1675-P: Reproductive and Intergenerational Impacts of Metformin Free

Recent data suggest that metformin can influence male reproductive health, directly or indirectly. Lastly, an epidemiologic cohort study demonstrated an association between preconceptional use of metformin in men and genital birthdefects in their offsprings. Given the need to test these associations in the absence of complex genetic and environmental factors in humans, we assessed the impact of metformin on both male reproductive health and health of offspring in C57/BL6J mice. Male mice age 8 weeks were treated with low fat (10% fat) or high fat (60% fat) diet to induce obesity; after two weeks, mice were randomized to continued dietary treatment, with or without metformin 350 mg/kg/day (n=8/group). After 12 weeks of treatment, metabolic status was assessed by glucose and insulin tolerance tests; as expected, metformin improved insulin sensitivity (21% improvement vs. HFD, p=0.008) despite no significant difference in body weight or glucose tolerance. To determine effect of male metformin treatment on reproductive success, HFD and HFD-MET males were bred with 6-8 week old females. Breeding was successful for 87.5% of HFD males, as compared with 37.5% for HFD-MET males (P=0.038). In both groups, insulin resistance (HOMA-IR) was strongly correlated with body weight (HFD: r=0.86, P=0.006; HFD-MET: r=0.92, P=0.001). However insulin resistance was inversely correlated with successful pregnancy rates only in HFD-MET mice (HFD: r=-0.3, P=0.21; HFD-MET: r=-0.68, P=0.04), suggesting that insulin sensitivity is a stronger and more significant determinant of fertility in metformin treated mice. Thus, we hypothesize that metformin may have dual impact on male reproductive health, with both beneficial increases in insulin sensitivity and potential adverse impact to reduce fertility. Additional studies are in progress to determine impact of male metformin treatment on hormonal and germ cell aspects of male reproductive health and offspring developmental phenotypes.