Title: Ovulation induction: From shot in the dark, a flat staircase and beyond
1Ovulation induction From shot in the dark, a
flat staircase and beyond
Zeev Shoham
Dep. Of OB/GYN Kaplan Hospital, Rehovot, Israel
2Developments in Reproductive Health
- Move toward all biosynthetic gonadotrophins.
- Increase treatment success rates.
- Enhance safety of stimulation regimens.
- Simplify treatment regimens.
3Simplifying procedure - improving results
- Replacing Laparoscopy with Trans-vaginal
ultrasound. - Using GnRH-a for down-regulation.
- Simplifying monitoring.
- S.C. administration for self-administration.
- Administration of GnRH-antagonists.
4Ovarian Hyperstimulation Syndrome
Multiple pregnancy
Prevention ?
5OHSS
A Mystery
6Strategies for prevention
Withholding hCG administration Reduced dose of
hCG Administration of native GnRH or
GnRH-a Administration of rec-LH Freeze the embryos
7Angiogenesis
Differentiation
Proteolysis
Luteinization
Demise of the CL
Apoptotic process
8...
Capillary permeability Angiogenesis Endothelial
cell proliferation
9Ovarian renin-angiotensin system
Ovarian Prorenin
Active Renin
Angiotensin I
ACE
Steroidogenesis Angiogenesis Hyperpermeability
Angiotensin II
PGs
10Patients at Risk
PCOD
hCG (Exo/Endo)
High serum E2
Multiple follicles
Younger age lt32
Lean Habitus
GnRH-a Protocols
11Human Albumin
Pathogenesis
hCG mediated factor produced by the corpus luteum
which increases capillary permeability
12Human Albumin
Maintains plasma oncotic pressure (70 to 80)
Carrier protein (Hormone, Drugs, Glucorticoids,
Fatty acids, Aldosterone, Bilirubin)
Tullis. Am J Med Assoc 1977
13Human Albumin
Administration of 50 g.
14Human Albumin
Process of Manufacturing
Sterile Solution
FDA Approved plasma
Cold ethanol fractionation
Hepatitis C antibody
Fraction IV or V paste
Hepatitis B surface antigen
Ion exchange chromatography
HIV-1 antibody
HIV-2 antibody
Diafiltration concentration
Pasteurization
Viral Safe
15hMG
Ovary
hCG
Ovulation
Corpus luteum
Factor X
Capillary permeability
Leak Syndrome
Albumin loss
Hypovolemia
Thromboembolic events
Oliguria
Renal Failure
Hemoconcetration
16hMG
Activation
Ovary
Renin-Angiotensin
hCG
Ovulation
Plasma Renin Activity
Angiotensin II like substance
Corpus luteum
Promote Angiogenesis
Factor X
Endothelial cell contraction
Capillary permeability
Binding capacity in plasma
Leak Syndrome
Albumin loss
Free/Biologically Active Factor?
Hypovolemia
Thromboembolic events
Oliguria
Renal Failure
Hemoconcetration
17hMG
Activation
Ovary
Renin-Angiotensin
hCG
Ovulation
Plasma Renin Activity
Release Angiotensin Converting Enzyme
Angiotensin II like substance
Corpus luteum
Promote Angiogenesis
Factor X
Endothelial cell contraction
ATII
Capillary permeability
Aldosterone Release
Binding capacity in plasma
Leak Syndrome
Albumin loss
Free/Biologically Active Factor?
Oncotic Pressure
Hypovolemia
Ascites
Thromboembolic events
Oliguria
Renal Failure
Hemoconcetration
18Study Type
Alb/OHSS
Cont/OHSS
Authors
Asch et al. Hum. Reprod. 1993
Prospective (25g x 2)
36/0
plt0.043
plt0.008
plt0.05
Shaken et al. Fertil Steril 1996
Prospective (40g x 2) Randomized
231/23
163/2
19Intra-venous albumin for preventing severe
ovarian hyperstimulation syndrome
Reviewers' conclusions This review shows a clear
benefit from administration of intra-venous
albumin at the time of oocyte retrieval in
prevention of severe OHSS in high-risk cases.
Cochrane Liberary 1999
20Hydroxyethyl Starch Solution
High molecular weight
Increase plasma oncotic pressure
Half-life of 10 h
Graf et al. Hum Reprod 122599, 1998
21Prophylactic intravenous hydroxethyle starch
solution
A prospective, randomized, double-blind,
placebo-controlled study. 1000 cc 6 HES vs. 1000
cc NaCl
Konig et al. Hum Reprod 132421, 1999
22Treat Group
Control Group
No. of Pat. Moderate OHSS Severe OHSS ModSev OHSS
51 1 0 1
50 6 1 7
plt0.031
Konig et al. Hum Reprod 132421, 1999
23Treat Group
Control Group
No. of Pat. No. of Pregnancy Moderate OHSS Severe
OHSS
100 28 10 2
82 24 32 7
plt0.000001
Graf et al. Hum Reprod 122599, 1998
24Lessons For The Future
Markers for detection of patients at
risk. Develop strategies to decrease neo-
vascularization and hyperprmeability
25Multiple Gestation
- From curiosity to epidemic
26(No Transcript)
27Septuplets following Ovulation induction Miracle
in Iowa?
28Multiple Gestation
Rate
- Japan 6.7/1000
- U.S/Europe 11/1000
- Africa 40/1000
- Monozygous 3.5/1000
- O.I./ART 37
29Complications
- Maternal Fetal
- Miscarriages IUGR
- Hypertension Congenital anomalies
- Operation Hydroamnios
- Postpartum hemorrhage Birth asphyxia
- Postpartum stress Neonatal
death -
30Multiple birth rate in Ovulation Induction and ART
Unacceptable high. Triplet and higher order is a
major medical problem. Twins are also a medical
problem. Can only be overcome by carefull
management of O.I. and reducing number of embryos
transferred.
31Twins born in Western Australia 1991
4 times more likely to be stillborn. 5 times more
likely to dies as neonates. 16 times more likely
to weight less 1500g at birth. CP 8 times more
often than a singeltone. Required neonatal
intensive care 8 times more often than singleton.
32Multiple pregnancy rate related to the number of
follicles gt 16 mm on hCG day
33FSH Administration Regimen
Chronic Low Dose (CLD) S. Franks et al. Step
Down (SD) B. Fauser et al. Sequential (SE) J.N.
Hugues et al.
hCG
150 IU
112.5 IU
75 IU
75 IU
Days
7
14
21
28
150 IU
112.5 IU
hCG
75 IU
Foll. ? 10 mm
½
150 IU
112.5 IU
75 IU
75 IU
hCG
6
12
Foll. ? 14 mm
34How to minimize the risk of multiple birth
Strict criteria for hCH administration. Replacing
hCG with rec-LH or GnRH-a
Optimize Follicular Development? The use of
different doses of rec-LH
35How to minimize the risk of multiple birth and
still achieve a good pregnancy rate/ started
stimulation?
Adjust the No. of embryos transferred depending
on risk factors for multiple gestation.
Age.
A good freezing program
36Complications
Embryo reduction
4-5
Miscarriage
Premature labor
75
Traumatic experience
37Conclusion
Identify groups who will benefit from having one
blastocyst only. We have to adopt a strategy
where we try to retrieve as many oocytes as
possible, replace one blastocyst and freeze the
others .
38Physician obligations are Do no harm. Assessing
the balance between risk and benefit.
39A major challenge for every physician is to
balance the immediate gain of a pregnancy against
the potential long term negative impact of
multiple gestation.