The last few years witnessed some major changes in ovarian stimulation and in this presentation , we tried to illustrate such changes

1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫الر‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬

2. Recent advances in ovulation
induction
2018
• Hesham Al-Inany, M.D, PhD
• Kaainih@yahoo.com
• Mobile : 01112220298

3. O.I
• Monofollicular development
• Multifollicular development

4. Monofollicular development
• Paradigm shift
• CC to Gn

5. • Pregnancies and live 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
• 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 ??

9. Reversed hMG/CC
(Al-Inany et al)
(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
CD3 hCG 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
LH on 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
• There is 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
• Pituitary desensitisation
• COH
• Triggering with hCG
• OPU
• Fertilization by IVF or ICSI
• Culture embryos
• ET
• Luteal support

17. The Ideal COH Protocol .. ..
• 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 exogenous GnRH
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
• Long luteal 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 OCP pretreatment
 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. Agonist
vs
Antagonist

23. Summary
GnRH = gonadotrophin-releasing hormone; 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 for further 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?
• Human menopausal gonadotropin(hMG)
• Highly purified FSH
• Recombinant FSH (r FSH)

27. 2008

28. Gn: 2016 Final Word
Madelon van Wely1, Irene Kwan2,
Anna L Burt3, Jane Thomas4, Andy
Vail5, Fulco Van der Veen6, Hesham G
Al-Inany

29. Conclusion : 7339 women
• Gonadotrophins
are
Gonadotrophins
are
Gonadotrophins

30. Be objective!
• Recombinant vs. 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 ?!!
• Triggering with GnRH a
• Long acting FSH
• Poor responders
• others

32. GnRH a vs hCG
• 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 reduced with
Antagonist / agonist triggering

34. Dopamine agonists for prevention 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
• Long acting FSH
• Under the name of Elonva
• Single shot
• Not self administered
• Not cheaper

37. disadvantages
• no dose adjustments
• 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 the future?
• Novel protocol
– Depot GnRHa
– Long acting FSH
• (Haydardedeoğlu , Kılıçdağ .2016)

39. High dose FSH at hCG triggering
• Novel concept
• Give four ampoules of FSH at time of hCG
injection
• 10% increase in PR??

40. LH surge is associated with FSH surge to a lesser extent

41. Poor Responders
• Paradigm shift
• Antagonist is now the preferred protocol

42. PRIMA 2017
Mild versus conventional
ovarian stimulation for IVF/ICSI treatment
• in women with poor ovarian reserve
• (PRIMA Trial)

43. 394 couples poor ovarian 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
• Ongoing pregnancy 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
stimulation in the same cycle

48. Why to waste these?

49. Euploid embryos

50. Oocyte cryopreservation :
Paradigm shift
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 till u 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 as ICSI
• No additional costs

54. 2018 : Paradigm shift
• Monofollicular O.I : Gn
• Prevention of OHSS : Dopmaine agonist
• Poor responders: Antagonist
• Oocyte cryopreservation

55. DIRMAS
Diploma in
Reproductive
Medicine & Surgery

56. Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com
Mobile : 01112220298