Marie K. Lindberg

Estrogen Receptor-β Inhibits Skeletal Growth and Has the Capacity to Mediate Growth Plate Fusion in Female Mice†

To determine the long‐term role of ERβ in the regulation of longitudinal bone growth, appendicular and axial skeletal growth was followed and compared in female ERβ−/−, ERα−/−, and ERα−/−β−/− mice. Our results show that ERβ inhibits appendicular and axial skeletal growth and has the capacity to induce fusion of the growth plates.

Two Different Pathways for the Maintenance of Trabecular Bone in Adult Male Mice

Androgens may regulate the male skeleton either directly via activation of the androgen receptor (AR) or indirectly via aromatization of androgens into estrogen and, thereafter, via activation of estrogen receptors (ERs). There are two known estrogen receptors, ER‐α and ER‐β. The aim of this study was to investigate the relative roles of ER‐α, ER‐β, and AR in the maintenance of trabecular bone in male mice. Seven‐month‐old male mice, lacking ER‐α (ERKO), ER‐β (BERKO), or both receptors (DERKO), were orchidectomized (orx) and treated for 3 weeks with 0.7 μg/mouse per day of 17β‐estradiol or vehicle. No reduction in trabecular bone mineral density (BMD) was seen in ERKO, BERKO, or DERKO mice before orx, showing that neither ER‐α nor ER‐β is required for the maintenance of a normal trabecular BMD in male mice. After orx, there was a pronounced decrease in trabecular BMD, similar for all groups, resulting in equal levels of trabecular BMD in all genotypes. This reduction was reversed completely in wild‐type (WT) and BERKO mice treated with estrogen, and no significant effect of estrogen was found in ERKO or DERKO mice. In summary, the trabecular bone is preserved both by a testicular factor, presumably testosterone acting via AR and by an estrogen‐induced activation of ER‐α. These results indicate that AR and ER‐α are redundant in the maintenance of the trabecular bone in male mice. In contrast, ER‐β is of no importance for the regulation of trabecular bone in male mice.

Dihydrotestosterone Treatment Results in Obesity and Altered Lipid Metabolism in Orchidectomized Mice

Objective: To determine the role of androgen receptor (AR) activation for adipose tissue metabolism. Sex steroids are important regulators of adipose tissue metabolism in men. Androgens may regulate the adipose tissue metabolism in men either directly by stimulation of the AR or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors. Previous studies have shown that estrogen receptor α stimulation results in reduced fat mass in men.

Identification of Estrogen-Regulated Genes of Potential Importance for the Regulation of Trabecular Bone Mineral Density†

Estrogen is of importance for the regulation of trabecular bone mineral density (BMD). The aim of this study was to search for possible mechanisms of action of estrogen on bone. Ovariectomized (OVX) mice were treated with 17β‐estradiol. Possible effects of estrogen on the expression of 125 different bone‐related genes in humerus were analyzed using the microarray technique. Estrogen regulated 12 of these genes, namely, two growth factor‐related genes, 8 cytokines, and 2 bone matrix‐related genes. Five of the 12 genes are known to be estrogen‐regulated, and the remaining 7 genes are novel estrogen‐regulated genes. Seven genes, including interleukin‐1 receptor antagonist (IL‐1ra), IL‐1receptor type II (IL‐1RII), insulin‐like growth factor‐binding protein 4 (IGFBP‐4), transforming growth factor β (TGF‐β), granulocyte colony‐stimulating factor receptor (G‐CSFR), leukemia inhibitory factor receptor (LIFR), and soluble IL‐4 receptor (sIL‐4R) were selected as probable candidate genes for the trabecular bone‐sparing effect of estrogen, as the mRNA levels of these genes were highly correlated (r2 > 0.65) to the trabecular BMD. The regulation of most of these seven genes was predominantly estrogen receptor α (ER‐α)‐mediated (5/7) while some genes (2/7) were regulated both via ER‐α and ER‐β. In conclusion, by using the microarray technique, we have identified four previously known and three novel estrogen‐regulated genes of potential importance for the trabecular bone‐sparing effect of estrogen.

Estren promotes androgen phenotypes in primary lymphoid organs and submandibular glands

BackgroundEstrogens and androgens have extensive effects on the immune system, for example they suppress both T and B lymphopoiesis in thymus and bone marrow. Submandibular glands are sexually dimorphic in rodents, resulting in larger granular convoluted tubules in males compared to females. The aim of the present experiments was to investigate the estrogenic and androgenic effects of 4-estren-3α,17β-diol (estren) on thymus, bone marrow and submandibular glands, and compare the effects to those of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT), respectively. Estrogen receptors (ERs) were blocked by treatment of mice with the ER-antagonist ICI 182,780; also, knock-out mice lacking one or both ERs were used.ResultsAs expected, the presence of functional ERs was mandatory for all the effects of E2. Similar to DHT-treatment, estren-treatment resulted in decreased thymus weight, as well as decreased frequency of bone marrow B cells. Treatment with estren or DHT also resulted in a shift in submandibular glands towards an androgen phenotype. All the effects of estren and DHT were independent of ERs.ConclusionOur study is the first to show that estren has similar effects as the androgen DHT on lymphopoiesis in thymus and bone marrow, and on submandibular glands, and that these effects are independent of estrogen receptors. This supports the hypothesis of estren being able to signal through the androgen receptor.