Managment

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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
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Indications

• Some cases of primary amenorrhea.
• Some cases of POF.
• Some cases of delayed puberty.

• Infertility ( anovulatory or ovulatory cycles).

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Objective

• To highlight the rationale , philosophy and
  different protocols of ovarian stimulation in
  cases of infertility

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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.

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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.

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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.

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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

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Physiological Key Points

• Each Month
• 600 650 occytes are destroyed (Atresia)
  (Apoptosis).

Only one oocyte ovulate
HOW?
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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
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Philosophy of Ovarian Stimulation

• Induction of a single dominant follicle.
• Induction of small number of follicles (1-4).
• Multiple follicular development (IVFICSI)

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Factors guiding Ovarian Stimulation

• Clinical circumstances( age ,wt ..).
• Aim
• Office therapy timed Sex.I.
• IUI
• IVF or ICSI.
• Number of eggs needed.

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Types of Ov. Stimulation

• Induction of ovulation.
• Superovulation.
• Controlled ovarian hyperstimulation (COH).

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Induction of Ovulation

• Use of medications to stim. Development of one
  (?) or more mature follicles in anovulatory
  cycles.

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Superovulation
Intentional

• Production of many mature follicles in one cycle
  triggered by medication that stim. Ovaries early
  in follicular phase.

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Controlled Ov. Hyperstim. (COH)

• Regulated Superovulation by turning off the
  patients own Hs (down regulation) followed by
  stim.
• Multiple follicles growth.
• Control timing of ovulation eggs can be
  surgically retrieved before they are ovulated.
• Prevention of premature LH surge.

Aim
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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 (!?)

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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).

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Problems with (cc)

• 1- long lasting(till 14-22 day of cycle)
• 2- ? subclinical pregnancy loss compared to
  normal population
• 3- ? LH sec gt 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.

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Gonadotropins

• Unlike CC Gn acts directly on the ovaries.

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Advantages of Recombinant Human Gonadotropins

• Better batch-to-batch consistency.
• Steady supply.
• A purified compound.
• Well tolerated.
• No antibodies formation.

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GnRH
Natural

• -Is a deca peptide ( ten AA ).
• -Half life time is 8 min (10 min bursts
  every 60 min)
• 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.

Synthetic
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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.

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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).

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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.

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How to induce a single dominant follicle?
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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.
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Low dose Step-down regimen
hCG
2 FSH/d
1½ FSH/d
1 FSH/d
D7
3-4 amp.
2-3 days
Day 3
3-4 amp.
2-3 days
Day 3
U/S
U/S E2
U/S
U/S E2
Foll
gt
11 mm
Foll
gt
11 mm

• FSH dose may be high or low
• Need to dose.
• Need to dose by one ampoule.

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How to Obtain Small Number of Follicles (1-4)
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protocols

• CC.
• CC FSH or HMG.
• Gn. Standard step-up protocol.
• Gn. Low dose step-up protocol.
• Gn. Low dose step-up, step-down protocol.

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Oocyte mature
Clomiphene 100 mg day2 for 5 days
38 hrs
Gonadotrophin stimulation from day 4 to day of HCG
Leading follicle gt 18mm
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Standard Step-up Protocol
Starting dose 150 IU/day
Follicle gt 12 mm E2 gt 400U
Continue 2 FSH/day
If
U/S and E2 3 FSH/day for 3 more days
Endocrine Rev. 1997 18 71
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Standard Step-up Protocol cont

• Complications
• Multifetal pregnancy (36)
• OHSS (14)

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Low dose Step-up regimen

• It allows the FSH threshold to be reached
  gradually, minimizing excessive stimulation
  decreasing the risk of multifollicular response.

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Low dose Step-up regimen
Starting dose 37.5-75 IU/day
37.5-75 FSH/hMG/day
5 days
5 days
Follicle gt 12 mm E2 gt 400US
Day 7
Continue 1 FSH/day
Day 3
Day 3
Day 7
If
no response 1.5 FSH/day for 1 more week
(max. 3 amp.)
Endocrine Rev. 1997 18 71
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Low dose Step-up Step-down regimen
Day 3
one FSH/day
step-up till 14 mm foll.
step-down
hCG
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Multiple Follicular Development
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• Rationale of COH
• To disturb the normal relationship between
  FSHE?by increase FSH available to follicles
  other than the dominant follicle?increase total
  number of follicles that reach the pre ovulatory
  stage.

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Aim of (COH)

• Production of sufficient number of very
  high-quality embryos (transfer 2-3 embryo\ cycle)
• Placement gt3 (? multiple pregnancy not ?
  pregnancy rate)
• Freeze remaining embryos (for 2nd use decrease
  number of stim. Cycles)

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Complication of GnRHa (COH) Programes

• Transient neurological disturbances (6).
• Ovarian cysts (14-29).
• Multiple pregnancy.
• OHSS.
• Hypoestrogenic effect?!
• Short luteal phase.

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Protocols for Multiple Follicular Development

• Long (suppression)utilizes pituitary
  desensitiz.
• Short (flare up)
• Ultrashort(sequential)
• Modifications

Shorter duration Lower doses difficult timing
and program

• - Microdose flare up.
• - Stop over technique (Norfolk protocols)
• - Step down regimen.
• GnRH antagonist.

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Luteal phase Downregulation
   
2
hCG
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Pre-Requisites for COH

• Pattern of Response to COH
• FSH on cycle day3 (provided E2 lt 50pg/ml)
• Low responder (FSHgt15 miu/ml)
• Intermdiate responder (FSH 10-15miu/ml).
• High ( FSH lt10).

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Selection of Protocol According to Responders

• Long (luteal)
• Good in intermediate high responders.
• Short (Flare up) protocol
• Good in poor responder.
• Winslow, 1991

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Long Protocol Criteria of Pituitary Suppression

• Serum LHlt 2.
• Serum Estradiol lt 50 pg/ml.
• Absence of ovarian cyst.
• Transvaginal sonographic measurement of
  endometrial thickness of lt6mm predicts pituitary
  down- regulation in over 95 of cases.

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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.

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Protocols of GNRH Antagonist
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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.

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Advantages of GnRH antagonist

• Immediate suppression of endogenous FSH and LH
  without flare up phenomenon.
• Shortening treatment period with relief of
  physical, psychological and financial burdens.
• Decreased number of HMG ampoules per cycle
  (Diedrich et al, 1994 and 2000).

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Lubeck ( multiple doses)
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Antagonist (Lubec) Vs GnRH-a Metaanalysis

• Cycle Day 6 Day of
• Day 2-3 of FSH hCG
• Cycle
  Down Day of
• Day 21-24 Regulation hCG
• 2-4 Weeks

FSH
GnRH antagonist
GnRH agonist
FSH
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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.

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Patients at Risk OHSS
PCOS HCG (Exo/Endo). High serum E2. Multiple
follicles. Younger age lt 32. GnRH-a protocols
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Prevention of OHSS

• Withholding HCG administration.
• Reduced dose of HCG.
• Administration of rec-LH.
• Freeze the embryos.
• coasting

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Conclusions

• You should know what is you need from ov
  stimulation before selecting a certain protocol

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Conclusions

• 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.

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Conclusions cont

• 3. Cases of poor response with short protocols,
  ovaries are stimulated either without analogues
  (ie HMG alone)
• with the usage of antagonist.

OR
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Thank you
Prof. DR. MOHAMMAD EMAM
Telfax 0020502319922 0020502312299 Email.
mae335_at_hotmail.com www.ivfmifc.com