Background: Fertile women that are about to undergo cancer treatment do not receive adequate information about fertility and fertility preservation. Not to have been able to make an active choice about undergoing fertility preservation may cause a suffering for these women. Purpose: To describe which experiences young women with cancer have of the information given about fertility and fertility preservation measures prior to the cancer treatment with regards to disease-suffering, care-suffering and life-suffering. Method: Literature review of qualitative and quantitative research. Results: Eight subcategories based on the three main categories disease-suffering, care-suffering and life-suffering were identified. Disease-suffering: (1) Anxiety and (2) Uncertainty. Care-suffering: (3) Attitudes and (4) Lack of information. Life-suffering: (5) Relations and Other social factors, (6) Psychological illness, (7) Longing for children and (8) Quality of life. Conclusion: Various measures are needed to ensure women’s right to information about fertility prior to cancer treatment in order to diminish disease-suffering, care-suffering and life-suffering. Caregivers need to talk with women about fertility related problems, both preventively and for healing purposes. Clinical significance: A clear and safer information policy is needed on fertility and fertility preservation for patients about to undergo cancer treatment.

Thesis (DMed (Obstetrics and Gynaecology))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Chapter 1 is a literature review investigating the incidence of cancer in children and young adults. It describes the most important treatment options including chemotherapy, radiotherapy and surgery and the effect of treatment on future endocrine development and fertility. Different primary cancer sites are discussed in more detail. Chapter 2 is a literature review on the effects of cancer surgery in women and the options for fertility sparing. Cervical cancer and pre-cancer are discussed in detail with options for more conservative surgery in selected patients. A summary of the available published cases of trachelectomy with pregnancy outcomes is included. Other gynaecological cancers requiring surgery are also discussed with reference to conservative options. Chapter 3 is a literature review about the medical (pharmacological) options for protection of ovarian function in patients undergoing oncotherapy. The role of gonadotrophin releasing hormone analogues and hormonal contraceptives in ovarian suppression is discussed in detail. Chapter 4 This chapter examines germ cell physiology with reference to cryopreservation. It includes two major parts. Part 1 is the description of germ cell- and follicle physiology, the principles of cryobiology followed by a review of oocyte cryopreservation and ovarian tissue preservation. Both slow freezing and vitrification techniques are described. The second part of chapter 4 is a report on a randomised controlled evaluation of two different slow freezing cryopreservation protocols. This experimental study compared ultrastructural changes in fresh and previously cryopreserved ovarian cortical tissue after equilibration and thawing using two different cryoprotectants. This is the first randomised investigation into DMSO and PROH as cryoprotectants. Chapter 5 is an investigation into cryopreservation of ovarian tissue as a strategy to protect hormonal function and fertility against gonadotoxic treatment. This chapter consists of two parts. The first part is a thorough literature review of all the published work about grafting of previously cryopreserved ovarian tissue. The largest case series found from a single institution was five patients. Another report of six patients included patients from various sites in Denmark. Part 2 is a description of a cohort of patients followed up after re-implantation of previously cryopreserved ovarian cortical tissue. Follow-up hormone levels of 13 individual cases are described in detail. This is the largest case series ever reported. The experimental study described in Chapter 4 and the clinical study described in Chapter 5 was approved by the ethical research committee of the Faculty of Health Sciences, Stellenbosch University, project number N05/10/182. Chapter 6 provides an integrated overview of the incidence and treatment of cancer in young women and how its negative effects may be prevented or mitigated. Aspects of chemotherapy, radiotherapy and surgery are evaluated where it may affect future reproductive health. The role of oocyte and ovarian tissue cryopreservation is discussed. Guidelines are provided for clinicians. / AFRIKAANSE OPSOMMING: Hoofstuk 1 Hierdie is ‘n literatuuroorsig wat die insidensie van kanker in kinders en jong volwassenes ondersoek. Dit sluit die mees belangrike behandelingsopsies in, naamlik chemoterapie, radioterapie en chirurgie en die effek wat behandeling mag hê op toekomstige endokriene ontwikkeling en fertiliteit. ‘n Verskeidenheid kanker tipes word in meer detail beskryf. Hoofstuk 2 Hoofstuk 2 is ‘n literatuuroorsig oor die effekte van kankerchirurgie in vroue en die geleenthede tot beskerming van fertiliteit. Servikale kanker en voorlopers van servikale kanker word bespreek en die opsies vir konserwatiewe chirurgie in uitgesoekte pasiënte word gegee. ‘n Opsomming van die inligting wat beskikbaar is oor tragelektomie en swangerskap uitkomste word ingesluit. Ander ginekologiese kankers wat chirurgie mag benodig, word ook bespreek met verwysing na konserwatiewe hantering. Hoofstuk 3 ‘n Literatuuroorsig oor die mediese (farmakologiese) opsies vir die beskerming van ovariële funksie in pasiënte wat behandeling ontvang vir kanker. Die rol van gonadotropien-vrystellingshormoon-analoë en hormonale kontrasepsie vir ovariële onderdrukking word in detail bespreek. Hoofstuk 4 Hierdie hoofstuk ondersoek kiemselfisiologie met verwysing na vriesbewaring. Dit is verdeel in twee dele. Deel 1 is ‘n beskrywing van kiemsel- en follikelfisiologie en die beginsels van vriesbiologie. Dit word gevolg deur ‘n oorsig van oösiet vriesbewaring en ovariële weefselbewaring. Stadige bevriesing en vitrifikasie- metodes word bespreek. Die tweede deel van hoofstuk 4 is ‘n verslag oor ‘n gerandomiseerde, gekontroleerde evaluasie van twee stadige bevriesingsmetodes. Hierdie eksperimentele studie het die ultrastrukturele veranderinge vergelyk in vars en voorheen bevrore ovariële kortikale weefsel na ekwilibrasie en ontdooiing met twee verskillende vriesbeskermers. Dit is die eerste gerandomiseerde studie oor DMSO en PROH as vriesbeskermers. Hoofstuk 5 Hierdie hoofstuk handel oor ‘n ondersoek na vriesbewaring van ovariële weefsel as ‘n benadering tot beskerming van hormonale funksie en fertiliteit teen gonadotoksiese behandeling. Die hoofstuk bestaan uit twee dele. Die eerste deel is ‘n deeglike oorsig van die literatuur oor al die beskikbare werk wat handel oor terugplasing van voorheen bevrore ovariële weefsel. Die grootste pasiëntreeks van ‘n enkel instelling was slegs vyf pasiënte. ‘n Ander beskrywing van ses pasiënte het pasiënte van verskeie eenhede in Denemarke ingesluit. Deel 2 is ‘n beskrywing van ‘n groep pasiënte wat opgevolg is na oorplanting van voorheen bevrore ovariële kortikale weefsel. Opvolg hormoonvlakke van 13 gevalle word in detail bespreek. Hierdie is die grootste pasiëntreeks wat tot nog toe beskryf is. Die eksperimentele studie wat in hoofstuk 4 beskryf word en die kliniese studie wat in hoofstuk 5 beskryf word, is goedgekeur deur die etiese navorsingskomitee van die Fakulteit Gesondheidswetenskappe van die Universiteit Stellenbosch met die projeknommer N05/10/182 Hoofstuk 6 Hierdie is ‘n geïntegreerde oorsig van die voorkoms en behandeling van kanker in jong vroue en hoe die negatiewe effekte daarvan voorkom of verminder kan word. Aspekte van chemoterapie, radioterapie en chirurgie word geëvalueer ten opsigte van die effek op toekomstige reproduktiewe gesondheid. Die rol van oösiet- en ovariële weefselvriesbewaring word bespreek. Riglyne vir klinici word gegee.

Producing competent and fertilizable oocytes from in vitro grown primordial follicles could revolutionize female infertility treatment, particularly using fertility preservation approaches that use cryopreserved ovarian tissue. However, the protracted length of folliculogenesis in humans makes follicular culture complex, and the mechanisms controlling the tightly-regulated activation of primordial follicles remain largely unknown. The delicate balance between follicular recruitment and quiescence might be affected by preservation procedures, such as ovarian fragmentation or in vitro culture, that disrupt crucial pathways, such as the Hippo and PI3K/Akt/mTOR signaling pathways, that are involved in this process. When activated, these pathways induce massive recruitment of primordial follicles and accelerate follicular growth in vitro, with potential negative consequences on future oocyte developmental competence. Therefore, we hypothesized that the inhibition of the PI3K/Akt/mTOR pathway might improve follicular growth by slowing down the activation process.In the first part of this thesis, we explored the potential benefit of inhibiting PI3K/Akt/mTOR signaling on the regulation of in vitro follicular activation and growth, as well as its impact on the Hippo pathway. The effect of everolimus (EVE), a specific mTORC1 inhibitor, was compared to the PI3K/Akt activators recently used to reinitiate the growth of residual follicles in the ovarian tissue of patients with premature ovarian insufficiency. We showed that short-term incubation of ovarian cortex with EVE partially delayed follicular recruitment while supporting follicle survival and steroidogenesis. However, morphological abnormalities were observed in all conditions, suggesting that EVE failed to protect follicles from accelerated in vitro growth-related defects.Our findings also provided evidence that ovarian fragmentation, which disrupts the Hippo pathway, contributes to the triggering of primordial follicle recruitment and early development of quiescent human follicles. Moreover, our data suggested that both PI3K/Akt and Hippo signaling could act synergistically to promote follicular activation and growth.In the second part of the project, we further investigated the integrity of EVE-treated follicles based on their ultrastructural and functional status. Our observations indicate that the integrity of oocyte and granulosa cells, as well as their physical contacts, were preserved in EVE and control conditions, although some in vitro grown follicles sustained cryopreservation- and culture- induced damage. We also found that short exposure to EVE allowed the maintenance of intra-follicular communication while preserving follicular developmental potential. Importantly, results obtained suggested that, at a similar developmental stage, cell coupling and oocyte growth may be improved in EVE-treated follicles.Altogether, these data provide better insight into the regulation of the follicular activation process and emphasize the importance of getting closer to physiological conditions to preserve follicle integrity. They also provide proof-of-concept evidence that reducing the initiation of growth is feasible, and suggest that mTORC1 inhibitors are a potentially useful pharmacological tool to regulate in vitro follicular growth. / La production d'ovocytes compétents et fécondables à partir de follicules primordiaux développés in vitro pourrait révolutionner les traitements liés à l'infertilité féminine, en particulier les approches de préservation de la fertilité à partir du tissu ovarien cryopréservé. Cependant, la longue durée de la folliculogenèse chez l'Homme rend la culture folliculaire complexe, et les mécanismes contrôlant l'activation des follicules primordiaux restent largement inconnus. L’équilibre fragile entre quiescence folliculaire et entrée en croissance pourrait être affecté par la fragmentation ovarienne ou la culture in vitro elle-même, qui perturbent deux voies de signalisation cruciales: les voies Hippo et PI3K/Akt/mTOR, respectivement. Lorsqu'elles sont activées, elles induisent un recrutement massif de follicules primordiaux et accélèrent la croissance folliculaire in vitro, avec des conséquences potentiellement néfastes sur la capacité future des ovocytes à devenir compétents. Par conséquent, nous avons émis l’hypothèse que l’inhibition de la voie PI3K/Akt/mTOR pourrait améliorer la croissance folliculaire via un ralentissement du processus d’activation.Dans la première partie de cette thèse, nous avons exploré le potentiel bénéfice d’une inhibition de la voie PI3K/Akt/mTOR sur la régulation de l'activation et de la croissance folliculaire in vitro, ainsi que son impact sur la voie Hippo. L’effet de l’évérolimus (EVE), un inhibiteur spécifique de mTORC1, a été comparé à ceux d’activateurs de PI3K/Akt, récemment utilisés afin d’initier la croissance des follicules résiduels au sein de tissus ovarien de patientes en insuffisance ovarienne précoce. Nous avons montré que l'exposition à court terme de cortex ovarien à l'EVE retardait partiellement le recrutement folliculaire tout en préservant la survie et la stéroidogenèse des follicules. Toutefois, des anomalies morphologiques ont été observées dans toutes les conditions, ce qui suggère que l’EVE ne préserve pas les follicules de défauts liés à une croissance accélérée.Nos résultats ont également prouvé que la fragmentation ovarienne, en perturbant la voie Hippo, contribue au recrutement et au développement précoce des follicules primordiaux. De plus, les données obtenues suggèrent que les voies PI3K/Akt/mTOR et Hippo pourraient agir de manière synergique pour promouvoir l'activation et la croissance folliculaire.Dans la deuxième partie du projet, nous avons étudié la qualité des follicules traités avec de l’EVE en se basant sur des critères ultrastructural et fonctionnel. Nos observations ont indiqué que l'intégrité des ovocytes et des cellules de la granulosa ainsi que leurs contacts physiques était préservée dans les conditions EVE et contrôle, bien que certains follicules en croissance présentent des signes de dommages induits par la cryopréservation et la culture. Nous avons également constaté qu'une courte exposition à l’EVE permettait de maintenir les communications intra-folliculaires tout en préservant le potentiel de développement des follicules. De façon importante, les résultats obtenus suggèrent qu’à un stade de développement similaire, le couplage cellulaire et la croissance des ovocytes pourraient être améliorés dans les follicules traités à l’EVE.En conclusion, ces données contribuent à une meilleure compréhension de la régulation de l'activation folliculaire in vitro, et soulignent l'importance de mimer les conditions physiologiques pour préserver l'intégrité des follicules. Elles apportent également la preuve qu’un ralentissement de l’initiation de la croissance est réalisable, et suggèrent que l’utilisation d’inhibiteurs de mTORC1 pourrait représenter un outil pharmacologique efficace pour réguler la croissance folliculaire in vitro. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

While incidence rates are increasing for many cancers in Puerto Rico, mortality rates are declining (Torres-Cintron, et al. 2010), resulting in growing numbers of survivors and creating a situation in which long-term survivorship concerns are beginning to emerge as priorities. The importance of quality-of-life among survivors of cancer is increasingly being recognized among healthcare providers, although there remains a gap in knowledge of how young adult survivors cope with long-term treatment-related physical effects, such as infertility, and of the impact of cancer on survivors' social relationships and future goals. Because understandings of "cancer survivorship," as well as of reproduction, vary according to cultural context, this study examined the physical and social impact of cancer on young adults in Puerto Rico, and specifically the importance of parenthood. A media analysis of women's magazines, key informant interviews with ten cancer researchers, as well as in-depth, semi-structured interviews with 23 young adult cancer survivors, 16 healthcare providers, nine cancer advocates, and two members of the clergy were conducted in order to shed light on the lived experiences, needs, and concerns of young Puerto Rican cancer survivors.

Introduction : La prise de décision concernant la préservation de la fertilité dans un contexte de prise en charge urgente de cancer du sein est complexe. Les objectifs de ce travail étaient de définir les attentes et les besoins des patientes en matière d’information, de concevoir un outil d’aide à la décision en ligne et d’évaluer sa validité apparente et son influence sur le choix éclairé des patientes.Méthodologie : Trois méthodes de recherche ont été menées pour répondre aux hypothèses : un focus group de cinq patientes pour l’étude qualitative, l’élaboration d’un outil d’aide à la décision selon la méthode d’Ottawa et une étude randomisée monocentrique. Cette dernière a été menée auprès de patientes âgées de 18 à 40 ans, adressées pour préservation de la fertilité dans un contexte de cancer du sein, randomisées au sein du groupe IRIS (information standard) ou du groupe DECISIF (avec outil d’aide à la décision en ligne). La mesure du choix éclairé était évaluée selon trois critères, à l’aide d’un questionnaire : les connaissances, l’attitude, et la mise en place ou non de techniques de préservation de la fertilité.Résultats : L’étude qualitative a permis de mettre en évidence que l’information transmise aux femmes et l’annonce de l’infertilité potentielle était à parfaire. L’outil d’aide à la décision en ligne a été élaboré suivant les recommandations des patientes et des professionnels de santé impliqués qui ont confirmé sa validité apparente. En ce qui concerne l’étude quantitative, au total 125 patientes ont été inclues et randomisées dans le groupe IRIS (n=65) ou DECISIF (n=60). Il a été mis en évidence une amélioration des connaissances dans le groupe DECISIF (8.6/10 (±1.34)) par rapport au groupe IRIS (6.49/10 (±1.89)). Dans les deux groupes, les patientes ont une attitude favorable envers la préservation de la fertilité (96 %). La décision finale n’est pas influencée par l’appartenance à un groupe ou un autre. Ainsi, à l’issue de la consultation de préservation de la fertilité, 73.6 % (92/125), soit 69.2 % (45/65) des patientes du groupe IRIS et 78.3 % (47/60) des patientes du groupe DECISIF vont choisir de conserver leurs ovocytes, embryons et/ou tissu ovarien. La proportion de choix éclairé était statistiquement plus élevée dans le groupe DECISIF que dans le groupe IRIS (respectivement 75 % versus 38.5 %, p<0.001). Par ailleurs, le niveau de conflit décisionnel chez les patientes du groupe DECISIF était moins élevé que chez celles du groupe IRIS (respectivement 14.4 (±2.94) versus 15.1 (±2.18), p=0.13).Conclusion : Nous avons conçu un outil d’aide à la décision en ligne pour accompagner les femmes atteintes d’un cancer du sein dans leur prise de décision concernant la préservation de la fertilité. Notre travail de recherche a permis de valider scientifiquement cet outil qui améliore les connaissances des patientes et leur autonomie de décision sans influencer leur attitude envers la préservation de la fertilité. / Introduction: Decision-making regarding fertility preservation in the context of urgent breast cancer management is complex. The objectives of this study were to define patients' expectations and information needs, develop an online decision support tool, and assess its apparent validity and influence on patients' informed choice.Methodology: Three research methods were used to address the hypotheses: a focus group of five patients for the qualitative study, the development of a decision support tool using the Ottawa method and a randomized, single-centre study. The latter was conducted with patients aged 18 to 40 years referred for fertility preservation in the context of breast cancer, randomized to the IRIS group (standard information) or the DECISIF group (with online decision support tool). The measurement of informed choice was evaluated according to three criteria using a questionnaire: knowledge, attitude, and whether fertility preservation techniques were available.Results: The qualitative study revealed that the information provided to women and the announcement of potential infertility needed to be improved. The online decision support tool was developed based on recommendations from the patients and health professionals involved, who confirmed its apparent validity. For the quantitative study, a total of 125 patients were included and randomized to the IRIS (n=65) or DECISIF (n=60) group. Better knowledge was found in the DECISIF group (8.6/10 (±1.34)) compared to the IRIS group (6.49/10 (±1.89)). In both groups, patients had a positive attitude towards fertility preservation (96%). The final decision was not influenced by membership in one group or another. Thus, at the end of the fertility preservation consultation, 73.6% (92/125), i.e. 69.2% (45/65) of patients in the IRIS group and 78.3% (47/60) of patients in the DECISIF group, chose to keep their oocytes, embryos and/or ovarian tissue. The proportion of informed choice was statistically higher in the DECISIF group than in the IRIS group (respectively 75% versus 38.5%, p<0.001). In addition, the level of decision-making conflict among patients in the DECISIF group was lower than in the IRIS group (respectively 14.4 (±2.94) versus 15.1 (±2.18), p=0.13).Conclusion: We have developed an online decision support tool to assist women with breast cancer in making decisions about fertility preservation. We have now validated this tool, which improves patients' knowledge and decision-making autonomy without influencing their attitude towards fertility preservation.

Although the survival rate of childhood cancer is high, nearly two thirds of these survivors experience negative long-term secondary side effects from cancer treatments. Infertility is one such side effect that can have a prominent impact on quality of life as the patient ages. It is important for nurses working with pediatric oncology patients to provide the patient and family with education about risk for infertility and fertility preservation (FP) in order to allow families to make decisions about FP before cancer treatment starts. However, pediatric oncology nurses report being uneducated about FP guidelines and are hesitant to broach this subject with families. The purpose of this HIM thesis is to review nurse perceived barriers related to educating patients and their families about the risk for infertility following cancer treatments and FP and to make recommendations for improving communication between nurses and families about FP. A search was performed using CINAHL, PreCINAHL, PsychINFO, PsychARTICLES, and Medline databases and examined peer-reviewed quantitative and qualitative research studies. Key terms used in the database searches were ped' OR child', onco' OR cancer', fert', and nurs'. Findings indicated that there were many barriers for pediatric oncology nurses, which inhibited the discussion of FP with patients and families such as lack of knowledge and resources, provider attitudes toward FP, and patient factors. Based on the findings, the researcher identified several interventions to aid pediatric oncology nurses in overcoming these barriers to FP discussion.

Fertility preservation remains a crucial component of Testicular Cancer patients’ health-related quality of life. Significant inconsistency is present in the availability and accessibility of information related to fertility preservation for patients with Testicular Cancer. The purpose of this critical review was to determine the quantity and quality of fertility preservation provided through the websites of top cancer care centers. A total of 15 centers were chosen based on the top cancer centers from US News and World Report and expanded upon using Definitive Healthcare’s top 10 centers treating Testicular Cancer by volume. Webpages were collected and graded for accessibility of Testicular Cancer and fertility preservation information using the original 2-part, 18-item Website Criteria Questionnaire. Each center received 2 grades of low or high based on the availability and usability of offered content. Of the 15 care centers surveyed, 8 (53.3%) demonstrated high scores on the usability of official institution website(s) for the purpose of fertility preservation. Two (13.2%) received high scores on the content depth and availability. While approximately half of the cancer centers surveyed has links or webpages leading to fertility preservation information or outside services, none had a direct contact to FP services provided by the institution. The results of this paper highlight the crucial need to improve accessibility of information regarding fertility preservation to patients with Testicular Cancer. With more patients turning to the internet for answers, there needs to be complete and valuable resources available to patients online.

En oncologie, les avancées diagnostiques et thérapeutiques ont permis une amélioration significative des taux de survie au prix d’une altération de la santé reproductive des patients due à la gonadotoxicité des traitements. L’attention accordée à la qualité de vie durant et après le cancer est devenue un enjeu majeur de la prise en charge et inclue particulièrement les problématiques liées aux troubles de la sexualité et de la fertilité notamment chez les jeunes femmes. Des stratégies de préservation de la santé reproductive avant initiation des traitements doivent désormais faire partie intégrante de la prise en charge multidisciplinaire du cancer de la femme.L’évaluation épidémiologique et clinique de ces stratégies est indispensable pour améliorer l’offre de soins. Pourtant, le recours à ces stratégies n’avait pas encore été évalué aux Antilles Françaises.Ce projet de thèse, s’appuyant sur quatre études, a tenté de répondre à cette problématique en réalisant un état des lieux des besoins et du recours en préservation de la santé reproductive féminine en contexte de cancer aux Antilles Françaises (Martinique, Guadeloupe). Les différentes parties de ce travail ont été valorisées par des publications scientifiques présentées dans ce manuscrit.Une première étude s’est intéressée aux parcours de soins et réseaux de préservation de la santé reproductive dans le monde. Cette étude a permis de définir le paysage international des modèles organisationnels et la chaîne de coordination de la préservation de la santé reproductive dans le monde pour les patientes atteintes d’un cancer. Elle apporte des arguments afin de réduire les disparités dans l’accès aux soins des jeunes femmes survivant à un cancer dans le monde. Une seconde étude s’est intéressée à explorer l’épidémiologie des cancers de la femme et a permis de proposer une estimation de la population concernée par une préservation de la fertilité aux Antilles Françaises.La troisième étude a permis de réaliser un bilan des pratiques de préservation de la santé reproductive aux Antilles Françaises par l’analyse de l’expérience du CECOS-Caraïbe en matière de préservation de la fertilité féminine puis par la réalisation d’une enquête de pratique menée auprès des médecins impliqués dans la prise en charge oncologique des femmes jeunes aux Antilles Françaises.Enfin, le dernier volet a exploré la prise en charge des cancers associés à la grossesse en Martinique. Cette étude a mis en évidence le véritable challenge thérapeutique que représentent ces cancers rares en contexte insulaire, nécessitant un travail collaboratif régional et interrégional. L’analyse de nos résultats a permis de montrer que l’organisation des soins en préservation de la santé reproductive aux Antilles Françaises reste à structurer et à améliorer sur plusieurs points : l’accès aux soins, l’information des patientes, l’identification de référents en oncofertilité, la formation des professionnels, l’interaction entre les centres d’assistance médicale à la procréation et les services d’oncologie. Pour répondre à ces besoins, des solutions innovantes sont possibles afin de mettre en réseau les différents acteurs. Le projet de Réseau Intercaribbéen Cancer et Santé Reproductive est un projet d’e-santé visant à structurer le parcours de soins des patientes jeunes atteintes de cancer et résidant en Martinique et en Guadeloupe, en construisant un parcours de coopération interrégionale pouvant faire face aux contraintes territoriales. Il s’agit également de porter des projets de recherche sur la thématique de la préservation de la santé reproductive dans nos régions dans le but d’améliorer la qualité de vie des jeunes survivantes résidant aux Antilles Françaises. / In oncology, diagnostic and therapeutic advances have allowed a significant improvement in survival rates at the cost of an alteration of the reproductive health of patients due to the gonadotoxicity of the treatments. The attention given to the quality of life during and after cancer has become a major issue of care and particularly includes issues related to sexual and fertility disorders, especially among young women. Strategies for preserving reproductive health before treatment initiation must now be an integral part of the multidisciplinary management of women's cancer. The epidemiological and clinical evaluation of these strategies is essential to improve the supply of care. However, the use of these strategies had not yet been evaluated in the French West Indies.This thesis project, based on four studies, tried to resolve this issue by realizing an inventory of recourse and needs in the preservation of female reproductive health in a context of cancer in the French West Indies (Martinique, Guadeloupe). The different parts of this work have been promoted through scientific publications presented in this manuscript.A first study looked at care pathways and networks for the preservation of reproductive health in the world. This study has defined the international landscape of organizational models and the chain of coordination for the preservation of reproductive health around the world for cancer patients. It brings arguments to reduce disparities in access to care for young women survivors of cancer around the world. A second study focused on exploring the epidemiology of women's cancers and proposed an estimate of the population concerned by fertility preservation in the French West Indies. The third study is dedicated to a review of the practices of preservation of reproductive health in the French West Indies by highlighting the experience of CECOS-Caraïbe in the preservation of female fertility and by the realization a practice survey conducted among doctors involved in the oncological management of young women in the French West Indies. Finally, the last part explored the management of cancers associated with pregnancy in the French West Indies. This study has highlighted the real therapeutic challenge represented by these rare cancers, requiring regional and interregional collaborative work.The analysis of our results made it possible to show that the organization of care in the preservation of fertility in the French West Indies remains to be structured and improved on several points: access to care, information of the patients, the identification of oncofertility referrals, training of professionals, interaction between the centers of medical assistance to procreation and oncology services.To meet these needs, innovative solutions are possible in order to network the different actors. The project Intercaribbean Network Cancer and Reproductive Health is an e-health project aimed at structuring the path of care of young cancer patients residing in Martinique and Guadeloupe, to build an inter-regional cooperation course that can cope with the constraints territorial. It also involves carrying out research projects on the theme of the preservation of reproductive health in our regions with the aim of improving the quality of life of young survivors living in the French West Indies.

Parte das mulheres com câncer de mama na menacme gostariam de tentar preservar sua fertilidade após o tratamento oncológico. Entretanto, as informações disponíveis sobre a extensão do dano aos ovários após o tratamento quimioterápico são insuficientes para estimar o risco de comprometimento da reserva ovariana. Dessa forma, como objetivo primário deste estudo propusemos caracterizar o impacto dos regimes quimioterápicos mais comumente utilizados no tratamento do câncer de mama em mulheres na menacme sobre a reserva ovariana avaliada por meio da aferição das concentrações séricas de hormônio antiMulleriano (HAM) e calendário menstrual, analisados antes e um ano após o término da quimioterapia. Cento e trinta e quatro pacientes foram analisadas para o objetivo primário do estudo. As concentrações séricas de HAM foram dosadas por meio do teste ELISA e foram representadas pela mediana e intervalo interquartil. Os testes não paramétricos de MannWhitney e de Kruskal-Wallis foram utilizados para comparar as medidas de HAM em relação as variáveis categóricas. A idade média foi de 36,67 anos (DP 3,95), sendo que 104 mulheres realizaram quimioterapia com regime antracíclico (AC-T), 13 regime não antracíclico (CMF) e 17 outros regimes quimioterápicos. Os níveis de HAM após 1 ano do término da quimioterapia reduziram de maneira significativa (mediana 0,13 ng/ml, intervalo interquartil 0,02; 0,35 ng/ml) quando comparados aos níveis basais (mediana 2,84 ng/ml, intervalo interquartil 1,26; 4,65 ng/ml; p<0,0001). Apesar da redução significativa dos níveis de HAM, 74,7% das mulheres apresentavam ciclos menstruais um ano após o término da quimioterapia. O tipo de regime quimioterápico influenciou de maneira significativa a redução dos níveis do HAM após 1 ano do término da quimioterapia. O grupo de tratamento que utilizou CMF apresentou maior redução da reserva ovariana quando comparado com o grupo de tratamento que utilizou outros regimes quimioterápicos. O uso adjuvante de tamoxifeno não alterou os níveis de HAM aferidos após 1 ano do término do tratamento quimioterápico. As concentrações séricas de HAM basais (p<0,0001), a idade (p=0,0438) e o regime de tratamento realizado (p=0,0259) foram relacionados com a redução dos níveis de HAM após um ano do término da quimioterapia. Mulheres com mutações BRCA apresentam menores concentrações basais de HAM e menores taxas de recuperação ovariana após otérmino do tratamento quimioterápico quando comparadas a mulheres sem a mutação e mulheres não testadas por apresentarem baixo risco de mutação. Esse estudo longitudinal demonstrou que o tratamento quimioterápico promoveu redução significativa das concentrações séricas de HAM um ano após o término do tratamento. O fato da maioria das pacientes apresentar ciclos menstruais, apesar dos baixos níveis de HAM, sugere que a presença de menstruação não é um marcador acurado de reserva ovariana. O tipo de regime quimioterápico utilizado no tratamento oncológico demonstrou influenciar o comprometimento da reserva ovariana. O tratamento adjuvante com tamoxifeno parece não exacerbar o comprometimento da reserva ovariana. Demonstramos que a idade, os níveis basais de HAM e o tipo de regime quimioterápico são os fatores de predição mais importantes da reserva ovariana após o tratamento citotóxico. Sendo assim, geramos o primeiro nomograma para predizer o impacto da quimioterapia na reserva ovariana. O nomograma descrito deve ser validado prospectivamente em novos estudos. Além disso, a presença de mutações BRCA pode colocar as mulheres em desvantagem reprodutiva quando expostas ao estresse genotóxico. Essas informações podem ser utilizadas para aconselhamento individual de mulheres em idade reprodutiva em relação a necessidade de tratamentos para tentativa de preservação da fertilidade. / Some women of reproductive age diagnosed with breast cancer wish to preserve their fertility and ovarian function after their oncological treatment. However, information available on the likelihood and extent of ovarian damage from chemotherapy is insufficient to predict the risk of ovarian reserve damage for individual women. Thus, the primary goal of this study is to delineate the extent of ovarian damage from chemotherapeutic treatment regimens by using serum AMH and menstrual calendars analyzed before and one year after the end of chemotherapy treatment. A prospective longitudinal IRB-approved study was performed. One hundred and thirty-four patients fulfilled the eligibility criteria and accepted to participate in the study, presenting blood samples with AMH measurement before and after one year of chemotherapy treatment. Serum AMH concentrations were measured by ELISA and were represented by median and interquartile range. The nonparametric tests of MannWhitney and Kruskal-Wallis were used to compare AMH concentrations in relation to the categorical variables. The mean age was 36.67 years (SD 3.95), and 104 women underwent chemotherapeutic regimen with anthracyclic regimen (AC-T), 13 non-anthracyclic regimen (CMF) and 17 other chemotherapeutic regimens. In the 134 women analyzed, the AMH levels after 1 year of chemotherapy were significantly reduced (median 0.13 ng/ml, interquartile range 0.02; 0.35 ng/ml) when compared to levels before chemotherapy (median 2.84 ng/ml, interquartile range 1.26; 4.65 ng/ml; p<0.0001). Despite the significant reduction in AMH levels, 74.7% of the women had return of menses by 1-year post treatment. The treatment regimen significantly influenced the reduction of AMH levels after 1-year post chemotherapy treatment. The CMF treatment group demonstrated a greater ovarian reserve reduction when compared to other chemotherapeutic regimens treatment group. Our study did not show statistical difference when other comparisons were made between the treatment groups. In addition, adjuvant tamoxifen use did not alter AMH levels 1-year post chemotherapy. Mixed effect model analysis confirmed that, for all the analyzed women (N=134), baseline serum AMH levels (p<0.0001), age (p=0.0438), and regimen (p=0.0259) were related to the reduction in AMH levels 1-year after chemotherapy treatment. Women treated for breast cancer with BRCA mutations have lower baseline serum AMH levels and lower rates of ovarian recovery after chemotherapy treatment compared to non-mutatedwomen and untested women with low risk of mutation. This longitudinal study demonstrated that chemotherapy regimens commonly used in the treatment of breast cancer in postmenopausal women significantly reduced serum concentrations of AMH 1-year after the end of treatment, suggesting a significant impairment of the ovarian reserve. The fact that most of the patients present menstrual cycles, despite the low levels of AMH, suggests that the presence of menstruation is not an accurate marker of ovarian reserve. The type of chemotherapy regimen used in oncological treatment has been shown to influence the ovarian reserve impairment. Adjuvant treatment with tamoxifen does not exacerbate the impairment of the chemotherapy-induced damage to ovarian reserve. We have shown that age, baseline AMH levels, and type of chemotherapy regimen are the most important predictors of ovarian reserve after cytotoxic treatment. In addition, we generated the first nomogram to predict the impact of chemotherapy on ovarian reserve in women diagnosed with breast cancer at reproductive age who will undergo chemotherapy. The nomogram described should be prospectively validated in new studies. In addition, the presence of mutations in BRCA may place women at reproductive disadvantage when exposed to genotoxic stress. These findings have significant bearing both on fertility preservation counseling as well as reproductive aging research and treatment.

Parte das mulheres com câncer de mama na menacme gostariam de tentar preservar sua fertilidade após o tratamento oncológico. Entretanto, as informações disponíveis sobre a extensão do dano aos ovários após o tratamento quimioterápico são insuficientes para estimar o risco de comprometimento da reserva ovariana. Dessa forma, como objetivo primário deste estudo propusemos caracterizar o impacto dos regimes quimioterápicos mais comumente utilizados no tratamento do câncer de mama em mulheres na menacme sobre a reserva ovariana avaliada por meio da aferição das concentrações séricas de hormônio antiMulleriano (HAM) e calendário menstrual, analisados antes e um ano após o término da quimioterapia. Cento e trinta e quatro pacientes foram analisadas para o objetivo primário do estudo. As concentrações séricas de HAM foram dosadas por meio do teste ELISA e foram representadas pela mediana e intervalo interquartil. Os testes não paramétricos de MannWhitney e de Kruskal-Wallis foram utilizados para comparar as medidas de HAM em relação as variáveis categóricas. A idade média foi de 36,67 anos (DP 3,95), sendo que 104 mulheres realizaram quimioterapia com regime antracíclico (AC-T), 13 regime não antracíclico (CMF) e 17 outros regimes quimioterápicos. Os níveis de HAM após 1 ano do término da quimioterapia reduziram de maneira significativa (mediana 0,13 ng/ml, intervalo interquartil 0,02; 0,35 ng/ml) quando comparados aos níveis basais (mediana 2,84 ng/ml, intervalo interquartil 1,26; 4,65 ng/ml; p<0,0001). Apesar da redução significativa dos níveis de HAM, 74,7% das mulheres apresentavam ciclos menstruais um ano após o término da quimioterapia. O tipo de regime quimioterápico influenciou de maneira significativa a redução dos níveis do HAM após 1 ano do término da quimioterapia. O grupo de tratamento que utilizou CMF apresentou maior redução da reserva ovariana quando comparado com o grupo de tratamento que utilizou outros regimes quimioterápicos. O uso adjuvante de tamoxifeno não alterou os níveis de HAM aferidos após 1 ano do término do tratamento quimioterápico. As concentrações séricas de HAM basais (p<0,0001), a idade (p=0,0438) e o regime de tratamento realizado (p=0,0259) foram relacionados com a redução dos níveis de HAM após um ano do término da quimioterapia. Mulheres com mutações BRCA apresentam menores concentrações basais de HAM e menores taxas de recuperação ovariana após otérmino do tratamento quimioterápico quando comparadas a mulheres sem a mutação e mulheres não testadas por apresentarem baixo risco de mutação. Esse estudo longitudinal demonstrou que o tratamento quimioterápico promoveu redução significativa das concentrações séricas de HAM um ano após o término do tratamento. O fato da maioria das pacientes apresentar ciclos menstruais, apesar dos baixos níveis de HAM, sugere que a presença de menstruação não é um marcador acurado de reserva ovariana. O tipo de regime quimioterápico utilizado no tratamento oncológico demonstrou influenciar o comprometimento da reserva ovariana. O tratamento adjuvante com tamoxifeno parece não exacerbar o comprometimento da reserva ovariana. Demonstramos que a idade, os níveis basais de HAM e o tipo de regime quimioterápico são os fatores de predição mais importantes da reserva ovariana após o tratamento citotóxico. Sendo assim, geramos o primeiro nomograma para predizer o impacto da quimioterapia na reserva ovariana. O nomograma descrito deve ser validado prospectivamente em novos estudos. Além disso, a presença de mutações BRCA pode colocar as mulheres em desvantagem reprodutiva quando expostas ao estresse genotóxico. Essas informações podem ser utilizadas para aconselhamento individual de mulheres em idade reprodutiva em relação a necessidade de tratamentos para tentativa de preservação da fertilidade. / Some women of reproductive age diagnosed with breast cancer wish to preserve their fertility and ovarian function after their oncological treatment. However, information available on the likelihood and extent of ovarian damage from chemotherapy is insufficient to predict the risk of ovarian reserve damage for individual women. Thus, the primary goal of this study is to delineate the extent of ovarian damage from chemotherapeutic treatment regimens by using serum AMH and menstrual calendars analyzed before and one year after the end of chemotherapy treatment. A prospective longitudinal IRB-approved study was performed. One hundred and thirty-four patients fulfilled the eligibility criteria and accepted to participate in the study, presenting blood samples with AMH measurement before and after one year of chemotherapy treatment. Serum AMH concentrations were measured by ELISA and were represented by median and interquartile range. The nonparametric tests of MannWhitney and Kruskal-Wallis were used to compare AMH concentrations in relation to the categorical variables. The mean age was 36.67 years (SD 3.95), and 104 women underwent chemotherapeutic regimen with anthracyclic regimen (AC-T), 13 non-anthracyclic regimen (CMF) and 17 other chemotherapeutic regimens. In the 134 women analyzed, the AMH levels after 1 year of chemotherapy were significantly reduced (median 0.13 ng/ml, interquartile range 0.02; 0.35 ng/ml) when compared to levels before chemotherapy (median 2.84 ng/ml, interquartile range 1.26; 4.65 ng/ml; p<0.0001). Despite the significant reduction in AMH levels, 74.7% of the women had return of menses by 1-year post treatment. The treatment regimen significantly influenced the reduction of AMH levels after 1-year post chemotherapy treatment. The CMF treatment group demonstrated a greater ovarian reserve reduction when compared to other chemotherapeutic regimens treatment group. Our study did not show statistical difference when other comparisons were made between the treatment groups. In addition, adjuvant tamoxifen use did not alter AMH levels 1-year post chemotherapy. Mixed effect model analysis confirmed that, for all the analyzed women (N=134), baseline serum AMH levels (p<0.0001), age (p=0.0438), and regimen (p=0.0259) were related to the reduction in AMH levels 1-year after chemotherapy treatment. Women treated for breast cancer with BRCA mutations have lower baseline serum AMH levels and lower rates of ovarian recovery after chemotherapy treatment compared to non-mutatedwomen and untested women with low risk of mutation. This longitudinal study demonstrated that chemotherapy regimens commonly used in the treatment of breast cancer in postmenopausal women significantly reduced serum concentrations of AMH 1-year after the end of treatment, suggesting a significant impairment of the ovarian reserve. The fact that most of the patients present menstrual cycles, despite the low levels of AMH, suggests that the presence of menstruation is not an accurate marker of ovarian reserve. The type of chemotherapy regimen used in oncological treatment has been shown to influence the ovarian reserve impairment. Adjuvant treatment with tamoxifen does not exacerbate the impairment of the chemotherapy-induced damage to ovarian reserve. We have shown that age, baseline AMH levels, and type of chemotherapy regimen are the most important predictors of ovarian reserve after cytotoxic treatment. In addition, we generated the first nomogram to predict the impact of chemotherapy on ovarian reserve in women diagnosed with breast cancer at reproductive age who will undergo chemotherapy. The nomogram described should be prospectively validated in new studies. In addition, the presence of mutations in BRCA may place women at reproductive disadvantage when exposed to genotoxic stress. These findings have significant bearing both on fertility preservation counseling as well as reproductive aging research and treatment.