External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor.
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.
Clark
R L
RL
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Antonello
J M
JM
Grossman
S J
SJ
Wise
L D
LD
Anderson
C
C
Bagdon
W J
WJ
Prahalada
S
S
MacDonald
J S
JS
Robertson
R T
RT
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000633:toxicity*; D000818:Animals; D001378:Azasteroids / Q000633:toxicity*; D005260:Female; D005333:Fetus; D018120:Finasteride; D005837:Genitalia, Male / Q000002:abnormalities*; D007021:Hypospadias / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D009558:Nipples / Q000002:abnormalities; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013260:Steroids, Heterocyclic / Q000633:toxicity*; D013723:Teratogens
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; D013260:Steroids, Heterocyclic; D013723:Teratogens; D018120:Finasteride