Effects of Metformin and Letrozole on uterus in a rat model of Polycystic Ovary

Abstract

Polycystic ovary syndrome (PCO) is a complex endocrine disorder associated with hyperandrogenism, anovulation and infertility. The chronic estrogen exposure due to ovarian dysfunction can result in endometrial carcinoma. Letrozole (Let) and metformin (Met) are used for ovulation induction in women with PCO but their effects on endometrium have not been elucidated. In this work, we investigate whether Met and Let (non-steroid aromatase inhibitor) affect the P450 aromatase (P450arom) mRNA expression in uterus of PCO rats and, if this is associated with changes in estradiol (E2) and nitric oxide (NO) release. We used a rat model of PCO induced by estradiol valerate (2mg/rat). Uterus (Ut) from PCO rat were incubated for 3 h in metabolic bath with: RPMI medium (basal), Let (104M), androstenedione (106M), Let plus androstenedione (106M) or Let plus Met (103M). The E2 release was measured by RIA, NO (as nitrites) by Griess reaction and gene expression of P450arom by RT-PCR. PCO-Ut released more E2 and expressed higher P450arom (p<0.05) than Control-Ut. Androstenedione increased E2 and NO release and P450arom expression compared to PCO-Ut in basal conditions (p<0.05). This effect was reversed in Let plus androstenedione (p<0.01). In PCO-Ut incubated with Let plus Met, the P450arom expression decrease together less E2 and NO release, compared to basal values (p<0.01). These results suggest that Met and Let induce a down-regulation on P450arom expression and reduce the local generation of E2 and NO. Also, Met and Let can improve the negative effects caused by androgens in PCO endometrium.