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

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

What are our chances of having a baby?

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

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.

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

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

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

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

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

Traditional COH HMG or FSH 300 IU on 2° day cycle HCG 10.000 IU on leading follicle >17 mm and at least two follicles >15 mm Pick-up after 33-36 h P4 50 mg i.m. for luteal supplementation

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 . 1986;62:1136–1144

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 . 1995;10:256–261

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

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

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

PR/transfer in Gn-RH-a Flare-up protocol 19.2% Long protocol 25.7% without analogues 23.2% FIV nel periodo 92-96 (da FIV-NAT ’97) sec. Barrière et al. 1999

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

Gn-RH-a long protocol 2 FSH/HMG 300-650 IU/day on 2nd cycle day to HCG day HCG 10.000 IU on the least two follicles >18 mm Pick-up after 33-36 hours P4 supplementation HCG 5.000 IU six days after E-T

Short (flare-up) protocol Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle day only FSH 225-600 IU/d on 3th day (step-down regimen) HCG 10.000 IU (18 mm + 15-16) Pick-up after 33-36 h HCG (+ P4)

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 300-650 UI/d on 3rd cycle day

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.

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

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

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

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;83:1372-1376

poor responders protocols

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

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; 84,3:555-569

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;89,5:1118-22

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

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

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 ≥ 3.700 pg/ml (range 3.000-7.500) 0% OHSS

Agonist vs. HCG as trigger Gn-RH-a: HCG 10.000 UI mature oocytes premature oocytes implantation rate clinical pregnancy ongoing pregnancy OHSS    

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 . 2000;15:2082–2086

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;86,1:230-232

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

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

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

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

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

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

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

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

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

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: 555-569

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: 555-569

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

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

?

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

Thank you