Effects of the prenatal administration of cimetidine on testicular descent and genital differentiation in rats.
BACKGROUND
Cimetidine has been shown to induce gonadal and sexual dysfunction in men. This study aimed to clarify the effect of cimetidine on testicular descent and genital development in utero.


METHODS
Pregnant rats (280 to 330 g) were separated into 4 groups. In group 1, the rats were injected subcutaneously with a dose of 600 mg/kg of cimetidine twice on days 15, 16, 17, and 18 of gestation. In group 2, the rats were injected with a dose of 300 mg/kg of cimetidine twice in the same way as in group 1. In group 3, the rats were injected with a dose of 150 mg/kg of ranitidine twice in the same manner as in the above groups. In group 4, the rats were injected with the same volume of saline. At birth the anogenital distance was measured, and the incidence of testicular descent was examined in male offspring at 90 days of age. Next, the testes were weighed and histologically examined. The chi-square test and Student t test were used to perform statistical analyses of the results.


RESULTS
At birth, the anogenital distance (AGD) index in male offspring decreased significantly in groups 1 and 2 in comparison with groups 3 or 4. However, there was no significant difference in the AGD index between groups 3 and 4. At 90 days of age, the incidence of cryptorchidism was 55.3% in group 1 and 25.9% in group 2. In contrast, all testes descended into the scrotum in both groups 3 and 4. The incidence of cryptorchidism was significantly higher in group 1 than in groups 2 (P <.05), 3, or 4 (P <.01), while the incidence of cryptorchidism was also significantly higher in group 2 than in groups 3 or 4 (P <.01). The weight of the testis decreased significantly more in the undescended testis than in the scrotal testis (P <.01); however, there was no significant difference in the weight of the scrotal testes among the 4 groups. The histologic development of the undescended testes showed an absence of germ cells and smaller tubes in comparison with those of scrotal testes, which showed an advanced differentiation of germ cells and larger tubes in all 4 groups.


CONCLUSIONS
These findings suggest that the antiandrogenic effect of cimetidine inhibits both the testicular descent and genital differentiation in fetuses and also causes cryptorchidism in postnatal rats. These same events might also occur in human fetuses when high doses of cimetidine are administered to pregnant women around the end of the first trimester.
Takeshi
Shono
S
Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kai
Hiroki
H
Suita
Sachiyo
S
D000367:Age Factors; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology*; D000075202:Contraindications; D003456:Cryptorchidism / Q000139:chemically induced* / Q000453:epidemiology; D005260:Female; D015994:Incidence; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012733:Sex Differentiation / Q000187:drug effects*
D000897:Anti-Ulcer Agents; D002927:Cimetidine