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  • Fertility Preservation in Cancer Patients

    Dr. Khaled R Darhouse, MRCOG

    Consultant Obstetrician & GynaecologistReproductive Medicine & Assisted Conception

    King Abdulaziz University HospitalJeddah Saudi Arabia

  • The Gonads

    The primary function of both ovaries and testis is REPRODUCTION

    Reproduction is the passage of parental genetic material onto the next generation

  • Life Expectancy

    In 1900 the average life expectancy of men was 46.3 years and of women was 48.3 years.

    At the turn of the millennium men now expect to live to be 73.8 and women to be 79.5 years old.

    In a hundred years life expectancy has nearly doubled.

  • National Geographic MagazineMay 2013

    THIS BABY WILL LIVE TO BE 120

    New science could lead to long lives

  • Longer life

    The longer the people live the more theyll expect to get cancer.

    Advantages in cancer treatment over the past two decades have led to remarkable improvements in survival rates.

    Indeed, during the past 5 years, the overall death rates from cancer have fallen by more than 1.6% per year.

  • General Fertility Preservation

    Women are increasingly postponing childbearing to later in life for social, career or financial reasons

    Incidence of most cancers increase with age

  • Cancer Fertility Preservation

    In women, ~10% of cancers occur in those 90% of girls and young women with diseases that require such treatments.

    However, these treatments can result in premature ovarian failure, depending on the follicular reserve, the age of the patient and the type and dose of drugs used.

  • Improved Five Year Survival(1966 -2000)

  • Five Year SurvivalChildhood Cancers

  • Cure for Children but at a Cost

    Sustain and improve survival rates Minimise late effects Treatment is in conflict with normal childhood

    growth and development

  • Risk Assessment for Fertility Preservation

    Intrinsic Factors Health status of the patient Consent of patient or parents Assessment of ovarian reserve

    Extrinsic Factors Nature of planned treatment Available time Availability of expertise

    Wallace H, Critchley H and Anderson R JCO 2012

  • Ovarian Reserve

  • Infertility Risk Factors

    Radiotherapy Irradiation of field of ovaries or testis Total body irradiation

    Chemotherapy Busulphan Cyclophosphamide Melphalan Mustine Procarbazine

  • Gonadotoxicity

    Presentation Copyright: Dr. Khaled R Darhouse

    Cytotoxic agents according to the degree of gonadotoxicity

    High risk Intermediate risk Low/no risk

    Cyclophosphamide Doxorubicin Methotrexate

    Busulfan Cisplatin Bleomycin

    Melphalan Carboplatin 5-Fluorouracil

    Chlorambucil Actinomycin-D

    Dacarbazine Mercaptopurine

    Procarbazine Vincristine

    Ifosfamide

    Thiotepa

    Nitrogen mustard

    Reference: Lobo R; N Engl J Med2005 353,6473.

  • Infertility Risk

    Low Risk (

  • Infertility Risk

    Medium Risk AML Osteosarcoma Ewings sarcoma II/III Nuroblastoma Brain tumours (RTx > 24Gy) Hodgkins lymphoma III/IV

  • Infertility Risk

    High Risk (

  • Radiation-Induced Ovarian Damage

    Human Oocyts Primordial follicles

    LD 50

  • Radiation-Induced Ovarian Damage

    Human Oocyts Primordial follicles

    LD 50

  • Effect and mean ovarian sterilizing doses of radiotherapy at increasing age

    On a 7 years old 19 Gyare needed to completely deplete the primordial follicle and sterilize the patient

    At the age of 42 only 11 Gy are needed to render the patient sterile

    Wallace H et al IJRBP (2005)

  • Uterine volume and age at irradiation

    Bath et al BJOG (2005)

  • Uterine function after cancer treatment

    Uterine damage, manifest by impaired growth and blood flow, is likely a consequence of pelvic irradiation.

    Uterine volume correlates with age at irradiation.

    Exposure to pelvic irradiation is associated with increased miscarriage, mid-trimester pregnancy loss, preterm labour low birth weight and post-partum haemorrhage.

  • Sex Hormone Therapy for Childhood Cancer Survivors

    The most appropriate dose and route of administration of sex hormone replacement to young women with ovarian failure after pelvic irradiation that provides adequate concentrations of oestrogen to ensure optimal uterine growth during adolescence has not yet been established

  • OPTIONS OF FERTILITY PRESERVATION

    Envolves: Oncologists, Paediatricians, Gynaecologists and Urologist/Andrologists

    Men: Sperm cryopreservation

    Women: Embryo cryopreservation Oocyte cryopreservation Ovarian tissue cryopreservation

  • OPTIONS OF FERTILITY PRESERVATION

    In pre-pubertal men testicular tissue cryopreservation is experimental, but is the only option currently available

    Sperm cryopreservation is a well established and successful method routinely used.

  • OPTIONS OF FERTILITY PRESERVATION

  • OPTIONS OF FERTILITY PRESERVATION

    Ovarian function suppression Oral contraceptive pills GnRHa

    Embryo cryopreservation Well-established with good success Married Post-pubertal Delay in cancer treatment Legal issues

  • OPTIONS OF FERTILITY PRESERVATION

    Oocyte cryopreservation Mature oocytes Immature oocytes with IVM Post-pubertal Delay in cancer treatment

    Ovarian tissue cryopreservation Pre-pubertal / Post-pubertal No delay in cancer treatment Expertise

  • Mature Oocyte Cryopreservation

    Need for a stimulated cycle Tailored stimulation protocols GnRHa trigger Should not delay chemo/radiotherapy Disastrous consequences with complications Harvest of good quality oocytes should be

    expected Not recommended after chemotherapy is

    initiated

  • Mature Oocyte Cryopreservation

    Survival rate of vitrified oocytes is now approximately 96.9%

    Pregnancy rates after oocyte vitrification 10 oocytes = 40% 12 oocytes = 60% 20 oocytes = 90%

  • Ovarian Tissue Cryopreservation

    Percentage of patients undergoing OTC: 96.2% of patients were < 35 years 52.5% of patients were < 24 years 17.2% of patients were < 14 years

  • Ovarian Tissue Cryopreservation

    Harvesting by laparotomy or laparoscopy How much of the ovarian cortex should be

    removed? Size and thickness of cortical strips Cellular injury and damage

    Hypoxia Dehydration Freezing

    Slow freezing or vitrification?

  • Ovarian Tissue Cryopreservation

    Re-implantation could be either orthotopic or hetrotopic

    More than 50% of primordial follicles are lost due to hypoxia

    Thawing process injury High FSH and low AMH deplete surviving

    primordial follicles

  • Harvesting and orthotopic re-implantation of OTC

  • FSH Levels Post-Orthotopicreimplantation

  • LH, FSH and E2 levels post reimplantation of OTC

  • Ovarian Tissue Cryopreservation

    Orthotopic reimplantation allows for spontaneous pregnancy

    Hetrotopic reimplantation necessitates IVF-ICSI

    Major concern is reintroduction of malignant cells after remission / cure.

  • Ovarian Tissue Cryopreservation

  • Ovarian Tissue Cryopreservation

    It is unknown how many cases of reimplantation were carried out throughout the world

    In a series of 60 reported cases the live birth rate is 23%

    Young children are the ideal candidates No pregnancies reported following the

    reimplanation of ovarain tissue harvested pre-pubertally

  • The Future

    In vitro follicular maturation after ovarian tissue culture

    Isolated primordial follicle culture in the lab Artificial ovaries

  • The Future

    Stem cell gamete production Experimental success in producing both eggs and

    sperms Successful in producing normal and fertile mice Must pass rigorous testing Might be available in at least 10 years

    Lyophilization and Freeze-Drying Eggs Sperms Embryos

  • Conclusion

    Fertility preservation has become an established branch of reproductive medicine.

    Multidisciplinary team approach and individualisation of cases are key to its success.

    Fertility preservation should be discussed with men and women in the fertile age group who are about to embark in cancer treatment

  • Conclusion

    Fertility preservation gives hope in future reproduction and hope of a life after cancer.

    Embryo freezing is most successful method to date.

    For prepubertal men and women gonadaltissue freezing is the only available method availlable.

    Many new promising methods wil be available in the near future.

  • Thank You

    Dr. Khaled R Darhouse, MRCOGConsultant Obstetrician & Gynaecologist

    Reproductive Medicine & Assisted ConceptionKing Abdulaziz University Hospital

    Jeddah Saudi Arabia

    Fertility Preservation in Cancer PatientsThe GonadsLife ExpectancyNational Geographic MagazineMay 2013Longer lifeGeneral Fertility Preservation Cancer Fertility PreservationImproved Five Year Survival(1966 -2000)Five Year SurvivalChildhood CancersCure for Children but at a CostRisk Assessment for Fertility PreservationOvarian ReserveInfertility Risk FactorsGonadotoxicityInfertility RiskInfertility RiskInfertility RiskRadiation-Induced Ovarian DamageSlide Number 19Effect and mean ovarian sterilizing doses of radiotherapy at increasing ageUterine volume and age at irradiationUterine function after cancer treatmentSex Hormone Therapy for Childhood C

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