Effect of Clomiphene Citrate on Ovarian, Endometrial, and Cervical Histologies in a Rat Model

Abstract

Objective: To examine the effect of clomiphene citrate (CC) on the ovarian, endometrial, and cervical histologies in a rat model. Methods: The rats (n = 40) were randomly assigned to 4 treatment groups: CC 50 (repetitive doses of 0.2 mg CC); CC 100 (repetitive doses of 0.4 mg CC); CC 200 (repetitive doses of 0.8 mg CC), and control (repetitive doses of normal saline). Each study group received its CC dose intraperitoneally in 2 ml saline for 5 days and the controls received 2 ml saline only. Each treatment cycle was repeated six times. Six months later the rats were euthanized. Their ovaries, uterine horns, and cervices were removed and examined for histologic changes. Results: We found no significant difference in the number of follicles and corpora lutea of the study groups (p > 0.05). The numbers of granulosa, theca, and luteal cells of the CC 100 and CC 200 groups were significantly higher than those of the CC 50 group and controls (p < 0.05). There was no important finding related to pre-malign and malign changes in ovarian, endometrial and cervical samples of the control and CC 50 groups. Focal atypia and atypical mitoses were noted in 2 cases of granulosa cells in the CC 100 and CC 200 groups. Conclusion: We did not find an association between the use of CC and ovarian, endometrial, and cervical neoplasms; nevertheless, we noticed an increase in granulosa, theca and luteal cells with high doses of CC, which may be a risk factor for granulosa, theca, and luteal cell tumors.

Fertility Drugs and the Risk of Breast and Gynecologic Cancers

“…Gonadotropins have been shown to induce granulosa cell tumors in rodents 67 and stimulate cells in human in vitro models, 68 and clomiphene has been shown to increase granulosa, theca, and luteal cells in a rat model. 69 Epidemiological studies of these rare tumor types are not available, but several descriptive analyses in Finland 70,71 fail to provide support for an effect of fertility drug use on granulosa cell tumors.…”

Effect of Adipose-derived stem cells versus clomiphen on treatment of experimental polycystic ovary in rats: Histological and Immunohistochemical study

“…This assumption could be supported by some reporters, who studied the effect of clomiphen on rat ovarian histology. They found that clomiphen could increase the number of granulosa cells and they raised the possibility that clomiphen may increase the risk of granulosa cell tumours especially if used in high doses [26] . In another study done, the ability of the human embryonic stem cells to differentiate into functioning granulosa cells was tested.…”

The Histopathological Changes in Rat Ovary and Endometrium Following Long Term Clomiphene Treatment

“…They also concluded that CC could be a risk factor for granulosa, theca and luteal cell tumors. 17 In the last decades many investigators focused on the relationship between infertility treatment and cancer. The most commonly used ovulation inducing medications, CC and gonadotropins, were implicated in the etiology of ovarian cancer.…”