Fertility Preservation

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Fertility Preservation In Cancer Patients
Barbara J. Stegmann, MD, MPH Assistant
Professor Reproductive Endocrinology and
Infertility University of Iowa Barbara-Stegmann_at_ui
owa.edu
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Patients diagnosed with cancer in US in 2005
4 under age 35
1,372,910 patients
55,000 under the age of 35
12,000 under the age of 19
Lee et al, J Clin Onc 2006
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Estimated Number of Cancer Survivors in U.S
(1971 to 2004)
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Cancer Fertility Crossroads

• Increasing Cancer Survival Rates
• Increased Emphasis on Quality of Life
• New Fertility Preservation
• Post-treatment Parenthood Options
• Patients Need Information About
• Fertility Risks Options

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Are cancer patients interested in interventions
to preserve fertility?

• Fertility preservation is of great importance to
  people diagnosed with cancer
• Most cancer survivors prefer to have biological
  offspring despite serious concerns
• Increased emotional distress in those who become
  infertile after cancer treatment
• Long-term quality of life is affected by
  unresolved grief and depression
• Patients may choose a less effective treatment
  strategy in order to avoid or reduce the risk of
  infertility

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Objectives

• What are the current and future options to
  preserve fertility in males?
• What are the current and future options to
  preserve fertility in females?
• Who will benefit from fertility preservation
  counselling?

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Causes of Male Infertility

• The disease itselfHodgkins Lymphoma
• Retrograde ejaculation or anejaculation
• 1o or 2o hormone insufficiency
• Damage or depletion of germinal stem cells

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Anti-tumor agents that can cause prolonged
azoospermia
Radiation (2.5 GY to testis) Cisplatin (500 mg/m2)
Chlorambucil (1.4 g/m2) Procarbazine (4 g/m2)
Cyclophosphamide (19 g/m2) Melphalan (140 mg/m2)

• Currently do not know how new agents affect sperm
  production
• New agents include oxaliplatin, irinotecan,
  monoclonal antibodies, tyrosine kinase inhibitors
  and taxanes

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Current options for Preservation of Fertility in
Males

• Sperm cryopreservation
• Antegrade ejaculate
• Retrograde ejaculate
• Testicular aspirate (outpatient surgery)
• Gonadal shielding during radiation
• Testicular suppression with GnRH analogs or
  antagonists not effective

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Use of cryopreserved sperm

• 10-30 of the men who banked sperm before
  cancer treatment return to use the sperm
• Storage fees are rarely the reason for specimen
  discard.

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Couple Bear Child Using 14-Year-Old Frozen Semen
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Before they got married, Rick explained to
Jessica all about his cancer history and the
possibility that he might be infertile. She was
not intimidated by the news. We knew we had
options, she said, referring to the banked
sperm. We had more anxiety when we went to do
this.
Quad City Times, Nov 11, 2010
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Causes of Female Infertility

• DNA damage to oocytes
• Destruction of the primordial follicles
• Hormonal imbalances due to damage to the
  pituitary
• Damage to uterus, ovaries and tubes

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Effect of Radiation on Female Fertility

• Direct indirect damage to DNA of oocytes
• Small primordial and growing follicles damaged
• Damage to the pituitary

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High Risk of Amenorrhea

• Bendamustine
• Busulfan
• Carboplatin
• Chlorambucil
• Cisplatin
• Cyclophosphamide
• Dacarbazine

• Isofamide
• Mechlorethamine
• Melphalan
• Procarbazine
• Temozolomide
• Thiotepa

Fertile Hope, Fast Facts for Oncology
Professionals, 2007
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Risk of ovarian involvement
LOW RISK
MODERATE RISK

• Wilms
• Lymphomas
• Stage I-III breast CA (infiltrating ductal)
• Nongenital rhabdomyosarcoma
• Osteogenic sarcoma
• Squamous cell cervix
• Ewing sarcoma

• Stage IV breast
• Adeno cervix
• Colorectal

HIGH RISK

• Leukemia
• Neuroblastoma
• Stage IV lobular breast

Sonmezer Oktay Human Reprod Update 2004.
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Oocyte Development
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Assessing Ovarian Reserve in Cancer Patients

• FSH
• Late biomarker
• Indirect measure of ovarian health

Lie Fong et al. Hum Reprod 200823(3)674-8.
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Initiation of Puberty
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Assessing Ovarian Reserve in Cancer Patients

• Ovarian volume

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Assessing Ovarian Reserve in Cancer Patients

• Antral Follicle Count (AFC)

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Assessing Ovarian Reserve in Cancer Patients

• AMH (anti-mullerian hormone)

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Assessing Ovarian Reserve in Cancer Patients

• Cycle regularity - use caution
• Regular cycles ?fertile
• Amenorrhea ? Infertile
• Remember to offer contraception when fertility
  is not desired

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Options for Fertility Preservation

• The Now
• Embryo cryopreservation
• Near Future
• Oocyte cryopreservation
• Still considered experimental
• Long Range Planning
• Ovarian tissue cryopreservation
• Cytotoxic protectants

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Embryo Cryopreservation

• Most established technique for fertility
  preservation
• Requires 8-12 days of ovarian stimulation
• Retrieval is an outpatient surgical procedure
• May delay treatment 2-6 weeks
• Success rate varies, depending on females age

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Limitations of embryo cryopreservation

• Time
• Need 2-6 weeks -gt may delay therapy
• Relationship status
• Must have partner or donor sperm
• Age
• Not acceptable for children
• Cost
• 12-15,000 / cycle and storage fees
• Risks
• Hyperstimulation syndrome
• Exposure to higher level of estradiol

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Oocyte cryopreservation

• Reproductive age women without partners
• Women with an ethical or religious objection to
  embryo storage
• An option for pubertal girls

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Limitations of oocyte cryopreservation

• Time
• Cost
• Risks

Similar to embryo cryopreservation
Oocyte cryopreservation is technically challengi
ng
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Ovarian Tissue Cryopreservation

• Advantages
• No partner required
• No ovarian stimulation required
• May be feasible for prepubertal children

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Ovarian Tissue Cryopreservation

• Tissue is removed laparoscopically and
  cryopreserved
• Primordial and primary follicles
• Reimplanted when ready to have children
• Oocytes are matured in the lab and fertilized

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Limitations of ovarian tissue cryopreservation

• Large follicular loss due to ischemia (about 25
  of primordial follicles are lost)
• Possibility of residual malignant cells
• Oocytes arrested in prophase I so must undergo
  in-vitro maturation if not reimplanted
• Cost
• 12,000 for harvest, freeze
• 10,000 for transplantation
• -15,000 for IVF

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Cytoprotective Agents

• NRF2 activators
• Sulforaphane
• Amifostine
• Trental/Vitamin E
• Dexrazoxane

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Cytoprotective Agents

• GnRH analogs or antagonists
• ? proven benefit
• ? Lower incidence of premature ovarian failure
  and infertility in prepubertal girls receiving
  alkylator
• Highly controversialbeing used without clear
  evidence of efficacy or understanding of
  risks/benefits

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Cytoprotective Agents

• GnRH analogs or antagonists
• Theorhetical mechanisms
• Downregulation of the ovary
• Antiapoptotic
• Decreases blood flow to ovary so less exposure

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Ovarian Transposition

• Oophoropexy offered with pelvic radiation is used
  for cancer treatment
• Must be performed close to the time of radiation
  treatment (risk of remigration)
• May be performed laparoscopically if laparotomy
  is not needed for treatment

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Ovarian Transposition

• Success rate judged by short-term menstrual
  function is 50.
• Failure is attributed to scatter radiation,
  alteration of the ovarian blood supply and total
  radiation dose.
• Ovarian repositioning may or may not be required.

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Special considerations for pediatric cancer
patients

• Impaired fertility difficult to conceptualize
• Spermarche occurs at 13-14 years
• Established methods (sperm and embryo
  cryopreservation) require BOTH patient assent and
  parental consent
• Experimental methods should only be attempted
  under IRB-approved protocols

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Average Treatment Costs
Nationally UIHC
Sperm Banking 1500 218 150/yr
Testicular tissue freezing 10,000 5500 150/yr
Embryo Freezing 10,000 10,000 - 11,000
Egg Freezing 8,000 NA
Ovarian Tissue Freezing 12,000 NA
GnRH analog treatment ? 500/mo
In Vitro Fertilization 10 14,000 11 - 13,000
Donor gametes or embryos 25,000 20 - 25,000
Adoption 2,500 35,000
Surrogacy 20 100,000 20 - 100,000
Pre-Treatment
Post-Treatment
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Barriers to accessing care(From fertile HOPE
fertility resources for cancer patients)

• Up to 90 of young cancer patients are at risk
  for infertility following treatment
• lt25 of oncologists inform eligible patients
  about their risks and options
• Fears and misconceptions exist from fertility
  treatments and the safety of pregnancy after
  cancer

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Conclusions

• Fertility preservation is often possible
• Sperm and embryo cryopreservation are the only
  non-experimental procedures available.
• A broader application of fertility preservation
  requires
• Education
• Provision of financial resources for these
  interventions
• Better understanding of the risks associated with
  fertility preservation

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Conclusions

• Information is important, but do not give false
  hope
• Consider referring to our study or our clinic for
  consultation
• Fertility preservation should not be pursued at
  the expense of cancer treatment and overall
  welfare

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• Questions?