Title: Gonadotropins in ART: patterns of use, trends in success rates, and assessing efficacy endpoints
1Gonadotropins in ARTpatterns of use, trends in
success rates, and assessing efficacy endpoints
- Jim Toner, MD, PhD
- Atlanta Center for Reproductive Medicine
2IVFs beginnings
- Louise Brown born July 25, 1978
- First IVF baby worldwide
- Pioneering work of Robert Edwards Patrick
Steptoe, England - Elizabeth Carr born December 28, 1981
- First American IVF baby
- Drs Howard Georgeanna Jones, Norfolk
3Progress
- Improving success rates
- Lower rates of multiple pregnancies
- New therapies
- Simpler therapies
- Flexibility of American system
- Advantage compared to Europe
- Risk of impeded progress with regulation
4Simpler treatments
- Laparoscopic egg retrieval
- Now transvaginal ultrasound-guided
- Laparoscopic replacement of eggs/embryos
- Now transcervical embryo transfer
- Daily monitoring of response
- Now every few days during stimulation
- Intramuscular injections of hormones
- Now many given subcutaneously
5New therapies
- Sperm problems ICSI (Intracytoplasmic sperm
injection) - Egg problems Donor Egg
- Uterine problems Gestational carrier
- Surplus embryos Cryopreservation
- Genetic problems PGD (Preimplantation genetic
diagnosis)
6Innovations
Clinical Pregnancy / Transfer
X
Nuclear Transfer
X
Cytoplasmic Transfer
PGD
Hatching
ICSI
Subzonal Insertion
Partial Zona Dissection
X
Co-Culture
ZIFT
GIFT
Donor Egg
Cryopreservation
7Fertility meds in U.S.
hMG
u-FSH
u-HP-FSH
r-FSH
1970 1980 1990 2000
Lupron
Antagonists
8Stimulation trends in U.S.
Natural cycle
2 hMG
4-6 hMG/FSH
Pure FSH
hMG/FSH
1970 1980 1990 2000
OCPs
Agonist flare
Antagonists
Agonist suppression
9Clinics
Cycles Deliveries
10U.S. success rates
11GIFT and ZIFT
12ICSI to overcome Male Factor
Fertil Steril 78943-50, 2002.
13Multiples
14Fewer Multiple Pregnancies
Quadruplet delivery rates
Triplet delivery rates
Fertil Steril 78943-50, 2002.
15Strong effect of womans age
16(No Transcript)
17Recipient age effects
17,339 cycles US 1996-1998
18US versus EuropeIVF, 1998
9.1
10.8
9.8
Fertil Steril 78943-50, 2002.
19Progress
- Improving success rates
- Lower rates of multiple
- pregnancies
- New therapies
- Simpler therapies
- Flexibility of American system
- Advantage compared to Europe
- Risk of impeded progress with regulation of
therapy
Fertil Steril 78943-50, 2002.
20Basis for Controlled Ovarian Hyperstimulation
(COH)
- Potential for multiple eggs / cycle
- Individual variation in ability to produce
multiple eggs / cycle - Different levels of Ovarian Reserve
- Management of those with differing Ovarian
Reserves - Implications for assessing gonadotropin efficacy
21Egg supply dictates Ovarian Reserve
Log ( eggs)
0.001 of 100,000 100
0.001 of 10,000 10
0.001 of 1,000 1
22Stimulation depends on reserve
Ideal for IUI
Ideal For IVF
Low reserve --Flare / hi dose
Average reserve --Antag / mid dose
High reserve --Luteal / low dose
NOTE inverse correlation between dose and
response across patients
23Estimating Ovarian Reserve
24Gonadotropin dose effects
- Dosage directly affects ovarian response (within
a fixed level of Ovarian Reserve) - Among High responders, stronger stimulation
yields more eggs - Dosage chosen is inversely correlated with
Ovarian Reserve - Low responders Strong stimulation
- High responders Gentle stimulation
25The process of IVF
Preparatory Phase
Stimulatory Phase
Egg Embryo
hCG Retrieval Transfer
menses
menses
Birth control pills
Ovarian stimulation (FSH LH injections)
1 2 3 10
12 15 -- 17
plus one of the following
Luteal phase Lupron
Microdose Flare
Antagonist
26The process of IVF
Preparatory Phase
Stimulatory Phase
Egg Embryo
hCG Retrieval Transfer
menses
menses
Birth control pills
Ovarian stimulation (FSH LH injections)
1 2 3 10
12 15 -- 17
plus one of the following
Luteal phase Lupron
Microdose Flare
Antagonist
27Microdose Flare cycle -low responders
BCPs x 14 days (start _at_ menses)
Gonadotropins
Dilute Lupron
menses
28Antagonist cycle -average responders
BCPs x 14 days (start _at_ menses)
Gonadotropins
GnRHa once 14mm
menses
menses
29Luteal Suppression cycle -high responders
Gonadotropins
menses
menses
/- BCPs x 21 days (start _at_ menses)
Lupron ?
30Typical progression
16 follicles
14 eggs
12 mature eggs
sperm
2 to 5 transferred
9 fertilize normally
5 divide normally
Extras frozen if good
4 stop dividing
30-40 of couples
31Qualitative effects
Eggs
85 70 60 50
32 y/o 42 y/o
Mature Eggs
60 20 50 10
Fertilized Eggs
Pregnancy
Good day 3 Embryos
Delivery
Good day 5 Embryos
32Qualitative effects illustratedAge affects
pregnancy, but not in vitro development
Day 0 Day 1
Day 3 Day 5
33Decreasing embryo quality
of embryos that yield pregnancy
Age of woman
Kooij et al., FS 66769-75, 1996
34Quantitative and Qualitative Effects
Ovarian Quantity reserve ()
Pregnancy Rate Age Quality
(Impl.Rate)
EGGS
35FSH and fertility in IVF
FSH level
36General Strategy
- Adjust stimulation to the predicted ovarian
reserve so as to produce 10 to 20 eggs (no matter
the age) - Adjust number of embryos to be transferred
according to their predicted quality (as judged
by maternal age and morphology)
37Inverse correlations
Eggs () and implantation rates ()
Stimulation strength
Hull et al., FS 65787, 1996
38Assessing Gonadotropin efficacy
- Both FSH and LH play critical and complementary
roles - FSH necessary for
- Folliculogenesis
- Limited steroidogenesis
- LH necessary for
- Estrogen production
- Healthy folliculogenesis
39The Goldilocks principle
- for normal folliculogenesis, LH has to be
just right, neither too much nor too little
40Factors besides FSH dose that affect egg
production (confounders)
- LH tone during stimulation
- Dose of GnRH analogs
- Use of BCPs in prior cycle
- Use of hMG vs FSH
- Use of metformin
- Use of hCG
- MD doing retrieval
41GnRH analogs
pharmacological
physiological
GnRH agonist
FSH LH
Pulsatile GnRH
GnRH FSH LH
GnRH antagonist
FSH LH
FSH LH
42Effect of Increasing Ganirelix Doses on Clinical
Outcomes
n 333
Ganirelix Study Grp. Hum Reprod 1998133023
43Agonist vs Antagonist-luteal control in both
cases
Olivennes, FS 73314,2000.
44LH in folliculogenesis
- LH in late follicular phase
- is sufficient without any FSH to sustain growth
of large but not small follicles - suppresses growth of small follicles in presence
of continued FSH - less luteinizing than is FSH at this stage
Filicori
45Metformin IVF in PCO patients
Stadtmauer et al., Fertil Steril 2001 75505
46Retrieval efficiency differs
47Endpoint considerations-many factors affect
outcomes
Influences on quality Maternal age
Prior quality Influences on quantity
Ovarian reserve Strength of stimulation
--LH tone --Metformin use --OC
pretreatment --GnRH analog use
--Gonadotropin dose --hCG administration
Delivery
Pregnancy
Embryos
Eggs
Maturity of eggs Sperm supply Fertilization Cultur
e condition
Quality of embryo Health of embryo Day of
transfer Method of transfer Number
transferred Luteal support
Quality of embryo Health of embryo Health of
sperm Luteal support
48Factors besides FSH dose that affect pregnancy
outcome (confounders)
- Egg / embryo quality
- Number transferred
- Stage of transfer
- Quality of transfer
- Normalcy of uterine cavity
- Luteal support
49Embryo appearance an imperfect predictorAge
affects pregnancy, but not in vitro development
Day 0 Day 1
Day 3 Day 5
50Day 3 embryos 20-30 implantation rate
8c, gr 1.0
8c, gr 3.0
8c, gr 2.0
51 Blastocysts 40-50 implantation rate
Trophectoderm
ICM
52Evaluation of cavity
53FSH and fertility in IVF
FSH level
54Endpoint considerations-predictability of
outcomes decreases at each step
Influences on quality Maternal
age Influences on quantity Basal FSH
R2 3.6 2.5 0.6 0.6
Ovarian Stimulation
Delivery
Pregnancy
Embryos
Eggs
R2 11.3 4.2 0.6
0.8
Toner et al., FS 55784, 1991
55Endpoint considerations -Proportions vs.
Frequencies
56Benefit of high ovarian response often not
apparent in fresh cycle
Toner et al., Hum Reprod 6284, 1991
57Endpoint considerations-many factors affect
outcomes
Influences on quality Maternal age
Prior quality Influences on quantity
Ovarian reserve Strength of stimulation
--LH tone --Metformin use --OC
pretreatment --GnRH analog use
--Gonadotropin dose --hCG administration
Delivery
Pregnancy
Embryos
Eggs
Maturity of eggs Sperm supply Fertilization Cultur
e condition
Quality of embryo Health of embryo Day of
transfer Method of transfer Number
transferred Luteal support
Quality of embryo Health of embryo Health of
sperm Luteal support
58Pre-retrieval markers of efficacy?
- Since eggs retrieved depends on hCG and MD
retrieval efficiency, is there an earlier time to
evaluate efficacy? - Follicle number and growth (FSH)
- Estradiol production (LH)
- Inhibin?
59Considerations
- FSH efficacy follicle growth.
- LH efficacy estradiol / follicle.
- Using pregnancy as primary endpoint instead
- Increases sample size needed
- Obscures benefit of high response (since any
extra embryos will be frozen, not transferred) - Confounded by other strong influences, such as
maternal age, sperm quality, lab quality,
transfer technique, and luteal support
60Consideration
- Examine follicle growth and estradiol production
as measure of gonadotropin efficacy - Within a defined age and Ovarian Reserve status
- Within a defined Stimulation strength
- Measure number and size of follicles at hCG
trigger, number of total and mature eggs
retrieved, and estradiol levels