External genitalia abnormalities in male rats exposed in utero to finasteride, a 5α‐reductase inhibitor

Abstract

A series of studies was conducted to determine the developmental toxicity of the 5 alpha-reductase inhibitor finasteride (MK-0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK-0906 treatment induced dosage-related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK-0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage-related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5 alpha-reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK-0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.

Low-dose effects of bisphenol A on early sexual development in male and female rats

“…However, other anti-androgenic chemicals show more shallow dose-response curves. One example of such a substance is the anti-androgenic drug and 5a-reductase inhibitor finasteride (Clark et al 1990, Bowman et al 2003, Christiansen et al 2009). Interestingly, a new study that examines the effects of short-term exposure to BPA on mRNA levels of 5a-reductase isozymes in prostate of adult castrated rats show that BPA significantly decreased the mRNA levels of both 5a-reductase isozymes (Sánchez et al 2013).…”

Molecular genetic cascades for external genitalia formation: An emerging organogenesis program

“…Evidence supporting the crucial role of androgen is based on pharmacological and genetic data. Androgen antagonists (Silversides et al, 1995;Suzuki et al, 2002) or inhibitors of its synthesis (Imperato-McGinley et al, 1985;Clark et al, 1990) interfere with testicular function and external genitalia development. Mutations in androgen receptor gene (Murakami, 1987;Yeh et al, 2002;Sato et al, 2003) or for androgen synthetic enzymes (Andersson et al, 1991;Wilson, 1992) result in abnormalities in male sexual differentiation and development.…”

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

“…Suppressive effects of flutamide on sexual maturation and behavior have been reported in rats when administered during the perinatal period Brand and Slob, 1991;Zimmerberg and Farley, 1993;Lund et al, 2000) or to offspring immediately after birth Clemens, 1978, 1980;Clemens et al, 1978;Brand and Slob, 1991;Vega Matuszczyk and Larsson, 1995;Miyata et al, 2002). Other chemicals such as antiandrogen drugs finasteride (Clark et al, 1990(Clark et al, , 1993Wise et al, 1991;Imperato-McGinley et al, 1992) and cyproterone acetate , and the estrogen-like chemical bisphenol A (Sato et al, 2001;Cagen et al, 1999) have been reported to cause various changes in morphology of the external genitalia and sexual maturation of the offspring born to mothers treated with these chemicals during pregnancy.…”