Clinical Effectiveness of Ovarian Tissue Cryopreservation and Transplantation Versus Oocyte Cryopreservation and Subsequent IVF in Adult Women Who Require Fertility Preservation Before Undergoing Gonadotoxic Treatments: A Review

Abstract

Introduction:

Ovarian tissue cryopreservation (OTC) and transplantation and oocyte cryopreservation (OC) are pivotal fertility preservation techniques for women facing infertility due to gonadotoxic treatments. This review compares the clinical effectiveness of these methods in adult women.

Methods:

A literature search on PubMed was conducted, identifying experimental, case–control and cohort studies from 1994 to 2025 that assessed OTC and transplantation versus OC and in vitro fertilisation (IVF).

Results:

A total of 13 studies involving 4,698 patients were included. OTC demonstrated promise for restoring ovarian function, particularly in young adult women, while OC yielded higher live-birth rates, especially among women under 35.

Conclusion:

Both OTC and transplantation and OC are clinically effective for fertility preservation in adult women. The choice of method should be individualised, considering the patient’s clinical scenario, age and personal preferences, ensuring informed reproductive decisions.

Introduction

Ovarian tissue cryopreservation (OTC) and transplantation and oocyte cryopreservation (OC) are two examples of primary methods for fertility preservation in women at risk of infertility due to gonadotoxic treatments, such as chemotherapy or radiation therapy.^[1] Each approach has its advantages and limitations, and recent literature has provided insights into their clinical effectiveness.^[2] While OTC is more beneficial for younger patients and those who need prompt intervention, OC often offers higher success rates for adult women, especially those under 35.^[3] The selection between these approaches will become more complex as knowledge and technology advance, enabling people to make well-informed choices regarding their reproductive prospects; however, both OTC and OC offer viable options for fertility preservation in women undergoing gonadotoxic treatments.^[1,2] The OTC technique may provide quicker restoration of ovarian function and potential for natural conception, while OC has established success rates and is preferable for women who can wait until treatment is completed.^[4] The choice between these methods should be individualised based on clinical circumstances, patient age and personal preferences.^[1,4]

The OTC and transplantation method involves the surgical removal of ovarian tissue, typically the cortex, which contains immature oocytes and follicles.^[5] The tissue is then frozen for future use.^[1] When the woman is ready to conceive, the tissue is reimplanted, allowing for potential restoration of ovarian function and natural hormone production.^[1,5] The OTC technique remains especially significant for its suitability for prepubertal girls and women who must immediately begin treatments like chemotherapy.^[6] During the process, a surgeon removes part of the ovarian cortex, which contains immature oocytes and follicles, and then cryopreserves it for future use.^[5] Upon desiring conception, the tissue is reimplanted, potentially restoring natural ovarian function. The strength of OTC lies in its potential to re-establish endocrine activity, thereby reinstating natural ovulation and normal hormonal production.^[5] In recent years, successful births have been reported using ovarian tissue that was cryopreserved for several years, marking a significant leap in medical science.^[5] Nevertheless, challenges such as the risk of reimplanting malignant cells, especially in cancer patients, present a significant hurdle, necessitating scrupulous screening and innovative research to mitigate such risks.^[7]

The OC technique involves stimulating the ovaries to produce multiple oocytes, which are then retrieved and frozen unfertilised.^[8] When the woman is ready for conception, the oocytes can be thawed and fertilised through in vitro fertilisation (IVF).^[9] The OC technique has surged forward as a more widely accepted and deployed fertility preservation method, catering primarily to women contemplating deferred childbearing.^[8] Egg freezing allows mature oocytes to be extracted post-ovulatory stimulation and then frozen unfertilised.^[10] This method offers the woman autonomy over her reproductive choices, independent of partner readiness or donor compatibility.^[8] Recent advances in vitrification, a rapid freezing technology, have drastically improved the survival rates of thawed oocytes, leading to higher pregnancy success rates.^[11] Among the notable advantages, OC allows synchronisation of fertility with personal, professional and partner considerations.^[9] It is a straightforward, repeatable procedure with comparatively less medical risks. However, elements such as age, ovarian reserve and lifestyle significantly impact the number of eggs retrievable, thus affecting pregnancy success rates.^[8,9] It is crucial to note that the OC procedure requires significant financial expenditure, often placing it beyond the reach of many without sufficient insurance benefits or access to subsidised healthcare programmes.^[12]

When evaluating the efficacy of OTC and transplantation versus OC and IVF, data from recent studies reveals varied success rates tailored by individual circumstances. The OC technique tends to meet higher success metrics in younger patients, often due to the quality of oocytes retrieved at an optimal reproductive age.^[13] This aligns with the prevailing data suggesting that vitrified eggs of women under 35 display commendable survival, fertilisation and pregnancy achievement rates.^[14] In contrast, OTC has showcased an impressive capability to restore pre-treatment ovarian activity and natural hormonal cycles in pre-pubertal patients facing the prospect of fertility loss. However, the long-term outcomes and live birth rates following OTC are still awaiting comprehensive investigation.^[15] Following cancer treatment, both OTC and OC show promise in maintaining fertility and chances of having children. However, globally, OC now produces the greatest number of live births and pregnancies.^[15] One possible explanation for OC’s success is because the technique has been utilised and proven to be effective for a long time, and it is mostly the first choice of patients attending fertility clinics.^[15]

The objective of this scooping review was to compare the clinical effectiveness of OTC and transplantation with OC and subsequent IVF in adult women requiring fertility preservation because they will be receiving a gonadotoxic intervention.

Methods

The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols are followed throughout the literature search approach, research selection and data extraction.^[16]

Inclusion Criteria

The inclusion criteria were that any selected study must be an experimental study, a case–control study, a cross-sectional study or a cohort study that assessed the clinical effectiveness of OTC and transplantation and/or OC and subsequent IVF in adult women requiring fertility preservation because they will be receiving a gonadotoxic intervention. Any study that did not comply with the above-mentioned criteria was excluded.

Literature Search Strategy

The PubMed database was searched for experimental studies, case–control studies, cross-sectional studies and cohort studies that compared the clinical effectiveness of OTC and transplantation with OC and subsequent IVF in adult women requiring fertility preservation because they will be receiving a gonadotoxic intervention from 1 January 1994 to 15 January 2025. The PubMed was searched using a combination of keywords, which are Medical Subject Headings phrases, as shown in Table 1. Zotero was used for arranging study selection and duplicate removal.

Table 1.

Database search terms for literature

Database	Search string	Results
PubMed	(((ovarian tissue cryopreservation) OR (((oocyte cryopreservation) AND IVF AND female patients with cancer)	2,554

Study Selection and Data Extraction

Included studies quantitively compared the clinical effectiveness of OTC and transplantation with OC and subsequent IVF in adult women requiring fertility preservation because they will be receiving a gonadotoxic intervention and were published from 1 January 1994 to 15 January 2025. Studies that used an uncategorised population, focused on subjects that were not related or had insufficient data were excluded. Duplicate reports, editorial letters, conference abstracts, reviews and papers using animal models were not included. The most recent or comprehensive version was chosen if there were duplicate research. The English version was chosen when the same data was described and published in more than one language. The initial author, the year of publication, the place of origin, the study design, the number and characteristics of participants, exposure, the results and the instruments used to measure them were the criteria used to extract the data. C.E.O. extracted and independently reviewed the data from all included studies.

Results

The PubMed database search yielded a total of 2,554 studies; 2,425 of them were discarded prior to Zotero screening. A total of 129 articles were chosen for full-text screening after a review of the abstracts and titles. Following an abstract examination and detailed reading of these materials, 78 were eliminated. Ultimately, the scoping review included 13 qualifying studies in all. The thorough research identification and selection procedure are shown in Figure 1.

Figure 1.

Selected studies’ PRISMA flow diagram

Study Characteristics

The 13 studies included were published between 2006 and 2022, covering a total of 4,698 patients. Sample sizes vary significantly across studies, from small-scale experimental studies (e.g., Oktay et al.^[25] with 2 participants) to large multicentre studies (Rodriguez-Wallberg et al.^[30] with 1,588 participants). Table 2 highlights various methodologies, sample sizes, aims and outcomes related to fertility preservation techniques in women undergoing cancer treatment. The methodologies employed in these studies range from clinical trials to retrospective analyses: clinical trials (Seshadri et al.,^[20] Fabbri et al.,^[21] Poirot et al.^[22]) and retrospective studies (Schmidt et al.,^[23] Dittrich et al.,^[26] Hashimoto et al.^[28]); observational studies (Moraes et al.^[27] and Diaz-Garcia et al.^[31]) and experimental studies (Oktay et al.^[25] and Grifo et al.^[32]).

Table 2.

The characteristics of the included investigations

Sl. no	First author	Year	Country	Study design	Sample size/number of adult women	Aim of the study	Main outcomes
1	Seshadri[20]	2006	Australia	Clinical trial	24	To examine harvested ovarian tissue for subclinical involvement with Hodgkin lymphoma by immune-histochemistry and to understand patient and treatment factors predictive of oocyte yield	The quality of ovarian tissue harvested was not degraded by patient age or prior chemotherapy
2	Fabbri[21]	2012	Italy	Randomised controlled trial	94	To describe a decade of experience with ovarian tissue cryopreservation in patients with breast cancer	There were no micro-metastases found in the ovarian tissue of 94 patients following cryopreservation, the density of viable follicles and the ovarian tissue’s morphology were comparable in frozen and fresh tissue. In both fresh and frozen tissue, follicular density declined as patients became older. There was a difference in follicular density between frozen and fresh tissue. According to these results, it is highly probable to preserve young female breast cancer patients’ fertility by ovarian tissue cryopreservation
3	Poirot[22]	2019	France	Clinical trial	31	To evaluate the revival of ovarian function and fertility in patients who had received ovarian tissue transplant	The proportion of women who succeeded in having one child or more was 23% (7/31) in the whole population, 0% (0/9) in the group ‘no previous chemotherapy’ and 32% (7/22) in the group ‘past chemotherapy’. These findings imply that previous chemotherapy should no longer be regarded as a barrier to ovarian tissue cryopreservation
4	Schmidt[23]	2011	Denmark	Retrospective study	296	296 adult women had their ovarian tissue cryopreserved before chemotherapy and/or radiation therapy. Later, 12 women received auto-transplantation of frozen-thawed cryopreserved ovarian tissue because of premature ovarian failure after cancer treatment	Auto-transplantation of ovarian tissue consistently leads to recovery of ovarian function after treatment-induced ovarian failure
5	von Wolff[24]	2009	Germany	Controlled clinical trial	40	To determine if starting ovarian stimulation during the follicular or luteal phase may produce oocytes in every patient prior to cancer therapy within two weeks	Regardless of the stage of the menstrual cycle, oocytes can be effectively acquired prior to cancer treatment
6	Oktay[25]	2018	United States	Experimental study	2	By using a human extracellular matrix scaffold to transplant frozen-banked ovarian tissue, the results of live birth and in vitro fertilisation are evaluated	Before undergoing preconditioning chemotherapy for haematopoietic stem cell transplantation, two individuals with haemophagocytic lymphohistiocytosis (patient A) and non-Hodgkin lymphoma (patient B) had their ovarian tissue cryopreserved at the age of 23. Following treatment, both had ovarian failure, and seven and twelve years later, their ovarian cortical tissues were transplanted into the contralateral menopausal ovary. Both patients successfully gave birth to healthy children
7	Dittrich[26]	2015	Germany	Retrospective analysis	20	To report the results of 20 orthotopic re-transplantations of cryopreserved ovarian tissue after cancer treatment	Between 2005 and 2009, ovarian tissue was extracted from patients at some German facilities. Every patient had radiation treatment and/or chemotherapy. Three individuals continued to exhibit some ovarian activity, while 17 patients had total premature ovarian insufficiency. In eight cases, tissue had to be transported overnight before freezing. In every instance, cryopreservation adhered to gradual freezing procedures. On average, retransplantation took place at Erlangen University Hospital 3.75 years following extraction. In 16 cases, thawed tissue was transplanted into a peritoneal pouch underneath the tube in the wide ligament area. In four cases, fragments were sutured into a peritoneal pouch and onto the surviving ovary. These findings unequivocally show that cryopreserving ovarian tissue is a safe and effective therapeutic alternative for preserved fertility prior to gonadotoxic treatments
8	Moraes[27]	2019	Brazil	Observation study	187	To assess whether a diagnosis of cancer interferes with ovarian function prior to the treatment of the disease	The number of harvested and frozen oocytes from cancer and non-cancer patients indicated that in the two groups response to ovarian stimulation was similar
9	Hashimoto[28]	2017	Japan	Retrospective study	62	To assess the efficacy of fertility preservation and the impact of chemotherapy on the reproductive potential of Japanese patients with breast cancer	For patients with breast cancer, fertility preservation with unfertilised oocytes before chemotherapy seems to be promising for achieving higher pregnancy rates, with no risk of minimal residual disease
10	Porcu[29]	2022	Italy	Prospective study	508	To demonstrate that oocyte cryopreservation is a feasible and efficient option for fertility preservation in cancer patients through the comparison of in vitro fertilisation treatments in oncological and non-oncological patients	No statistically significant differences were observed between oncological patients and non-oncological patients. A total of 15 babies were born from oncological patients. Children born showed normal growth and development. One minor malformation was detected
11	Rodriguez-Wallberg[30]	2016	Nordic countries	Multicentre study	1588	To present ovarian tissue cryopreservation as one of the fertility preservation options available in the Nordic nations	Cryopreservation of ovarian tissue is safe. Methods of slow freezing are still recommended. Nordic nations that have started ovarian tissue transplantation treatments have reported encouraging fertility recovery outcomes. The tissue was primarily removed laparoscopically by unilateral oophorectomy, and most patients chosen for ovarian tissue cryopreservation had just received a cancer diagnosis. There were just minor complications noted. With the goal of restoring fertility, 46 women have had ovarian tissue transplants in all; 17 healthy children have been born, and several more pregnancies are continuing. Oocyte cryopreservation following hormonal stimulation is still the recommended method for preserving fertility whenever the clinical state of the patient permits it in Nordic countries
12	Diaz-Garcia[31]	2018	Spain	Observational study	One cohort included 1,024 patients undergoing oocyte vitrification; the other cohort included 800 patients undergoing ovarian cortex cryopreservation and transplantation.	To evaluate the effectiveness of ovarian cortex cryopreservation and transplantation versus oocyte vitrification in women receiving gonadotoxic therapies	There was a higher live-birth rate after oocyte vitrification. Oocyte vitrification and ovarian cortex transplantation are very effective methods to preserve fertility, allow for natural pregnancy and restore ovarian function. In clinical scenarios where oocyte vitrification is not feasible, ovarian cortex transplantation remains the fertility preservation technique of choice
13	Grifo[32]	2010	United States	Experimental study	22	To examine the use of oocyte cryopreservation as a fertility preservation technique	The rates of blastocyst formation, 2-pronuclei fertilisation and oocyte survival were 43%, 79% and 92% respectively. With 14 conceptions, 1 miscarriage, 10 deliveries of 13 viable infants and 3 ongoing pregnancies, the ongoing/delivered pregnancy rate is 57%. Compared to cycles carried out sequentially in age-matched controls utilising fresh, nonfrozen autologous or donor oocytes during a comparable time span, this outcome was not significantly different

Evaluation of Bias Risk and Evidence Grading

A modified Newcastle–Ottawa Scale (NOS) was used to independently evaluate the methodological quality of each included study.^[17] The 13-item version of the Research Triangle Institute Item Bank tool, which is an extension of the original 29-item questionnaire, was used to identify and evaluate potential risk of bias.^[18] The Grading of Recommendations Assessment, Development, and Evaluation technique (GRADE) was used to establish the level of confidence in the estimate for the result.^[19] Refer to Table 3.

Table 3.

Evaluation of bias risk and evidence rating

Sl. no.	First author	Symbol	Quality	Risk of bias
1	Seshadri[20]	⊕⊕⊕	Moderate	Low
2	Fabbri[21]	⊕⊕⊕	Moderate	Low
3	Poirot[22]	⊕⊕⊕	Moderate	Low
4	Schmidt[23]	⊕⊕⊕	Moderate	Low
5	von Wolff[24]	⊕⊕⊕	Moderate	Low
6	Oktay[25]	⊕⊕	Low	Moderate
7	Dittrich[26]	⊕⊕⊕⊕	High	Low
8	Moraes[27]	⊕⊕⊕	Moderate	Low
9	Hashimoto[28]	⊕⊕⊕⊕	High	Low
10	Porcu[29]	⊕⊕⊕⊕	High	Low
11	Rodriguez-Wallberg[30]	⊕⊕⊕⊕	High	Moderate
12	Diaz-Garcia[31]	⊕⊕⊕	Moderate	Low
13	Grifo[32]	⊕⊕⊕	Moderate	Moderate

Discussion

Gonadotoxic intervention such as radiation and chemotherapy can cause early ovarian insufficiency, which leads to fertility loss.^[2] The OC technique is recommended by current guidelines to treat early ovarian insufficiency.^[15] However, OTC is the first choice for prepubertal patients and those who are unable to postpone the commencement of chemotherapy or radiotherapy, it has also recently gained acceptance as a means of preserving fertility.^[14,15] By using laparoscopy to obtain ovarian tissue, it can be cryopreserved prior to commencing chemotherapy.^[2] To enable ovarian function to resume at the appropriate period of childbearing, ovarian tissue may be thawed and re-implanted either orthotopically into the pelvic region or heterotopically, such as in the abdominal cavity or the forearm.^[15] Several OTC and transplantation births have been documented worldwide, suggesting that it has the potential to be successful. Based on the outcomes of the present study, the results of OTC and OC thus far indicate that both methods are effective and prospective for preserving fertility and the likelihood of having children after cancer treatment.

With regard to OTC and transplantation, the study by Seshadri et al.^[20] demonstrated that the quality of harvested ovarian tissue is not adversely affected by patient age or prior chemotherapy, indicating its potential as a viable fertility preservation method. Fabbri et al.^[21] reported no micro-metastases in harvested ovarian tissue from breast cancer patients, suggesting that OTC and transplantation are safe and effective for preserving fertility in young women. Poirot et al.^[22] found that 23% of women who underwent OTC achieved live births, with a higher success rate in those who had prior chemotherapy. Schmidt et al.^[23] and Dittrich et al.^[26] provided evidence that auto-transplantation of cryopreserved ovarian tissue can restore ovarian function after treatment-induced ovarian failure, confirming its effectiveness as a fertility preservation strategy. Rodriguez-Wallberg et al.^[30] noted promising fertility recovery outcomes in Nordic countries, with several births following ovarian tissue transplantation, further supporting its safety and effectiveness. Regarding OC and IVF, von Wolff et al.^[24] established that oocytes can be effectively harvested regardless of the menstrual cycle phase before cancer treatment. Hashimoto et al.^[28] and Porcu et al.^[29] highlighted the effectiveness of OC in achieving higher pregnancy rates, with no significant differences in outcomes between oncological and non-oncological patients. Moreover, Diaz-Garcia et al.^[31] provided a critical comparison, showing that oocyte vitrification yielded a higher live-birth rate compared to ovarian cortex transplantation, advocating for OC when feasible.

Strengths and Limitations

This scoping review presents a comprehensive evaluation of the clinical effectiveness of OTC and transplantation compared to OC and subsequent IVF in adult women requiring fertility preservation due to gonadotoxic interventions. One of the primary strengths of this review is its rigorous methodology, which adheres to the PRISMA guidelines for systematic reviews. By incorporating a variety of study designs, including clinical trials, cohort studies and retrospective analyses, this review captures a broad spectrum of evidence regarding the effectiveness of both fertility preservation techniques. Additionally, the inclusion of 13 studies involving a significant sample size of 4,698 patients provides a robust foundation for drawing conclusions about the comparative effectiveness of OTC and OC.

However, there are notable limitations. The variability in study designs and sample sizes may introduce biases that complicate direct comparisons between the two methods. Moreover, the review highlights the limited long-term data available for OTC, particularly regarding live birth rates and the risk of reintroducing malignant cells. This uncertainty emphasises the need for further research to establish the safety and efficacy of OTC and transplantation, especially for patients diagnosed with cancer. Additionally, financial considerations surrounding OTC and transplantation can create accessibility issues, as many women may face challenges in affording this option without adequate insurance coverage.

Recommendations and Future Directions

Given the findings of this review, it is recommended that healthcare providers engage in thorough discussions with patients regarding their fertility preservation options, emphasising the unique benefits and risks associated with OTC and transplantation and OC and IVF. Patient education should include considerations of age, urgency of treatment and personal preferences to facilitate informed decision-making.

Future research should focus on longitudinal studies that assess the long-term outcomes of both OTC and transplantation and OC and subsequent IVF, particularly regarding live birth rates and the psychosocial impacts on patients post-treatment. Investigations into innovative techniques that mitigate the risks associated with malignant cell reintroduction during OTC and transplantation are essential, especially in patients with blood cancers such as leukaemia. Additionally, studies exploring the cost-effectiveness and accessibility of both methods will provide valuable insights for healthcare policymakers. However, while both OTC and transplantation and OC offer viable pathways for fertility preservation in women facing gonadotoxic treatments, a nuanced understanding of their respective strengths, limitations and the evolving landscape of reproductive technologies will be crucial for optimising patient outcomes. Continuous advancements and research in this field will enhance clinical practices and improve the reproductive prospects for women undergoing fertility preservation.

Conclusion

The results of the reviewed studies show that both OTC and transplantation and OC and subsequent IVF are clinically effective fertility preservation methods. The OTC and transplantation is an effective technique for fertility preservation, ovarian function restoration and natural pregnancy. The OTC has a high success rate after auto-transplantation and is highly recommended for women at high risk of ovarian insufficiency following gonadotoxic intervention. However, there is a risk that stored ovarian tissue will contain malignant cells that survive cryopreservation and could potentially be transplanted back into the woman during transplantation, especially in haematological cancer. Unlike OC, OTC can be done immediately without the need to wait for an ovulation cycle, and so it will not delay treatment if urgent chemotherapy is recommended. OTC is also a more cost-effective fertility preservation method than OC. However, OTC has a low usage rate compared to OC. The OC method appears to have a higher live-birth rate, making it the preferred option when clinically possible. Nevertheless, OTC remains a valuable alternative for patients who cannot undergo OC, particularly in cases of urgent gonadotoxic treatments. Each method has its unique advantages, and the choice of technique should be tailored to the individual patient’s circumstances and treatment plans.