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Fertility Preservation: Beyond OncologyFertility Preservation: Beyond Oncology
Leslie A. Appiah, M.D.Associate Professor of Obstetrics and Gynecology
Chief, Division of Gynecologic Subspecialties
Director of Oncofertility
University of Kentucky College of Medicine
Holly Hoefgen, M.D.Assistant Professor of Obstetrics and Gynecology
Division of Pediatric and Adolescent Gynecology
Co‐Director, Comprehensive Fertility Care & Preservation Program
Cincinnati Children’s Hospital Medical Center
No No ffinancial disclosures or conflicts of interestinancial disclosures or conflicts of interest
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• Explain oncologic and non‐oncologic conditions that benefit from fertility preservation therapies
Learning ObjectivesLearning Objectives
benefit from fertility preservation therapies
• Describe standard and novel fertility preservation options in special populations
• Discuss the process of incorporating a fertility preservation program into practice
Cancer and Fertility
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Case 1Case 121 yo G2P1011 with Hodgkin Lymphoma s/p 6 cycles of (ABVD) adriamycin, bleomycin, vinblastine and dacarbazine 2 years prior now withvinblastine and dacarbazine 2 years prior now with recurrence. Receiving ifosfamide, carboplatin and etoposide. Using OCPs and amenorrheic.
Does not recall fertility preservation consultation prior to initial chemotherapy.prior to initial chemotherapy.
Recommend ovarian reserve testing at completion of therapy and intrauterine device for contraception.
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High Risk TherapyHigh Risk Therapy
Alkylating‐intensive chemotherapy
• cyclophosphamide cumulative dose ≥7,500 mg/m2
• cyclophosphamide equivalent dose (CED) ≥ 7,500 mg/m2 y p p q g
• any treatment regimen containing procarbazine
• busulfan cumulative dose >600 mg/m2
• alkylating chemotherapy conditioning prior to SCT
• whole abdomen/pelvic irradiation ≥15Gy in pre‐pubertal girls
l b d i di i• total body irradiation
• combination of any alkylating agent with total body irradiation or whole abdomen or pelvic radiation
• cranial radiation ≥30 Gy
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Estimating Risk Estimating Risk ‐‐ CEDCED
Green et al. Pediatr Blood Cancer. 2014;61:53‐67
Chemotherapy and FertilityChemotherapy and Fertility
Ovarian Failure Testicular Failure
Meirow. Clin Obset and Gynecol 2010;53(4):727‐739 Howell. J Natl Cancer Inst Monogr 2005;34:12‐17
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Estimating Risk: Estimating Risk: Radiation in Females Radiation in Females
Green. J Clin Oncol. 2009;27(16):2677‐2685
Estimating Risk: Radiation in MalesEstimating Risk: Radiation in Males
Spermatogenesis Following Single Dose Radiation
Howell. J Natl Cancer Inst Monogr 2005;34:12‐17
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Minimizing RiskMinimizing RiskProtective Agent Mechanism of action Treatment interactions
GnRH analog Suppresses HPO axis; unclear No interference
Imatinib Inhibit c‐Abl kinase apoptosis
h
May interfere w/ apoptosis
pathway
Sphingosine‐1‐Phosphate Inhibit sphingomyelin apoptosis
pathway
May interfere w/ apoptosis
Tamoxifen Anti‐apoptotic activity;
Antioxidant activity via IGF‐1 axis;
Possible HPO axis suppression
No interference
AS101 Inhibits P13K/PTEN Akt follicle
activation pathway; anti‐apoptosis
No interference; may have
additive/synergistic
interaction
Bone marrow
mesenchymal stem cells
Tissue differentiation, angiogenesis,
anti‐apoptosis
May cause drug resistance
with Cisplatin
Granulocyte‐Colony
Stimulating Factor (G‐CSF)
Unclear: possibly angiogenesis;
anti‐apoptosis
No interference
Expert Consensus Position StatementsExpert Consensus Position Statements
• American Society of Clinical Oncology (ASCO)• American Society for Reproductive Medicine (ASRM)• Association of Pediatric Hematology/Oncology Nurses (APHON)(APHON)
– “As part of education and informed consent before cancer therapy”…physicians should inform cancer patients about options for fertility preservation and future reproduction … “or refer to reproductive specialists…”
– “…regardless of the patient’s age, gender, culture, socioeconomic status or healthcare team bias ”status, or healthcare team bias…
– “…and continue throughout treatment and survivorship in a manner appropriate to the patient’s developmental stage at that time.”
Statements supported by American College of Obstetricians and Gynecologists (ACOG) and American Academy of Pediatrics (AAP).
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GapGap Less than 30% receive fertility
preservation therapies
Quinn GP et al. J Clin Oncol. 2009; 27:5952–5957Gwede CK et al. Pract Radiat Oncol. 2012;2:242‐247.
Fertility Preservation BarriersFertility Preservation Barriers
“the only fertility preservation method most oncologists felt knowledgeable about was sperm cryopreservation g p y p(64%)”Adams 2013, BJC
“referrals to reproductive endocrinologists made approximately39% of the time ”Forman 2010, Fertil Steril
“patient is too ill to delay treatment” ‐ 50% of respondents in national survey of pediatric nephrologistsMiller 2014 J Renal Care
“lack of patient interest in fertility preservation (38%)”
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Patient ExperiencesPatient Experiences
“75% of cancer survivors without children stated they wanted to have children in the future.
“A third of survivors who already had at least one child wanted another”
“Patients experience less regret and have improved quality of life when counseled about fertility preservation options
if ti i d”
Moffat et al. Arch Gynecol Obstet. 2012;286(6):1521‐1527.Letourneau. Cancer. 2012;118(6):1710‐1717.Partridge et al. Clin Breast Cancer. 2008;8(1):65‐69Chandra et al. Fertil Steril.2010;93(3):725‐736
even if no option is pursued”
Non‐oncologic conditions
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Case 2Case 211 yo female with sickle cell anemia refractory to first‐line therapy. Plan for hematopoietic stem cell transplantation (HSCT) Received fertilitytransplantation (HSCT). Received fertility preservation counseling.
Ovarian reserve testing at baseline: AMH: 1.1 ng/ml, FSH 5 mIU/ml, Estradiol 7.6 pg/mL
Given high risk of ovarian failure, family elected OTC. Procedure was performed in conjunction with central line placement without complication.
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SStem cell transplantationtem cell transplantation
Autologous SCT
Allogeneic SCT
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Anemia Autoimmuneconditions
Other
A l ti i M lti l S bi d
Stem cell transplant:Stem cell transplant:NonNon‐‐oncologic conditionsoncologic conditions
Aplastic anemiaFanconi’sDiamond Blackfan
Multiple sclerosis
Severe combined immuno‐deficiency
Sickle‐cell anemia Systemicsclerosis
Wiskott‐Aldrichdisease
Thalassemia Systemic lupus Metabolic storage defects
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erythematosus MucopolysaccaridosesAmyloidosisGaucher’s disease
Rheumatoidarthritis
Pandey. Radiol Clin N Am 2016;54:375‐396
Case 3Case 315 yo with immune complex mediated membranous glomerulonephritis s/p therapy with 3 g/m2
cyclophosphamide. Treated with GnRHa for menstrual C l l d dsuppression. Currently on cyclosporine and steroids.
Treatment course complicated by VTE on anticoagulation.
Ovarian reserve testing 12 months post‐completion of therapy: AMH 1.98 ng/ml.
Given anticoagulation and persistent renal disease with menorrhagia, continued on GnRHa. Dose increased to 22.5 mg due to continued bleeding and incomplete HPO axis suppression.
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Renal disease and fertilityRenal disease and fertility
• Classic regimen: 0.75 – 1 g/m2 cyclophosphamide per month for up to 6 months then every 3 months for up to 2 years (cumulative dose > 7500 mg/m2)yea s (cu u ati e dose 500 g/ )
• Mycophenolate mofetil (CellCept) preferred induction agent for patients desiring fertility; Cytoxan continues to be important during induction in severe renal disease or relapsed pediatric patients
• Newer regimens: 0.75 – 1 g/m2 cyclophosphamide for 3 to 6 months with conversion to mycophenolate or tapering to low dose cyclophosphamide or azathioprine
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Gajjar. Pediatr Nephrol 2015;30(16):1099‐1106
Case 4Case 4
19 yo G0 diagnosed with primary ovarian insufficiency at age 14. Received HRT with adequate breast development and switched to OCPs for ease of use.
Labs at consultation: FSH 67.3 mIU/ml, Estradiol 30 pg/ml, AMH <0.03 ng/ml; 46 XX, FMR1, anti‐thyroid pg g yand anti‐adrenal antibody testing negative
Counseled on attempt at oocyte freezing ‐ declined
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• 37 infertile women with POI
• N=31
• > 1 year amenorrhea with FSH levels > 40 mIU/ml
• N=6
• > 4 months amenorrhea with FSH levels > 35 mIU/ml 4 months amenorrhea with FSH levels 35 mIU/ml
• Oophorectomy, vitrification and transplantation
• Gonadotropin injections
• Monitoring with U/S and serum estrogen levels
Suzuki et al. Human Reproduction 2015; 30(3): 608‐615
• ICSI and embryo cryopreservation
• Uterine priming and embryo transfer
3 i• 3 pregnancies
‐ 1 miscarriage and 2 successful live births
• Greater follicular growth with earlier intervention
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Case 5Case 5
5 year old female with 45XO,46XY Turner mosaicism for gonadectomy. Negative ultrasound and tumor markers.
Family interested in fertility preservation. Oophorectomy performed after pre‐operative discussion with pathology.
Frozen section revealed no oocytes; ovarian stromal tissue present; suspect gonadoblastoma therefore no tissue was frozenpresent; suspect gonadoblastoma therefore no tissue was frozen. Final pathology revealed bilateral gonadoblastomas.
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• Previous classification - conditions associated with:
Individually rare but in aggregate not uncommon – 1/4600
Disorders of Sexual DifferencesDisorders of Sexual Differences
• Gonadal dysgenesis• Undervirilization of 46 XY individuals• Prenatal virilization of 46 XX individuals
• Current classification of DSDs• Sex chromosome DSDs• 46 XX DSDs• 46 XY DSDs
Lawson Wilkins Pediatric Endocrine Society and European Society for Paediatric Endocrinology
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• 5 cases of premature ovarian failure5 cases of premature ovarian failure
• 3 Turner syndrome; 1 germ‐cell tumor; 1 leukemia
• Ages 11‐15
• Standard ovarian stimulation protocol
• Transabdominal U/S for monitoring
l U/ d h f l• Transvaginal U/S under anesthesia for retrieval
• 4‐11 mature oocytes cryopreserved; in vitro maturation performed on retrieved germinal vesicles JPAG 2014;27:342‐346
Ovarian stimulation in adolescentsOvarian stimulation in adolescents
• No large studies of stimulation in adolescents
• Adolescent females are able to participate in informed assent
• Gonadotropin doses similar to adult patients
• Consider GnRHa trigger instead of hCG to minimize OHSS risk
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• Gonadal dysgenesis, hypoplastic uterus, normal fallopian tubes
• Uterine priming and hormone replacement
• Oocyte donation with GIFT and semen insemination
• Full term male infant delivered by cesareany
• Reported pregnancies in 46 XY females have all been secondary
to oocyte or embryo donation
Fertility and Sterility 2002;78(2):419‐420
• Mixed gonadal dysgenesis
‐ Few case reports of successful paternity in phenotypic males
‐ No reports on extraction of immature oocytes for IVM in phenotypic females
‐ No reports on stimulation of ovarian follicles
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Sugawara 2012;25(4):96‐9Flannigan 2014;8(1‐2)e:108‐10
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Case 6Case 6
• 20 yo MTF transgender patient planning to undergo gender affirming hormone therapyg g py
• Fully identified as female for 1 year with good family support
• High desire for future biological children
• Counseled on fertility preservation options
• Underwent sperm cryopreservation‐ 2 collections (5 vials/collection) to ensure “at least 3 kids”
• Approximately half of MTF and FTM transgender persons express a wish for future children
• Transgender persons with children score higher on mental & vitality scores than those withouton mental & vitality scores than those without
• Parenting noted as a suicide protective factor in transgender women
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M j it f t d b li f tilit• Majority of transgender persons believe fertility preservation should be discussed & offered
₋ urgency for a rapid transition may prevent fertility preservation
• Discussion of fertility options with patients prior to• Discussion of fertility options with patients prior to treatment or medical intervention is recommended
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De Sutter et al 2002, De Roo et al 2016World Professional Association for Transgender Health Standards of Care 7th version
Gender Reassignment Therapy & FertilityGender Reassignment Therapy & Fertility
• Estrogen decreased testicular volume, poor semen quality
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g p q yand azoospermia with possible reversal
• Testosterone reversible amenorrhea without follicle depletion; pregnancies reported in FTM individuals on/after T
• Genital reconstructive surgery irreversible infertility
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Transgender: Fertility Preservation OptionsTransgender: Fertility Preservation Options
• Standard and experimental options
• Special Considerations• Special Considerations
− FTM patient
∙ Vaginal examination & procedures
− MTF patient
∙ Need for masturbation, semen production & storage
∙ Testicular sperm extraction/aspiration (TESE/TESA)Testicular sperm extraction/aspiration (TESE/TESA)
• Ovarian & Testicular Tissue Cryopreservation
₋ Removed at time of genital reconstructive surgery
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De Roo et al 2016, Wallace et al 2014
Fertility Preservation Methods
Method Considerations
Sperm cryopreservation Standard; no partner needed; specimen may be suboptimal due to malignancy and HRT
Mature oocyte cryopreservation
(35 ‐ 50% success rate)
Standard; no partner needed; 10 – 14 days stimulation; surgical procedure; costs; no ovarian function preserved
Stimulation may occur at any phase of the cycle
Embryo cryopreservation
Standard; partner or sperm donor needed; 10 –14 days stimulation; surgical procedure; costs;
ti f i f ti b(40% success rate)
no preservation of ovarian function; embryo ownership concerns
Ovarian transposition(Success rates of 88‐90%)
Standard; underutilized
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Fertility Preservation Methods
Method Considerations
Immature oocyte cryopreservation
Investigational; no partner needed; no stimulation; surgical procedure; costs; no ovarian function preserved
Ovarian and testicular freezing
Investigational; surgical procedure; costs; transplantation not suitable with high gonadal involvement; preservation of gonadal function
GnRHa ovarian suppression
Investigational; conflicting data; limited data on reproductive outcomes
Ovarian Tissue CryopreservationOvarian Tissue Cryopreservation
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Ovarian Tissue Cryopreservation
Cortex Dissected from Medulla
Jadoul P et al. Hum. Reprod. Update 2010;16:617‐630
Thickness = 1 mm
Orthotopic Transplantation:Ovarian Fossa
Donnez et al. Frontiers in Bioscience 2012
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Orthotopic Transplantation:Contralateral Ovary
Donnez J et al. Hum. Reprod. Update 2006;12:519‐535
Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark
Jensen et al. Hum. Reprod. 2015;0(0):1‐8
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Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark
• Ovarian tissue cryopreservation initiated in Denmark in 2000
• 800 patients have undergone ovarian tissue cryopreservation
• Annual activity of 13‐14 cases per million inhabitants per year
• 53 transplantations to 41 patients over 10 years
A 32 i h i h 24 li i l
Jensen et al. Hum. Reprod. 2015;0(0):1‐8
• Among 32 women with a pregnancy‐wish, 24 clinical pregnancies and 10(31%) had a child/children
• Transplanted ovarian tissue may last 10 years
Restoration of Hormonal Function
Silber. Ovarian cryopreservation and transplantation for fertility preservation. MHR 2012
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• 218 premenopausal patients age < 50
Moore. N Engl J Med 2015 March;372:10
218 premenopausal patients age < 50
• Stage IIA ER/PR‐negative breast cancer
• Randomized to cyclophosphamide w/ or w/o Goserelin (GN) 3.6 mg SQ 1 week before tx
• Primary: 2‐year amenorrhea + elevated FSH
• Secondary endpoints: pregnancy and survivalPrimary ovarian insufficiency ‐ 22% standard group‐ 8% Goserelin groupP = 0.04
Pregnancies‐ 12 standard group‐ 22 Goserelin groupP = 0.03
Fertility Preservation Costs
Method Considerations
Sperm cryopreservation $400 + $175 for semen analysisp y p y
Oocyte cryopreservation $8000 plus meds$4000 ‐ $6000 (reduced costs through Livestrong) plus meds
Embryo cryopreservationIVF
$5500 ‐ $13000$7800 ‐ $12000 plus meds
Long term storage $275g g $$75 reduced costs
Ovarian tissue cryopreservation
$10000 ‐ $30000 for oophorectomy (funding)$500 for tissue processing (funding)
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Donor Embryos
Donor Oocytes
Gestational Surrogate
Adoption
Family Building OptionsFamily Building Options
Embryos donated
Success rate > frozen embryo/IVF transfers
$5 000 7 000 +
Oocytes donated
40‐50% success rate
$5 000 15 000 +
Pregnancy carried for patient
Success rate similar to fresh cycle IVF
$10 000 100 000
Legalparent‐childrelationshipcreated
$2500 35000$5,000‐7,000 + IVF costs
$5,000‐15,000 + IVF costs
$10,000‐100,000 $2500‐35000
Levine J, Canada A, Stern CJ. Fertility Preservation in Adolescents and Young Adults with Cancer. J Clin Oncol 2010; 28: 1‐11.
Preimplantation Genetic DiagnosisPreimplantation Genetic Diagnosis
P tIVF/ICSII
• Pregnancy success rates: 27 – 39% per embryo transfer
• No increased risk of i l d hperinatal deaths or
congenital malformations
Derks‐Smeets. Breast Cancer Res Treat. 2014;145:673‐681
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Ovarian reserve testingOvarian reserve testing
Fertil Steril 2009;92:1586‐93.
Baseline testing and 12 months after completion of therapy
AntiAnti‐‐Mullerian HormoneMullerian Hormone
Primary Secondaryfollicle
Secondaryfollicle
La Marca A. Et al. Anti‐mullerian hormone (AMH) as a predictive marker in assisted reproductive technologies ART). Hum Reprod Update 2010;16(2):113‐130.
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AntiAnti‐‐Mullerian HormoneMullerian Hormone
Serum AMH (picomoles per liter) in 926 healthy infants, girls, adolescents, and adult women.La Marca A. et al. Anti‐mullerian hormone (AMH) as a predictive marker in assited
reproductive technologies ART. Hum Reprod Update 2010;16(2):113‐130.
Ovarian reserve testingOvarian reserve testing1AMHng/ml
Clinical Situation Implications
Very Low(0 5)
Impending onset of premature menopause
Predicts low ovarian response to stimulation(0.5) premature menopause response to stimulation
Low (< 1.0)
Limited egg supply Shortened reproductive window
Mid‐range (1‐3.5)
Normal testing Consider preservation if high risk chemotherapy
Elevated PCO or PCO‐like Risk of OHSS
1Modified, Toner. Fertil Steril 20132Broer. Hum Reprod Update. 2013;19(1):26‐36
(>3.5) ovaries
• Fluctuations can be observed over the course of year(s)• Does not reliably predict pregnancy rates
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Implementing a fertility preservation program
Oncofertility Program Website:Oncofertility Program Website:www.ukhealthcare.uky.edu/fertilitywww.ukhealthcare.uky.edu/fertility‐‐preservationpreservation
Team MembersCharity Rogers, RN ‐ GynecologyDiana Holtzhaeur, RN ‐ OncologyLeslee Bertram DNP OncologyLeslee Bertram, DNP ‐ OncologyChristina Conley, APN ‐ Oncology
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Oncofertility Program Oncofertility Program [email protected]@uky.edu
Program Work-flow
New patient presents
Oncology treatment
plan
Fertility
Consult
Prepubertal
Male Female
Pubertal
Male Female
Testicular tissue
freezing*
Ovarian Tissue
Freezing*
Sperm/Testicular Freezing*
Egg/Embryo
Ovarian Freezing*
• Patient Navigator or Clinical Research Nurse – central point of contact
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Fertility Preservation Process
FERTILITY CONSULTATION WORKFLOW
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Oncofertility ReferralOncofertility ReferralElectronic Medical Record
• Physician note
• Nursing systems assessment
Oncofertility ReferralOncofertility Referral
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EMR Data Management EMR Data Management
EPIC Fertility Synopsis (Testing Phase)
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CollaborationCollaboration
Oncology/ Endocrinology Care Managersgy
Optimize Outcome
Gynecology/Surgery/REI
PCP
Care Managers
Social Work
EthicsPCP
Patient/Family
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Future DirectionsFuture Directions
• Identify agents that minimize risk prior to and during gonadotoxic therapy
• Advance reproductive technologies such as in‐vitro maturation of immature ovarian follicles and spermatogonial stem cells
• Sta da di e a d st ea li e cou seli g a d• Standardize and streamline counseling and implementation of fertility preservation therapies
Challenging Cases ‐Audience
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