Intrauterine insemination is well established in the treatment of infertility. But which pretreatment leads to the best results? Do we have to trigger ovulation? What about luteal phase support? Whar patients do have the best chances? When do we have to switch to IVF? Evidence based answers to these questions an a bit of experience based suggestions.

1. OVARIAN HYPERSTIMULATION
FOR IUI
DR. ELMAR BREITBACH
DEUTSCHE KLINIK
BAD MÜNDER - HANNOVER

2. STIMULATION FOR IUI: GOALS
1. Improvement of Follicular Growth
2. Increasing the Number of Follicles
3. Treatment of Anovulation (PCOS)
4. Better Timing
5. Improvement of Luteal Phase

3. Is IUI worthwhile? And when? And how?
10%
unknown
32% 35%
both
23%

4. Is IUI worthwhile? And when? And how?
10%
unknown
1. Unexplained Infertility
32% 35%
2. Male subfertility
both
23%

5. IUI AND IDIOPATHIC STERILITY
What does the holy oracle of EBM say?
Cochrane Database Syst Rev. 2012
Sep 12;9:CD001838

6. IUI AND IDIOPATHIC STERILITY
1. IUI with OH increases the live birth rate compared to IUI
alone
2. PR increased for treatment with IUI compared to TI in
stimulated cycles
3. No increase of PR with IUI in natural cycles compared to
TI in natural cycles
Cochrane Database Syst Rev. 2012 Sep 12;9:CD001838

7. IUI AND IDIOPATHIC STERILITY
1. IUI helps
2. But only when combined with OH
Cochrane Database Syst Rev. 2012 Sep 12;9:CD001838

8. IUI AND MALE SUBFERTILITY
Again, we look at the Cochrane Database
Cochrane Database Syst Rev. 2007 Oct
17;(4):CD000360

9. IUI AND MALE SUBFERTILITY
1. Insufficient evidence for IUI to be superior above TI
with or without OH
2. Tendency for IUI plus OH against natural cycle but
only referring to PR not birthrate
Conclusion: Carefull selection like
asthenozoospermia with normal
spermcount
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD000360

10. IUI OVARIAN HYPERSTIMULATION
1. significant higher PR with gonadotrophins compared with
clomifen (OR 1.8, 95% CI 1.2 to 2.7)
2. Clomifen compared with aromatase inhibitors reporting
no significant difference
3. No significant difference depending on type of
gonadotrophin
4. Adding GnRH agonists increased multiple PR
5. High dosage gonadotrophin increases risks, not PR
Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005356

11. “EXPERIENCE BASED”CONCLUSIONS SO FAR
1. Choose the patients carefully
• Age
• Duration of infertility and reasons
• Sperm parameters
2. Ovarian Hyperstimulation > 30y
• Clomifen is a cheap good choice with some
limitations (cysts, flat endometrium)
• Low dose gonadotrophins alone (or combined with
CC) is the next step

12. Clomifen
1. First day of menstruation: Patient calls the
clinic
2. Basal hormonal assessment + US on day 3-5
3. Begin treatment starting 50mg daily
appointment for next examination (d 10-12)
4. Ultrasound, E2, LH, Prog, Cervixscore
5. Ovulation induction (hCG)
6. Insemination

13. WAIT! WHAT ABOUT HCG?
1. Insemination should be performed before ovulation
occurs
2. hCG could acertain that
3. It might induce a better luteal phase
Is it neccessary?

14. IS HCG NECCESSARY AT ALL?
1. Timing with spontaneous LH-surge significantly better
compared with hCG
Kyrou et al. Reprod Biomed Online. 2012
2. No difference between the two procedures
Zreig et al. Fertil Steril. 1999
Kosmas et al. Fertil Steril. 2007
Cochrane Database Syst Rev. 2010

15. HCG 24 HOURS OR 36 HOURS?
1. In IVF (with supressed endogenous LH) ovulation will not
occur before 40 hours after the injection
2. In IUI this might be different, depending on follicle size
and individual LH-surge
No difference between the two procedures
Rahman et al. Arch Gynecol Obstet. 2011
Robb et al. J Natl Med Assoc. 2004

16. HCG AT WHAT SIZE OF FOLLICLE??
16 - 17 mm (early) or
18 – 20 mm (late): No difference
da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012

17. OVULATIONS TRIGGER EBM
1. LH-Surge (with test sticks)
2. GnRH
3. hCG
Cochrane Database found no significant differences in
favour of any these procedures, but:
The choice should be based on hospital facilities, convenience for the patient, medical
staff, costs and drop-out levels. Since different time intervals between hCG and IUI did not
result in different pregnancy rates, a more flexible approach might be allowed.
Cochrane Database Syst Rev. 2010

18. OVULATIONS TRIGGER EXPERIENCEBASED
1. Timing of IUI ist easier with hCG
2. More convenience for patients
3. Easier planning of schedules in the clinic
4. Safer, when planning the IUI prior to ovulation

19. Clomifen
1. First day of menstruation: Patient calls the
clinic
2. Basal hormonal assessment + US on day 3-5
3. Begin treatment starting 50mg daily
appointment for next examination (d 10-12)
4. Ultrasound, E2, LH, Prog, Cervixscore
5. Ovulation induction (hCG)
6. Insemination

20. LUTEAL PHASE SUPPORT
1. micronized progesterone vaginal/oral administration
2. synthetic progesteron
3. hCG
RCT IUI with gonadotrophins: Significant improvement with
vaginal application
Erdem et al. Fertil Steril. 2009

21. Patient flow chart.
Kyrou D et al. Hum. Reprod. 2010;25:2501-2506
© The Author 2010. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oxfordjournals.org

22. LUTEAL PHASE SUPPORT
No improvement of pregnancy rates in normo-ovulatory
women stimulated with clomiphene citrate for IUI
Kyrou et al. Hum Reprod. 2010

23. LUTEAL PHASE EBM
1. Significant improvement with progesterone
2. Favouring synthetic progesterone over micronized
progesterone
3. hCG increases risk for OHSS
4. Estradiol is of no use
5. GnRH increases live birth rate
Cochrane Database Conclusion:
“For now, progesterone seems to be the best option as luteal phase support, with better
pregnancy results when synthetic progesterone is used.”
Cochrane Database Syst Rev. 2011

24. LUTEAL PHASE SUPPORT EXPERIENCEBASED
1. In normoovulatory women not neccessary
2. hCG is sufficent in those cases (with no risk for OHSS)
3. Age > 35 hormonal disturbances or irregular cyclus or
spotting: Progesteron vaginally
4. Independant of pretreatment

25. CLOMIFEN: SIDE EFFECTS
1. Unsolved: Induction of neoplasia if used more than 6x?
2. Insler-Score often reduced
3. Reduction of endometrial growth
4. Long term effects (half-life-time)
5. Rising LH-Levels (confuses the doctor, lowers the Quality of oocytes)
Adititional E2 or gonadotrophins.

26. Clomifen + hMG
1. Start on day three
2. Basal hormonal assessment + US
3. Begin treatment starting 50mg daily + hMG
every second day
4. Ultrasound, E2, LH, Prog, Cervixscore
5. Ovulation induction (hCG)
6. Insemination

27. CLOMIFEN + HMG
1. CC helps reduce the use of expensive gonadotropins
2. hMG reduces Clomifen side effects (flat endometrium,
cervixscore etc.)
3. In cases of clomifen resistance worth a try

28. Gonadotrophins
1. Start on day three
2. Basal hormonal assessment + US
3. Begin treatment starting 1 Inj. daily + hMG
every second day
4. Ultrasound, E2, LH, Prog, Cervixscore
5. Ovulation trigger (hCG)
6. Insemination

29. SUCCESS?

30. OHSS
1. Only in rare cases
2. PCOS patients are at risk
3. hCG triggers OHSS

31. BEST DOSAGE?
1. Depends on various factors
2. High age or low sperm count lowers the risk of multiples,
therefore even 3 or 4 follicles could be reasonable
3. low age, high AMH or signs of PCOS should lead to
lower dosage.
4. Better start too low rather than too high. 50 mg of
clomifen, 1 amp. hMG or 75 IU FSH are a good starting
dosage in most cases.

32. HOW OFTEN?
% 50
40
30
20
10
0
1. 2. 3. 4. 5.
pro Zyklus
Kumulativ
2 4
cycle

33. CONCLUSIONS
1. Indications: Unexplained infertility, carefully chosen
cases of male factor cases
2. Stimulation helps, gonadotrophins significantly better
than CC. Combine CC with hMG (reduce costs)
3. HCG for better planning/convenience, timing does not
matter (follicle size, time till IUI)
4. Luteal phase support: Progesteron first choice. HCG
more convenient, sufficient in young women with no
homonal problems.
5. IUI just for 3-4 times. After that, statistics works against
you (& your patient)

34. Thank You