Fertility Preservation Procedures Research Articles

6626 Fertility considerations in Klinefelter Syndrome complicated by hypogonadotrophic hypogonadism

Abstract Disclosure: M. Govinna: None. S. Sarlos: None. C.A. Allan: None. R. Giri: None. Background: Klinefelter syndrome (KS) remains underdiagnosed with less than 50% of men ever diagnosed and >90% of diagnoses only occurring when fertility is sought. MicroTESE (microscopic testicular sperm extraction) is now successful in 47-69% [1]. Optimal timing of the procedure is uncertain. Case: A 14-year-old male student with a history of renal stones (normal genitourinary tract anatomy) and anxiety presented with a six-day history of new onset headaches and transient visual blurring. MRI scan showed a 2.1cm pituitary lesion with local mass effect and minimal compression of the optic chiasm. Pre-operative pituitary panel: FSH 29.8 IU/L (1.2 - 5.2 IU/L); LH 8.8 IU/L (2.0 - 8.0 IU/L); testosterone 10.9 nmol/L (0.7 - 17.6 nmol/L). Remainder of anterior pituitary function was normal; no AVP deficiency. On examination, Tanner stage P4 G4, testicular volumes 5-6ml (right) and 6-8ml (left) (expected range 15-20ml). Height 175cm (75th centile) and weight 60.1kg (63rd centile). Transsphenoidal resection (TSS) of the pituitary lesion was performed. Intraoperative appearances were suggestive of craniopharyngioma adherent to the pituitary stalk, with stalk transection to achieve complete resection. Post-operatively AVP-deficiency, hypocortisolism and secondary hypothyroidism required replacement therapy. Histopathology was subsequently consistent with Rathke’s cleft cyst. Karyotype testing confirmed 47 XXY genotype (Klinefelter syndrome). Post-TSS FSH and LH levels were 0.7IU/L (1.2 - 5.2 IU/L) and 0.3 IU/L (2.0 - 8.0 IU/L); with testosterone <0.1 nmol/L (0.7 - 17.6 nmol/L), consistent with hypogonadotrophic hypogonadism superimposed on a background of primary hypogonadism. Testosterone replacement therapy was commenced following discussion regarding potential future fertility options. Discussion: This diagnosis of KS highlights the importance of thorough assessment of pubertal development and testicular examination. Small testes with hypergonadotrophic hypogonadism in the context of pituitary pathology should trigger further assessment. Fertility preservation procedures in prepubertal and adolescent boys with KS remain controversial [2]. This patient represents a unique scenario whereby he is LH and FSH deficient post TSS. Whilst prior treatment with hCG does not increase sperm retrieval in non-mosaic KS [3] there may be a role for gonadotrophin therapy prior to undertaking microTESE in our patient. To date, there are no reported cases.

6626 Fertility considerations in Klinefelter Syndrome complicated by hypogonadotrophic hypogonadism

Abstract Disclosure: M. Govinna: None. S. Sarlos: None. C.A. Allan: None. R. Giri: None. Background: Klinefelter syndrome (KS) remains underdiagnosed with less than 50% of men ever diagnosed and >90% of diagnoses only occurring when fertility is sought. MicroTESE (microscopic testicular sperm extraction) is now successful in 47-69% [1]. Optimal timing of the procedure is uncertain. Case: A 14-year-old male student with a history of renal stones (normal genitourinary tract anatomy) and anxiety presented with a six-day history of new onset headaches and transient visual blurring. MRI scan showed a 2.1cm pituitary lesion with local mass effect and minimal compression of the optic chiasm. Pre-operative pituitary panel: FSH 29.8 IU/L (1.2 - 5.2 IU/L); LH 8.8 IU/L (2.0 - 8.0 IU/L); testosterone 10.9 nmol/L (0.7 - 17.6 nmol/L). Remainder of anterior pituitary function was normal; no AVP deficiency. On examination, Tanner stage P4 G4, testicular volumes 5-6ml (right) and 6-8ml (left) (expected range 15-20ml). Height 175cm (75th centile) and weight 60.1kg (63rd centile). Transsphenoidal resection (TSS) of the pituitary lesion was performed. Intraoperative appearances were suggestive of craniopharyngioma adherent to the pituitary stalk, with stalk transection to achieve complete resection. Post-operatively AVP-deficiency, hypocortisolism and secondary hypothyroidism required replacement therapy. Histopathology was subsequently consistent with Rathke’s cleft cyst. Karyotype testing confirmed 47 XXY genotype (Klinefelter syndrome). Post-TSS FSH and LH levels were 0.7IU/L (1.2 - 5.2 IU/L) and 0.3 IU/L (2.0 - 8.0 IU/L); with testosterone <0.1 nmol/L (0.7 - 17.6 nmol/L), consistent with hypogonadotrophic hypogonadism superimposed on a background of primary hypogonadism. Testosterone replacement therapy was commenced following discussion regarding potential future fertility options. Discussion: This diagnosis of KS highlights the importance of thorough assessment of pubertal development and testicular examination. Small testes with hypergonadotrophic hypogonadism in the context of pituitary pathology should trigger further assessment. Fertility preservation procedures in prepubertal and adolescent boys with KS remain controversial [2]. This patient represents a unique scenario whereby he is LH and FSH deficient post TSS. Whilst prior treatment with hCG does not increase sperm retrieval in non-mosaic KS [3] there may be a role for gonadotrophin therapy prior to undertaking microTESE in our patient. To date, there are no reported cases.

Transrectal oocyte retrieval for fertility preservation in virginal women

Research QuestionFertility preservation faces barriers due to sociocultural and religious factors in some countries for nulliparous women who are virgins. Transrectal oocyte retrieval is an alternative technique which can address this by circumventing sensitivities around pelvic procedures in such women who require to have oocyte cryopreservation for medical or social reasons. The study aims to evaluate safety and efficacy of Transrectal oocyte retrieval (TROR) procedure for fertility preservation in these women. DesignA retrospective single centre study of 105 nulliparous women from five satellites of Fakih IVF in the United Arab Emirates, who underwent TROR for oocyte cryopreservation. Extensive bowel preparation and rectal cleansing was performed prior to oocyte retrieval. Outcome and safety data were collected on patient characteristics, stimulation protocols, oocyte yield in relation to age, AMH, number of follicles, and BMI. ResultsThis study evaluated 105 patients who underwent 152 cycles of ovarian stimulation and TROR. The most common indication was social fertility preservation. Correlation with patient characteristics included age, and AMH were performed. AMH showed a statically significant positive correlation with number of oocytes (p≤0.003). No intraoperative or postoperative complications were observed. ConclusionOur study demonstrated that TROR is Our study demonstrated that TROR is an alternative and clinically-effective oocyte harvesting procedure in ART, producing good results in terms of oocyte yield, with no complications and good safety profile. Although Transvaginal oocyte retrieval remains the gold standard treatment, for virginal women where transvaginal oocyte retrieval is not an option, TROR is safe and effective.

Behavior, attitude, perception, and knowledge regarding fertility preservation among Chinese pediatric oncologists: a survey in China.

Clinical specialists are supposed to inform childhood cancer patients of infertility risk and conduct fertility preservation (FP). However, little is known about whether doctors in China are fully prepared. This study aimed to investigate behavior, attitude, perception, and knowledge regarding FP among pediatric oncological specialists in a nation wide survey, to set the stage for improvements in current clinicalpracticepatterns. This study was conducted on physicians and surgeons specialized in pediatric oncology using a questionnaire through theWeChat platform. The behavior, attitude, perception, and knowledge were assessed by Likert questions and results were quantified to obtainscores. Data were then described and analyzed using R and GraphPad. Totally 373 specialists in pediatric tumors were included in the analysis. Hematologists, oncological surgeons, and reproductive medicine specialists won most trusts to be responsible for FP job. Most respondents did not have habits of delivering FP information or cooperating with FP specialists during treatment though they were well equipped with FP knowledge and desired for uniform national guideline for FP procedures. The severity of illness was regarded as the primary barrier of FP delivery. When a doctor was more educated and experienced, he was more likely to have better performance in FP. The total score, the knowledge score, and the single score concerning frequency of patients' inquiry showed aggregational trend on geographic distribution. Chinese pediatric oncologists demonstrated unsatisfactory practice behaviors based upon this self-reporting survey, although their attitude towards FP was generally positive.

Fertility preservation in Malaysian pediatric cohort: a survey of healthcare providers' knowledge, practice, attitude, perceptions and barriers.

Impaired future fertility potential secondary to gonadotoxic therapies for childhood cancer is a shattering aftermath faced by childhood cancer survivors. Fertility preservation (FP) has emerged as a key to mitigate this unwelcomed sequelae. FP services catering to the needs of children and adolescents (C&A) population in developing countries are limited. Malaysia recently launched its pioneering pediatrics FP services. To evaluate healthcare providers' (HCPs) FP knowledge, practice behaviors, attitudes, perceptions, and barriers towards FP counseling/services (C/S) for the C&A cohort. A questionnaire-based study was conducted utilizing a questionnaire consisting of 51 items which was adapted from G.Quinn et al. The questionnaire was distributed both online and physically amongst HCPs in a tertiary center. Ethical committee approval was granted by the Research Ethical Committee, Universiti Kebangsaan Malaysia. A total of 102 HCPs completed the questionnaires. The majority of respondents were Malays (74.5%), females (80.4%), gynecology/pediatrics specialty (76.5%), and had children (88.2%). Nearly 72% of HCPs demonstrated good knowledge of FP. Almost 73% of HCPs consulted reproductive specialists (RES) on potential fertility issues and over 80% of HCPs referred patients who enquired on fertility issues to RES. Only 17% of HCPs practiced FP discussion, 12% reported no available person to discuss FP, and 10% of HCPs were unaware of who to discuss FP with. Patients' inability to afford FP (30.4%) tops the list of barriers to FP C/S, followed by limited available information on FP for patients (17.6%) and patients too ill to delay treatment (12.7%). Most HCPs (88.2%) demonstrated unfavorable attitudes towards FP C/S. In general, the majority of our HCP respondents demonstrated good current FP knowledge and practice behaviors. Mitigating several controversial issues in FP would improve HCPs' attitude towards FP. Main barriers to the uptake of FP C/S for C&A were patient and resource barriers. Addressing these issues by funding aid for FP procedures, increasing FP knowledge dispersion, as well as developing age-appropriate FP-related educational materials would improve FP service provision for C&A in the future. In conclusion, successful corrective action combined with strategic planning points to a promising future for Malaysia's FP services provision for C&A.

Establishing a Standard Operating Procedure for Fertility Preservation in Adolescent and Young Adult Male Survivors of Childhood Cancers: Addressing a Gap in Care in the Republic of Ireland

Establishing a Standard Operating Procedure for Fertility Preservation in Adolescent and Young Adult Male Survivors of Childhood Cancers: Addressing a Gap in Care in the Republic of Ireland

Trends and Regional Differences for Fertility Preservation Procedures in Women With Breast Cancer

IntroductionBreast cancer is the most common malignancy in women of reproductive age and chemotherapy protocols impair fertility, frequently necessitating fertility preservation (FP) referral. Embryo, oocyte, or ovarian tissue cryopreservation are established FP modalities in women with breast cancer but there are few data on their uptake over time. In this study our aim was to determine the regional time trends and utility differences for fertility preservation methods of reproductive tissue cryopreservation. MethodsThis multicenter study included 1623 women diagnosed with breast cancer from 7 tertiary centers in 6 countries (Brazil, Italy, Scotland, South Korea, Turkey, USA). Participant centers provided the details of FP cryopreservation approaches broken down annually from 2012 to 2021. Women with newly diagnosed breast cancer, aged 18-45 years who were referred for FP at participating centers and had normal ovarian function at the time were included. ResultsWe found a mean increase of 7% per year (P = .002, adjusting for centers) in the number of women referred for FP. Of those who were referred (n = 1623), a mean 38.7% underwent FP (n = 629), with a range of 12% in South Korea) to 95% in Brazil. The number of women undergoing ovarian stimulation for FP continually increased until 2021, with oocyte cryopreservation being the most common procedure throughout the study period (P = .014 for time trend). The proportion of random start ovarian stimulation cycles increased each year from 58.3% in 2012 to 86.8% in 2021, (P = .005 for time trend, and P = .04 for 2012 vs. 2021). ConclusionsThe utility of FP has steadily increased for young women with breast cancer over the last decade, although regional differences significantly influence FP practices. The findings of our study could have value for policy making in FP care for young women with breast cancer at the local, regional, or global level.

Use of tamoxifene-controlled ovarian hyperstimulation for fertility preservation before breast cancer treatment: A prospective cohort study with a 5-year follow-up

PurposeFertility issues are of great concern for young women undergoing treatment for breast cancer (BC). Fertility preservation (FP) protocols using controlled ovarian stimulation (COS) with letrozole have been widely used with overall good results. However, letrozole cannot be used in every country in this context. This study aimed to assess the efficacy of tamoxifen for COS in women with early BC undergoing FP. MethodsThis multicentric prospective study included patients aged 18–40, diagnosed with stage I, II and III invasive BC, undergoing tamoxifen-COS before adjuvant or neoadjuvant chemotherapy (NAC). The primary endpoint was the efficacy of tamoxifen-COS protocol evaluated by the number of oocytes collected and vitrified. Secondary endpoints included the time interval before chemotherapy, breast cancer (BC) recurrence rates, and reproductive outcomes. ResultsNinety-five patients were included between 2014 and 2017, aged 31.5 ± 4 years on average. 37.9 % received NAC and 62.1 % received adjuvant chemotherapy. FP procedure was successful in 89.5 % of the cycles. The mean number of collected and vitrified oocytes was 12.8 ± 7.9 and 9.8 ± 6.2, respectively. The mean duration of COS was 10.4 ± 1.9 days. Median time before chemotherapy initiation was 3.6 weeks (IQR 3.1; 4.1) for women receiving NAC. Five-year relapse-free and overall survival rates were in-line with those expected in this population. Twenty-one women had spontaneous full-term pregnancies, while 5 underwent IVF cycles with frozen-thawed oocytes, without pregnancy. ConclusionTamoxifen-COS protocols appear to be feasible before adjuvant or NAC treatment in young BC patients and efficient in terms of oocyte yield.

Pathways to motherhood: A single-center retrospective study on fertility preservation and reproductive outcomes in patients with breast cancer

BackgroundBreast cancer treatments often have negative effects on fertility, which pose challenges among patients who want to be parents in the future. This study aimed to examine the efficacy of oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation in patients with breast cancer. MethodsThis retrospective review evaluated 42 patients with breast cancer who underwent fertility preservation at our center from January 2012 to December 2022. This review encompassed the demographic characteristics of the patients, cancer stages, treatment details, and types of fertility preservation procedures and their outcomes. ResultsThe average age at disease diagnosis was 33.4 years. Approximately 90.4% of patients presented with early-stage cancer (≤2). Of 42 patients, 26 underwent oocyte cryopreservation; 17, embryo cryopreservation; and 2, ovarian tissue cryopreservation. Further, three patients received mixed treatment. The overall live birth rate was 63.2%. There are more live births in embryo cryopreservation group. The successful pregnancy group was significantly younger and had a remarkably higher quantity of preserved oocytes/embryos than the nonsuccessful pregnancy group. The oocyte and embryo utilization rates in cryopreservation were 7.69% and 52.94%, respectively. These findings underscored the importance of prompt, informed discussions about fertility preservation options. ConclusionFertility preservation in patients with breast cancer have promising reproductive outcomes, with embryo cryopreservation being particularly effective. Prompt counseling and individualized fertility preservation strategies are important for improving the likelihood of posttreatment pregnancy. Nevertheless, future research on the long-term psychological and emotional effects of different fertility preservation methods must be performed.

O-086 Risk of serious adverse event after fertility preservation procedures: a comparison of cancer and non-cancer patients

Abstract Study question Do cancer patients have a higher risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients ? Summary answer No increased risk of adverse event after fertility preservation procedures was identified in cancer patients compared to non-cancer patients undergoing fertility preservation for other indications. What is known already Current recommendations encourage a prompt and exhaustive discussion on the different techniques of fertility preservation that can be performed in cancer patients of reproductive age prior to cancer treatments. Although cryopreservation of mature oocytes and/or embryos is the technique of reference in the absence of contraindication, ovarian stimulation and subsequent oocyte retrieval are associated to complications. Cancer patients might present an additional risk given tumoral hypervascularity and proinflammatory environment, as well as possible immune or coagulation disorders. However, whether cancer patients have an increased risk of serious adverse event associated to fertility preservation procedures compared to non-cancer patients remains unknown. Study design, size, duration A bicentric, retrospective study between January 1st, 2014 and December 31st, 2021. Participants/materials, setting, methods All women undergoing fertility preservation procedures by oocyte and/or embryo cryopreservation after controlled ovarian stimulation or in vitro maturation.The main endpoint was the occurrence of a serious adverse event (hospitalization for ovarian hyperstimulation syndrome, hemorrhage, infection, thromboembolic event, ovarian torsion, acute urine retention or death) in cancer patients compared to non-cancer patients undergoing fertility procedures. Main results and the role of chance A total of 4476 cycles (n = 3180 patients) were included, of which 3761 after controlled ovarian stimulation and 715 in vitro maturation cycles. Among the 4476 cycles, 1678 were performed in an oncological context (n = 1546 cancer patients) and 2798 were fertility preservation cycles for an indication other than cancer (n = 1634 patients). A total of 29 serious adverse events associated to fertility preservation procedures were registered, of which 17 intraperitoneal hemorrhages, 8 cases of ovarian hyperstimulation syndrome, 3 cases of infection and 1 case of acute urine retention. The risk of serious adverse event associated to fertility preservation procedures was not significantly different between cancer patients and non-cancer patients (0.36% vs. 0.82%, respectively, P = 0.06). Young age (P = 0.002), a higher number of oocytes retrieved (P = 0.006) and a higher number of oocytes vitrified (P = 0.002) were significantly associated to the risk of presenting a serious adverse event after fertility preservation. Limitations, reasons for caution Although rates of serious adverse events in our study are similar to that reported in previous literature and that the declaration and registration of any serious adverse event is mandatory according to French legislation, it is possible that not all serious adverse events were declared and registered. Wider implications of the findings Given the trend of delaying parenthood and the improved survival rates after cancer treatments, these findings are of particular importance, emphasizing the safety of performing fertility preservation procedures for cancer patients of reproductive age who might have a pregnancy desire after cancer treatment. Trial registration number not applicable

O-084 Outcomes of female fertility preservation with cryopreservation of oocytes or embryos: a population-based study

Abstract Study question What are the reproductive outcomes observed of patients who cryopreserved oocytes or embryos in the context of fertility preservation in the Netherlands? Summary answer After 10 years follow-up, 25.5% of the women used their cryopreserved oocytes or embryos to attempt pregnancy and of these, 34.6% had a live birth. What is known already Fertility preservation through freezing oocytes or embryos is an established treatment for women with a risk of premature ovarian failure (caused by a benign or oncological disease) or physiological age-related fertility decline. Little is known about the success of freezing protocols, utilization rate of oocytes or embryos and live birth rates. Study design, size, duration A retrospective nationwide observational study was performed in the Netherlands. Data were collected between 2017-2019 from all women who cryopreserved oocytes or embryos more than two years ago in the context of fertility preservation in ten out of twelve IVF centers in the Netherlands. Participants/materials, setting, methods In total 1112 women were included in this study. Medical files and patient databases were used to extract data. The study protocol was approved by the medical ethics committee. Main results and the role of chance Fertility preservation cycles are performed increasingly over the years. In the first years (2004-2007) less than 10 cycles per year were performed, which increased to more than 300 cycles per year in ten years’ time (since 2016). Initially embryos were frozen in the context of fertility preservation. In the later years cryopreservation of oocytes became the standard approach. The median number of oocytes cryopreserved was 13 per woman (range 1-52) and of embryos cryopreserved was 6 (range 1-32). Cryopreservation of oocytes versus embryos resulted in a comparable median number of eligible embryos for transfer (3 and 4 embryos respectively). The 5-year utilization rate was 12.3% and 10-year utilization rate was 25.5%. The cumulative clinical pregnancy rate after embryo transfer of cryopreserved oocytes or embryos was 39.2% and the live birth rate was 34.6% per patient. The return rate of those who had fertility preservation due to benign diseases was higher than for the other indications after five years, namely 17.1% (p < 0.05). After ten years the return rates for the other indications increased to similar percentages for all indications. Limitations, reasons for caution The follow-up period varied between patients and not all cryopreserved material was used yet at the end of this study. This might have led to underestimated pregnancy rates. Further, intention-to-treat analysis could not be performed since women who had a fertility preservation procedure without freezing were not included. Wider implications of the findings This study provides data on the reproductive outcomes after fertility preservation. This knowledge can be informative for professionals and future patients to improve counseling and informed decision making regarding ovarian stimulation in the context of fertility preservation. Trial registration number n/a

O impacto do processo transexualizador na saúde reprodutiva da população transgênero

Introduction: From a health care perspective, gender identity is a vulnerability factor. Transgender people generally seek health services at reproductive age for the transsexualization process, unaware of its impact on fertility. Objective: To determine the percentage of transgender people who are advised on reproductive health and the impacts of the transsexualization process. Method: Descriptive cross-sectional study applied using Google Forms. Transgender participants aged 18 or over were included, captured by disseminating the reserch on social media in partnership with Non-Governmental Organizations (NGOs) involved with the LGBTQIA+ public. Results: 105 individuals were evaluated, the majority of them underwent hormonal therapy and were not advised on fertility preservation, although more than 90% would liked to have been. 25.7% would be willing to postpone the transsexualization process to increase the chance of having biological children. Discussion: Although it alleviates dysphoric symptoms, the transsexualization process can pose risks to fertility. Fertility preservation procedures are rarely performed by transgender people, due to cost, lack of information and the desire not to delay the transsexualization process. Conclusion: 67.5% of participants were not instructed on fertility preservation, highlighting the gap in transgender health care for safe family planning and reproductive satisfaction.

Ovarian Stem Cells for Women's Infertility: State of the Art.

Today, women's infertility is considered a social disease in females, occurring not only as an effect of POF (premature ovarian failure) but also as CTRI (cancer treatment-related infertility) in oncologic patients. Several procedures for FP (fertility preservation) are currently adopted to prevent this condition, mostly based on utilization of retrieved eggs from the patients with subsequent IVF (in vitro fertilization) or cryopreservation. However, great interest has recently been devoted to OSCs (ovarian stem cells), whose isolation from female ovaries, followed by their in vitro culture, led to their maturation to OLCs (oocyte-like cells), namely, neo-oocytes comparable to viable eggs suitable for IVF. Translation of these data to FP clinical application creates new hope in the treatment of infertility. Thus, in line with the significant progress in using stem cells in the regenerative medicine field, neo-oogenesis via OSCs, which is currently unapplicable in fertility preservation procedures, will provide novel possibilities for young and adult females in motherhood programs in the future.

Enhancement of Vascularization and Ovarian Follicle Survival Using Stem Cells in Cryopreserved Ovarian Tissue Transplantation-A Systematic Review.

The increase in cancer survival rates has put a focus on ensuring fertility preservation procedures for cancer patients. Ovarian tissue cryopreservation presents the only option for prepubertal girls and patients who require immediate start of treatment and, therefore, cannot undergo controlled ovarian stimulation. We aimed to provide an assessment of stem cells' impact on cryopreserved ovarian tissue grafts in regard to the expression of growth factors, angiogenesis promotion, tissue oxygenation, ovarian follicle survival and restoration of endocrine function. For this systematic review, we searched the Scopus and PubMed databases and included reports of trials using murine and/or human cryopreserved ovarian tissue for transplantation or in vitro culture in combination with mesenchymal stem cell administration to the grafting site. Of the 1201 articles identified, 10 met the criteria. The application of stem cells to the grafting site has been proven to support vascular promotion and thereby shorten the period of tissue hypoxia, which is reflected in the increased number of remaining viable follicles and faster recovery of ovarian endocrine function. Further research is needed before implementing the use of stem cells in OT cryopreservation and transplantation procedures in clinical practice. Complex ethical dilemmas make this process more difficult.

Fertility Preservation in BRCA1/2 Germline Mutation Carriers: An Overview.

BRCA1 and BRCA2 mutations are responsible for a higher incidence of breast and ovarian cancer (from 55% up to 70% vs. 12% in the general population). If their functions have been widely investigated in the onset of these malignancies, still little is known about their role in fertility impairment. Cancer patients treated with antineoplastic drugs can be susceptible to their gonadotoxicity and, in women, some of them can induce apoptotic program in premature ovarian follicles, progressive depletion of ovarian reserve and, consequently, cancer treatment-related infertility (CTRI). BRCA variants seem to be associated with early infertility, thus accelerating treatment impairment of ovaries and making women face the concrete possibility of an early pregnancy. In this regard, fertility preservation (FP) procedures should be discussed in oncofertility counseling-from the first line of prevention with risk-reducing salpingo-oophorectomy (RRSO) to the new experimental ovarian stem cells (OSCs) model as a new way to obtain in vitro-differentiated oocytes, several techniques may represent a valid option to BRCA-mutated patients. In this review, we revisit knowledge about BRCA involvement in lower fertility, pregnancy feasibility, and the fertility preservation (FP) options available.

Mechanisms underlying human sperm cryodamage: the role of reactive oxygen species (ROS) and antioxidants

Sperm cryopreservation is an efficient procedure for male fertility preservation, although the freeze-thaw procedure causes irreversible structural and functional changes in human spermatozoa. Indeed, the procedure is responsible for harmful changes that may affect sperm biology. In mammalian cells, cryopreservation induces a shift of redox homeostasis towards increasing generation of reactive oxygen species (ROS). The characteristics of ROS and the cellular outcomes depend on the cell type. Supra-physiological ROS levels during cryopreservation severely impact sperm survival, reproductive potential and DNA integrity, the latter a fundamental factor for fertilisation and transmission of paternal genetic information to offspring. The aim of this review is to summarise current knowledge of the main molecular mechanisms underlying ROS generation during sperm cryopreservation and its subsequent effects. In addition, we report current experimental approaches based on the supplementation of cryopreservation media with enzymatic and non-enzymatic antioxidants with the aim of minimising the harmful effects of ROS, and thus improving post-thaw sperm quality. Current data indicate that the potential use of antioxidants as constituents of the sperm freezing solution in clinical settings would require considerable attention. KEY WORDS: Spermatozoa, cryopreservation, ROS, oxidative stress, antioxidants.

Evaluation of the Gonadotoxicity of Cancer Therapies to Improve Counseling of Patients About Fertility and Fertility Preservation Measures: Protocol for a Retrospective Systematic Data Analysis and a Prospective Cohort Study.

Cytotoxic treatments such as chemo- and radiotherapy and immune therapies are required in cancer diseases. These therapies have the potential to cure patients but may also have an impact on gonadal function and, therefore, on fertility. Consequently, fertility preservation treatments such as freezing of gametes and gonadal tissue might be required. However, as detailed data about the necessity to perform fertility preservation treatment are very limited, this study was designed to fill this data gap. Primary objective of this study is to analyze the impact of cancer therapies and chemotherapies on the ovarian reserve and sperm quality. Secondary objectives are to analyze the (1) impact of cancer therapies and chemotherapies on other fertility parameters and (2) probability of undergoing fertility preservation treatments in relation to specific cancer diseases and treatment protocols and the probability to use the frozen gametes and gonadal tissue to achieve pregnancies. First, previously published studies on the gonadotoxicity of chemo- and radiotherapies among patients with cancer will be systematically analyzed. Second, a prospective cohort study set up by approximately 70 centers in Germany, Switzerland, and Austria will collect the following data: ovarian function by analyzing anti-Müllerian hormone (AMH) concentrations and testicular function by analyzing sperm parameters and total testosterone immediately before and around 1 year after gonadotoxic therapies (short-term fertility). A follow-up of these fertility parameters, including history of conceptions, will be performed 5 and 10 years after gonadotoxic therapies (long-term fertility). Additionally, the proportion of patients undergoing fertility-preserving procedures, their satisfaction with these procedures, and the amount of gametes and gonadal tissue and the children achieved by using the frozen material will be analyzed. Third, the data will be merged to create the internet-based data platform FertiTOX. The platform will be structured in accordance with the ICD (International Classification of Diseases) classification of cancer diseases and will be easily be accessible using a specific App. Several funding bodies have funded this study. Ten systematic reviews are in progress and the first one has been accepted for publication. All Swiss and many German and Austrian ethics committees have provided their approval for the prospective cohort study. The study registry has been set up, and a study website has been created. In total, 50 infertility centers have already been prepared for data collection, which started on December 1, 2023. The study can be expected to bridge the data gap regarding the gonadotoxicity of cancer therapies to better counsel patients about their infertility risk and their need to undergo fertility preservation procedures. Initial data are expected to be uploaded on the FertiTOX platform in 2026. ClinicalTrials.gov NCT05885048; https://clinicaltrials.gov/study/NCT05885048. DERR1-10.2196/51145.

Current practice with operative hysteroscopy for fertility preservation in endometrial cancer and endometrial premalignancies.

The primary aim was to analyze the current practices on the use of operative hysteroscopy for preserving fertility in patients diagnosed with endometrial cancer and premalignancies. Our secondary objectives included investigating medical therapy and analyzing reported pregnancy-related outcomes subsequent to fertility preservation procedures. We performed a semi-systematic literature review on PubMed, employing pertinent terms related to hysteroscopy, fertility preservation, and endometrial cancer and premalignancies. Patients undergoing operative hysteroscopy with or without following medical treatment were included. We adhered to the PRISMA 2020 statement and utilized Covidence software to manage our systematic review. We performed a pooled analysis on various outcomes. Our final analysis included 15 studies evaluating 458 patients, where 238 (52.0%) were diagnosed with endometrial cancer, and 220 (48.0%) had endometrial premalignancies. With 146 pregnancies in our study, the overall pregnancy rate was 31.9%. Among these, 97 resulted in live births, accounting for 66.4% of the reported pregnancies. In terms of medical treatment, various forms of progestins were reported. Complications or adverse effects related to operative hysteroscopy were not reported in more than half of the studies. Among those studies that did report them, no complications nor adverse effects were documented. After hysteroscopic resection, complete response to medical treatment has been reported in 65.5% of the overall cases. Our review sheds light on the contemporary landscape of operative hysteroscopy for fertility preservation in endometrial cancer and premalignancies. Future studies should include the integration of molecular classification into fertility-preserving management of endometrial malignancies to offer a more personalized and precise strategy.

Ovarian Tissue Cryopreservation versus Other Fertility Techniques for Chemoradiation-Induced Premature Ovarian Insufficiency in Women: A Systematic Review and Future Directions.

Current advances in cancer therapy have increased survival, emphasizing the need for life quality improvement. Fertility loss is common post-chemotherapy. Current guidelines establish embryo and oocyte cryopreservation to address premature ovarian insufficiency (POI). Ovarian tissue cryopreservation has also recently become an acceptable option for fertility preservation, particularly as it is the only option for pre-pubertal patients. Few definitions for optimum fertility outcomes, and few systematic reviews comparing embryo, oocyte, and ovarian tissue cryopreservation as a means of fertility preservation (FP) in pre- and post-pubertal female cancer patients exist. This systematic review aims to improve understanding of gonadotoxic effects of chemoradiation therapy in cancer patients, to analyze the different fertility preservation techniques and procedures available to women with chemoradiation induced ovarian insufficiency, and to compare and recognize the benefits of each technique in restoring fertility, sexual hormone function, and quality of life. Searches were conducted electronically on PubMed, Cochrane, and EBSCOHost, including clinical trials, prospective, and retrospective studies of female cancer patients undergoing anti-cancer therapy, with predefined MeSH terminology. Data were collected, analyzed, and compared. Non-randomized clinical studies were evaluated for risk bias through the Newcastle-Ottawa Scale. In total, 23 studies were included. From there, 647 patients opted for oocyte cryopreservation, 267 for embryo cryopreservation, and 1382 for ovarian tissue cryopreservation (OTC). A total of 175, 18, and 121 live births resulted respectively from oocyte, embryo, and OTC, respectively. Studies without live births discussed other fertility markers as indicators of improvement in sexual hormone function and fertility. The gonadotoxic effects of chemotherapy call for FP intervention. Oocyte and embryo cryopreservation/implantation are well-established procedures. With changing trends and life quality consideration, OTC is a promising interventional method for pre-pubertal patients facing the prospect of fertility loss.

Fertility protection: a novel approach using pretreatment with mesenchymal stem cell exosomes to prevent chemotherapy–induced ovarian damage in a mouse model

BackgroundPrimary ovarian insufficiency (POI) refers to the loss of ovarian functionbefore the age of 40 years and results in amenorrhea and infertility. POI has diverse causes, but a common cause is exposure to gonadotoxic chemotherapy for cancer treatment. Due to the risk of developing POI, patients who want to preserve their fertility may consider various procedures for fertility preservation. However, current fertility preservation options are highly invasive, carry substantial risks, and have uncertain success rates. Recent studies from our group and others reported that mesenchymal stem cells (MSCs) and MSC-derived exosomes can restore ovarian functions in preclinical models of POI by restoring damaged cells and inhibiting apoptosis. Although the restorative effect of MSC-derived exosomes has been well reported in previous studies, the potential of MSC-derived exosomes for preventing ovarian damage has not been fully elucidated. ObjectiveWe hypothesized that the antiapoptotic potential of MSC-derived exosomes may protect ovarian tissue from chemotherapy-induced damage. Study designIn this study, we delivered MSC-derived exosomes directly into mouse ovaries before chemotherapy. Sixty mice were divided into three groups (20 per group), which were labeled the control, CTx (chemotherapy), and FP (fertility protection) groups. Only the FP group mice received exosomes, while the control and CTx group mice received saline. After exosome injection, the CTx and FP groups of mice were subjected to chemotherapy treatment to induce ovarian damage. After chemotherapy, we evaluated the protective effects of exosome treatment on ovarian function, such as estrus cyclicity, serum hormone levels, and the fertility rate, by comparing these outcomes between the CTx and FP groups. These outcomes were also compared with those of the control group for comparison with outcomes under healthy conditions. ResultsAfter intraovarian injection of exosomes before chemotherapy, the mice were able to maintain their estrus cycle (4–5-day cyclicity), serum AMH level (66.06±26.40 ng/ml, not significantly different from that of the healthy controls), folliculogenesis (32.2±11.3 in the CTx group/46.4±14.1 in the FP group, p<0.05), steroidogenesis marker StAR gene expression (0.44±0.11-fold in the CTx group and 0.88±0.31-fold in the FP group, p<0.05), and fertility (2 of 8 in the CTx group and 5 of 8 in the FP group), preventing chemotherapy-induced damage. We found that exosome treatment before chemotherapy can preserve ovarian function and protect fertility through the overexpression of ABC transporters, such as ABCB1b (10.17±17.75-fold in the CTx group and 44.14±33.25-fold in the FP group; p<0.05), and ABCC10 (3.25±0.59-fold in the CTx group and 5.36±1.86-fold in the FP group; p<0.05). ConclusionIn this study, we present a novel fertility protection method using MSC-derived exosomes. We conclude that MSC-derived exosomes are a promising simple treatment option for fertility protection in reproductive-age patients receiving gonadotoxic chemotherapy.