Genetic contributions of the endothelial nitric oxide synthase gene to ovulation and menopause in a mouse model

Objective: To investigate the influence of the endothelial nitric oxide syn thase gene (Nos3) on ovulatory capacity and reproductive senescence. Design: Prospective, controlled study. Setting: Academic research institution. Subject(s): Laboratory mice with targeted mutagenesis of Nos3. Intervention(s): Hyperstimulation protocol, oocyte culture, and ovarian his tology using wild-type (Nos3(+/+) n = 20), heterozygous (Nos3(+/m); n = 39) , and homozygous deficient (Nos3(m/m); n = 11) female mice; observation of reproductive outcomes. Main Outcome Measure(s): Number and survival of oocytes; onset of menarche and menopause. Result(s): The mean number of superovulated oocytes (18 +/- 36 vs. 41 +/- 4 ) and the 48-hour overall survival rate of embryos (65% vs. 81%) were signi ficantly reduced for Nos3(m/m) female mice compared with Nos3(+/+) female m ice. Nos3(m/m) females showed a significantly reduced number and size of an tral follicles and corpora lutea compared with wild-type controls. Compared with Nos3(+/m) x Nos3(+/m) breedings, Nos3(m/m) x Nos3(m/m) breedings show ed a higher female age at first litter(76.2 +/- 10.3 vs. 107.8 +/- 26.6 day s), fewer litters(l0.5 +/- 3.6 vs. 7.8 +/- 4.2), and a lower female age at reproductive senescence (400.2 +/- 64.5 vs. 332.1 +/- 27.4 days), respectiv ely. Conclusion(s): Our data suggest that Nos3 deficiency is associated with red uced ovulatory capacity and impaired early embryonic viability and that it influences the onset of menarche and menopause. (Fertil Steril(R) 2000;73:1 025-31. (C) 2000 by American Society for Reproductive Medicine).