AN IDEAL OVULATION INDUCTION REGIMEN

1. AN IDEAL OVULATION INDUCTION REGIMEN

2. Types of ovarian stimulation • Ovulation induction • Superovulation • Controlled ovarian hyperstimulation

3. OVULATION INDUCTION The goal to develop follicles in anovulatory cycles as in PCOS and in hypogonadotrophichypogonadism PCOS-aim for monofollicular development

4. SUPEROVULATION Intentional production of more(≤ 4 ) mature follicles in a patient with: • unexplained infertility • Minimal and mild endometriosis • Mild male factor infertility

5. Controlled Ovarian Stimulation (COS) • The goal is to recruit multiple follicles that may yield mature oocytes, without inducing OHSS • In general, aim is to achieve 8 to 15 follicles characterizes an acceptable response. • Greater than 15 is considered a high response • COS is done for IVF-ICSI cycles

6. Drugs In Ovarian Stimulation • Clomiphene citrate and Tamoxifen • Letrozole/Anastrozole • Gonadotropins • GnRH analogues • GnRH agonists • GnRH antagonists

7. Protocols in COS • AGONIST PROTOCOLS - Long Protocol/ Stop Protocol/ Short Protocol/ Ultrashort Protocol/ Microflare • ANTAGONIST PROTOCOL -Fixed/ Flexible • Mild Stimulation Protocol / Softer protocols • Special Cases - Endometriosis- Ultra Long Protocol - Poor ovarian reserve- double stimulation Protocols -PCOS- Stair Step and Chronic Low dose Step up Protocols

8. Long follicular Gn GnRHa 1 2 14 1 2 3 OPU hCG Agonist given from Day 2 of previous cycle till day of trigger

9. Long luteal GnRHa Gn 1 2 14 21 1 2 3 OPU hCG Agonist given from Day 21 of previous cycle till day of trigger, dose is halved once gonadotrophins are added

10. Long Protocols • Protocol starts in the previous cycle ( follicular / luteal ) • Initial Flare up effect for 3-4 days • Followed by pituitary desensitisation and receptor down regulation • Agonist continued till trigger day, ensures prevention of LH surge

11. Short protocol Gn GnRHa 1 2 3 OPU hCG • Agonist given till day of trigger • Flare Up Effect f/b down regulation

12. Short / Flare Up protocol • Initial Flare Up Effect increases recruitment of follicles & augments growth • Overall lesser amount of gonadotrophins decreased costs. • Mainly used in poor responders • Disadvantage : High LH in initial part of the cycle High Androgen levels Benefits not supported by evidence.

13. Ultra short protocol Gn GnRHa 1 2 3 4 5 6 OPU hCG • Agonist given for 3 days • Flare Up Effect • Used in poor responders

14. GnRH Antagonist Protocol Multiple Dose Protocol : Cetrorelix0.25 mg S /C ( Long German - Lubec Protocol ) Ganirelix0.25 mg S / C * Half – Life - 13 Hours * Daily Injections till the Day of HCG Single Dose Protocol : Cetrorelix3 mg S / C ( Short French Protocol ) * Actions lasts for 96 hours ( 3 – 4 Days )

15. Antagonist Protocol CETRORELIX/GANIRELIX - 0.25 mg/day Fixed Day Regimen Multiple doses hCG r FSH/hMG 0 1 2 3 5 6 7 8 9 10 4 Cycle Day r FSH/hMG Single dose hCG CETRORELIX - 3 mg The antagonist is administered on day 5 / 6 of stimulation

16. Antagonist Protocol CETRORELIX 0.25 mg /day Flexible Regimen Multiple doses hCG r FSH/hMG 0 1 2 3 5 6 7 8 9 10 4 Cycle Day r FSH/hMG CETRORELIX 3 mg Single dose hCG The antagonist is administered when the lead follicle is 12- 14 mm, or E2 reaches 300 - 400 pg/ml

17. Definition Human Reproduction, Sept,2007.

18. Definition • Natural Cycle IVF: Oocyte collected in spontaneous menstrual cycle without administration of any medication at any time in the cycle. • Modified Natural Cycle: Administration of drugs in a spontaneous cycle with the aim of collecting a naturally selected single oocyte but with a reduction in chance of cycle cancellation. • Mild Stimulation IVF:FSH or HMG is administered at lower doses, and/or for a shorter duration in a GnRH antagonist co-treated cycle, with or without oral compounds.

19. Agonist vs Antagonist vs Mild

20. Kato Protocol DF >18 mm E2 >300 pg/mL/Oocyte No need for adding antagonist as clomiphene prevents premature LH surge GnRH agonist trigger D2 ET OPU 32-35 Hrs Clomiphene Citrate 50 50 50 50 50 50 50 50 50 150 150 150 FSH D3 4 5 6 7 9 10 11 15 16 8 12 13 14 17 S Teramoto, O Kato; Minimal ovarian stimulation with CC: A Large-scale retrospective Study: RBM Online: Volume 15, No 2, August 2007

21. LETROZOLE IN SOFT STIMULATION hCG ET Step Up Letrozole OPU 5.0 7.5 10.0 2.5 FSH Ultra Flare GnRHa 150 150 150 150 150 D3 4 5 6 7 9 10 11 15 8 12 13 14 Antagonist 0.25 mg sc/day

22. Ultra Long Protocol for Endometriosis GnRH Agonist for a period of 3 to 6 months prior to treatment with ART improves Clinical Pregnancy rates and decreases miscarriage rates in Infertile women with Endometriosis ESHRE Guidelines on Endometriosis Sept, 2013

23. ENDOMETRIOSIS

24. Various protocols that are beneficial in POR • Mild stimulation • Short agonist • Microflare • Shanghai protocol

25. Kuang et al; 2014 Antral follicles in the follicular phase and luteal phase recruited Combines two stimulation protocols in one cycle 2 oocyte retrievals in a single menstrual cycle Increase the number of oocytes and viable embryos RCT’s are required to evaluate the outcome

26. Double Stimulation protocol 2nd phase of stimulation if atleast 2 AFC (2-8 mm) post OPU

27. Long gonadotropin-releasing hormone agonist versus short agonist versus antagonist regimens in poor responders undergoing in vitro fertilization: A RCT (PRINT) Sunkara et al, Fert Stert Jan 2014 Results • Number of oocytes retrieved was significantly higher with long GnRH agonist compared with the short agonist regimen. • Duration of stimulation and total gonadotropin dose were significantly higher with long agonist compared with short agonist and antagonist regimens. Conclusion(s): Long GnRH agonist and antagonist regimens offer a suitable choice for poor responders, whereas the short agonist regimen may be less effective because of fewer eggs retrieved.

28. GnRH Antagonist Vs GnRH Agonist • IVF Live Birth Rates Similar for GnRH Antagonist and GnRH Agonist Protocols. -Al – Inany HG, Youssef MA,Aboulghar M, et al 2011 Gonadotropin – releasing hormone antagonists for ART Cochrane Database, Syst Rev 11, CDOO1750 • May be Preferred for - Poor Responders - Women with Diminished Ovarian Reserve

29. Individualised COS (ICOS) The main objective of individualisation of treatment in IVF is to offer every single woman the best treatment • Tailored to her unique characteristics • Maximizing success • Eliminating iatrogenic risks, such as OHSS • Minimizing the risk of cycle cancellation

31. Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patientsBosch E, Ezcurra D; ReprodBiolEndocrinol; 2011 Jun • COS in IVF - significantly improved outcomes, but current stimulation protocols are not optimal for all patient groups. • Alternatives to standard COS protocols, including mild and natural cycles, have shown some success, but no single approach is appropriate for all patients in a given population. • Treatment should be adapted for individual patients through iCOS and that, together with the further development of objective biomarkers of response, will be an important first step towards implementing personalised medicine in reproductive science