Trends in Molecular Medicine
ReviewSpecial Issue: Reproductive and Sexual HealthFertility Preservation: The Challenge of Freezing and Transplanting Ovarian Tissue
Section snippets
Fertility Preservation for Oncological Diseases: Where Are We?
In recent years, demand for fertility preservation for oncological diseases, benign conditions, and social reasons, coupled with age-related fertility decline, has increased dramatically [1,2]. Meeting this rising demand is challenging, despite endorsement of three methods of fertility preservation (embryo cryopreservation, oocyte cryopreservation after ovarian stimulation, and ovarian tissue cryopreservation) by the American Society for Reproductive Medicine [3]. Oocyte vitrification (see
The Ovarian Reserve: The Core of Creation
The term ovarian reserve is typically used to refer to the population of primordial follicles (PMFs) [19]. Initiation of the resting follicle reserve commences in the fetus, when around 100–2000 primordial germ cells colonize the genital ridges and embark on a massive proliferation process that results in 7 million potential oocytes at mid-gestation. In the human ovary, 85% of these potential oocytes are lost before birth [19]. The decline in follicle numbers continues throughout reproductive
Chemotherapy-Induced PMF Loss
The effects of chemotherapeutic drugs on female reproduction began to be reported in the 1970s. The first accounts associated one particular alkylating agent, cyclophosphamide (CPM) [20,21], with premature ovarian insufficiency.
Hypoxia and Oxidative Stress in Ovarian Grafts
As ovarian cortical strips are transplanted without vascular anastomosis, they experience a period of hypoxia, the duration of which is contingent on the progressive revascularization process. Partial pressure of O2 (pO2) was previously measured in grafted human tissue using electronic paramagnetic resonance [74]. Hypoxic values were found to persist for 5 days after transplantation and subsequently improve until they reached a plateau from day 10, suggesting active revascularization through
Evaluating the Risk of Reimplantation of Malignant Cells
Indications for ovarian tissue cryopreservation and subsequent transplantation in adults are most commonly hematological malignancies (Hodgkin’s and non-Hodgkin’s lymphoma and leukemia) and breast cancer [1]. In children, leukemia and myeloproliferative or myelodysplastic diseases tend to dominate, followed by sarcoma [113]. It is therefore vital that we address the threat of reimplanting malignant cells along with grafted tissue (Table 2).
Since malignant leukemic cells are found in the
Concluding Remarks
There is now enough evidence to support the feasibility and efficacy of ovarian tissue cryopreservation and further transplantation for fertility restoration purposes in clinical practice. However, some concerns still preclude application of ovarian tissue transplantation in all patient categories. Indeed, massive follicle loss occurring soon after transplantation limits its effectiveness, especially in patients with a diminished ovarian reserve from the start. There is also a risk of
Acknowledgments
The authors thank Mira Hryniuk, BA, for reviewing the English language of the article and Deborah Godefroidt for her administrative assistance. Grants from the Fonds National de la Recherche Scientifique de Belgique (grant 5/4/150/5, FNRS-PDR Convention T.0077.14, and the Excellence of Science FNRS–EOS number 30443682) were awarded to Marie-Madeleine Dolmans and (F.R.S.-FNRS/FRIA FC29657) to Luciana Cacciottola.
Glossary
- Alkylating agents
- chemotherapeutic drugs used in gynecological oncology (carboplatin, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, altretamine) to prevent cell division by crosslinking DNA strands.
- Burn-out hypothesis
- this theory is based on the observation of primordial follicle behavior in response to injury in the ovary, namely after both chemotherapy and ovarian tissue transplantation. According to this hypothesis, the ovarian reserve accelerates its activation, resulting in massive
References (155)
Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation
Lancet Oncol.
(2014)Live birth after transplantation of frozen-thawed ovarian tissue after bilateral oophorectomy for benign disease
Fertil. Steril.
(2012)Ovarian cortex transplantation: time to move on from experimental studies to open clinical application
Fertil. Steril.
(2015)Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria
Fertil. Steril.
(2016)Evaluation of ovarian tissue transplantation: results from three clinical centers
Fertil. Steril.
(2020)Importance of patient selection to analyze in vitro fertilization outcome with transplanted cryopreserved ovarian tissue
Fertil. Steril.
(2020)Multiple late complications of therapy with cyclophosphamide, including ovarian destruction
Am. J. Med.
(1971)Long-term adverse effects of cyclophosphamide on follicular growth and angiogenesis in mouse ovaries
Reprod. Biol.
(2014)Follicle loss and apoptosis in cyclophosphamide-treated mice: what’s the matter?
Int. J. Mol. Sci.
(2016)Prevention of chemotherapy-induced ovarian damage
Fertil. Steril.
(2016)
Utility of gonadotropin-releasing hormone agonists for fertility preservation in women receiving chemotherapy: pros and cons
Fertil. Steril.
Chemotherapy and decline of the ovarian reserve: how can we explain it and how to prevent it?
Fertil. Steril.
Drug-free in-vitro activation of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve
Reprod. BioMed. Online
Drug-free in-vitro activation of ovarian cortex; can it really activate the 'ovarian gold reserve'?
Reprod. BioMed. Online
Human umbilical cord blood-mesenchymal stem cells transplantation renovates the ovarian surface epithelium in a rat model of premature ovarian failure: possible direct and indirect effects
Tissue Cell
Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism
Stem Cell Res. Ther.
Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage
Cytotherapy
The restorative effects of adipose-derived mesenchymal stem cells on damaged ovarian function
Lab. Investig.
Role of autologous bone marrow-derived stem cell therapy for follicular recruitment in premature ovarian insufficiency: review of literature and a case report of world’s first baby with ovarian autologous stem cell therapy in a perimenopausal woman of age 45 year
J. Human Reprod. Sci.
Electron paramagnetic resonance as a tool to evaluate human ovarian tissue reoxygenation after xenografting
Fertil. Steril.
Re-vascularisation in human ovarian tissue after conventional freezing or vitrification and xenotransplantation
Eur. J. Obstet. Gynecol. Reprod. Biol.
Both host and graft vessels contribute to revascularization of xenografted human ovarian tissue in a murine model
Fertil. Steril.
Histologic and ultrastructural evaluation of fresh and frozen-thawed human ovarian xenografts in nude mice
Fertil. Steril.
Low oxygen level increases proliferation and metabolic changes in bovine granulosa cells
Mol. Cell. Endocrinol.
Does the Akt pathway play a role in follicle activation after grafting of human ovarian tissue?
Reprod. BioMed. Online
Fertility preservation in women
N. Engl. J. Med.
Fertility preservation in women
Nat. Rev. Endocrinol.
Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion
Fertil. Steril.
Ovarian tissue cryopreservation and transplantation: a review
Hum. Reprod. Update
Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue
Hum. Reprod.
Ovarian transplantation between monozygotic twins discordant for premature ovarian failure
N. Engl. J. Med.
Livebirth after orthotopic transplantation of cryopreserved ovarian tissue
Lancet
Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice
J. Assist. Reprod. Genet.
Ovarian tissue transplantation: experience from Germany and worldwide efficacy
Clin. Med. Insights Reprod. Health
FertiPROTEKT network. Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates
Hum. Reprod.
Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience
Acta Obstet. Gynecol. Scand.
86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children
J. Assist. Reprod. Genet.
Human ovarian reserve from conception to the menopause
PLoS One
Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer
Cancer.
Ovarian damage from chemotherapy and current approaches to its protection
Hum. Reprod. Update
The effects of radiotherapy and chemotherapy on female reproduction
Hum. Reprod. Update
The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells
Hum. Reprod.
Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations
Hum. Reprod.
Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility
Sci. Transl. Med.
Prevention of chemotherapy-induced ovarian damage: possible roles for hormonal and non-hormonal attenuating agents
Hum. Reprod. Update
mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy
Proc. Natl. Acad. Sci. U. S. A.
Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide
J. Endocrinol.
Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility
Cell Death Dis.
Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death
Hum. Reprod.
Sphingosine-1-phosphate suppresses cyclophosphamide induced follicle apoptosis in human fetal ovarian xenografts in nude mice
Fertil. Steril.
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