Danazol regulates the functions of normal human endometrial stromal cell subpopulations by modifying endometrial cytokine networks

Abstract

Abstract. Local danazol therapy can improve endometriotic signs and symptoms without causing any menstrual disorders. As a consequence, certain direct actions of danazol on endometriotic tissues have been proposed, but the mechanisms of these actions have not been clarified. In the present study, the direct effects of danazol on normal human endometrial stromal cells (ESCs) were examined using in vitro decidualization assays. Danazol did not affect the viable cell numbers of unstimulated ESCs or 8Br-cAMP-stimulated decidualized ESCs, but significantly enhanced the viable cell numbers of 8-Br-cAMP-stimulated ESCs during decidualization in a dose-dependent manner. Danazol had no effect on PRL secretion by 8-Br-cAMP-stimulated decidualized ESCs. Danazol, as well as progesterone and medroxyprogesterone acetate (MPA), induced ESC decidualization. Danazol synergistically enhanced the differentiation process of 8-BrcAMP-stimulated ESCs during decidualization. Although progesterone and MPA increased G-CSF and IL-8 secretion by ESCs in similar manner to 8-Br-cAMP, danazol had no such effects. Moreover, remarkable increases in G-CSF and IL-8 secretions by 8-Br-cAMP-stimulated ESCs during decidualization were completely inhibited by cotreatment with danazol. These results indicate that danazol has specific pharmacological effects on ESCs, rather than progesteronelike effects or similar effects to those reported for endometrial cytokines. According to the results, normal human ESCs can be classified into at least four functional subpopulations. Therefore, under certain circumstances, danazol has similar or opposite effects on ESCs to certain endometrial cytokines, suggesting that it regulates functional cellular subpopulation ratios of normal human ESCs by modifying the endometrial cytokine network in endometrial stromal tissues.

A role for Danazol in chronic lymphocytic leukemia

“…Danazol has been reported to decrease the production of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-a, which may limit their ability to cause proliferation of CLL cells in vivo. 13 Danazol can also intercalate into cell membranes, 14 which may dysrupt growth-promoting signaling processes and account for a mechanism of action apparently independent of glucocorticoid, estrogen and androgen receptors (Figure 1d).…”

Danazol induces apoptosis and cytotoxicity of leukemic cells alone and in combination with purine nucleoside analogs in chronic lymphocytic leukemia

“…Tung et al [ 19 ] proposed that a reduction in blood CD23 level by danazol observed during endometriosis treatment suggested a direct effect on activated B cells in CLL [ 25 , 26 ]. Similarly, danazol can decrease production of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, which probably can restrict their ability to induce proliferation of CLL cells in vivo [ 10 , 27 ].…”