1. Ovulation induction TAQI Consultant OB/GYN,Infertility,IVF
Operative laparoscopy,and Ultrasonography.
AS-SALMA Hospital

2. Over the years Patient Expectations have not changed…
xx/xx/xxxx
‘to become Pregnant and to have a healthy
Baby’
Editor: Presentation name here

3. What are our chances of having a baby?

4. Objective
To highlight the rationale, principles and different protocols of ovarian stimulation in cases of I.V.F

5. There is no golden standards, guidelines or protocol.
Any of the following slides is packed up with hundreds of reputed studies.
But …..still can be logically criticized
As there is no golden rule,inuction of ovulation depends largely on the provider experience and patients merits.
Think twice before starting induction, and avoid the routine.

6. From “one size fits all” to taylor made COS
Taylor made for perfect individualization
1st step for success: Take the exact measurements
In this meeting we are going to talk about individualization. And individualization is ment for opyimization. In other words, what we are looking for, is to the taylor made aproach, for a perfect individualization.
However, and in order to make the taylor mde suit, the first thing that we need to do, is to take the exact measurements, to know what is going to be the best choice for the customer

7. Many variables can impact treatment success
xx/xx/xxxx
Many variables can impact treatment success
Patient characteristics
Age
Type of infertility
Psychological stress
Oocyte / Embryo Competence
Laboratory Conditions
Embryo transfer procedure
Type of stimulation regimen
Type of gonadotrophin preparation
Keck RBM Online , 2005
Editor: Presentation name here

8. Aim of COH
Regulated superovulation by turning off the patient’s own HPO system (down regulation) followed by stimulation.
Recruiting multiple follicles
Control timing of ovulation (eggs can be surgically retrieved before they are ovulated)
Prevention of premature LH surge
To time the insemination
Increase the pregnancy rate

9. Monitoring To time HCG injection Decreases OHSS
Decreases multiple pregnancy
Follicular monitoring from D9
S. estradiol levels did not give any additional information in various studies

10. Monitoring ovarian stimulation
Transvaginal ultrasound scanning :
. No. & size of follicles
. Pattern & thickness of endometrium
 Estrogen blood level

11. Traditional COH HMG or FSH 300 IU on 2° day cycle
HCG IU on leading follicle >17 mm and at least two follicles >15 mm
Pick-up after h
P4 50 mg i.m. for luteal supplementation

12. Traditional COH FSH remain elevated
recruitment and growth of ovarian follicles continues throughout treatment
This FSH serum pattern profoundly diverges
from the spontaneous menstrual cycle
* Filicori M: Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle . J Clin Endocrinol Metab ;62:1136–1144

13. Traditional COH
heterogeneous size cohorts of follicles are often found at hCG day
the optimal outcome of COH would be the selective attainment of numerous large mature homogeneous follicles.
* Arnot AM , Vandekerckhove P , DeBono MA , Rutherford AJ . Follicular volume and number during in-vitro fertilization (association with oocyte developmental capacity and pregnancy rate) . Hum Reprod ;10:256–261

14. Gn-RH-a protocols long protocol short (“flare-up”) protocol
ultrashort protocol
microdose flare protocol

15. Long protocol: Avoid pre-menses FSH surge Follicles timing
Avoid premature LH surge
Higher follicular recruitment (synchronization)
Improvement immune attitude
Expensive cost
High responders
PCOS

16. short protocols follicles timing avoid premature LH surge
lower follicular recruitment
make procedures easier
Poor responders

17. PR/transfer in Gn-RH-a
Flare-up protocol
19.2%
Long protocol
25.7%
without analogues
23.2%
FIV nel periodo (da FIV-NAT ’97) sec. Barrière et al. 1999

18. Gn-RH-a Long protocol 1
Gn-Rh-a depot 3.75 mg in one dose on 21st day only of previous cycle or
Gn-Rh-a low-dose daily on the 21st day of previous cicle to HCG day:
Buserelin (Suprefact fl 5.5 ml) 0.3 ml fl s.c.
Buserelin nasally 1 buff x 3/d (300 μg)
Leuproreline (Enantone die fl s.c.) 0.2 ml/day
Triptoreline (Decapeptyl die fl s.c.) 0.2 ml or
on any day when:
LH <0.5
E2 <30
No ovarian cyst >10 mm

19. Gn-RH-a long protocol 2
FSH/HMG IU/day on 2nd cycle day to HCG day
HCG IU on the least two follicles >18 mm
Pick-up after hours
P4 supplementation
HCG IU six days after E-T

20. Short (flare-up) protocol
Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle day only
FSH IU/d on 3th day (step-down regimen)
HCG IU (18 mm )
Pick-up after h
HCG (+ P4)

21. Gn-RH-a flare low dose protocol
EE-P for 1-2 cycles
on 1st cycle day at HCG day:
Triptoreline (decapeptyl die) 0.2 ml (0.1 mg) s.c. daily
Leuproreline acetate (enantone die) 0.2 ml (1 mg) s.c. daily
Buserelin (Suprefact flac 5.5 ml) 0.3 ml s.c.
Buserelin nasally 3 buff/day (300 μg) or
on any day when:
LH <0.5
E2 <30
No ovarian cyst >10 mm
r-FSH/HMG UI/d on 3rd cycle day

22. on 1° days Gn stimulation on 5°-6° days one leading follicle ≥14 mm
Antagonists protocol
on 1° days Gn stimulation
on 5°-6° days
one leading follicle ≥14 mm
HMG or FSH + LH added
Fixed and early start of the antagonist is probably more effective than an individualized and late start.

23. Gn-RH Antagonist disavantages advantages:  peak E2 on HCG day
 mature follicles
 oocytes
 embryos
 PR
advantages:
Prevention surge LH
larger cohort of follicles
Avoidance of adverse effects of agonists
More friendly stimulation protocol
 OHSS

24. Luteal supplementation in agonists/antagonists protocols
Pituitary depletion
Pituitary desensitization
Negative estrogen feed-back
Compulsory supplementation E/P
HCG supplementation absolutely necessary !!!

25. P4 secretion Follicular phase Luteal phase * Ovary 48% 95%
Adrenal gland 4%
from pregnenolone 1%
*P4 serum level: 4 ng/ml is low level; 40 ng/ml is high

26. Luteal E2 supplementation
In IVF cycles, the levels of E2 and P4 drop in the mid-late luteal phase
Lower E2 at 11 days after pick-up is associated with lower pregnancy rate
E2 orally 2-6 mg/d (Progynova cpr 2 mg) *
Start on:
E-T day or
7 days after E-T
Increases implantation rate
Increases pregnancy rate
* Lukaszuk K: Fertil Steril 2005;83:

27. poor responders protocols

28. Poor responders diminished ovarian reserve
A lower expression of FSH receptor in the granulosa cells
Advanced maternal age
E2 < 500 pg/mL on day of hCG
<4 de Graaf follicles on HCG day
lower fertilization rates
lower cleavage rates
lower resulting embryos
Lower implantation rate
lower pregnancy rates
“occult ovarian failure”
10–25% of the ART population*
* Keay et al., 1997 ; Karande and Gleicher, 1999 ; Fasouliotis et al., 2000 ; Tarlatzis et al., 2003

29. increase Gn dose first and simplest approach
limited benefit to 450 IU per day
300 IU FSH + hMG 150 IU
beyond this amount little or no improvement
Murat Arslan: Fertil Steril 2005; 84,3:

30. Luteal estradiol protocol *
outcome
All cycles
Luteal Estradiol
Standard protocol
Clinical Pr
38,3%
40,9%
31,3%
Miscarriage rate
43,5%
38,9%
60,0%
Delivery rate
20.0%
25.0%
12.5%
* Frattarelli J, et al: “A luteal estradiol protocol for expected poor-responders improves embryo number and quality” Fertil Steril 2008;89,5:

31. High responders protocol
CC 100 mg/d 3°-7° days
FSH 150 UI s.c. on cycle day 9 at HCG day
antagonist 0.25 mg/d delayed regimen
Aspirin 100 mg/d on 1° at 45° cycle day

32. High responders protocol 2
Gn 225 UI/d on 2° cycle days
step-down regimen
antagonist 0.25 mg/d on 2° day up HCG day
Doxycycline* 80 mg/Kg/day (inhibits vascular leakage)
* Folkman HJ: fertil Steril 2007;88,S1:O14
*Bassado cpr 100 mg

33. AA high responders III 0% OHSS
FSH 225 IU/d on the 2° cycle day (step-down regimen)
antagonist 0.25 mg/d on the 2° cycle at HCG day
Agonist (0.50 mg) as HCG trigger to achieve an endogenous LH surge
when E2 ≥ pg/ml (range )
0% OHSS

34. Agonist vs. HCG as trigger
Gn-RH-a:
HCG UI
mature oocytes
premature oocytes
implantation rate
clinical pregnancy
ongoing pregnancy
OHSS    

35. OHSS/Coasting Until drop of estrogen level <3.000 pg/ml
Coasting >3 days no affects on Pr
Egbase PE , Al Sharhan M , Berlingieri P , Grudzinskas JG . Serum oestradiol and progesterone concentrations during prolonged coasting in 15 women at risk of ovarian hyperstimulation syndrome following ovarian stimulation for assisted reproduction treatment . Hum Reprod ;15:2082–2086

36. PCOS Protocol Pre-treatment with metformin ≥6 months 2.000 mg/day
Improvment in menstrual cyclicity
Long-protocol agonist
Higher pregnancy outcome F
Essah et al Fertil Steril 2006;86,1:

37. The core of an assisted reproduction program is oocyte quality
Recognition of the right maturation state of oocytes obtained from stimulated cycles
remains the major problem
Polar body extrusion indicates only meiotic or nuclear maturation
3/25/2017

38. Acquisition of developmental competence “cytoplasmic maturation”, is a fundamental event that render the oocyte competent to be fertilized and able to support the embryo cleavage
Insufficient or incomplete cytoplasmic maturation of the oocyte has a negative effect on IVF outcome
3/25/2017

39. Although nuclear and cytoplasmic maturation can proceed as an independent processes, developmental competence of oocytes is conferred only when the two processes are closely integrated.
Meiotic and cytoplasmic maturation of oocytes collected in stimulated cycle is asynchronous (Sundstrom and Nilson 1988).
3/25/2017

40. Estradiol and cytoplasmic maturation
There are evidences that estradiol exerts a direct effect on oocyte cytoplasmic maturation via a non genomic calcium-mediated mechanism which contribute to oocyte competence
Tesarik 1995 and 1997
Revelli 1998
Zheng 2003
3/25/2017

41. Considerations
Over 30 years passed since the first IVF success, but the implantation rate did not substantially improved.
Although a great improvements in ART technologies and ovarian stimulation regimens, around 80% of produced embryos does not implant
The number of oocytes per pregnancy/birth remains high if not increased.
Increasing number of harvested oocytes
Lower oocyte utilization rate
3/25/2017

42. The efficiency of oocyte utilization has not improved significantly since the early 1980s
irrespective to the improved level of ovarian stimulation, the problem continue to lie with finding and identifying the “right oocyte”
3/25/2017

43. The major limiting factor is oocyte quality
However:
Despite the impressive improvements and innovations in human assisted reproduction treatment:
The pregnancy rate per retrieved oocyte remains far too low (Nayudu et al 1989b Inge et al. 2005)
The major limiting factor is oocyte quality
Oocytes developmental competence is mainly acquired during folliculogenesis

44. Oocyte maturation assessment
Retrieved eggs were immediately denuded and assessed for their maturity, and then inseminated by ICSI GV MI
MII
Immature oocytes
Slightly immature oocytes
Mature oocytes
3/25/2017

45. Embryo grading
Embryos were scored on the basis of morphological appearance:
size of blastomeres and degree of
fragmentation
3/25/2017

46. SUMMARY Controversies on gonadotropins Controversies on analogues
Controversies on E-P pills
Controversies on LH added
Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr” Fertil Steril 2005;84,3:

47. Conclusion(s)
Ovarian stimulation is a critical step in in vitro fertilization therapy.
A variety of controlled ovarian hyperstimulation regimens are available and efficacious,
but individualization of management is essential and depends on assessment of the ovarian reserve.
Identification of the etiologies of poor ovarian response constitutes a formidable challenge facing reproductive endocrinologists.
Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr” Fertil Steril 2005;84,3:

48. Conclusion
Ovarian stimulation is the fundamental tool of subfertility treatment
Different options pose challenges
Choice depends on doctors expertise and patients condition, choice
Increases the pregnancy rate
Judicious monitoring to avoid complications

50. ONE SATISFIED PATIENT IS WORTH THOUSANDS OF GUIDELINES AND PROTOCALS
P0INT TO REMENBER
ONE SATISFIED PATIENT IS WORTH THOUSANDS OF GUIDELINES AND PROTOCALS

51. ?

53. ONE SATISFIED PATIENT IS WORTH THOUSANDS OF GUIDELINES AND PROTOCALS
P0INT TO REMENBER
ONE SATISFIED PATIENT IS WORTH THOUSANDS OF GUIDELINES AND PROTOCALS

54. Thank you