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Gonadotropins in ART: patterns of use, trends in success rates, and assessing efficacy endpoints. Jim Toner, MD, PhD Atlanta Center for Reproductive Medicine. IVF’s beginnings. Louise Brown born July 25, 1978 First IVF baby worldwide

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Gonadotropins in art patterns of use trends in success rates and assessing efficacy endpoints l.jpg

Gonadotropins in ART:patterns of use, trends in success rates, and assessing efficacy endpoints

Jim Toner, MD, PhD

Atlanta Center for Reproductive Medicine


Ivf s beginnings l.jpg
IVF’s 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


Progress l.jpg
Progress

  • 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


Simpler treatments l.jpg
Simpler 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


New therapies l.jpg
New therapies

  • Sperm problems: ICSI(Intracytoplasmic sperm injection)

  • Egg problems: Donor Egg

  • Uterine problems: Gestational carrier

  • Surplus embryos: Cryopreservation

  • Genetic problems: PGD(Preimplantation genetic diagnosis)


Innovations l.jpg
Innovations

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


Fertility meds in u s l.jpg
Fertility meds in U.S.

hMG

u-FSH

u-HP-FSH

r-FSH

1970 1980 1990 2000

Lupron

Antagonists


Stimulation trends in u s l.jpg
Stimulation 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


Slide9 l.jpg

Clinics

Cycles & Deliveries




Icsi to overcome male factor l.jpg
ICSI to overcome Male Factor

Fertil Steril 78:943-50, 2002.



Fewer multiple pregnancies l.jpg
Fewer Multiple Pregnancies

Quadruplet delivery rates

Triplet delivery rates

Fertil Steril 78:943-50, 2002.



Recipient age effects l.jpg
Recipient age effects

17,339 cycles; US 1996-1998


Us versus europe ivf 1998 l.jpg
US versus EuropeIVF, 1998

+9.1

+10.8

+9.8

Fertil Steril 78:943-50, 2002.


Progress19 l.jpg
Progress

  • 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 78:943-50, 2002.


Basis for controlled ovarian hyperstimulation coh l.jpg
Basis 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


Egg supply dictates ovarian reserve l.jpg
Egg supply dictates Ovarian Reserve

Log

(# eggs)

0.001% of 100,000 =

100

0.001% of 10,000 =

10

0.001% of 1,000 =

1


Stimulation depends on reserve l.jpg
Stimulation 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



Gonadotropin dose effects l.jpg
Gonadotropin 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


Slide25 l.jpg

The 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”


Slide26 l.jpg

The 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”


Microdose flare cycle low responders l.jpg
“Microdose Flare” cycle -low responders

BCPs x 14 days (start @ menses)

Gonadotropins

menses

Dilute Lupron


Antagonist cycle average responders l.jpg
”Antagonist” cycle-average responders

BCPs x 14 days (start @ menses)

Gonadotropins

menses

menses

GnRHa once 14mm


Slide29 l.jpg

“Luteal Suppression” cycle

-high responders

Gonadotropins

menses

menses

+/- BCPs x 21 days (start @ menses)

Lupron 


Slide30 l.jpg

Typical progression

16 follicles

14 eggs

12 mature eggs

& sperm

9 fertilize normally

2 to 5 transferred

5 divide normally

Extras frozen if good

4 stop dividing

30-40% of couples


Qualitative effects l.jpg
Qualitative 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


Qualitative effects illustrated age affects pregnancy but not in vitro development l.jpg
Qualitative effects illustratedAge affects pregnancy, but not in vitro development

Day 0 Day 1 Day 3 Day 5


Decreasing embryo quality l.jpg
Decreasing embryo quality

% of

embryos

that yield

pregnancy

Age of woman

Kooij et al., F&S 66:769-75, 1996


Quantitative and qualitative effects l.jpg
Quantitative and Qualitative Effects

Ovarian Quantity

reserve (#)

Pregnancy

Rate

Age Quality

(Impl.Rate)

EGGS



General strategy l.jpg
General 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)


Assessing gonadotropin efficacy l.jpg
Assessing Gonadotropin efficacy

  • Both FSH and LH play critical and complementary roles

  • FSH necessary for:

    • Folliculogenesis

    • Limited steroidogenesis

  • LH necessary for:

    • Estrogen production

    • ‘Healthy’ folliculogenesis


The goldilocks principle l.jpg
The Goldilocks principle:

- for normal folliculogenesis,

LH has to be ‘just right’, neither

‘too much’ nor ‘too little’


Factors besides fsh dose that affect egg production confounders l.jpg
Factors 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


Slide40 l.jpg

GnRH analogs (‘confounders’)

pharmacological

physiological

GnRH agonist

FSH

& LH

Pulsatile GnRH

GnRH

FSH LH

GnRH antagonist

FSH

& LH

FSH

& LH


Effect of increasing ganirelix doses on clinical outcomes l.jpg

Ganirelix (‘confounders’)(mg/d) 0.0625 0.125 0.25 0.5 1.0 2.0

LH (IU/L) 3.6 2.5 1.7 1.0 0.6 0.4

E2 (pg/mL) 1475 1130 1160 823 703 430

# Eggs 9.0 9.5 10.0 8.8 9.3 8.6

# Good embr. 3.8 3.3 3.3 2.5 3.3 3.5

Effect of Increasing Ganirelix Doses on Clinical Outcomes

n = 333

%

Ganirelix Study Grp. Hum Reprod 1998;13:3023


Metformin ivf in pco patients l.jpg
Metformin & IVF in PCO patients (‘confounders’)

Stadtmauer et al., Fertil Steril 2001; 75:505


Retrieval efficiency differs l.jpg
Retrieval efficiency differs (‘confounders’)


Endpoint considerations many factors affect outcomes l.jpg
Endpoint considerations (‘confounders’)-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

Eggs

Embryos

Pregnancy

Delivery

Maturity of eggs

Sperm supply

Fertilization

Culture 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


Factors besides fsh dose that affect pregnancy outcome confounders l.jpg
Factors 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


Embryo appearance an imperfect predictor age affects pregnancy but not in vitro development l.jpg
Embryo appearance an imperfect predictor (‘confounders’)Age affects pregnancy, but not in vitro development

Day 0 Day 1 Day 3 Day 5


Slide47 l.jpg

“Day 3” embryos (‘confounders’)

20-30% implantation rate

8c, gr 1.0

8c, gr 3.0

8c, gr 2.0


Slide48 l.jpg

Blastocysts (‘confounders’)

40-50% implantation rate

Trophectoderm

ICM


Evaluation of cavity l.jpg
Evaluation of cavity (‘confounders’)


Fsh and fertility in ivf50 l.jpg
FSH and fertility in IVF (‘confounders’)

FSH level:


Endpoint considerations predictability of outcomes decreases at each step l.jpg
Endpoint considerations (‘confounders’)-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

Eggs

Embryos

Pregnancy

Delivery

R2 = 11.3% 4.2% 0.6% 0.8%

Toner et al., F&S 55:784, 1991


Endpoint considerations proportions vs frequencies l.jpg
Endpoint considerations: (‘confounders’) -Proportions vs. Frequencies


Benefit of high ovarian response often not apparent in fresh cycle l.jpg
Benefit of high ovarian response often (‘confounders’)not apparent in fresh cycle

Toner et al., Hum Reprod 6:284, 1991


Endpoint considerations many factors affect outcomes54 l.jpg
Endpoint considerations (‘confounders’)-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

Eggs

Embryos

Pregnancy

Delivery

Maturity of eggs

Sperm supply

Fertilization

Culture 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


Pre retrieval markers of efficacy l.jpg
Pre-retrieval markers of efficacy? (‘confounders’)

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?


Considerations l.jpg
Considerations (‘confounders’)

  • 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


Consideration l.jpg
Consideration (‘confounders’)

  • 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