Use of a murine endometriosis interna model for the characterization of compounds that effectively treat human endometriosis.

Endometriosis is a chronic, estrogen-dependent disease characterized by the presence of ectopic endometrium either in the pelvic cavity (endometriosis externa) or within the uterus (endometriosis interna, adenomyosis). Key symptoms are pelvic pain, dysmenorrhea and infertility. Established rodent animal models used for drug research in endometriosis have certain limitations. Since rodents do not menstruate, they cannot develop endometriosis externa spontaneously, but they suffer from endometriosis interna. There is growing evidence that human endometriosis externa and interna represent two faces of the same disease. Both are estrogen-dependent and respond to similar treatment paradigms. Here, we addressed the question whether a murine endometriosis interna model may also be suitable for the characterization of drugs employed in human endometriosis. We examined the effects of danazol, Faslodex and cetrorelix in SHN mice that developed endometriosis interna after pituitary grafting. The GnRH antagonist cetrorelix and the estrogen receptor antagonist Faslodex, which negatively interfered with estrogen-mediated signaling, completely inhibited endometriosis interna, whereas danazol, an androgenic progestin, showed significant therapeutic activity in the majority of SHN mice. We conclude that this murine endometriosis interna model may be a valuable complement to established endometriosis externa models to support drug research in human endometriosis.

Estradiol release kinetics determine tissue response in ovariectomized rats.

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.

Effect of estradiol sulfamate (ES-J995) on affinity of hemoglobin for oxygen, cardiovascular function and acid-base balance in ovariectomized rats.

Oral administration of estradiol sulfamate (ES, prodrug of estradiol) leads to increased systemic and reduced hepatic effects than estradiol because ES is accumulated in erythrocytes. However, possible alterations of erythrocytic oxygen transport by intraerythrocytic ES accumulation has not been studied. Therefore, ovariectomized adult female rats (n = 58; body wt.) were randomly treated orally either with single doses (day 1) or multiple dose (days 1-4) with vehicle, with estradiol sulfamate (ES-J995, 1 mg x kg(-1) b.w.) or with estradiol (30 mg x kg(-1) b.w.). Under general anesthesia arterial blood pressure, heart rate, blood gases, and acid-base balance were measured. Hypoxia was performed by lowering the inspired fraction of oxygen from 0.35 to 0.12. In addition, individual oxygen dissociation curves and ES-J995 distribution in blood and plasma were estimated. ES-J995 was accumulated in erythrocytes by approximately 98% (P < 0.01), but oxygen transport capacity was not altered (P50: 35.6 +/- 1.0 mm Hg to 37.1 +/- 1.1 mm Hg). Blood gases and acid-base balance parameters were not altered after ES-J995 treatment under normoxic and hypoxic conditions. In conclusion, ES-J995 accumulation in erythrocytes does not alter the affinity of hemoglobin for oxygen nor any function which would indicate an impaired oxygen delivery to the body.