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Consequences of β-Thalassemia or Sickle Cell Disease for Ovarian Follicle Number and Morphology in Girls Who Had Ovarian Tissue Cryopreserved.

ABSTRACT: Women with β-thalassemia (BT) and sickle cell disease (SCD) have a high risk of infertility and premature ovarian insufficiency. Different fertility preserving strategies, including ovarian tissue cryopreservation (OTC) and oocyte cryopreservation has been considered, and healthy babies have been born after successful OTC and transplantation. We evaluated follicle number and follicle health in ovarian tissue from a cohort of BT and SCD patients who underwent OTC before the age of 18 years. Patients undergoing OTC from 2002 to 2019 were included. A total of 14 girls and adolescents with BT and four with SCD, aged 2.8-17.4 years at OTC were included together with a reference group of 43 girls and adolescents with non-anemia diseases considered to have normal ovaries aged 0.6-17.9 years at OTC. Ovarian follicle density was measured in cortex biopsies and compared to the reference group. Expression of proteins associated with follicular health was evaluated using immunohistochemistry. Follicles were detected in the ovarian cortex biopsies from all patients with BT and SCD. The follicle densities were within the 95% prediction interval of the reference group in all cases. A similar expression of six proteins essential for follicular health was detected using immunohistochemistry in BT, SCD, and references. OTC should be considered an option for young girls and adolescents with BT and SCD.

SUBMITTER: Mamsen LS

PROVIDER: S-EPMC7844814 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Consequences of <i>β</i>-Thalassemia or Sickle Cell Disease for Ovarian Follicle Number and Morphology in Girls Who Had Ovarian Tissue Cryopreserved.

Mamsen Linn Salto LS Kristensen Stine Gry SG Pors Susanne Elisabeth SE Bøtkjær Jane Alrø JA Ernst Erik E Macklon Kirsten Tryde KT Gook Debra D Kumar Ajay A Kalra Bhanu B Andersen Claus Yding CY

Frontiers in endocrinology 20210115

Women with <i>β</i>-thalassemia (BT) and sickle cell disease (SCD) have a high risk of infertility and premature ovarian insufficiency. Different fertility preserving strategies, including ovarian tissue cryopreservation (OTC) and oocyte cryopreservation has been considered, and healthy babies have been born after successful OTC and transplantation. We evaluated follicle number and follicle health in ovarian tissue from a cohort of BT and SCD patients who underwent OTC before the age of 18 years ...[more]

PMID: 33519708

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Project description:Study questionDoes first-line chemotherapy affect the quality of ovarian pre-antral follicles and stromal tissue in a population of young patients?Summary answerExposure to first-line chemotherapy significantly impacts follicle viability, size of residual intact follicles, steroid secretion in culture and quality of the stromal compartment.What is known alreadyFirst-line chemotherapy is considered to have a low gonadotoxic potential, and as such, does not represent an indication for fertility preservation. Studies investigating the effects of chemotherapy on the quality of ovarian tissue stored for fertility preservation in young patients are limited and the results sometimes contradictory.Study design, size, durationWe conducted a retrospective cohort study including young patients referred to three centers (Helsinki, Oslo and Tampere) to perform ovarian tissue cryopreservation for fertility preservation between 2003 and 2018.Participants/materials, setting, methodsA total of 43 patients (age 1-24 years) were included in the study. A total of 25 were exposed to first-line chemotherapy before cryopreservation, whereas 18 patients were not. Density and size of follicles divided by developmental stages, prevalence of atretic follicles, health of the stromal compartment and functionality of the tissue in culture were evaluated and related to age and chemotherapy exposure. Activation of dormant follicles and DNA damage were also assessed.Main results and the role of chancePatients exposed to first-line chemotherapy showed a significantly higher density of atretic primordial and intermediary follicles than untreated patients. The intact primordial and intermediary follicles were significantly smaller in size in patients exposed to chemotherapy. Production of steroids in culture was also significantly impaired and a higher content of collagen and DNA damage was observed in the stromal compartment of treated patients. Collectively, these observations may indicate reduced quality and developmental capacity of follicles as a consequence of first-line chemotherapy exposure. Neither increased activation of dormant follicles nor elevated levels of DNA damage in oocyte nuclei were found in patients exposed to chemotherapy.Limitations, reasons for cautionThe two groups were not homogeneous in terms of age and the patients were exposed to different treatments, which did not allow us to distinguish the effect of specific agents. The limited material availability did not allow us to perform all the analyses on the entire set of patients.Wider implication of the findingsThis study provides for the first time a comprehensive analysis of the effects of first-line chemotherapy on the health, density and functionality of follicles categorized according to the developmental stage in patients under 24 years of age. When exposed to these treatments, patients were considered at low/medium risk of infertility. Our data suggest a profound impact of these relatively safe therapies on ovarian health and encourages further exploration of this effect in follow-up studies in order to optimize fertility preservation for young cancer patients.Study funding/competing interest(s)This study was funded by the Swedish Childhood Cancer Foundation, the Finnish Cancer Society, the Finnish Pediatric Research Foundation, the Väre Foundation for Pediatric Cancer Research, The Swedish Research Council, the Stockholm County Council (ALF project) and Karolinska Institutet. The authors have no conflict of interest to declare.

Project description:ObjectiveOvarian tissue cryopreservation is one of the crucial options for fertility preservation. Transplantation of cryopreserved ovarian tissue was proven to restore ovarian endocrine function in patients with premature ovarian insufficiency. Ovaries from deceased donors potentially serve as an excellent and readily available tissue for the translational and basic research. In this study, we used ovaries obtained from 5 deceased donors aged 18-26 years, to evaluate the number and quality of ovarian follicles isolated before and after cryopreservation.DesignPreclinical.SettingAcademic biomedical research laboratory.PatientsDe-identified deceased human donors.InterventionsSlow-freeze cryopreservation and thawing.Main outcome measuresFollicle count, follicle density, follicle viability using immunohistochemical staining (TUNEL).ResultsThe follicle density negatively correlated with age in both cryopreserved/thawed and fresh group. A total of 2803 follicles from fresh and 1608 follicles from cryopreserved tissues were classified and analyzed using Hematoxylin and eosin staining. There was no significant difference in the percent of morphologically normal follicles between two groups. TUNEL assay indicated no higher DNA damage in the follicles and the stroma cells after cryopreservation. Morphologically normal preantral follicles were enzymatically isolated from both fresh and cryopreserved tissue with 88.51 ± 5.93% (mean ± SD) of the isolated follicles confirmed viable using LIVE/DEAD evaluation.ConclusionsOur results indicate the ovarian tissue from deceased donors maintain high quality after long time extracorporeal circulation and transportation from the hospital to the laboratory. High survival rate of follicles at different developmental stages suggested tolerance to the cryopreservation process. Human ovarian tissues obtained from deceased donors is an ample source tissue and can be applied to promoting research and future clinical applications.

Project description:BackgroundWe have shown recently that maternal undernutrition (UN) advanced female pubertal onset in a manner that is dependent upon the timing of UN. The long-term consequence of this accelerated puberty on ovarian function is unknown. Recent findings suggest that oxidative stress may be one mechanism whereby early life events impact on later physiological functioning. Therefore, using an established rodent model of maternal UN at critical windows of development, we examined maternal UN-induced changes in offspring ovarian function and determined whether these changes were underpinned by ovarian oxidative stress.Methodology/principal findingsOur study is the first to show that maternal UN significantly reduced primordial and secondary follicle number in offspring in a manner that was dependent upon the timing of maternal UN. Specifically, a reduction in these early stage follicles was observed in offspring born to mothers undernourished throughout both pregnancy and lactation. Additionally, antral follicle number was reduced in offspring born to all mothers that were UN regardless of whether the period of UN was restricted to pregnancy or lactation or both. These reductions were associated with decreased mRNA levels of genes critical for follicle maturation and ovulation. Increased ovarian protein carbonyls were observed in offspring born to mothers UN during pregnancy and/or lactation and this was associated with peroxiredoxin 3 hyperoxidation and reduced mRNA levels; suggesting compromised antioxidant defence. This was not observed in offspring of mothers UN during lactation alone.ConclusionsWe propose that maternal UN, particularly at a time-point that includes pregnancy, results in reduced offspring ovarian follicle numbers and mRNA levels of regulatory genes and may be mediated by increased ovarian oxidative stress coupled with a decreased ability to repair the resultant oxidative damage. Together these data are suggestive of maternal UN potentially contributing to premature ovarian ageing in offspring.

Dataset Information

Consequences of β-Thalassemia or Sickle Cell Disease for Ovarian Follicle Number and Morphology in Girls Who Had Ovarian Tissue Cryopreserved.

Publications

Consequences of <i>β</i>-Thalassemia or Sickle Cell Disease for Ovarian Follicle Number and Morphology in Girls Who Had Ovarian Tissue Cryopreserved.

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