Leydig cell hyperplasia and adenomas in mice treated with finasteride, a 5 alpha-reductase inhibitor: a possible mechanism.
Finasteride is a selective inhibitor of the enzyme 5 alpha-reductase which is responsible for the conversion of testosterone (T) to dihydrotestosterone (DHT). Finasteride is indicated for the treatment of benign prostatic hyperplasia in man (approximately 0.1 mg/kg/day). The effect of long-term treatment was studied in mice given high doses (2.5, 25, and 250 mg/kg/day) of finasteride for 83 weeks. In finasteride-treated mice, increased incidences of testicular Leydig cell hyperplasia (52% compared to 24% in control group) at doses equal to or greater than 25 mg/kg/day and Leydig cell adenomas (32% compared to 0.5% in control group) at 250 mg/kg/day were observed. There were no drug-related effects on the seminiferous tubules. Since luteinizing hormone (LH) is a trophic hormone for Leydig cells, short-term studies (5 to 14 weeks) were done to investigate the relationship between Leydig cell hyperplasia and serum LH levels in finasteride-treated mice. In these studies, there was a positive correlation between the drug-related increased incidence of Leydig cell hyperplasia and a statistically significant (p < or = 0.05) increase in serum LH levels in finasteride-treated (250 mg/kg/day) mice. Furthermore, studies in castrated male mice showed that the suppression of serum LH levels by T is reversible by inhibition of conversion of T to DHT with finasteride (250 mg/kg/day), supporting the hypothesis that DHT is involved in the regulation of LH release in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Prahalada
S
S
Merck Research Laboratories, Merck & Company, Inc., West Point, Pennsylvania 19486.
Majka
J A
JA
Soper
K A
KA
Nett
T M
TM
Bagdon
W J
WJ
Peter
C P
CP
Burek
J D
JD
MacDonald
J S
JS
van Zwieten
M J
MJ
D058891:5-alpha Reductase Inhibitors; D000236:Adenoma / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism; D018120:Finasteride / Q000633:toxicity*; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D007984:Leydig Cell Tumor / Q000139:chemically induced* / Q000473:pathology; D007985:Leydig Cells / Q000187:drug effects*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009919:Orchiectomy; D012671:Seminiferous Tubules / Q000187:drug effects; D013736:Testicular Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013737:Testis / Q000473:pathology*; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology
D058891:5-alpha Reductase Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D007986:Luteinizing Hormone