Estrogen Responsiveness and the Estrogen Receptor during Development of the Murine Female Reproductive Tract. (estrogen receptor/autoradiography/female reproductive tract)

The porcine female reproductive tract undergoes estrogen receptor (ER) α-dependent development after birth (postnatal day=PND 0), the course of which can determine adult uterine function. Uterotrophic effects of relaxin (RLX) in the porcine neonate are age specific and may involve ER activation. Here, objectives were to determine effects of RLX and estrogen administered from birth on uterine and cervical growth and expression of ERα, vascular endothelial growth factor (VEGF), and the RLX receptor (RXFP1). On PND 0, gilts were treated with the antiestrogen ICI 182 780 (ICI) or vehicle alone and, 2 h later, were given estradiol-17β (E) or porcine RLX for 2 days. Neither RLX nor E affected uterine wet weight or protein content on PND 2. However, RLX, but not E, increased cervical wet weight and protein content when compared with controls. Pretreatment with ICI did not inhibit RLX-stimulated cervical growth. Uterine and cervical ERα increased in response to RLX, but not E. Both RLX and E increased VEGF in the uterus and cervix on PND 2. Pretreatment with ICI increased VEGF in both tissues and increased RLX-induced cervical VEGF. In the uterus E, but not RLX, increased RXFP1 mRNA. In the cervix, E increased RXFP1 gene expression whereas RLX decreased it. Results indicate that the neonatal uterus and cervix are sensitive to E and RLX and that growth responses to RLX in these tissues differ by PND 2. Effects of RLX on uterine and cervical ERα and VEGF expression may be important for neonatal reproductive tract development.

Download Full-text

G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

Obstetrics and Gynecology International ◽

10.1155/2013/472720 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 76

Author(s):

Whitney K. Petrie ◽

Megan K. Dennis ◽

Chelin Hu ◽

Donghai Dai ◽

Jeffrey B. Arterburn ◽

...

Keyword(s):

Estrogen Receptor ◽

Endometrial Cancer ◽

Tumor Growth ◽

G Protein ◽

Reproductive Tract ◽

Female Reproductive Tract ◽

Endometrial Tumor ◽

Selective Ligands ◽

G Protein Coupled

Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERαand ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activityin vivoprevents estrogen-mediated tumor growth.

Download Full-text

Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.90.23.11162 ◽

1993 ◽

Vol 90 (23) ◽

pp. 11162-11166 ◽

Cited By ~ 1199

Author(s):

D B Lubahn ◽

J S Moyer ◽

T S Golding ◽

J F Couse ◽

K S Korach ◽

...

Keyword(s):

Estrogen Receptor ◽

Reproductive Tract ◽

Receptor Gene ◽

Fold Increase ◽

Female Reproductive Tract ◽

Corpora Lutea ◽

Loss Of Function ◽

Estrogen Receptor Gene ◽

Estradiol Treatment ◽

Male And Female

Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human estrogen receptor gene mutations are known, unlike the androgen receptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disrupting the estrogen receptor gene by gene targeting. Both male and female animals survive to adulthood with normal gross external phenotypes. Females are infertile; males have a decreased fertility. Females have hypoplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatment at 40 micrograms/kg stimulates a 3- to 4-fold increase in uterine wet weight and alters vaginal cornification, but the uteri and vagina do not respond in the animals with the estrogen receptor gene disruption. Prenatal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.

Download Full-text

Estrogen Receptor-α Knockout Mice Exhibit Resistance to the Developmental Effects of Neonatal Diethylstilbestrol Exposure on the Female Reproductive Tract

Developmental Biology ◽

10.1006/dbio.2001.0413 ◽

2001 ◽

Vol 238 (2) ◽

pp. 224-238 ◽

Cited By ~ 133

Author(s):

John F. Couse ◽

Darlene Dixon ◽

Mariana Yates ◽

Alicia B. Moore ◽

Liang Ma ◽

...

Keyword(s):

Estrogen Receptor ◽

Knockout Mice ◽

Reproductive Tract ◽

Estrogen Receptor Α ◽

Female Reproductive Tract ◽

Developmental Effects

Download Full-text

Selective Loss of Estrogen Receptor Alpha in Female Reproductive Tract Causes Infertility and Loss of Estrogen Induced Uterine Responses.

Biology of Reproduction ◽

10.1093/biolreprod/87.s1.334 ◽

2012 ◽

Vol 87 (Suppl_1) ◽

pp. 334-334

Author(s):

Wipawee Winuthayanon ◽

Sylvia C. Hewitt ◽

John P. Lydon ◽

Francesco J. DeMayo ◽

Kenneth S. Korach

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Alpha ◽

Reproductive Tract ◽

Female Reproductive Tract ◽

Receptor Alpha ◽

Selective Loss

Download Full-text

Oviductal Retention of Embryos in Female Mice Lacking Estrogen Receptor α in the Isthmus and the Uterus

Endocrinology ◽

10.1210/endocr/bqz033 ◽

2019 ◽

Vol 161 (2) ◽

Author(s):

Gerardo G B Herrera ◽

Sydney L Lierz ◽

Emily A Harris ◽

Lauren J Donoghue ◽

Sylvia C Hewitt ◽

...

Keyword(s):

Estrogen Receptor ◽

Reproductive Tract ◽

Estrogen Receptor Α ◽

Female Reproductive Tract ◽

Conditional Knockout ◽

Developmental Defect ◽

Female Reproduction ◽

Serum Progesterone ◽

Reproductive Tissues ◽

Embryo Transport

Abstract Estrogen receptor α (ESR1; encoded by Esr1) is a crucial nuclear transcription factor for female reproduction and is expressed throughout the female reproductive tract. To assess the function of ESR1 in reproductive tissues without confounding effects from a potential developmental defect arising from global deletion of ESR1, we generated a mouse model in which Esr1 was specifically ablated during postnatal development. To accomplish this, a progesterone receptor Cre line (PgrCre) was bred with Esr1f/f mice to create conditional knockout of Esr1 in reproductive tissues (called PgrCreEsr1KO mice) beginning around 6 days after birth. In the PgrCreEsr1KO oviduct, ESR1 was most efficiently ablated in the isthmic region. We found that at 3.5 days post coitus (dpc), embryos were retrieved from the uterus in control littermates while all embryos were retained in the PgrCreEsr1KO oviduct. Additionally, serum progesterone (P4) levels were significantly lower in PgrCreEsr1KO compared to controls at 3.5 dpc. This finding suggests that expression of ESR1 in the isthmus and normal P4 levels allow for successful embryo transport from the oviduct to the uterus. Therefore, alterations in oviductal isthmus ESR1 signaling and circulating P4 levels could be related to female infertility conditions such as tubal pregnancy.

Download Full-text

An Estrogen Receptor-α Knock-In Mutation Provides Evidence of Ligand-Independent Signaling and Allows Modulation of Ligand-Induced Pathways in Vivo

Endocrinology ◽

10.1210/en.2007-1526 ◽

2008 ◽

Vol 149 (6) ◽

pp. 2970-2979 ◽

Cited By ~ 45

Author(s):

Kerstin W. Sinkevicius ◽

Joanna E. Burdette ◽

Karolina Woloszyn ◽

Sylvia C. Hewitt ◽

Katherine Hamilton ◽

...

Keyword(s):

Estrogen Receptor ◽

Mammary Gland ◽

Growth Factor ◽

Reproductive Tract ◽

Estrogen Receptor Α ◽

Female Reproductive Tract ◽

In Vivo Evaluation ◽

Gland Development

Estrogen-nonresponsive estrogen receptor-α (ERα) knock-in (ENERKI) mice were generated to distinguish between ligand-induced and ligand-independent ER-α actions in vivo. These mice have a mutation [glycine 525 to leucine (G525L)] in the ligand-binding domain of ERα, which significantly reduces ERα interaction with and response to endogenous estrogens, whereas not affecting growth factor activation of ligand-independent pathways. ENERKI mice had hypoplastic uterine tissues and rudimentary mammary gland ductal trees. Females were infertile due to anovulation, and their ovaries contained hemorrhagic cystic follicles because of chronically elevated levels of LH. The ENERKI phenotype confirmed that ligand-induced activation of ERα is crucial in the female reproductive tract and mammary gland development. Growth factor treatments induced uterine epithelial proliferation in ovariectomized ENERKI females, directly demonstrating that ERα ligand-independent pathways were active. In addition, the synthetic ERα selective agonist propyl pyrazole triol (PPT) and ER agonist diethylstilbestrol (DES) were still able to activate ligand-induced G525L ERα pathways in vitro. PPT treatments initiated at puberty stimulated ENERKI uterine development, whereas neonatal treatments were needed to restore mammary gland ductal elongation, indicating that neonatal ligand-induced ERα activation may prime mammary ducts to become more responsive to estrogens in adult tissues. This is a useful model for in vivo evaluation of ligand-induced ERα pathways and temporal patterns of response. DES did not stimulate an ENERKI uterotrophic response. Because ERβ may modulate ERα activation and have an antiproliferative function in the uterus, we hypothesize that ENERKI animals were particularly sensitive to DES-induced inhibition of ERα due to up-regulated uterine ERβ levels.

Download Full-text