1. History and Fundamentals of Oocyte Maturation in Vitro
H. I. Nielsen
Libya
日本国
2007
H. I. Nielsen
2007

2. - so we thought! History of IVM 1935 Pincus & Enzmann IVM in rabbit
1965 Edwards IVM of human oocytes
1983 Veeck First IVM baby (‘GV rescue‘)
1989 Cha et al. First IVM babies (triplets) (unstimulated, donor)
1993 Cha et al. Further 4 IVM babies
1994 Trounson et al. First IVM baby from PCOS
1995 Barnes et al. PCOS
From 1996 Increasing number of groups worldwide
End of 2006: Probably around 500 IVM babies worldwide
- so we thought!

3. Deliveries and ongoing pregnancies (facts and educated guesses)
Countries
Deliveries and ongoing pregnancies
Scandinavia
150
Italy 77
France 40
Germany 20
Rest of Europe 33
Total Europe
320

4. Deliveries and ongoing pregnancies (facts and educated guesses)
Countries
Deliveries and ongoing pregnancies
Middle East 21
Japan
100
Vietnam 26
China (incl. HK) 60
Korea (Cha Hosp.) 57
Korea (Maria Cl.)
≈ 400
Rest of Asia 15
Total Asia
679

5. Deliveries and ongoing pregnancies (facts and educated guesses)
Countries
Deliveries and ongoing pregnancies
Canada
120
USA 5
Australia
Total
130

6. Deliveries and ongoing pregnancies (facts and educated guesses)
Countries
Deliveries and ongoing pregnancies
Asia
679
Europe
320
North America
125
Australia 5
Grand Total
1129

7. OHSS in PCO(S) patients
Why do IVM ?
Safety
Ethics
OHSS in PCO(S) patients
male factor
Costs
patients
community
IVF Center

8. Why do IVM ? chance Extension of fertility Poor (slow) responders
Another
chance
Extension of
fertility
Poor (slow) responders
Repeated poor embryo quality
Repeated failure of ovulation
induction
Cryopreservation prior to
cancer treatment
Career and life style
considerations
Preservation / extension of fertility
- Cryopreservation prior to cancer treatment
- Career and life style considerations

9. Why do IVM ? - future Post-OPU maturation
GV rescue
GV oocytes from stimulated cycles
Stimulated cycles
- Bridging cancer treatment
- Career and life style considerations
- Source of donor oocytes for treatment
- Source of donor oocytes for stem cells
Primary oocytes / primordial follicles
Ovarian biopsies

10. Scientific background for IVM
Oogenesis
Follicular development
Follicular selection
Follicular atresia

11. Gametogenesis
Mitosis
Initiation of meiosis

12. Gametogenesis Mitosis Initiation of meiosis Arrest
Resumption of meiosis
Arrest

13. Gametogenesis Mitosis Arrest Initiation of meiosis Arrest
Resumption of meiosis
Arrest

14. Gametogenesis Mitosis Initiation of meiosis Arrest IVM
Resumption of meiosis
IVF
Arrest

15. Development of an Ovarian Follicle
IVM
IVF
Modified from Ross et al. Histology A Text and Atlas, 3rd Ed.

16. Follicle selection and atresia
Natural ovulation
IVM
Figure 2. Duration of follicle recruitment and selection in human and rat ovaries. Primordial follicles undergo initial recruitment to enter the growing pool of primary follicles. Due to its protracted nature, the duration required for this step is unknown. In the human ovary, greater than 120 days are required for the primary follicles to reach the secondary follicle stage, whereas 71 days are needed to grow from the secondary to the early antral stage. During cyclic recruitment, increases in circulating FSH allow a cohort of antral follicles (2–5 mm in diameter) to escape apoptotic demise. Among this cohort, a leading follicle emerges as dominant by secreting high levels of estrogens and inhibins to suppress pituitary FSH release. The result is a negative selection of the remaining cohort, leading to its ultimate demise. Concomitantly, increases in local growth factors and vasculature allow a positive selection of the dominant follicle, thus ensuring its final growth and eventual ovulation. After cyclic recruitment, it takes only 2 weeks for an antral follicle to become a dominant Graafian follicle. In the rat, the duration of follicle development is much shorter than that needed for human follicles. The time required between the initial recruitment of a primordial follicle and its growth to the secondary stage is more than 30 days, whereas the time for a secondary follicle to reach the early antral stage is about 28 days. Once reaching the early antral stage (0.2–0.4 in diameter), the follicles are subjected to cyclic recruitment, and only 2–3 days are needed for them to grow into preovulatory follicles.
Geneva Foundation for Medical Education and Research

17. Unstimulated IVM cycle
Estradiol
Day -1
Day 2 or day 3
Unstimulated IVM cycle
Day 0
Day 1
Cycle day 3
US scanning
(Blood sample)
Cycle day 7-10
US scanning
(Blood sample)
(Beskriv billedet trin for trin)
Follicle development is observed by ultrasound examinations, and
oocyte pick-up is scheduled, when a leading follicle of mm and an endometrium of at least 5 mm are observed by ultrasound scanning – usually on day 8-11.
If the leading follicle is more than 14 mm, the OPU is cancelled.
Endometrial priming starts with 17-ß-estradiol from the day of oocyte pick-up, followed by progesterone from the second day after OPU.
Progesterone -endometrial priming
Cycle day 8-11
US scanning (lead follicle mm)
Blood sample
Oocyte pick-up

18. Traditional IVF versus IVM
Relatively many oocytes/embryos
’High’ pregnancy rate / OPU
Down regulation
Daily hormone injections
hCG injection
Emotional stress
Long treatment time weeks
Potential side effects (e.g. OHSS)
Fewer oocytes and embryos
Lower pregnancy rate / OPU - BUT
No down regulation, no manipulation of hormone balance
No hormone injections – or
Minimal hormone injections (PCOS)
(No hCG injection)
Reduced psychological impact
Reduced treatment time – 2 weeks
Reduced interference with daily life
No known side effects (e.g. OHSS)

19. Average
3.0 29

20. Average
2.0 20

21. What needs to be improved in IVM?
IVM has a lower pregnancy rate per OPU - due to lower no. of oocytes/embryos resulting in lower transfer rate
IVM has a lower pregnancy rate per ET - due to lower no. of embryos resulting in lack of selection possibilities, and possibly in a smaller no. of embryos transferred
IVM has a lower implantation rate - due to lower no. of embryos resulting in lack of selection possibilities
IVM has probably a higher rate of early pregnancy loss?

22. Shukran