This document summarizes new directions in in vitro fertilization (IVF) being explored at FertilitySA to address common problems experienced by couples. These include using growth hormone to increase egg yield for those with low ovarian reserve, selecting sperm for ICSI based on hyaluron receptors, preimplantation genetic testing to identify genetic problems, endometrial biopsies to improve implantation, and culturing embryos in media containing GM-CSF to help with recurrent miscarriage. Ongoing trials are exploring the use of corifollitropin alfa to reduce injections and improve outcomes. The overall aim is to continue improving treatment through research and providing individualized care.

1. New Directions in
IVF
Dr Louise Hull
Senior Lecturer and
Fertility Consultant

2. The IVF story

3. The
Untold
Story

4. Why don’t couples conceive with IVF?
They have problems:
We understand but can’t fix We don’t understand well
Low ovarian reserve Implantation problems
Poor sperm quality Miscarriage
Genetic problems High levels of stress
Improve selection Test new ideas

5. Low Ovarian Reserve
patient centred options + supportive choices + outstanding results

6. 25
The march of
32 the eggs
38
42
45

7. Not many eggs to
select from

8. We can’t make more eggs
Can we get more eggs onto the bridge for IVF ?

9. Higher levels of estrogen in the
follicle may entice eggs onto the
bridge
Growth hormone can increase
estrogen levels in the follicle

10. Puregon and Gonal F
androgens estrogen

11. Puregon and Gonal F
Growth Hormone
androgens estrogen

12. Does Growth hormone work?
• We’re not sure:
• Growth Hormone made no difference for all
women undertaking IVF
• In women with low ovarian reserve there
was a trend to improved outcomes.

13. The Light Study (74 recruits)
Women under 41 with low ovarian reserve
Randomised trial to see if Growth hormone:
1.increases the numbers of eggs
2.Improves pregnancy outcomes
At FertilitySA
50% pregnancy rate on the trial
But we don’t know who had growth hormone

14. Poor sperm quality

15. Fertilisation requires lots of
sperm

16. Hyaluron receptors on sperm aid
selection for natural fertilisation

17. How do we choose the best
sperm for ICSI?
The embryologist chooses on how they look

18. Selecting for the Hyaluron
Receptor
PICSI
plates

19. At FertilitySA
More than 20 PICSI pregnancies last 7 months
–first approx 30 weeks gestation now
Clear benefit in fertilisation and embryo development
for some couples
No benefit :
very poor samples
very good samples
Surgical sperm

20. Genetic Problems
A person will not know they have a translocation until investigated

21. Prenatal Genetic Diagnosis

22. Fluorescent In Situ Hybridisation
Small number of
Y 21 chromosomes tested
21
Subjectively assessed by
21
X embryologist looking down
the microscope
Down’s Syndrome
But:
Studies showed increased chance of livebirth if didn’t use test

23. Array Prenatal Diagnosis
24 sure = Blue Gnome = CGH arrays
Technological improvements:
All chromosomes checked
Several probes for each chromosome
Results objectively read by machine

24. Are the outcomes better?
Initial studies are very promising but large studies
over time not done.
Melbourne IVF has the most experience in Australia
FertilitySA
Small numbers of cycles and good results
Performing the biopsy in our lab
Sending the cells to Melbourne IVF for Array testing
Replacing genetically competent embryos in Adelaide

25. Implantation Problems
Beautiful Embryos but not implanting in the endometrium

26. Optimise lifestyle and Investigate

27. Endometrial biopsy before an IVF cycle

28. Why might a biopsy work?
Human cycles with surgical instrumentation of the
uterus have higher pregnancy rates (historical)
Can induce endometrial receptivity in animals by
instrumenting the uterus

29. Does it work?
Cochrane Database Syst Rev. 2012;7: (last week)
Review of all randomised control trials (294 +297
women)
– Higher clinical pregnancy rate and live birth rate
– Benefit when biopsy 1 week prior to an IVF cycle
How does it work?
? Induces a repair process similar to implantation
? Releases factors that help implantation
? Promotes stem cell activity to facilitate implantation

30. At FertilitySA
Perform outpatient biopsy or hysteroscopy and
biopsy in implantation window
Send the tissue to the lab
IVF cycle with following period
Outcomes:
Several patients have become pregnant with good
outcomes
Effect lasts for at least 3 months

31. Recurrent Miscarriage

32. Optimise lifestyle and Investigate

33. Embryogen
• IVF media with GMCSF growth factor
• In Adelaide, laboratory and animal studies
showed that culture media with this growth
factor was associated with:
– better embryos
– better pregnancy outcomes

34. Human embryos have GM-CSF
receptor
21
Day 8 embryo Day 5 embryo
Sjolblom et al Biol Reprod 2002
GM-CSF is in fallopian tubes, lining of womb and uterine
fluid
But : IVF culture medias do not contain GM-CSF

35. In human embryos
control GM-CSF
Total dead cells
p<0.001 Robertson et al Biol Reprod 2001
5
6
4
3
2
1
APOPTOSIS Control
GM-CSF
%
Total cell no.
p<0.001
0
0
0
0
0
0
0
0

36. Improved Outcomes for women with a previous
miscarriage in a large European trial
Ongoing Implantation EmbryoGen® Control Diff. P-value
rate mean (%)
Previous miscarriage patients
(327 subjects, 142/147 transfer cycles)
Week 7 24.5 17.0 44.1 0.001
Week 12 23.2 16.5 40.6 0.003
* During the course of the study the concentration of human serum albumin (HSA) was increased in EmbryoGen ® as well as in EmbryoAssist™.
This was done to improve the overall performance and robustness of EmbryoAssist™
36

37. Safety study:
GM-CSF has no effect on embryonic chromosomal constitution
Embryos (%)
Agerholm et al., 2010

38. At FertilitySA
• Embryogen Trial
• FertilitySA is the only unit registered to prescribe
embryogen in South Australia (Only 2 units in
Australia are registered to use Embryogen)
• Inclusion criteria:
• Women with a previous miscarriage under 41 years.
• Couples can buy media outside trial
• Day 3 transfer –growing frozen embryos out to Day 5

39. Results so far:
6 patients have participated in the trial
4 have completed the cycle -2 pregnancies -1 scanned
Outcomes
Good embryo quality
The first embryogen
pregnancy in Australia
had a normal first scan

40. Stress

41. Why couples withdraw from IVF

42. Can we make IVF easier?

43. Reducing the number of
injections

44. Stimulation protocols have required multiple injections
Long GnRH
1 2 3 4 5 6 7 8 9 10 agonist
protocol
GnRH
Flare-up
1 2 3 4 5 6 7 8 9 10 antagonist
protocol
Pituitary downregulation
LH Direct
gonadotrophin
suppression
Time
Figure adapted from de Greef R et al., 2010,1 The European Orgalutran Study Group, 20002 and Hodgen GD,1990.3

45. Long acting FSH -ELONVA
rFSH hCG
Corifollitropin alfa
1 2 3 4 5 6 7 8 9 10
Before use After use
81% cumulative pregnancy rate in initial trials in good prognosis patients
References: 1. Elonva Product Information, July 2010.

46. The Create Trial
Inclusion Criteria:
Women on an antagonist cycle
<90kg
At low risk of hyperstimulation syndrome
Women in study use either Elonva or traditional injections
Participation:
Answer 2 surveys regarding the ease and stress of IVF cycle
Monitor outcomes during the cycle

47. Research and Education is important
Benefits to our patients
Our doctors stay up to date with the improvements in IVF
Care can be individualised if its well understood
We continually try to improve our treatment for every
couple under our care
Some couples will become pregnant that wouldn’t have
otherwise
Everything we learn will help someone

48. Thank -You
Staff and patients at FertilitySA
Prof Sarah Robertson –University of Adelaide
Dr Michael Henman –Origio
Dr Brett Johnson -MSD

49. patient centred options + supportive choices + outstanding results