Transcript Is there a consensus view on what is PCOS

Safety and efficacy of
FSH drugs in ART for
polycystic ovarian disease
M. Aboulghar
Cairo, Egypt
Safety of FSH
Urinary and recombinant
gonadotrophins are being used
for many years with 100% safety
record concerning transmission
of infection and with no serious
allergic reaction.
The only risk of the use of both
types of FSH is the development
of OHSS. This is not uncommon
complication in PCO patients as
those patients are particularly
liable to OHSS.
Ovarian stimulation for PCOS
patients is associated with
complications.
Under- and over-stimulation are
relatively common (Urman 2004).
Polycystic ovaries and OHSS: a
systematic review (Tummon et al 2005)
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10 studies were included with PCOS and
available data on OHSS.
Combined OR for OHSS was 6.8 (CI 4.9 – 9.6)
There is a significant consistent relation between
PCOS and OHSS.
How can we prevent OHSS in PCOS?
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Smaller dose of FSH
Close monitoring.
Coasting
Use of GnRH antagonist as a protocol of
stimulation or to prevent OHSS in
hyperstimulated patients.
Small dose of hCG 5000 IU.
Efficacy of FSH in ART for
PCOS
Outcome IVF in PCO and controls matched
for age, cause of infertility and stimulation
protocol (MacDougall et al 1993)
N
FSH
E2
Oocytes
FR
PR
OHSS
PCO
76
Smaller dose
Higher
More
Less
25.4%
10.5%
Non PCO
76
Higher dose
Lower
Less
More
23%
Zero
P
NS
S
S
S
S
NS
S
Outcome of IVF in women with US finding of
polycystic ovaries (Engmann et al. 1999)
46 (PCO by
US)
97 IVF cycles
More follicles
More oocytes
More embryos
191 women
145 matched
(normal ovary by US)
Long GnRHa protocol
332 IVF
cycles
Less follicles
Less oocytes
Less embryos
Equal fertilization, cleavage, miscarriage rates
Odds of achieving pregnancy within 3cycles were 69% higher in PCO
Odds of achieving live birth in 3cycles were 82% higher in PCO
During simple ovulation
induction for PCOS patients,
hMG, urinary FSH, and
recombinant FSH appear to be
equal in achieving pregnancy
(Van Wely et al 2003)
A meta-analysis of outcomes of IVF in PCOS and a
matched non PCOS group (Heijnen 2006)
458 PCOS patients
(From 9 studies)
Rotterdam criteria
694 non PCOS
patients.
793cycles
1116 cycles
Significantly more oocytes retrieved in PCOS
(OR = 3.4, 95% CI = 1.7 – 5.1)
No significant difference between mean
number of fertilized oocytes
No significant difference in PR (OR = 1.0 95% CI = 0.8 – 1.3)
OHSS was rarely reported.
Oocyte quality in patients with severe ovarian
hyperstimulation syndrome.
(Aboulghar et al 1997; Fabregues 2004)
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Significantly more oocytes
Significantly lower FR
Similar number and quality of available embryos
Similar implantation and pregnancy rates.
We will present the results of the first
prospective randomized study in the world
literature comparing highly purified FSH
with recombinant FSH for IVF/ICSI in
PCOS patients.
(Aboulghar et al Fertil Steril, in press).
Declaration of conflict of interest
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This randomized study was sponsored in
part by IBSA Institute Biochimique SA
Study design:
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A prospective randomized study of IVF/ICSI
for patients with PCOS comparing
recombinant FSH (Gonal F, Merk-Serono)
and highly purified urinary FSH (Fostimon,
IBSA).
A sample size of 42 women in each arm is
sufficient to detect a difference of 10% in
oocyte maturity to ensure a power of 80%
based on the oocyte maturity in our study
(Aboulghar et al. 1997).
Protocol of treatment
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We used our routine long GnRHa protocol
(Aboulghar et al.2008)
Start dose of FSH was 2-3 ampoules depending
on age and weight of patient, from day 6 of
stimulation, adjustment could be done.
Frequency of E2 assays depended on the
number of follicles, and the rate of growth.
Triggering ovulation when follicle reaches 18
mm (according to our routine protocol).
(Aboulghar et al.2008)
In case of risk of OHSS, coasting
was performed according to our
coasting protocol (Mansour et al
2005). We stopped FSH treatment
when the lead follicle reached 15-16
mm and waited until E2 level
dropped to 3000 pg/ml or less, then a
dose of 10,000 hCG was given.
Indication for IVF/ICSI
Fostimon
GF
Male factor
73.8%
61.9% NS
Tubal factor
14.3%
21.4% NS
Failure of ovulation
induction
12.9%
18.7% NS
Patients’ characteristics
Fostimon
GF
Age
28.29±4.04
27.36±3.50 NS
Period of
infertility
5.03±3.60
5.77±3.42
BMI
29.80±4.74
29.90±4.65 NS
NS
Ovarian stimulation data
FSH dose and duration
Fostimon
GF
p
Start FSH dose (Ampoules)
2.71±0.46
2.67±0.47
NS
Mean Total ampoules
29.98±9.17
28.29±7.95 NS
Days of stimulation
11.05±2.59
11.21±2.82 NS
Days of coasting
1.88±0.96
1.80±0.77
NS
Coasting
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Done in 16 patients in fostimon
Done in 20 patients in Gonal F
15 patients: one day
13 patients: two days
7 patients:
three days
1 patient:four days
Outcome in both groups
Retrieved oocytes
Mature Oocytes
Fostimon
17.1±8.66
12.8±7.78
GF
13.83±7.07
10.45±5.69
p
0.064 NS
0.106 NS
Fertilized oocytes
9.52±6.78
6.76±5.44
0.043
Fertilization rate
Top quality embryos
74.5±20.14 62.96±24.2
2.79±0.55 2.18±0.95
0.021
0.021
Good quality embryos
2.64±0.85
2.19±0.75
0.060 NS
Outcome in both groups
Patients with frozen embryos
Total n of cryo embryos
No. of embryos transferred
Fostimon
28 (66.7%)
207
2.88±0.55
GF
14 (33.3%)
96
2.80±0.51
p
0.006
Frozen embryos per patient
Positive BHCG
4.9±6.4
26 (63.4%)
2.57±4.5
24 (58.5%)
0.015 *
NS
Clinical pregnancies
Ongoing pregnancies
21 (50%)
19 (45.2%)
22 (50.2%)
20 (47.6%)
NS
NS
NS
In the current study, 84 patients
of IVF/ICSI were performed for
one or more of these indications
in a single large center during the
relatively short period of 8
months, denoting that the
indication for IVF/ICSI in PCOS
patients in not uncommon.
In previous studies on IVF/ICSI for PCOS
(Urman et al 2004)
High cancellation rate was reported
Due to
Small dose
of FSH for
fear of
OHSS
High FSH dose
for fear of
cancellation
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In the present study only 2 cycles out of 84 cycles
were canceled due to poor response.
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Coasting used liberally in 36 out of 84 patients
(42.8%) in our study and without affecting the
clinical pregnancy rate which was 50%.
Dose of FSH and BMI
Fostimone
GF
Mean starting dose
2.71±0.5
2.67±0.5
BMI
29.8±4.8
29.9±4.6
We noted that the use of small dose of FSH
in patients with high BMI frequently result in
high cancellation rate
The study reported a high clinical
pregnancy rate, 21 pregnancies (50%)
in Group A and 22 pregnancies
(50.23%). However, the study also
reported very high multiple
pregnancies, 9 out of 22 in Group A
and 11 out of 22 in Group B.
The difference in the mean fertilized oocytes,
fertilization rate, top quality embryos and
number of cryopreserved embryos could
possibly be explained by the difference in the
FSH isoform composition of commercial
gonadotrophin preparations. The difference
although statistically significant did not reflect
on the clinically important pregnancy rate.
However, FSH isoform composition is usually
considered to have negligible effect on clinical
outcome (Andersen et al 2004)
On the other hand, the distribution of
FSH isoforms in human-derived
products may have a higher average
glycosylation as compared to the
recombinant ones. Thus the urinary
product may possibly provide some
balancing to the excessive activity of
granulosa cells of PCOS, which could
result in some clinical benefits (Sharron
et al 2007).
During fresh cycles, the best
available embryos were selected for
transfer in both groups. The
significantly more cryopreserved
embryos in the urinary FSH group
may possibly make a difference in
the pregnancy rate between both
groups after embryo transfer of
frozen-thawed embryos.
The multiple pregnancy is extremely
high in the present study and our
policy of transferring between two and
three embryos should be in the future
restricted to a maximum of two
embryos transferred. The final
solution to the problem of multiple
pregnancy will be achieved by single
embryo transfer (Gelbaya et al 2009)
Our study has shown that
IVF/ICSI in PCOS patients, even
with high BMI can be managed
safely with minimal occurrence of
OHSS and with an excellent
pregnancy rate. Both highly
purified and recombinant FSH
produce similar pregnancy rates.
Conclusions
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IVF/ICSI results in excellent pregnancy rate in PCOS
patients.
There is a high risk of OHSS in PCOS which could be
minimized by proper preventive methods.
Although highly purified FSH resulted in a significantly
higher fertilization rate, higher number of fertilized
oocytes and higher number of top quality and frozen
embryos as compared to recombinant FSH, yet there
was no difference in clinical or ongoing pregnancy
rates.
This study has shown that ovarian
stimulation for IVF/ICSI in PCOS
patients can result in excellent
pregnancy rates and if carefully
managed and precautions to prevent
OHSS are taken, the high risk of
OHSS could be avoided to a great
extent.
As clinical pregnancy rate is not
significantly different between
both groups, the cost of medicine
may play a role in the choice of
FSH product.
The Egyptian IVF-ET Center
 Clinical directors:
• M. Aboulghar, M. D.
• G. Serour, M. D.
- Clinical associates:
• Y. Amin, M. D.
• M. Sattar, M. D.
• A. Ramzy, M. D.
• L. Mansour, M. D.
• M. Metwally, M. D.
• H. Aboulghar, M. D.
• M. Aboulghar, M. D.
• H. Al Inany, M. D.
• A. Abou-Setta, M. D.
- Andrology:
• I. Fahmy, M. D.
• A. El-Gindy
 Scientific director & Program manager:
• Ragaa Mansour, M. D., Ph. D.
- Embryology and micromanipulation
• S. Mansour, M. D.
• A. Kamal, M. D.
• A. Mostafa, M. D.
• N. Tawab, B.Sc.
• G. Afifi, B.Sc.
• M. Hammam, B.A.
- Cryobiology and
- Cytogenetics
Andrology
• H. Fayek, Ph. D.
• D. Saad, B.Sc.
• A. Abdel-Razek, M. D. • Y. Demery, B.Sc.
• A. Amer, B.Sc.
• A. Barakat, B.Sc.
• A. Khalil, Ph. D.
• M. Serour , B.Sc.
• A. Naser, Ph. D.
• N. Salah , B.Sc.
• O. Kamal, B.S.
• H. Fanous , B.Sc.
• S. Mostafa
• A. Mohamed , B.Sc.