Critical developmental periods for effects on male rat genitalia induced by finasteride, a 5 alpha-reductase inhibitor.
The conversion of testosterone to 5 alpha-dihydrotestosterone by the enzyme 5 alpha-reductase is inhibited by finasteride. In a study in which maternal dosing with finasteride commenced on Gestational Day 15 and terminated on Postpartum Day 21, there were 13 and 27% decreases in anogenital distance of male pups on Postnatal Day 1 at 0.03 and 3 mg/kg/day, respectively. These decreases were largely reversed by Postnatal Day 22 even though treatment of the dams continued. Treatment at 3 mg/kg/day also resulted in hypospadias with cleft prepuce and a 5-day delay in the separation of the prepuce from the glans penis in those animals without hypospadias. A second study in which 20 mg/kg/day finasteride was administered on successive 2-day periods during late gestation in rats demonstrated that the period of Gestational Days 16 to 17 was the most sensitive (critical period) for finasteride-induced hypospadias, cleft prepuce, decreased anogenital distance, reduced prostate weight, and nipple formation in F1 male offspring. This critical period is just prior to the appearance on Day 18 of gestation of a midline mesenchymal plate between the urogenital sinus and the rectum in normal male fetuses. This midline plate does not appear in finasteride-exposed fetuses destined to have hypospadias as demonstrated in a previous study. Based on these observations, we hypothesize that finasteride causes hypospadias by preventing the formation of the medial mesenchymal plate which is necessary for assisting the movement of the urogenital sinus from the base to the tip of the genital tubercle.
Clark
R L
RL
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
Anderson
C A
CA
Prahalada
S
S
Robertson
R T
RT
Lochry
E A
EA
Leonard
Y M
YM
Stevens
J L
JL
Hoberman
A M
AM
D058891:5-alpha Reductase Inhibitors; D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000736:Androstenes / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001378:Azasteroids / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D018120:Finasteride; D005837:Genitalia, Male / Q000187:drug effects*; D007021:Hypospadias / Q000139:chemically induced*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010413:Penis / Q000002:abnormalities / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011467:Prostate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; D018120:Finasteride