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

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

Locking and Unlocking: Oocyte Meiosis and PGC differentiation

Yasui et al 2012

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

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

Reproductive BioMedicine Online (2012) Vol. 25

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

Intrinsic Fertility of Human Oocytes Silber et al. 2017

Fertility Of The Human Oocyte Related to Age

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

IDENTICAL TWINS DISCORDANT FOR PREMATURE OVARIAN FAILURE

Melanie and Stephanie case # 1

Ovary Transplant Tissue Quilting Clip 1

Ovary Transplant Tissue Quilting Clip 2

Ovary Transplant Tissue Quilting Clip 3

Ovary Transplant Transplant Clip 5

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

Monozygotic twin pregnancies: IPS Cell Study (Amanda Clark) 33% 65% 2% DICHORIONI C Placentas MONOCHORIONIC Sacs Fetuses Days MONOAMNIOTIC SIAMES E 0 3 9 12 15

Reproductive BioMedicine Online (2012) Vol. 25

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

TRANSPLANT STILL WORKING (8 YEARS): AGE 46

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

OVARY: 6 YEAR OLD WITH RHABDOSARCOMA

6 Year Old Ovary

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

Normal Ovarian Cortex: Note Similarity to Tunica Albuginea of Testis

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

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

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

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

Byskoff And Anderson University Of Copenhagen

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

Stromal Density Gradient in Ovarian Cortex Most Dense Stroma

Stromal Density Gradient in Ovarian Cortex Less Dense Stroma

Stromal Density Gradient in Ovarian Cortex Least Dense Stroma

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.

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

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

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.

WHAT IS IT THAT LOCKS AND RELEASES THE PRIMORDIAL FOLLICLE

WHAT IF WE WERE TO BYPASS THE PRIMORDIAL FOLLICLE?

Katsuhiko Hayashi Kyushu, Japan

Hikabe et al. Nature 2016

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)

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.

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

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

Kawamura et al 2013

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

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

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

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

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

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

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

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

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.