Estrogen Receptor α Antagonists Mediate Changes in CCL20 and CXCL1 Secretions in the Murine Female Reproductive Tract

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.

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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.

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Decreased Expression of Wnt7a mRNA Is Inversely Associated with the Expression of Estrogen Receptor-α in Human Uterine Leiomyoma

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.1.7276 ◽

2001 ◽

Vol 86 (1) ◽

pp. 454-457

Author(s):

Shuanfang Li ◽

Tung-Chin Chiang ◽

Gloria R. Davis ◽

Rachele M. Williams ◽

Valerie P. Wilson ◽

...

Keyword(s):

Estrogen Receptor ◽

Uterine Leiomyoma ◽

Molecular Mechanisms ◽

Reproductive Tract ◽

Mrna Level ◽

Critical Role ◽

Estrogen Receptor Α ◽

Female Reproductive Tract ◽

Inverse Association ◽

Sex Steroid Hormone

Wnt-7a gene not only guides the development of the anterior-posterior axis in the female reproductive tract, but also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function. This gene is also responsive to changes in the levels of sex steroid hormone in the female reproductive tract. To explore the molecular mechanisms underlying the pathogenesis of uterine leiomyoma, the expression of Wnt7a mRNA in the leiomyoma has been assessed. RT-PCR was performed on uterine leiomyomas and the adjacent myometria. Of 30 cases of leiomyomas studied, 67% showed a decreased mRNA level as compared to the paired myometria. On the other hand, estrogen receptor-α (ER-α) mRNA is hyper-expressed in 67% of the leiomyomas as compared to their paired myometrium. An inverse association at mRNA expression was found between Wnt7a and ER-α. Miller et alhas shown that fetal exposure of DES results in de-regulation of Wnt7a during uterine morphogenesis. Referring to their results, we have postulated that hypersensitivity of leiomyoma cells to estrogen may deregulate the Wnt7a expression. Decreased expression of Wnt7a may lead to loss of control in patterning of the myometrium and result in development of leiomyoma

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In ovo treatment with an estrogen receptor alpha selective agonist causes precocious development of the female reproductive tract of the American alligator (Alligator mississippiensis)

General and Comparative Endocrinology ◽

10.1016/j.ygcen.2016.02.026 ◽

2016 ◽

Vol 238 ◽

pp. 96-104 ◽

Cited By ~ 5

Author(s):

Brenna M. Doheny ◽

Satomi Kohno ◽

Benjamin B. Parrott ◽

Louis J. Guillette

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Alpha ◽

Reproductive Tract ◽

Female Reproductive Tract ◽

Alligator Mississippiensis ◽

American Alligator ◽

In Ovo ◽

Receptor Alpha ◽

Selective Agonist ◽

Precocious Development

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ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile

Endocrinology ◽

10.1210/endocr/bqaa050 ◽

2020 ◽

Vol 161 (6) ◽

Cited By ~ 1

Author(s):

Yin Li ◽

Katherine J Hamilton ◽

Lalith Perera ◽

Tianyuan Wang ◽

Artiom Gruzdev ◽

...

Keyword(s):

Molecular Mechanisms ◽

Reproductive Tract ◽

Biological Effects ◽

Estrogen Receptor Α ◽

Female Reproductive Tract ◽

Receptor Complexes ◽

Esr1 Gene ◽

Esr1 Mutations

Abstract Estrogen insensitivity syndrome (EIS) arises from rare mutations in estrogen receptor-α (ERα, encoded by ESR1 gene) resulting in the inability of estrogen to exert its biological effects. Due to its rarity, mutations in ESR1 gene and the underlying molecular mechanisms of EIS have not been thoroughly studied. Here, we investigate known ESR1 mutants, Q375H and R394H, associated with EIS patients using in vitro and in vivo systems. Comparison of the transcriptome and deoxyribonucleic acid methylome from stable cell lines of both Q375H and R394H clinical mutants shows a differential profile compared with wild-type ERα, resulting in loss of estrogen responsiveness. Molecular dynamic simulation shows that both ESR1 mutations change the ERα conformation of the ligand-receptor complexes. Furthermore, we generated a mouse model Esr1-Q harboring the human mutation using CRISPR/Cas9 genome editing. Female and male Esr1-Q mice are infertile and have similar phenotypes to αERKO mice. Overall phenotypes of the Esr1-Q mice correspond to those observed in the patient with Q375H. Finally, we explore the effects of a synthetic progestogen and a gonadotropin-releasing hormone inhibitor in the Esr1-Q mice for potentially reversing the impaired female reproductive tract function. These findings provide an important basis for understanding the molecular mechanistic consequences associated with EIS.

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