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![666 Women
• Gn group had more livebirths than CC
• [52%] vs [41%] p=0·012
• Addition of IUI did not increase
livebirths compared with intercourse
p=0·11
• But what about cost ??](https://image.slidesharecdn.com/recentadvances-180110204140/75/ovarian-stimulation-a-2018-update-8-2048.jpg)
Uploaded byHesham Al-Inany
ovarian stimulation : a 2018 update
The document discusses recent advances in ovulation induction (OI) and compares the effectiveness of low-dose FSH and CC treatments for women with PCOS and anovulatory infertility. It highlights that low-dose FSH leads to higher pregnancy rates but considers costs and convenience in treatment decisions. The text also examines protocols for OI, innovations in gonadotropin use, and the management of poor responders, underscoring the shift in practices and potential future directions in fertility treatments.
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ovarian stimulation : a 2018 update
- 1. ا ِن َٰمْحهالرِ هاَّلل ِمْسِبِيم ِحهلر
- 2. Recent advances inovulation induction 2018 • Hesham Al-Inany, M.D, PhD • [email protected] • Mobile : 01112220298
- 3. O.I • Monofollicular development •Multifollicular development
- 4. Monofollicular development • Paradigmshift • CC to Gn
- 5. • Pregnancies andlive births are achieved more effectively and faster after OI with low-dose FSH than with CC. • This result has to be balanced by convenience and cost in favour of CC. • FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients. Homburg et al, 2012 CC vs low-dose FSH for treatment of infertile women with PCOS: a randomized multinational study
- 6. CC Gn P-value Clinical pregnancies(per patient) 54 (44%) 76 (58%) 0.03 Ongoing pregnancies (per patient) 48 (39%) 68 (52%) 0.04 Clinical pregnancies (per cycle) 54 (17.4%) 76 (26.4%) 0.008 Ectopic pregnancies 1 1 Miscarriage rate per pregnancya 5 (9.2%) 7 (9.2%) Multiple pregnancies (twins only) 0 2 (3.4%) Cumulative pregnancy rate Cycle 1 12.9% 25.6% Cycle 2 29.3% 44.8% Cycle 3 41.2% 52.1% 0.02
- 7. The M-OVIN (Lancet,Dec. 2017)
- 8. 666 Women • Gngroup had more livebirths than CC • [52%] vs [41%] p=0·012 • Addition of IUI did not increase livebirths compared with intercourse p=0·11 • But what about cost ??
- 9. Reversed hMG/CC (Al-Inany etal) (ACTRN12607000568415)
- 10. hMG (4 days)then CC 75 IU/HMG CD3 CD7 150 mg CC hCG IUI DF ≥ 18 mm 34-36h
- 11. Control group 75 IU/HMG CD3hCG IUI DF ≥ 18 mm CD7 34-36h
- 12. Both groups • Folliculometry •hCG when follicle reach 18mm or more • Serum LH on day of hCG • IUI 34-36hs later • Micronised progesterone for 18 days
- 13. Assessed for eligibility(n= 245) Excluded (n= 15) Not meeting inclusion criteria (n=7) Refused to participate (n=5) Social reasons (n=3) Received IUI (110) Analyzed (n=110) Cycles cancelled (n=5) Inadequate response (n=4) Hyper-response (n=1) Group I (n=115) received Merional + CC Cycles cancelled (n=8) Inadequate response (n=6) Hyper-response (n=2) Group II (n=115) received Merional alone Received IUI (107) Analyzed (n=107) Allocation Analysis Follow-Up Enrollment Randomized (n=230)
- 14. Results Variable HMG/CC (n=110) HMG (n=107) P value LHon day of hCG (miu/ml) for cases with no premature LH surge 7.3 ± 1.8 7.8 ± 2.2 NS Number of Follicles ≥ 16 mm 2.4 ± 0.97 1.3 ± 1.1 P < 0.05* Number of patients with premature LH surge 6 (5.45%) 17 (15.89%) P<0.001* End. Thickness (mm) 5.9 ± 0.7 4.9 ± 1.9 NS Clinical Pregnancy 11 (10%) 9 (8.41%) NS
- 15. Monofollicular :Conclusion • Thereis a clear evidence that justify shift from CC to Gn low dose for O.I • hMG for 4 days followed by CC seems to be cost effective regimen
- 16. Multifollicular development • Pituitarydesensitisation • COH • Triggering with hCG • OPU • Fertilization by IVF or ICSI • Culture embryos • ET • Luteal support
- 17. The Ideal COHProtocol .. .. • Improve pregnancy rate • Reduce complications (OHSS) • Consider the financial status of patients.
- 18. Reaching a consencus •Which protocol • Which Gn • Is there a room for innovations
- 19. Induction with exogenousGnRH Ultralong Long (luteal down-regulation) Long ( follicular down-regulation) short ultrashort Day 1 Day 3 Day 10 hCG 1-3 mo 21 Gonadotropin GnRHa
- 20. Decapeptyl 0.1 • Longluteal phase protocol Day 15 21 281 GnRHa 10-14 day hMG 225-300 IU* Thin endometrial thickness Estradiol < 50 pg/ml Most frequent protocol
- 21. No OCPpretreatment Check patient cycle day 2 FSH 100-225 IU Antagonist earlier than later LH not necessary GnRH Antagonist Protocol Cycle day 2 Transvaginal US + (if desired) hormonal profile For regular IVF patients: 5-9 antral follicles per ovary Age <35 years No PCOS No history of poor responses No endometriosis Duration of treatment based on clinical judgment in consultation with patient (usually 2 USs) Cycle day 2/3 Start FSH 150-200 IU. Continue Stimulation days 5-6 Start GnRH antagonist administered daily. Continue Monitoring according to clinic practice US (+ blood test if required) FSH dose adjustments may be considered 3 follicles 15-17 mm Day of triggering Ensure interval between antagonist and hCG does not exceed 30 h hCG 5000-10,000 IU Oocyte retrieval 34 h YES NO US = ultrasonogram; OCP = oral contraceptive pill. Devroey et al. Hum Reprod. 2009;24:764.
- 22.
- 23. Summary GnRH = gonadotrophin-releasinghormone; IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; RCT = randomized, controlled trial. Al-Inany H, et al. Cochrane Database Syst Rev 2011; May 11;5:CD001750. No statistically significant difference in live birth rate (9 RCTs; OR 0.86, 95% CI, 0.69 to 1.08) No significant difference in ongoing pregnancy rate (28 RCTs; OR 0.88, 95% CI, 0.77 to 1.00) Significantly lower incidence of OHSS (29 RCTs; OR 0.43, 95% CI, 0.33 to 0.57) ‒ 50% relative reduction
- 24. No need forfurther research • Al-Inany et al, 2016 included 7640 participants. • It is very unlikely to get a research that can change these findings
- 25. Next • Which protocol •Which Gn
- 26. Which Gonadotropin? • Humanmenopausal gonadotropin(hMG) • Highly purified FSH • Recombinant FSH (r FSH)
- 27.
- 28. Gn: 2016 FinalWord Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G Al-Inany
- 29. Conclusion : 7339women • Gonadotrophins are Gonadotrophins are Gonadotrophins
- 30. Be objective! • Recombinantvs. Urinary gonadotrophins – No difference, known since mid 1990s “It is obvious why 7339 patients were included in redundant trials: industry funding” 30 10-1-2018
- 31. Innovations ?!! • Triggeringwith GnRH a • Long acting FSH • Poor responders • others
- 32. GnRH a vshCG • Aiming to reduce severe OHSS • Only in Antagonist cycles • GnRHa works for 48hrs max • hCG works for 8-10 days • If safer, why not to apply for all cases?
- 33. Pregnancy rates reducedwith Antagonist / agonist triggering
- 34. Dopamine agonists forprevention of OHSS • VEGF induces VP (vascular permeability)1,2 • Effects of Dopamine agonist attributable to VEGF receptor dephosphorylation3 • Dopamine agonist prevents VP in a dose dependent manner without affecting angiogenesis and implantation in humans (n = 35 treated in face of OHSS)4 • Dopamine agonist reduced the amount of ascites, hemoconcentration and incidence of moderate-severe OHSS5 • Dopamine agonist once daily x 10 days starting day of trigger 1) McClure, et al, Lancet, 1994; 344: 235-236. 2) Bates, et al, Vascul Pharmacol, 2002; 39: 225-237. 3) Gomez, et al, Endocrinology, 2006; 147: 5400-5411. 4) Alvarez, et al, Hum Reprod, 2007; 22: 3210-3214. 5) Alvarez, et al, J Clin Endocrinol Metab, 2007; 92: 2931-2937.
- 36. Corifolitropin alfa • Longacting FSH • Under the name of Elonva • Single shot • Not self administered • Not cheaper
- 37. disadvantages • no doseadjustments • Once given, can not be withdrawn • Corifollitropin alfa is not suitable for mild or mono-follicular stimulation (Fauser et al., 2010) • Contraindicated in PCOS
- 38. Is it thefuture? • Novel protocol – Depot GnRHa – Long acting FSH • (Haydardedeoğlu , Kılıçdağ .2016)
- 39. High dose FSHat hCG triggering • Novel concept • Give four ampoules of FSH at time of hCG injection • 10% increase in PR??
- 40. LH surge isassociated with FSH surge to a lesser extent
- 41. Poor Responders • Paradigmshift • Antagonist is now the preferred protocol
- 42. PRIMA 2017 Mild versusconventional ovarian stimulation for IVF/ICSI treatment • in women with poor ovarian reserve • (PRIMA Trial)
- 43. 394 couples poorovarian reserve 197 couples Mild IVF 197 couples Conventional IVF treatmenttime OCP+ 150 IU FSH + GnRH antagonist Mid-Luteal Long GnRH agonist + 450 IU HMG Ongoing Pregnancy recruitmentendpoint PRIMA trial design
- 44. 450 IU HMG/day mid-luteal GnRH agonist hCG OPU ET Menstr. Mild Ovarian stimulation IVF Conventional Ovarian stimulation/IVF Interventions 150 IU FSH/day 5 days After laatste pil GnRH antagonist Sd 6 hCG OPU ET PIL ( 10 days) Cd2-3 Menstr.
- 45. Outcomes Primary outcome • Ongoingpregnancy rate Secondary outcomes • Clinical pregnancy • Biochemical pregnancy • Multiple pregnancy • Mmiscarriage rate, • Total FSH/HMG doses used for ovarian stimulation, • Cancellation rate • No. oocytes retrieved, no. metaphase II oocytes, • Fertilization rate • No. embryos obtained, embryo transfers, embryos frozen • Drop-out rate
- 46. Pregnancy outcomes Mild ovarian stimulation (N=197) Conventional stimulation (N=197) RR(95% CI) Ongoing pregnancy rate, n (%) 23 (12) 28 (14.6) 0.82 (0.49-1.37) Clinical pregnancy rate, n (%) 30 (15.7) 35 (18.2) 0.86 (0.55-1.34) Biochemical pregnancy rate, n (%) 41 (21.5) 38 (19.8) 1.08 (0.73- 1.60) Early Miscarriage rate, n (%) 7.0 (23) 7.0 (20) 1.0 (0.36-2.80) Multiple pregnancy rate 2.0 (6.0) 2.0 (5.0) 1.0 (0.14- 7.03)
- 47. Poor Responders: Double stimulationin the same cycle
- 48. Why to wastethese?
- 49.
- 50. Oocyte cryopreservation : Paradigmshift The American Society of Reproductive Medicine The Society of Assisted Reproductive Technology “……mature oocyte vitrification and warming should no longer be considered as an experimental procedure..” ASRM & SART 2013
- 51. Keep it tillu need it • Single woman > 35 • SLE • Rheumatoid • Cancer patient • Poor responder
- 52. For Virgin • Transrectal •Very easy • Accurate resolution • Needs bowel preparation • Needs umbrella of antibiotics
- 53. Cost • Same asICSI • No additional costs
- 54. 2018 : Paradigmshift • Monofollicular O.I : Gn • Prevention of OHSS : Dopmaine agonist • Poor responders: Antagonist • Oocyte cryopreservation
- 55.
- 56. Thank you Dr. HeshamAl-Inany MD, PhD e-mail : [email protected] Mobile : 01112220298