Elective egg freezing and its underlying socio-demography: a binational analysis with global implications.

BACKGROUND: What are the underlying socio-demographic factors that lead healthy women to preserve their fertility through elective egg freezing (EEF)? Many recent reviews suggest that women are intentionally postponing fertility through EEF to pursue careers and achieve reproductive autonomy. However, emerging empirical evidence suggests that women may be resorting to EEF for other reasons, primarily the lack of a partner with whom to pursue childbearing. The aim of this study is thus to understand what socio-demographic factors may underlie women's use of EEF. METHODS: A binational qualitative study was conducted from June 2014 to August 2016 to assess the socio-demographic characteristics and life circumstances of 150 healthy women who had undertaken at least one cycle of elective egg freezing (EEF) in the United States and Israel, two countries where EEF has been offered in IVF clinics over the past 7-8 years. One hundred fourteen American women who completed EEF were recruited from 4 IVF clinics in the US (2 academic, 2 private) and 36 women from 3 IVF clinics in Israel (1 academic, 2 private). In-depth, audio-recorded interviews lasting from 0.5 to 2 h were undertaken and later transcribed verbatim for qualitative data analysis. RESULTS: Women in both countries were educated professionals (100%), and 85% undertook EEF because they lacked a partner. This "lack of a partner" problem was reflected in women's own assessments of why they were single in their late 30s, despite their desires for marriage and childbearing. Women themselves assessed partnership problems from four perspectives: 1) women's higher expectations; 2) men's lower commitments; 3) skewed gender demography; and 4) self-blame. DISCUSSION: The "lack of a partner" problem reflects growing, but little discussed international socio-demographic disparities in educational achievement. University-educated women now significantly outnumber university-educated men in the US, Israel, and nearly 75 other societies around the globe, according to World Bank data. Thus, educated women increasingly face a deficit of educated men with whom to pursue childbearing. CONCLUSION: Among healthy women, EEF is a technological concession to gender-based socio-demographic disparities, which leave many highly educated women without partners during their prime childbearing years. This information is important for reproductive specialists who counsel single EEF patients, and for future research on EEF in diverse national settings.

The role of fertility preservation in patients with endometriosis.

Patients affected with severe endometriosis are at significant risk for ovarian tissue damage, which may lead to infertility, reduced response to ovarian stimulation, and occasionally, premature ovarian failure. The risk for a compromised ovarian reserve in young patients is especially high following repeated surgical intervention and in the presence of bilateral endometriomas. In many cases, enhanced loss of ovarian reserve may also result from the damaging effect of the pathologic process on follicle reservoir even without surgical interventions. Women diagnosed with severe endometriosis and those designated for extensive ovarian surgical intervention are frequently not planning to conceive. In light of recent advances in fertility preservation techniques (FPT), such as oocytes and ovarian tissue freezing, as well as their increasing success rates, we critically evaluate the options for FPT in patients suffering from endometriosis. Personalized counseling should be offered to all patients with endometriosis taking into account age, extent of ovarian involvement, current ovarian reserve, previous and impending surgeries for endometriosis, along with current success rates and possible risks associated with FPT.

Combination of ovarian tissue harvesting and immature oocyte collection for fertility preservation increases preservation yield.

The aim of this study was to evaluate the safety and efficacy of combined ovarian tissue cryopreservation and oocyte aspiration just before ovarian tissue cryobanking. A retrospective cohort study of fertility preservation patients treated in 2007-2013 in one tertiary centre was performed. A total of 255 cancer patients were admitted for fertility preservation: 142 patients underwent ovarian tissue cryopreservation only (OTC), 56 underwent OTC plus oocyte retrieval from ovarian tissue (OTIVM), nine underwent oocyte aspiration and in-vitro maturation (AIVM) and 48 underwent all three procedures. The total number of oocytes, total number of metaphase II (MII) oocytes, maturation rate, fertilization rate and total number of cryopreserved oocytes between groups were compared. The study found significantly more oocytes (P < 0.001), more MII oocytes (P < 0.001), better maturation rate (P < 0.01) and more cryopreserved oocytes (P < 0.05) with all three compared with OTIVM or OTC. No adverse outcome was observed by performing oocyte retrieval before ovarian resection for cryopreservation. In conclusion, oocyte aspiration just before ovarian tissue cryobanking is safe and gains more oocytes with a better maturation rate than ovarian tissue oocyte cryobanking alone. Better results were obtained with 3 days of stimulation before oocyte retrieval.

IVF for fertility preservation in breast cancer patients--efficacy and safety issues.

BACKGROUND: Potential risks on future fertility have become a dominant issue in consultation and management of newly diagnosed young cancer patients. Several fertility preservation strategies are currently available. Of those, ovarian stimulation followed by IVF and embryo cryopreservation is the most established one and is especially applicable in reproductive aged breast cancer patients. AIM: The aim of this study is to provide a comprehensive review on ovarian stimulation and IVF for fertility preservation in newly diagnosed breast cancer patients. METHODS: Review of relevant literature is available through PubMed and Google scholar. RESULTS: The use of IVF for fertility preservation in breast cancer patients raises dilemmas regarding efficacy and safety of controlled ovarian stimulation. Among these are the suggested role of malignancy and BRCA mutation in reducing ovarian response to stimulation, strategies designated to protect against hyper-estrogenic state associated with stimulation (co-treatment with tamoxifen or letrozole), and possible adjustments to accommodate oncologic-related time constraints. CONCLUSION: Ovarian stimulation followed by IVF forms an important fertility preservation strategy for newly diagnosed young breast cancer patients, though live born rates following thawed embryo transfer in these patients are still lacking. Recent advances in controlled ovarian stimulation protocols provide practical options for some of the challenges that breast cancer patients present.

IVF outcome with cryopreserved testicular sperm.

The introduction of intracytoplasmic sperm injection and the use of spermatozoa extracted from the testicles have changed the option for conception for azoospermic patients. The purpose of the present study was to evaluate the IVF outcome after using cryopreserved testicular sperm samples in comparison with fresh ones. A total of 667 in vitro fertilisation cycles with fresh or cryopreserved testicular sperm obtained by an open biopsy and testicular needle aspiration were evaluated. Sperm motility was present in 70.9% of the cycles in Group-I, 77.8% cycles in Group-II and in 83.3% In Group-III (NS). The fertilisation rates were similar in the three study groups (50%, 48.6% and 54.8% respectively). The pregnancy rates were 26.7%, 22.2% and 16.3% respectively (NS). The delivery rate, however, was significantly lower in Group-III (4.1%) than in Group-I and -II (18.4% and 15.9%, respectively, P < 0.05). The IVF results after use of cryopreserved testicular sperm are comparable with those obtained with the fresh specimens. Lack of sperm motility before cryopreservation does not exclude favourable outcome and therefore testicular sperm freezing is feasible whenever there are enough sperm cells in the extracted testicular tissue.

Protective effect of the immunomodulator AS101 against cyclophosphamide-induced testicular damage in mice.

BACKGROUND: Cyclophosphamide (Cy), a widely used anticancer drug, is associated with significant testicular damage and sterility. Co-administration of the immunomodulating compound AS101 during chemotherapy treatments was previously shown to protect organs against cytotoxic damage, without attenuating the drug's anticancer effect. In this animal study, we investigated the effect of AS101 on testicular damage, sperm DNA damage and infertility induced by Cy. Akt and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation were investigated as a possible chemoprotective mechanism. METHODS: Mature male mice, 10 in each group, were injected intraperitoneally with 200 mg/kg Cy once a week for 5 weeks, with or without concurrent treatment with 10 microg per mouse AS101 three times per week. Damage to testicular tubules and sperm production was determined, sperm chromatin damage was analyzed and fertility was gauged. Akt and GSK-3beta phosphorylation were evaluated. RESULTS: Co-treatment with AS101 during the course of Cy administration significantly reduced the percentage of damaged seminiferous tubules (76.0 +/- 10.8% versus 40.3 +/- 2.6%), and reduced sperm DNA fragmentation (%DFI) from 44.7 +/- 1.0% to 25 +/- 6.5%. Co-treatment with AS101 also partially protected against the decrease in numbers of impregnated females and litter size. AS101 increased Akt and GSK-3beta phosphorylation. CONCLUSIONS: Our results indicate that AS101 can significantly protect against Cy-induced testicular damage and sperm DNA damage, probably by acting through Akt/GSK-3beta phosphorylation.

Does controlled ovarian stimulation prior to chemotherapy increase primordial follicle loss and diminish ovarian reserve? An animal study.

BACKGROUND: Storage of embryos for fertility preservation before chemotherapy is widely practiced. For multiple oocyte collection, the ovaries are hyperstimulated with gonadotrophins that significantly alter ovarian physiology. The effects of ovarian stimulation prior to chemotherapy on future ovarian reserve were investigated in an animal model. METHODS: Cyclophosphamide (Cy) in doses of 0, 50 or 100 mg/kg was administered to 38 adult mice (control, unstimulated). A second group of 12 mice were superovulated with equine chorionic gonadotrophin (eCG, 10 IU on Day 0) before Cy administration; hCG (10 IU) was administered (Day 2) followed by 0, 50 or 100 mg/kg Cy (Day 4). In both groups ovaries were removed, serially sectioned (7-day post-Cy), primordial follicles were counted and differences between groups evaluated. RESULTS: Follicle number dropped from 469 +/- 24 (mean +/- SE) to 307 +/- 27 and 234 +/- 19 with 50 or 100 mg/kg Cy, respectively (P < 0.0001). In the eCG pretreated group, follicle count dropped from 480 +/- 31 to 345 +/- 16 and 211 +/- 26 when 50 or 100 mg/kg Cy were administered (P < 0.0001). There were no significant differences in follicle count between the pretreated eCG group and controls for each chemotherapy dose. CONCLUSIONS: This animal study indicates that ovarian stimulation before administration of Cy does not adversely affect ovarian reserve post-treatment. These results provide support for the safety of fertility preservation using ovarian stimulation and IVF-embryo cryopreservation procedures prior to chemotherapy.

Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury.

BACKGROUND: Chemotherapy destroys primordial follicles and can lead to ovarian atrophy. Although reports indicate that apoptosis is the mechanism responsible for follicle loss, additional pathways can be involved. This study investigates the damage in human ovaries after administration of non-sterilizing doses of chemotherapy. METHODS: In a blind study, pathological changes in ovarian tissue harvested for cryopreservation were evaluated. The study group comprised young non-sterile cancer patients, previously exposed to chemotherapy who were (mean +/- SD), when compared with non-exposed patients. RESULTS: Thirty-five cancer patients aged 28.7 +/- 6.74; 17 were previously exposed to non-sterilizing chemotherapy and 18 were not. In all samples, primordial follicles were present. In previously exposed patients, damage to cortical blood vessel and proliferation of small vessels was observed. The cortex showed focal areas of fibrosis with disappearance of follicles (sensitivity 76%, positive predictive value 75% for <37 years old patients). Older patients, not exposed to chemotherapy (5/7) showed similar pathological changes. CONCLUSIONS: Injury to blood vessels and focal ovarian cortical fibrosis are aspects of ovarian damage caused by chemotherapy. These findings indicate a potential additional mechanism of damage to the direct apoptotic effect of chemotherapy on follicles. The possibility that these changes are involved in ageing ovaries should be further investigated.

The effects of radiotherapy and chemotherapy on female reproduction.

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.

Genetic and teratogenic effects of cancer treatments on gametes and embryos.

Male and female germ cells vary in their sensitivity to the mutagenic effects of chemotherapy and radiotherapy, depending on their stage of maturation and the agent used. Although sperm DNA damage exists following treatment, no increase in genetic defects or congenital malformations was detected among children conceived to parents who have previously undergone chemotherapy or radiotherapy. The use of assisted reproductive technologies and micromanipulation techniques might increase this risk; hence caution should be exercised. In female cancer patients, miscarriage and congenital malformations are not increased following chemotherapy. However, when IVF and embryo cryopreservation is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence the babies should be screened. During pregnancy, the potential teratogenic effects of chemotherapy influence the choice and timing of therapy. Termination is usually recommended in the first trimester. Second- and third-trimester exposure does not usually increase the teratogenic risk and cognitive development, but it may increase the risk of poor obstetric outcome and fetal myelosuppression. During the first two weeks after fertilization of the embryo, radiation is lethal but not teratogenic. High doses of radiation during pregnancy induce anomalies, impaired growth and mental retardation, and there may be an increased risk of childhood leukaemia and other tumours in the offspring.

Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations.

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.

Reproduction post-chemotherapy in young cancer patients.

High-dose chemotherapy and radiotherapy has increased long-term survival of young patients with cancer. Sometimes however, the price paid is ovarian failure and sterility. It is highly important to detect who are the patients at risk in order to verify when fertility preservation is indicated. With conventional chemotherapy, there is significant differences in ovarian failure rate according to patients age, disease for which patients are treated for, and the drugs used. Bone marrow transplantation in cancer patients almost invariably induced ovarian failure, irrespective of patient age, treatment protocol or administration of hormonal treatment. Moreover, normal reproductive parameters post-chemotherapy does not necessarily imply that the ovaries escaped damage; ovarian injury is not an all or none phenomenon--partial loss of primordial follicle reserve can result in premature menopause as a delayed reaction to treatment. This should be taken into account while consulting former cancer patients about future planed pregnancies. The direct mechanisms of chemotherapy induced ovarian failure are poorly understood. An in vitro study has demonstrated that in the human ovary chemotherapy acts primarily on primordial follicles through induction of apoptotic changes in pregranulosa cells which lead to follicle loss. Protecting fertility potential in females exposed to chemotherapy with IVF and embryo cryopreservation or cryopreservation of ovarian tissue is practiced. Ovarian tissue cryopreservation: A recent study has demonstrated that laparoscopic ovarian biopsy performed with the round biopter is a safe and efficient method for collecting ovarian tissue for cryopreservation in cancer patients. In order to avoid possible hazards of transferring malignant cells, genetic and immunohistochemical markers for detection of minimal residual cancer cells in ovarian tissue are currently used. However, the reproductive potential of this method is still questionable. IVF: IVF and embryocryopreservation is currently used in infertile patients, however, several obstacles prevent it's wide implementation in cancer patients such as the need for male partner and the time needed for ovarian stimulation. A highly important issue is the possible risk of performing IVF and embryo cryopreservation to preserve fertility in females already exposed to chemotherapy. An animal study has raised serious concerns regarding the consequences of chemotherapy on future pregnancies. High abortion and malformation rates related to the different stages of oocyte maturation at the time of exposure to chemotherapy were demonstrated. These results should be taken into account when considering the use of IVF and embryo cryopreservation following chemotherapy treatment in cancer patients.

Vaginal outflow tract obstruction by graft-versus-host reaction.

We describe a 25-year-old patient suffering from vaginal outflow obstruction which presented as secondary amenorrhea during hormone replacement therapy. The patient had undergone bone marrow transplantation for acute myelocytic leukemia, which caused ovarian failure. Oral mucositis associated with a chronic GVH reaction also occurred. For 3 years she was treated with HRT and had regular menses which gradually ceased and were associated with dyspareunia and abdominal cramps. Abdominal US examination demonstrated hematocolpus. Sonography guided adhesiolysis of a dense vaginal obstruction allowed free drainage with histologic confirmation of a graft-versus-host reaction. The possibility of vaginal stricture or obstruction should be considered in all patients after BMT who suffer from graft-versus-host disease.

Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool.

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.

A laparoscopic technique for obtaining ovarian cortical biopsy specimens for fertility conservation in patients with cancer.

OBJECTIVE: To evaluate the efficacy of a newly designed round biopter as a practical and safe method for collecting ovarian tissue for cryopreservation in young women with cancer before chemotherapy. DESIGN: Prospective study of young women volunteering for research (Leeds, United Kingdom) and patients with cancer (Jerusalem, Israel and Leeds, United Kingdom) undergoing laparoscopic ovarian cortical tissue biopsy and cryopreservation before administration of high-dose radiochemotherapy. SETTING: Two university-based tertiary referral centers of oncology and gynecology (Hadassah Medical Center, Israel; Leeds General Infirmary, United Kingdom). PATIENT(S): Twenty female volunteers undergoing routine laparoscopic gynecologic procedures (age, 25-34 years) and 20 young women (age, 11-30 years) with advanced cancer requiring potentially sterilizing radiochemotherapy. INTERVENTION(S): Cortical ovarian tissue biopsies performed under laparoscopy with use of the round biopter. RESULT(S): The laparoscopic sampling procedure was uncomplicated in all cases. In treated patients, five to six samples were obtained (5 mm in diameter; 2-3 mm in depth) using the round biopter, and radiochemotherapy was administered without delay. In volunteers, no adhesions were noted at repeat laparoscopy (9 patients). All biopsy specimens were cryopreserved, and histologic examination confirmed the presence of many primordial follicles. CONCLUSION(S): Laparoscopic ovarian biopsy performed with the round biopter is a safe and efficient method for collecting ovarian tissue for cryopreservation in patients with cancer.

Ovarian injury and modern options to preserve fertility in female cancer patients treated with high dose radio-chemotherapy for hemato-oncological neoplasias and other cancers.

High dose chemotherapy and radiotherapy have radically increased long term survival of young cancer patients. Among the side effects of chemotherapy treatments are ovarian failure and infertility, which are of particularly great concern to young cancer patients. Recently, cryopreservation procedures such as in vitro fertilization and embryo storage, or ovarian tissue cryopreservation have been used to preserve fertility in patients subjected to cancer treatments. Knowledge of the risks and probabilities of ovarian failure as well as the risks of the cryopreservation procedures is crucial for patients and physicians in order to make informed choices that will best serve the patients interests. This article presents data of a prospective study that determines the risk of ovarian failure following exposure to chemotherapy as well as a review of related publications. Progressive, dose-related depletion of primordial follicles is noted on histology, explaining the risk of undergoing premature ovarian failure years after exposure to chemotherapy. The safety of ovarian tissue cryopreservation procedures with a new round biopter was evaluated, as well as the risk of malignant cell transmission. It has been shown that laproscopic ovarian biopsy performed with the round biopter is a safe and efficient method for collection of ovarian tissue in cancer patients. In Hodgkin's disease patients' ovarian cortical tissue obtained for cryopreservation does not contain malignant cells. However the risk of cryopreserving and transferring malignant cells should be tested separately for each disease according to the risk of ovarian metastasis and the ability to detect single malignant cells.

Parasitic ovarian dermoid tumor of the omentum-A review of the literature and report of two new cases.

Two cases of a parasitic omental teratoma which originated from an ovarian dermoid that underwent torsion, autoamputation and omental reimplantation are presented. A review of the literature revealed 23 additional cases of omental teratoma which occurred mostly in females. In some cases, the mature teratoma of the omentum showed histological evidence of ovarian stroma, and was associated with a dermoid tumor of the remaining contralateral ovary. It is generally believed that autoamputation and reimplantation of an ovarian dermoid cyst is the most common etiology of omental teratomas. Abdominal pain is the main presenting symptom of these tumors, and on physical examination a mobile abdominal or pelvic mass is often found. Both ultrasonography with colour flow Doppler and CT-scan are helpful in the diagnosis of dermoid tumors, but the correct diagnosis of omental localisation is extremely difficult. Mature omental teratomas may be treated by simple resection. The immature teratomas of the greater omentum, however, are potentially malignant tumors requiring postoperative chemotherapy and radiotherapy.