Expression of key steroidogenic genes and the role of androgens in the development of ovarian tumors in hCG transgenic mice

BETINA GONZALEZ; MATTI POUTANEN; ILPO HUHTANIEMI; RICARDO S. CALANDRA; SUSANA B. RULLI

Rio de Janeiro, Brasil

Congreso; International Congress of Endocrinology (ICE); 2008

International Society of Endocrinology

Chronic hypersecretion of human chorionic gonadotropin (hCG) induces the production of elevated levels of steroids and the development of ovarian teratomas in transgenic (TG) mice. These tumors originate from spontaneously activated oocytes within the ovary, are composed of disorganized tissues derived from embryonic and extraembryonic cells, and appear between the 6th and 8th week of age. The aims of our study were: a) to analyze the expression of key genes involved in steroidogenesis (cyp11a1, cyp19 and cyp17) at different stages of tumor development (2- to 6-week-old TG mice) by semi quantitative RT-PCR and immunohistochemistry for cyp11a1, b) to evaluate the influence of androgens in the ovarian phenotype by treating TG mice with the antiandrogen flutamide (s.c. implants of 20 mg, from 9 day-old to 4 or 6 week-old mice). At 2-week-old the TG ovaries showed higher expression of cyp11a1 mRNA, with positive immunolabeling in theca cells. At 3-week-old the TG ovaries presented with an increased expression of cyp11a1 and cyp19 mRNA; the immunolocalization of cyp11a1 showed a stronger mark in theca cells and the presence of early luteinized areas, absent in the wt ovary. At 4-week-old the TG ovary appeared highly atretic, with follicular cysts, many hemorrhagic; no significant changes in gene expression were detected. At this age, the treatment with flutamide induced a decrease in the ovary weight (p<0.01) and reduced the number of hemorrhagic cysts (p<0.01). At 6-week-old the TG ovary appeared highly luteinized, with sites of thophoblast invasion as a first sign of oocyte activation, increased expression of cyp11a1 mRNA, with positive immunolabeling in the luteinized cells. The treatment with flutamide at this age showed a decrease in the ovary weight (p<0.05) and reduced hemorraghic areas at the sites of trophoblast invasion. In summary, chronic hypersecretion of hCG induced premature steroidogenic activity of the ovary, associated with evident hemorrhage as the tumor progressed. The treament with flutamide was able to reduce hemorrhage but not prevent ovarian tumor development in TG mice overexpressing hCG.