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

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Presentation on theme: "TAQI TAQI Consultant OB/GYN,Infertility,IVF Operative laparoscopy,and Ultrasonography. AS-SALMA Hospital."— Presentation transcript:

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

2 2 Over the years Patient Expectations have not changed… to become Pregnant and to have a healthy Baby

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

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

8 Aim of COH Regulated superovulation by turning off the patients own HPO system (down regulation) followed by stimulation. 1. Recruiting multiple follicles 2. Control timing of ovulation (eggs can be surgically retrieved before they are ovulated) 3. Prevention of premature LH surge 4. To time the insemination 5. Increase the pregnancy rate

9 Monitoring To time HCG injection To time HCG injection Decreases OHSS Decreases OHSS Decreases multiple pregnancy Decreases multiple pregnancy Follicular monitoring from D9 Follicular monitoring from D9 S. estradiol levels did not give any additional information in various studies 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 HMG or FSH 300 IU on 2° day cycle HCG IU on leading follicle >17 mm and at least two follicles >15 mm HCG IU on leading follicle >17 mm and at least two follicles >15 mm Pick-up after h Pick-up after h P 4 50 mg i.m. for luteal supplementation P 4 50 mg i.m. for luteal supplementation

12 Traditional COH FSH remain elevated FSH remain elevated recruitment and growth of ovarian follicles continues throughout treatment recruitment and growth of ovarian follicles continues throughout treatment * Filicori M: Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. J Clin Endocrinol Metab. 1986;62:1136–1144 This FSH serum pattern profoundly diverges from the spontaneous menstrual cycle

13 Traditional COH heterogeneous size cohorts of follicles are often found at hCG day 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. 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. 1995;10:256–261

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

15 Long protocol: 1. Avoid pre-menses FSH surge 2. Follicles timing 3. Avoid premature LH surge 4. Higher follicular recruitment (synchronization) 5. Improvement immune attitude 6. Expensive cost High responders PCOS

16 short protocols 1. follicles timing 2. avoid premature LH surge 3. lower follicular recruitment 4. make procedures easier Poor responders

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

18 Gn-RH-a Long protocol 1 Gn-Rh-a depot 3.75 mg in one dose on 21 st day only of previous cycle or Gn-Rh-a depot 3.75 mg in one dose on 21 st day only of previous cycle or Gn-Rh-a low-dose daily on the 21 st day of previous cicle to HCG day: Gn-Rh-a low-dose daily on the 21 st day of previous cicle to HCG day: Buserelin (Suprefact fl 5.5 ml) 0.3 ml fl s.c. Buserelin (Suprefact fl 5.5 ml) 0.3 ml fl s.c. Buserelin nasally 1 buff x 3/d (300 μg) Buserelin nasally 1 buff x 3/d (300 μg) Leuproreline (Enantone die fl s.c.) 0.2 ml/day Leuproreline (Enantone die fl s.c.) 0.2 ml/day Triptoreline (Decapeptyl die fl s.c.) 0.2 ml Triptoreline (Decapeptyl die fl s.c.) 0.2 ml or or on any day when: on any day when: LH <0.5 LH <0.5 E 2 <30 E 2 <30 No ovarian cyst >10 mm No ovarian cyst >10 mm

19 Gn-RH-a long protocol 2 FSH/HMG IU/day on 2 nd cycle day to HCG dayFSH/HMG IU/day on 2 nd cycle day to HCG day HCG IU on the least two follicles >18 mmHCG IU on the least two follicles >18 mm Pick-up after hoursPick-up after hours P4 supplementationP4 supplementation HCG IU six days after E-THCG 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 Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle day only FSH IU/d on 3 th day (step-down regimen) FSH IU/d on 3 th day (step-down regimen) HCG IU (18 mm ) HCG IU (18 mm ) Pick-up after h Pick-up after h HCG (+ P4) HCG (+ P4)

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

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

23 Gn-RH Antagonist advantages: Prevention surge LH Prevention surge LH larger cohort of follicles larger cohort of follicles Avoidance of adverse effects of agonists Avoidance of adverse effects of agonists More friendly stimulation protocol More friendly stimulation protocol OHSS OHSS disavantages peak E 2 on HCG day peak E 2 on HCG day mature follicles mature follicles oocytes oocytes embryos embryos PR PR

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

25 P 4 secretion Follicular phase Luteal phase * Ovary48%95% Adrenal gland 48%4% from pregnenolone 4%1% *P 4 serum level:4 ng/ml is low level; 40 ng/ml is high *P 4 serum level: 4 ng/ml is low level; 40 ng/ml is high

26 Luteal E 2 supplementation E 2 orally 2-6 mg/d (Progynova cpr 2 mg) * E 2 orally 2-6 mg/d (Progynova cpr 2 mg) * Start on: Start on: E-T day E-T dayor 7 days after E-T 7 days after E-T Increases implantation rate Increases implantation rate Increases pregnancy rate Increases pregnancy rate In IVF cycles, the levels of E 2 and P 4 drop in the mid-late luteal phase Lower E 2 at 11 days after pick-up is associated with lower pregnancy rate * Lukaszuk K: Fertil Steril 2005;83:

27 poor responders protocols

28 Poor responders diminished ovarian reserve diminished ovarian reserve A lower expression of FSH receptor in the granulosa cells A lower expression of FSH receptor in the granulosa cells Advanced maternal age Advanced maternal age E 2 < 500 pg/mL on day of hCG E 2 < 500 pg/mL on day of hCG <4 de Graaf follicles on HCG day <4 de Graaf follicles on HCG day lower fertilization rates lower fertilization rates lower cleavage rates lower cleavage rates lower resulting embryos lower resulting embryos Lower implantation rate Lower implantation rate lower pregnancy rates lower pregnancy rates 10–25% of the ART population* * Keay et al., 1997 ; Karande and Gleicher, 1999 ; Fasouliotis et al., 2000 ; Tarlatzis et al., 2003 occult ovarian failure

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

30 Luteal estradiol protocol * outcomeAll cycles Luteal Estradiol Standard protocol Clinical Pr38,3%40,9%31,3% Miscarriag e 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 CC 100 mg/d 3°-7° days FSH 150 UI s.c. on cycle day 9 at HCG day FSH 150 UI s.c. on cycle day 9 at HCG day antagonist 0.25 mg/d delayed regimen antagonist 0.25 mg/d delayed regimen Aspirin 100 mg/d on 1° at 45° cycle day Aspirin 100 mg/d on 1° at 45° cycle day

32 High responders protocol 2 Gn 225 UI/d on 2° cycle daysGn 225 UI/d on 2° cycle days step-down regimenstep-down regimen antagonist 0.25 mg/d on 2° day up HCG dayantagonist 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 * Folkman HJ: fertil Steril 2007;88,S1:O14 *Bassado cpr 100 mg

33 AA high responders III FSH 225 IU/d on the 2° cycle day (step-down regimen) FSH 225 IU/d on the 2° cycle day (step-down regimen) antagonist 0.25 mg/d on the 2° cycle at HCG day 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 Agonist (0.50 mg) as HCG trigger to achieve an endogenous LH surge when E pg/ml (range ) when E pg/ml (range ) 0% OHSS 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 Until drop of estrogen level <3.000 pg/ml Coasting >3 days no affects on Pr 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. 2000;15:2082–2086

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

37 37 The core of an assisted reproduction program is oocyte quality The core of an assisted reproduction program is oocyte quality Recognition of the right maturation state of oocytes obtained from stimulated cycles 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 Polar body extrusion indicates only meiotic or nuclear maturation 1/6/2014

38 38 Acquisition of developmental competencecytoplasmic maturation, is a fundamental event that render the oocyte competent to be fertilized and able to support the embryo cleavage Acquisition of developmental competencecytoplasmic 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 Insufficient or incomplete cytoplasmic maturation of the oocyte has a negative effect on IVF outcome 1/6/2014

39 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. 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). Meiotic and cytoplasmic maturation of oocytes collected in stimulated cycle is asynchronous (Sundstrom and Nilson 1988). 1/6/2014

40 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 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 Tesarik 1995 and 1997 Revelli 1998 Revelli 1998 Zheng 2003 Zheng /6/2014

41 Considerations 41 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

42 The efficiency of oocyte utilization has not improved significantly since the early 1980s 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 421/6/2014

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

44 44 Retrieved eggs were immediately denuded and assessed for their maturity, and then inseminated by ICSI Immature oocytes Slightly immature oocytes Mature oocytes Oocyte maturation assessment 1/6/2014 GV MI MII

45 45 Embryo grading Embryos were scored on the basis of morphological appearance: size of blastomeres and degree of fragmentation 1/6/2014

46 SUMMARY Controversies on gonadotropins Controversies on gonadotropins Controversies on analogues Controversies on analogues Controversies on E-P pills Controversies on E-P pills Controversies on LH added 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 CarrFertil Steril 2005;84,3: 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. Ovarian stimulation is a critical step in in vitro fertilization therapy. A variety of controlled ovarian hyperstimulation regimens are available and efficacious, 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. 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. 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 CarrFertil Steril 2005;84,3: 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 Conclusion Ovarian stimulation is the fundamental tool of subfertility treatment Ovarian stimulation is the fundamental tool of subfertility treatment Different options pose challenges Different options pose challenges Choice depends on doctors expertise and patients condition, choice Choice depends on doctors expertise and patients condition, choice Increases the pregnancy rate Increases the pregnancy rate Judicious monitoring to avoid complications Judicious monitoring to avoid complications

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

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

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