Endocrine Abstracts

Research in the field of reproductive biology is largely based on informative mouse models. Almost all of these mouse models (~99%) exhibit an unfavourable reproductive phenotype - these mouse models are subfertile or infertile in one or possibly both sexes. In contrast, the number of animal models that show an enhanced reproductive phenotype is extremely rare. Nevertheless, these mouse models could be very informative in identifying mechanisms and pathways associated with enhanced fertility. We analyse two Dummerstorf outbred mouse lines that have been selected for high fertility for 200 generations (fertility lines 1 and 2; FL1, FL2). In both mouse lines, the number of offspring per litter almost doubled (from 11.5 (ctrl) to 20.6 (FL1) and 21.4 (FL2)), without the offspring showing any signs of growth retardation compared to animals from a non-selected control line. We analysed the lifetime fecundity of all three lines and found significant differences. Control and FL1 females gave birth to up to 10 litters, whereas FL2 only gave birth to a maximum of six litters per female per lifetime. In a first set of experiments, we analysed the ovarian phenotype of FL1 females. We noticed a reduced concentration of FSH, both on serum hormone levels (-60%) as well as in pituitary gene transcription (-90%). In line with this decreased FSH levels also hypothalamic GnRH transcription was decreased by 70% compared to ctrl. Gene expression analysis in ovaries revealed that multiple genes associated with follicular development, such as Lhcgr, Esr1, Kit or Foxl2 are differentially expressed in FL1 mice. Holistic gene expression analysis in ovarian granulosa cells further identified a differential regulation of multiple genes involved in follicular atresia. These data suggest that the phenotype of FL1 is at least partly due to attenuated follicular atresia leading to increased follicular survival. More successful folliculogenesis is in turn associated with higher ovulation rates (from 13 (ctrl) to 24 (FL1) oocytes per cycle). There is evidence that the complex interplay of endocrine and molecular changes leading to enhanced follicular development in FL1 females is associated with good reproductive longevity and health. Several genes associated with reproductive lifespan, such as Per2, Kl, Tex14 and Rora, are differentially expressed in the ovaries and granulosa cells of FL1 mice. These data suggest that the unique ovarian phenotype of FL1 females selected for high fertility provides valuable approaches for the search for molecular mechanisms predisposing to increased fertility.