Diminished Ovarian Reserve Chemotherapy-Induced Mouse Model: A Tool for the Preclinical Assessment of New Therapies for
- PDF / 9,436,278 Bytes
- 11 Pages / 602.986 x 782.986 pts Page_size
- 62 Downloads / 223 Views
Diminished Ovarian Reserve Chemotherapy-Induced Mouse Model: A Tool for the Preclinical Assessment of New Therapies for Ovarian Damage
Reproductive Sciences 1-11 ª The Author(s) 2019 DOI: 10.1007/s43032-020-00191-w
Anna Buigues, BSc1,2, Maria Marchante, BSc1,2, Sonia Herraiz, PhD1,3,4, and Antonio Pellicer, MD1,3,5
Abstract Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are primary factors leading to infertility. However, there is a lack of appropriate animal models of DOR usable for assessing new therapeutic strategies. In this study, we aimed to evaluate whether chemotherapy treatment in mice could reproduce features similar of that observed in women with DOR. Twenty-one Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) female mice were allocated to 3 groups (n ¼ 7/group): control, single dose of vehicle (Dimethyl Sulfoxide [DMSO]); DOR, single reduced chemotherapy dose; and POI, single standard chemotherapy dose. After 21 days, mice underwent ovarian hyperstimulation and mating. Part of the animals were harvested to analyze ovarian reserve, ovulation and fertilization rates, and morphology, apoptosis, and vascularization of the ovarian stroma. The remaining mice underwent multiple matings to assess pregnancy rates and litter sizes. The DOR and POI mice showed an impaired estrous cyclicity and a decrease in ovarian mass, number of follicles, Metaphase II (MII) oocytes, and embryos as well as in ovarian stroma vascularization. Mice in both models showed also an increase in the percentage of morphologically abnormal follicles, stromal degeneration, and apoptosis. Similar to that observed in DOR and POI patients, these impairments were less severe in DOR than in POI mice. None of the POI females were able to achieve a pregnancy. Meanwhile, DOR females achieved several consecutive pregnancies, although litter size was decreased when compared to controls. In conclusion, a mouse model which displayed most of the ovarian characteristics and fertility outcomes of women with DOR has been established using a single dose of chemotherapy. Keywords diminished ovarian reserve, primary ovarian insufficiency, chemotherapy, mouse model, ovarian damage
Introduction Female infertility has increased in the recent decades. The primary factors leading to infertility are due to delayed childbearing, which is associated with reproductive aging and diminished ovarian reserve (DOR).1 Although research efforts into infertility have increased, identifying the physiological and molecular underpinnings of DOR remains challenging in humans. Further, there is a lack of appropriate, affordable, and reproducible animal models in which to assess new therapeutic strategies to increased their fertility. A DOR associates with poor fertility outcomes and occurs as women get older, since their ovarian reserve naturally declines with age.2 A DOR is distinct from primary ovarian insufficiency (POI), in which patients show amenorrhea and a complete loss of ovarian function before the age of 40 years. The POI repre
Data Loading...
