Morphological and immunohistochemical analysis in ovaries and fallopian tubes of tamoxifen, letrozole and clomiphene-treated rats.

PURPOSE: Ovarian and tubal dysplasia may be precursors to ovarian cancer. The goal of this study was to check whether these histopathological lesions would be found after ovulation induction using tamoxifen, clomiphene citrate and letrozole. METHODS: Seventy-two rats were divided into four groups. In the first group, 24 rats received normal saline. The second group (16 rats) received clomiphene citrate for six cycles. The third group, divided into two sub-groups of eight rats each, were stimulated with tamoxifen for six cycles, with a dosage, respectively, of 0.4 and 0.8 mg/kg/day. In the last group, eight rats received letrozole 0.1 mg/kg/day and eight other rats received letrozole 0.5 mg/kg/day, for six cycles. Once the six cycles had been completed the rats were killed in order to remove ovaries and tubes for histopathological analysis (morphological, p53 and Ki67 immunohistochemical assessment). RESULTS: Histopathological lesions were found in both ovaries and tubes. The mean ovarian dysplasia score was significantly higher in the tamoxifen group whatever the dosage (p = 0.006 and 0.0002) and in the letrozole group with 0.5 mg/kg/day (p = 0.0002) compared with the control group. The mean tubal dysplasia score was significantly higher in all groups that received drug treatment compared with the control group, whatever the dosage used. The proliferation index (Ki67) was significantly higher in the tamoxifen and letrozole groups while no significant difference was found for apoptosis marker p53. CONCLUSIONS: Ovulation induction may induce histopathological abnormalities in ovaries and tubes with a different immunohistochemical profile in comparison with salpingo-oophorectomies for genetic risk.

Tubo-ovarian dysplasia in relationship with ovulation induction in rats.

OBJECTIVE: To assess tubo-ovarian dysplasia via morphologic and immunohistochemical study of rats exposed to ovulation stimulation protocols. DESIGN: Animal experimental study. SETTING: Academic research hospital. ANIMAL(S): 72 female Wistar rats divided into three groups. INTERVENTION(S): Stimulation protocols using follicle-stimulating hormone (FSH) or clomiphene citrate for 3, 6, or 12 cycles, after which the animals were killed. MAIN OUTCOME MEASURE(S): Ovarian and tubal dysplasia score and immunohistochemical assessment using p53 and Ki67. RESULT(S): The ovarian dysplasia score was statistically significantly higher after 12 stimulation cycles in the groups receiving FSH (group B) or clomiphene citrate (group C) compared with control (group A). The tubal dysplasia score was statistically significantly increased after only three stimulation cycles in groups B and C. The Ki67 proliferation marker was statistically significantly expressed in the ovaries from group C, and in the fallopian tubes from groups B and C. P53 was constantly low in all three groups. CONCLUSION(S): Ovulation stimulation may induce tubal and ovarian histopathologic and immunohistochemical abnormalities with a dose effect. The role of the fallopian tubes and their interaction with the ovaries require further study.