Comparison of tamoxifen effects on the actions of triiodothyronine or growth hormone in the ovariectomized-hypothyroid rat.
Recent studies have suggested that a subset of estrogen responses arise via modulation of triiodothyronine (T3) actions, and depend on T3 for expression: other estrogen responses are not T3-dependent. Moreover, tamoxifen acts as a full estrogen agonist in T3-dependent responses but behaves as an antiestrogen in T3-independent responses. T3 directly induces a variety of metabolic enzymes and proteins, and also induces rat growth hormone (GH). Thus, some T3-dependent tamoxifen effects might reflect modulation of GH rather than T3 actions. To address this issue, tamoxifen effects on somatotropic and metabolic actions of T3 and GH were compared in ovariectomized rats with methimazole-induced hypothyroidism. Rats were given T3 (10 micrograms/kg/day) or ovine GH (2 mg/kg/day) with or without tamoxifen (0.5 mg/kg/day) for 30 days. GH was poorly effective in producing a sustained increase in somatic growth in hypothyroid rats compared to T3; nonetheless, GH effects to increase body weight, tibia length and serum insulin-like growth factor I while decreasing fat mass and evoking small increases in body temperature were not inhibited by tamoxifen. Tamoxifen also did not inhibit GH trends to increase tibia bone mineral density. T3 increased body temperature, insulin-like growth factor I levels and all measures of somatic growth and, unlike GH, increased food intake and tended to decrease tibia bone mineral density. Tamoxifen inhibited the somatotropic actions of T3 (including increases in insulin-like growth factor I levels), and produced significant increases in tibia bone mineral density only in T3-treated rats. Tamoxifen had no effect on T3 actions to increase food intake or body temperature. T3 alone increased fat mass and exhibited a tendency to decrease serum triglycerides: tamoxifen had no effect on these parameters in the absence of T3. However, coadministration of tamoxifen with T3 produced a marked decrease in fat mass and increased serum triglycerides. GH had no effect on serum triglycerides in either the presence or absence of tamoxifen. Serum glucose levels appeared normal in all groups. The data indicate that multiple tamoxifen effects on growth and metabolism may reflect modulation of T3 rather than GH actions.
Fitts
J M
JM
Department of Pharmacology, New York Medical College, Valhalla, USA.
Klein
R M
RM
Powers
C A
CA
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001831:Body Temperature / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D007037:Hypothyroidism / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007668:Kidney / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D014284:Triiodothyronine / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D004965:Estrogen Antagonists; D014280:Triglycerides; D014284:Triiodothyronine; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone