4 cycle of ovarian stimulation which may not be possible when chemotherapy needs to be commenced immediately or where stimulation is contraindicated due to hormone- sensitive tumours [49, 51, 52]. In contrast, oocyte cryopreservation may be utilised in some adolescent girls as it does not require partner or donor sperm. However, the method also requires the use of ovarian stimulation [53] and its success is dependent on the total number of oocytes retrieved (<10 oocytes is associated with minimal chance of pregnancy), which is often diﬃcult in sexually immature patients [54, 55]. Ongoing advances in oocyte cryopreservation technique and the use of intracytoplasmic sperm injection (ICSI) appear to have improved success rates [53, 54]. In a prospective randomised controlled trial (RCT) conducted by Smith et al. [56], oocyte survival, fertilization, and establishment of pregnancy were signiﬁcantly higher following vitriﬁcation/warming compared with freezing/thawing. In another RCT [57] fertil- isation and embryo development rates using vitriﬁed oocytes followed by ICSI approached that of fresh oocytes after ICSI. Cryopreservation of oocytes has also been described in association with ovarian tissue cryopreservation (OTC) in prepubertal girls, whereby any antral follicles observed on the ovarian surface at the time of biopsy are aspirated, matured in vitro and cryopreserved [55, 58]. Accordingly, Revel et al. [58] were able to cryopreserve 11 mature oocytes from three prepubertal girls aged 5, 8, and 10 years. Ovarian tissue cryopreservation is the only means of preserving fertility in prepubertal girls [49, 51, 53, 59] and may also be utilised in girls who do not have enough time to undergo ovarian stimulation for oocyte and embryo cryopreservation [49, 51, 53, 57]. Ovarian cortical tissue is harvested laparoscopically without preparation, cryopre- served using standard slow-programmed freezing, and is reimplanted into the pelvic cavity (orthoptic site) or a heterotopic site once the patient is in remission [51]. The option has greater fertility potential in prepubertal girls due to a greater density of primordial follicles in the harvested tissue [54, 55]. This process has the added advantage of endogenous hormone production by the ovarian tissue, and avoidance of hormone therapy for bone health maintenance. To date, ten live births have been reported following orthop- tic reimplantation of frozen-thawed ovarian cortex harvested from postpubertal girls [55], although the origins of these pregnancies are not deﬁnite as a vast majority of patients have demonstrated restoration of follicular growth and ovulation [55]. Risks of OTC include the surgical risks asso- ciated with the invasive procedure. An additional concern is reimplantation of the primary tumour and/or malignant transformation of reimplanted tissue, which is possible with leukaemias, neuroblastoma, and Burkitt’s lymphoma which are common during childhood and metastasise to the ovaries [49, 53], although histological analysis of the cryopreserved ovarian cortex and further methods for monitoring minimal residual disease have been developed over recent years [55]. 8.2. Interventions to Minimise Damage Caused by Cancer Therapies. Transposition of the ovaries (oophoropexy) out- side of the ﬁeld of radiation may be performed to reduce Obstetrics and Gynecology International the ovarian radiation dose to 5–10% of that if the ovaries remained in situ [60]. The ovaries can either be relocated outside of the pelvis, in the case of pelvic irradiation, or, in the case of craniospinal irradiation, ﬁxed laterally as far as possible from the spine [55]. Preserved ovarian function following oophoropexy outside of the pelvis has been reported between 16–90% [49, 54]; the wide variability is due to the inability to calculate and prevent scatter, combination chemotherapy and diﬀerent radiation doses [49, 54]. A disadvantage of this technique is the invasive procedure which needs to occur at a time when the patient is planning cancer treatment. Moreover, ovarian failure may ensue if the ovaries are not transposed far enough or if they revert back to their original position or if the vascular supply of the ovary is aﬀected by the surgical procedure [49]. Additional issues to consider prior to performing extrapelvic oophoropexy include problems achieving a spontaneous pregnancy and diﬃculties with oocyte retrieval for in vitro fertilisation (IVF) unless a second procedure is performed to relocate the ovaries back to the pelvis [49, 53]; this problem is often avoided in the case of lateral oophoropexy for cranial irradiation as the anatomic relations of the ovary with the uterus and fallopian tubes are maintained [55]. Commonly, ovarian biopsy and transposition is performed simultane- ously for patients undergoing combination therapies. GnRH (gonadotropin-releasing hormone) analogues have been suggested as chemoprotective agents. The exact mechanism remains unclear, although it is hypothesised that suppression of pituitary gonadotropin production with subsequent reductions in ovarian follicular cell division and growth render the follicles less vulnerable to cytotoxic agents [49]. Their use is limited in prepubertal girls who are hypogonadal. To date, the evidence for the use of GnRH analogues is controversial. There are several case series and small cohort studies that claim beneﬁt [61–63], and a meta-analysis has shown beneﬁt in this technique; however, when only high quality studies are included, the results are not signiﬁcant [64]. A recent randomised study of 49 breast cancer patients with 30-month followup additionally found no diﬀerence in the incidence of ovarian failure [65]; however, a prospective multicentre study is currently underway with anticipated results. 9. Late Effects of Radiotherapy to the Uterus Radiation to the uterus can impair uterine function, causing reduced uterine volume, decreased myometrial elasticity, and some uterine vascular damage [4, 25, 66–68]. Although data on threshold doses for uterine dysfunction is limited, earlier studies have reported reduced uterine length, poor endometrial thickness in response to oestradiol therapy, and absence of uterine artery blood ﬂow detectable by Doppler ultrasound in patients treated with 14–30 Gy of radiation to the uterus [67, 69, 70]. The risk of uterine dysfunction increases with higher radiation doses and ﬁelds involving a greater uterine volume [4]. Radiation prior to puberty has also been associated with irreversible damage to the uterus, with prepubertal uterine morphology observed in postpubertal patients [68].