Techniques and endocrine‐reproductive outcomes of ovarian transposition prior to pelvic radiotherapy in both gynecologic and non‐gynecologic cancers: A systematic review and meta‐analysis

Premature ovarian failure may be a consequence of radiotherapy administered for the treatment of various female oncologic diseases. Before radiotherapy, fertility may be preserved through ovarian transposition (OT), which consists of moving the ovaries away from the radiation field.


| INTRODUC TI ON
It is well known that premature ovarian failure (POF) can negatively impact quality of life, causing a variety of climacteric symptoms, urogenital and sexual dysfunctions, emotional disturbances, decreased bone mineral density, and impaired lipid profile. 1 POF may be the consequence of radiotherapy administered for the treatment of various female oncologic diseases, in which the radiation field includes the pelvis. 2Thanks to recent advancements in cancer treatment, the rates of complete remission are improved, so a greater effort is necessary for the preservation of both fertility and gonadal endocrine function, especially in young or prepubertal patients requiring radiotherapy. 1,3Before radiotherapy, fertility may be preserved through one of the following methods: cryoconservation and subsequent transplantation of ovarian tissue 4 ; oocyte cryopreservation 5 ; and ovarian transposition (OT). 6e latter involves moving the ovaries away from the radiation field.Such a procedure was first performed in young women with Hodgkin's lymphoma in 1968 at Stanford University Medical Center. 7It is estimated that oncologic patients, who require external beam radiotherapy and/or brachytherapy for various types of cancer, receive more than 30 Gy as a total dose of pelvic radiation.As a much lower dose, less than 4 Gy, can destroy 50% of immature oocytes, a POF, more or less severe, may be expected as a possible consequence of every pelvic radiotherapy if not preceded by OT. 8 The clinical scenario may be even worse in prepuberal patients treated with pelvic radiotherapy without previous OT, because the radiation-induced gonadal damage and the consequent various degrees of estrogenic deficiency may impair uterine growth and the development of secondary sexual characteristics. 9sides Hodgkin's lymphoma, OT has been employed in other non-gynecologic tumors, such as urogenital rhabdomyosarcoma and medulloblastoma, arising in prepuberal and premenopausal patients.Regarding gynecologic tumors, OT is currently almost exclusively used in cervical cancer and occasionally vaginal cancer. 10,11nsidering the worldwide ongoing use of pelvic radiotherapy in the treatment of various gynecologic and non-gynecologic cancers arising in prepubertal and young women and the need to protect the gonadal function of these patients, the authors conducted a systematic review of the literature to ascertain all types of surgical techniques employed for OT, outline the endocrine and reproductive outcomes of each one of them, and find out if one works better than others.

| MATERIAL S AND ME THODS
A systematic literature review was conducted using Medline, Embase, Cochrane Database of Systematic Reviews, and Clini calTr ials.gov from inception to June 2023.The following keywords were used: "ovarian transposition"; "gonadal preservation"; "premature ovarian failure"; and "pelvic radiotherapy."The authors included only papers written in English; review articles, case reports with fewer than three patients, and meeting abstracts were excluded.
One author (EZ) independently screened titles and abstracts and included those for full-text review.The eligible studies were assessed independently by another author as full text (FG), based on two main criteria: the presence of a description of the surgical technique used and a report of the reproductive outcomes, in terms of post-radiotherapy endocrine ovarian function, pregnancy rate, and live birth rate.Papers to be included in the review were decided by a previous discussion among authors (GGI, FAG, FDG).Every disagreement was resolved through the collaboration of another author (MP).
tumors, whereas the medial approach was performed only for non-gynecologic cancers (Hodgkin's lymphoma).The difference between medial OT and lateral OT was not significant regarding the preservation of endocrine function (OR 0.65, P = 0.120).
However, midline OT worked better in terms of reproductive outcomes.In fact, the percentage of patients with pregnancy (49.2%) and live births (45%) associated with medial OT was significantly higher than that associated with lateral OT, 6.5% and 13.4%, respectively, and the difference between such data was statistically significant (OR 7.04, P = 0.001 and OR 5.29, P = 0.003, respectively).

Conclusions:
Ovarian transposition is an important method to preserve fertility before radiotherapy, considering the worldwide ongoing use of this treatment for various cancers arising in young women.The surgical method depends on the type of disease, but OT-especially medial OT when feasible-is effective in terms of ovarian function preservation and reproductive outcomes.
endocrine system, gynecologic surgery, infertility, ovary, premature ovarian failure, radiotherapy The review process is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 12 (Figure 1; Table S1).
After excluding case reports, reviews, and meeting abstracts, 40 full articles, out of 96 initially selected, were further screened.Subsequently, 31 other studies were discarded because they did not analyze the relationship between OT and reproductive outcomes.
[15][16][17][18][19][20][21] Another author (DB) estimated the risk of bias for each study included in this review using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. 22The scores have been reported in the chart generated using the robvis online tool 23 (Figure 2).The primary endpoint of this study was to briefly extrapolate from the literature the various techniques employed for OT before pelvic radiotherapy in both gynecologic and non-gynecologic tumors, while the secondary endpoint was to compare such techniques in terms of endocrine and reproductive outcomes.
The authors used odds ratios (ORs) with 95% confidence intervals (CI) to compare endocrine and reproductive outcomes between two patient groups: those that underwent midline OT and those that underwent lateral OT.The χ 2 test was employed for the statistical analysis and a P value of less than 0.05 was considered significant.
Two assumptions were made, one relative to a study in which the number of patients with normal ovarian function after radiotherapy was not specified, 20 but it was hypothesized that all women who remained pregnant after radiotherapy had their endocrine function preserved.The second assumption regarded another study, 14 in which the number of women who remained pregnant after lateral OT was not reported, and the authors assumed that it was, as a minimum, equal to the number of live births.

| RE SULTS
A total of 323 patients aged between 7 and 51 years underwent OT between 1976 and 2020 in different institutions and for various reasons, as summarized in Table 1.
The results of the risk of bias assessment are graphically reported in Figure 2, and an overall low risk of bias was estimated.
F I G U R E 1 Study selection process according to the PRISMA guidelines.
Regarding the surgical techniques employed, two main surgical approaches have been described in the literature: lateral and medial OT, performed either by laparotomy or by laparoscopy, under general anesthesia.
In medial oophoropexy, a single ovary or both ovaries are fixed behind the uterus, with permanent or delayed absorbable sutures, but the ovarian ligaments and mesosalpinges are not sectioned.In the lateral approach, the utero-ovarian ligaments are divided.The ovaries are then mobilized on the infundibulo-pelvic ligaments.
The fallopian tube may be left intact to maintain the possibility of spontaneous pregnancy or may be separated from the uterus and transposed with the ovary.The peritoneum medial to the infundibulo-pelvic ligaments is incised to permit direct visualization of the ureter.The ovaries or the adnexa (if the ovary is transposed with the fallopian tube) are repositioned, sometimes through a retroperitoneal tunnel ("alternative lateral OT"), at the paracolic gutters, as high as possible, with an adequate angle to maintain good blood supply.The upper and lower poles of the ovaries may be marked with hemoclips or titanium spirals. 24In this regard, the use of absorbable sutures to fix the ovary to the paracolic gutter, although it may have the advantage of giving a spontaneous ovarian repositioning, could determine a migration of ovaries back to the irradiation field before the end of the treatment.For completeness, another technique of OT, defined as "percutaneous needle transposition," proposed by Gareer et al., 25 should be mentioned.In this technique, both ovaries are attached with a non-adsorbable suture to the anterior abdominal wall and repositioned into the pelvis by simply cutting the anchoring suture at the end of radiotherapy; this modality of fixation is not part of the present review, because of its limited and temporary use only when a short irradiation period is expected.
The surgical technique employed (lateral/midline, bilateral /unilateral OT, alternative lateral OT) and relative outcomes are reported for each study in Table 2.
In the studies analyzed, OT was performed during the surgical procedure for primary cancer treatment or staging or as a standalone intervention.
The option of open or laparoscopic surgery depended on age, irradiation area, and type of primary tumor treatment.The procedure was performed by laparotomy in 122 (37.8%) patients, laparoscopy in 66 (20.4%) patients, and no surgical approach was specified in 135 (41.8%) patients. 14 give some examples: laparotomy was performed for radical hysterectomy in cervical cancer, 18 for the removal of neuroblastoma, 21 and for the staging of Hodgkin's lymphoma in young women. 13,20In only one case, robotic surgery was employed for OT, before radical trachelectomy for locally advanced cervical cancer. 19nce 1992, the laparoscopic approach has been the preferred one for elective procedures because of its minimally invasive nature, reduced recovery time, fewer postoperative complications, and less postoperative pain development compared with other techniques. 16,26e OT was monolateral in 102 (31.6%) patients and bilateral in the remaining 221 (68.4%) women, depending on the type of primary disease.Some authors reported unilateral OT in cases of oophorectomy for ovarian dysgerminoma 14 and risk of metastasis and previous oophorectomy. 17fore external pelvic irradiation, 71 (22%) women underwent medial OT for Hodgkin's (70 women) and non-Hodgkin's (one woman) lymphomas, while 252 (78%) patients had lateral (monoor bi-) OT.Lateral OT was used in a similar percentage of cases for gynecologic and non-gynecologic tumors (Figure 3), whereas the  TA B L E 2 Summary of the outcomes.In all the remaining cases (43, 21.7%) (including pelvic sarcoma, rectal carcinoma, medulloblastoma, neuroblastoma, rhabdomyosarcoma, and Ewing's sarcoma, and 18 unspecified tumors indicated with the term "others"), except for one case of non-Hodgkin lymphoma, a lateral OT was performed to move the ovaries to the opposite side of the central pelvic mass.

Year of publication
Figure 6 shows that lateral OT was the only technique chosen for gynecologic tumors in prepubescent patients (ovarian dysgerminoma, vaginal carcinoma) and premenopausal women (cervical cancer).
The endocrine and reproductive outcomes associated with medial and lateral OT are summarized in Table 3.
Regarding the preservation of endocrine function, the results of the present study show that the difference between the two groups of patients (medial OT and lateral OT) was not statistically significant (OR 0.65, P = 0.120).In fact, steroidogenic gonadal activity was maintained in 43 of 71 (60%) women undergoing midline OT and in 177 of 252 (70.2%) women undergoing lateral OT.
Regarding reproductive outcomes (number of patients with spontaneous and in vitro fertilization (IVF) pregnancy with or without surrogate mother and the number of patients with live birth from spontaneous and IVF pregnancy with or without surrogate mother), the authors found that midline OT was more effective than lateral OT.The percentage of patients with pregnancy (49.2%) and live births (45%) associated with medial OT was significantly higher than those associated with lateral OT, 6.5% and 13.4%, respectively, and the difference between such data was statistically significant (OR 7.04, P = 0.001 and OR 5.29, P = 0.003, respectively), as shown in Table 3.

| DISCUSS ION
Several studies in the literature demonstrate the efficacy of OT in patients with non-gynecologic cancers: in women with Hodgkin's  lymphoma and bilateral impairment of iliac nodes, retro-uterine bilateral OT seems to be very effective not only for endocrine ovarian preservation but also for the possibility of a future spontaneous pregnancy. 25,27,28 A recent meta-analysis 30 based on 24 studies, confirms that, when indicated, OT in cervical cancer treatment is associated with a high rate of ovarian function preservation, an acceptable rate of ovarian cysts, and a low risk of metastases in the transposed ovaries.
Regarding the reproductive outcome, successful surrogate pregnancies after OT and subsequent pelvic irradiation have been achieved in young women with early-stage cervical cancer who had their uterus removed at the time of OT. 31,32 For instance, Perri et al. 18 described a case of oocyte retrieval, 15 months after the therapy, using a surrogate mother to give birth to healthy twins.
Medial OT, as shown by the present systematic review, is an especially effective technique for the preservation of ovarian function in 37%-100% of patients undergoing pelvic radiotherapy for cancer treatment.
However, it should be noted that the reproductive outcomes elicited by OT are influenced by various factors, given by the heterogeneity of the patient's age, the type of underlying tumor, the use of concomitant chemotherapy, and the type of surgical procedure employed.
Regarding the patient's age at the time of cancer diagnosis, Hoekman et al. 1 showed that OT is particularly effective in women up to 35 years of age and that the older the patient at the time of radiation exposure, the faster is the onset of menopause.Considering the types of tumors that may require OT, a distinction between non-gynecologic and gynecologic tumors in relation to the age of onset becomes necessary.This highlights the importance of personalization of management in these patients. 33ring childhood, the main non-gynecologic tumors that may require OT are rhabdomyosarcoma of the pelvic organs, Ewing's sarcoma, medulloblastoma, and Wilms' tumor. 34Hodgkin's lymphoma is the most common tumor requiring a high dose of radiotherapy in young adolescents, 35 whereas rectal cancer becomes relevant in adult patients. 36In the case of pediatric medulloblastoma and urogenital rhabdomyosarcoma, lateral OT is encouraged, but the therapeutic strategy should also include ovarian cryopreservation if the degree of gonadal protection is uncertain, and the risk of metastasis is low. 35The same consideration should be given to gynecologic tumors of childhood: vaginal carcinoma and ovarian dysgerminoma.
In this review, two studies 13,14 describe the lateral transposition of a single ovary in the management of ovarian dysgerminoma.
Chemotherapy, however, is the fundamental pillar in the treatment protocols of patients with germ-cell cancer in whom, unfortunately, OT has a limited role, because it does not limit the gonadal damage caused by the chemotherapeutic agents. 37ncerning the surgical procedure to be used, the medial approach allows preservation of the tube-ovarian unit, making patients able to obtain a spontaneous pregnancy.A key strength of the present study lies in its comprehensive analysis and systematic review approach, drawing data from a span of several decades and across various institutions.This offers a more robust understanding of the various surgical techniques employed and their respective outcomes.However, the study is not without limitations.A significant proportion of the patient data (41.8%)did not specify the surgical approach employed, which might affect the overall conclusions.Additionally, although we have covered a wide range of tumor types, certain rare conditions might not have been sufficiently represented.
This study underscores the importance of considering OT for young patients undergoing pelvic radiotherapy for cancer treatment, especially given its potential for preserving ovarian function and fertility.Clinicians are provided with insights that could guide surgical decisions, specifically the benefits of medial OT over lateral approaches in terms of reproductive outcomes, probably because the anatomic ovarian relocation does not require separation of the tube and so it is more favorable for spontaneous conception.The chance of spontaneous pregnancy after OT can be higher than expected if the ovaries are not repositioned.However, such pregnancies, although spontaneous, have the burden of an increased risk of obstetrical complications and adverse pregnancy outcomes, such as early pregnancy loss, preterm birth, and delivery of low-or very low-birthweight infants. 39Therefore, on the one hand, the use of OT should be encouraged in clinical practice.On the other hand, clinicians should be aware that it does not always work and even spontaneous pregnancies occurring after OT should be regarded as risk pregnancies, requiring careful prenatal care.
In conclusion, these findings align with previous studies that highlight the efficacy of OT in preserving ovarian endocrine function.The emphasis on the advantages of medial OT over lateral OT in terms of reproductive outcomes is consistent with current literature.

AUTH O R CO NTR I B UTI O N S
FG contributed to the conceptualization, methodology, investigation, and writing the original draft; EZ contributed to the investigation The authors collected a maximum of seven parameters from each study: baseline patient characteristics; type of primary cancer; chemo-radiation treatment; surgical technique employed; duration of follow-up; endocrine outcomes (assessed either by measuring the serum levels of follicle-stimulating hormone, luteinizing hormone, and estradiol, or by asking patients about the onset of climacteric symptoms); and reproductive outcomes (number of pregnancies and live births).

F I G U R E 2
Risk of bias assessment for the individual studies.TA B L E 1 Description of the studies' characteristics.lymphoma n = 82 Cervical carcinoma n = 21 Ovarian dysgerminoma n = 12 Vaginal carcinoma n = 8 Pelvic sarcoma n = 3 Others n

F I G U R E 3 F I G U R E 5
Lateral ovarian transposition performed in gynecologic and non-gynecologic cancers.F I G U R E 4 Midline ovarian transposition, which was performed only in non-gynecologic cancers.Number of patients with various types of non-gynecologic cancer who underwent midline or lateral ovarian transposition.medial approach was only used for non-gynecologic cancer and only in 70 of the 155 (45%) patients affected by Hodgkin's lymphoma (Figure 4).As shown in Figure 5, 155 out of 198 (78.3%) cases of non-gynecologic tumors included in the present review were Hodgkin's lymphomas, for which the midline and lateral OT were used in almost equal measures.

F I G U R E 6
Number of patients with various types of gynecologic cancers who underwent lateral ovarian transposition.TA B L E 3 Endocrine and reproductive outcomes associated with medial and lateral ovarian transposition.

Surgical technique Follow up, months Ovarian function preservation a Reproductive outcome
2 , estradiol; FSH, follicle-stimulating hormone; IVF, in vitro fertilization; NR, not reported; RT, radiotherapy; TsT, titanium spiral track.aData are presented as number of patients/total number.
Among gynecologic cancers affecting patients of young reproductive age, the one that can especially benefit from OT is cervical carcinoma, at least until FIGO (International Federation of 38omas et al.13describe a pregnancy rate of 27% among young women with Hodgkin's lymphoma.As Laios et al.38point out in their review, the chance of