Fresh and Frozen Ovary Tissue Transplants: Mechanism of Adult Primordial Follicle Recruitment And Fetal Oocyte Arrest

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1 Fresh and Frozen Ovary Tissue Transplants: Mechanism of Adult Primordial Follicle Recruitment And Fetal Oocyte Arrest

2 Locking and Unlocking: Oocyte Meiosis and PGC differentiation

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5 Yasui et al 2012

6 Factors associated with premature ovarian failure, early menopause and earlier onset of menopause in Japanese women Yasui et al 2012

7 Factors associated with premature ovarian failure, early menopause and earlier onset of menopause in Japanese women Yasui et al 2012

8 Reproductive BioMedicine Online (2012) Vol. 25

9 Number of non-growing follicles recruited per month Why do the ovarian transplants maintain endocrine function for such extented periods of time? The recruitment rate of primordial follicles becomes reduced in parallel to a reduced ovarian reserve. By replacing one single piece of cortex at a time recruitment rate will constantly be very low and utilisation of follicles may be augmented compared to nature. Age (years) It is likely that one ovary or part of an ovary will have the capacity to provide menstrual cycles for a considerable period of time. Wallace H et al. PlosOne, 2010;5:e8772

10 Intrinsic Fertility of Human Oocytes Silber et al. 2017

11 Fertility Of The Human Oocyte Related to Age

12 The number of oocytes required to make one live baby varied with the age of the female partner. Under 35, the live baby born per oocyte was 26%. Over age 42, it decreased to 1%. Robust logistic function curve, which is at first steady (horizontal), followed by a linear decline after age 35 with a 10% loss every year until age 43, and then a flattening out (horizontal) by age 44. Silber et al. 2017

13 IDENTICAL TWINS DISCORDANT FOR PREMATURE OVARIAN FAILURE

14 Melanie and Stephanie case # 1

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17 Ovary Transplant Tissue Quilting Clip 1

18 Ovary Transplant Tissue Quilting Clip 2

19 Ovary Transplant Tissue Quilting Clip 3

20 Ovary Transplant Transplant Clip 5

21 Holding four year old from fresh ovary transplant. Pregnant from frozen ovary transplant.

22 Monozygotic twin pregnancies: IPS Cell Study (Amanda Clark) 33% 65% 2% DICHORIONI C Placentas MONOCHORIONIC Sacs Fetuses Days MONOAMNIOTIC SIAMES E

23 Reproductive BioMedicine Online (2012) Vol. 25

24 Identical Twin Case # 2 Crystal and Bonnie 38 YEARS 0LD

25 TRANSPLANT STILL WORKING (8 YEARS): AGE 46

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27 Primordial Follicles Are Located in the Fibrous Cortex, (Tunica Albuginea of the Testis)

28 OVARY: 6 YEAR OLD WITH RHABDOSARCOMA

29 6 Year Old Ovary

30 Normal Testis: Note Similarity of Tunica Albuginea of Testis and The Ovarian Cortex

31 Normal Ovarian Cortex: Note Similarity to Tunica Albuginea of Testis

32 (20 y.o.) Transplant of Thawed Ovarian Tissue #7 June 17, 2011

33 FSH & AMH in Donor and Recipient: First Allograft AMH Donor FSH Recip AMH Recip Days Since Transplant Elder Allograft FSH Elder AMH Donor s AMH

34 Stimulated ovary post transplantation of fresh ovarian tissue \ \ APPEARS TO BE NO FOLLICLE LOSS FROM ISCHEMIA

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36 WHAT CAN THE PRIMORDIAL OOGONIA DO: TO PREVENT THEMSELVES FROM CONTINUING THROUGH MEIOSIS AND DISAPPEARING BY THE TIME OF BIRTH?

37 Byskoff And Anderson University Of Copenhagen

38 WHAT CONTROLS THE RECRUITMENT OF FOLLICLES IN ADULTS FROM THE RESTING PHASE? GRADUAL RELEASE FROM THE FIBROUS CORTEX. (JUST LIKE IN THE FETUS)

39 Stromal Density Gradient in Ovarian Cortex Most Dense Stroma

40 Stromal Density Gradient in Ovarian Cortex Less Dense Stroma

41 Stromal Density Gradient in Ovarian Cortex Least Dense Stroma

42 These Small Pieces of Ovarian Tissue Last a Very Long Time If we were to add up the duration of a piece one fourth of the ovarian cortex and multiply by four, This tissue which is lasting up to ten years, would represent much more then expected if left in vivo till menopause.

43 OVARY: 6 YEAR OLD WITH RHABDOSARCOMA PURPOSE OF THE PRIMORDIAL FOLLICLE, AND THE OVARIAN FIBROUS CORTEX?

44 WHAT CONTROLS THE RECRUITMENT OF FOLLICLES IN ADULTS FROM THE RESTING PHASE? GRADUAL RELEASE FROM THE FIBROUS CORTEX. (JUST LIKE IN THE FETUS)

45 TISSUE PRESSURE Over-recruitment of primordial follicles, followed by depletion. Decreased primordial follicle recruitment with decreasing ovarian reserve. Long duration of transplant function despite very low AMH. Late menopause in multips. Think about the horse ovary.

46 WHAT IS IT THAT LOCKS AND RELEASES THE PRIMORDIAL FOLLICLE

47 WHAT IF WE WERE TO BYPASS THE PRIMORDIAL FOLLICLE?

48 Katsuhiko Hayashi Kyushu, Japan

49 Hikabe et al. Nature 2016

50 In Vitro Vs In Vivo Derived Oocytes Oocytes (in) PGCs Oogonia Entering meiosis Primordial follicle Primary follicle Secondary follicle Antral follicle MII (Mature) in vivo in vitro IVD IVG & IVM ESCs PGCLCs PGCs (i rec o s tituted o ary) Secondary follicle MII (Mature)

51 Primordial Germ Cells Primordial Germ Cells - the origin of all germ cell lineage - expressing pluripotent genes - Undergoing genome-wide reprogramming (massive DNA demethylation and conversion of histone modifications) Yamaji et al (2008) Nat.Genet. - When transferred into testis or ovary, PGCs give rise to functional sperm or oocytes.

52 Functional primordial germ cells can be derived from ES/iPS cells (mouse) ES/ With Prof. Mitnori Saitou

53 Reconstitution in vitro of the entire cycle of the female germline Still need embry (Automatic) (HCG) (FSH)

54 Kawamura et al 2013

55 Ovarian fragmentation and grafting promoted follicle growth in mice. Paired ovaries from juvenile mice were grafted into kidneys of adult ovariectomized mice (intact, IN; pieces, PI). Hosts were injected with FSH daily for 5 d before graft retrieval. Kawamura et al 2013

56 Fragmentation of murine ovaries increased actin polymerization, disrupted Hippo signaling, and increased CCN growth factors and apoptosis inhibitors. Kawamura et al 2013

57 Additive effects of Hippo signaling disruption and Akt stimulation promoted secondary follicle growth. Kawamura et al 2013

58 Ovarian fragmentation/akt stimulation followed by autografting promoted follicle growth in POI patients to generate mature oocytes for IVF embryo transfer, pregnancy, and delivery. Kawamura et al 2013

59 Ovarian fragmentation/akt stimulation followed by autografting promoted follicle growth in POI patients to generate mature oocytes for IVF embryo transfer, pregnancy, and delivery. Kawamura et al 2013

60 SO EGGS DETERIORATE WITH AGE: (BECAUSE THERE IS NO REPLICATION. JUST CONTROLLED MEIOIC ARREST). WHAT EVOLUTIONARY ADVANTAGE CAN THAT BE?

61 sperm is a different story: constant replication. they never age: but most mutations come from replication errors that occur in the testis.

62 SINCE SPERM ARE CONSTANTLY BEING RENEWED BY STEM CELLS: WHAT IS THE EVOLUTIONARY ADVANTAGE OF EGGS DETERIORATING WITH AGE?

63 WHAT IS THE POINT OF EGGS BEING HELD IN MEIOTIC ARREST BY THE PRIMORDIAL FOLLICLE IN THE CORTEX, ONLY TO DETERIORATE OVER TIME? ANSWER: 1) SPERM ALLOW FOR EVOLUTION TO OCCUR. 2) EGGS STABILIZE THE SPECIES.