Zeev Shoham M.D.

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PCO Different treatment protocols for different
indications.
Zeev Shoham M.D.
Dep. Of OB/GYN Kaplan Hospital, Rehovot, Israel
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PCOD Goals of treatment

• To induce ovulation ended in pregnancy

• Minimize the incidence of miscarriage

• Prevent multiple gestations

• Minimize the risk of OHSS

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Live birth of a singleton from a healthy mother
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Two thirds of the triplet pregnancies and higher
order pregnancies are due to gonadotropin therapy
Increase in perinatal morbidity and mortality
rates Increase incidence of obstetric
complications Impose major emotional,domestic and
financial burdens on the family and the society.
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Cycle evaluation during CC treatment
Ov. Endo.
Foll. Endo.
36 h
5 days
Menses
Day 5 to 9
Day 13-14
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Anovulatory infertility in PCOS

• 50-80 will ovulate on CC
• Only 40-50 will conceive

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Study Control
Cudmore and Tupper, Fertil Steril 1966
22 19
Garcia et al, Fertil Steril 1985
24 22
Johnson et al, Int J Fertil 1966
65 65
Ovulation
20/106
61/111
Pregnancy
4/96
13/96
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CC Induce ovulation and improve fertility
significantly. The incidence of pregnancy
outcome was not addressed.
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Gonadotropin Treatment
hMG versus uFSH versus rec-FSH With or
without GnRH-a
Different modalities of gonadotropin
administration Conventional
Chronic low dose step up
Step-down
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How do we measure the outcome?
Ovulation rate ? Pregnancy rate ? Miscarriage
rate ? Multiple pregnancy rate ? OHSS rate ?
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FSH vs hMG (with or without GnRH-a). Pregnancy
rate
Nugent et al Cochrane 2000
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OHSS Rate
Nugent et al Cochrane 2000
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Will the concomitant administration of GnRH-a
improve results ?
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Relation of basal (LH) to in vitro fertilization
rates of human ova
Stanger and Yovich 1985
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Follicular phase high LH concentrations have been
found to be associate with
Poor oocytes quality Reduced rate of
fertilization Reduced pregnancy rate Increase
incidence of miscarriage
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Pregnancy rate
Nugent et al Cochrane 2000
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OHSS rate
Nugent et al Cochrane 2000
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Miscarriage rate
GnRH-a Gonadotropin
Gonadotropin
No difference was found
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Adding GnRH-a to gonadotropin treatment ?
These studies are too small to clearly
demonstrate clinical significance difference in
pregnancy, miscarriage and OHSS rate, therefore
it should not be recommended as a standard
treatment for patients with PCOD.
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Expression of hFSH in CHO Cells
a
Incorporation into host cell Chromosome
Nucleus
Transfection
Transcription
b
a
mRNA produced
Golgi apparatus
Maturation
Translation
ER
Secretion
b
a
Mature hFSH molecule
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Rec-FSH is more effective than uFSH in women with
cc-resistant PCO. A prospective, multicenter,
assessor-blind, randomized clinical trial.
Coelingh Bennink et al. Fertil Steril 1998
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Results from 24 randomized studies comparing
rec-FSH with uFSH in IVF programs showed
Clinical pregnancy rate per cycle
Daya and Gunby, Cochrane 2000
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Drug to be use
Results from ovulation induction study and those
of IVF recommend the use of rec-FSH
Purity of the drug. Batch to batch
consistency. Shortening of treatment
period. Using significant lower dose of
gonadotropin.
Rec-FSH drug of choice
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Multiple pregnancy
Prevention ?
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Multiple pregnancy rate related to the number of
follicles gt 16 mm on hCG day
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How to minimize the risk of multiple birth


Strict criteria for hCG administration.
Optimize Follicular Development?
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FSH administration regimens
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
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150 IU
112.5 IU
hCG
75 IU
Foll. ³ 10 mm
½
150 IU
112.5 IU
75 IU
75 IU
hCG
6
12
Foll. ³ 14 mm
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Compensatory Hyperinsulinemia
Insulin resistance
?
Ovary
Cause-and-effect relationship
Androgens
Serum insulin
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Impact of insulin secretion on ovarian response
to FSH stimulation in PCOS
Relationship between Circulating insulin
levels Follicular growth Ovarian
hormone secretion
Fulghesu et al., J Clin Endocrinol Metab 1997
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Stimulation outcome
Normo-insulinemic patients
Hyper-insulinemic patients
No. of Cy.
Dose/BMI
FSH dose
Ovul. rate
OHSS
Plt0.05
Pregnancy
Abortion
Fulghesu et al. J.C.E.M. 1997
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Diameter gt12 mm and lt 16 mm
7
6
5
Plt0.01
Number of follicles
4
Hyperins
Normoins
3
2
1
0
Basal
-
5
-
4
-
3
-
2
-
1
0
Days from hCG injection
Fulghesu et al. J.C.E.M. 1997
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61women with BMI gt28
USA
Venezuela
Italy
PCOS
26 women received - Placebo
1 ovulated
Plt0.001
35 women received - Metformin 1500 mg/day
14 ovulated
1
14
28
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Prog. gt25 nmol/L
Nestler et al., New Engl J Med 1998
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CC 50 mg
25 women received - Placebo
2 ovulated
Plt0.001
21 women received - Metformin 1500 mg/day
19 ovulated
1
5
10
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Area under the curve (micU/ml/min) 75 g of
glucose (0,60,120 min)
Pre-
Post
Metformin Placebo
65981267 65581030
3479455 510055
Plt0.03
Nestler et al., New Engl J Med 1998
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Conclusions Effects of metformin
on gonadotropin-induced ovulation in PCOS
Reduction of intermediate follicles. Reduction in
E2 levels on hCG day. Reduction in cycle
cancellation. Lower incidence of OHSS.
De Leo et al., Fertil Steril 1999 72282-5
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How to minimize the risk of multiple birth and
still achieve a good pregnancy rate?


Best and primary treatment to patients with PCOD
is IVF
Adjust the No. of embryos transferred depending
on risk factors for multiple gestation.
A good freezing program
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Conclusions
Use of Metformin is recommended. Treatment should
start with CC up to 6 cycles. Rec-FSH should be
used when gonadotropin treatment is indicated.
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Conclusions
Treatment should start with the conventional
protocol continuing with low-dose step-up or down
as preferable. There is no need for GnRH-a
administration. We prefer to do IUI in all
treatment cycles.
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Conclusions
We always need to balance the immediate gain of a
pregnancy against the potential long term
negative impact of the treatment.
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