Reinhold G. Erben Estrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammary gland epithelial cell proliferation as well as hepatic estrogenicity. In this study, we examined the influence of differ- ent estradiol release kinetics on tissue responsivity in ovariecto- mized (OVX) rats. Pulsed release kinetics was achieved by ip or sc administration of estradiol dissolved in physiological saline con- taining 10% ethanol (EtOH/NaC!) whereas continuous release kinetics was achieved by sc injection of estradiol dissolved in benzylbenzoate/ricinus oil (1+4, vol/vol). Initial 3-d experi- ments in OVX rats showed that pulsed ip estradiol adminis- tration had profoundly reduced stimulatory effects on the uterus and the liver compared with continuous release kinet- ics. On the other hand, both administration forms prevented severe vaginal atrophy. Based on these results, we compared the effects of pulsed (sc in ELOH/NaCl) vs. continuous (sc in benzylbenzoate/ricinus oil) estradiol release kinetics on bone, uterus, mammary gland, and liver in a 4-month study in OVX rats. Ovariectomy-induced bone loss was prevented by both administration regimes. However, pulsed estradiol resulted in lower uterine weight, reduced induction of hepatic gene ex- pression, and reduced mammary epithelial hyperplasia rela- tive to continuous estradiol exposure. We conclude that organ responsivity is influenced by different hormone release kinet- ics, a fact that might be exploited to reduce undesired estra- diol effects in postmenopausal women.
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