Managment

Ovarian Stimulation An

overview

BY

Mohammad A. Emam

Prof. of Obstetrics and Gynecology

Mansoura Faculty of Medicine

Mansoura Integrated Fertility center (MIFC)

EGYPT 2005

www.ivfmifc.com

Indications

• Some cases of primary amenorrhea.

• Some cases of POF.

• Some cases of delayed puberty.

• Infertility ( anovulatory or ovulatory cycles).

Objective



• To highlight the

rationale , philosophy

and different protocols

of ovarian stimulation in

cases of infertility

Introduction



• First child, Louise brown 1978 was the

product of ovulation in a sopontaneous

cycle (Steptoe & edwards)



• First I.V.F pregnancy using ovarian stim.

Was ectopic.

Ov. Stim. Vs

Spontaneous cycle

- Advantages of spontaneous cycle ovulation:

Avoidance: - Endocrine abnormalities

- Luteal phase defect (LPD)



-Advantages of ovarian Stimulation:

– Avoidance Low pregnancy rate (single pre -

ovulatory follicle.

–Avoidance Difficulty of monitoring

a spontaneous cycle(need 24hs)

– oocytes embryopregnancy.

Advances in Ov. Stim.

Over the past decade (Triad):

• Major advances in understanding of ovarian

physiology.

• New medical technologies for management of

infertility(GNRH analogue , self administered).

• New Monitoring techniques(TVS replace

Laparoscopy).





Simplifying procedure + improving

results.

Ovarian physiology



Two roles

– gametogenic

– endocrine

• The gametogenic potential is

established early in the fetus

• Endocrine role of the ovary is not

realized until puberty

Physiological Key

Points

Each Month:

600 – 650 occytes are destroyed (Atresia)=

(Apoptosis).



Only one oocyte ovulate



HOW?

Physiological Key Point

Normally : A cohort of primordial follicles

Continuously intiating follicular

growth (Independent of Gn stim. =

intrinsic mechanism)



Preantral stage



Disturb mechanism Need FSH in appropriate level

Ov.Stim

Pre- ovulatory stage

 E + FSH FSH

receptor content



Dominant follicle  E

 FSH  atresia of

less developed foll.s

Many follicles

Philosophy of Ovarian

Stimulation

1. Induction of a single

dominant follicle.

2. Induction of small number of

follicles (1-4).

3. Multiple follicular

development (IVF&ICSI)

Factors guiding

Ovarian Stimulation

1. Clinical circumstances( age ,wt …..).

2. Aim:

• Office therapy + timed Sex.I.

• IUI

• IVF or ICSI.

3. Number of eggs needed.

Types of Ov. Stimulation



1. Induction of ovulation.

2. Superovulation.

3. Controlled ovarian

hyperstimulation (COH).

Induction of

Ovulation

• Use of medications to stim.

Development of one (?) or more

mature follicles in anovulatory

cycles.

Superovulation

Intentional

Production of

many mature

follicles in one

cycle triggered

by medication

that stim.

Ovaries early in

follicular phase.

Controlled Ov. Hyperstim.

(COH)

Regulated Superovulation by turning off the

patient’s own Hs (down regulation) followed by

stim.

Aim:

1. Multiple follicles growth.

2. Control timing of ovulation eggs can be

surgically retrieved before they are ovulated.

3. Prevention of premature LH surge.

Drugs for Ov. Stim.

• cc

•Gonadotrophins:

• HMG

• highly purified ur FSH

•Rec. FSH

•Rec LH

• GnRH (pulsatile).

• GnRHa (intranasal-S.C- I.M)

• GnRH ant (involved in final steps of oocyte

maturation).

• HCG & Bromocripitine (!?)

CC

• Competitive inhibitor of E2

blocks E receptor in hypothalamus.

GnRH FSH & LH.

Follicles

• After last tablet by one W:

Freeing of hypothalamus receptors

from blockage.

Trigger LH surge (response to E2).

Problems with (cc)

1- long lasting(till 14-22 day of cycle)

2-  subclinical pregnancy loss compared to normal

population

3-  LH sec > FSH  miscarriage

4- (LUF)syndrome(unexplained infertility)

5- Anti E(cx &endometrium)

6-  ectopic (tubal transport)

7- side effect : -Minor (nausea-vomiting-flush skin-

hair loss)

OHS

Multiple pregnancy.

Gonadotropins



Unlike CC – Gn acts directly

on the ovaries.

Advantages of Recombinant

Human Gonadotropins

•Better batch-to-batch consistency.

•Steady supply.

•A purified compound.

• Well tolerated.

•No antibodies formation.

GnRH

Natural

-Is a deca peptide ( ten AA ).

-Half life time is 8 min (10 min bursts

every 60 min)

Synthetic

- By selective A.A or ethylamide

substitutions at 6 and/or 10 (Gly) postions.

- -  affinity for GnRH receptors (100-200

times).

- 1/2 life to 5 hours.

GnRHa

Advantages

• Prevent the possibility of premature LH

surges (as a result of  E in response to

Gn)cancealed cycles.

• Suppression of endogenous basal LH

levels recruitment of a larger cohort of

follicles.

• Decrease LH stimulation of ovarian

androgen production (may interfere with

follicular development)

Allow better timing of oocyte retrival

&synchronise follicular growth.

GnRHa

Routes:

- Intranasal.

- S.C.

- Depot (Longer period + need higher doses Gn+

need more luteal support) (Devreken et al

,1996).

Effect:

- Agonistic (flare up) phase LH & FSH .

- Down regulation (on continuous administration)

Within two weeks).

GnRH Antagonist

• Chemically it is also a decapeptide

with changing the aminoacid

sequense at positions 1,2,3,6 and 10.



• When GnRH antagonist is applied for

short period it leads to abortion of

LH peak, diminished E2 production

and impairment of follicular growth.

How to induce a

single dominant

follicle?

Induction of a Dominant

Single Follicle?!

• Induction ovulation protocol which

mimic more closely the FSH

threshold and window of the natural

cycle?!.



Low dose step down

Gn. Stim. Regimen.

Low dose Step-down

regimen

hCG

2 FSH/d 1½ FSH/d 1 FSH/d

D7

Day 3 3-4 amp. U/S & E2 2-3 days U/S

Day 3 3-4 amp. U/S & E2 2-3 days U/S

Foll >11 mm

Foll >11 mm



FSH dose may be high or low:

• Need to dose.



•Need to dose by one ampoule.

How to Obtain

Small Number of

Follicles (1-4)

protocols

1. CC.

2. CC ± FSH or ± HMG.

3. Gn. Standard step-up protocol.

4. Gn. Low dose step-up protocol.

5. Gn. Low dose step-up, step-

down protocol.

Unripe Ripening Ovulation Corpus Regression of

follicle follicle luteum Corpus luteum









Oocyte mature

Clomiphene Gonadotrophin 38 hrs

100 mg day2 stimulation from

for 5 days day 4 to day of

HCG

HCG Leading follicle > 18mm

Standard Step-up

Protocol

Starting dose = 150 IU/day



2 FSH/hMG/day

5 days

Day 3 5 days Day 7 Follicle > 12 mm

Day 3 Day 7 Continue

E2 > 400U 2 FSH/day





If U/S and E2  3 FSH/day

for 3 more days

Endocrine Rev. 1997; 18: 71

Standard Step-up

Protocol cont…

Complications :

Multifetal pregnancy (36%)

OHSS (14%)

Low dose Step-up

regimen

It allows the FSH threshold to be

reached gradually, minimizing

excessive stimulation

decreasing the risk of

multifollicular response.

Low dose Step-up

regimen

Starting dose = 37.5-75 IU/day



37.5-75 FSH/hMG/day



Day 3 5 days

5 days Day 7 Follicle > 12 mm

Day 3 Day 7 Continue

E2 > 400US 1 FSH/day





If no response  1.5 FSH/day

for 1 more week (max. 3 amp.)

Endocrine Rev. 1997; 18: 71

Low dose Step-up

Step-down regimen

Day 3

one FSH/day step-up till 14 mm foll.



step-down



hCG

Multiple

Follicular

Development

• Rationale of COH:

To disturb the normal relationship

between FSH&Eby increase FSH

available to follicles other than the

dominant follicleincrease total

number of follicles that reach the pre

ovulatory stage.

Aim of (COH)



•Production of sufficient number of very

high-quality embryos (transfer 2-3

embryo\ cycle)

•Placement >3 :( multiple

pregnancy not  pregnancy rate)

•Freeze remaining embryos (for 2nd

use & decrease number of stim.

Cycles)

Complication of GnRHa

(COH) Programes

• Transient neurological disturbances (6%).

• Ovarian cysts (14-29%).

• Multiple pregnancy.

• OHSS.

• Hypoestrogenic effect?!

• Short luteal phase.

Protocols for Multiple

Follicular Development

• Long (suppression):utilizes pituitary desensitiz.

• Short (flare –up) Shorter duration

Lower doses

• Ultrashort(sequential):

difficult timing and program

• Modifications

- Microdose flare up.

- Stop over technique (Norfolk protocols)

- Step down regimen.

•GnRH antagonist.

Flare Protocol GnRH-a



hMG







Follicular phase GnRH-a

Downregulation

hMG









Luteal phase GnRH-a

Downregulation hMG



Ultrashort Protocol

GnRH-a

hMG





21 1 2 hCG Embryo

Transfer

Oocyte

Cycle day Retrieval

Pre-Requisites for

COH

Pattern of Response to COH:

FSH on cycle day3 (provided E2 15 miu/ml)

Intermdiate responder (FSH 10-

15miu/ml).

High ( FSH <10).

Selection of Protocol

According to Responders

Long (luteal):

Good in intermediate & high

responders.

Short: (Flare up) protocol:

Good in poor responder.

Winslow, 1991

Long Protocol

Criteria of Pituitary Suppression

Serum LH< 2.

Serum Estradiol < 50 pg/ml.

Absence of ovarian cyst.

Transvaginal sonographic measurement

of endometrial thickness of <6mm

predicts pituitary down- regulation in

over 95% of cases.

Support of Luteal

Phase

Direct: (progesterone substitutions)

• 2x100 mgm supp.or micronized 3-6x100

(from day of embryo transfer).

Indirect: (HCG)

- Hyperstim

- False pregnancy test.

Protocols of

GNRH

Antagonist

HMG or FSH on day 2-3 of

the cycle

+

Two Protocols of

Antagonist

Lubeck ( multiple doses) (0.25mgS.C - 7th

day of the cycle till the day of HCG).

French: (Single dose) ( 2-3 mg as single or

dual around day 9).

NB: Another “soft protocol”= FSH + GnRH ant.

Advantages of

GnRH antagonist

1. Immediate suppression of endogenous

FSH and LH without flare up

phenomenon.

2. Shortening treatment period with relief of

physical, psychological and financial

burdens.

3. Decreased number of HMG ampoules per

cycle (Diedrich et al, 1994 and 2000).

Lubeck ( multiple doses)

Antagonist (Lubec) Vs

GnRH-a Metaanalysis

Cycle Day 6 Day of

Day 2-3 of FSH hCG







FSH



GnRH antagonist



Cycle Down Day of

Day 21-24 Regulation hCG

2-4 Weeks



GnRH agonist

FSH

Antagonist (Lubec) Vs GnRH-a

Metaanalysis “Inany, 2002 ”

• No significant difference in prevention

of LH surge.

• Lower number of oocytes retrieved.

• Lower pregnancy rate in spite of

transfer of an equal number of

embryos.

• No significant difference in prevention

of severe OHSS.

Patients at Risk

OHSS

PCOS

HCG (Exo/Endo).

High serum E2.

Multiple follicles.

Younger age < 32.

GnRH-a protocols

Prevention of OHSS

Withholding HCG administration.

Reduced dose of HCG.

Administration of rec-LH.

Freeze the embryos.

coasting

Conclusions

• You should know

what is you need from

ov stimulation before

selecting a certain

protocol

Conclusions

1. Long protocols: they are the golden

standard for all ART candidates

especially those with young age, normal

base line pituitary hormones, average

size ovaries (more than 3ml) and normal

BMI.

2. Short protocols: they are used in ART

candidates with previous poor response,

older women with relatively high FSH.

Conclusions cont…

3. Cases of poor response with short

protocols, ovaries are stimulated either

without analogues (ie HMG alone)

OR

with the usage of antagonist.

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Email. mae335@hotmail.com

www.ivfmifc.com