Advances in the Treatment and Prevention of Chemotherapy-Induced Ovarian Toxicity

Due to improvements in chemotherapeutic agents, cancer treatment efficacy and cancer patient survival rates have greatly improved, but unfortunately gonadal damage remains a major complication. Gonadotoxic chemotherapy, including alkylating agents during reproductive age, can lead to iatrogenic premature ovarian insufficiency (POI), and loss of fertility. In recent years, the demand for fertility preservation has increased dramatically among female cancer patients. Currently, embryo and oocyte cryopreservation are the only established options for fertility preservation in women. However, there is growing evidence for other experimental techniques including ovarian tissue cryopreservation, oocyte in vitro maturation, artificial ovaries, stem cell technologies, and ovarian suppression. To prevent fertility loss in women with cancer, individualized fertility preservation options including established and experimental techniques that take into consideration the patient’s age, marital status, chemotherapy regimen, and the possibility of treatment delay should be provided. In addition, effective multidisciplinary oncofertility strategies that involve a highly skilled and experienced oncofertility team consisting of medical oncologists, gynecologists, reproductive biologists, surgical oncologists, patient care coordinators, and research scientists are necessary to provide cancer patients with high-quality care.

Download Full-text

Current and Future Perspectives for Improving Ovarian Tissue Cryopreservation and Transplantation Outcomes for Cancer Patients

Reproductive Sciences ◽

10.1007/s43032-021-00517-2 ◽

2021 ◽

Author(s):

Sanghoon Lee ◽

Sinan Ozkavukcu ◽

Seung-Yup Ku

Keyword(s):

Cancer Treatment ◽

Cancer Patients ◽

Fertility Preservation ◽

Cancer Survival ◽

Ovarian Tissue ◽

Survival Rates ◽

Reproductive Age ◽

Ovarian Tissue Cryopreservation ◽

Tissue Cryopreservation ◽

Transplantation Outcomes

AbstractAlthough advances in cancer treatment and early diagnosis have significantly improved cancer survival rates, cancer therapies can cause serious side effects, including ovarian failure and infertility, in women of reproductive age. Infertility following cancer treatment can have significant adverse effects on the quality of life. However, established methods for fertility preservation, including embryo or oocyte cryopreservation, are not always suitable for female cancer patients because of complicated individual conditions and treatment methods. Ovarian tissue cryopreservation and transplantation is a promising option for fertility preservation in pre-pubertal girls and adult patients with cancer who require immediate treatment, or who are not eligible to undergo ovarian stimulation. This review introduces various methods and strategies to improve ovarian tissue cryopreservation and transplantation outcomes, to help patients and clinicians choose the best option when considering the potential complexity of a patient’s situation. Effective multidisciplinary oncofertility strategies, involving the inclusion of a highly skilled and experienced oncofertility team that considers cryopreservation methods, thawing processes and devices, surgical procedures for transplantation, and advances in technologies, are necessary to provide high-quality care to a cancer patient.

Download Full-text

Cryopreservation Options to Preserve Fertility in Female Cancer Patients: Available Clinical Practice and Investigational Strategies from the Oncology Guidelines Point of View

Basic & Clinical Cancer Research ◽

10.18502/bccr.v12i1.5726 ◽

2021 ◽

Author(s):

Leila Mirzaeian ◽

Haniyeh Rafipour ◽

Saadeh Hashemi ◽

Sara Zabihzadeh ◽

Saeid Amanpour

Keyword(s):

Cancer Patients ◽

Fertility Preservation ◽

Clinical Oncology ◽

Ovarian Tissue ◽

Point Of View ◽

Reproductive Age ◽

Ovarian Tissue Cryopreservation ◽

Female Cancer Patients ◽

Restoration Strategies ◽

Oncology Practice

In recent years, advances in cancer treatment have improved the survival rate of cancer patients significantly. However, destructive damage to ovaries due to the therapies or cancer itself can cause different degrees of infertility in women of reproductive age that can affect their quality of life seriously. In this study, fertility cryopreservation options for female cancer patients in oncology guidelines were reviewed. Cryopreservation methods have a long history in reproductive biology and oncology. However, embryo and oocyte cryopreservation were the eligible restoration strategies in clinical oncology practice. Ovarian tissue cryopreservation (OTC) is the latest option recommended for fertility preservation in pre-pubertal and adult patients who cannot delay their treatment or in whom taking IVF hormones may have adverse effects on their cancer. Reports show that frozen-thawed ovarian tissue transplantation has led to more than 130 live births so far in patients, most of whom were cancer patients. Although OTC is indeed generally recognized as an investigational method, it is recommended in some important guidelines, such as ASCO 2018. Therefore, based on many clinical pieces of evidence , it is predicted that the investigational label will soon be removed, and OTC might be considered as one of the main fertility preservation options for female cancer patients in clinical oncology practice.

Download Full-text

Role of Stem Cells in the Ovarian Tissue Cryopreservation and Transplantation for Fertility Preservation

International Journal of Molecular Sciences ◽

10.3390/ijms222212482 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12482

Author(s):

Jeong Min Kim ◽

Seongmin Kim ◽

Sanghoon Lee

Keyword(s):

Stem Cells ◽

Cancer Treatment ◽

Fertility Preservation ◽

Ovarian Tissue ◽

Survival Rates ◽

Reproductive Age ◽

Ovarian Tissue Cryopreservation ◽

Special Focus ◽

Preservation Methods ◽

Tissue Cryopreservation

Although the cancer survival rate has increased, cancer treatments, including chemotherapy and radiotherapy, can cause ovarian failure and infertility in women of reproductive age. Preserving fertility throughout cancer treatment is critical for maintaining quality of life. Fertility experts should propose individualized fertility preservation methods based on the patient’s marital status, pubertal status, partner status, and the urgency of treatment. Widely practiced fertility preservation methods, including ovarian transposition and embryo and oocyte cryopreservation, are inappropriate for prepubertal girls or those needing urgent initiation of cancer treatment. Ovarian tissue cryopreservation and transplantation, an emerging new technology, may be a solution for these cancer patients. The use of stem cells in ovarian tissue cryopreservation and transplantation increases oxygenation, angiogenesis, and follicle survival rates. This review discusses the recent advances in ovarian tissue cryopreservation and transplantation with special focus on the use of stem cells to improve fertilization techniques.

Download Full-text

P–431 Human oocytes in-vitro maturation efficacy from infancy to adulthood – is there an optimal age?

Human Reproduction ◽

10.1093/humrep/deab130.430 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

G Karavani ◽

P Wasserzug-Pash ◽

T Mordechai-Daniel ◽

M Klutstein ◽

T Imbar

Keyword(s):

Fertility Preservation ◽

In Vitro Maturation ◽

Ovarian Tissue ◽

Age Groups ◽

Ovarian Tissue Cryopreservation ◽

Success Rates ◽

Human Oocytes ◽

Tertiary Center ◽

Significant Difference

Abstract Study question Does human oocytes in-vitro maturation (IVM) effectiveness change throughout childhood, adolescence and adulthood in girls and women undergoing fertility preservation via ovarian tissue cryopreservation (OTC) prior to chemo-radiotherapy exposure? Summary answer The optimal age for IVM is from menarche to 25 years, while pre-menarche girls and women older than 30 years have extremely low maturation rates. What is known already In vitro maturation of oocytes from antral follicles seen during tissue harvesting is a fertility preservation technique with potential advantages over OTC, as mature frozen and later thawed oocyte used for fertilization poses decreased risk of malignant cells re-seeding, as compared to ovarian tissue implantation. We previously demonstrated that IVM performed following OTC in fertility preservation patients, even in pre-menarche girls, yields a fair amount of oocytes available for IVM and freezing for future use. Study design, size, duration A retrospective cohort study, evaluating IVM outcomes in chemotherapy naïve patients referred for fertility preservation by OTC that had oocyte collected from the medium with attempted IVM between 2003 and 2020 in a university affiliated tertiary center. Participants/materials, setting, methods A total of 133 chemotherapy naïve patients aged 1–35 years with attempted IVM were included in the study. The primary outcome was IVM rate in the different age groups – pre-menarche (1–5 years and ≥6 years), post-menarche (menarche–17 years), young adults (18–24 years) and adults (25–29 and 30–35 years). Comparison between paired groups for significant difference in the IVM rate parameter was done using the Tukey’s Studentized Range (HSD) Test. Main results and the role of chance A gradual increase in mean IVM rate was demonstrated in the age groups over 1 to 25 years (4.6% (1–5 years), 23.8% (6 years to menarche) and 28.4% (menarche to 17 years), with a peak of 38.3% in the 18–24 years group, followed by a decrease in the 25–29 years group (19.3%), down to a very low IVM rate (8.9%) in the 30–35 years group. A significant difference in IVM rates was noted between the age extremes – the very young (1–5 years) and the oldest (30–35 years) groups, as compared with the 18–24-year group (p < 0.001). Number of oocytes matured, percent of patients with matured oocytes and overall maturation rate differed significantly (p < 0.001). Limitations, reasons for caution Data regarding ovarian reserve evaluation was not available for most of the patients, due to our pre-op OTC procedures protocol. None of our patients have used their frozen in-vitro matured oocytes, as such further implications of age on in-vitro matured oocytes quality and implantation potential has yet to be evaluated. Wider implications of the findings: Our finding of extremely low success rates in those very young (under 6 years) and older (≥30 years) patients suggest that IVM of oocyte retrieved during OTC prior to chemotherapy should not be attempted in these age group. Trial registration number N/A

Download Full-text

Fertility Preservation in Female Cancer Patients

ISRN Obstetrics and Gynecology ◽

10.5402/2012/807302 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Chung-Hoon Kim ◽

Gyun-Ho Jeon

Keyword(s):

Cancer Patients ◽

Fertility Preservation ◽

Survival Rates ◽

Young Patients ◽

Gynecologic Surgery ◽

Embryo Cryopreservation ◽

Future Fertility ◽

Female Cancer Patients ◽

Gestational Surrogacy

With improved survival rates among cancer patients, fertility preservation is now being recognized as an issue of great importance. There are currently several methods of fertility preservation available in female cancer patients and the options and techniques via assisted reproduction and cryopreservation are increasing, but some are still experimental and continues to be evaluated. The established means of preserving fertility include embryo cryopreservation, gonadal shielding during radiation therapy, ovarian transposition, conservative gynecologic surgery such as radical trachelectomy, donor embryos/oocytes, gestational surrogacy, and adoption. The experimental methods include oocyte cryopreservation, ovarian cryopreservation and transplantation, in vitro maturation, and ovarian suppression. With advances in methods for the preservation of fertility, providing information about risk of infertility and possible options of fertility preservation to all young patients with cancer, and discussing future fertility with them should be also considered as one of the important parts of consultation at the time of cancer diagnosis.

Download Full-text

Successful in vitro culture of pre-antral follicles derived from vitrified murine ovarian tissue: oocyte maturation, fertilization, and live births

Reproduction ◽

10.1530/rep-10-0383 ◽

2011 ◽

Vol 141 (2) ◽

pp. 183-191 ◽

Cited By ~ 47

Author(s):

Xiaoqian Wang ◽

Sally Catt ◽

Mulyoto Pangestu ◽

Peter Temple-Smith

Keyword(s):

Cancer Patients ◽

Oocyte Maturation ◽

Ovarian Tissue ◽

Blastocyst Stage ◽

Ovarian Tissue Cryopreservation ◽

Antral Follicles ◽

Live Births ◽

And Function ◽

Tissue Cryopreservation

Cryopreservation of ovarian tissue is an important option for preserving the fertility of cancer patients undergoing chemotherapy and radiotherapy. In this study, we examined the viability and function of oocytes derivedin vitrofrom pre-antral follicles as an alternative method for restoring fertility. Pre-antral follicles (specified as secondary follicle with a diameter around 100–130 μm) were mechanically isolated from vitrified-warmed and fresh adult mouse ovarian tissues and cultured for 12 days followed by an ovulation induction protocol at the end of this period to initiate oocyte maturation. Oocytes were then released from these follicles, fertilizedin vitro, and cultured to the blastocyst stage and vitrified. After storage in liquid nitrogen for 2 weeks, groups of vitrified blastocysts were warmed and transferred into pseudo-pregnant recipient females. Although most of the isolated mouse pre-antral follicles from fresh (79.4%) and vitrified (75.0%) ovarian tissues survived the 12-dayin vitroculture period, significantly fewer mature oocytes developed from vitrified-warmed pre-antral follicles than from the fresh controls (62.2 vs 86.4%,P<0.05). No difference was observed in embryo cleavage rates between these two groups, but the proportion of embryos that developed into blastocysts in the vitrification group was only half that of the controls (24.2 vs 47.2%,P<0.05). Nevertheless, live births of healthy normal pups were achieved after transfer of vitrified blastocysts derived from both experimental groups. This study shows that successful production of healthy offspring using anin vitrofollicle culture system is feasible, and suggests that this procedure could be used in cancer patients who wish to preserve their fertility using ovarian tissue cryopreservation.

Download Full-text

Female fertility preservation strategies: cryopreservation and ovarian tissuein vitroculture, current state of the art and future perspectives

Zygote ◽

10.1017/s096719941600006x ◽

2016 ◽

Vol 24 (5) ◽

pp. 635-653 ◽

Cited By ~ 11

Author(s):

M.A. Filatov ◽

Y.V. Khramova ◽

M.V. Kiseleva ◽

I.V. Malinova ◽

E.V. Komarova ◽

...

Keyword(s):

Fertility Preservation ◽

State Of The Art ◽

Ovarian Tissue ◽

Female Fertility ◽

Ovarian Tissue Cryopreservation ◽

Future Perspectives ◽

Current State ◽

Female Fertility Preservation ◽

Tissue Cryopreservation

SummaryIn the present review, the main strategies of female fertility preservation are covered. Procedures of fertility preservation are necessary for women who suffer from diseases whose treatment requires the use of aggressive therapies, such as chemotherapy and radiotherapy. These kinds of therapy negatively influence the health of gametes and their progenitors. The most commonly used method of female fertility preservation is ovarian tissue cryopreservation, followed by the retransplantation of thawed tissue. Another approach to female fertility preservation that has been actively developed lately is the ovarian tissuein vitroculture. The principal methods, advantages and drawbacks of these two strategies are discussed in this article.

Download Full-text

A Review of Oncologist’s Knowledge and Awareness Regarding Fertility Preservation

Reproductive Medicine Gynaecology & Obstetrics ◽

10.24966/rmgo-2574/100084 ◽

2021 ◽

Vol 6 (3) ◽

pp. 1-4

Author(s):

Ghina Ghazeeri ◽

Keyword(s):

Quality Of Life ◽

Cancer Patients ◽

Fertility Preservation ◽

Survival Rates ◽

Reproductive Age ◽

The Core

The recent quantum leaps in various management modalities in oncology have led to unanticipated survival rates. This has constituted a plea for amelioration in the quality of life of cancer patients of reproductive age, at the core of which is Fertility Preservation (FP).

Download Full-text

The role of gonadotropin-releasing hormone agonists in female fertility preservation

Clinical and Experimental Reproductive Medicine ◽

10.5653/cerm.2020.04049 ◽

2021 ◽

Vol 48 (1) ◽

pp. 11-26

Author(s):

Jae Hoon Lee ◽

Young Sik Choi

Keyword(s):

Cancer Patients ◽

Fertility Preservation ◽

Young Women ◽

Large Scale ◽

Ovarian Tissue ◽

Gonadotropin Releasing Hormone ◽

Ovarian Tissue Cryopreservation ◽

Breast Cancer Patients ◽

Ovarian Suppression ◽

Releasing Hormone

Advances in anticancer treatments have resulted in increasing survival rates among cancer patients. Accordingly, the quality of life after treatment, particularly the preservation of fertility, has gradually emerged as an essential consideration. Cryopreservation of embryos or unfertilized oocytes has been considered as the standard method of fertility preservation among young women facing gonadotoxic chemotherapy. Other methods, including ovarian suppression and ovarian tissue cryopreservation, have been considered experimental. Recent large-scale randomized controlled trials have demonstrated that temporary ovarian suppression using gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy is beneficial for preventing chemotherapy-induced premature ovarian insufficiency in breast cancer patients. It should also be emphasized that GnRHa use during chemotherapy does not replace established fertility preservation methods. All young women facing gonadotoxic chemotherapy should be counseled about and offered various options for fertility preservation, including both GnRHa use and cryopreservation of embryos, oocytes, and/or ovarian tissue.

Download Full-text

Female Fertility Preservation through Stem Cell-based Ovarian Tissue Reconstitution In Vitro and Ovarian Regeneration In Vivo

Clinical Medicine Insights Reproductive Health ◽

10.1177/1179558119848007 ◽

2019 ◽

Vol 13 ◽

pp. 117955811984800 ◽

Cited By ~ 9

Author(s):

Taichi Akahori ◽

Dori C Woods ◽

Jonathan L Tilly

Keyword(s):

Fertility Preservation ◽

Ovarian Tissue ◽

Mammalian Species ◽

Reproductive Age ◽

Embryo Cryopreservation ◽

Novel Approach ◽

Future Fertility ◽

Female Fertility Preservation

Historically, approaches designed to offer women diagnosed with cancer the prospects of having a genetically matched child after completion of their cytotoxic treatments focused on the existing oocyte population as the sole resource available for clinical management of infertility. In this regard, elective oocyte and embryo cryopreservation, as well as autologous ovarian cortical tissue grafting posttreatment, have gained widespread support as options for young girls and reproductive-age women who are faced with cancer to consider. In addition, the use of ovarian protective therapies, including gonadotropin-releasing hormone agonists and sphingosine-1-phosphate analogs, has been put forth as an alternative way to preserve fertility by shielding existing oocytes in the ovaries in vivo from the side-effect damage caused by radiotherapy and many chemotherapeutic regimens. This viewpoint changed with the publication of now numerous reports that adult ovaries of many mammalian species, including humans, contain a rare population of oocyte-producing germ cells—referred to as female germline or oogonial stem cells (OSCs). This new line of study has fueled research into the prospects of generating new oocytes, rather than working with existing oocytes, as a novel approach to sustain or restore fertility in female cancer survivors. Here, we overview the history of work from laboratories around the world focused on improving our understanding of the biology of OSCs and how these cells may be used to reconstitute “artificial” ovarian tissue in vitro or to regenerate damaged ovarian tissue in vivo as future fertility-preservation options.

Download Full-text