title: Estradiol release kinetics determine tissue response in ovariectomized rats.
abstract: 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 different estradiol release kinetics on tissue responsivity in ovariectomized (OVX) rats. Pulsed release kinetics was achieved by ip or sc administration of estradiol dissolved in physiological saline containing 10% ethanol (EtOH/NaCl) whereas continuous release kinetics was achieved by sc injection of estradiol dissolved in benzylbenzoate/ricinus oil (1+4, vol/vol). Initial 3-d experiments in OVX rats showed that pulsed ip estradiol administration had profoundly reduced stimulatory effects on the uterus and the liver compared with continuous release kinetics. On the other hand, both administration forms prevented severe vaginal atrophy. Based on these results, we compared the effects of pulsed (sc in EtOH/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 expression, and reduced mammary epithelial hyperplasia relative to continuous estradiol exposure. We conclude that organ responsivity is influenced by different hormone release kinetics, a fact that might be exploited to reduce undesired estradiol effects in postmenopausal women.
authors.affiliation: TRG Oncology & Gynecological Therapy, Bayer Pharma AG, 13342 Berlin. christiane.otto@bayer.com
authors.forename: Christiane
authors.initials: C
authors.lastname: Otto
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kantner
authors.forename: Reinhard
authors.initials: R
authors.lastname: Nubbemeyer
authors.forename: Jenny
authors.initials: J
authors.lastname: Schkoldow
authors.forename: Iris
authors.initials: I
authors.lastname: Fuchs
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Krahl
authors.forename: Richardus
authors.initials: R
authors.lastname: Vonk
authors.forename: Christiane
authors.initials: C
authors.lastname: Schüler
authors.forename: Karl-Heinrich
authors.initials: KH
authors.lastname: Fritzemeier
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced; D007267:Injections; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D023421:Models, Animal; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014599:Uterus / Q000187:drug effects* / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000473:pathology
chemical_list: D004958:Estradiol