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Fertility PreservationPhoebe H. Leonard M.D.
Assistant Professor
University of Minnesota Reproductive Medicine CenterReproductive Medicine Center
No financial disclosures
Objectives
1. Discuss fertility risks related to chemotherapy and radiation for treatmentchemotherapy and radiation for treatment of cancer and other diseases.
2. Review current fertility preservation options for women and men.
3. Discuss fertility preservation options for women of advancing age.
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Fertility preservation
• Emerging field
• Encompasses a variety of therapies• Encompasses a variety of therapies
• Therapies promote or conserve fertility in health and disease
• Applicable beyond cancer For example, myelodysplasia, aplastic anemia, thalassemia, lupus, Turner mosaics, women who wish to delay childbearing
Cancer and Future Fertility
• ~10% of individuals diagnosed with cancer are <45 years of age
O ll l ti 5 i l f th 50 i 80%• Overall relative 5‐year survival for those <50 is 80%Source: SEER data, www.seer.cancer.gov
• Cancer therapy can be life‐saving but can result in infertility or premature gonadal failure
• Quality of Life issues
• 75% of childless individuals <35 at time of cancer diagnosis desire children in future
Source: Schover LR 1999 Cancer 86:697=709
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Infertility impact on quality of life
“The infertile women had global symptom l h dscores equivalent to the cancer, cardiac
rehabilitation and hypertension patients.”
Source: Domar et al J Psychosom Obstet Gynaecol. 1993
American Society of Clinical Oncology (ASCO) ASCO guideline:
All patients diagnosed with cancer should have the possibility of infertility discussed with them as well as all potential fertility preservation options.
Source: ASCO guidelines Update 2013
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Cancer treatment and fertility
Sperm and eggs are susceptible to damage by chemotherapy or radiationchemotherapy or radiation
Female Patients
• Women are born with a fixed number of eggs (primordial follicles):
Maximal at 5 months gestation
Declines with age:
Loss accelerates around age 37
Most eggs are in a resting state
• Even resting eggs can be damaged by cancer treatment
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OOGENESIS TIME LINE
4-5 weeks MENOPAUSEPUBERTY20 weeks
BIRTH
1000 7 MILLION 2 MILLION 300,000 0
Source: Fritz and Speroff 8th Edition 2011
Multiple cytotoxic effects of chemotherapy:
• Dividing cells vulnerable to cytotoxic agents
• Non‐cycle cycle specific agents may damage oocytes and pregranulosa cells of primordial follicles
• Drugs may interrupt follicular maturation
Bines et al J. Clinical Oncology 1996,
Aubard et al Eur J Obstet Gynecol Reprod Biol. 2001
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Female chemotherapy related risk
Not all chemotherapy drugs are equal
Alkylating agents >80% risk of permanent ovarian damage
• Not cell‐cycle specificNot cell cycle specific
• Can damage “resting” oocytes and support cells
• Odds ratio 3.98 for complete ovarian failure with cyclophosphamide compared to unexposed patients
Examples include—
• Cyclophosphamide (Endoxan, Cytoxan, Neosar, Revimmune)
Chl b il (L k )• Chlorambucil (Leukeran)
• Busulfan (Busulfex, Myleran)
• Melphalan (Alkeran)
Source: Meirow D. Lukemia and Lymphoma 1999
Chemotherapy and Odds Ratio For Ovarian Failure
Source: Mierow, et. Al. Human reproduction update 2001
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Risk of chemotherapy‐related amenorrhea depends on:
• Patient’s age
• Agent(s) used and dosage
Chemotherapy‐related amenorrhea (%) by age
Treatment Age <30 Age 30-40 Age >40
CMF = Cyclophosphamide, Methotrexate, 5‐FU
F ll i d 12 th
None ~ 0 <5 20-25
CMF x 6 19 31-38 76-96
Follow‐up period = 12 monthsSource: Partridge AH 2007 Breast 16:S175‐181
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Age‐female related risk for loss of fertility
• Younger is a better prognosis
• Not much data for age <30Not much data for age 30
• Age >40 appears to be significant risk factor
• Return of menses ≠ fertility
Female radiation risk
• Key factors: Age at exposure, site, and extent/type of radiotherapyextent/type of radiotherapy
• Abdominal, pelvic or spinal radiation increases risk of ovarian failure—scattered irradiation can affect ovaries even when outside of field
Source: Sonmezer M 2004 Hum Reprod Update 10:251‐266
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Female Radiation Risk
• Oocyte loss is dose‐relatedGosden R, 1997, Human Reprod
• LD50 (dose to kill 50% of oocytes) of human ovary is <2 GyWallace W, 2003, Human Reprod
• Younger ovaries are more resistant6 Gy may lead to irreversible damage in women >40y y g
10‐20 Gy needed to induce permanent failure in pediatric patients
Male Patients
http://bio1152.nicerweb.com
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Male fertility risk
• Agents used and dose of ChemotherapyMales treated with 6 cycles of chemo
90% of infertility with alkylating agents
33% of infertility without alkylating agents
Waring AB, Hospital Medicine, 2000
• Harmful radiation doses may be lower in males 1.2 Gy2
Howell S. Endocrinology Metabolism Clinics of North America,1998
Fertility preservation
• What options are available?
• When are certain options more appropriate• When are certain options more appropriate than others?
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Male fertility preservation
• First live birth from frozen sperm: 1953• Sperm is relatively easy to freeze/thawSperm is relatively easy to freeze/thaw• Sperm banking is well‐established • Options for prepubescent males are
experimental only
• Provide counseling on how banked specimens are to be used
Female fertility preservation options
1. In Vitro Fertilization (IVF) with Embryo Cryopreservation
2. Oocyte Cryopreservation
3. Ovarian Tissue Cryopreservation— adjunct oocyte maturation and cryopreservation
4. Medical (suppressive) therapy
5. Surgical therapy
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Current fertility preservation strategies
Source: Jensen JR, Mayo Clinic Proceedings, 2011
Current fertility preservation strategies
Source: Jensen JR, Mayo Clinic Proceedings, 2011
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Fertility Preservation Treatment Algorithm
Does the patient have 3 weeks?
Yes
Married/Partner Single
No
Ovarian Tissue Cryopreservation
No Treatment or GNRH Agonist
Embryo Cryopreservation
Embryo Cryopreservation
with Donor Sperm or
OocyteCryopreservation
Time needed for embryo/oocyte cryopreservation:
2‐3 Weeks for Controlled Ovarian Stimulation
Rapid referral essential
Do not take patient off OCP
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Timing
• Interval between surgery and chemotherapy was longer for patients undergoing IVF:
45.1 vs 33.5 daysAzim AA 2008 J Clin Oncol 26:2630‐2635
• Multiple studies have demonstrated no effect on survival or recurrence if chemotherapy was started ≤ 12 weeks after surgeryLohrisch C 2006 J Clin Oncol 24:4888‐4894Cold S 2005 Br J Cancer 93:627‐632
Embryo Cryopreservation vsvs
Oocyte Cryopreservation
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Embryo vs Oocyte Cryopreservation
• Both involve controlled ovarian stimulation
• Both require same amount of timeBoth require same amount of time
• Key difference is whether or not oocytes are fertilized at time of freezing
Source : http://womenshealthandfertility.blogspot.com/2012/07/a‐step‐by‐step‐guide‐to‐ivf‐process.html
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1. Embryo cryopreservation
Description
• Controlled Ovarian Stimulation oocyte retrieval IVF F ll bIVF Freeze all embryos
• Cancer pts: reduced response to Gonadotropin stim
Same amount of drug: 11.7 vs. 13.5 oocytes, P=.002
Friedler S., Fertil Steril ,2012
Success Rates
• Live births per frozen embryo transfer 16.9‐39.3%, depending on maternal age
SART, Success Rates, 2011
1. Embryo cryopreservation continued
Embryos can be frozen at several different stagesseveral different stages
http://www.readcube.com/articles
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1. Embryo cryopreservation continued
• Major benefit: Embryos are very resistant to freezing damage
• Post‐thaw survival: ~75‐95%
• Pregnancy rates for women <35: 40‐50%
• Depending on number of embryos frozen
– Possibility for multiple attempts at pregnancy
15‐year follow up of embryo cryo for fertility preservation
Barcroft, Journal of Assisted Reproduction and Genetics, 2013
UK StudyUK Study • 39 patients with frozen embryos (Mean age 31.9)
• 5 patients, 9 frozen‐thaw cycles, resulting in 2 live births
• 6 patients deceased, 3 conceived naturally, 2 couples separated, 14 discarded embryos, 22 have embryos remaining in cryostorage
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1. Embryo cryopreservation continued
Modifications – Estrogen‐sensitive tumors
During Controlled ovarian stimulation (COS), E2 levels can be 10‐15x physiologic levelsbe 10 15x physiologic levels
• Effect on tumor growth?
Aromatase inhibitor (letrozole) during COS
• Decrease estrogen exposure
• No impact on IVF outcomes Oktay, J Clin Endo Met, 2006y, ,
• Oncologic outcomesBreast ca pts no diff in recurrence rate and survival btw COS(+Letrozole)/IVF vs. no COS/IVF Azim AA., J Clin Oncol, 2008
Oocyte CryopreservationOocyte Cryopreservation
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2. Oocyte cryopreservation
History First human birth from frozen
i 1953sperm was in 1953
First human birth from frozen embryo was in 1984
First human birth from frozen oocyte in 1986—success was low due to fragile MII oocyte,low due to fragile MII oocyte, large size water content and meiotic spindle
http://3.bp.blogspot.com/_
Source: ASRM practice committee 2012
2. Oocyte cryopreservation continued
Slow Freeze VS Vitrification Technique Vit‐ultra‐rapid cooling to solidify
h ll l l kthe cell into a glass like state without the formation of ice
Survive the thaw better 81% vs 67%
Vitrification now used for oocytes embryos andfor oocytes embryos and ovarian tissue
http://3.bp.blogspot.comSource: ASRM practice committee 2012
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2. Oocyte cryopreservation continued
• RAPID advancement in oocyte freezing t h ltechnology
• Now >1000 children born worldwide
• Oocyte cryopreservation‐removed from experimental list by ASRM in October 2012
Source: ASRM Practice Committee Opinion 2012
Oocyte cryopreservation challenges
Theoretical concernDamage to metaphase spindle of oocyte risk ofDamage to metaphase spindle of oocyte risk of karyotypic abnormaliteis in offspring
Not observed to date; limited experience
Good option for single women who do not wish to use donor spermnot wish to use donor sperm
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Fertility preservation options
1. In Vitro Fertilization (IVF) with Embryo CryopreservationEmbryo Cryopreservation
2. Oocyte Cryopreservation
3. Ovarian Tissue Cryopreservation—adjunct oocyte maturation and cryopreservation
4. Medical (suppressive) therapy
5. Surgical therapy
3. Ovarian tissue cryopreservation
• No need for stimulation
• All egg containing follicles are in the outer gg g1mm of the ovarian tissue
20mm strips
• Strips can be examined for oocytes with the potential for In vitro Maturation (IVM)
• Still considered experimental
• Future option for pediatric/ adolescent patients
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http://www.repropedia.org/secondary-ovarian-follicle
http://www.businessinsider.com
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3. Ovarian tissue cryopreservation continued
• 9 transplants using ovarian tissue from identical twins
• 13 women live births after auto transplantation of cryopreserved ovarian tissue
Silber et al Fertility and Sterility 2010
Risk of reintroducing malignancy
Contraindication—Leukemia
Areas for concern— gastric or colorectalAreas for concern gastric or colorectal cancer, possibly endometrial cancer
Less concern—cervical, breast
Least concern—Lymphoma
Source: Bastings et al. Human reproduction Update. June 2013
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In vitro maturation (IVM) of oocytes
• Immature oocytes harvested— in situ, excised ovarian tissueovarian tissue
• Before freezing—implantation rates (10‐15%) significantly lower and early pregnancy losses higher than conventional IVF‐ICSISource: Smitz JE., Semin Reprod Med 2011
• After freezing—few pregnancies reported
4. Medical suppressive therapy
• GnRH agonists—induce ovarian quiescence and temporary menopause
• Studies are conflicting—2013 ASCO guidelines includedStudies are conflicting 2013 ASCO guidelines included changed recommendations stating:
“Currently, there is insufficient evidence regarding the effectiveness of gonadotropin releasing hormone analogs (GnRHa) and other means of ovarian suppression on fertility preservation. However, GnRHamay have other benefits such as reduced menstrualmay have other benefits such as reduced menstrual bleeding.”
• Might be an option if no other choice
• Beneficial side effects
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5. Surgical Therapy
Oophoropexy
• Surgically move ovaries out of radiation fieldSurgically move ovaries out of radiation field
• Requires elective surgery
• Radiation damage may spread beyond field
• Risk of ovaries migrating back to anatomic position
Unresolved Issues
• What is “safe” ovarian stimulation for hormonally sensitive cancers?
• How long can patients delay cancer therapy?
• When to attempt pregnancy after cancer?
• Are some cancers too advanced to consider this fertility preservation? y p
• Who should pay?
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Other areas of interest
Women of advancing age or those at risk of early ovarian failure
• Awareness is increasing
• Women are choosing to delay childbearing until later in their reproductive years
• Prevalence of infertility increases significantly after age 35 and by 45, 99% are infertile
• Options for Turner syndrome mosaics or• Options for Turner syndrome mosaics or Fragile X premutation carriersSource: Menken J et al, Science, 1986
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OOGENESIS TIME LINE
4-5 weeks MENOPAUSEPUBERTY20 weeks
BIRTH
1000 7 MILLION 2 MILLION 300,000 0
Source: Fritz and Speroff 8th Edition 2011
Figure 2
Source: Ata et al. Reproductive BioMedicine Online 2012(DOI:10.1016/j.rbmo.2012.02.009 )
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Oocyte cryopreservation
Vitrified oocytes
• 81% survive the thaw
• 74% fertilize
• 45% clinical pregnancy rate
• 36% live birth rate
• ~4% of thawed oocytes result i li bi thin a live birth
http://www.genea.com.
Oocyte cryopreservation
• 20 frozen oocytes
• 16 survive the thaw
• 12 embryos12 embryos
• 1st transfer 36/100
• 2nd transfer 59/100
• 3rd transfer 73/100
• 4th transfer 83/100
• 5th transfer 89/100/
• 6th transfer 93/100
• Calculates to needing 20‐25 oocytes for 1 live birth!!!
• This is with an average of age of 33 when oocyteswere frozen
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Considerations
• Planned age of childbearing
• Aneuploidy and risk of SAB• Aneuploidy and risk of SAB
• COST –average US cost $7,000‐12,500 per cycle of controlled stimulation with egg retrieval or cyropreservation
Source http://www.resolve.org/family‐building‐options/insurance_coverage/the‐costs‐of‐infertility‐treatment.html
Fertility preservation summary
• Rapid referral is essential
• Providers need to help patients understandProviders need to help patients understand fertility issues and provide on‐going education and information
• Long‐term follow up and hormone therapy is essential
• For women who wish to delay childbearing or of advancing age, refer for fertility counseling discussion
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Acknowledgements
• Dr. Mark Damario and Dr. William Phipps
• Dr. Jani Jensen
Questions??
Reproductive Medicine Center at the University of MinnesotaPhone: 612‐372‐7050
University of Minnesota Medical Center, FairviewRiverside Professional Building606 24th Ave. S, Suite 500 Minneapolis, MN 55454
http://www.umphysicians.org/Clinics/ReproductiveMedicineCenter/index htm#sthash lNz7Su3d dpufter/index.htm#sthash.lNz7Su3d.dpuf
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Resources
• American Society of Clinical OncologyFertility preservation Guidelines and Updatehttp://www asco org/institute‐quality/fertility‐preservation‐patients‐cancer‐http://www.asco.org/institute quality/fertility preservation patients canceramerican‐society‐clinical‐oncology
• Fertile Hopewww.fertilehope.org
• The Oncofertility Consortiumwww.myoncofertility.org
• American Society for Reproductive Medicine (ASRM)www.asrm.org
Summary of Citations• Alison W. Loren, Pamela B. Mangu, Lindsay Nohr Beck, Lawrence Brennan, Anthony J. Magdalinski, Ann H.
Partridge, Gwendolyn Quinn, W. Hamish Wallace and Kutluk Oktay. Fertility Preservation in Patients with Cancer: American Society of Clinical Oncology Guideline Update. Published online before print May 28, 2013, doi: 10.1200/JCO.2013.49.2678http://www.asco.org/institute‐quality/fertility‐preservation‐patients‐cancer‐american‐society‐clinical‐oncology
A B K l B D H Gl M O hl M T SL M é S A CGH l i h h• Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, Munné S. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online. 2012 Jun;24(6):614‐20. doi: 10.1016/j.rbmo.2012.02.009. Epub 2012 Feb 25.
• Aubard Y, Piver P, Pech JC, Galinat S, Teissier MP. Ovarian tissuecryopreservation and gynecologic oncology: a review. Eur J Obstet Gynecol Reprod Biol. 2001 Jul;97(1):5‐14. Review.
• Azim AA, Costantini‐Ferrando M, Oktay K. Safety of fertility preservation byovarian stimulation with letrozole and gonadotropins in patients with breastcancer: a prospective controlled study. J Clin Oncol. 2008 Jun 1;26(16):2630‐5.doi: 10.1200/JCO.2007.14.8700
• Barcroft J, Dayoub N, Thong KJ. Fifteen year follow‐up of embryos cryopreserved in cancer patients for fertility preservation. J Assist Reprod Genet. 2013 Jul 9. [Epub ahead of print]
• Bastings L, Beerendonk CC, Westphal JR, Massuger LF, Kaal SE, van Leeuwen FE, Braat DD, Peek R. Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review. Hum Reprod Update. 2013 Sep‐Oct;19(5):483‐506. doi: 0.1093/humupd/dmt020. Epub 2013 Jun 30.
• Bines J, Oleske DM, Cobleigh MA Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer .J Clin Oncol. 1996 May;14(5):1718‐29. Review.
• Cold S, Düring M, Ewertz M, Knoop A, Møller S. Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG). Br J Cancer. 2005 Sep19;93(6): 627‐32
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Summary of Citations• Friedler S, Koc O, Gidoni Y, Raziel A, Ron‐El R. Ovarian response to stimulation for fertility preservation in women with
malignant disease: a systematic review and meta‐analysis. Fertil Steril. 2012 Jan;97(1):125‐33. doi: 0.1016/j.fertnstert.2011.10.014. Epub 2011 Nov 10. Review.
• Fritz, M and Speroff, L. Clinical Gynecologic Endocrinology and Infertility. 8th Edition. Lipincott and Williams 2011. pgs 200‐201.
• Gosden RG Wade JC Fraser HM Sandow J Faddy MJ Impact of congenital orexperimental hypogonadotrophism on the• Gosden RG, Wade JC, Fraser HM, Sandow J, Faddy MJ. Impact of congenital orexperimental hypogonadotrophism on the radiation sensitivity of the mouse ovary. Hum Reprod. 1997 Nov;12(11):2483‐8.
• Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy.Endocrinol Metab Clin North Am. 1998 Dec;27(4):927‐43. Review.
• Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975‐2010, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER web site, April 2013.
• Jensen JR, Morbeck DE, Coddington CC 3rd. Fertility preservation. Mayo ClinProc. 2011 Jan;86(1):45‐9. doi: 10.4065/mcp.2010.0564. Review.
• Lohrisch C, Paltiel C, Gelmon K, Speers C, Taylor S, Barnett J, Olivotto IA.Impact on survival of time from definitive surgery to initiation of adjuvantchemotherapy for early‐stage breast cancer. J Clin Oncol. 2006 Oct20;24(30):4888‐94. Epub 2006 Oct 2.
• Menken J, Trussell J, Larsen U. Age and infertility. Science. 1986 Sep 26;233(4771):1389‐94. Erratum in: Science 1986 Oct 24;234(5775):413.
• Meirow D. Ovarian injury and modern options to preserve fertility in femalecancer patients treated with high dose radio‐chemotherapy for hemato‐oncological neoplasias and other cancers. Leuk Lymphoma. 1999 Mar;33(1‐2):65‐76. Review.
• Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on femalereproduction. Hum Reprod Update. 2001 Nov‐Dec;7(6):535‐43. Review
• Partridge AH, Ruddy KJ. Fertility and adjuvant treatment in young women with breast cancer. Breast. 2007 Dec;16 Suppl2:S175‐81. Epub 2007 Sep 4. Review
Summary of Citations• Practice Committees of American Society for Reproductive Medicine; Society for Assisted Reproductive
Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013 Jan;99(1):37‐43. doi: 10.1016/j.fertnstert.2012.09.028. Epub 2012 Oct 22.
• Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, Bang H. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before g p p g gchemotherapy. J Clin Endocrinol Metab. 2006 Oct;91(10):3885‐90. Epub 2006 Aug 1.
• Schover LR, Rybicki LA, Martin BA, Bringelsen KA. Having children after cancer: a pilot survey of survivors’ attitudes and experiences. Cancer. 1999; 86 (4): 697‐709.
• Silber S, Kagawa N, Kuwayama M, Gosden R. Duration of fertility after fresh and frozen ovary transplantation. Fertil Steril. 2010 Nov;94(6):2191‐6. doi: 10.1016/j.fertnstert.2009.12.073. Epub 2010 Feb 19.
• Smitz JE, Thompson JG, Gilchrist RB. The promise of in vitro maturation in assisted reproduction and fertility preservation. Semin Reprod Med. 2011 Jan;29(1):24‐37. doi: 10.1055/s‐0030‐1268701. Epub 2011 Jan 4. Review.
• Society for assisted reproductive technology y p gy(SART)https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0
• Sonmezer M, Oktay K. Fertility preservation in female patients. Hum ReprodUpdate. 2004 May‐Jun;10(3):251‐66. Review
• Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte.Hum Reprod. 2003 Jan;18(1):117‐21.
• Waring AB, Wallace WH. Subfertility following treatment for childhood cancer. Hosp Med. 2000 Aug;61(8):550‐7. Review.