Impaired reproductive function and fertility preservation in a woman with a dyskeratosis congenita
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FERTILITY PRESERVATION
Impaired reproductive function and fertility preservation in a woman with a dyskeratosis congenita LeRoy G. Robinson Jr 1 & Ricardo Pimentel 1 & Fang Wang 1 & Yael G. Kramer 2 & Damla C. Gonullu 1 & Suneet Agarwal 3 & Paula A. Navarro 4 & David McCulloh 2 & David L. Keefe 1,2 Received: 6 December 2019 / Accepted: 20 March 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose To determine the impact of accelerated telomere shortening on the fertility parameters and treatment outcomes of a woman with dyskeratosis congenita (DKC). Methods A case study of the clinical data, blood, discarded oocytes, and arrested embryos of a woman with DKC and donated cryopreserved embryos from unaffected patients. Mean telomere length in blood cells was analyzed by flow cytometry– fluorescence in situ hybridization (flow-FISH) and qPCR. The load of short telomeres in blood cells was measured by universal single telomere length analysis (Universal STELA). The mean telomere length in embryos was analyzed by single-cell amplification of telomere repeats (SCATR) PCR. Results Comparison of clinical parameters revealed that the DKC patient had reduced anti-Mullerian hormone (0.3 vs 4.1 ± 5.7 ng/ML), reduced oocytes retrieved (7 vs 18.5 ± 9.5), reduced fertilization rate, and reduced euploidy rate relative to unaffected patients. Additionally, mean telomere length in DKC embryos were shorter than unaffected embryos. However, hormone treatment led to increased leukocyte telomere length, while the load of short telomeres was also shown to decrease during the course of treatment. Conclusions We demonstrate for the first time the direct detrimental impacts of short telomeres on female fertility. We further demonstrate positive effects of hormone treatments for people with telomere disorders. Keywords Female reproductive aging . Telomeres . Oocytes . Dyskeratosis congenita
Introduction Telomeres are repetitive DNA sequences, (TTAGGG) n, that work in concert with the protein complex known as shelterin to protect chromosome ends [1]. Telomeres are maintained primarily by the enzyme, telomerase. Telomerase activity is absent in most adult cells in humans, leading to progressive
* David L. Keefe [email protected] 1
Department of Obstetrics and Gynecology, New York University Langone Health, 550 First Avenue, NBV-9N1A, New York, NY 10016, USA
2
New York University Langone Fertility Center, New York, NY, USA
3
Children’s Hospital, Boston, MA, USA
4
Department of Obstetrics and Gynecology, University of Sao Paulo, Ribeirao Preto, Brazil
telomere shortening over time in tissues which lack a stem cell compartment [2–4]. Germline stem cells in females are lost by about 20 weeks of fetal development. Thus, the adult female germline lacks appreciable telomerase activity [5, 6]. In contrast, the male maintains a germline stem cell population with robust telomerase activity throughout his lifespan. Oocyte attrition, embryo developmental arrest, and miscarriage increase with advancing m
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