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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.
The online version of this article Heritability and twin studies have identified a strong genetic component that is likely polygenic [ 2 — 4 ]. Recent genome-wide association studies have reported multiple susceptibility loci associated with an increased risk of developing PCOS [ 5 ].
Environmental factors, such as prenatal exposure to androgens may also play a role in the etiology of PCOS [ 6 ]. Currently, diagnosis is made using the Rotterdam Consensus criteria , which require at least two of the following: hyperandrogenism, oligo- or amenorrhea and polycystic ovaries [ 1 ]. Studies have shown that women with PCOS often suffer from profound, long-term health issues [ 7 ]. PCOS is the leading cause of anovulatory infertility in women and increases the likelihood of miscarriage and pregnancy complications [ 8 , 9 ].