Stimulatory effect of luteinizing hormone on the development and maintenance of 5 alpha-reduced steroid-producing testicular interstitial cell tumors in Fischer 344 rats.
The development and maintenance of testicular interstitial cell (IC) tumors under the conditions of low LH levels were examined in aged Fischer 344 rats, and the enzyme activities for androgen synthesis in the tumors were estimated. Sixty-week old rats received injections of an LH-RH agonist (LH-RHa) for 28 weeks or were subjected to a procedure by which Silastic tubes containing testosterone (T) or estradiol-17 beta (E) were subcutaneously implanted. All 88-week old control animals had bilateral IC tumors, whereas 100% of the T-, E- and LH-RHa-treated rats at week 88 were tumor free. These treated rats showed significantly reduced peripheral LH levels compared to the control animals. No hyperplasia or tumors of the IC were noted in 70-week old animals receiving T for 28 weeks, while all age-matched untreated animals showed IC tumors or hyperplasia. The IC tumors in rats 69 weeks of age decreased in size in response to 4-week treatment involving the subcutaneous implantation of tubes containing T. After removal of the tubes, however, the tumors once again increased in size. Reduced and subsequently elevated serum LH levels were also observed with this treatment. These changes in tumor mass volume were mainly due to a change in the tumor cell volume which was possibly related to LH levels, i.e., large cells were predominant under relatively high peripheral LH levels and intermediate cells were predominant under low LH levels. Quantitative analyses of the in vitro products formed from [3H]progesterone and [14C]4-androstenedione in tissue-homogenates revealed a low 17 alpha-hydroxylase activity and a high 5 alpha-reductase activity in the IC tumors compared to those activities in the testicular tissues; in the tumors, low production of T and high production of 5 alpha-metabolites of progesterone were observed. From these data, it seems reasonable to conclude that sufficient levels of LH are essential for the induction of IC tumors or hyperplasia and the maintenance of tumor mass, and that the low production of T in the tumors is due, at least in part, to decreased 17 alpha-hydroxylase and increased 5 alpha-reductase activities under active steroidogenesis.
Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
F
F
Chatani
T
T
Nonoyama
K
K
Sudo
H
H
Miyajima
M
M
Takeyama
D
D
Takatsuka
H
H
Mori
K
K
Matsumoto
D000367:Age Factors; D000818:Animals; D004967:Estrogens / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006965:Hyperplasia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D007984:Leydig Cell Tumor / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007986:Luteinizing Hormone / Q000097:blood / Q000494:pharmacology*; D008297:Male; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013736:Testicular Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000494:pharmacology
D004967:Estrogens; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D011374:Progesterone; D007986:Luteinizing Hormone