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

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www.IVFauthority.com

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