Review
Special Issue: Reproductive and Sexual Health
Fertility Preservation: The Challenge of Freezing and Transplanting Ovarian Tissue

https://doi.org/10.1016/j.molmed.2020.11.003Get rights and content

Highlights

  • Chemotherapy triggers direct primordial follicle depletion by increasing apoptosis and disrupting signaling pathways involved in quiescence maintenance and indirect damage by injury to the vascular network and stromal cells.

  • Ovarian tissue cryopreservation and transplantation is an effective fertility preservation strategy, leading to endocrine restoration in more than 95% of cases and a pregnancy rate of 40%.

  • The avascular nature of ovarian tissue transplantation causes major follicle loss of 50–90%, occurring before complete graft revascularization.

  • The goal of a transplantable artificial ovary development is to be able to safely graft ovarian follicles, ensuring their survival and development, which can be achieved by use of a biocompatible scaffold implanted together with ovarian stromal cells.

Cancer treatments are increasingly effective, but can result in iatrogenic premature ovarian insufficiency. Ovarian tissue cryopreservation is the only option available to preserve fertility in prepubertal girls and young women who require immediate chemotherapy. Ovarian tissue transplantation has been shown to restore hormonal cycles and fertility, but a large proportion of the follicle reserve is lost as a consequence of exposure to hypoxia. Another crucial concern is the risk of reimplanting malignant cells together with the grafted tissue. In this review, the authors advance some challenging propositions, from prevention of chemotherapy-related gonadotoxicity to ovarian tissue cryopreservation and transplantation, including the artificial ovary approach.

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)

  • M.M. Dolmans

    Utility of gonadotropin-releasing hormone agonists for fertility preservation in women receiving chemotherapy: pros and cons

    Fertil. Steril.

    (2020)
  • J. Donnez

    Chemotherapy and decline of the ovarian reserve: how can we explain it and how to prevent it?

    Fertil. Steril.

    (2020)
  • K. Kawamura

    Drug-free in-vitro activation of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve

    Reprod. BioMed. Online

    (2020)
  • G. Griesinger et al.

    Drug-free in-vitro activation of ovarian cortex; can it really activate the 'ovarian gold reserve'?

    Reprod. BioMed. Online

    (2020)
  • A.K. Elfayomy

    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

    (2016)
  • J. Li

    Human umbilical cord mesenchymal stem cells improve the reserve function of perimenopausal ovary via a paracrine mechanism

    Stem Cell Res. Ther.

    (2017)
  • X. Fu

    Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage

    Cytotherapy

    (2008)
  • Y. Takehara

    The restorative effects of adipose-derived mesenchymal stem cells on damaged ovarian function

    Lab. Investig.

    (2013)
  • S. Gupta

    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.

    (2018)
  • A.S. Van Eyck

    Electron paramagnetic resonance as a tool to evaluate human ovarian tissue reoxygenation after xenografting

    Fertil. Steril.

    (2009)
  • G. Rahimi

    Re-vascularisation in human ovarian tissue after conventional freezing or vitrification and xenotransplantation

    Eur. J. Obstet. Gynecol. Reprod. Biol.

    (2010)
  • A.S. Van Eyck

    Both host and graft vessels contribute to revascularization of xenografted human ovarian tissue in a murine model

    Fertil. Steril.

    (2010)
  • M. Nisolle

    Histologic and ultrastructural evaluation of fresh and frozen-thawed human ovarian xenografts in nude mice

    Fertil. Steril.

    (2000)
  • S. Shiratsuki

    Low oxygen level increases proliferation and metabolic changes in bovine granulosa cells

    Mol. Cell. Endocrinol.

    (2016)
  • R. Masciangelo

    Does the Akt pathway play a role in follicle activation after grafting of human ovarian tissue?

    Reprod. BioMed. Online

    (2019)
  • J. Donnez et al.

    Fertility preservation in women

    N. Engl. J. Med.

    (2017)
  • J. Donnez et al.

    Fertility preservation in women

    Nat. Rev. Endocrinol.

    (2013)
  • Practice Committee of the American Society for Reproductive Medicine

    Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion

    Fertil. Steril.

    (2019)
  • J. Donnez

    Ovarian tissue cryopreservation and transplantation: a review

    Hum. Reprod. Update

    (2006)
  • C.Y. Andersen

    Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue

    Hum. Reprod.

    (2008)
  • S.J. Silber

    Ovarian transplantation between monozygotic twins discordant for premature ovarian failure

    N. Engl. J. Med.

    (2005)
  • J. Donnez

    Livebirth after orthotopic transplantation of cryopreserved ovarian tissue

    Lancet

    (2004)
  • J. Donnez et al.

    Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice

    J. Assist. Reprod. Genet.

    (2015)
  • L. Lotz

    Ovarian tissue transplantation: experience from Germany and worldwide efficacy

    Clin. Med. Insights Reprod. Health

    (2019)
  • H. Van der Ven

    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.

    (2016)
  • K.A. Rodriguez-Wallberg

    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.

    (2016)
  • A.K. Jensen

    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.

    (2017)
  • W.H. Wallace et al.

    Human ovarian reserve from conception to the menopause

    PLoS One

    (2010)
  • H. Koyama

    Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer

    Cancer.

    (1977)
  • N. Spears

    Ovarian damage from chemotherapy and current approaches to its protection

    Hum. Reprod. Update

    (2019)
  • D. Meirow et al.

    The effects of radiotherapy and chemotherapy on female reproduction

    Hum. Reprod. Update

    (2001)
  • A. Yuksel

    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.

    (2015)
  • D. Meirow

    Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations

    Hum. Reprod.

    (2001)
  • L. Kalich-Philosoph

    Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility

    Sci. Transl. Med.

    (2013)
  • H. Roness

    Prevention of chemotherapy-induced ovarian damage: possible roles for hormonal and non-hormonal attenuating agents

    Hum. Reprod. Update

    (2014)
  • K.N. Goldman

    mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy

    Proc. Natl. Acad. Sci. U. S. A.

    (2017)
  • Y. Luan

    Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide

    J. Endocrinol.

    (2019)
  • Q.N. Nguyen

    Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility

    Cell Death Dis.

    (2018)
  • F. Li

    Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death

    Hum. Reprod.

    (2014)
  • Y. Meng

    Sphingosine-1-phosphate suppresses cyclophosphamide induced follicle apoptosis in human fetal ovarian xenografts in nude mice

    Fertil. Steril.

    (2014)
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