Hypothyroidism caused by phenobarbital affects patterns of estrous cyclicity in rats.

We found that repeated treatment with phenobarbital (PB), a thyroid modulator, resulted in a persistent estrous stage in the present study. Although the effects of PB in blocking the surge release of luteinizing hormone (LH), inducing anovulation and prolonging the diestrous period has been well established, there is still no research describing the appearance of persistent estrous states in normal cycling rats dosed with PB. To further study this phenomenon, female rats exhibiting regular estrous cycle were administered an oral dose of PB for 14 consecutive days. Consecutively, vaginal smears were observed and rats from all the groups were sacrificed and serum hormone levels for prolactin, progesterone, estradiol, triiodothyronin (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) were measured. Pituitary, thyroid, liver, uteri and ovaries were excised, weighed and further subjected to histological observations. We found that PB induced irregular estrous cycles, especially persistent estrus in rats. Histopathologically, the persistent estrous stages are characterized by persistent vaginal cornification in the vagina, cystic follicles and anovulation in the ovaries. Endocrinologically, serum T3 and T4 levels were significantly lower, and TSH was higher in treated-female rats compared to control females. The serum estradiol level and the estradiol/progesterone ratio tend to increase in treated-females. Furthermore, PB-treated animals with irregular estrous cycle were reduced by T4 replacement. Our data indicate that treatment with PB resulted in hypothyroidism and irregular estrous cycle, particularly a persistent estrous stage in normal cycling female rats.

Collaborative work on evaluation of ovarian toxicity. 15) Two- or four-week repeated-dose studies and fertility study of bromocriptine in female rats.

The main focus of this study is to determine the optimal administration period concerning toxic effects on ovarian morphological changes in a repeated-dose toxicity study. To assess morphological and functional changes induced in the ovary by bromocriptine, the compound was administered to female rats at dose levels of 0, 0.08, 0.4 and 2 mg/kg for the 2- or 4-week repeated-dose toxicity study, and for the female fertility study from 2 weeks prior to mating to day 7 of gestation. In the 2-week repeated-dose toxicity study, increase of ovarian weights was observed at 2 mg/kg. In the 4-week repeated-dose toxicity study, ovarian weights were increased at 0.4 and 2 mg/kg. The number of corpora luteum was increased in the 0.4 and 2 mg/kg groups of the 2- and 4-week repeated-dose toxicity studies by histopathological examination of the ovaries. Bromocriptine did not affect estrous cyclicity in 2- and 4-week repeated dosing. In the female fertility study, although animals in any groups mated successfully, no females in 0.4 and 2 mg/kg groups were pregnant. There were no adverse effects on reproductive performance in the 0.08 mg/kg group. Based on these findings, the histopathological changes in the ovary are considered important parameters for evaluation of drugs including ovarian damage. We conclude that a 2-week administration period is sufficient to detect ovarian toxicity of bromocriptine in a repeated-dose toxicity study.