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Article: Cryopreservation of Ovarian Tissue: Opportunities Beyond Fertility Preservation and a Positive View Into the Future.

Kristensen, Stine G / Andersen, Claus Y

2018 Volume 9, Page(s) 347

Abstract: In current years, ovarian tissue cryopreservation (OTC) and transplantation is gaining ground as a successful method of preserving fertility in young women with primarily cancer diseases, hereby giving them a chance of becoming biological mothers later ... ...

Abstract	In current years, ovarian tissue cryopreservation (OTC) and transplantation is gaining ground as a successful method of preserving fertility in young women with primarily cancer diseases, hereby giving them a chance of becoming biological mothers later on. However, OTC preserves more than just the reproductive potential; it restores the ovarian endocrine function and thus the entire female reproductive cycle with natural levels of essential hormones. In a female population with an increased prevalence in the loss of ovarian function due to induced primary ovarian insufficiency (POI) and aging, there is now, a need to develop new treatments and provide new opportunities to utilize the enormous surplus of follicles that most females are born with and overcome major health issues associated with the lack of ovarian hormones. Cell/tissue-based hormone replacement therapy (cHRT) by the use of stored ovarian tissue could be one such option comprising both induction of puberty in prepubertal POI girls, treatment of POI and premature menopause, and as primary prevention at the onset of menopause. In the current review, we explore known and entirely new applications for the potential utilization of OTC including cHRT, social freezing, culture of immature oocytes, and a modern ovarian resection for women with polycystic ovaries, and discuss the indications hereof.
Language	English
Publishing date	2018
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2018.00347
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Article ; Online: Mitochondria and reproduction: possibilities for testing and treatment.

Kristensen, Stine G / Humaidan, Peter / Coetzee, Kevin

Panminerva medica

2018 Volume 61, Issue 1, Page(s) 82–96

Abstract: Mitochondria, known as the energy factories in all cells, are key regulators of multiple vital cellular processes and affect all aspects of mammalian reproduction, being essential for oocyte maturation, fertilization and embryonic development. ... ...

Abstract	Mitochondria, known as the energy factories in all cells, are key regulators of multiple vital cellular processes and affect all aspects of mammalian reproduction, being essential for oocyte maturation, fertilization and embryonic development. Mitochondrial dysfunction is consequently implicated in disease as well as age-related infertility. Since mitochondria are inherited exclusively from the mother, the female gamete is central to reproductive outcome and therapeutic interventions, such as mitochondrial replacement therapy (MRT), and development of new diagnostic tools. The primary purpose of MRT is to improve oocyte quality, embryogenesis and fetal development by correcting the imbalance between mutant and wild-type mitochondrial DNA (mtDNA) in the oocyte or zygote, either by replacing mutant mtDNA or supplementing with wild-type counterparts from heterologous or autologous sources. However, the efficacy and safety of these new technologies have not yet been tested in clinical trials, and various concerns exist. Nonetheless, the perspectives for such procedures are intriguing and include two distinct patient populations that could potentially benefit from the clinical implementation of MRT; 1) patients with mtDNA-disease transmission risk; 2) patients undergoing IVF with recurrent poor embryo outcomes due to advanced maternal age. In this review, we outline the intrinsic roles of mitochondria during oogenesis and early embryogenesis in relation to disease and infertility, and discuss the progress in MRT with the developments in reproductive technologies and the related concerns. In addition, we assess the use of mtDNA as a potential biomarker for embryo viability in assisted reproduction.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Cell Nucleus ; Clinical Trials as Topic ; DNA, Mitochondrial/metabolism ; Embryonic Development ; Female ; Fertilization in Vitro/methods ; Genome ; Humans ; Infertility, Female/therapy ; Mitochondria/metabolism ; Mitochondrial Diseases/genetics ; Oocytes/metabolism ; Oogenesis ; Ovary/metabolism ; Pregnancy ; Risk ; Zygote/metabolism
Chemical Substances	Biomarkers ; DNA, Mitochondrial
Language	English
Publishing date	2018-06-28
Publishing country	Italy
Document type	Journal Article ; Review
ZDB-ID	123572-2
ISSN	1827-1898 ; 0031-0808
ISSN (online)	1827-1898
ISSN	0031-0808
DOI	10.23736/S0031-0808.18.03510-3
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Article: Reproductive and Endocrine Outcomes in a Cohort of Danish Women following Auto-Transplantation of Frozen/Thawed Ovarian Tissue from a Single Center.

Colmorn, Lotte B / Pedersen, Anette T / Larsen, Elisabeth C / Hansen, Alexandra S / Rosendahl, Mikkel / Andersen, Claus Yding / Kristensen, Stine G / Macklon, Kirsten T

Cancers

2022 Volume 14, Issue 23

Abstract: Ovarian tissue cryopreservation (OTC) is a method of fertility preservation in girls and young women prior to gonadotoxic treatment. It is a safe and promising method to restore fertility. The initial recovery of endocrine function is high, but the ... ...

Abstract	Ovarian tissue cryopreservation (OTC) is a method of fertility preservation in girls and young women prior to gonadotoxic treatment. It is a safe and promising method to restore fertility. The initial recovery of endocrine function is high, but the longevity of the grafted tissue varies. In this single-center, combined retro- and prospective cohort study, we report the reproductive outcome and hormonal recovery following ovarian tissue transplantation (OTT) and evaluate possible predictors of the chance of pregnancy. The study includes 40 women from eastern Denmark undergoing 53 OTTs between 2003 and 2021. Permission to obtain retrospective data was given by the Danish Patient Safety Authorities and prospective data-collection by informed consent. Initial recovery of endocrine function was seen in 18/19 women with POI, and ongoing function of the grafted tissue in 7/14 two years from OTT. Live birth rate (LBR) was 41%, with 20 children to 39 women trying to conceive. Women who conceived had higher AFC at the time of OTC than women who did not (
Language	English
Publishing date	2022-11-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14235873
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Article ; Online: Revascularization of human ovarian grafts is equally efficient from both sides of the cortex tissue.

Kristensen, Stine G / Olesen, Hanna Ø / Zeuthen, Mette C / Pors, Susanne E / Andersen, Claus Y / Mamsen, Linn S

Reproductive biomedicine online

2022 Volume 44, Issue 6, Page(s) 991–994

Abstract: Research question: Does revascularization of human ovarian grafts in a mouse model occur with equal efficiency from both sides of the cortex tissue?: Design: Twenty-four frozen-thawed ovarian cortex pieces from 12 women were transplanted to ... ...

Abstract	Research question: Does revascularization of human ovarian grafts in a mouse model occur with equal efficiency from both sides of the cortex tissue? Design: Twenty-four frozen-thawed ovarian cortex pieces from 12 women were transplanted to immunodeficient mice, for 8 days to analyse graft revascularization using immunohistochemical detection of murine CD31, or for 8 weeks to evaluate follicle density (follicles/mm Results: No significant difference in the mean percentage of the CD31-positive vessel area was found between the three ROI (cortical side: 3.9% ± 0.2%; centre: 3.5% ± 0.2%; medullary side: 4.0% ± 0.3%; P = 0.17), but a significantly lower density of vessels was found in the centre of the human ovarian grafts compared with the cortical and medullary sides (cortical side: 323 ± 14 vessels/mm Conclusions: Host revascularization was established equally efficiently from both sides of transplanted human ovarian cortex, suggesting that transplantation techniques ensuring revascularization from both sides of the ovarian graft could potentially facilitate faster graft revascularization.
MeSH term(s)	Animals ; Cryopreservation/methods ; Female ; Humans ; Mice ; Ovarian Follicle/transplantation ; Ovary/transplantation ; Transplantation, Heterologous/methods
Language	English
Publishing date	2022-02-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2113823-0
ISSN	1472-6491 ; 1472-6483
ISSN (online)	1472-6491
ISSN	1472-6483
DOI	10.1016/j.rbmo.2022.02.009
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Article ; Online: Diving into the oocyte pool.

Kristensen, Stine G / Pors, Susanne E / Andersen, Claus Y

Current opinion in obstetrics & gynecology

2017 Volume 29, Issue 3, Page(s) 112–118

Abstract: Purpose of review: The ovarian reserve comprises an enormous surplus of follicles. Despite this, some women produce insufficient numbers of oocytes by conventional fertility treatments. However, recent technical accomplishments may transform assisted ... ...

Abstract	Purpose of review: The ovarian reserve comprises an enormous surplus of follicles. Despite this, some women produce insufficient numbers of oocytes by conventional fertility treatments. However, recent technical accomplishments may transform assisted reproductive technology (ART) in such a way that oocytes are not necessarily the limiting factor. In this review, we present possible new strategies for enhancing the quantity of mature oocytes, and current views on autologous oocytes as potential sources of mitochondria to lift performance of compromised oocytes. Recent findings: New discoveries of the signaling pathways activating dormant follicles and breakthroughs in techniques for autologous transfer of mitochondria have opened new doors to unexploited sources of oocytes and attractive ways of revitalizing oocytes. Extended numbers of mature oocytes may be obtained by in-vitro activation of dormant follicles in cortical biopsies or in-vitro maturation of immature oocytes during the natural or stimulated cycle, and used directly for fertility treatment or as a source of autologous mitochondria. Summary: New approaches utilizing the abundant resources of immature oocytes combined with techniques for revitalizing deficient oocytes may transform ART, and potentially enhance both quantity and quality of fertilizable oocytes; hereby augmenting the pregnancy potential of women with poor reproductive performance.
Language	English
Publishing date	2017-06
Publishing country	England
Document type	Journal Article
ZDB-ID	1049382-7
ISSN	1473-656X ; 1040-872X
ISSN (online)	1473-656X
ISSN	1040-872X
DOI	10.1097/GCO.0000000000000359
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Article ; Online: Hippo signaling, actin polymerization, and follicle activation in fragmented human ovarian cortex.

Lunding, Stine A / Andersen, Anders N / Hardardottir, Lilja / Olesen, Hanna Ø / Kristensen, Stine G / Andersen, Claus Y / Pors, Susanne E

Molecular reproduction and development

2020 Volume 87, Issue 6, Page(s) 711–719

Abstract: The Hippo pathway has been associated with regulation of early follicle growth. Studies of murine ovaries suggest that changes in the actin cytoskeleton, caused by fragmentation, result in inhibition of the Hippo pathway, and in turn, may activate ... ...

Abstract	The Hippo pathway has been associated with regulation of early follicle growth. Studies of murine ovaries suggest that changes in the actin cytoskeleton, caused by fragmentation, result in inhibition of the Hippo pathway, and in turn, may activate follicle growth. In humans, the connections between fragmentation, the actin cytoskeleton, and follicle activation are yet to be confirmed. In this study, we investigated the impact in vitro fragmentation of a human ovarian cortex on (a) actin polymerization, (b) components of the Hippo pathway, and (c) follicle growth in vivo. The results showed that the ratio between globular and filamentous actin remained unchanged at all timepoints (0, 10, 30, 60, 120, and 240 min) following tissue fragmentation. Neither was the Hippo pathway effector protein YES-associated protein upregulated nor was gene expression of the downstream growth factors CCN2, CCN3, or CCN5 increased at any timepoint in the fragmented cortex. Furthermore, the number of growing follicles was similar in fragmented and intact cortex pieces after 6 weeks' xenotransplantation. However, the total number of surviving follicles was considerably lower in the fragmented cortex compared with intact tissue, suggesting detrimental effects of fragmentation on tissue grafting. These results indicate that fragmentation is likely to be ineffective to activate follicle growth in the human ovarian cortex.
MeSH term(s)	Actins/metabolism ; Adult ; Cells, Cultured ; Female ; Humans ; Microdissection ; Oogenesis/physiology ; Ovarian Follicle/physiology ; Ovary/cytology ; Ovary/metabolism ; Protein Multimerization ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction/genetics
Chemical Substances	Actins ; Hippo protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2020-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	20321-x
ISSN	1098-2795 ; 1040-452X
ISSN (online)	1098-2795
ISSN	1040-452X
DOI	10.1002/mrd.23353
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Article ; Online: Education, education, education-now more than ever?

Andersen, Claus Yding / Kristensen, Stine G / Mamsen, Linn Salto / Barratt, Christopher L R

Molecular human reproduction

2018 Volume 24, Issue 8, Page(s) 426–429

Abstract: The generation of scientists and physicians that took part in starting the whole era of modern-assisted reproduction is currently close to retirement or has already left research. A new generation is about to take over and the profession is facing a ... ...

Abstract	The generation of scientists and physicians that took part in starting the whole era of modern-assisted reproduction is currently close to retirement or has already left research. A new generation is about to take over and the profession is facing a massive transgenerational transition. Since current treatments have reached a plateau in success rates and costs, new research and development is required to further advance the field. Today, multi-disciplinary platforms including numerous research areas, not previously integrated in our field, are fundamental to achieve new clinical approaches. Structured, broader and purposeful education of young researchers should be intensified and prioritized, and innovative educational initiatives are needed to facilitate 'thinkers' and advance developments in the field of assisted reproduction.
MeSH term(s)	Education, Medical ; Humans ; Reproductive Techniques, Assisted ; Research
Language	English
Publishing date	2018-06-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1324348-2
ISSN	1460-2407 ; 1360-9947
ISSN (online)	1460-2407
ISSN	1360-9947
DOI	10.1093/molehr/gay028
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Article ; Online: Parental Acceptance Rate of Testicular Tissue Cryopreservation in Danish Boys with Cryptorchidism.

Hildorf, Simone / Cortes, Dina / Gül, Murat / Dong, Lihua / Kristensen, Stine G / Jensen, Christian F S / Clasen-Linde, Erik / Fedder, Jens / Andersen, Claus Y / Hoffmann, Eva R / Sønksen, Jens / Fossum, Magdalena / Thorup, Jørgen

Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation

2020 Volume 13, Issue 5-6, Page(s) 246–257

Abstract: Despite orchidopexy within the first year of life, 20-25% of boys with nonsyndromic cryptorchidism may risk infertility according to histological and hormonal data obtained during surgery. The aim of this study was to evaluate the acceptance rate of ... ...

Abstract	Despite orchidopexy within the first year of life, 20-25% of boys with nonsyndromic cryptorchidism may risk infertility according to histological and hormonal data obtained during surgery. The aim of this study was to evaluate the acceptance rate of testicular tissue cryopreservation among parents of prepubertal boys with cryptorchidism. Fourteen boys with cryptorchidism and high infertility risk were offered cryopreservation as an additional procedure after orchidopexy based on abnormal histopathological findings at primary surgery, whereas 27 boys with bilateral cryptorchidism were offered cryopreservation at the initial orchidopexy. A total of 90% of parents (37/41, 13/14, and 24/27) gave consent to perform cryopreservation, despite being well-informed that the procedural efficacy is largely unproven and may only be needed in about 20% of cases. The number of germ cells per tubule cross-section was 0.03-1.70 (median 0.37) and 22 boys (54%, 22/41) had a value below the lower range. Twelve boys (29%, 12/41) had no type A dark spermatogonia in their biopsy. Cryopreservation of testicular tissue is the first step to introduce spermatogonial stem cell-based therapy into clinical male infertility treatment. At the time of orchidopexy, a testicular biopsy can be collected to ascertain the infertility risk, and it may be an option for boys with bilateral cryptorchidism to have spermatogonial stem cells frozen as a fertility reserve.
Language	English
Publishing date	2020-10-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2253672-3
ISSN	1661-5433 ; 1661-5425
ISSN (online)	1661-5433
ISSN	1661-5425
DOI	10.1159/000511158
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Article ; Online: Developmental competence of oocytes isolated from surplus medulla tissue in connection with cryopreservation of ovarian tissue for fertility preservation.

Wilken-Jensen, Helle N / Kristensen, Stine G / Jeppesen, Janni V / Yding Andersen, Claus

Acta obstetricia et gynecologica Scandinavica

2014 Volume 93, Issue 1, Page(s) 32–37

Abstract: Objective: Evaluating the developmental competence of immature oocytes collected from surplus medulla tissue in connection with ovarian tissue cryopreservation for fertility preservation.: Design: Cohort comparative study.: Setting: University ... ...

Abstract	Objective: Evaluating the developmental competence of immature oocytes collected from surplus medulla tissue in connection with ovarian tissue cryopreservation for fertility preservation. Design: Cohort comparative study. Setting: University laboratory in Denmark from 2011-2012. Population: 69 girls and women (0-38 years of age) who each had one ovary cryopreserved for fertility preservation. Methods: Ovaries were obtained directly from the local hospital or from collaborating hospitals (two to five hours' transport on ice). Immature oocytes were aspirated from large antral follicles visible on the ovaries, and collected from the saline solution, containing surplus medulla tissue, following dissection of the ovarian cortical tissue for cryopreservation. The immature oocytes were cultured for 48 h in an Embryoscope™ Time-lapse System or in culture dishes overlaid with liquid paraffin using commercial and in-house supplemented culture media. Main outcome measures: Maturation rate for immature oocytes reaching metaphase II. Results: With a maturation rate of 3.1%, only 21 of 682 immature oocytes reached metaphase II. Immature oocytes from ovaries that had been transported on ice for two to five hours performed significantly poorer than those recovered immediately after surgery. Addition of epidermal growth factor and follicle fluid from human small antral follicles to the culture medium did not augment the maturation rate. Immature oocytes cultured in the Embryoscope performed significantly better than those in conventional culture dishes. Conclusions: In vitro maturation of immature oocytes should only be attempted clinically from visible antral follicles and where the ovary is not subjected to a cooling period prior to recovery of immature oocytes.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Cryopreservation/methods ; Female ; Fertility Preservation/methods ; Humans ; Infant ; Infant, Newborn ; Oocytes/cytology ; Oocytes/growth & development ; Ovarian Follicle/cytology ; Ovarian Follicle/growth & development
Language	English
Publishing date	2014-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80019-3
ISSN	1600-0412 ; 0001-6349
ISSN (online)	1600-0412
ISSN	0001-6349
DOI	10.1111/aogs.12264
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Article ; Online: Characterization of follicles in girls and young women with Turner syndrome who underwent ovarian tissue cryopreservation.

Mamsen, Linn Salto / Charkiewicz, Karol / Anderson, Richard A / Telfer, Evelyn E / McLaughlin, Marie / Kelsey, Thomas W / Kristensen, Stine G / Gook, Debra A / Ernst, Erik / Andersen, Claus Yding

Fertility and sterility

2019 Volume 111, Issue 6, Page(s) 1217–1225.e3

Abstract: Objective: To characterize ovarian follicles of girls and young women with Turner syndrome (TS) who underwent ovarian tissue cryopreservation (OTC).: Design: Retrospective case-control study.: Setting: University hospital.: Patient(s): Fifteen ... ...

Abstract	Objective: To characterize ovarian follicles of girls and young women with Turner syndrome (TS) who underwent ovarian tissue cryopreservation (OTC). Design: Retrospective case-control study. Setting: University hospital. Patient(s): Fifteen girls and young women with TS aged 5-22 years at OTC were included, together with 42 control girls and young women aged 1-25 years who underwent OTC because of cancer. Intervention(s): None. Main outcome measure(s): Follicle density (follicles/mm Result(s): Follicles were found in 60% of the biopsies (9 of 15) from TS ovaries. In 78% of the ovaries (7 of 9) with follicles, the follicle density was within the 95% confidence interval of the control group. There was a high rate of abnormal follicle morphology. Six follicle-specific proteins were expressed similarly in TS and control ovaries. However, apoptosis and zona pellucida protein expression were found to be abnormal in TS. Turner syndrome follicle fluid from small antral follicles had lower concentrations of estrogen and testosterone and higher concentrations of antimüllerian hormone than controls. Thirty-one cumulus oocyte complexes were collected from one patient and cultured for 48 hours in vitro, resulting in five metaphase II oocytes (maturation rate 16%, degeneration rate 19%). Conclusion(s): The benefits of OTC may be limited to a highly selected group of TS mosaic patients in whom a sizeable pool of normal follicles is present at OTC.
MeSH term(s)	Adolescent ; Adult ; Biopsy ; Child ; Child, Preschool ; Clinical Decision-Making ; Cryopreservation ; Female ; Fertility ; Fertility Preservation/methods ; Follicular Fluid/chemistry ; Genetic Predisposition to Disease ; Humans ; In Vitro Oocyte Maturation Techniques ; Infant ; Infertility, Female/etiology ; Infertility, Female/pathology ; Infertility, Female/physiopathology ; Infertility, Female/therapy ; Ovarian Follicle/chemistry ; Ovarian Follicle/pathology ; Ovarian Follicle/transplantation ; Ovary/chemistry ; Ovary/pathology ; Ovary/transplantation ; Patient Selection ; Phenotype ; Predictive Value of Tests ; Reproductive Techniques, Assisted ; Retrospective Studies ; Turner Syndrome/complications ; Turner Syndrome/genetics ; Turner Syndrome/pathology ; Young Adult
Language	English
Publishing date	2019-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80133-1
ISSN	1556-5653 ; 0015-0282
ISSN (online)	1556-5653
ISSN	0015-0282
DOI	10.1016/j.fertnstert.2019.02.003
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