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History and Fundamentals of Oocyte Maturation in Vitro

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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


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