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Tibolone and metabolites induce prolactin production in human endometrial stromal cells in vitro: evidence for cell-specific metabolism |
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| Authors: | Groothuis P G De Gooyer M E ten Kate J Menheere P P Dunselman G A J de Goeij A F P M Verbost P Ederveen A G H Kloosterboer H J |
| Affiliation: | aResearch Institute Growth and Development (GROW), Department of Obstetrics and Gynaecology, University Hospital Maastricht, Maastricht, The Netherlands bDepartment of Pharmacology, Organon N.V., Oss, The Netherlands cLaboratory for Clinical Chemistry and Haematology, Maaslandziekenhuis, Sittard, The Netherlands dGROW, Department of Clinical Chemistry, University Hospital Maastricht and Maastricht University, Maastricht, The Netherlands eGROW, Department of Pathology, University Hospital Maastricht and Maastricht University, Maastricht, The Netherlands |
| Abstract: | In this study, we assessed the effects of tibolone and its metabolites on the production of a progesterone sensitive parameter, prolactin, in human endometrium stroma cells in vitro. In addition, the metabolism of the compounds by isolated stromal and epithelial cells was evaluated. The reference compounds, progesterone, Org 2058, and DHT all induced prolactin production. Oestradiol also slightly induced prolactin production and enhanced the response to Org 2058. Tibolone and Δ4-tibolone were similar with regard to potency to induce prolactin levels in the culture supernatant. Their potency was lower than that of Org 2058, similar to that of progesterone and higher than that of DHT. The efficacies of tibolone, Δ4-tibolone and Org 2058 were similar (200-fold induction). The estrogenic tibolone metabolites 3- and 3β-OH tibolone also significantly stimulated prolactin production. Their potency, however, was low since significance was reached only at the highest concentrations tested. The PR antagonist Org 31710 inhibited both tibolone- and Δ4-tibolone-induced prolactin production. The responses of tibolone and Δ4-tibolone were not affected by co-incubation with the androgen receptor antagonist OH-flutamide. The effect of tibolone, but not Δ4-tibolone, was antagonized approximately 50% in combination with the highest dose (1 μM) estrogen receptor antagonist, ICI 164384. The induction of prolactin by 3- and 3β-OH tibolone was antagonized most potently by Org 31710, but also by ICI 164384 and OH-flutamide. Tibolone is metabolized differently in epithelial and stromal cells of the human endometrium. The epithelial cells mostly produce the progestagenic/androgenic Δ4-tibolone. The stromal cells produce predominantly the 3β-OH tibolone, and some Δ4-tibolone, but the net effect observed with regard to prolactin production is progestagenic. When the metabolites 3-OH, 3β-OH, and Δ4-tibolone were added to the cultures no conversions were observed. The HPLC analyses showed no evidence for the production of sulfated metabolites. In conclusion, the net effects on endometrial stromal cells are predominantly progestagenic. Tibolone is converted by epithelial cells into Δ4-tibolone which displays progestagenic and androgenic activities, whereas in stromal cells also the estrogenic metabolites 3- and 3β-OH tibolone are formed. |
| Keywords: | Stroma Epithelium Endometrium Prolactin Tibolone |
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