High dose chemotherapy and radiotherapy have radically increased long-term survival of young cancer patients, but major side effects of these treatments are ovarian failure and infertility. Knowledge of the risks and probabilities of ovarian failure caused by treatment is crucial for patients and physicians in order to make informed choices that will best serve patients' interests. This review presents data on ovarian damage and failure following exposure to radiotherapy, chemotherapy and ablative therapy. The risk is evaluated from the published literature according to patient's age, treatment protocol and also according to the diagnosis of some common malignancies. Many of these patients will not be sterilized immediately following treatment, but will suffer from premature menopause. In order to prevent sterilization, ovarian transposition before pelvic irradiation is mandatory. Besides cryopreservation of ovarian tissue and embryos before administration of chemotherapy, the possible protective effect of pituitary-ovarian down-regulation is discussed. The mechanism of primordial follicles damage induced by radio/chemotherapy is presented as well as the role of apoptosis signalling pathways underlying destruction. Increased knowledge of these mechanisms could help to identify potential effective inhibitors that can block the path of primordial follicles destruction and reduce ovarian failure rate.

Studies have shown that ovarian failure is a common side-effect of chemotherapy treatment; however, continuation of regular menses post-treatment does not necessarily imply that the ovaries have escaped damage. This animal study measures directly the primordial follicle (PMF) loss following exposure to chemotherapy and evaluates reproductive outcome following significant destruction of the PMF population. Inbred Balb/c mice aged 5-6 weeks were administered different doses of an alkylating agent, cyclophosphamide, and the total number of PMF remaining in both ovaries was counted. Results show that cyclophosphamide causes PMF destruction in proportion to increasing dose (P = 0.0001). Reproductive performance was assessed after exposure to 75 mg/kg cyclophosphamide, a dose which destroys approximately 50% of PMF reserve, by evaluation of ovulation, mating and pregnancy rates. Reproductive potential of treated mice was not affected compared with controls despite the significant loss of PMF. Our results indicate that reproductive performance is not an accurate parameter for assessing ovarian injury. Rather, histological counting of PMF number more directly reflects the damage caused by chemotherapy to the ovary. This method can be used as a sensitive, inexpensive tool to gauge the damage to fertility caused by new chemotherapy agents or protocols.

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Pregnancies achieved from oocyte, sperm or embryo donation are unique, since they have resulted from donor gametes that are immunologically foreign to the mother. Thus, studying the obstetric outcome of such pregnancies may shed some light on the pathophysiology of preeclampsia, particularly in women conceiving with donated embryos, since the entire fetal genome is allogenic in these pregnancies. In this retrospective cohort study, a total of 144 women were studied. Of these, 72 were infertility patients who had conceived as a result of sperm, ovum or embryo donation and the other 72 women were age- and parity-matched control patients who became pregnant with their own gametes, either spontaneously, or following intrauterine insemination with their partner's spermatozoa. Study patients were divided into three groups depending on the origin of the donated gametes. Group 1 consisted of pregnancies achieved by intrauterine insemination with washed donor spermatozoa (n = 33). Group 2 included women who conceived using donated oocytes (n = 27) and group 3 consisted of women who conceived as a result of embryo donation (n = 12). The incidence of pregnancy-induced hypertension in the donated gametes study group was 12.5% (9/72) compared with 2.8% (2/72) in the control group. In addition, pre-eclampsia was diagnosed in 18.1% (13/72) of the donated gametes study group compared to 1.4% (1/72) in the age- and parity-matched controls. The increased incidence of gestational hypertension in pregnancies resulting from donated gametes gives evidence for a maternal genetic component, with an equally strong fetal influence, in the complicated aetiology of gestational hypertension, and pre-eclampsia in particular.

Ovarian cortical tissue cryopreservation with subsequent autografting is a potential strategy for the preservation of fertility in patients undergoing systemic chemotherapy and pelvic radiotherapy. Non-vascular

This study assessed reproductive performance, fetal viability and teratogenicity in female mice exposed to cyclophosphamide across a timeline corresponding to different stages of follicle maturation. Pregnancies were established in female Balb/c mice 1-4 weeks after administration of a non-sterilizing dose of cyclophosphamide (75 mg/kg). Each mating group represented a different stage of follicular growth at the time of cyclophosphamide exposure. The number of corpora lutea, pregnancies and fetal resorptions were determined. Surviving fetuses were evaluated for gross malformations. Results indicated that conceptions attributable to follicles exposed to cyclophosphamide at a mature stage had a significantly lower number of implantation sites, 4.82 +/- 1.01 versus 8.27 +/- 0.81 in controls (P = 0.001) and a high resorption rate, 56% +/- 0.11 versus 34% +/- 0.07 in controls (P = 0.05). The proportion of corpora lutea in this group which resulted in viable fetuses was extremely low, 0.2 +/- 0.06 versus 0.51 +/- 0.07 in controls (P = 0.001). Malformation rate was more than 10 times higher in all treated groups (P < 0.05) and a particularly high incidence of 33% (P = 0.0014) was observed in conceptions attributable to oocytes exposed to cyclophosphamide at the earliest stages of follicle growth. With an extended interval between exposure and mating the malformation rate gradually decreased towards normal values in the 12th week group. This study suggests that the effect of cyclophosphamide on female gametes and subsequently on future reproduction is influenced by the stage of oocyte maturation at the time of exposure. Early fertilization post-chemotherapy can result in a high rate of pregnancy failure and high malformation rate. This should be taken into account when considering the use of oocyte retrieval, IVF and embryo cryopreservation in patients currently undergoing chemotherapy.

PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

The use of transplantation in reproductive medicine has been considered by physicians and scientists alike for many years. Despite being side-tracked into futile pursuits of rejuvenation in the early days, the possibility of usefulness remains, particularly for preserving fertility in patients undergoing ablative chemo- or radiotherapy. These aims have been enhanced by advances in tissue cryopreservation. When isolated primordial follicles are transferred in the mouse, or ovarian tissue slices are grafted into sheep, it is possible to obtain follicular survival with subsequent maturation and oestrogen secretion and even restore fertility to sterilized hosts. For preservation of fertility, autografts avoid both the immunological problems of allografts and the ethical dilemmas when using donor tissue. In the male, the concept of spermatogonial cell transfer after isolation and frozen storage of cells recovered from a testicular biopsy is most attractive, since it may provide another option for rescuing fertility in cancer patients, and provide a much needed one in children. Recent results demonstrate that gonocytes from immature mice injected into the tubules of sterilized hosts restore spermatogenesis and produce fertile spermatozoa. Furthermore, the gonocytes can be stored frozen prior to transfer and still produce fertile tubules. This review presents a broad history of transplantation in the male and female genital tracts as well as attempts to anticipate possible future developments.