Endocrine Abstracts

Continuous administration of 400 μg/day of letrozole (LET), a non-steroidal inhibitor of P450 aromatase, with start pre-pubertally to female rats, induces hyperandrogenemia and reproductive abnormalities similar to those observed in women with polycystic ovary syndrome (PCOS). However, these rats do not develop metabolic abnormalities, despite high circulating testosterone. A possible explanation may be that the dose was too high and thus completely inhibited the estrogen synthesis in insulin-sensitive tissues. Therefore, lower doses of LET may induce not only reproductive disturbances, but also metabolic abnormalities. Here, we present a dose-response study with continuous administration of three different doses of LET during 12 weeks and their effects on metabolic and reproductive variables. At 21 days of age, 61 female Wistar rats were divided into four groups: LET1: 83 μg/day; LET2: 100 μg/day; LET3: 200 μg/day or control: placebo. The body weight development and food intake (FI) were registered. Respiratory exchange ratio (RER) during 24-h was determined by indirect calorimetry and body composition by dual-emission X-ray absorptiometry. Blood samples were taken for analysis of sex steroids. Insulin sensitivity (IS) was evaluated by euglycemic-hyperinsulinemic clamp. All LET-groups were acyclic and gained more in body weight compared with control (P<0.001). Body fat and lean body mass in relation to body weight, FI and RER were comparable between groups. Testosterone concentration was higher in LET-groups after five (P<0.001) and 10 weeks (P<0.001) of LET-exposure, compared to control. The IS index was lower in all LET-groups compared to controls (P<0.001) and the mean adipose size in inguinal and mesenteric depot was higher in LET3 compared to controls (P<0.01). These results highlight the importance of the dose of LET for development of metabolic abnormalities. The LET doses applied in this study may be used to develop a rat PCOS model including both reproductive and metabolic abnormalities.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.