Cryptotanshinone reverses reproductive and metabolic disturbances in prenatally androgenized rats via regulation of ovarian signaling mechanisms and androgen synthesis

Abstract

This trial explores 1) prenatally androgenized (PNA) rats as a model of polycystic ovary syndrome (PCOS) and 2) reproductive and metabolic effects of cryptotanshinone in PNA ovaries. On days 16– 18 of pregnancy, 10 rats were injected with testosterone propionate (PNA mothers) and 10 with sesame oil (control mothers). At age 3 mo, 12 female offspring from each group were randomly assigned to receive saline and 12 cryptotanshinone treatment during 2 wk. Before treatment, compared with the 24 controls, the 24 PNA rats had 1) disrupted estrous cycles, 2) higher 17-hydroxyprogesterone ( P = 0.030), androstenedione ( P = 0.016), testosterone and insulin ( P values = 0.000), and glucose ( P = 0.047) levels, and 3) higher areas under the curve (AUC) for glucose (AUC-Glu, P = 0.025) and homeostatic model assessment for insulin resistance (HOMA-IR, P = 0.008). After treatment, compared with vehicle-treated PNA rats, cryptotanshinone-treated PNA rats had 1) improved estrous cycles ( P = 0.045), 2) reduced 17-hydroxyprogesterone ( P = 0.041), androstenedione ( P = 0.038), testosterone ( P = 0.003), glucose ( P = 0.036), and insulin ( P = 0.041) levels, and 3) lower AUC-Glu ( P = 0.045) and HOMA-IR ( P = 0.024). Western blot showed that cryptotanshinone reversed the altered protein expressions of insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase p85α, glucose transporter-4, ERK-1, and 17α-hydroxylase within PNA ovaries. We conclude that PNA model rats exhibit reproductive and metabolic phenotypes of human PCOS and that regulation of key molecules in insulin signaling and androgen synthesis within PNA ovaries may explain cryptotanshinone's therapeutic effects.