Growth-stimulating effect of dienogest, a synthetic steroid, on rodent, canine, and primate mammary glands.
We observed hyperplasia of the mammary gland in female beagle dogs, but not in female rats and monkeys, in 91-day toxicity studies on dienogest. In order to elucidate a possible mechanism for its development and to account for this species difference, we determined the plasma level of growth hormone (GH) in dogs, rats, and monkeys treated orally with dienogest for 91 days. As a result, dogs with mammary hyperplasia showed a prominent, dose-dependent increase in their GH level; and, contrarily, rats and monkeys without the hyperplasia of this organ failed to show any such increase. These results were supported by evidence from immunohistochemical and morphometric analysis of the pituitary gland. In addition, dienogest and medroxyprogesterone acetate (MPA) stimulated the growth of canine mammary epithelial cells in the presence of estradiol in vitro, but had no effect on rat and human mammary epithelial cells incubated under the same conditions. In conclusion, dienogest with progestational activity caused proliferation of the mammary gland in beagle dogs by increasing the secretion of GH, as do other progestational compounds. This change may be partially dependent on the direct effect of the drug.
Ishikawa
T
T
Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, 426-8640, Shizuoka, Japan. tsutomu@mochida.co.jp
Inoue
S
S
Kakinuma
C
C
Kuwayama
C
C
Hamada
Y
Y
Shibutani
Y
Y
D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development; D005260:Female; D006727:Hormone Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D051381:Rats; D013268:Stimulation, Chemical
D006727:Hormone Antagonists; D045167:Progesterone Congeners; D019382:Human Growth Hormone; C023635:dienogest; D009277:Nandrolone; D017258:Medroxyprogesterone Acetate