This document summarizes three clinical studies on IVF outcomes for women with PCOS: 1. A study comparing fresh versus frozen-thawed embryo transfer, finding higher clinical pregnancy and live birth rates with fresh transfers. 2. An analysis of over 4,000 IVF cycles from SART, finding no significant difference in outcomes between IVF and ICSI for couples with PCOS and normal sperm. 3. A study examining the impact of metformin on outcomes in overweight/obese PCOS women, with conflicting previous results noted.

1. ‫الرحي‬‫الرحمن‬‫هللا‬ ‫بسم‬‫م‬

2. “IVF Outcomes for Women with PCOS
after Fresh and Frozen Embryo
Transfer “
Osama S. Abdalmageed
Assistant lecturer OB/GYN , Assiut University

3. Mentors
Prof. Dr. Sayed Abdelhamid Abdullah, MD
Professor of Obstetrics and Gynecology
Faculty of Medicine, Assiut University, Assiut, Egypt
Prof. Dr. Atef Mohamad Mostafa Darwish,
MD, PHD
Professor of Obstetrics and Gynecology
Faculty of Medicine, Assiut University, Assiut, Egypt
Prof. Dr. Alaa Eldin Mahmoud Ismail, MD
Professor of Obstetrics and Gynecology
Faculty of Medicine, Assiut University, Assiut, Egypt
Prof. Ashok Agarwal
Director and Professor, Center for Reproductive Medicine
Cleveland Clinic, Cleveland, Ohio, USA

4. Introduction
PCOS
 Common 8-25%
 40-70% infertile.
 Rotterdam criteria,
2004.
 Lines of infertility
ttt, ASRM,2007.
1st • OI using CC
2nd • LOD/ Gonadotropins
3rd • IVF
(Sirmans and Pate 2013)
(Teede, Deeks et al. 2010)

5. Introduction
PCOS may be Challenging in IVF
 OHSS
 More oocytes are retrieved BUT
Poorer Fertilization rate.
Higher total fertilization failure.
No much improvement in PR.
Higher miscarriage rate.
 Risk for pregnancy and neonatal complications.
 ?
(Balen, Tan et al. 1993)
(Dor, Shulman et al. 1990)
(Dale, Tanbo et al. 1991)
(Boomsma, Eijkemans et al. 2006)

6. Introduction
Development of In Vitro Fertilization
1978
• Conventional IVF
• Robert Edward & Patrick Steptoe
1988
• PZD (partial zona dissection)
• Cohen et al
1988
• SUZI (subzonal insemination)
• Ng et al
1992
• ICSI
• Michal Tucker

7. Introduction
ICSI
It has been suggested that ICSI, which was
initially developed to overcome male factor
infertility, can be applied in other non male
factor infertility such as complete fertilization
failure or low fertilization rate.
BUT!! The use of ICSI as a method of fertilization
has been abruptly increased without associated
justified indications.
(Oehninger and Gosden 2002)
(Mahutte and Arici 2003)
(Boulet, Mehta et al. 2015)

8. Introduction
Trends of ICSI (2004-2013) in US

9. Introduction
Trends ICSI for fertilization in Europe, 2005

10. Introduction
Is ICSI advantageous for PCOS?!!
The wide use of ICSI in the couples with
normo-zoospermic semen parameters catches
doubt on its possible advantages over
conventional IVF regarding the outcomes in
PCOS.
Limited number of studies and the results
are still conflicting !!
(Walls, Junk et al. 2012)
(Bahceci and Ulug 2005)

11. Introduction
Superovulation and Fresh ET
Superovulation may carry and additional
risk for an abnormal pregnancies.
Elevated peak E2 increase the risk of
pregnancy complications in women conceived
via IVF.
(Hayashi, Nakai et al. 2012)
(Thomopoulos, Tsioufis et al. 2013)
(Haavaldsen, Tanbo et al. 2012)
(Imudia, Goldman et al. 2014)
(Imudia, Awonuga et al. 2012)

12. Introduction
Frozen-Thawed ET
Frozen-thawed ET may have better obstetric
outcomes when compared to fresh ET cycles.
It is suggested that elective cryopreservation
of all embryos reduced the pregnancy
complications as opposed to fresh ET of
elevated E2 > 3450 pg/dl
(Maheshwari, Pandey et al. 2012)
(Weinerman and Mainigi 2014)
(Sazonova, Kallen et al. 2012)
(Imudia, Awonuga et al. 2013)

13. Introduction
Is Frozen-thawed ET Better than Fresh ET in
PCOS?!!
PCOS women undergoing IVF cycles with fresh
ET are expected to have superovulation and
supra-physiological levels of steroid
hormones.
(Jabara and Coutifaris 2003)

14. Introduction
IR and PCOS
IR has a central role in the pathogenesis of
PCOS.
The unfavorable outcomes in PCOS women
can be related to
Higher BMI
Higher waist-to-hip ratio
IR
(Tsilchorozidou, Overton et al. 2004)
(Fedorcsak, Storeng et al. 2000)
(Dale, Tanbo et al. 1991)

15. Introduction
Metformin
Conflicting results in PCOS.
2015 worldwide web-based survey: no
clear evidence to support the use of
metformin to improve the IVF outcomes in
PCOS women.
(Moll, van der Veen et al. 2007)
(Stadtmauer, Toma et al. 2001)
(Christianson, Wu et al. 2015)

16. Introduction
When to use Metformin in PCOS women?!!
Metformin in PCOS is recommended to be
restricted to women with glucose intolerance
and/or insulin resistance.
However, metformin has commonly been used
as a co-treatment with COH in PCOS women
undergo IVF.
It is not clear which group will benefit from
metformin administration in IVF. (ASRM/ESHRE, 2008)
(Bouchard 2010)
(Nestler 2002)

17. Thesis
Clinical Study (1)
Fresh versus
Frozen-Thawed
ET in Women
with PCOS
Undergoing
Autologous IVF
Cycles
Clinical Study (2)
IVF versus ICSI
for Couples with
PCOS and
Normozoosperm
ic Semen: An
Analysis of 4679
Cycles from SART
Clinical Study (3)
Impact of
Metformin on
IVF Outcomes in
Overweight and
Obese Women
with PCOS

18. Clinical Study (1)
Fresh versus Frozen-Thawed ET in
Women with PCOS Undergoing
Autologous IVF Cycles

19. Clinical Study (1)
Objectives
To compare CPR between fresh and frozen-
thawed embryo transfer in women with PCOS
undergoing autologous IVF cycles.
To compare implantation, miscarriage, and
LBRs between the fresh and frozen-thawed ET.
To examine the various predictors that may
influence the favorable CPR in the fresh or
frozen-thawed cycles.

20. Clinical Study (1)
Patients & Methods
Type of the study: Retrospective and
prospective study during the period 2010
through 2015.
Patients enrollment:
Inclusion criteria
Exclusion Criteria
Data collection tool:

21. Clinical Study (1)
Results
 Reviewing of 600 cycles autologous IVF, 133 cycles
met the inclusion criteria. 67 of them were fresh
cycles.
 Demographic and basal cycle characteristics of the
study population:

22. Clinical Study (1)
Results
 Cycle outcomes:

23.  Relation between CPR with different studied parameters
Cycle outcome
Test of sig. p
No pregnancy
(n = 62)
IUP
(n = 71)
No. % No. %
Type of the Cycle
Frozen-Thawed ET x-donor 40 64.5 26 36.6 2=
10.303*
0.001*
Fresh ET x-donor 22 35.5 45 63.4
AMH level (ng/ml) 7.74 ± 6.28 6.77 ± 4.76 Z= 0.885 0.376
D2 FSH level (mIU/ml) 6.16 ± 1.66 5.95 ± 1.67 Z=0.276 0.782
Peak estradiol level (pg/ml) 1602.76 ± 1631.02 2127.45 ± 1503.97 Z=2.323* 0.020*
Antral Follicles Count 29.0 ± 14.18 28.80 ± 14.22 Z=0.018 0.986
Embryo transferred 2.0 ± 0.72 2.23 ± 0.59 t= 1.976* 0.050*

24. Clinical Study (1)
Discussion
Our study is the first study illustrated the
comparison between the fresh and the frozen-
thawed ET in PCOS women.
We hypothesized that the supraphysiological
levels of steroid hormones in the fresh ET might
adversely impact the IVF outcomes in PCOS.
Surprisingly, we found that the CPL,
Implantation rate and LBR are much better in
the fresh cycles as compared to the frozen-
thawed PCOS cycles.

25. Clinical Study (1)
Discussion
In agreement with our study:
Author Study Question Methods Main Results
Sunkara et
al.
(2011)
Association between
number of eggs and
LBR in IVF
Retrospective cohort
study.
400,135 IVF cycles
(1991-2008, UK)
Strong association
between the number
of oocytes retrieved
and LBR until about 15
oocytes and plateau
from 15-20 then
decline beyond 20
Baker et al.
(2015)
Association between
the number of
retrieved oocytes
with LBR and low
birth weight.
Retrospective SART
data analysis (2004-
2010)
analysis of 231,815
cycles
Increase number of
retrieved oocytes 
higher LBR and lower
lower birth weight.

26. Clinical Study (1)
Discussion
In agreement with our study:
Author Study Question Methods Main Results
Rehman et al.
(2012)
Effect of E2 levels
on Pregnancy
outcomes in obese
women
Quasi-experimental
study.
323 women
grouped according
to BMI
Obese women had
lower estradiol
women with
decreased CPR.
Chen CH et al.
(2003)
Relationship
between peak
serum estradiol
levels and
treatment outcome
in in vitro
fertilization cycles
Retrospective
697 IVF-ET cycles
1999 to 2001
high peak E2 was
associated with
improved
pregnancy rates
after ET on day 5
but not on day 3.

27. Clinical Study (1)
Discussion
Against!
Author Study Question Methods Main Results
Simon et al.
(1998)
Increasing uterine
receptivity by
decreasing E2 levels
during
preimplantation
periods in high
responders during
FSH step down
protocol
-prospective
controlled study.
-91 IVF cycles (high
responders)
-not randomized.
-Stepdown
protocol.
With the use of
step-down protocol
in the prospective
high responders,
endometrial
receptivity can be
improved when E2
decreased in the
preimplantation
period.

28. Clinical Study (1)
Discussion
Against!!
Author Study Question Methods Main Results
Shapiro et al.
(2011)
Evidence of
impaired
endometrial
receptivity after
ovarian stimulation
for IVF
-prospective
randomized
controlled trial
-122 patients with
AFC>15
-main outcome was
CPR
CPR was 80% in the
cryopreservation
group and 65% in
the fresh group.

29. Clinical Study (1)
Conclusion
Our study suggests that CPR and LBR is
better in the fresh ET cycles in comparison to
frozen-thawed ET in PCOS women.

30. Clinical Study (2)
IVF versus ICSI for Couples with
PCOS and Normozoospermic Semen:
An Analysis of 4679 Cycles from
SART

31. Clinical Study (2)
Objectives
The main objective of this study was to
determine whether patients with PCOS have
better pregnancy outcomes following ICSI
versus IVF.

32. Clinical Study (2)
Patients & Methods
Retrospective cohort study
319584 autologous IVF cycles were reported in SART in the
period between January 1st 2011 until December 31 2012
cleavage stage
n=1634
IVF=822
ICSI=812
blastocyst stage
n=3045
IVF=1395
ICSI=1650
Exclusion criteria:
1-Any abnormal semen parameters.
2-Women age 40 years and more
2-women who had one or more causes of
infertility (other than PCOS)
3-Donor and frozen-thawed ET cycles
4-cycles with split fertilization of the oocytes
(both IVF and ICSI)

33. Clinical Study (2)
Patients & Methods
Outcome measures:
Statistical analysis:

34. Clinical Study (2)
Results
Cleavage (day 2-3, age <40, only PCOS), n = 1634
ICSI IVF P value
n 812 822 NA
Age (at the start of the cycle) years 32.6 32.50 0.63
Basal FSH (mIU/ml) 6.7 6.3 0.01
BMI 28.60 27.40 0.002

35. Clinical Study (2)
Results
Blastocyst (day 5-6, age <40, only PCOS), n = 3045
ICSI IVF P value
n 1650 1395 NA
Age (at the start of the cycle) years 32.10 31.80 0.07
Basal FSH (mIU/ml) 6.40 6.20 0.02
BMI 26.90 26.10 0.005
# of days of stimulation 11.96 11.96 0.96T

36. Clinical Study (2)
Results

37. Clinical Study (2)
Results
 Cycle outcomes table:
Cleavage , n = 1634 Blastocyst , n = 3045
ICSI IVF P value ICSI IVF P value
n 812 822 NA 1650 1395 NA
#Oocytes retrieved 11.47 13.05 <0.001 17.96 18.63 2.97E-02
#2PN 5.89 6.89 <0.001 11.17 11.92 <0.001
Fertilization rate 54.60 55.60 0.52 64.00 66.00 0.005

38. Clinical Study (2)
Results
 Cycle outcomes (the cleavage stage ET):
Cleavage (day 2-3, age <40, only PCOS), n = 1634
ICSI IVF P value
n 822 812 NA
Clinical pregnancy rate (%) 46.9 50.0 0.34
Live birth rate (%) 38.7 39.9 0.3
Implantation rate (%) 69 63 0.7

39. Clinical Study (2)
Results

40. Clinical Study (2)
Results
 Cycle outcomes (the blastocyst stage ET):
Blastocyst stage (day 2-3, age <40, only PCOS), n =****
ICSI IVF P value
n 1395 1650 NA
Clinical pregnancy rate (%) 61 67.5 0.01
Live birth rate (%) 51.2 58.7 0.01
Implantation rate (%) 76 83 <0.001

41. Clinical Study (2)
Results

42. Clinical Study (2)
Discussion
Against!

43. Clinical Study (2)
Discussion
With!!!
IVF ICSI
n (total oocytes) 72 78
IVM oocytes (%) 79% 71%
Fertilization rate (%) 59% 68%
Blastocyst (%) 61% 55%
Cumulative implantation rate
(%)
42.86% 42.86%

44. Clinical Study (2)
Conclusion
Contrary to previous studies, ICSI does not offer an
advantage over conventional IVF in terms of number
of oocytes fertilized, CPR, or LBR in PCOS women
undergoing IVF.

45. Clinical Study (3)
Impact of Metformin on in vitro
fertilization (IVF) Outcomes in
Overweight and Obese Women with
Polycystic Ovary Syndrome (PCOS)

46. Clinical Study (3)
Objectives
The aim of this study was to determine if
metformin therapy improves in vitro
fertilization (IVF) outcomes in overweight and
obese polycystic ovarian syndrome (PCOS)
subjects.

47. Clinical Study (3)
Patients & Methods
Type of the study: Prospective non randomized
and retrospective controlled study.
Study population:
Inclusion and exclusion criteria:
Recruitment:
Outcome measures:

48. Clinical Study (3)
Results
(+) Metformin (-) Metformin p value
Number of the cycles (n) 51 51 N/A
Age (Mean± SD) 31.1 ± 3.7 32.89 ± 3.7 0.61
BMI (Mean± SD) 33.80 ± 4.4 32.90 ± 6.7 0.11
Duration of infertility (Mean± SD) 2.50 ± 1.1 2.79 ± 1.4 0.38
 Patient’s baseline characters

49. Clinical Study (3)
Results
 IVF cycle characters:
(+) Metformin (-) Metformin p-value
Number of the cycles 51 51 N/A
Basal estradiol* (Day 2) 25.16±17.8 23.59±8.4 0.57
Number of Antral Follicle Count (AFC)* (Day 2-5) 34.35 ± 13.77 30.43 ± 16.89 0.21
Basal FSH* (Day 2) 6.59 ± 1.95 6.05 ± 2.06 0.18
Basal LH* (Day 2) 7.44 ± 2.11 7.63 ± 2.74 0.85
TSH* 1.51 ± 0.81 1.79 ± 0.78 0.21
Triggering estradiol* 2098.33±
859.30
2997.89±
1540.69
0.005
Total gonadotropin doses* 1708.1±
533.42
1856.69±
761.63
0.23

50. Clinical Study (3)
Results
 The reproductive outcomes:
(+) Metformin (-) Metformin p value
Number of the cycles 51 51 N/A
Retrieved oocytes* 9.06 ± 4.23 16.86 ± 8.30 < 0.01
# 2pn* 5.65 ± 2.66 9 ± 4.55 < 0.01
Fertilization rate (%) (288/462)62.33 (459/860)53.37 0.10
Clinical Pregnancy rate (%) (17/51) 33 (14/51) 27.5 0.52
Implantation rate (Sacs per total ET) % (24/153) 15.67 (18/153) 11.76 0.32
Miscarriage rate(%) (4/17) 23.52 (5/14) 35.71 0.46
Multiple pregnancy rate (%) (7/51) 13.37 (2/51) 3.9 0.08
Live birth rate (%) (13/51) 25.49 (9/51) 17.65 0.34

51. Clinical Study (3)
Discussion
 In agreement with our study:
Author Study Question Methods Main Results
Palomba et al.
(2011)
Does metformin affect
the ovarian response to
gonadotropins for in
vitro fertilization
treatment in patients
with polycystic ovary
syndrome and reduced
ovarian reserve?
Prospective, parallel,
randomized, double-
blind, placebo-
controlled clinical trial
Enrollment was stopped
after 88 participants
had been randomized
and analyzed due to an
unacceptable increased
risk of poor ovarian
response in the
metformin arm.
Costello et al.
(2006)
&
Palomba et al.
(2013)
metformin co-
administration during
gonadotrophin
ovulation induction or
IVF in women with
polycystic ovary
syndrome
A systematic review and
meta-analysis of
randomized controlled
trials
co-administration of
metformin to
gonadotrophin OI does
not significantly
improve ovulation or
pregnancy rates or live
birth rates but reduces
the risk of OHSS

52. Clinical Study (3)
Conclusion
The prospective hyperresponders overweight and
obese PCOS subjects will not benefit from short-
term Metformin administration regarding the IVF
outcomes.

53. International publications and presentations
(1)

54. International publications and presentations
(2)

55. International publications and presentations
(3)

56. International publications and presentations
(4)

57. International publications and presentations
(2)

58. Acknowledgement
To my dear supervisors for their great help, guidance in the study
design and organization of the work.
To the members of Health sciences research department, Duke
University , United States for analyzing the data and statistical work.
To the patients for their consent to participate in the study
To my colleagues and to the nursing staff for their kind assistance
during the whole period of the study.
To my family whose love and support enabled me to keep the focus and
drive towards carrying out this work.