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 synthase 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 histology 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 significantly reduced for Nos3(m/m) female mice compared with Nos3(+/+) female mice. Nos3(m/m) females showed a significantly reduced number and size of antral 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 showed a higher female age at first litter (76.2 +/- 10.3 vs. 107.8 +/- 26.6 days), fewer litters (10.5 +/- 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), respectively.

CONCLUSION(S): Our data suggest that Nos3 deficiency is associated with reduced ovulatory capacity and impaired early embryonic viability and that it influences the onset of menarche and menopause.