Abstract

Evidence for the involvement of adenosine 3', 5'-monophosphate (cyclic AMP) in estrogen action has been obtained by examining the ability of exogenously administered cyclic AMP to mimic the estradiol-induced stimulation of certain key glycolytic and hexose monophosphate shunt enzymes as well as of uterine glycogen synthesis. Cyclic AMP, when injected concurrently with theophylline, significantly elevated the activities of uterine hexokinase, phosphofructokinase, pyruvate kinase, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase and increased glycogen content in uteri of immature rats. Increases in uterine glycogen and enzyme activities were related to the dose of cyclic AMP and as little as 0.2 mg of cyclic AMP per rat was sufficient to produce a significant glycogenic effect. The observed responses appeared specific to cyclic AMP since neither adenosine nor several other adenine nucleotides produced any appreciable effects. Treatment with cyclic AMP and theophylline resulted in no siginificant change in any of these parameters in lung and thymus, two tissues not responsive to estrogens. Two uterine enzymes, isocitrate dehydrogenase and α-glycerophosphate dehydrogenase, which did not respond to estradiol, also failed to display any appreciable response to this cyclic nucleotide. Cyclic AMP and theophylline produced stimulation of key glycolytic and hexose monophosphate shunt enzymes in uteri of ovariectomized and adrenalectomized-ovariectomized rats; the N⁶, O^2'-dibutyryl analog of cyclic AMP was more potent than the parent compound. Pretreatment of these animals with actinomycin or cycloheximide significantly inhibited the cyclic AMP and theophylline-induced increases in various enzyme activities, indicating that neither the stimulation by cyclic AMP nor the prevention of these enzymatic responses by inhibitors of ribonucleic acid and protein synthesis was dependent upon adrenal function. Our results support the suggestion that cyclic AMP may be involved in mediating the known metabolic effects of estrogens on the uterus.