Molecular mechanism of estrogen action in the male: insights from the estrogen receptor null mice

2001 ◽  
Vol 13 (4) ◽  
pp. 211 ◽  
Author(s):  
John F. Couse ◽  
Dipak Mahato ◽  
Edward M. Eddy ◽  
Kenneth S. Korach
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Male Reproduction ◽  
Estrogen Signaling ◽  
Male Mice ◽  
Signaling System ◽  
Estrogen Action ◽  
Behavioral Deficits ◽  
Testicular Dysfunction ◽  
17Β Estradiol

Until recently, 17β-estradiol was thought to be of little importance in male fertility. However, the descriptions of testicular dysfunction and behavioral deficits leading to complete infertility in male mice lacking estrogen receptor α (ERα) have indicated the importance of estrogen action in fertility of the male rodent. In contrast, male mice lacking the newly discovered estrogen receptor β (ERβ) exhibit no compromised fertility. Recently, elaborate sperm transplantation studies have shown that the altered sperm function characteristic of the ERα knockout male are the result of the loss of ERα actions in the supporting somatic cells of the testis and epididymis rather than in the germ cell. This brief review will discuss the roles of estrogen action in male reproduction as revealed by mice lacking both known forms of the ER. A brief review of the estrogen signaling system is also included.

Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

2018 ◽  
Vol 239 (3) ◽  
pp. 303-312 ◽  
Author(s):  
H H Farman ◽  
K L Gustafsson ◽  
P Henning ◽  
L Grahnemo ◽  
V Lionikaite ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Areal Bone Mineral Density ◽  
Male Mice ◽  
Mineral Density ◽  
Intact Male ◽  
Trabecular Thickness ◽  
Total Body

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

scholarly journals Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions

2017 ◽  
Vol 37 (5) ◽  
pp. 909-919 ◽  
Author(s):  
Caroline Chenu ◽  
Marine Adlanmerini ◽  
Frederic Boudou ◽  
Elodie Chantalat ◽  
Anne-Laure Guihot ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Direct Action ◽  
Skin Flap ◽  
Treatment Strategies ◽  
Estrogen Receptor Α ◽  
Male Mice ◽  
Resistance Arteries ◽  
Estradiol Treatment ◽  
Impaired Wound Healing ◽  
17Β Estradiol

Objective— Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. Approach and Results— Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. Conclusions— Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.

scholarly journals 17β-Estradiol Inhibits Wound Healing in Male Mice via Estrogen Receptor-α

2010 ◽  
Vol 176 (6) ◽  
pp. 2707-2721 ◽  
Author(s):  
Stephen C. Gilliver ◽  
Elaine Emmerson ◽  
Laura Campbell ◽  
Pierre Chambon ◽  
Matthew J. Hardman ◽  
...  
Keyword(s):  
Wound Healing ◽  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Male Mice ◽  
17Β Estradiol

scholarly journals PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 623
Author(s):  
Marit Rasmussen ◽  
Susanna Tan ◽  
Venkata S. Somisetty ◽  
David Hutin ◽  
Ninni Elise Olafsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Modification ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Adp Ribosylation ◽  
Protein Levels ◽  
17Β Estradiol ◽  
Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

scholarly journals AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer

2008 ◽  
Vol 28 (24) ◽  
pp. 7487-7503 ◽  
Author(s):  
Poornima Bhat-Nakshatri ◽  
Guohua Wang ◽  
Hitesh Appaiah ◽  
Nikhil Luktuke ◽  
Jason S. Carroll ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Binding Sites ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Primary Tumors ◽  
Genome Wide ◽  
Extracellular Signal

ABSTRACT Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

scholarly journals 17β-Estradiol activates Cl− channels via the estrogen receptor α pathway in human thyroid cells

Channels ◽  
2021 ◽  
Vol 15 (1) ◽  
pp. 516-527
Author(s):  
Meisheng Yu ◽  
Yuan Wei ◽  
Yanfang Zheng ◽  
Lili Yang ◽  
Long Meng ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Human Thyroid ◽  
Thyroid Cells ◽  
Cl Channels ◽  
17Β Estradiol

scholarly journals Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

2020 ◽  
Author(s):  
Shivani N. Mann ◽  
Niran Hadad ◽  
Molly Nelson-Holte ◽  
Alicia R. Rothman ◽  
Roshini Sathiaseelan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Chronic Diseases ◽  
Transcriptional Activation ◽  
Estrogen Receptor Α ◽  
Metabolic Parameters ◽  
Metabolic Effects ◽  
Male Rats ◽  
Male Mice ◽  
Dietary Interventions ◽  
Estradiol Treatment

ABSTRACTMetabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 acts primarily through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

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