Studies were performed in guinea pigs to elucidate alterations in endogenous uterine norepinephrine (NE) levels and changes in the contractile response to exogenous NE following local sympathetic denervation, oophorectomy, or treatment with sex steroids. Both in intact and oophorectomized animals the myometrial NE concentration was reduced after sex steroid treatment (0.5 µg 17-β-estradiol, or 0.1 µg estradiol plus 2 mg progesterone, during 2 weeks), mainly as a result of increased uterine weight. After surgical removal of the hypogastric nerves and section of the suspensory ligaments, a similar response to sex steroids was seen if the animals had previously been oophorectomized. The myometrial contractile activity induced by exogenous NE was measured in vitro. The EC50 values (NE concentration giving 50% of the maximal response) showed a similar pattern of variations after hormonal treatment and oophorectomy as did the concentration of endogenous NE. Thus, exposure to the steroids leading to a reduction of neuronal NE also caused an increased sensitivity of the myometrial smooth musculature to exogenous NE, and in the various experimental groups the two parameters showed a close and significant relationship. The underlying mechanism may induce a denervation supersensitivity to NE induced by exposure to estrogen and progestero