Role Of Estrogen Receptor Beta Research Articles

Transcriptomic profiling of the oocyte-cumulus-granulosa cell complex from estrogen receptor β knockout mice

To study the role of estrogen receptor beta in follicle development and maturation and in the response to gonadotropin stimulation aiming at superovulation DESIGN: Experimental study and transcriptomic analysis. Healthy wild-type and estrogen receptor beta (ERβ) knockout female mice undergoing superovulation at 4-weeks, 7-weeks, and 6-months of age. Oocyte yield after superovulation, transcriptomic profiling of cumulus-granulosa cell complexes and oocytes, and immunohistochemical analyses. Superovulation of ERβ knockout (Esr2-KO) mice resulted in reduced oocyte yield at 6-months of age compared to wild-type (WT) mice, but younger mice had similar yields. RNA-seq analysis of cumulus cells from superovulated WT and Esr2-KO mice identified genes and pathways associated with among others adhesion, proliferation, Wnt-signaling, and placed ERβ in bipotential granulosa cell cluster. Loss of ERβ increased expression of the other estrogen receptors Esr1 and Gper1. Our results show that ERβ has an important role in regulating ovulation in response to exogenous gonadotropins in 6-month-old mice, but not in younger mice. Our transcriptomic and immunohistochemical observations suggest a dysregulation of the granulosa cell communication and lack of tight coordination between granulosa cell replication and antrum expansion. A significant upregulation of other estrogen receptors may support a compensatory mechanism sustaining fertility during younger age in Esr2-KO mice.

Signal Crosstalk and the Role of Estrogen Receptor beta (ERβ) in Prostate Cancer.

Prostate cancer remains the most prevalent cancer among men worldwide; however, as a sex hormone-dependent cancer, sex hormones and their receptor signaling play an important role in the development and progression of cancer. Most current treatment options for prostate cancer thus revolve around the inhibition of androgen signaling (eg, ADT), which, although effective in the early stages, eventually progresses to treatment-resistant prostate cancer with no effective follow-up options. Recent studies have shown that among the nuclear receptor family members, in addition to androgen receptors, estrogen receptor (ER) plays an important biological function as a transcription factor and regulatory protein in various cancers, acting either directly or indirectly by forming homodimers or heterodimers with ligands. In this paper, we review the application of ERβ in animal models and in vitro experiments in the last 5 years, as well as the presence and role of some of its splice variants. We summarize the overview and update of ERβ in prostate cancer, and provide a corresponding analysis of some current research disagreements. Its crosstalk action on some important cancer growth-related signaling pathways (eg, TGF-β and ERK), regulation of downstream target proteins (eg, nuclear translocation of EGFR and expression of oncogenic-related protein MMP-2), and interactions with related ERβ co-regulators (eg, ZFHX3), agonists, and antagonists in prostate cancer are highlighted, and the resulting effects on tumor progression are described. In addition, the paper describes its current potential clinical application as a novel therapeutic strategy and some of the challenges it faces.

Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes.

Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERβ) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERβ mediates this effect. To investigate the functional role of intestinal ERβ during colitis-associated CRC we used intestine-specific ERβ knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNFα signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERβ. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERβ knockout, accompanied by enhanced local expression of TNFα, deregulation of key NFκB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERβ protects against TNFα-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERβ binds to cis-regulatory chromatin areas of key NFκB regulators. Our results support a protective role of intestinal ERβ against colitis-associated CRC, proposing new therapeutic strategies.

Estrogen Receptor beta (ERβ) Regulation of Lipid Homeostasis-Does Sex Matter?

In this communication, we aim to summarize the role of estrogen receptor beta (ERβ) in lipid metabolism in the main metabolic organs with a special focus on sex differences. The action of ERβ is tissue-specific and acts in a sex-dependent manner, emphasizing the necessity of developing sex- and tissue-selective targeting drugs in the future.

The Evaluation of Estrogen Receptor β as a Potential Prognosis Factor in Melanoma

Differences across sexes in cutaneous melanoma incidence, metastatic pathways and disease outcome are consistently observed, with women having a significant survival advantage compared with men. This suggests that gender could play a role as a prognostic indicator through sex hormone signaling, but the mechanism is still unclear. This article focuses on available literature data concerning the influence of estrogen receptor beta (ERβ) expression as a host-related biological protective factor for female patients with melanoma. Furthermore, it highlights the potential role of estrogen receptor beta (ERβ) as a prognostic biologic marker in cutaneous melanoma. Keywords: melanoma, sex, hormone receptors, estrogen receptor β

<p>Estrogen Receptor Beta Inhibits The Proliferation, Migration, And Angiogenesis Of Gastric Cancer Cells Through Inhibiting Nuclear Factor-Kappa B Signaling</p>

PurposeThis study aimed to investigate the regulatory roles of estrogen receptor beta (ERβ) on gastric cancer (GC) cells, and reveal the potential mechanisms relating to nuclear factor-kappa B (NF-κB) signaling.MethodsGC cell lines SGC7901 and MKN45 were transfected with pEGFP-C1-ERβ to overexpress ERβ, and treated with PMA (a NF-κB activator) to activate NF-κB signaling. The cell proliferation and migration, as well as the formation of vessel-like structures in human venous endothelial cells (HUVECs) were detected. The expression of ERβ, NF-κB p65, p-NF-κB p65, Ki67 (a proliferation marker), vascular endothelial growth factor A (VEGF-A) and matrix metalloproteinase 2 (MMP-2), the DNA binding activity of NF-κB p65, the content of VEGF-A, and the activity of MMP-2 were detected in SGC7901 and MKN45 cells.ResultsThe transfection of pEGFP-C1-ERβ significantly increased the expression of ERβ in SGC7901 and MKN45 cells (P < 0.05). Overexpression of ERβ in SGC7901 and MKN45 cells significantly decreased the cell activity, cell number in G2/M phase, cell migration, the expression of Ki67, VEGF-A and MMP-2, VEGF-A content, MMP-2 activity, as well as the number of vessel-like structures formed by HUVECs (P < 0.05). Overexpression of ERβ also significantly decreased the DNA binding activity and the expression of p-NF-κB p65 in SGC7901 and MKN45 cells (P < 0.05). The anti-tumor effect of ERβ overexpression on GC cells was reversed by the intervention of PMA (P < 0.05).ConclusionOverexpression of ERβ inhibited the proliferation, migration, and angiogenesis of GC cells through inhibiting NF-κB signaling.

The Role of Oestrogen Receptor Beta (ERβ) in the Aetiology and Treatment of Type 2 Diabetes Mellitus.

Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERβ) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERβ as a therapeutic target. Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERβ shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERβ receptor and underscore its therapeutic potential. Studies are needed to further elucidate the exact mechanism underlying the role of ERβ activation as a therapeutic approach in the management of type 2 diabetes.

Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma.

The role of estrogen receptor beta (ER-β) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-β may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-β, phosphorylated ER-β (pER-β), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from the archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. High nuclear expression of ER-β was found in 61.7% and pER-β in 80.6% of the tumors. STAT3 was expressed in 54.3% of the tumor samples, pSTAT3 in 68% and IL-6 in 76.6%. The median overall survival for patients with low pER-β expression was 29 months, whereas for patients with high pER-β expression was 15.1 months (p = 0.016). Multivariate analysis revealed that pER-β expression was an independent factor correlating with shorter overall survival (hazard ratio 1.9; p = 0.013) and disease-free survival (hazard ratio 1.9; p = 0.029). Expression of pER-β constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. These data may help in identifying novel drug targets in PDAC and patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.

140P - The predictive role of estrogen receptor beta (ER-β) in androgen receptor (AR)-positive triple-negative breast cancer (TNBC)

140P - The predictive role of estrogen receptor beta (ER-β) in androgen receptor (AR)-positive triple-negative breast cancer (TNBC)

The pathogenic role of estrogen receptor beta drives in endometriosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

White-to-brown adipose differentiation: role of estrogen receptor beta and the isoflavone genistein

White-to-brown adipose differentiation: role of estrogen receptor beta and the isoflavone genistein

Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells

The ability to propagate mature cells and tissue from pluripotent stem cells offers enormous promise for treating many diseases, including neurodegenerative diseases. Before such cells can be used successfully in neurodegenerative diseases without causing unwanted cell growth and migration, genes regulating growth and migration of neural stem cells need to be well characterized. Estrogen receptor beta (ERβ) is essential for migration of neurons and glial cells in the developing mouse brain. To examine whether ERβ influences differentiation of mouse embryonic stem cells (mESC) into neural lineages, we compared control and ERβ knockout (BERKO) mESCs at defined stages of neural development and examined the effects of an ERβ-selective ligand (LY3201) with a combination of global and targeted gene-expression profiling and the expression of key pluripotency markers. We found that ERβ was induced in embryoid bodies (EBs) and neural precursor cells (NPCs) during development. Proliferation was higher in BERKO NPCs and was inhibited by LY3201. Neurogenesis was reduced in BERKO ES cells, and oligodendrogliogenesis was enhanced. BERKO EBs expressed higher levels of key ectodermal and neural progenitor markers and lower levels of markers for mesoderm and endoderm lineages. ERβ-regulated factors are involved in cell adhesion, axon guidance, and signaling of Notch and GABA receptor pathways, as well as factors important for the differentiation of neuronal precursors into dopaminergic neurons (Engrailed 1) and for the oligodendrocyte fate acquisition (Olig2). Our data suggest that ERβ is an important component for differentiation into midbrain neurons as well as for preventing precocious oligodendrogliogenesis.

The role of estrogen receptor beta in development of the early endometriotic lesion

Ovarian steroids are primary regulators of the growth and maintenance of established endometriotic implants. Sampson’s theory suggests that endometrial cells transported retrograde through the fallopian tubes implant on peritoneal mesothelial cells (PMCs) to initiate the early endometriotic lesions. Our previous studies have shown that menstrual endometrial epithelial cells (EECs) from women with endometriosis demonstrate increased adherence to PMCs compared to similar cells from women without endometriosis. Han et. al. emphasized the importance of estrogen receptor- beta (ER-β) in the growth of the endometriotic lesion and showed that overexpression of ER-β increased invasion in endometriotic cells (1). Here, we examine the effect of ER-β knockdown on the attachment menstrual EECs to PMCs. In vitro studies EECs were immortalized using a telomerase vector. Immortalized cells and parental cells were characterized by genotyping and expression of ER-β as well as other epithelial cell markers. ER-β was knocked-down in immortalized EECs using lentivirus-mediated shRNA transduction. ER-β knockdown was confirmed by RTqPCR and Western analysis. EEC cells with or without ER-β knockdown were used to assess attachment to PMCs in an established in vitro assay (2). Results were analyzed with student t- test. Primary and immortalized cells were 46XX, cytokeratin positive, and vimentin negative confirming their epithelial origin. ER-β knockdown EECs had a significant decrease in attachment compared to parental cells (p=0.02). These findings demonstrate that ER-β knockdown decreases attachment of immortalized EECs to PMCs. Taken together with previous studies demonstrating that overexpression of ER-β increased invasion of endometriotic lesions suggests that ER-β plays a role in the development of the early endometriotic lesion.

Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

Sex-associated differences in bone metastasis formation from breast, lung, and prostate cancer exist in clinical studies, but have not been systematically reviewed. Differences in the bone marrow niche can be attributed to sexual dimorphism, to genetic variations that affect sex hormone levels, or to the direct effects of sex hormones, natural or exogenously delivered. This review describes the present understanding of sex-associated and sex hormone level differences in the marrow niche and in formation of bone metastasis during the transition of these three cancers from treatable disease to an often untreatable, lethal metastatic one. Our purpose is to provide insight into some underlying molecular mechanisms for hormonal influence in bone metastasis formation, and to the potential influence of sexual dimorphism, genetic differences affecting sex assignment, and sex hormone level differences on the bone niche and its favorability for metastasis formation. We reviewed publications in PubMed and EMBASE, including full length manuscripts, case reports, and clinical studies of relevance to our topic. We focused on bone metastasis formation in breast, lung, and prostate cancer because all three commonly present with bone metastases. Several clear observations emerged. For breast cancer bone metastasis formation, estrogen receptor (ER) signaling pathways indicate a role for ER beta (ERβ). Estrogen influences the bone microenvironment, creating and conditioning a favorable niche for colonization and breast cancer progression. For lung cancer, studies support the hypothesis that females have a more favorable bone microenvironment for metastasis formation. For prostate cancer, a decrease in the relative androgen to estrogen balance or a “feminization” of bone marrow favors bone metastasis formation, with a potentially important role for ERβ that may be similar to that in breast cancer. Long-term estrogen administration or androgen blockade in males may feminize the bone marrow niche to one more favorable for bone metastases in prostate cancer. Administration of androgens in females, especially combined with mastectomy, may reduce risk of developing bone metastatic breast cancer. We conclude that it should be considered that females, those with female-leaning genetic variations, or hormonal states that feminize the bone marrow, may offer favorable sites for bone metastases.

Effects of low-dose Bisphenol A on calcium ion influx and on genes of proliferation and differentiation in immortalized human gingival cells in vitro: The role of estrogen receptor beta

ObjectivesRelating to low-dose Bisphenol-A (BPA), there is still a lack of mechanistic studies in oral cells, representing the first targets of BPA by oral intake. The objective of this study was to investigate an assumed mechanistic interrelationship between both low-dose BPA-modulated Calcium ion (Ca2+) influx and cell behavior, and the estrogen receptor β (ERβ), in oral mucosal cells. MethodsIndirect immunofluorescence (IIF) was conducted on estrogen receptor beta (ERβ) activity after 1, 3, and 6days in response to 39nM BPA, 15μM BPA, and 200 pM 17β-Estradiol (E2). In addition to Ca2+ concentration measurement, qPCR for proliferation and differentiation biomarkers was performed, to examine cell behavior. Fulvestrant-mediated ER inhibition was employed to seek for a mechanistic role of ERβ in regulating BPA-emanating effects. ResultsWhile both E2 and BPA yielded ERβ activation, 39nM BPA and 200 pM E2 did not change MKI67 proliferation marker expression, but reduced transcription of differentiation markers. Conversely, 15μM BPA reduced MKI67 transcription, but significantly increased differentiation gene expression and intracellular Ca2+ levels. Fulvestrant-induced ERβ inhibition yielded complete elimination of all E2− and BPA-triggered modulatory effects, suggesting a mechanistic role of activated ERβ for BPA-mediated Ca2+ influx and keratinocyte differentiation. SignificanceConcerning cell behavior, these findings provide significant evidence of a threshold-dependent transcription of proliferation and differentiation-related genes as well as Ca2+ influx in response to 39nM and 15μM low-dose BPA, which identify a mechanistic role of activated ERβ in oral keratinocytes.

Abstract 5640: The prognostic role of estrogen receptor beta in a female cohort of colorectal cancer

Abstract Background: The estrogen receptor beta (ERβ) is the predominant estrogen receptor in the colon mucosa, and has been reported to have anti-proliferative and pro-apoptotic effects. However, the role of estrogen signaling in colorectal cancer (CRC) progression remains unclear. Aim: To investigate the prognostic role of ERβ in a female cohort of CRC. Methods: A tumor tissue microarray of primary CRCs from 333 female patients was stained with a mouse monoclonal anti-ERβ antibody. The intensity of staining was evaluated using immunohistochemistry technique. The expression of ERβ was scored using the semi-quantitative method [IRS (immune-reactive score) = SI (staining intensity) x PP (percentage of positive nuclei)]. Overall survival (OS) and disease-free survival (DFS) were the primary outcomes. Preliminary results are presented. Results: From 321 patients eligible for survival analysis only 315 had successful measurement of ERβ (141 with low expression and 174 with high expression). The univariate analysis showed no effect of ERβ on OS, but high ERβ was associated with lower risk of cancer recurrence as indicated by DFS (HR, 0.61; CI, 0.38-1.02). Cox multivariate analysis indicated that, compared to low expression, high expression of ERβ was significantly associated with a decreased risk of cancer recurrence (HR, 0.39; CI, 0.20-0.77), after adjustment for age, tumor stage, tumor intravascular invasion and hormonal contraception use. Likewise, high ERβ expression was associated with better OS in patients with cancer stage I-III (HR, 0.52; CI, 0.29-0.94) that did not receive adjuvant treatment after operation. Premenopausal women had a higher mean of IRS for ERβ compared to postmenopausal women (p = 0.03). Conclusion: High levels of ERβ significantly correlate with a decreased risk of cancer recurrence in CRC patients. We also noted longer overall survival in the subgroup of patients with cancer stage I-III that had not received adjuvant treatment after operation. The same results of OS were observed for colon cancer patients, but not for rectal cancer patients. A possible explanation could be that most of the rectal cancer patients have undergone radiotherapy before surgery, which might affect the status of ERβ. Citation Format: Geriolda Topi, Roy Ehrnström, Ingrid Palmquist, Marie-Louise Lydrup, Anita Sjölander. The prognostic role of estrogen receptor beta in a female cohort of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5640. doi:10.1158/1538-7445.AM2017-5640

The role of Estrogen Receptor Beta in Prostate Cancer.

The role of Estrogen Receptor Beta in Prostate Cancer.

ER\u03b21 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

BackgroundIncreasing evidence has indicated an important role for estrogen receptor beta 1 (ERβ1) in breast cancer. However, the role of ERβ1 in the metastasis of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) and the underlying mechanisms are still unknown.MethodsStable ERβ1-expressing TNBC cell lines were generated for this study. We detected the abilities of cell migration and invasion by wound-healing and transwell assays and the expression of E-cadherin and N-cadherin by quantitative RT-PCR (qRT-PCR) and western blotting assays in TNBC cell lines. Chromatin immunoprecipitation (ChIP) analysis was performed to assess the effect of AR on ERβ1 promoter. Tumor metastasis was evaluated in vivo using a lung metastasis mouse model. Lastly, immunohistochemical expression of ERβ1 in TNBC tissues was analyzed and correlated with clinicopathological features.ResultsERβ1 suppressed the invasion and migration abilities of AR-positive TNBC cells and induced the downregulation of ZEB1. ZEB1 overexpression abrogated the increase in E-cadherin expression and the decrease in N-cadherin expression modulated by ERβ1. A lung metastasis mouse model showed that the incidence of metastasis was lower in ERβ1-expressing TNBC cells. Further, AR activation increased the anti-metastatic effect of ERβ1 in AR-positive TNBC cells, which accelerated ERβ1 transcription by functioning as a transcription factor that bound to the promoter of ERβ1. No significant change was observed in AR expression induced by ERβ1. Immunohistochemistry (IHC) analysis of TNBC clinical samples showed that ERβ1 and AR were positive in 31.7% and 23.2% of samples, respectively. ERβ1 expression was negatively correlated with ZEB1 expression and lymph node metastasis, and positively correlated with the expression of AR and E-cadherin.ConclusionOur findings suggested a potential role of ERβ1 in metastasis of AR-positive TNBC and provided novel insights into the mechanism of action of ERβ1 and the possible relationship between ERβ1 and AR.

Estrogen receptor beta as a prognostic factor in breast cancer patients: A systematic review and meta-analysis.

BackgroundThe prognostic role of estrogen receptor beta (ERβ) in early-stage breast cancer is unclear. We performed a systematic review and meta-analysis to evaluate the prognostic value of ERβ in early-stage breast cancer patients.MethodWe searched Medline, Embase, and the Web of Science for studies published between 1990 and 2015 that assessed ERβ status in breast cancer patients. A total of 25 studies comprising 9919 patients fitting our inclusion and exclusion criteria were included. The hazard ratios of ERβ status were extracted for diseases free survival (DFS)/) and overall survival (OS). Random or fixed-effects models were used when appropriate, and between-study heterogeneity was assessed.ResultsIn the 20 studies that assessed ERβ status using immunohistochemical (IHC) methods, we observed significantly improved DFS in patients positive for ERβ-1 (HR=0.56, 95%CI 0.40-0.78, P=0.0007) and ERβ-2 (HR=0.67, 95%CI 0.45-1.00, P=0.05). Improved OS was associated with a positive status for pan-ERβ (HR=0.60, 95%CI 0.45-0.80, P=0.0004) and ERβ-2 (HR=0.44, 95%CI 0.31-0.62, P<0.0001). In ERα-positive patients, ERβ positivity was not associated with DFS (HR=0.77, 95%CI 0.46-1.27, P=0.31) or OS (HR=0.64, 95%CI 0.37-1.11, P=0.11). In contrast, ERβ expression was significantly associated with increased DFS (HR=0.37, 95%CI 0.14-0.93, P=0.03) or OS (HR=0.44, 95%CI 0.30-0.65, P<0.0001) in ERα-negative patients. We did not observe an association between ERβ mRNA levels and DFS and OS.ConclusionIn this study, we showed that IHC ERβ status, rather than mRNA levels, is a prognostic factor that is associated with DFS and OS in breast cancer patients. The prognostic value of ERβ may be higher in ERα-negative patients than in ERα-positive patients.

Revisiting the neural role of estrogen receptor beta in male sexual behavior by conditional mutagenesis

Estradiol derived from neural aromatization of gonadal testosterone plays a key role in the perinatal organization of the neural circuitry underlying male sexual behavior. The aim of this study was to investigate the contribution of neural estrogen receptor (ER) β in estradiol-induced effects without interfering with its peripheral functions. For this purpose, male mice lacking ERβ in the nervous system were generated. Analyses of males in two consecutive tests with a time interval of two weeks showed an effect of experience, but not of genotype, on the latencies to the first mount, intromission, pelvic thrusting and ejaculation. Similarly, there was an effect of experience, but not of genotype, on the number of thrusts and mating length. Neural ERβ deletion had no effect on the ability of males to adopt a lordosis posture in response to male mounts, after castration and priming with estradiol and progesterone. Indeed, only low percentages of both genotypes exhibited a low lordosis quotient. It also did not affect their olfactory preference. Quantification of tyrosine hydroxylase- and kisspeptin-immunoreactive neurons in the preoptic area showed unaffected sexual dimorphism of both populations in mutants. By contrast, the number of androgen receptor- and ERα-immunoreactive cells was significantly increased in the bed nucleus of stria terminalis of mutant males.These data show that neural ERβ does not play a crucial role in the organization and activation of the neural circuitry underlying male sexual behavior. These discrepancies with the phenotype of global ERβ knockout models are discussed.