SELECTING THE IDEAL STIMULATION PROTOCOL: A CRITICAL DETERMINANT
OF IVF OUTCOME
GEOFFREY SHER M.D.GEOFFREY SHER M.D.
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SELECTING THE IDEAL PROTOCOL FOR OVARIAN STIMULATION
THE MOST IMPORTANT DETERMINANT OF IVF OUTCOME:
Day 2 - Cleaved Embryo
Day 3 - 8-Cell Embryo
16-18 Hrs. Post Fertilization
Day 5-6: Expanded Blastocyst
Fisch et al., 2001
Embryo Development
A competent (euploid) embryo has 46 chromosomes &
can propagate a healthy baby
Embryo “Competence”
An incompetent (aneuploid) embryohas an irregular quota of
chromosomes & cannnot propagate a healthy baby
Embryo “Competence”
It is primarily the egg, rather than the sperm, that determines
embryo “competence”!
IMMATURE EGG (M-1)
MATURE EGG (M-2)
MeiosisMeiosis
Intracytoplasmic Sperm injection (ICSI)
Blastocysts (Hatching)
EMBRYO ANEUPLOIDY
THE RATE LIMITING FACTOR IN HUMAN
REPRODUCTION!
No embryology laboratory can yield “competent” quality embryos out of
“aneuploid” eggs!
Factors in IVF that Govern Embryo Aneuploidy
Woman’s age
Protocol for controlled ovarian stimulation (COS)
Embryology Laboratory
Determining the Best Protocol for Controlled Ovarian Stimulation
1. Age
2. Ovarian Reserve (FSH/AMH/inhibin-B)
3. Previous Response to COS
Orchestration of Follicle/Egg Development
IN THE STROMA:LH promotes production by stroma/theca of male hormone
(androgen)
IN THE FOLLICLE:FSH converts testosterone to estradiol
THE EGG IS THE CONDUCTOR OF FOLLICLE EVENTS
Granulosa Cells(Produce Estrogen)
Stroma/Theca(Produces Androgen)
Follicle
Egg
Ovary
Role of Ovarian Male Hormones (Androgens)
A small amount testosterone is essential for follicle and egg development
Excessive testosterone is a cause of poor follicle and egg development.
Who is Most Vulnerable to Excessive Androgens?
Older Women
Women with ovarian Lesions (cysts, endometriomas & tumors)
Women with polycystic Ovarian Syndrome (PCOS)
Effects of Excessive Androgens
Poor-follicle development (premature luteinization, “empty” follicles)
Poor- egg/embryo quality (increased aneuploidy)
Poor- endometrial development
Poor-endometrial development and implantation rate
Poor -IVF Success
What leads to Increased Exposure to Androgens?
HIGH LH
INAPPROPRIATE OVARIAN STIMULATION
PROTOCOLS
OVARIAN LESIONS
ANDROGEN ADMINISTRATION
Age Ovarian resistance / failure PCOS
“Flare protocols” Clomiphene Menotropins
Endometriomas Functional cysts Tumors
Testosterone DHEA?
How to Limit Exposure to Androgens
Limit exposure to exogenous LHUse purified FSH
Treat ovarian lesions pre-COSEndometriomasCysts
Suppress endogenous LH pre-COSUse “long” GnRH agonist / antagonist
protocols (esp. in DOR and PCOS)Avoid “flare” protocols (esp. in DOR & PCOS)Avoid Clomid/Femara
Drugs Used for Ovarian Stimulation
Clomid/Femara
Gonadotropins (Folistim, Puregon, Gonal-F ,Bravelle, Menopur)
Agonists (Lupron, Superfact)
Antagonists (Ganirelix, Cetrotide, Orgalutron) hCG (Pregnyl, Profasi, Novarel, Ovidrel)
Estrogen (I.M. estradiol valerate, estrogen skin patches, oral estrace)
Long Pituitary Agonist-Down-Regulation Protocol
Menses
Agonist (Lupron/Buserelin)
Menses
10 days + 5-10 days
FSH(Follistim/Gonal-F/Puregon)
hCG 10,000UOvidrel 500mcg
7-14(+) days
Agonist/ Antagonist Conversion Protocol (A/ACP)
Menses
BCP
Agonist (Lupron/
Buserelin)
Menses
Antagonist(Ganirelix/Cetrotide/Orgalutron)
10 days + 5-10 days
FSH(Follistim)
7-14 (+) days
FSH +HMG
(Menopu)
hCG 10.000UOvidrel 500mcg
Short Agonist (Micro) “Flare” Protocol
Spontaneous Menstruation
Agonist (Lupron/Buserelin)
FSH(Follistim/Gonal-F/Puregon)
hCG 10,000UOvidrel 500mcg
7-14(+) days
Short Antagonist Protocol
Menses
Antagonist(Ganirelix/’Cetrotide/Orgalutron)
Day 6-8
FSH(Follistim/Gonal-F/Puregon)
hCG 10,000UOvidrel 500mcg
Mini-IVF / EZ-IVF
Menses
Day 2 Day5
Clomiphene/Femara
7-10 (+) days
(Menotropin)+/-
hCG 10.000UOvidrel 500mcg
Natural Cycle IVF
Menses
Day 1 Day 10
(Monitoring) US/ blood LH
+/-hCG 10.000UOvidrel 500mcg
Additional Considerations
1. Under-response A/ACP+E2V Human Growth hormone DHEA Egg Donor
2. Over-response (Hyperstimulation - OHSS) “Prolonged Coasting”
3. Thin Uterine Lining Viagra
4. Premature Luteinization (“Premature LH Surge”)
5. “Empty Follicle” Syndrome
Under-Response
A/ACP + E2V Human Growth Hormone (HGH)? DHEA?? Egg Donor
Agonist/ Antagonist Conversion with Estrogen Priming (A/ACP+ E2V)
Menses
BCP
Agonist (Lupron/
Buserelin)
Menses
Antagonist(Ganirelix/Cetrotide/Orgalutron)
10 days+ 5-10 days
Estrogen (E2V)
Priming
FSH(Follistim)
7-10 days
FSH +Menotropin(Menopur)
hCG
5 days 4-14 days
Who Can Benefit from A/ACP + E2V?
1. Advanced Maternal Age: (41+)
2. Women With Decreased Ovarian Reserve: (AFC/AMH/FSH)
Over-Response/Hyperstimulation (OHSS)
“Prolonged Coasting”
Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) through “Prolonged Coasting”
Agonist
STOP FSH!!Initiate “coasting”
>25 follicles (50%=14MM+)E2 = >2500pg/ml E2=<2500pg/ml
FSH
7-10 days 2-5days 36 hrs
Stop ER “coast” + hCG-10,000U
A THIN UTERINE LINING & VIAGRA
1. Endometritis
2. Surgical
3. Clomiphene
4. DES
5. PCOS
6. Reduced uterine blood flow Age Adenomyosis fibroids
Endometrial Lining (Pre-Viagra)
Endometrial Lining (Post-Viagra)
Triggering Ovulation 36 Hrs. Prior to ER
hCGu 10,000 IU (Pregnyl/Profasi/Novarel)hCGr (Ovidrel), if used ideally should be 500mcg.Criteria:
2 lead follicles at least 18mm in diameter1/2 of total number of follicle at least 15mm in
diameterEndometrial lining at least >9mm with trilaminar
pattern
Thank You!
If you would like to schedule a
consultation with Dr. Sher,
please call 1-800-780-7437
Read Dr. Sher’s Blog at:
www.IVFauthority.com
SIRM Website: www.haveababy.com
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