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Letrozole treatment of adult female mice results in a similar reproductive
phenotype but distinct changes in metabolism and the gut microbiome compared to
Torres PJ, Skarra DV, Ho BS, Sau L, Anvar AR, Kelley ST, Thackray VG
Submitted Externally on 4/8/2019
Volume : Pages
19 : 57
A majority of women with polycystic ovary syndrome (PCOS) have metabolic
dysfunction that results in an increased risk of type 2 diabetes. We previously
developed a pubertal mouse model using the aromatase inhibitor, letrozole, which
recapitulates many of the reproductive and metabolic features of PCOS. To
further our understanding of the effects of androgen excess, we compared the
effects of letrozole treatment initiated in puberty versus adulthood on
reproductive and metabolic phenotypes as well as on the gut microbiome.,
Letrozole treatment of both pubertal and adult female mice resulted in
reproductive hallmarks of PCOS, including hyperandrogenemia, anovulation and
polycystic ovaries. However, unlike pubertal mice, treatment of adult female
mice resulted in modest weight gain and abdominal adiposity, minimal elevation
in fasting blood glucose and insulin levels, and no detectable insulin
resistance. In addition, letrozole treatment of adult mice was associated with a
distinct shift in gut microbial diversity compared to letrozole treatment of
pubertal mice., Our results indicate that dysregulation of metabolism and the
gut microbiome in PCOS may be influenced by the timing of androgen exposure. In
addition, the minimal weight gain and lack of insulin resistance in adult female
mice after letrozole treatment indicates that this model may be useful for
investigating the effects of hyperandrogenemia on the
hypothalamic-pituitary-gonadal axis and the periphery without the influence of
substantial metabolic dysregulation.
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