Estradiol-induced depression of myelopoiesis in the mouse and dog

Abstract

The effects of estradiol on myelopoiesis and marrow fibroblasts were studied in C57B1/6J mice and dogs. Marrow cells from mice and dogs were grown in vitro with 10('-8) to 10('-4) M 17(beta)-estradiol sulfate. Mice and dogs were treated once with 17(beta)-estradiol cyclopentylpropionate. The hematology, marrow morphology, marrow granulocyte-macrophage colony-forming units (CFU-GM) and plaque-forming units in culture (PFU-C), granulopoietic ability of marrow fibroblasts, and morphology of selected tissues were examined in estradiol-treated animals. Estradiol-treated mice were lymphopenic and eosinopenic at 2 and 4 weeks, while neutropenia occurred only at 4 weeks. Marrow lymphoid cells were decreased at 2 and 4 weeks, and granulocytic precursors were increased at 4 weeks. The cellularity of the humeral marrow and marrow CFU-GM were decreased at 2 and 4 weeks. The growth of marrow PFU-C and granulopoietic ability of marrow fibroblasts were not affected in estradiol-treated mice or by in vitro exposure to estradiol. Thymic atrophy, osteopetrosis, and neutrophilic infiltration of the uterus occurred in estradiol-treated mice. Dogs developed thrombocytopenia and neutrophilic leukocytosis at 2 and 3 weeks after treatment with estradiol. Afterwards, some dogs remained thrombocytopenic and became neutropenic. The marrow was characterized by megakaryocytopenia, erythroid hypoplasia, and granulocytic hyperplasia. Marrow megakaryocytes and erythroid cells later returned to adequate levels, but dogs with continued thrombocytopenia and neutropenia developed marrow hypoplasia with increased plasma cells and mast cells. Marrow CFU-GM were decreased at 2 weeks and afterwards, while PFU-C were decreased at 1 and 2 weeks. The granulopoietic ability of marrow fibroblasts was unchanged. Estradiol did not affect the in vitro growth of canine CFU-GM and PFU-C colonies, or the granulopoietic ability of marrow fibroblasts. Lesions found in dogs were marrow hypoplasia and increased splenic erythropoiesis. The transient decrease in marrow PFU-C of estradiol-treated dogs indicated an impairment of the marrow microenvironment, but this change could not be directly attributed to estradiol using in vitro tests. The initially increased granulopoiesis in estradiol-treated dogs and lack of in vitro inhibition of canine CFU-GM by estradiol are not suggestive of cytotoxic injury to hematopoietic stem cells.