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5/2/15
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Marcelle I. Cedars, M.D. Professor and Director
Division of Reproductive Endocrinology and Infertility
Disclosures
� Research Funding – investigator initiated � Ferring Pharmaceutical
� Off-‐label drug usage � letrozole
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Learning Objec2ves � At the completion of this presentation, the practitioner should be able to: � Counsel women regarding impact of aging on fertility
� Use evidence-‐based approaches to ovulation induction
� Develop a cost-‐effective treatment strategy
Reproduc2ve Aging -‐ Quan2ty
Conception
Fetal Life
12 wks 20 wks
PGCs~1,000
PGC migration& proliferation5-7 million
Birth
1 million oocytes/follicles
Puberty Age ~12
Ovulation begins500,000 oocytes
Age ~37Menopause
Age ~51
Fertility declines~25,000 ooyctes Ovulation ends
<1,000 ooyctes
oogonia entermeiosis & differentiate
Figure 1. The life history of a woman’s oocyte endowment, from conception to menopause. The life history of a woman’s oocyte endowment
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Reproduc2ve Aging: Quan2ty vs. Quality � Quantity: decline in follicle number ultimately leads to menopause
� Quality: decreased implantation potential � Increase in meiotic non-‐disjunction
� “Production-‐line” theory � Accumulated damage � Deficiencies of the granulosa cell function
Concurrent Loss of Quan2ty and Quality
Broekmans FJ 2009
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Rosen MP, Fertil Steril 2010
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An2-‐mullerian Hormone (AMH) � Member of the TGFβ super-‐family of growth and differentiation factors
� Secreted by the granulosa cells of pre-‐antral and early antral follicles
� Inhibitory effect on recruitment of primordial follicles
� Inhibitory effect on follicular sensitivity to FSH
Follicular development and the role of AMH
Broer SL, Hum Reprod 2013
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AMH vs. AFC
AMH = 0.2305*AFC - 0.0363
0
5
10
15
20
0 5 10 15 20 25 30 35 40 45 50
AMH (ng/mL)
Total AFC
Modeling AMH
Kelsey TW, 2011 PLoS One
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Importance of Rate of change
Freeman EW, 2012 Fertil Steril
Rate of loss for low vs. high baseline count
05
1015
2025
3035
4045
AFC
25 30 35 40 45Age (years)
Low AFC fitted Low AFCHigh AFC fitted High AFC
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Impact of contracep2ve
Kallio S 2013
So can AMH predict future fer2lity? � Estimate of current “ovarian reserve”
� Estimate of maximal response with stimulation � Correlates with number of oocytes remaining
� Cannot predict rate of loss moving forward � Does not reflect quality – likelihood for pregnancy � Even with assisted reproduction
� Age trumps everything
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Age: the “other” biomarker � Natural fecundity declines with increasing age
� National Survey of Family Growth -‐ 23% reduction in fecundability among women ages 35-‐40 compared to women ages 20-‐24 years of age (FR 0.77, 95% CI 0.62-‐0.97).
� Chronologic age is an excellent predictor of fertility among infertile women undergoing ART. � Centers for Disease Control (147,260 fresh, non-‐donor cycles) � success rates are relatively stable until age 34 but decline
linearly until they approach 0% after 44 years of age. � Meta-‐analysis (5705 women undergoing ART)
� for every one year increase in age -‐ the probability of conceiving in an ART cycle decreases by 6% (OR 0.94, 95% confidence interval (CI):0.89-‐0.99).
Assessing ovarian reserve � In the normal cycling reproductive age female
� Age of maternal menopause � Cycle interval � Prior surgery/endometriosis � STOP smoking
� High risk women � Consider AMH � If on OCPs – must stop at least one month
� Who should preserve oocytes?
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O
Oocyte Cryopreservation Time Line
1986 First report of live birth
from cryo’d egg
2007 Experi-‐mental label given to
oocyte cryo-‐ by
ASRM
2010’s Evidence of improved success rates
Increased use for
cancer and some
elective cryo
2012: 50% of clinics report offering cryo of eggs
2013 Experi-‐mental Label
removed by ASRM
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Impact of Age: Individual patient data Meta-‐analysis
Meta-‐analysis of 2,265 cycles from 1,805 patients freezing surplus oocytes due to legal or ethical concerns
Cil et al Fertility and Sterility 2013
Why success rates decline with age � Intrinsic decline in oocyte health with aging
� Risk to the spindle with freezing � Oocytes from older women likely at greater risk
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Ques2ons about oocyte cryopreserva2on � Is there an ideal age for a woman to freeze her eggs?
� Will freezing eggs make women too complacent? -‐-‐ Will women assume they have a “guaranteed baby” in the freezer? -‐-‐ How will this impact women’s decision making about life choices?
� Should all nulliparous women of a certain age be informed about this technology by health care professionals?
How do we counsel? � Success rate per cycle? � Success rate per transfer? � Success rate per oocyte?
� Fertile patients (s/p BTL) � Kim 2010 � 15 oocytes/live birth � 11 mature oocytes/live birth
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Social egg freezing � Societal trends encourage later childbearing � Women remain relatively unaware of reality of fertility decline
� Oocyte Cryopreservation with vitrification has shown increasing promise as a means of fertility preservation
� Ideal age for oocyte cryopreservation is by mid-‐thirties
� Much remains to be learned about how this technology should be used.
Wall Street Journal – May 2012
Essay Why I Froze My Eggs (And You Should, Too) Amid all the talk of 'leaning in' and 'having it all,' we've ignored the most powerful gender-‐equalizer.
By Sarah Elizabeth Richards
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Ovulation Induction
PCOS: Overview § Characterized by oligo-‐ovulation, hirsutism, polycystic ovaries
§ 5-‐10% Reproductive age females § Pathogenesis unclear:
-‐ Androgen -‐ Insulin -‐ Pituitary
� Familial clustering: genetic etiology ?
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Reproduc2ve Medicine Network
Legro et al. NEJM 2007; 35:551-‐66
• Multicenter
• Double blind
• 626 women with PCOS
Clomiphene Metformin Both
Randomized
Results of RMN trial -‐ PPCOS
0%
10%
20%
30%
40%
50%
60%
OVULATION Conception Livebirth Pregnancy loss
Metformin Clomid Both
P<.001
P<.001
P<.001
Legro et al. NEJM 2007; 35:551-‐66
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Pregnancy in Polycys2c Ovary Syndrome II, a Mul2-‐center Randomized Clinical Trail (PPCOS II)
� Primary hypothesis: Ovulation induction with letrozole is more likely to result in live birth than ovulation induction with clomiphene citrate (CC)
RMN trial: Clomiphene vs. Letrozole
Legro RS, NEJM 2014
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AMH in PCOS � By definition (AMH correlates with antral follicle count-‐ AFC) AMH levels are high in women with PCOS � Known increased risk for OHSS with stimulation BUT � Is there clinical significance to this value for mono-‐follicular development
Impact on AMH on response to ovula2on induc2on � Exogenous FSH
� Genro VF, Hum Reprod 2010 � Koninger A, Hum Reprod 2013 � Amer SA, Reprod Bio and Endocrinol 2013
� Endogenous FSH (clomiphene citrate) � Mahran A, J Clin Endocrinol Metab 2013
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AMH levels Ovulation Clomiphene
citrate Letrozole
1st dose AMH 5.48 (3.40, 9.00) 4.77 (2.83, 7.51)
2nd dose AMH 5.74 (3.48, 9.30) 7.33 (4.04, 11.43)
3rd dose AMH 6.98 (4.14, 9.36) 6.33 (3.94, 10.08)
Never AMH 6.96 (4.47, 12.64) 8.08 (4.08, 12.63)
Failure to Conceive � Treat as “unexplained infertility”
� Confirm tubal patency � Confirm normal sperm function
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Failure to ovulate � Exogenous gonadotropins
� Normal stimulation -‐ risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy
� “low-‐slow” gonadotropin � Sequential -‐ CC/letrozole-‐ gonadotropin
� Ovarian “drilling” � surgical
� ART � Avoid OHSS by newer stimulation protocols (use of agonist for endogenous LH surge)
� Avoid multiple pregnancy by retrieval and eSET
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Unexplained infer2lity � Evidence of ovulation
� Regular, cyclic, predictable menses � Evidence of tubal patency
� HSG � Saline hystero-‐sonogram with tubal flow
� Evidence of adequate sperm contribution � Concentration > 16M/mL � Motility > 50% � TMC > 20M
Unexplained infer2lity Treatment op2ons
� Increase number of follicles � Improve endocrine environment
� Clomiphene citrate (letrozole) +IUI � Gonadotropins + IUI � ART
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Time to pregnancy – the FASTT
Reindollar RH, 2010
Cost-‐effec2veness -‐ FASTT
Reindollar RH, 2010
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The FORT-‐T (ages 38-‐42)
Goldman MB, 2014
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Pre-‐implanta2on gene2c screening (PGS) – prevalence of aneuploidy by age
Franasiak JM, 2014 Age (years)
Randomized controlled trial -‐ PGS
Scott RT, 2013
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Cumula2ve LBR – age 38-‐42 assuming up to 2 ETs � Cumulative LBR
� Accounting for no embryos to transfer (PGS or Non-‐PGS group) � Accounting for no euploid embryos (PGS group)
� PGS: 67% � Non-‐PGS: 68%
What does PGS do? � Decreases negative pregnancy test � Decreases loss rate � Shortens time to conception
� Cost effectiveness not known � Potential negative impact of blast culture and/or biopsy not known
� Limited data re: error rate with diagnostics
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Summary � No prospective marker of FUTURE fertility potential � Age trumps everything � Oocyte cryopreservation – viable but expensive option for women delaying childbearing
� PCOS � No role for metformin � Start with letrozole
Summary � Unexplained infertility
� CC – IUI then to IVF � ? Treatment for older reproductive age
� Time vs. finances
� ART and the role for genetic screening � For all? � For older patients? � Need for trials randomized at retrieval taking all patients
