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Abstract More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.

Abstract Background Sperm quality at cancer diagnosis is often compromised by the disease and any given gonadotoxic treatment will further diminish fertility. Objectives Here, we aim to analyze the cryopreserved sperm quality according to the cancer types as well as the fertility outcomes. Methods Our study included all cancer patients who cryopreserved sperm over 20 years at Erasme Hospital Brussels (from 1999 to 2019). First sperm samples from 111 hematologic, 104 testicular, 19 prostate, 28 gastrointestinal, and 16 neurological cancer patients were compared. Results Oligozoo‐asthenozoospermia was observed in 30% of the samples, including 19.33% with severe oligozoospermia (

In the last decade, fertility preservation has risen as a major field of interest, creating new interactions between oncologists and gynecologists. Various options, such as cryopreservation of ovarian tissue, have been developed and are currently routinely proposed in many centers. However, many of the options remain experimental and should be offered to patients only after adequate counseling. This paper addresses the efficiency and the potential of the different fertility preservation approaches.

: BACKGROUND Anti-Müllerian hormone (AMH), secreted by the granulosa cells of preantral and small antral follicles, has been described as a potential marker of the ovarian reserve. The aim of this prospective study is to investigate the variations of AMH during the menstrual cycle in a young selected population of normo-ovulatory women and to analyse the correlation with other cyclic hormones. : METHODS Twenty healthy volunteers from 19 to 35 years old, with regular menstrual cycles (26–31 days), normal ovulation (day 10–16), normal hormonal profile and normal body mass index (18–26 kg/m2) were recruited. AMH, inhibin B, LH, FSH, estradiol and progesterone were measured on days 3, 7, 10, 11, 12, 13, 14, 15, 16, 18, 21 and 25 of a spontaneous cycle. : RESULTS AMH serum levels, either expressed by cycle day or aligned according to the ovulation day, did not show any significant variations during the menstrual cycle. : CONCLUSIONS No significant fluctuation of the AMH level during the menstrual cycle was observed. Therefore, this hormone is particularly interesting for clinical evaluation of the ovarian reserve as it may be used at any time during the cycle. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to synthesize the existing evidence on perinatal outcomes after autologous cryopreserved ovarian tissue transplantation, concurrently identifying key factors influencing these outcomes., Data Sources: A comprehensive search was performed on MEDLINE, Embase, and Cochrane Library databases to identify relevant studies on the effect of autologous cryopreserved ovarian tissue transplantation on perinatal outcomes from inception to October 22, 2023. Where there was missing information, the authors were contacted for updated data., Study Eligibility Criteria: Observational studies, such as cohort studies, case series, and case reports that reported a live birth after autologous cryopreserved ovarian tissue transplantation, were considered eligible. Studies lacking data on women's demographic characteristics, autologous cryopreserved ovarian tissue transplantation procedure details, or perinatal outcomes were excluded. In addition, cases involving fresh or nonautologous transplantations and those addressing primary ovarian insufficiency were excluded., Methods: Two reviewers (M.E. and E.U.) independently performed the study selection, data extraction, and risk of bias assessment, and the results were then reviewed together. The PRISMA guidelines were followed, and the protocol was registered on PROSPERO (CRD42023469296)., Results: This review included 58 studies composed of 122 women with 162 deliveries (154 singletons and 8 twins) after autologous cryopreserved ovarian tissue transplantation, resulting in 170 newborns. Of note, 83.6% of the women had a malignant disease. Moreover, most of these women (51.0%) were exposed to some form of chemotherapy before ovarian tissue cryopreservation. Of the 162 childbirths, 108 (66.7%) were conceived naturally, and 54 (33.3%) were conceived through assisted reproductive techniques. The birthweight of 88.5% of newborns was appropriate for gestational age, whereas 8.3% and 3.1% were small for gestational age and large for gestational age, respectively. The preterm birth rate was 9.4%, with the remaining being term deliveries. Hypertensive disorders of pregnancy were noted in 18.9% of women, including pregnancy-induced hypertension in 7.6%, preeclampsia in 9.4%, and hemolysis, elevated liver enzymes, and low platelet count in 1.9%. The incidences of gestational diabetes mellitus and preterm premature rupture of membranes were 3.8% for each condition. Neonatal anomalies were reported in 3 transplant recipients with 4 newborns: arthrogryposis, congenital cataract, and diaphragmatic hernia in a twin. Finally, among the recipients' characteristics, not receiving chemotherapy before ovarian tissue cryopreservation (odds ratio, 0.23; 95% confidence interval, 0.07-0.72; P=.012) and natural conception (odds ratio, 0.29; 95% confidence interval, 0.09-0.92; P=.035) were associated with a lower perinatal complication rate., Conclusion: On the basis of low certainty evidence from observational studies, perinatal complication rates did not increase after autologous cryopreserved ovarian tissue transplantation compared with the general pregnant population, except for preeclampsia. This could be due to chemotherapy exposure, underlying medical conditions, and the common use of assisted reproductive techniques. Further larger studies are needed to explore the causes of increased preeclampsia incidence in autologous cryopreserved ovarian tissue transplantation pregnancies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy., Patients and Methods: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months., Results: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5)., Conclusion: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Oncological treatments have dramatically improved over the last decade, and as a result, survival rates for cancer patients have also improved. Quality of life, including concerns about fertility, has become a major focus for both oncologists and patients. While oncologic treatments are often highly effective at suppressing neoplastic growth, they are frequently associated with severe gonadotoxicity, leading to infertility. For male patients, the therapeutic option to preserve fertility is semen cryopreservation. In prepubertal patients, immature testicular tissue can be sampled and stored to allow post-cure transplantation of the tissue, immature germ cells, or in vitro spermatogenesis. However, experimental techniques have not yet been proven effective for restoring sperm production for these patients. MicroRNAs (miRNAs) have emerged as promising molecular markers and therapeutic tools in various diseases. These small regulatory RNAs possess the unique characteristic of having multiple gene targets. MiRNA-based therapeutics can, therefore, be used to modulate the expression of different genes involved in signaling pathways dysregulated by changes in the physiological environment (disease, temperature, ex vivo culture, pharmacological agents). This review discusses the possible role of miRNA as an innovative treatment option in male fertility preservation-restoration strategies and describes the diverse applications where these new therapeutic tools could serve as fertility protection agents.

Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer ( BRCA ) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA -mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.

Background: Despite increasing evidence on the safety of pregnancy after anticancer treatments in breast cancer survivors, many physicians and patients remain concerned about a potential risk of pregnancy specifically in the case of hormone receptor-positive breast cancer., Materials and Methods: A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to 31 March 2023 was carried out. To be included, articles had to be retrospective and prospective case-control and cohort studies as well as clinical trials comparing survival outcomes of premenopausal women with or without a pregnancy after prior diagnosis of hormone receptor-positive breast cancer. Disease-free survival (DFS) and overall survival (OS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Study protocol is registered in PROSPERO (n. CRD42023394232)., Results: Out of 7796 screened studies, 8 were eligible to be included in the final analysis. A total of 3805 patients with hormone receptor-positive invasive early breast cancer were included in these studies, of whom 1285 had a pregnancy after breast cancer diagnosis. Median follow-up time ranged from 3.8 to 15.8 years and was similar in the pregnancy and non-pregnancy cohorts. In three studies (n = 987 patients) reporting on DFS, no difference was observed between patients with and those without a subsequent pregnancy (HR 0.96, 95% CI 0.75-1.24, P = 0.781). In the six studies (n = 3504 patients) reporting on OS, patients with a pregnancy after breast cancer had a statistically significant better OS than those without a pregnancy (HR 0.46, 95% CI 0.27-0.77, P < 0.05)., Conclusions: This systematic review and meta-analysis of retrospective cohort studies provides updated evidence that having a pregnancy in patients with prior history of hormone receptor-positive invasive early breast cancer appears safe without detrimental effect on prognosis., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although effective in terms of the chances of future live birth, the current methods for fertility preservation, such as oocyte, embryo, or ovarian tissue cryopreservation, cannot be offered to all cancer patients in all clinical contexts. Expanding options for fertility preservation is crucial to addressing the need to encompass all situations. One emerging strategy is pharmacoprotection, a non-invasive approach that has the potential to fill existing gaps in fertility preservation. In addition to the identification of the most effective therapeutic agents, the potential for off-target effects remains one of the main limitations of this strategy for clinical application, particularly when healthy ovarian tissue is targeted. This review focuses on the advances in pharmacoprotective approaches and the challenge of targeting the ovaries to deliver these agents. The unique properties of gold nanoparticles (AuNPs) make them an attractive candidate for this purpose. We discuss how AuNPs meet many of the requirements for an ideal drug delivery system, as well as the existing limitations that have hindered the progression of AuNP research into more clinical trials. Additionally, the review highlights microRNA (miRNA) therapy as a next-generation approach to address the issues of fertility preservation and discusses the obstacles that currently impede its clinical availability.

The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2- advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2- disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.

The Hippo pathway plays a crucial role in the regulation of follicular activation, which constitutes the first step of the folliculogenesis process. Disruption of this pathway occurs in several non-physiological contexts, after fragmentation for ovarian tissue cryopreservation procedures or chemotherapy exposure, leading to massive follicular growth and depletion. This study aimed to investigate the effect of controlling the Hippo pathway using verteporfin (VERT) during in vitro ovarian culture and to evaluate its potential preventive effects on chemotherapy-induced follicle activation using a mouse model. After exposure of cut ovaries to different concentrations of VERT for 3 h, a dose-dependent effect of VERT was observed that reached significant inhibition of YAP activity at 3 µmol/L. To assess the potential effect of controlling chemotherapy-induced Hippo pathway disruption, whole mouse ovaries were exposed to VERT alone or as a co-treatment with 4-hydroperoxycylophosphamide (4HC). VERT co-treatment prevented chemotherapy-induced YAP activation but had a limited impact on downstream effector gene, Ccn2. Surprisingly, VERT co-treatment also prevented mTOR and survival signaling pathway alterations following chemotherapy exposure. These results suggest an interaction between the two main signaling pathways regulating follicle activation and a protective effect of VERT on 4HC-induced DNA damage., (© 2023. Springer Nature Limited.)

Background: Several studies have suggested that breast cancer (BC) and germline BRCA pathogenic variants (gBRCA PVs) could have a deleterious impact on ovarian reserve. Nevertheless, data are limited and mixed. Our objective was to evaluate the performance of fertility preservation (FP) in terms of the number of collected mature oocytes after ovarian stimulation (OS) in young women carrying a gBRCA PV, associated or not with BC., Methods: We conducted a retrospective monocentric study at HUB-Hôpital Erasme in Brussels. All women aged between 18 and 41 years diagnosed with invasive non-metastatic BC and/or gBRCA PV carriers who underwent OS for FP or preimplantation genetic testing for monogenic disorder (PGT-M) between November 2012 and October 2021 were included. Three groups were compared: BC patients without a gBRCA PV, BC patients with a gBRCA PV, and healthy gBRCA PV carriers. Ovarian reserve was evaluated based on the efficacy of OS and AMH levels., Results: A total of 85 patients underwent 100 cycles. The mean age (32.2 ± 3.9 years; p = 0.61) and median AMH level (1.9 [0.2-13] μg/L; p = 0.22) were similar between groups. Correlations between the number of mature oocytes and AMH level ( p < 0.001) and between AMH and age ( p < 0.001) were observed. No differences in the number of retrieved mature oocytes were observed between groups ( p = 0.41), or for other OS parameters., Conclusion: Neither BC nor a gBRCA PV significantly affects ovarian reserve and FP efficacy in terms of the number of mature oocytes retrieved.

Study Question: Does chemotherapy exposure prior to ovarian tissue cryopreservation (OTC) impact the signaling pathways governing follicle activation and survival for prepubertal and postpubertal patients?, Summary Answer: Chemotherapy exposure prior OTC increases follicle apoptosis rates but not follicular activation, although the PI3K/AKT/mTOR and Hippo signaling pathways were modified in the cortex., What Is Known Already: OTC is currently the only available fertility preservation procedure for children and for patients who have already started their treatment. While previous studies have not observed harmful impacts of first chemotherapy exposure on OTC outcomes, the consequences of treatment on follicle activation and survival need to be further investigated. To address this question, we evaluated signaling pathway modifications induced by chemotherapy exposure according to pubertal status., Study Design, Size, Duration: Cryopreserved ovarian tissues from postpubertal (12-29 years old, n = 8) and prepubertal (3-10 years old, n = 8) cancer patients donated for research were thawed and cultured for 24 h. Analyses of the survival of the follicles and stroma, and of the PI3K/AKT/mTOR and Hippo signaling pathways, were conducted at thawing and after culture. Ovarian fragments exposed to chemotherapy before collection were compared to non-exposed controls., Participants/materials, Setting, Methods: Histological investigations were performed to assess the distribution of the follicles, stroma fibrosis, vessel integrity, and apoptosis levels. It included follicular counting, collagen staining, immunostaining on CD31 and gH2AX, as well as TUNEL staining. To explore follicle activation in the different groups, the PI3K/AKT/mTOR and Hippo signaling pathways were investigated by gene expression analyses of isolated follicles and protein analyses on whole fragments through western blots and immunostaining., Main Results and the Role of Chance: We first assessed the impact of a first exposure to chemotherapy on the collagen density and vessels in ovarian tissues at thawing and after culture. While no differences in collagen density were observed according to age or previous treatment, the vascularization area (CD31+) was significantly lower in tissue from previously exposed patients compared to non-treated ones. Apoptosis analyses (TUNEL) revealed an acute deleterious impact on follicle survival after chemotherapy exposure without affecting the follicular density. Surprisingly, leukemic patients had a significantly higher percentage of gH2AX-positive follicles, indicating a DNA damage response, compared to the other patients. The proportion of activated follicles appeared to decrease following exposure to chemotherapy, suggesting that it at least did not increase activation process. Stable KIT LIGAND gene and protein expression and cKIT protein levels were observed among the groups, confirming the absence of activation. Analysis of the PI3K pathway did not reveal a difference in the AKT phosphorylation level between the groups, but pRPS6 was significantly higher in tissue from patients previously exposed to chemotherapy compared to that from non-exposed patients. Finally, protein and gene analyses on Hippo pathway signaling showed a higher LATS1 protein level in the cortex after chemotherapy exposure., Limitations, Reasons for Caution: The heterogeneity of the human fragments, and the limited number of patients included in the cohort have to be considered as important study limitations. Moreover, this study did not explore the long-term consequences of chemotherapy on follicular development. Therefore, the results should be interpreted with caution., Wider Implications of the Findings: These results underscore the deleterious effect of previous chemotherapeutic treatment on follicle survival. Although follicular density was not reduced, these data suggested that exposure to chemotherapy impacts follicular apoptosis and the DNA damage response. Chemotherapy-induced activation was not observed despite the impact on mTOR and Hippo signaling pathways in the whole cortex., Study Funding/competing Interest(s): This work was funded by an Excellence of Science (EOS) Grant (ID: 30443682) and was supported by Fonds Erasme. I.D. and M.-M.D. are associate researchers at Fonds National de la Recherche Scientifique de Belgique (FNRS). There are no competing interests., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The ovary is a heterogeneous organ composed of different cell types. To study the molecular mechanisms occurring during folliculogenesis, the localization of proteins and gene expression can be performed on fixed tissue. However, to properly assess gene expression levels in a human follicle, this complex and delicate structure must be isolated. Hence, an adapted protocol previously described by Woodruff's laboratory has been developed to separate follicles (the oocyte and the granulosa cells) from their surrounding environment. The ovarian cortical tissue is first manually processed to obtain small fragments using two tools: a tissue slicer and a tissue chopper. The tissue is then enzymatically digested with 0.2% collagenase and 0.02% DNase for at least 40 min. This digestion step is performed at 37 °C and 5% CO2 and is accompanied by mechanical pipetting of the medium every 10 min. After incubation, the isolated follicles are collected manually using a calibrated microcapillary pipette under microscope magnification. If follicles are still present in the pieces of tissue, the procedure is completed with manual microdissection. The follicles are collected on ice in a culture medium and are rinsed twice in droplets of phosphate-buffered saline solution. This digestion procedure must be carefully controlled to avoid follicle deterioration. As soon as the structure of the follicles appears to be compromised or after a maximum of 90 min, the reaction is stopped with a 4 °C blocking solution containing 10% fetal bovine serum. A minimum of 20 isolated follicles (sized under 75 µm) should be collected to obtain an adequate amount of total RNA after RNA extraction for real-time quantitative polymerase chain reaction (RT-qPCR). After extraction, the quantification of total RNA from 20 follicles reaches a mean value of 5 ng/µL. The total RNA is then retrotranscribed into cDNA, and the genes of interest are further analyzed using RT-qPCR.

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity., Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy)., Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk., Conclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Introduction: Fertility preservation (FP) is recommended in young breast cancer (BC) patients before (neo)adjuvant treatment. Letrozole-associated controlled ovarian hyperstimulation (LetCOH) is used worldwide to collect mature oocytes for FP, but its efficacy and safety compared to conventional protocols (cCOH) are still debated., Aims: To compare efficacy and safety of FP procedure using LetCOH or cCOH in BC patients in terms of oocyte maturation rate and disease-free survival rates after at least two years of follow-up., Methods: This multicenter retrospective study compared outcomes of 107 cycles in 97 non-metastatic BC patients aged ≤40 years who underwent cCOH (n = 56) or LetCOH (n = 41) for FP in CHU-Lille and Erasme Hospital, respectively, between December 2012 and January 2017., Results: Patients and oncological characteristics were similar except for tumor size and HER2 status which were less favorable in the LetCOH group. Patients underwent adjuvant chemotherapy in 96.4% and 48.8% of the cases in cCOH and LetCOH groups, respectively. Hence, 51.2% of LetCOH patients underwent neoadjuvant chemotherapy (p &lt; 0.001). Estradiol peak at ovulation trigger was lower in LetCOH compared to cCOH group while oocyte maturation rates were significantly higher (p &lt; 0.001), without impacting the final number of mature oocytes collected. Seven and four patients relapsed in LetCOH and cCOH groups, respectively, and one patient died in each group after a median follow-up of four years., Conclusion: LetCOH is as effective as cCOH for FP. At this time point, there were no safety concerns regarding cCOH in the adjuvant setting but a longer follow-up is warranted., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isabelle Demeestere acted as consultant/advisor for Roche, has received speaker's honoraria from Novartis and support for congress participation from Ferring and Theramex, outside of the present study. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Sperm quality at cancer diagnosis is often compromised by the disease and any given gonadotoxic treatment will further diminish fertility., Objectives: Here, we aim to analyze the cryopreserved sperm quality according to the cancer types as well as the fertility outcomes., Methods: Our study included all cancer patients who cryopreserved sperm over 20 years at Erasme Hospital Brussels (from 1999 to 2019). First sperm samples from 111 hematologic, 104 testicular, 19 prostate, 28 gastrointestinal, and 16 neurological cancer patients were compared., Results: Oligozoo-asthenozoospermia was observed in 30% of the samples, including 19.33% with severe oligozoospermia (<5 million/ml). Our results showed a significant reduction in sperm concentration among testicular cancer ( p  < 0.01). No significant differences in progressive motility, sperm volume, and number of frozen straws were observed. Significant correlations were found between sperm concentration and cancer type ( p  <0.01) as well as patients' age ( p  <0.01). Twenty-eight cancer survivors returned for using their cryopreserved sperm (9.33%), fertilization rate was 60.5% and implantation rate was 29.6%. There was no correlation between sperm concentration and fertility outcomes., Conclusion: Our results confirm the negative impact of cancer on sperm quality without affecting assisted reproductive technology (ART) success rate, which is utterly important as a male reproductive health perspective. All cancer patients should be counselled and offered fertility preservation options as a gold standard., Competing Interests: David Pening, Marnie Constant, and Manon Bruynbroeck have no conflicts of interest to declare. Anne Delbaere acted as advisory board and received grants or lecture fees from Merck, Gedeon‐Richter, Ferring Pharmaceuticals, and OVVI Diagnostics and travel grants from Merck, Theramex, and Ferring Pharmaceuticals unrelated to the present study. Isabelle Demeestere has acted as a scientific advisory board member and received grant from ROCHE, speaker's fees from Novartis and ROCHE, and travel grants from Theramex and Ferring, outside the submitted work., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Pharmacological approaches offer a non-invasive and promising option for fertility preservation in young female cancer patients undergoing gonadotoxic therapy. The GnRH-agonists are the only clinically available drugs in this indication, but their use and mechanisms of protection are still controversial. Recently, we have investigated new targeted drugs based on microRNA (miRNA) replacement therapy, and have identified the let-7a miRNA as candidate for fertility preservation strategies. Here, the effect of let-7a replacement during chemotherapy exposure on follicular growth and oocyte maturation capacity was investigated using a mouse ovarian-kidney transplantation model. Newborn mouse ovaries were cultured under different conditions; control, chemotherapy exposure (4-hydroperoxycyclophosphamide, 4-HC), and co-treatment with 4-HC and let-7a mimic transfection (4-HC + let-7a). The ovaries were then transplanted under the kidney capsule of recipient mice and follicular growth, survival, and oocyte in vitro maturation were assessed after 3 weeks. The results showed that the follicular pool was highest in the control group but higher in the 4-HC + let-7a group than the 4-HC group. DNA-damage/apoptosis ratios were higher in all 4-HC-exposed groups compared to control but were reduced in the 4-HC + let-7a group. In addition, the post-transplantation oocyte in vitro maturation rate was higher in the 4-HC + let-7a group compared to the 4-HC group, suggesting better oocyte quality. These results provide new information regarding the beneficial effects of let-7a replacement against chemotherapy-induced ovarian damage and open new perspectives for future in vivo applications., (© 2022. The Author(s).)

Study Question: Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients?, Summary Answer: Performing COS before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS)., What Is Known Already: COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments., Study Design, Size, Duration: The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021., Participants/materials, Setting, Methods: To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale., Main Results and the Role of Chance: A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11)., Limitations, Reasons for Caution: This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences., Wider Implications of the Findings: Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy., Study Funding/competing Interest(s): Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 × 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication., Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood., Objective and Rationale: To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review., Search Methods: A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up., Outcomes: Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients., Wider Implications: AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below -190°C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series., Objective and Rationale: The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen-thawed transplant, fresh or donor graft., Search Methods: The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model., Outcomes: The review included 87 studies (735 women). Twenty studies reported on ≥5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32-43%) for pregnancy, 28% (95% CI: 24-34%) for live birth and 37% (95% CI: 30-46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9-155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4-729; mean difference: 228.24; 95% CI: 180.5-276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8-84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9-17.3; mean difference 61.8; 95% CI: 57-66.6). The median time to return of FSH to a value <25 IU/l was 19 weeks (interquartile range: 15-26 weeks; range: 0.4-208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4-3.4 years; range: 0.7-5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes., Wider Implications: Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Ovarian stimulation for oocyte and embryo cryopreservation is the standard of care for fertility preservation in young breast cancer patients before gonadotoxic chemotherapy. The procedure should be started as soon as possible to avoid delay of treatment; thus, it is often performed concomitantly with tumor staging assessments. However, questions remain regarding the potential negative impact on oocyte quality that may occur due to exposure to scattered ionizing radiation from imaging techniques when staging assessment is conducted at the same time as ovarian stimulation., Methods: We conducted a retrospective study on all breast cancer patients who performed ovarian stimulation for fertility preservation at our center between November 2012 and May 2020., Results: Gynecologic and oncological characteristics were similar between patients exposed (n = 14) or not (n = 60) to ionizing radiation. Exposed patients started the ovarian stimulation sooner after diagnosis than non-exposed patients (11.5 vs 28 days, respectively, P < 0.01). Cycle parameters, including the median number of oocytes collected (10.5 vs 7, P = 0.16), maturation rates (92.5% vs 85.7%, P = 0.54), and fertilization rates (62.2% vs 65.4%, P = 0.70), were similar between groups., Conclusion: This study shows that scattered ionizing radiation due to staging assessment appears to be safe without compromising follicular growth and maturation. Larger studies on fertility and obstetrical outcomes are needed to confirm these preliminary data., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To report the case of a young woman diagnosed with Turner syndrome (TS) who achieved a live birth using her own oocytes that had been vitrified for fertility preservation., Methods: A 25-year-old woman with mosaic (45,X/46,XX) TS was referred for fertility preservation (FP) counseling. Serum anti-Müllerian hormone (AMH) level was normal (6.4 µg/L). In view of the unpredictable rate of follicle loss in TS individuals, she requested FP and underwent two cycles of ovarian stimulation (OS) for oocyte cryopreservation (OoC) using a GnRH antagonist protocol and recombinant follicle stimulating hormone (rFSH), 200-250 IU daily for 8 resp. 12 days., Results: In total, 29 metaphase II oocytes (MII) were vitrified after OS. After conceiving spontaneously and achieving a live birth, she returned to the clinic five years after OoC with a desire for pregnancy using in vitro fertilization (IVF) of her cryopreserved oocytes and preimplantation genetic testing (PGT-A). All 29 MII oocytes were thawed; 23 oocytes survived (79.3%) and were inseminated with partner sperm using intracytoplasmic sperm injection (ICSI). Thirteen oocytes were fertilized resulting in three good quality blastocysts which were vitrified after trophectoderm biopsy for PGT-A using array-CGH. Two blastocysts were found to be euploid. One was thawed and transferred to the uterus using a HRT priming protocol. An uneventful pregnancy occurred. The patient delivered a healthy baby girl weighing 3490 g at 40 weeks of gestation., Conclusions: We report the first live birth achieved using cryopreserved oocytes in a woman diagnosed with mosaic TS. Cryopreservation of oocytes after ovarian stimulation is a realistic option for FP in selected post menarche individuals with mosaic TS. Whether PGT-A may reduce the risk of pregnancy loss in TS has to be confirmed by further studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk., (© 2022. The Author(s).)

Study Question: Can severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA be detected in the reproductive tract of asymptomatic patients undergoing ART?, Summary Answer: SARS-CoV-2 mRNA is not detectable in semen, follicular fluid, vaginal secretions or residual medulla from ovarian tissue cryopreservation procedures in asymptomatic patients who undergo ART, irrespective of the results of a triage questionnaire and a nasopharyngeal SARS-CoV-2 RNA detection test., What Is Known Already: The SARS-CoV-2 pandemic had a huge impact on the activities of fertility clinics. Although some studies reported the presence of SARS-CoV-2 mRNA in the reproductive system during or after acute COVID-19 symptomatic infections, uncertainties remain regarding the presence of viral mRNA in the reproductive material and follicular fluid of asymptomatic patients undergoing ART., Study Design, Size, Duration: An observational cohort trial of residual material samples including semen, follicular fluid, vaginal secretions and ovarian medulla was conducted during the second pandemic wave in Brussels from September 2020 to April 2021., Participants/materials, Setting, Methods: All patients who underwent ART (IUI, IVF/ICSI, oocyte and ovarian tissue cryopreservation) responded to a triage questionnaire at the beginning and end of the cycle and underwent nasopharyngeal swab collection for SARS-CoV-2 RNA detection by RT-PCR before the procedure according to standard recommendations. For semen analysis, only the questionnaire was requested the day before the sample collection. The ART cycles of patients with positive nasopharyngeal SARS-CoV-2 RNA detection tests and/or questionnaires were cancelled except for those that could not be postponed. After providing informed consent, swabs on residual materials were collected the day of the oocyte, ovarian tissue or semen collection and were processed for RT-qPCR., Main Results and the Role of Chance: A total of 394 samples from 291 patients were analysed. Amongst them, 20 samples were obtained from patients with a positive questionnaire but negative nasopharyngeal SARS-CoV-2 test and 20 others were from patients with a positive nasopharyngeal SARS-CoV-2 test. The remaining samples were collected from patients with a negative or unknown nasopharyngeal SARS-CoV-2 test and/or a negative or unknown triage questionnaire. Viral RNA for SARS-CoV-2 was undetectable in all of the samples., Limitations, Reasons for Caution: Considering the cancellation policy, only a limited number of samples from patients with positive triage questionnaires or nasopharyngeal SARS-CoV-2 tests were included in the analysis., Wider Implications of the Findings: The study suggested that there was no risk of reproductive tract contamination by SARS-CoV-2 in asymptomatic patients, irrespective of the results from a triage questionnaire or nasopharyngeal SARS-CoV-2 test. The results suggested that no additional measures to prevent staff or cross-patient contamination need to be implemented in the IVF and andrology laboratories., Study Funding/competing Interest(s): This study was funded by the Université Libre de Bruxelles and by a grant from Ferring. A.D. and I.D. received a grant from Ferring for the study. The authors have no other conflict of interest to declare related to this study., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants., Patients and Methods: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy., Results: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group., Conclusion: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing., Competing Interests: Disclosure EdA has acted as a scientific advisory board member and has received honoraria from Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; has received travel grants from Roche/GNE and GlaxoSmithKline (GSK)/Novartis; and has received research grants through his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier, outside the submitted work. FAP has acted as consultant for Ipsen, Roche Diagnostic, and Merck outside the submitted work. CRJ has acted as a scientific advisory board member and her institution has received honoraria from Bristol Myers Squibb (BMS), Theramex, and Roche; and her institution has received speaker's fees from Theramex and BMS, outside the submitted work. AS has acted as a consultant for Eli Lilly, Pfizer, Novartis, and Roche; has received speaker's fees from Teva, Roche, Pfizer, and Novartis; has received travel grants from Neopharm, Celgene, and Medison; and has received grant support from Novartis and Roche, outside the submitted work. CVG has acted as a consultant, as a scientific advisory board member, and has received speaker's fees from Roche, Novartis, Pfizer, Lilly, and Merck Sharp & Dohme (MSD); and has received research funding from AstraZeneca, Roche, and Pfizer, outside the submitted work. OCC has acted as a scientific advisory board member for Ascires Sistemas Genómicos; and has received grant support from Roche Diagnostics, Neomedic, and Takeda, outside the submitted work. KP has acted as a scientific advisory board member for AstraZeneca, Eli Lilly, Gilead Sciences, MSD, Novartis, Pierre Fabre, Roche, Teva, and Vifor Pharma; has acted as a consultant for AstraZeneca, Novartis, Pfizer, and Roche; has received speaker's fees from Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer, and Roche; has received travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche, outside the submitted work. FP has acted as a scientific advisory board member and has received speaker's fees from Amgen, AstraZeneca, Daichi-Sankyo, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, and Takeda; has received travel grants from Celgene, GlaxoSmithKline, and Roche; and has received research funding from AstraZeneca, Eisai, and Roche, outside the submitted work. ARF has received honoraria from Bayer, Daiichi Sankyo, Novartis, and Roche; and has received travel grants from Roche, outside the submitted work. JB has acted as consultant for AstraZeneca and Pfizer outside the submitted work. ID has acted as a scientific advisory board member and received grant from Roche; has received speaker's fees from Novartis; and has received travel grants from Theramex and Ferring, outside the submitted work. ML has acted as a consultant for Roche, Lilly, AstraZeneca, Exact Sciences, and Novartis; and has received honoraria from Sandoz, Roche, Lilly, Pfizer, Novartis, Ipsen, and Takeda, outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP escalated ) in early responders on the basis of a positron emission tomography (PET)-driven strategy was safe and minimized toxicity compared with standard 6 BEACOPP escalated cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old., Methods: Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up., Results: A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; P = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, P = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPP escalated group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; P < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; P = .004)., Conclusion: Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma., Competing Interests: Isabelle DemeestereConsulting or Advisory Role: RocheResearch Funding: Roche diagnosisTravel, Accommodations, Expenses: Ferring Jehan DupuisConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: Gilead Sciences Franck MorschhauserConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Celgene, Bristol Myers Squibb, AbbVie, Epizyme, ServierSpeakers' Bureau: RocheExpert Testimony: Roche/Genentech Virginie De WildeConsulting or Advisory Role: Takeda, Janssen Oncology Julien LazaroviciTravel, Accommodations, Expenses: Roche, Novartis, Sandoz, Janssen-Cilag, Jazz Pharmaceuticals France, Daiichi Sankyo Oncology France, Mundipharma, Pfizer, AbbVie Hervé GhesquieresHonoraria: Gilead Sciences, Janssen, Celgene, RocheConsulting or Advisory Role: Gilead Sciences, Celgene, Roche, MundipharmaTravel, Accommodations, Expenses: Roche, Gilead Sciences, Celgene, Takeda Mohamed TouatiHonoraria: AmgenConsulting or Advisory Role: Janssen, Bristol Myers Squibb/Celgene David SibonConsulting or Advisory Role: Takeda, Iqone healthcare, Janssen, RocheTravel, Accommodations, Expenses: Takeda, Janssen Luc-Matthieu ForneckerConsulting or Advisory Role: Takeda, RocheTravel, Accommodations, Expenses: Takeda, Roche Marc AndréConsulting or Advisory Role: Takeda, BMSiResearch Funding: Takeda, RocheTravel, Accommodations, Expenses: Roche, Celgene, Gilead Sciences René-Olivier CasasnovasHonoraria: Roche/Genentech, Takeda, Gilead Sciences, Bristol Myers Squibb, Merck, AbbVie, Celgene, Janssen, AmgenConsulting or Advisory Role: Roche/Genentech, Takeda, Gilead Sciences, Bristol Myers Squibb, Merck, AbbVie, Celgene, Janssen, IncyteResearch Funding: Roche/Genentech, Gilead Sciences, TakedaTravel, Accommodations, Expenses: Roche/Genentech, Takeda, Gilead Sciences, JanssenNo other potential conflicts of interest were reported.