Collaborative work on evaluation of ovarian toxicity 3) Effects of 2- or 4- week repeated-dose toxicity and fertility studies with tamoxifen in female rats

Abstract

To assess whether ovarian histopathological examination in repeated-dose rodent toxicity study could reliably anticipate toxic effects on female reproductive function and to assess whether ovarian change could be detected in a 2-week repeated-dose toxicity study, tamoxifen was administrated orally to female rats at 0.005, 0.03, or 0.2 mg/kg/day for 2 and 4 weeks in the repeated-dose toxicity studies, and for 2 weeks prior to cohabitation, during cohabitation, and through Gestation Day 7 in a female fertility study. The relationship between ovarian histopathological findings and fertility results was investigated. Findings at 0.03 and 0.2 mg/kg/day included decreases in body weight gains associated with decreases in food consumption, in 2- and 4-week repeated-dose toxicity studies and fertility study. The ovarian histopathological findings included increases in large atretic follicles, increases in interstitium cells and absence of newly-formed corpus lutea at 0.2 mg/kg/day in the 2-week study and at 0.03 and 0.2 mg/kg/day in the 4-week study. The treatment induced estrogenic and antiestrogenic reactions in the uterus, while mucinous degeneration was detected in the vagina. Effects on female fertility consisted primarily of disturbance of estrus cycle and decreases in numbers of pregnant rats which were considered to be related to ovarian histopathological changes. Based on these findings, ovarian histopathological evaluation in the repeated-dose toxicity study could anticipate the effects of tamoxifen on female fertility via ovarian dysfunction at slightly toxic doses, and 2-week treatment of tamoxifen at appropriate dose could be sufficient to detect ovarian toxicity by microscopic examination.

Effect of tamoxifen on ovarian reserve: A randomized controlled assessor-blind trial in a mouse model

“…PCNA immune-stained sections confirmed the similar numbers of small-and medium-sized follicles in TMX and control groups. Unchanged numbers of small follicles, which represent gonadotropin-insensitive primordial and primary follicles, accompanied by decreased numbers of pre-antral and antral follicles, as well as decreased numbers of corpora lutea, were observations that were common to all of the studies mentioned above (7)(8)(9)(10)(11). This suggests that TMX per se is not harmful for resting primordial and gonadotropin-insensitive small follicles.…”

“…TMX exposure led to anovulation in the majority of rats in all but one study assessing estrous cycles-70% of TMX-exposed rats were anovulatory in the study by Donath and Nishino (8,9,11). Compared to controls, both absolute and relative ovarian weight was found to be significantly decreased following TMX exposure in all but one study (7)(8)(9)(10)(11). Similar to our findings, Matsuda et al (7) and Tsujioka et al (11) noted a decrease in the number and size of corpora lutea in TMX-treated groups.…”

“…However, there are limited data about the direct effects on the ovary and ovarian follicles. The effects of TMX on various organ systems, the estrous cycle, and fertility potential were investigated in a number of rodent studies (7)(8)(9)(10)(11). In these studies, TMX was administered orally (7, 9-11) or subcutaneously (8) for 2 to 4 weeks.…”

What lies behind chemotherapy-induced ovarian toxicity?

“…The pre-clinical data are not consistent: few studies have implied that the addition of tamoxifen to cyclophosphamide resulted in decreased follicle loss and improved reproductive function in rats (Kim et al 2010. Another toxicological study on rats that employed a higher dose of tamoxifen showed a disturbance of estrus cycle and a decrease in the number of pregnant rats that were considered to be related to ovarian histopathological changes (Tsujioka et al 2009). Two clinical studies indicate that tamoxifen may affect the follicular pool, resulting in a delayed fall in AMH in a group of patients receiving tamoxifen and goserelin.…”

Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats

“…Reference: Tsujioka et al (2009) Primordial follicle damaging agents 4-vinylcyclohexene diepoxide (VCD) -1 -ess of apoptosis in small follicles Company: Toa Eiyo Ltd. Studies: Repeated toxicity study Animals: Sprague-Dawley rats (Slc:SD) rats Doses, route and duration: Intraperitoneally treatment at 5, 20 and 80 mg/kg once a day for 2-or 4-weeks in the repeated toxicity study.…”