Fertility Preservation in Female Patients with Cancer Part II: Royan Institute Clinical Practice Guideline for Girls and Women with Cancer; A Review Study

Abstract

The fertility preservation (FP) is a paramount concern for oncology patients and should be regarded as an essential component of their overall cancer management strategy. The magnitude of this issue has been recognized in FP guidelines. The formulation and execution of harmonized guidelines and policies concerning the provision of FP services, inclusive of therapeutic strategies and standardization of procedures, are crucial to surmount disagreements regarding the delivery of these therapeutic services and avert delays in cancer treatment. The matter of FP and the methodology for managing the treatment and follow-up of cancer patients should be documented as a component of their management guideline, thereby providing patients with clear recommendations on fertility preservation. In this manuscript, we provide a succinct overview of existing international guidelines history and reference comprehensive networks of FP services for oncology patients. Furthermore, we present the Royan Institute’s guideline specifically designed for preserving the fertility of female oncology patients.

Introduction

The fertility preservation (FP) is a paramount concern for oncology patients and should be regarded as an essential component of their overall cancer management strategy. The magnitude of this issue has been recognized in FP guidelines. These guidelines underscore that FP, in conjunction with sexual health and function, should be a fundamental aspect of the management of oncology patients who may face infertility risks due to oncological treatments (1).

Despite the progress in assisted reproductive technologies (ART) offering potential solutions for safeguarding the fertility of oncology patients, there exist impediments that obstruct the efficacious execution of these strategies. One such impediment is the delivery of optimal and integrated services, which can be addressed by formulating FP guidelines specifically tailored for oncology patients and implementing policies concerning the provision of these services to this demographic (2).

Clinical practice guidelines offer a transparent decisionmaking framework for FP, aiding healthcare practitioners in providing optimal and integrated services, thereby enhancing the quality of life for oncology patients and survivors. In a particular study, 25 clinical practice guidelines were identified for FP in pediatric, adolescent, and adult oncology patients. However, only one-third of these guidelines were deemed to meet the requisite quality standards. These guidelines display significant variation in their recommendations pertaining to FP, reflecting a lack of consensus on specific recommendations and an inability to deliver high-quality services (3).

The Royan Institute has undertaken initiatives to enhance the quality of FP services for oncology patients by formulating FP guideline. In this manuscript, we provide a succinct overview of existing international guidelines history and reference comprehensive networks of FP services for oncology patients. Furthermore, we present the Royan Institute’s guideline specifically designed for preserving the fertility of female oncology patients.

International guidelines history of fertility preservation in cancer patients

The International Society for Fertility Preservation (ISFP) was established by Donnez in 2007. This society published its guidelines on FP in patients with lymphoma, leukemia, and breast cancer in 2012. Since its establishment, the ISFP has been holding biennial conferences with the aim of achieving international consensus on FP approaches in cancer patients, with researchers from around the world in attendance.

The FP guidelines in the United States have been outlined by the American Society for Reproductive Medicine (ASRM) and the American Society of Clinical Oncology (ASCO), as well as by the National Comprehensive Cancer Network (NCCN).

ASCO published its first international guideline on FP in cancer patients in 2006. This guideline, based on articles published between 1987 and 2005, has been updated in 2013 and 2018 (4).

The NCCN Clinical Practice Guidelines in Oncology are the authors’ consensus statement on currently accepted approaches to cancer treatment. The NCCN guidelines specifically focus on therapy considerations and management for adolescents and young adults (AYA) with cancer because these patients need unique services such as supportive care which includes fertility counseling and psychosocial and behavioral issues. The NCCN Guidelines for AYA oncology address additional aspects of care for AYA patients, including risk factors, screening, diagnosis, and survival. The 1.2023 version of the guidelines also deals with the risks associated with cancer treatment, fertility, FP before cancer treatment, fertility after cancer treatment, and prevention of pregnancy during cancer treatment (5).

In Europe, international guidelines on FP are developed by the European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Medical Oncology (ESMO). At the national level, we see the provision of FP guidelines by the French National Cancer Institute and Biomedicine Agency, the English National Institute for Health and Care Excellence (NICE), the Australian Oncofertility Consortium, among others (6).

ESHRE established a special working group focused on FP programs in early 2017. The aim was to support collaboration among European countries with relevant organizations and professional societies. The society’s guidelines on FP are updated annually following international specialist meetings (7). The ESHRE guidelines on female’s FP were published in 2020 to provide clinicians with clear evidence-based recommendations on female FP. These guidelines help healthcare providers to meet the increasing demand for FP by different groups of patients, including patients with cancer or benign diseases undergoing gonadotoxic treatments and women requesting oocyte cryopreservation (OC) due to age-related fertility decline. The ESHRE guidelines provide 78 recommendations on evaluations before FP, FP interventions, and posttreatment care (8).

ESMO has a special working group for FP. This group is responsible for enhancing the knowledge of healthcare workers and patients about oncofertility through national and international collaborations among specialist service providers, with the aim of promoting new approaches to FP (6). The core topics of these guidelines, in addition to FP in cancer patients, include the management of patients whose cancer has been diagnosed during pregnancy, as well as the management of pregnancies diagnosed while the patient is undergoing anti-cancer treatments (9).

The Children’s Oncology Group Long-Term Followup Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG–LTFU Guidelines) were initially published in 2003. These guidelines are updated biennially based on review studies and expert consensus, encompassing recommendations for screening and managing the delayed effects of oncological treatments. As per these guidelines, the follow-up of an oncology survivor who is asymptomatic should persist for more than two years post-treatment completion. Importantly, this specialist group offers recommendations encompassing all facets of fertility health and sexual health to patients via the educational link http://www.survivorshipguidelines.org (10, 11).

The FertiPROTEKT scientific network, instituted by von Wolf in 2006 for the German-speaking regions, disseminates guidelines for preserving fertility in female oncology patients for specific anti-cancer treatments. This scientific network, comprising 100 assisted reproduction centers across Germany, Austria, and Switzerland, published its clinical guidelines in two parts in 2017.

The first part pertains to breast cancer, Hodgkin’s lymphoma, borderline ovarian malignant tumors, cervical cancer, endometrial cancer, rheumatic and autoimmune diseases, Ewing’s sarcoma, osteosarcoma, colorectal carcinoma, acute lymphoblastic leukemia, and acute myeloid leukemia. It provides detailed information on the prognosis of the disease, risk of infertility, risk of ovarian metastasis, and FP for each disease. The effects of radiation therapy on the ovaries and uterus are also delineated.

The second part elucidates the history, effectiveness, risks, and clinical approach to controlled ovarian stimulation (COS) and OC, ovarian tissue cryopreservation (OTC) and transplantation, and ovarian protection. It also imparts information on laboratory maturation and experimental methods of FP. Notably, this network currently registers its projects in the “International Cancer, Infertility and Pregnancy Network” (12, 13).

Comprehensive service networks for preserving fertility capabilities in cancer patients: Organizational backing for FP programs for oncology patients on a global scale, as well as health and wellness networks to bolster care coordination, is indispensable. Augmenting these collaborations poses a significant challenge for enhancing the performance of the healthcare system. The requisite support to mobilize all necessary resources and ensure an efficient health cycle is imperative. Large international networks have been instituted to facilitate scientific exchange among nations and standardize FP services for oncology patients.

The International Cancer, Infertility, and Pregnancy Network has instituted an international registry system for cancer during pregnancy and FP during oncological treatment, and promotes research to augment the knowledge of service providers and the general populace. The data collected encompasses information related to oncology, women, and obstetrics, and covers a variety of cancer types and treatment methodologies. This international network endeavors to collaborate closely with existing networks, particularly the European Society of Gynaecological Oncology (ESGO). In 2015, the “International Cancer, Infertility, and Pregnancy Network” became part of the “Cancer in Pregnancy” registry system that was established in 2005 (9, 14).

The Oncofertility Consortium Network, situated at Northwestern University in Chicago, USA, serves as a nexus connecting active centers that provide FP services across the United States and globally. This national consortium is an interdisciplinary initiative conceived by Wood Ruff in 2007 to investigate the future fertility of oncology survivors and concentrates on the following dimensions: i. Mechanisms through which oncological treatments induce infertility, ii. Techniques for freezing, storing, and transplanting ovarian tissue, iii. Cultivation of follicles in a laboratory setting and maturation of eggs utilizing three-dimensional culture media, iv. Communication barriers existing between patients and healthcare pro viders, and v. Ethical and legal considerations pertaining to the application of FP methods in oncology patients (15).

Oncofertility Consortium’s National Physicians Cooperative (OC-NPC) was also established in 2007 to examine fertility challenges related to cancer treatment and other fertility-related conditions. There are 38 institutions across Europe that are members of this consortium. Sixteen of the 38 institutions specifically focus on children and adolescents (ages 0-17). This consortium also has partners in 35 countries around the world, which collaborate through the Oncofertility Consortium’s Global Partner Network (16).

The Scottish Intercollegiate Guideline Network (SIGN) has been operational since 2013 and focuses on long-term follow-ups of children who have survived cancer, with the aim of helping identify, evaluate, and manage the late effects of cancer treatment. This network identifies late effects of cancer treatment that occur a decade after patient survival and determines the need for lifelong follow-ups. These follow-ups require the establishment of a three-tier structure that includes: risk of disease-related complications, risk of treatment-related complications, and a list of required specialists.

The guidelines of this network encompass recommendations for cardiovascular care, bone density measurement, metabolic disorders, psychological support, growth-related factors, endocrine and thyroid function disorders, and information on a healthy lifestyle for oncology survivors. These services are provided at three distinct levels, contingent on the conditions and needs of each patient.

Level one care comprises endocrine, cardiovascular, metabolic evaluations, and monitoring of a healthy lifestyle; Level two care involves monitoring child growth, puberty, thyroid function, and cognitive-neurological development until adulthood (at this level of care, communication with the child’s school may be necessary); Level three care is designated for high-risk patients who have had brain, pelvic or bone tumors and are at risk of hypothalamic-pituitary function disorders and infertility and necessitate specialized counseling.

It is important to note that determining the level of necessary care for children who have survived cancer is highly variable, and controlled evaluations of optimal frequencies, duration, and quality of follow-ups are still required to ascertain the effectiveness of services (17).

In France, the regional network ONCOPACA has laid the intellectual groundwork and regional charter with a focus on cancer and fertility. FP programs were among the objectives of the French National Cancer Plan during the period 2014-2019, although a national network structure does not yet exist.

The Japan Society of Fertility Preservation (JSFP) and Korean Society for Fertility Preservation (KSFP), instituted in 2012 and 2013 respectively, have established national FP networks, inclusive of oncology patients (15).

The Oncofertility working group of the Royan Institute: The provision of FP services to cancer patients in Iran, as a developing country, is relatively recent. The Royan Institute, as a research and treatment center for infertility, is one of the active entities in this field. The institute has been offering comprehensive FP services through a multidisciplinary team to cancer patients since 2014. The specialized oncofertility working group was also established at this institute in 2017. The institute offers various methods of FP, including ovarian transposition, gamete (oocyte and sperm) and embryo cryopreservation, gonadal tissue (ovary and testis) cryopreservation to children, adolescents, and adult women and men. It also has ongoing research projects in areas such as stem cells, tissue engineering, and artificial gonads to improve current treatment methods. The members of the specialized working group at the Royan Institute are divided into clinical and research subgroups including the reproductive endocrinologist and urologist, oncologist, perinatologist, advanced laparoscopic surgeon, psychologist, embryologist, anesthesiologist, pathologist, radiologist, genetic, ethics and forensic specialist, epidemiologist, stem cell & developmental biologist, coordinator clinical midwife, and research midwife (responsible for communication regarding clinical trials). Since 2014, more than 500 women with cancer have been offered FP services before starting their cancer treatment, including oocyte, embryo, and OTC and ovarian transposition. Given the short duration of these services at this institute, so far 10 live births from oocyte or embryos cryopreservation, and two cases of ovarian tissue transplantation (OTT) have been recorded (18).

Royan Institute clinical practice guideline for girls and women with cancer

Guideline question: What are FP options for cancer patients who will receive anticancer treatment?

Target population: Female cancer patients at infertility risk due to anticancer treatment.

Target audience: Medical oncologists, gynecologic oncologists, pediatric oncologists, reproductive endocrinologist, andrologists, embryologists, advanced laparoscopic surgeons, midwifes, nurses, social workers, psychologists, and other non-physician providers.

Initial patient visit by infertility specialist:

• Assessing the patient’s general health

• Evaluating the patient’s pubertal status

• Discussing the necessity of FP and suggest suitable methods

• Obtaining consent from the patient or parents (for patients under 18 years old) for FP services

Specialized consultations: Oncology specialist consultation:

• Determining the necessity of FP

• Estimating the rate of ovarian failure following cancer treatment

• Estimating the ovarian metastasis risk

• Determining the cancer treatment option (surgery, chemotherapy, radiotherapy, or a combined approach)

• Determining the available time until the start of cancer treatment, and determine the possibility of hormonal treatment for ovarian stimulation for oocyte or embryo cryopreservation

Anesthesia consultation

Psychological consultation

Other specialized consultations as necessary (depending on the individual’s underlying disease)

Forensic consultation (in virgin patients, if the patient requests, this consultation is done)

Para clinical evaluations: Initial laboratory assessment:

• Determining the patient's pregnancy status (beta-human chorionic gonadotropin (Beta-HCG) test)

• Ovarian reserve evaluation (follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH))

Complete blood count with differential (CBC-diff)

Secondary laboratory assessment:

• Estradiol

• Progesterone

• Thyroid stimulating hormone (TSH)

• Fasting blood sugar (FBS)

• Blood urea nitrogen (BUN)

• Creatinine

• Blood group/ Rh

• VDRL

• Hepatitis B virus surface antigen (HBS-Ag)

• Hepatitis C virus antibody (HCV-Ab)

• Human immunodeficiency virus antibody (HIV-Ab)

Assessment of imaging:

• Abdominal and pelvic ultrasound

Embryo cryopreservation

Definition: EC is a FP option that is commonly used to store excess embryos following in vitro fertilization (IVF). Several oocytes are collected following COS; then they are fertilized with sperm and the resulting embryos are frozen at the cleavage or blastocyst stage. They are thawed and then transferred into the uterus when the patient intends to use their stored embryos. Generally, it is recommended as the primary FP option provided that the individual is of post-puberty age, has the necessary time for ovarian stimulation (at least two weeks), and has access to sperm. It should be emphasized that EC is actually FP for a couple, and therefore the use of stored embryos is only possible with the consent of both parents (4, 8, 19).

The eligibility criteria for EC:

• Sexual puberty

• Married

• Age: from puberty to 45 years old

• The possibility of delaying cancer treatment for at least two weeks

• No chemotherapy treatment within the past six months

Assessment of the male partner:

Andrologist visit

Laboratory assessment:

• Semen analysis

• HBS-Ag

• HCV-Ab

• HIV-Ab

Oocyte cryopreservation

Definition: OC is a FP option that is particularly suitable for single women. This method is offered in the field of ARTs to infertile patients. The only difference between oocyte and embryo storage is that in the OC process, the collected oocytes are not fertilized and are frozen directly. When the patient intends to use their stored e and LHeggs, they must first thaw the frozen oocytes, then fertilize them with sperm, and then transfer the resulting embryo into their uterus (4, 8, 19).

Recommendation: Married individuals are advised to store both oocytes and embryos.

The eligibility criteria for OC:

• Sexual puberty

• Single and/or married

• Age: from puberty to 45 years old

• The possibility of delaying cancer treatment for at least two weeks

• No chemotherapy treatment within the past six months

Ovarian stimulation

Time: Before chemotherapy and/or radiotherapy (in patients with chemotherapy history: at least six months after chemotherapy).

Standard protocol for ovarian stimulation in cancer patients: Standard COS entails utilizing gonadotropin releasing hormone (GnRH) antagonist. Additionally, the use of anti-estrogen agents, such as letrozole, during ovarian stimulation may be considered for estrogen-sensitive tumors, including breast, endometrial, and borderline ovarian cancer (4, 12, 20).

Random start controlled ovarian stimulation

Early follicular phase: Begins from the start to the middle of the follicular phase (dominant follicle is smaller than 12 mm and progesterone level less than 1.5 ng/ml). Ovarian stimulation is initiated through the administration of gonadotropin containing FSH or human menopausal gonadotropin (HMG). Upon observation of a follicle measuring 12-14 millimeters (mm), a GnRH antagonist is administered. The triggering final oocyte maturation is performed upon observation of more than three follicles larger than or equal to 17 mm, through the administration of a low dose of GnRH agonist. The duration of ovarian stimulation using gonadotropins typically varies from 9-14 days (21).

Late follicular phase: It is characterized by the presence of a dominant follicle larger than 12 mm and progesterone level less than 1.5 ng/ml. Initially, the patient receives GnRH antagonist for three consecutive days or a single injection of a GnRH agonist is administered to induce the luteal phase. Three days later, ovarian stimulation is initiated through the administration of gonadotropin containing FSH or HMG. Upon observation of a new dominant follicle measuring 12-14 mm, a GnRH antagonist is administered. After observing a follicle measuring 18 mm, ovulation is induced through the administration of a GnRH agonist.

Luteal phase: It is characterized by the progesterone level more than 1.5 ng/ml. Ovarian stimulation is initiated similarly to the conventional method through the administration of gonadotropin containing FSH or HMG, and a GnRH antagonist is administered upon observation of a follicle measuring 12-14 mm. The triggering final oocyte maturation is also performed through the administration of a low dose of GnRH agonist (13, 22).

Double ovarian stimulation: Occurs in a single menstrual cycle, both in the follicular and luteal phases. The goal of using this method is to achieve the maximum number of oocytes and improve cumulative pregnancy rates without delaying cancer treatment. This method, which takes about 30 days to complete, involves ovarian stimulation through the administration of GnRH antagonist. The triggering final oocyte maturation must also be performed through the administration of GnRH agonist. The start of the first phase of ovarian stimulation can be on any day of the menstrual cycle. At the time of follicle aspiration, small follicles are ignored and the second phase of ovarian stimulation begins five days after follicle aspiration.

Ovarian stimulation in patients with estrogen-sensitive cancers: In cases of estrogen-sensitive cancers, it is recommended to administer letrozole at the onset of ovarian stimulation, concurrently with the initiation of gonadotropin administration. The starting dose of letrozole should be 2.5-5 mg/day, and serum estradiol levels should be monitored at each follicle size assessment. The dose of letrozole may be increased up to 10 mg/day in order to maintain estradiol levels below 500 pico-grams per milliliter (pg/ml). On the oocyte retrieval day, serum estradiol levels should be measured, and if it exceeds 500 pg/ml, letrozole administration should continue until estradiol levels fall below this threshold or until menstruation commences (13, 22, 23).

Dose of gonadotropin for ovarian stimulation: The optimal dose of gonadotropin for ovarian stimulation should be determined based on ovarian reserve markers such as AMH levels and antral follicle count (AFC) as assessed by sonography.

Final oocyte maturation: The administration of a low dose of GnRH agonist is recommended. The triggering final oocyte maturation by GnRH agonists can reduce ovarian hyperstimulation syndrome (OHSS).

The baseline LH less than 5 mIU/mL is a risk factor for suboptimal response to agonist trigger. If the baseline LH is less than 5 mIU/mL the patient is reevaluated and if there is no risk for OHSS, human chorionic gonadotropin (HCG) triggering is elected. And if the patient is high risk for OHSS final oocyte maturation is induced through the administration of a GnRH agonist.

Threshold of 19 follicles of ≥11 mm on triggering final oocyte maturation day predicted moderate to severe OHSS in GnRH antagonist protocol.

In case of the baseline LH less than 5 mIU/mL to ensure that the GnRH trigger was effective it is imperative to check serum progesterone and LH levels ~ 8-14 hours following a GnRH agonist trigger. In general, an inadequate response is defined as a progesterone <3 ng/ml and an LH <15 IU/L.

In case of inadequate GnRH agonist trigger the patient is reevaluated again the patient receives antagonist and retriggered with low dose HCG (2500 IU) and oocytes retrieval is scheduled 36 hours later.

Delaying the initiation of long-acting GnRH agonist for 1 weeks after oocyte retrieval in patients who are at high risk for developing OHSS should be considered to allow for resolution of luteinization before the flare phase which followed after long-acting GnRH agonist. In this patients we continue antagonist for one week after oocyte retrieval (22, 24, 25).

Ovarian stimulation in adolescent patients

Adolescent definition: Adolescents are defined as individuals between the ages of 10 and 19 years by the World Health Organization (WHO). There is a lack of information on whether adolescents respond similarly to gonadotropin exposure or have similar cycle outcomes, such as mature oocyte yield. Currently, the published data in adolescents are limited to case series (26).

Important points:

In order to estimate the gonadotropin dose required to yield maximum oocyte number, AFC and AMH are sensitive markers of ovarian reserve. During puberty, there is a slight but consistent transient decrease in AMH. Arguments about the value of an AMH assessment for adolescent girls also exist.

In pubertal girls, limited data are available on the context of dose specific dosing schedules. According to limited data GnRH antagonist protocol can be afforded. The 8 to 12 days required for ovarian stimulation, without jeopardizing their oncologic care and random start antagonist protocols, can be initiated at any point in the menstrual cycle.

Trans-abdominal ultrasound is used for follicular monitoring. Despite studies suggesting that trans-abdominal ultrasound may decrease the accuracy of AFC, this issue did not have a significant impact in adolescents.

There is no definitive data on the use of FSH alone or FSH plus LH for pubertal girls. FSH/LH preparation was selected as the preferred strategy due to the predicted immaturity of the hypothalamus-pituitary-ovarian (HPO) axis. To limit the risk of OHSS may be to use of a GnRH agonist trigger instead of HCG.

Due to lack of the maturity of the HPO axis, there are concerns using GnRH agonists in the adolescent population. Therefore, to ensure that the GnRH agonist triggering for final oocyte maturation is effective, it is imperative to check serum progesterone and LH levels ~ 8-14 hours following a GnRH agonist trigger. In general, an inadequate response is defined as a progesterone <3 ng/ ml and an LH <15 IU/L.

It is recommended that GnRH agonist be used for final oocyte maturation only in the patients who are at risk to developing OHSS (27-31).

Oocyte retrieval: Oocyte retrieval is performed 34-36 hours after triggering via trans-vaginal ultrasound-guided follicle aspiration under local or general anesthesia. Retrieved oocytes may be cryopreserved or fertilized and then embryo cryopreserved.

Ovarian tissue cryopreservation

Definition: OTC is an experimental method of FP for prepubescent girls, children, and adult women. This technique involves the laparoscopic (or, if necessary, laparotomy) removal and cryopreservation of ovarian tissue prior to the initiation of gonadotoxic cancer treatment, thereby preserving the primordial follicles contained within the tissue. Following the completion of treatment and confirmation of the patient’s health, the thawed ovarian tissue may be re-implanted into the patient’s body (4, 8, 19).

Eligibility criteria for OTC:

• Age: prepubescent girls, children, and women up to 35 years old (or 38 years old for those with high ovarian reserve)

• Premature ovarian failure risk due to gonadotoxic treatment exceeding 50%

• Inability to delay cancer treatment for at least two weeks to allow for ovarian stimulation or contraindications to COS

OTC can be offered as FP option for patients who have already received low gonadotoxic treatment or a previous course of chemotherapy.

Contraindications to OTC: cancers with a high risk of ovarian metastasis, such as leukemia, neuroblastoma, Burkitt lymphoma, and ovarian carcinoma (12, 13, 19).

Harvesting ovarian tissue:

Ovarian cortical tissue biopsy may be performed via laparoscopy or in conjunction with an open surgical procedure, such as during primary tumor resection. Regardless of the surgical approach, the preferred site for tissue removal is an area devoid of dominant follicles or corpus luteum. The objective is to maximize the number of primordial follicles per tissue sample while minimizing damage to the remaining ovarian tissue’s vasculature. Ovarian cortex samples should have a minimum thickness of 1-1.5 mm, as primordial follicles are located at a depth of approximately 0.8 mm from the mesothelium.

Partial oophorectomy involves the extraction of a single piece of cortex from one or both ovaries while preserving the remaining tissue in situ. In most cases, the right ovary is selected due to its anatomical position relative to the sigmoid colon. Tissue should not be removed from areas adjacent to the corpus luteum, as this may compromise tissue quality. Approximately 50% of the ovarian tissue is excised from the anterior mesenteric using scissors without electrocoagulation capability. The surgical site is inspected for bleeding points, typically located beneath the cortical area, but closure of the surgical surface is not necessary.

Complete oophorectomy is often recommended for girls before puberty due to the small size of their ovaries. In this method, the right ovary is also preferred for retrieval due to its anatomical position. No specific complications have been reported following the use of this method (13, 32-34).

Ovarian tissue transplantation

Definition: OTT is a process in which stored ovarian tissue pieces are thawed and surgically returned to the individual’s body. Tissue transplantation is divided into two types based on the location of the transplant: heterotopic and orthotopic. Heterotopic transplantation refers to tissue transplantation in areas other than the physiological origin of the tissue. Heterotopic OTT includes tissue transplantation in various areas, including the abdominal wall, forearm, kidney capsule, breast, etc. Orthotopic transplantation refers to tissue transplantation at its original and physiological origin, which for ovarian tissue is the pelvic cavity. The orthotopic method is the suggested method for transplantation, and the heterotopic method is not recommended.

Volume and dimensions of transplanted tissue: The number of transplanted tissue pieces is determined based on ovarian reserve and, if possible, follicular density based on histological evaluation and the patient’s age at the time of tissue retrieval. The amount of tissue transplanted is approximately 15-25% of a complete ovary. Tissue pieces measuring 5×10 mm square with a thickness of 1-2 mm are suitable dimensions for successful results.

Practical approach: Orthotopic transplantation of thawedfrozen ovarian tissue is performed using laparoscopy.

OTT into the pelvic peritoneum: A half to one centimeter incision is made in the lateral peritoneal wall, in the area where the ovaries are located. A pocket-like space is created under the peritoneum and tissue pieces are transferred into it, parallel to each other, so that the cortex surface faces the pelvis. The peritoneal surface is closed with interrupted sutures. Fibrin glue can be used if necessary.

OTT into the ovary: In this method, ovarian tissue pieces are usually transplanted into the larger ovary. Through an incision, a pocket-like space is created under the cortex and ovarian tissue pieces are transplanted into it so that the tissue surface faces the ovary surface. In the end, the ovarian surface is closed using sutures.

OTT onto ovarian remnants: For this purpose, an incision is made on the ovarian remnants using scissors to create a surface for tissue transplantation. Atrophied cortex tissue must first be removed and then thawed tissue pieces are transplanted onto protrusions on the ovarian tissue surface. Each piece of tissue is attached to the ovarian remnants with a separate suture. Creating a tunnel-like space under the tissue where ovarian tissue pieces will be transplanted is recommended to facilitate vascularization. Tissue transplantation onto ovarian remnants has the best anatomical and physiological compatibility but requires an expert laparoscopic specialist in microsurgery and usually takes 1-2 hours to complete due to the time required for surgery (35, 36).

Follow-up after ovarian tissue transplantation:

The follow-up of patients after OTT is usually performed by a gynecologist who is a member of the oncofertility team. The resumption of menstrual cycles and monthly examination of endometrial thickness, ovarian volume, follicle count, and dimensions using sonography are considered indicators of ovarian function recovery after transplantation.

Hormonal profile assessment:

Following ovarian tissue transplantation, serum levels of LH, FSH, and estradiol are measured to assess the resumption of ovarian function.

Timing of hormonal profile assessment:

Serum levels of the mentioned hormones are assessed in the day of ovarian tissue retrieval, in the day of tissue transplantation, and monthly after tissue transplantation. Hormonal profile assessment and sonographic examinations to ensure the continued function of the ovary after transplantation are recommended at least monthly for one year after the resumption of ovarian function.

Combined approach to OTC, concurrent with oocyte or embryo preservation:

In this method, half of the tissue from one of the ovaries is removed using laparoscopy and ovarian stimulation begins after 1-2 days. According to studies, this method has not been associated with any known complications and the number of oocytes retrieved has not significantly decreased after ovarian tissue retrieval. The time required to combine both treatment methods is approximately two and a half weeks (37, 38).

Ovarian suppression with GnRH analogues

Definition: Ovarian suppression with GnRH analogs before or during chemotherapy to preserve ovarian function is proposed as an adjunct method, along with accepted FP options. These analogs suppress the HPO axis, reducing ovarian sensitivity to the toxic effects of chemotherapy. These agents prevent an increase in FSH levels and thus suppress follicular growth and reduce the rate of ovarian follicle depletion, as well as reducing ovarian blood flow, protecting follicles from destruction during chemotherapy.

Eligibility criteria for ovarian suppression:

• Patients who are candidates for chemotherapy

Practical approach: The ideal time to start administering GnRH analogs is 2-4 weeks before starting chemotherapy. These agents are usually administered subcutaneously or intramuscularly, monthly or every three months, and should continue for 1-2 weeks after chemotherapy (4, 8).

Ovarian transposition (oophoropexy)

Definition: By changing their anatomical position, the ovaries are moved away from the radiation field and can be protected from radiation damage. The goal of ovarian transposition is to preserve their hormonal function and the possibility of pregnancy after cancer treatment and is recommended in combination with other FP methods for patients undergoing abdominal or pelvic radiation therapy. This method is not suitable for patients undergoing whole-body radiation therapy.

Eligibility criteria for oophoropexy:

• Patients with cervical, rectal, and colon cancer, pelvic, Hodgkin lymphoma, and Ewing’s sarcoma

• In cases where pelvic radiotherapy is planned without the inclusion of chemotherapy

Recommendations:

• Patients who are younger than 35 should be considered for treatment due to their ovarian reserve.

• Women with reduced ovarian reserve and patients at risk of ovarian metastases are inappropriate candidates for ovarian transposition.

• In patients who are scheduled to receive pelvic radiation, ovarian transposition can be performed concurrently with OTC.

Practical approach: The ovaries are removed from the direct radiation field through laparoscopy and their future position will vary based on the patient’s anatomy and planned treatment. After treatment, the ovaries are returned to their physiological position to resume their fertility function. Ovarian transposition methods vary depending on the size and area of radiation, and the ovaries can be moved to various locations from their original position. To perform this method, interaction between the surgeon and radiotherapist is necessary. Given the possibility of returning ovaries to their anatomical position, this method should be performed as close as possible to radiation therapy.

Medial transposition vs lateral transposition: Depending on the area of radiation, two surgical approaches have been described, lateral and medial transposition techniques. In studies, lateral transposition is associated with a higher rate of ovarian function preservation.

Single unilateral transposition versus bilateral transposition: A single unilateral transposition has been proposed as similarly successful to bilateral transposition.

Additional surgery considerations and concomitant salpingectomy: Salpingectomy is recommended at the same time as ovarian transposition to allow microscopic investigation of occult cancer in the tube (4, 8, 39).

Conclusion

The formulation and execution of harmonized guidelines and policies concerning the provision of FP services, inclusive of therapeutic strategies and standardization of procedures, are crucial to surmount disagreements regarding the delivery of these therapeutic services and avert delays in cancer treatment. The matter of FP and the methodology for managing the treatment and follow-up of cancer patients should be documented as a component of their management guideline. The design and execution of studies at an international level are required to document information pertaining to FP and the short-term and long-term risks associated with novel treatments, thereby providing patients with clear recommendations on fertility preservation. Physicians active in the field of oncology treatment should also contribute to the collection of information on FP to document the challenges and concerns related to fertility arising from cancer treatment, and gather and record information on the advantages of FP strategies.

Authors’ Contributions

A.Y., E.M.M., F.Gh.; Have made contributions to the writing of the manuscript. All authors have approved the submitted version of the article and agreed to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work. All authors read and approved the final manuscript.