSTULBOLFS�EJF�FJDFMMFO�PG�FNCSZP�T�MBUFO�JOWSJF[FO��5FHF-

MJKLFSUJKE�IFCCFO�XF�IFU�EPFM�PN�HFHFWFOT�UF�WFS[BNFMFO�PWFS�EF�WFJMJHIFJE�WBO�HF-

SAMENVATTING

169

DPOUSPMFFSEF�PWBSJÑMF�TUJNVMBUJF�EPPS�MBOHF�UFSNJKO�GPMMPX�VQ�HFHFWFOT�UF�WFS[BNFMFO�

WBO�BMMF�WSPVXFO�EJF�EFFMOFNFO�BBO�EF�TUVEJF��%F�45*.�USJBM�JT�FFO�NVMUJ�DFOUSVN�

open-label gerandomiseerde studie. De studiepopulatie bestaat uit vrouwen tussen

EF��FO��KBBS�EJF�CPSTULBOLFS�IFCCFO�FO�FJDFMMFO�PG�FNCSZP�T�HBBO�JOWSJF[FO��%F�

primaire uitkomstmaat is het aantal eicellen dat wordt verkregen bij follikelaspira-

UJF��4FDVOEBJSF�VJULPNTUNBUFO�[JKO�IFU�BBOUBM�SJKQF�FJDFMMFO�EBU�XPSEU�WFSLSFHFO �IFU�

BBOUBM�FJDFMMFO�PG�FNCSZP�T�EBU�XPSEU� JOHFWSPSFO�FO�IFU�QJFL�PFTUSBEJPM� UJKEFOT�HF-

DPOUSPMFFSEF�PWBSJÑMF� TUJNVMBUJF��0N�FFO� UXFF[JKEJH�WFSTDIJM� BBO� UF� UPOFO�WBO�WJFS�

eicellen, met een alfa van 5% en een power van 90%, moeten we 48 vrouwen in elke

HSPFQ�JODMVEFSFO��0N�UF�DPNQFOTFSFO�WBO��WFSMJFT�UJKEFOT�GPMMPX�VQ �[BM�FS�HF-

tracht worden 53 vrouwen per groep te laten deelnemen. Dat betekent 159 vrouwen

JO�UPUBBM��%F[F�TUVEJFHSPPUUF�JT�WPMEPFOEF�PN�[PXFM�UBNPYJGFO�FO�MFUSP[PM�NFU�FMLBBS�

UF�WFSHFMJKLFO�BMT�NFU�EF�DPOUSPMF�HSPFQ�TUBOEBBSE�PWBSJÑMF�TUJNVMBUJF��%F�TUVEJF�JT�

JO�KBOVBSJ��HFTUBSU�NFU�IFU�JODMVEFSFO�WBO�WSPVXFO��0Q�EJU�NPNFOU�[JKO�FS��

WSPVXFO�HFÕODMVEFFSE�JO�EF�TUVEJF�

In hoofdstuk 6 presenteren we een kwalitatieve studie die als doel heeft te onder-

[PFLFO�IPF�WSPVXFO�IFU�FSWBSFO�PN�IVO�FJDFMMFO�PG�FNCSZP�T� JO�UF�WSJF[FO�UFSXJKM�

[F�POMBOHT�[JKO�HFEJBHOPTUJDFFSE�NFU�CPSTULBOLFS��&S�[JKO�XFMJTXBBS�TUVEJFT�CFTDIJL-

baar over hoe borstkanker overlevers nadenken over het krijgen van kinderen. Ook

[JKO�FS�TUVEJFT�CFTDIJLCBBS�PWFS�EF�CFTMVJUWPSNJOH�SPOEPN�GFSUJMJUFJUTQSFTFSWBUJF�WPPS�

CPSTULBOLFSQBUJÑOUFO��&S�[JKO�FDIUFS�HFFO�TUVEJFT�WFSSJDIU�PWFS�EF�FSWBSJOH�WBO�IFU�

POEFSHBBO�WBO�GFSUJMJUFJUTQSFTFSWBUJF��%JU�HFCSFL�BBO�LFOOJT�LPNU�EF�QBUJÑOU�OJFU�UFO�

HPFEF ��PNEBU�JO[JDIU�JO�EF�FSWBSJOHFO�WBO�WSPVXFO�UJKEFOT�IVO�CFIBOEFMJOH�OPPE-

[BLFMJKL�JT�WPPS�BEFRVBUF�QTZDIPTPDJBMF�[PSH�FO�TUFVO�UJKEFOT�IVO�WSVDIUCBBSIFJETCF-

IBOEFMJOH��%F[F�QTZDIPTPDJBMF�[PSH �EJF�WFSSJDIU�LBO�XPSEFO�EPPS�BMMF�TUBGnFEFO�WBO�

FFO�GFSUJMJUFJUTDFOUSVN �JT�SFDFOU�EPPS�EF�i&VSPQFBO�4PDJFUZ�PG�)VNBO�3FQSPEVDUJWF�

BOE�&NCSZPMPHZw�&4)3&�UPU�FFO�WFSFJTUF�VJUHFSPFQFO�WPPS�GFSUJMJFJUT[PSH�WBO�IPHF�

LXBMJUFJU��0N�EJF�SFEFO�IFFGU�EF[F�TUVEJF�IFU�EPFM�PN�UF�POEFS[PFLFO�IPF�WSPVXFO�

IFU�FSWBSFO�PN�IVO�FJDFMMFO�PG�FNCSZP�T�JO�UF�WSJF[FO�UFSXJKM�[F�POMBOHT�[JKO�HFEJBH-

OPTUJDFFSE�NFU�CPSTULBOLFS��8F�LP[FO�WPPS�FFO� GFOPNFOPMPHJTDI�POUXFSQ�WBO�EF�

TUVEJF �PNEBU�EJU�CJOOFO�EF�NFUIPEPMPHJF�WBO�LXBMJUBUJFWF�POEFS[PFL�FFO�BBOHFXF-

[FO�NBOJFS�JT�PN�FSWBSJOHFO�UF�POEFS[PFLFO�FO�UF�CFHSJKQFO��"MMF�WSPVXFO�NFU�CPSTU-

LBOLFS�UVTTFO�EF��FO��KBBS �EJF�FJDFMMFO�PG�FNCSZP�T�MJFUFO�JOWSJF[FO�UVTTFO�KBOVBSJ�

��FO�KVMJ��JO�IFU�"DBEFNJTDI�.FEJTDI�$FOUSVN�JO�"NTUFSEBN�PG�IFU�6USFDIUT�

.FEJTDI�$FOUSVN �LPOEFO�EFFMOFNFO�BBO�EF�TUVEJF��/BEBU�FS�TDISJGUFMJKLF�UPFTUFN-

CHAPTER 10

170

NJOH�XBT�WFSLSFHFO �WFS[BNFMEFO�XF�NJEEFMT�FFO�WSBHFOMJKTU�EFNPHSBmTDIF�FO�NF-

dische gegevens. Daarna voerden we oog-in-oog diepte-interviews uit, die tussen de

��FO��NJOVUFO�EVVSEFO��8F�OPEJHEFO�JO�UPUBBM��WSPVXFO�VJU �XBBSWBO��WSPV-

XFO� UPFTUFNEFO� UPU�EFFMOBNF��%F��HFÕOUFSWJFXEF�WSPVXFO�XBSFO�HFNJEEFME��

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was fertiliteitspreservatie de start, en daarmee een integraal deel, van hun borstkan-

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en het Nederlands Netwerk voor Fertiliteitspreservatie” hebben veel inspanningen

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is onbekend, omdat er een gebrek is aan gedegen follow-up van vrouwen die vanwege

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UF�XPSEFO�FO�EF�FWFOUVFMF�VJULPNTUFO�WBO�EF[F�QPHJOHFO �FO�WPPSHFOPNFO�QMBOOFO�

voor toekomstig gebruik van de ingevroren eicellen.

Een totaal van 68 vrouwen, die gemiddeld 25,3 maanden later waren ondervraagd,

stuurden de ingevulde vragenlijst terug (percentage vrouwen die respondeerden:

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EJFOFO�EF[F�TQPOUBOF�[XBOHFSTDIBQTLBOTFO�HFOPFNE�UF�XPSEFO��0PL�CJK�IFU�POUXFS-

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MVFSFO �EJFOU�FS�NFU�TQPOUBOF�[XBOHFSTDIBQTLBOTFO�SFLFOJOH�UF�XPSEFO�HFIPVEFO�

CHAPTER 10

172

In hoofdstuk 8�CFEJTDVTTJÑSFO�XJK�EF�CFWJOEJOHFO�WBO�EJU�QSPFGTDISJGU�FO�SFnFDUFSFO�

XF�PQ�EF�LMJOJTDIF�JNQMJDBUJFT�WBO�PO[F�TUVEJFT��8F�CFTDISJKWFO�EF�OPPE[BBL�PN�FWB-

MVBUJF�POEFS[PFL�UF�CFEFOLFO�FO�UF�WFSSJDIUFO�CJOOFO�IFU�WFME�WBO�GFSUJMJUFJUTQSFTFS-

WBUJF�FO�CFTDISJKWFO�JEFFÑO�WPPS�POEFS[PFLFO�EJF�EJU�EPFM�LVOOFO�CFSFJLFO �[PBMT�IFU�

idee om lange-termijn follow-up te integreren in studies over fertiliteitspreservatie.

174

CHAPTER X

175

XXXXXXX

APPENDICES

APPENDICES

176

LIST OF CO-AUTHORS AND AFFILIATIONS

�% E.M.E. Balkenende,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �"DBEFNJD�.FE-

ical Centre, Amsterdam, the Netherlands.

�% C.C.M. Beerendonk,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �3BECPVE�6OJ-

WFSTJUZ�/JKNFHFO�.FEJDBM�$FOUSF �/JKNFHFO �UIF�/FUIFSMBOET�

�% J.H. Beijnen, Department of Pharmacy and Pharmacology, Netherlands Cancer

*OTUJUVUF �4MPUFSWBBSU�)PTQJUBM �"NTUFSEBN�

�% A.M.E. Bos,� %FQBSUNFOU� PG� 0CTUFUSJDT� BOE� (ZOBFDPMPHZ � 6OJWFSTJUZ� .FEJDBM�

Centre, Utrecht, the Netherlands.

�% A.E.P. Cantineau �%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �(SPOJOHFO�.FEJ-

cal Center, Groningen, the Netherlands.

�% E.A.F. Dancet,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�BOE�

(ZOBFDPMPHZ �"DBEFNJD�.FEJDBM�$FOUSF �"NTUFSEBN �UIF�/FUIFSMBOET�

�% K. Fleischer,�%FQBSUNFOU�PG�0CTUFUSJDT� BOE�(ZOBFDPMPHZ �3BECPVE�6OJWFSTJUZ�

/JKNFHFO�.FEJDBM�$FOUSF �/JKNFHFO �UIF�/FUIFSMBOET�

�% M. Goddijn,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�BOE�

(ZOBFDPMPHZ �"DBEFNJD�.FEJDBM�$FOUFS �"NTUFSEBN �UIF�/FUIFSMBOET�

�% R. van Golde,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �.BBTUSJDIU�.FEJDBM�

Center.

�% A. Hoek,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �(SPOJOHFO�.FEJDBM�$FOU-

er, Groningen, the Netherlands.

�% N.G.L. Jager, Department of Pharmacy and Pharmacology, Netherlands Cancer

*OTUJUVUF�4MPUFSWBBSU�)PTQJUBM �"NTUFSEBN�

LIST OF CO-AUTHORS AND AFFILIATIONS

177

�% G.G. Kenter, Department of Obstetrics and Gynecology, Centre for Gynecologic

0ODPMPHZ�"NTUFSEBN �"DBEFNJD�.FEJDBM�$FOUFS �UIF�/FUIFSMBOET�

�% Y. Kopeika, Department of Obstetrics and Gynaecology,Assisted Conception

6OJU �(VZ�T�)PTQJUBM �-POEPO �6,�

�% C.B. Lambalk,� %JWJTJPO� PG� 3FQSPEVDUJWF�.FEJDJOF � %FQBSUNFOU� PG�0CTUFUSJDT�

BOE�(ZOBFDPMPHZ �76�.FEJDBM�$FOUSF �"NTUFSEBN �UIF�/FUIFSMBOET�

�% J.S.E. Laven,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �&SBTNVT�.FEJDBM�$FOU-

FS �3PUUFSEBN �UIF�/FUIFSMBOET�

�% S.C. Linn,�/FUIFSMBOET�$BODFS�*OTUJUVUF �%FQBSUNFOU�PG�.FEJDBM�0ODPMPHZ �"O-

UPOJ�WBO�-FFVXFOIPFL�)PTQJUBM �"NTUFSEBN �UIF�/FUIFSMBOET�

�% L.A. Louwé,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �-FJEFO�.FEJDBM�$FOUFS �

Leiden, the Netherlands.

�% A.M. de Melker,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�

BOE�(ZOBFDPMPHZ �"DBEFNJD�.FEJDBM�$FOUSF �"NTUFSEBN �UIF�/FUIFSMBOET�

�% D.V. Miedema,� $FOUSF� GPS� 3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU� PG�0CTUFUSJDT�


�% F. Mol,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(Z-

OBFDPMPHZ �"DBEFNJD�.FEJDBM�$FOUSF �"NTUFSEBN �UIF�/FUIFSMBOET�

�% R. Nevedita, Department of Obstetrics and Gynaecology, Assisted Conception

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�% R. Schats,�%JWJTJPO�PG�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(Z-

OBFDPMPHZ �76�.FEJDBM�$FOUSF �"NTUFSEBN �UIF�/FUIFSMBOET�

�% J. Schipper,�%FQBSUNFOU�PG�0CTUFUSJDT�BOE�(ZOBFDPMPHZ �&SBTNVT�.FEJDBM�$FOU-

FS �3PUUFSEBN �UIF�/FUIFSMBOET�

APPENDICES

178

�% J. Smeenk,�%FQBSUNFOU�PG�0CTUFUSJDT� BOE�(ZOBFDPMPHZ �4U�&MJTBCFUI�)PTQJUBM �

Tilburg, the Netherlands.

�% D. Stoop,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �6OJWFSTJUZ�)PTQJUBM�#SVTTFMT �#SVT-

sels, Belgium.

�% F. van der Veen,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�


�% M. van Wely,�$FOUSF�GPS�3FQSPEVDUJWF�.FEJDJOF �%FQBSUNFOU�PG�0CTUFUSJDT�BOE�

(ZOBFDPMPHZ �"DBEFNJD�.FEJDBM�$FOUSF �"NTUFSEBN �UIF�/FUIFSMBOET�

APPENDICES

180180

LIST OF PUBLICATIONS

�% &�.�&��#BMLFOFOEF �T. Dahhan �4��3FQQJOH �"��EF�.FMLFS �'��WBO�EFS�7FFO �.�(PE-

EJKO��&JDFMWJUSJmDBUJF��WPPS�XJF�FJHFOMJKL �Ned Tijdschr Geneeskd. 2015; 159:A9361.

�% T. Dahhan �'��.PM �(�(��,FOUFS �&�.�&��#BMLFOFOEF �"�.��EF�.FMLFS �'��WBO�EFS�

7FFO �&�"�'��%BODFU �.��(PEEJKO��'FSUJMJUZ�QSFTFSWBUJPO��B�DIBMMFOHF�GPS�*7'�DMJO-

ics. Eur J Obstet Gynecol Reprod Biol, 2015; 194:78-84.

�% T. Dahhan �&�"��%BODFU �%�7��.JFEFNB �'��WBO�EFS�7FFO �.��(PEEJKO��3FQSPEVD-

UJWF�DIPJDFT�BOE�PVUDPNFT�BGUFS�GSFF[JOH�PPDZUFT�GPS�NFEJDBM�SFBTPOT��B�GPMMPX�VQ�

study. Human Reproduction 2014; 29(9):1925-30.

�% T. Dahhan �1�4�*��WBO�5POHFSFO �#�+��#JFNPOE �4��3FQQJOH �.��(PEEJKO �.�%��)B-

[FOCFSH��'FSUJMJUFJUTQSFTFSWBUJF�CJK�QBUJÑOUFO�NFU�FFO�IFNBUPMPHJTDIF�NBMJHOJUFJU�

Nederlands tijdschrift voor Hematologie 2014; 11:164-702.

�% T. Dahhan, &�.�&� Balkenende, S.C. Linn, .��WBO�8FMZ �.��(PEEJKO��5BNPYJGFO�

PS� MFUSP[PMF� WFSTVT� TUBOEBSE� NFUIPET� GPS� XPNFO� XJUI� FTUSPHFO�SFDFQUPS� QPT-

itive breast cancer undergoing oocyte or embryo cryopreservation in assisted

SFQSPEVDUJPO�4ZTUFNBUJD�3FWJFX��Cochrane Database of Systematic Reviews, 2013; 11:CD010240.

�% T. Dahhan � .�� (PEEJKO � '�� 7BO� EFS� 7FFO�� )PPGETUVL� �� 'FSUJMUFJUTQSFTFS-

vatie. Handboek voor Voortplantingsgeneeskunde, uitgeverij Tijdstroom, 2013; ISBN 9789058982278.

�% &�.�&� Balkenende, T. Dahhan, /��+BHFS, S.C. Linn, +�)��#FJKOFO, .��(PEEJKO��"�

prospective case series of women with estrogen receptor-positive breast cancer:

levels of tamoxifen metabolites in controlled ovarian stimulation with high-dose

tamoxifen. Human Reproduction, 2013; 28:953-9.

�% &�.�&��#BMLFOFOEF �T. Dahhan �'��WBO�EFS�7FFO �.��(PEEJKO��$PNNFOU�PO�(O3)�

analogue cotreatment with chemotherapy for preservation of ovarian function.

Fertil Steril, 2011; 96:155-6.

LIST OF PUBLICATIONS

181

�% .�+��7BMTUBS �T. Dahhan �#�1��1PPSUIVJT �*��4OPFDL �'�"��8JKCVSH��-BOHEVSJHF�OFP-

natale icterus met later ataxie, verticale blikparese en progressieve mentale ach-

UFSVJUHBOH��EF�[JFLUF�WBO�/JFNBOO�1JDL�UZQF�$��Tijdschrift voor Kindergeneeskunde, 2010; 78:77-80.

�% T. Dahhan �(��'POT �.��#VJTU �'��UFO�,BUF �+��WBO�EFS�7FMEFO��5IF�FGmDBDZ�PG�IPS-

monal treatment for residual or recurrent low-grade endometrial stromal sarco-

ma. A retrospective study. Eur J Obstet Gynecol Reprod Biol, 2009; 144:80-84.

APPENDICES

182

PORTFOLIO

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"OUPOJ�WBO�-FFVXFOIPFL�[JFLFOIVJT �"NTUFSEBN

(ECTS)

PORTFOLIO

183

i'FSUJMJUZ�QSFTFSWBUJPO�GPS�XPNFOw� � � � ��

Brussel-Amsterdam meeting, Brussels

i0SHBOJTBUJF�WBO�BDVUF�GFSUJMJUFJUTQSFTFSWBUJF��

bij vrouwen”

Gynaecongres, Leeuwarden

Poster Presentations

Controlled ovarian hyperstimulation in 2011 0.5

women with breast cancer:

B�QSPTQFDUJWF�DBTF�TFSJFT�PO�UIF�FGmDBDZ�PG�UBNPYJGFO��

2nd�8PSME�$POHSFTT�PG�UIF�*OUFSOBUJPOBM�4PDJFUZ�GPS�'FSUJMJUZ�1SFTFOUBUJPO �

.JBNJ�'- �64"�

Controlled ovarian hyperstimulation in 2011 0.5

women with breast cancer:

B�QSPTQFDUJWF�DBTF�TFSJFT�PO�UIF�FGmDBDZ�PG�UBNPYJGFO��

4ZNQPTJVN�'FSJMJUFJUTQSFTFSWBUJF�,BOLFS�FO�,JOEFSXFOT �

Oegstgeest, Nederland.

The outpatient fertility preservation unit: 2013 0.5

a multidisciplinary challenge.

Oncofertility Conference, Chicago, USA.

The safety of controlled ovarian stimulation 2013 0.5

JO�XPNFO�XJUI�CSFBTU�DBODFS��UIF�45*.�USJBM��

Oncofertility Conference, Chicago, USA.

A prospective case series of women 2013 0.5

with estrogen receptor-positive breast cancer:

levels of tamoxifen metabolites in

controlled ovarian stimulation with high-dose tamoxifen.

The international congress

on Oncological Perspectives on Fertility Preservation,

Berlin, Germany.

APPENDICES

184

Conferences

&4)3&�$BNQVT�8PSLTIPQ�

A'FSUJMJUZ�QSFTFSWBUJPO��GSPN�UFDIOJRVF��

UP�JNQMFNFOUBUJPO�JO�DMJOJDBM�QSBDUJDF�

Amsterdam

2. TEACHING

4UVEFOU�DPBDIJOH�NFOUPSJOH�TDJFOUJmD�SFTFBSDI�QSPKFDU��

4UVEFOU�DPBDIJOH�NFOUPSJOH�TDJFOUJmD�SFTFBSDI�QSPKFDU��

4UVEFOU�DPBDIJOH�NFOUPSJOH�TDJFOUJmD�SFTFBSDI�QSPKFDU 2013 1

Tutoring skills to second year medical students 2013 0.1

3. PARAMETERS OF ESTEEM

3FTFBSDI�HSBOU�CZ�1JOL�3JCCPO�JO��å��

ECTS system: workload of 28 hours = 1 ECTS.

APPENDICES

186

DANKWOORD

Ik bedank de volgende mensen voor de totstandkoming van dit proefschrift:

Allereerst dank ik alle vrouwen die belangeloos hebben deelgenomen aan de studies

EJF�HFQSFTFOUFFSE�[JKO�JO�EJU�QSPFGTDISJGU�

.JKO�QSPNPUPS�prof. dr. F. van der Veen. Beste Fulco, jouw begeleiding als promotor

JT�JEJPTZODSBUJTDI��&FO�XPPSE�EBU�JL�WBO�KPV�IFC�HFMFFSE��+F�IFCU�NJKO�XFUFOTDIBQ-

pelijk en klinisch denken gevormd, mij geleerd wat integere voortplantingsgenees-

LVOEF�JT �FO�XBU�AMFTT�JT�NPSF��CFUFLFOU�BMT�TDISJKGTUJKM��.BBS�EF�CFMBOHSJKLTUF�MFT�EJF�JL�

van je heb gekregen stond op het kaartje dat ik namens de afdeling kreeg vlak na mijn

CFWBMMJOH��%BBSPQ� TUPOE� JO� KPVX�IBOFOQPUFOIBOETDISJGU�� A)JFS�HBBU�IFU�PN��/PPJU�

WFSHFUFO��)FU�XBT�FFO�WPPSSFDIU�PN�KPV�BMT�QSPNPUPS�UF�IFCCFO��

.JKO�DPQSPNPUPS�dr. M. Goddijn. Beste .BSJFUUF �EBOL[JK� KPVX�TUSBLLF�FO�CFUSPL-

ken begeleiding heb ik de focus kunnen behouden in mijn proefschrift. Daardoor is

NJKO�HSPPUTUF�WBMLVJM �IFU�UFWFFM�UFHFMJKL�XJMMFO�EPFO �UJKEFOT�NJKO�QSPNPUJFPOEFS[PFL�

PWFSXPOOFO��*L�CFO�KF�EBBS�POU[FUUFOE�EBOLCBBS�WPPS��&MLF�XFFL�FFO�IBMG�VVSUKF�CJK-

QSBUFO�PWFS�POT�POEFS[PFL �XBU�[BLFO�ABGIBNFSFO��FO�JL�LPO�XFFS�EPPS��*L�IFC�WFFM�

WBO�KPVX�HFEVME �[PSHWVMEJHIFJE�FO�LVOEJHIFJE�HFMFFSE�

.JKO�DPQSPNPUPS�dr. E.A.F. Dancet. Beste Eline, sinds dat jij betrokken bent geraakt

CJK�EJU�QSPFGTDISJGU �LJKL�JL�NFU�BOEFSF�PHFO�OBBS�NJKO�FJHFO�POEFS[PFL��+JK�IFCU�EF�

QBUJÑOU�DFOUSBBM�HFTUFME�JO�NJKO�POEFS[PFL�FO�EBBS�CFO�JL�KF�FSH�EBOLCBBS�WPPS��%BBS-

OBBTU�IFC�JL�BMUJKE�FSH�HFOPUFO�WBO�PO[F�LPGmFNPNFOUFO�XBBSCJK�IFU�HFMVLLJH�PPL�

WBBL�HJOH�PWFS�IFFM�BOEFSF�[BLFO�EBO�IFU�POEFS[PFL��%BOL�WPPS�BM�EF[F�NPNFOUFO�

FO�CPWFOBM�EBU�KF�NJK�IFCU�HFÑOUIPVTJBTNFFSE�WPPS�EF�NFOTFMJKLF�LBOU�WBO�EF�XFUFO-

schap.

.JKO�QSPNPUPS�prof. dr. S. C. Linn. Beste Sabine, jouw expertise op het gebied van

CPSTULBOLFS�XBT�WBO�PONJTCBSF�XBBSEF��+PVX�JOIPVEFMJKLF�FO�LSJUJTDIF�CMJL�XBSFO�

FFO�ESJKWFOEF�LSBDIU�WPPS�IFU�PQ[FUUFO�FO�IFU�VJUWPFSFO�WBO�EF�45*.�USJBM��7FFM�EBOL�

daarvoor.

DANKWOORD

187

De overige leden van de promotiecommissie; Prof. Dr. C.B. Lambalk, Prof. Dr. S.

Repping, Prof. Dr. A.M. Stiggelbout, Dr. D. Stoop en Dr. M.P. van den Tol. Dank

voor de tijd en inspanning die jullie hebben besteed aan mijn proefschrift en jullie

CFSFJEIFJE�[JUUJOH�UF�OFNFO�JO�EF�QSPNPUJFDPNNJTTJF.

%BOL�BBO�4UJDIUJOH�1JOL�3JCCPO�WPPS�IFU�mOBODJFSFO�WBO�EF�45*.�USJBM�

Dank aan Fonds NutsOhra en Virtutis Opus voor het mogelijk maken van de studie

gepresenteerd in hoofdstuk twee van dit proefschrift.

*L�EBOL�PPL�HSBBH�BM�NJKO�NFEFBVUFVST��)FU�CMJKGU�FFO�CJK[POEFS�HFWPFM�BMT�BMMF�OFV[FO�

EF[FMGEF�LBOU�PQ�LPNFO�UF�TUBBO�OB�FFO�MBOHF�SFFLT�NBJMXJTTFMJOHFO�FO�AUSBDL�DIBOHF��

documenten. Dank voor jullie volharding om van ieder stuk het beste te maken. In

IFU�CJK[POEFS�EBOL�JL�Eva Balkenende. Beste Eva, vanaf de eerste dag dat ik je bege-

leidde als wetenschappelijke stage-student wist ik; dit is een blijver. Dank voor de

BMUJKE�QSFUUJHF�TBNFOXFSLJOH�FO�WPPS�KF�JO[FU�CJK�EF�WPPSU[FUUJOH�WBO�EF�45*.�USJBM��

Marjolein Tijsterman en Beatrix van Hattum; dank voor alles wat jullie achter en

WPPS�EF�DPNQVUFS�TDIFSNFO�WPPS�NJK�IFCCFO�HFEBBO�PN�EJU�QSPFGTDISJGU�UPU�TUBOE�

te laten komen.

.JKO�DPMMFHB�POEFS[PFLFST��EBOL�EBU�JL�BMUJKE�NJKO�IBSU�NPDIU�LPNFO�MVDIUFO�BMT�JL�

WBTUMJFQ�FO�PN�BEWJF[FO�LPO�WSBHFO�XBOOFFS�JL�EBBS�CFIPFGUF�BBO�IBE��

*O�IFU�CJK[POEFS�EBOL�JL�NJKO�POEFS[PFLTLBNFSHFOPUFO��0OEFS�IFU�HFOPU�WBO�ESPQ�FO�

thee met Hannah van Meurs, Katrien Oude Rengerink, Maaike Weber en Myrthe

Peelen�XBT�POEFS[PFL�EPFO�PQ�LBNFS�I��FMLF�EBH�XFFS�HF[FMMJH�

Alle medewerkers van het Centrum voor Voortplantingsgeneeskunde in het Acade-

NJTDI�.FEJTDI�$FOUSVN��%BOL�WPPS�IFU�XBSNF�CBE�XBBSJO�JL�UFSFDIU�LXBN�BMT�QBT�

BGHFTUVEFFSEF�DPBTTJTUFOU�FO�WPPS�EF�mKOF�XFSLQMFL��

De medewerkers van de afdeling gynaecologie en verloskunde van het voormalig Sint

Lucas Andreas Ziekenhuis. Dank dat jullie mij de ruimte wilden geven om als arts-on-

EFS[PFLFS�LMJOJTDIF�FSWBSJOH�PQ�UF�EPFO��

APPENDICES

188

.JKO�IVJEJHF�DPMMFHB�T�JO�IFU�'MFWP[JFLFOIVJT�JO�"MNFSF��KVMMJF�IFCCFO�NJK�BMT�"NTUFS-

EBNNFS�MBUFO�[JFO�EBU�FS�MFWFO�JT�CVJUFO�EF�SJOH�"��%BOL�WPPS�BMMF�FOFSHJF�EJF�KVMMJF�

in mij steken om van mij een goede gynaecoloog te maken.

.JKO�MJFWF�QBSBOJNGFO��Hella Doets en Silke Manschot��+VMMJF�[JKO�OJFU�BMMFFO�EF�FFS-

TUF�AHFUVJHFO��WBO�NJKO�WFSEFEJHJOH�NBBS�PPL�WBO�POHFWFFS�BMMF�BOEFSF�HSPUF�FO�LMFJOF�

gebeurtenissen in mijn leven de afgelopen 15 jaar. Dank dat jullie mij bij willen staan

tijdens mijn promotie.

.JKO�USPVXF�MJFWF�WSJFOEFO��Nikki Vosters, Tyche Tjebbes, Sophie Tabouret, Me-

lissa Marijnen, Franka Adeyinka, Dunya Khayame, Milena Holdert, Erdal Kiran

en Jan Geusebroek��"MT� JL� FS� FWFO�EPPSIFFO�[BU�NFU�EJU�QSPFGTDISJGU�LPO� JL� KVMMJF�

BMUJKE�CFMMFO�WPPS�FFO�SFMBUJWFSFOE�HFTQSFL�PWFS�BMMF�[JO�FO�PO[JO�WBO�IFU�MFWFO��*L�CFO�

dankbaar met jullie in mijn leven. Lieve Deniz Karaman, een Skype-date met jou in

Istanbul en binnen enkele dagen heb je samen met #FċMà�,BSBIBO de lay-out voor dit

QSPFGTDISJGU�WFS[PSHE��8BU�FFO�WSFVHEF�EBU�KF�XFFS�JO�"NTUFSEBN�LPNU�XPOFO�

/BBTU�QFSTPOFO �HBBU�NJKO�CJK[POEFSF�EBOL�PPL�VJU�OBBS�NJKO�TUBE��"NTUFSEBN��%BOL-

[JK�EF�QSBDIUJHF�CJCMJPUIFLFO �PQ�EF�NPPJTUF�MPDBUJFT �XBT�QSPNPWFSFO�JO�EFFMUJKE�FFO�

genot.

.JKO� MJFWF� TDIPPOGBNJMJF��Aleid Brederode, Jurriaan Röntgen, Annette Brederode

en Kees Degenkamp��-JFWF�"MFJE �KF�CFOU�EF�MJFGTUF�FO�[PSH[BBNTUF�TDIPPONPFEFS�EJF�

ik mij kan wensen. Dank voor alle keren dat je er voor mij, Alexander en de kinderen

CFOU��-JFWF�+VSSJBBO �TQFDJBMF�EBOL�WPPS�KF�UJKE�FO�FOFSHJF�PN�NJK�UF�IFMQFO�NFU�EF�

MBBUTUF�GBTF�WBO�EJU�QSPFGTDISJGU��EF�UFLTUWFSXFSLJOH�FO�IFU�NFFMF[FO�

Lieve Annette, dank voor de ontelbare keren dat we op je mochten rekenen en voor

BMMF�CJK[POEFSF�NPNFOUFO�EJF�XF�EFMFO��-JFWF�,FFT��EF�QFSTPPOMJKLF�HFTQSFLLFO�EJF�

JL�NFU�KPV�LPO�WPFSFO�PWFS�NJKO�QSPFGTDISJGU�XBSFO�BMUJKE�POU[FUUFOE�XBBSEFWPM��7FFM�

dank daarvoor.

.JKO�PPN�Mouhcine Dahhan en tante Marianne van der Horst. Dank voor alle steun

die ik van jullie heb ontvangen voor alles wat ik doe.

.JKO�HSPPUPVEFST��NJKO�PNB�Saidia Marfouk, mijn oma Fatima Belahcen Cherradi

FO�NJKO�XJKMFO�PQB�T�Mustafa Arib en Abdelkader Dahhan��+VMMJF�IBSEF�XFSLFO�IFFGU�

DANKWOORD

189

OPPJU�HFSFTVMUFFSE�JO�EJQMPNB�T�PG�UJUFMT��*L�FFS�BMMFT�XBU�KVMMJF�IFCCFO�NPFUFO�EPPS-

staan om het leven dat ik leef mogelijk te maken.

.JKO� MJFWF�CSPFST��Ghassan en Wadië Dahhan�� +VMMJF�XFUFO�NJK� BMUJKE� WBO�LSJUJTDI�

XFFSXPPSE� UF� WPPS[JFO��%BOL�WPPS� BMMF�EJTDVTTJFT�EJF�NJKO�EFOLFO�BMUJKE�XFUFO� UF�

TUJNVMFSFO��*L�CFO�USPUT�KVMMJF�[VT�UF�[JKO�

.JKO�PVEFST�Khadija Arib en Nordine Dahhan. Lieve mamma en babba, ik kan niet

BOEFST�EBO�EJU�QSPFGTDISJGU�BBO�KVMMJF�PQHFESBHFO��+VMMJF�IFCCFO�EF�CBTJT�HFWPSNE�WPPS�

EF�LBOTFO�EJF�JL�IFC�HFLSFHFO�FO�CFOVU��+VMMJF�MFFSEFO�NJK�EBU�[FMGWFSUSPVXFO �EPPS-

[FUUJOHTWFSNPHFO �NBBUTDIBQQFMJKL�CFXVTU[JKO�BMMFFO�OVU�IFFGU�BMT�KF�IFU�DPNCJOFFSU�

NFU�IVNPS�FO�XBSNUF��8BU�CFO�JL�EBOLCBBS�KVMMJF�EPDIUFS�UF�[JKO�

*O� IFU� CJK[POEFS� CFEBOL� JL�NJKO�NFFTU� EJFSCBSFO�� Alexander Röntgen, Dehlia en

Louiza.

-JFWF�"MFYBOEFS �NJKO�MJFGEF��8BU�IFCCFO�XF�IFU�mKO�TBNFO��*L�CFO�FMLF�EBH�EBOLCBBS�

dat ik mijn leven met jou mag delen.

-JFWF�%FIMJB�FO�-PVJ[B �TJOET�EBU�KVMMJF�JO�POT�MFWFO�[JKO�JT�FMLF�EBH�FFO�ESVL�GFFTUKF��

+VMMJF�CJKESBHF�BBO�EJU�QSPFGTDISJGU�JT�EBU�KVMMJF�NJK�WBBL�IFCCFO�HFEXPOHFO�EF�MBQUPQ�

EJDIU�UF�LMBQQFO�PN�NJK�CF[JH�UF�IPVEFO�NFU�EF�TDIPPOIFJE�WBO�IFU�MFWFO��LJKLFO�OBBS�

EF�NBBO �[JOHFO �EBOTFO�PG�UFLFOFO��%BBS�CFO�JL�KVMMJF �NFFS�EBO�XJF�EBO�PPL�JO�EJU�

dankwoord, dankbaar voor.

CURRICULUM VITAE

190

CURRICULUM VITAE

/B�WFSXFLU�UF�[JKO�TQPOUBBO�UJKEFOT�FFO�SPOESFJT�WBO�IBBS�PVEFST�EPPS�4ZSJÑ �XFSE�

5BHISJEF�%BIIBO�PQ��OPWFNCFS��JO�IFU�"DBEFNJTDI�.FEJTDI�$FOUSVN�JO�"N-

TUFSEBN�HFCPSFO��)BBS�SPFQOBBN�XFSE�i4BCSBw �FFO�OBBN�EJF�WFSXJKTU�OBBS�IFU�1BM-

FTUJKOTF�WMVDIUFMJOHFOLBNQ�i4BCSB�FO�4IBUJMBw�JO�#FJSVU �-JCBOPO��4BCSB�HSPFJEF�PQ�

in de binnenstad van Amsterdam. Na het behalen van haar diploma aan het Barlaeus

HZNOBTJVN� JO�"NTUFSEBN � HJOH� [JK� HFOFFTLVOEF� TUVEFSFO� BBO� EF�6OJWFSTJUFJU� WBO�

"NTUFSEBN��)BBS�TUVEJF�XFSE�WFSHF[FME�EPPS�UBM�WBO�NBBUTDIBQQFMJKLF�BDUJWJUFJUFO�

waaronder het schrijven van columns voor de Volkskrant en vrijwilligerswerk in het

.JEEFO�0PTUFO�

5JKEFOT� IBBS� DPTDIBQ� HZOBFDPMPHJF� JO� IFU� i0O[F� -JFWF� 7SPVXF� (BTUIVJTw� JO� "N-

TUFSEBN� �� CFTMPPU� [JK� HZOBFDPMPPH� UF� XJMMFO� XPSEFO�� (FGBTDJOFFSE� EPPS� IFU�

NBBUTDIBQQFMJKLF�EFCBU�PWFS�IFU� JOWSJF[FO�WBO�FJDFMMFO�PQ�[PHFOBBNEF� ATPDJBMF� JO-

EJDBUJF� �CFTMPPU�[JK�BBO�UF�LMPQQFO�CJK�1SPG��%S��'��WBO�EFS�7FFO�NFU�EF�WSBBH�PG�[JK�OB�

IBBS�DPTDIBQQFO�OBBS�EJU�POEFSXFSQ�POEFS[PFL�LPO�HBBO�EPFO��;JK�XFSE�BBOHFOPNFO�

en kon in 2011 direct na haar coschappen beginnen als IVF-arts in het Academisch

.FEJTDI� $FOUSVN�� ;JK� TUBSUUF� FOLFMF� NBBOEFO� MBUFS� NFU� IBBS� QBSUUJNF� QSPNP-

UJFPOEFS[PFL��*O�BVHVTUVT��XFSE�[JK�EF�USPUTF�NPFEFS�WBO�%FIMJB�FO�-PVJ[B��5PU�

BVHVTUVT��LPO�[JK�WPMUJKE�BBO�IBBS�QSPNPUJFPOEFS[PFL�XFSLFO��%BBSOB�JT�[JK�HBBO�

werken als arts-assistent in het voormalig Sint Lucas Andreas Ziekenhuis in Amster-

EBN��.PNFOUFFM�XFSLU�4BCSB�BMT�BSUT�BTTJTUFOU�JO�PQMFJEJOH�UPU�HZOBFDPMPPH�DMVTUFS�

"DBEFNJTDI�.FEJTDI�$FOUSVN�JO�IFU�'MFWP[JFLFOIVJT�JO�"MNFSF��

uva-dare (digital academic repository) fertility preservation in …€¦ · 64 'ppe boe %svh...

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