Tamoxifen attenuates pulsatile growth hormone secretion: mediation in part by somatostatin.
Tamoxifen, a partial competitive antagonist to the estrogen receptor, is a potent inhibitor of the proliferation of experimental mammary carcinoma in the rat and is widely used clinically in the treatment of breast cancer. Blockade of estrogen receptors present on neoplastic cells represents the classic mechanism of action of tamoxifen, but the drug has a variety of other actions that may contribute to its antiproliferative properties. While it is recognized that estrogens play an important role in modulating pulsatile GH release, the effect of antagonists to sex steroid receptors on GH secretory dynamics has not previously been described. In the present study we examined the effect of tamoxifen on pulsatile GH secretion in free-moving adult male and female rats. The drug, when administered in a manner previously shown to be associated with antineoplastic activity, caused a marked suppression of the amplitude of spontaneous GH secretory bursts and significantly reduced mean 6-h plasma GH levels in both sexes compared to those in their respective peanut oil-injected controls. Inhibition of spontaneous GH pulses persisted for up to 7 weeks after tamoxifen administration in both sexes. Immunoneutralization of endogenous somatostatin in tamoxifen-treated male rats completely restored both GH pulse amplitude (121.6 +/- 9.5 vs. 62.5 +/- 13.5 ng/ml in tamoxifen-treated rats given normal sheep serum; P less than 0.02) and mean 6-h plasma GH levels (53.3 +/- 6.6 vs. 17.9 +/- 3.6 ng/ml in normal sheep serum-treated rats; P less than 0.01) to levels observed in our peanut oil-injected controls. These results demonstrate that 1) tamoxifen has potent inhibitory effects on pulsatile GH secretion; and 2) the blunting of GH pulse amplitude by tamoxifen is mediated at least in part by increased release of endogenous somatostatin. These findings motivate further investigation of the clinical significance of tamoxifen-induced suppression of GH secretion in relation to the antineoplastic activity of this commonly used drug.
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
G S
GS
Tannenbaum
W
W
Gurd
M
M
Lapointe
M
M
Pollak
D000204:Activity Cycles; D000818:Animals; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D007106:Immune Sera; D007116:Immunization, Passive; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012727:Sex Characteristics; D013004:Somatostatin / Q000276:immunology / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology*
D007106:Immune Sera; D013629:Tamoxifen; D013004:Somatostatin; D013006:Growth Hormone