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

Endocrinology ◽  
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.

Loss of Basigin expression in uterine cells leads to subfertility in female mice

2021 ◽  
Author(s):  
Kailiang Li ◽  
Quanxi Li ◽  
Shah Tauseef Bashir ◽  
Brent M Bany ◽  
Romana A Nowak
Keyword(s):  
Knockout Mice ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Female Reproductive Tract ◽  
Conditional Knockout ◽  
Monocarboxylate Transporter ◽  
Female Reproduction ◽  
Serum Progesterone ◽  
Monocarboxylate Transporter 1 ◽  
Conditional Knockout Mice

Abstract Basigin (BSG) is a transmembrane glycoprotein involved in cell proliferation, angiogenesis and tissue remodeling. BSG has been shown to be essential for male and female reproduction although little is known about its role in normal uterine function. To study the potential function of BSG in the female reproductive tract, we generated mice with conditional knockout of Bsg in uterine cells using progesterone receptor-Cre and hypothesized that BSG is required for normal pregnancy in mice. Fertility study data showed that the conditional knockout mice had significantly reduced fertility compared to controls. Ovarian function of the conditional knockout mice appeared normal with no difference in the number of superovulated oocytes collected or in serum progesterone levels between the conditional knockout and the control mice. Uterine tissues collected at various times of gestation showed increased abnormalities in implantation, decidualization, placentation and parturition in the conditional knockout mice. Uterine cross sections on day 5 of pregnancy showed implantation failure and abnormal uterine epithelial differentiation in a large proportion of the conditional knockout mice. There was a compromised decidual response to artificial decidualization stimuli and decreased mRNA and protein levels for decidualization genes in the uteri of the conditional knockout mice. We also observed altered protein expression of monocarboxylate transporter 1 (MCT1), as well as impaired angiogenesis in the conditional knockout uteri compared to the controls. These results support that BSG is required for successful pregnancy through its functions in implantation and decidualization.

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

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2970-2979 ◽  
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.

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

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

scholarly journals Seminal Plasma Triggers the Differential Expression of the Glucocorticoid Receptor (NR3C1/GR) in the Rabbit Reproductive Tract

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2158
Author(s):  
Mateo Ruiz-Conca ◽  
Jaume Gardela ◽  
Amaia Jauregi-Miguel ◽  
Cristina A. Martinez ◽  
Heriberto Rodríguez-Martinez ◽  
...  
Keyword(s):  
Differential Expression ◽  
Seminal Plasma ◽  
Time Course ◽  
Reproductive Tract ◽  
Receptor Gene ◽  
Early Embryo ◽  
Female Reproductive Tract ◽  
Relevant Role ◽  
Morula Stage ◽  
Embryo Transport

Rabbits are interesting as research animal models for reproduction, due to their condition of species of induced ovulation, with the release of endogenous gonadotropin-releasing hormone (GnRH) due to coitus. Glucocorticoid (GC) signaling, crucial for physiological homeostasis, is mediated through a yet unclear mechanism, by the GC receptor (NR3C1/GR). After mating, the female reproductive tract undergoes dynamic modifications, triggered by gene transcription, a pre-amble for fertilization and pregnancy. This study tested the hypothesis that when ovulation is induced, the expression of NR3C1 is influenced by sperm-free seminal plasma (SP), similarly to after mating (whole semen), along the different segments of the internal reproductive tract of female rabbits. Semen (mating) was compared to vaginal infusion of sperm-free SP (Experiment 1), and changes over time were also evaluated, i.e., 10, 24, 36, 68, and 72 h post-mating, corresponding to specific stages, i.e., ovulation, fertilization, and the interval of early embryo development up to the morula stage (Experiment 2). All does were treated with GnRH to induce ovulation. Samples were retrieved from seven segments of the reproductive tract (from the cervix to infundibulum), at 20 h post-mating or sperm-free SP infusion (Experiment 1) or at 10, 24, 36, 68, and 72 h post-mating (Experiment 2). Gene expression of NR3C1 was analyzed by qPCR. Results showed an increase in NR3C1 expression in the infundibulum compared to the other anatomical regions in the absence of spermatozoa when sperm-free SP infusion was performed (Experiment 1). Moreover, during the embryo transport through the oviduct, the distal isthmus was time-course upregulated, especially at 72 h, when morulae are retained in this anatomical region, while it was downregulated in the distal uterus at 68 h (Experiment 2). The overall results suggest that NR3C1, the GC receptor gene, assessed in the reproductive tract of does for the first time, shows differential expression changes during the interval of oviductal and uterine embryo transport that may imply a relevant role of the GC action, not only close to the site of ovulation and fertilization, but also in the endometrium.

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

Endocrinology ◽  
2020 ◽  
Vol 161 (6) ◽  
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.

scholarly journals Oestradiol transmission from males to females in the context of the Bruce and Vandenbergh effects in mice (Mus musculus)

Reproduction ◽  
2012 ◽  
Vol 143 (4) ◽  
pp. 539-548 ◽  
Author(s):  
Adam C Guzzo ◽  
Jihwan Jheon ◽  
Faizan Imtiaz ◽  
Denys deCatanzaro
Keyword(s):  
Mus Musculus ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Male Mice ◽  
Reproductive Maturity ◽  
Reproductive Tissues ◽  
Uterine Growth ◽  
Blastocyst Implantation ◽  
Bladder Urine

Male mice actively direct their urine at nearby females, and this urine reliably contains unconjugated oestradiol (E2) and other steroids. Giving inseminated females minute doses of exogenous E2, either systemically or intranasally, can cause failure of blastocyst implantation. Giving juvenile females minute doses of exogenous E2 promotes measures of reproductive maturity such as uterine mass. Here we show that tritium-labelled E2 (3H-E2) can be traced from injection into novel male mice to tissues of cohabiting inseminated and juvenile females. We show the presence of 3H-E2 in male excretions, transmission to the circulation of females and arrival in the female reproductive tract. In males, 3H-E2 given systemically was readily found in reproductive tissues and was especially abundant in bladder urine. In females, 3H-E2 was found to enter the system via both nasal and percutaneous routes, and was measurable in the uterus and other tissues. As supraoptimal E2 levels can both interfere with blastocyst implantation in inseminated females and promote uterine growth in juvenile females, we suggest that absorption of male-excreted E2 can account for major aspects of the Bruce and Vandenbergh effects.

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