2 The purpose of this paper is to summarise the liter- ature regarding the inﬂuence of childhood cancer ther- apies on female reproductive late eﬀects, measures to as- sess ovarian reserve, and options for fertility preservation. Literature was obtained from electronic resources includ- ing Medline, Embase, PubMed Central, Journals@Ovid, and The Cochrane Library (including The Cochrane Database Of Systematic Reviews). The Medical Subject Headings (MeSH) and keywords “childhood cancer,” “pediatrics/child/ paediatric,” “neoplasms/malignancy,” “menarche,” “meno- pause/premature menopause/amenorrhea/female infertility/ ovarian failure,” “pregnancy/pregnancy complications/preg- nancy outcome,” “fertility preservation,” “GnRH ana- logues/GnRH agonist,’ “ovarian tissue cryopreservation,” “embryo freezing/em-bryo cryopreservation,” and “oocyte cryopreservation” were used. Relevant references cited by the obtained literature were also acquired independently. 2. Late Effects of Radiotherapy to the Hypothalamic-Pituitary-Ovarian Axis Children who receive radiation to the brain are at risk of damage to the hypothalamus and pituitary with subsequent changes in the release of pituitary gonadotropins to stimulate the ovaries [8]. Earlier timing of menarche has an association with cranial radiation. Low dose radiation (18–24 Gy), as part of treatment for acute lymphoblastic leukaemia (ALL), and early menarche has been reported in previous studies [9–14]. Currently, although many ALL treatment protocols favour more intensive alkylating agent chemotherapy, 10–15% of patients continue to receive cranial radiation upfront [15]. Within this cohort there remains a link with early menarche; however, there is no increased risk amongst patients treated for ALL with chemotherapy only [15]. Patients treated with higher doses of radiation for CNS tumours are also at risk of an earlier menarche, with one study of 235 survivors exposed to cranial radiation prior to menarche determining doses >50 Gy to be a signiﬁcant independent risk factor [16]. Furthermore, a younger age at cranial radiation has been independently associated with early menarche in patients treated for ALL and CNS tumours (<5 years and <4 years, resp.) [15, 16]. Patients who receive radiation to the lumbar-sacral spine have an increased risk of delayed menarche [11–13, 15]. This is presumably due to indirect radiation eﬀects on the ovaries. However, as some of these patients also receive radiation to the brain, it is possible that gonadotropin deﬁciency may contribute to their delayed menarche. Radiation doses >50 Gy to the hypothalamus/pituitary in combination with spinal radiation have been reported to increase the risk of delayed menarche 12-fold compared to patients who do not receive radiation [16]. Although alkylating agent exposure is known to increase the risk of gonadal damage, no such associations have been noted to date. Lower pregnancy rates have been described in patients who received cranial radiation, although the radiation doses reported to decrease the risk of a pregnancy are variable. In one study of 5149 female survivors [17] radiation doses Obstetrics and Gynecology International >30 Gy to the hypothalamus/pituitary were a signiﬁcant risk factor for not having a pregnancy, whilst in another study [18] a decreased risk of pregnancy was noted in patients receiving >22 Gy to the hypothalamus/pituitary. Lower dose exposures (18–24 Gy) used in the treatment of ALL have also been shown to decrease fertility rates in female survivors compared to sibling controls [19, 20], particularly in patients who receive 18–24 Gy to the brain within two years of menar- che and whose age at ﬁrst pregnancy is 18–21 years [19]. Further studies of proven fertility are limited to clarify these ﬁndings; however, Bath et al. [21] have observed decreased luteinizing hormone (LH) excretion, decreased LH surge, and high frequency of short (≤11 days) luteal phase (despite regular (26–30 day) ovulatory menstrual cycles) in 12 ALL survivors treated with 18–24 Gy cranial irradiation. These ﬁndings could suggest subnormal mid-cycle LH surge and decreased progesterone production by the corpus luteum as one of the causal factors for delayed endometrial maturation and subsequent implantation failure and/or infertility [18]. It has been suggested that cranial radiation increases the risk of miscarriage (<24 weeks) possibly through impairment of HPO axis function [22]. Two studies have shown some support for this hypothesis reporting 1.8- and 1.4-fold signiﬁcantly increased risks, respectively, amongst survivors treated with cranial radiation only [23, 24]. Another study reported an increased risk amongst patients treated with cranial and craniospinal radiation; however, there was no distinction in the risk of ﬁrst-trimester miscarriage (<12 weeks) between these treatment groups [25]. 3. Late Effects of Treatment to the Ovaries There is a relationship between age and the number of primordial follicles in human ovaries [2]. At 5-6 months gestation, the number of follicles reaches a maximum of approximately 7 × 106. Thereafter, there is an exponential decline with approximately 400 follicles released as mature oocytes during the reproductive lifespan. Accelerated decline in follicle number occurs after 35 years until menopause occurs. This occurs at an average age of 50.4 years in the Western world [2, 26–30]. Any radiation or chemotherapy will deplete the number of follicles and induce damage to the ovaries [2]. Patients who are older at the time of either treatment have an increased risk of ovarian damage as there is a greater reserve of primordial follicles in younger patients [2, 25, 28]. It has also been suggested that the oocytes present in older patients are more vulnerable to gonadal toxins [31, 32]. Accordingly the mean sterilising dose of radiation to the ovary at 12 years of age has been estimated at 18 Gy compared to 9.5 Gy at 45 years of age [33]. 4. Direct Radiotherapy to the Ovaries Additional to scatter from lumbar-sacral radiation, the ovaries can also be irradiated directly as part of abdom- inal, pelvic, or total body irradiation. Premature ovarian failure may take the form of either acute ovarian failure (AOF), where there is a loss of ovarian function during or