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Putative pathway of gonadotrophin stimulation of uterine prostaglandins. LH and FSH bind to their receptors (R) and, acting through G-protein (G), activate both adenylate cyclase (AC) and phospholipase C (PLC) pathways. In our putative model, gonadotrophin receptor is coupled to Gi or Gq proteins, or both, to activate PLC and Gs to activate AC. Products of both the AC and PLC pathways mobilize Ca 2+ from intracellular stores in the endoplasmic reticulum. Activation of protein kinase C (PKC) by Ca 2+ and diacylglycerol (DAG), activation of protein kinase A (PKA) by cAMP and activation of calmodulin by Ca 2+ then act, independently or synergically, to promote an increase in cyclooxygenase (COX)-2.
Source publication
Binding sites for LH/hCG are found in the uterus of several species, including humans. In cattle and pigs, the LH receptor, its mRNA and LH receptor protein are present in the uterus throughout the oestrous cycle, and maximum expression occurs at the luteal phase. GnRH receptor is also expressed maximally in the human endometrium at the luteal phas...
Context in source publication
Context 1
... . The increased amounts of free Ca 2+ can bind to regulatory proteins such as calmodulin (Berridge, 1993). Ca 2+ -bound calmodulin can interact with many enzymes and may enhance or suppress their activity, for example, COX-2 and production of PG. Increasing Ca 2+ in concert with DAG is also essential for activating protein kinase C to promote PGs (Fig. ...
Citations
... Hormones involved in human bone metabolism, including sex hormones, growth hormone and parathyroid hormone, show a disturbed pattern of production and secretion in PCOS [41]. Given the LH receptor expression in the endometrium [42,43], high LH level in PCOS could directly influence endometrial pathophysiology. In high responders, decreased embryo implantation has been reported regardless of embryo quality, possibly due to a negative effect of supraphysiological circulating estradiol on the endometrium [44,45]. ...
Background
To compare the expression levels of long non-coding RNA (lncRNA) and messenger RNA (mRNA) in pre-receptive endometrium between patients with Polycystic Ovary Syndrome (PCOS)and normal ovulation undergoing in vitro fertilization-embryo transfer (IVF-ET).
Methods
Endometrial tissues were collected with endometrial vacuum curette in pre-receptive phase (3 days after oocytes retrieval) from PCOS and control groups. LncRNAs and mRNAs of endometrium were identified via RNA sequencing and alignments. A subset of 9 differentially expressed lncRNAs and 11 mRNAs were validated by quantitative reverse transcription polymerase chain reaction(qRT-PCR)in 22 PCOS patients and 18 ovulation patients. The function of mRNAs with differential expression patterns were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG).
Results
We found out 687 up-regulated and 680 down-regulated mRNAs, as well as 345 up-regulated and 63 down-regulated lncRNAs in the PCOS patients in contrast to normal ovulation patients. qRT-PCR was used to detect the expression of 11 mRNAs, and validated that the expression of these 6 mRNAs CXCR4, RABL6, OPN3, SYBU, IDH1, NOP10 were significantly elevated among PCOS patients, and the expression of ZEB1 was significantly decreased. qRT-PCR was performed to detect the expression of 9 lncRNAs, and validated that the expression of these 7 lncRNAs IDH1-AS1, PCAT14, FTX, DANCR, PRKCQ-AS1, SNHG8, TPT1-AS1 were significantly enhanced among PCOS patients. Bioinformatics analysis showed that differentially expressed genes (DEGs) involved KEGG pathway were tyrosine metabolism, PI3K-Akt pathway, metabolic pathway, Jak-STAT pathway, pyruvate metabolism, protein processing in endoplasmic reticulum, oxidative phosphorylation and proteasome. The up-regulation of GO classification was involved in ATP metabolic process, oxidative phosphorylation, RNA catabolic process, and down-regulation of GO classification was response to corticosteroid, steroid hormone, and T cell activation.
Conclusion
Our results determined the characteristics and expression profile of endometrial lncRNAs and mRNAs in PCOS patients in pre-receptive phase, which is the day 3 after oocytes retrival. The possible pathways and related genes of endometrial receptivity disorders were found, and those lncRNAs may be developed as a predictive biomarker of endometrium in pre-receptive phase.
... VOL: 16 ISSUE: 10 OCTOBER 2023 Licensed under CC BY 4.0 endometrium in endometriosis patients has steroidogenic factor 1 (SF-1) and aromatase, leading to increased estradiol production. Estradiol enhances the expression of COX-2 and the formation of Prostaglandin E2 (PGE2) [9]. COX-2 influences the synthesis of prostaglandins, particularly Prostaglandin F-2α (PGF-2α), in the luminal endometrial epithelium and plays a crucial role in the inflammatory process. ...
The endometrium produces MUCIN-1 (MUC-1) and cyclooxygenase-2 (COX-2), which are essential for implantation. MUC-1 is required for adhesion, while COX-2 is necessary for decidualization. Variations or polymorphisms in MUC-1 and COX-2 can lead to changes in endometrial receptivity. This study investigated the relationship between MUC-1 and COX-2 polymorphisms and endometrial receptivity in endometriosis patients. Blood DNA samples were collected from 35 patients with endometriosis and 32 healthy patients between days 19 to 24 of their menstrual cycle (secretory phase). MUC-1 polymorphism was determined using the Amplification Refractory Mutation System (ARMS), and COX-2 gene polymorphism was assessed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). The frequency distribution of gene polymorphisms between the two groups was compared using bivariate analysis. There were seven genotypic combinations of MUC-1 and COX-2: AAGC; AAGG; GACC; GAGC; GAGG; GGGC; GGGG. The AAGC genotype combination test was significant, with an OR=6.43 (95% CI:1.09–7.62) and p=0.01. In conclusion, combining MUC-1 and COX-2 (AAGC) genotypes results in endometrial receptivity defects in endometriosis.
... GnRH analogs may have the potential to act on the endometrium and early stages of embryos. Both GnRH and GnRH-R have been reported to be expressed in both the epithelium and the stroma of the endometrium and reach the highest levels in the secretory phase of the menstrual cycle [7,8,30,31], suggesting that the GnRH-GnRH-R pathway has functional roles in endometrium receptivity and implantation. GnRHa therapy may enhance the expression of endometrial integrin αvβ3, an adhesive molecule, and implantationrelated factors, such as HOXA10 and LIF, in humans [11,12] and mice [32,33]. ...
Background
GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression.
Methods
The retrospective cohort study included a total of 350 patients undergoing GnRHa-HRT FET cycles. The study group included 179 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 171 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups.
Results
Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 2.04, 95% CI 1.20–3.47, P = 0.008) and live birth (OR 2.03, 95% CI 1.20–3.45, P = 0.009). When the subgroup of patients with recurrent implantation failure was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 4.55, 95% CI 1.69–12.30, P = 0.003) and live birth (OR 4.30, 95% CI 1.59–11.65, P = 0.004).
Conclusions
Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol.
... GnRH analogs may have the potential to act on the endometrium and early stages of embryos. Both GnRH and GnRH-R have been reported to be expressed in both the epithelium and the stroma of the endometrium and reach the highest levels in the secretory phase of the menstrual cycle (7,8,29,30), suggesting that the GnRH-GnRH-R pathway has functional roles in endometrium receptivity and implantation. GnRHa therapy may enhance the expression of endometrial integrin αvβ3, an adhesive molecule, and implantation-related factors, such as HOXA10 and LIF, in humans (11,12) and mice (31,32). ...
Background
GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression.
Methods
The retrospective cohort study included a total of 414 patients undergoing GnRHa-HRT FET cycles. The study group included 216 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 198 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups.
Results
Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 1.66, 95% CI 1.01–2.72, P = 0.048) and live birth (OR 1.67, 95% CI 1.01–2.75, P = 0.044). When the subgroup of patients with recurrent implantation failure (RIF) was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 2.79, 95% CI 1.14–6.82, P = 0.024) and live birth (OR 2.89, 95% CI 1.15–7.22, P = 0.023).
Conclusions
Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol, especially in RIF patients.
... FSHR has been reported to be expressed in the endometrium (38,39,41,90,91), and aberrantly expressed in endometriosis (49,50), a condition that increases risk of EC (92). Considering the high circulating FSH levels in premenopausal women with EC, and in postmenopausal women where EC incidence is highest, may suggest a role for FSH/FSHR in these patient groups. ...
Follicle-stimulating hormone (FSH) and its G protein-coupled receptor, FSHR, represents a paradigm for receptor signaling systems that activate multiple and complex pathways. Classically, FSHR activates Gαs to increase intracellular levels of cAMP, but its ability to activate other G proteins, and β-arrestin-mediated signaling is well documented in many different cell systems. The pleiotropic signal capacity of FSHR offers a mechanism for how FSH drives multiple and dynamic downstream functions in both gonadal and non-gonadal cell types, including distinct diseases, and how signal bias may be achieved at a pharmacological and cell system-specific manner. In this study, we identify an additional mechanism of FSH-mediated signaling and downstream function in the endometrial adenocarcinoma Ishikawa cell line. While FSH did not induce increases in cAMP levels, this hormone potently activated pertussis toxin sensitive Gαi/o signaling. A selective allosteric FSHR ligand, B3, also activated Gαi/o signaling in these cells, supporting a role for receptor-mediated activation despite the low levels of FSHR mRNA. The low expression levels may attribute to the lack of Gαs/cAMP signaling as increasing FSHR expression resulted in FSH-mediated activation of the Gαs pathway. Unlike prior reports for FSH-mediated Gαs/cAMP signaling, FSH-mediated Gαi/o signaling was not affected by inhibition of dynamin-dependent receptor internalization. While chronic FSH did not alter cell viability, FSH was able to increase lipid droplet size. The β-arrestins are key adaptor proteins known to regulate FSHR signaling. Indeed, a rapid, FSH-dependent increase in interactions between β-arrestin1 and Gαi1 was observed via NanoBiT complementation in Ishikawa cells. Furthermore, both inhibition of Gαi/o signaling and siRNA knockdown of β-arrestin 1/2 significantly reduced FSH-induced lipid droplet accumulation, implying a role for a Gαi/o/β-arrestin complex in FSH functions in this cell type. As FSH/FSHR has been implicated in distinct hormone-dependent cancers, including endometrial cancer, analysis of the cancer genome database from 575 human endometrial adenocarcinoma tumors revealed that a subpopulation of samples expressed FSHR. Overall, this study highlights a novel mechanism for FSHR signal pleiotropy that may be exploited for future personalized therapeutic approaches.
... There have been several reports regarding the extragonadal expression of FSHR, suggesting the physiological functions of FSH.Shemesh reported that the gonadotropin receptor showing a dynamic pattern of expression in extragonadal reproductive tissue indicated its substantial role in the molecular autocrine-paracrine regulation of the oestrous cycle. 8) Furthermore, the LH receptor was expressed in the endometrium, myometrium, and cervix, but the FSH receptor was expressed mainly in the cervix.8) Julie et al. ...
Follicle-stimulating hormone receptor (FSHR) mutation is a rare cause of amenorrhea. We report the first case of FSHR mutations in Korea. Two female siblings, aged 16 (patient 1) and 19 (patient 2) years, were referred to the pediatric endocrinology clinic because of primary amenorrhea despite normal breast budding. Gonadotropin-releasing hormone stimulation test showed markedly elevated luteinizing hormone and follicle-stimulating hormone with a relatively low level of estrogen, suggesting hypergonadotropic hypogonadism. Pelvic magnetic resonance imaging revealed a bicornuate uterus in patient 1 and uterine hypoplasia with thinning of the endometrium in patient 2. The progesterone challenge test revealed no withdrawal of bleeding. After two months of administration of combined oral contraceptives, menarche was initiated at regular intervals. To determine the genetic cause of amenorrhea in these patients, whole exome sequencing (WES) was performed, which revealed a compound heterozygous FSHR mutation, c.1364T>G (p.Val455Gly) on exon 10, and c.374T>G (p.Leu125Arg) on exon 4; both of which were novel mutations and were confirmed by Sanger sequencing. The patients maintained regular menstruation and improved bone mineral density while taking combined oral contraceptives, calcium, and vitamin D. Therefore, FSHR mutations can be the cause of amenorrhea in Koreans, and WES facilitates diagnosing the rare cause of amenorrhea.
... Hormonal modulation of uterine contractility is proven by steroid hormones, oxytocin and B 2 adrenergic agonists and their receptor expression [6]. There are several in vitro and in vivo studies investigating the dose-dependent, species-specific and in different sexual phase effect of various reproductive hormones including estradiol [3], progestogens [7,8], chorionic gonadotrophin [9,10], prostaglandins [11,12] and oxytocin [13,14] on uterine contractile activity. However, there is limited information about the effects of GnRH and synthetic GnRH agonists on uterine contractility. ...
... Therefore, an observed decrease in A4 production by myometrial tissue exposed to an EMF [8] may decrease the myometrial potential for structural remodeling required during pregnancy. Importantly, embryo-maternal dialog during the early stages of pregnancy involves elements of the immune system and the action of cytokines, gonadotropins, and growth factors [15][16][17]. It was established that cytokines, gonadotropins, and growth factors affect myometrial activity [18][19][20][21]. ...
The electromagnetic field (EMF) affects the physiological processes in mammals, but the molecular background of the observed alterations remains not well established. In this study was tested the effect of short duration (2 h) of the EMF treatment (50 Hz, 8 mT) on global transcriptomic alterations in the myometrium of pigs during the peri-implantation period using next-generation sequencing. As a result, the EMF treatment affected the expression of 215 transcript active regions (TARs), and among them, the assigned gene protein-coding biotype possessed 90 ones (differentially expressed genes, DEGs), categorized mostly to gene ontology terms connected with defense and immune responses, and secretion and export. Evaluated DEGs enrich the KEGG TNF signaling pathway, and regulation of IFNA signaling and interferon-alpha/beta signaling REACTOME pathways. There were evaluated 12 differentially expressed long non-coding RNAs (DE-lnc-RNAs) and 182 predicted single nucleotide variants (SNVs) substitutions within RNA editing sites. In conclusion, the EMF treatment in the myometrium collected during the peri-implantation period affects the expression of genes involved in defense and immune responses. The study also gives new insight into the mechanisms of the EMF action in the regulation of the transcriptomic profile through lnc-RNAs and SNVs.
... During IVF, GnRH-ant inhibits the luteinizing hormone (LH) peak by competitive binding with GnRH to GnRH receptors on the surface of hypothalamus and adenohypophysis cells. However, the GnRH receptor is also expressed in endometrial tissue, and GnRH-ant could act antagonize GnRH signaling in endometrial cells [5][6][7], which may be detrimental to endometrial receptivity. GnRH-ant treatment can alter the migration of endometrial epithelial cells [8], and can increase abundance of uterine natural killer (uNK) cell numbers and elevate perforin expression [9]. ...
Background
The gonadotropin-releasing hormone (GnRH) antagonist protocol for in vitro fertilization (IVF) often leads to lower pregnancy rates compared to the GnRH agonist protocol. Decreased endometrial receptivity is one reason for the lower success rate, but the mechanisms underlying this phenomenon remain poorly understood. The S100 calcium protein P (S100P) is a biomarker for endometrial receptivity. Both GnRH antagonist and S100P are involved in mediating cell apoptosis. However, the involvement of S100P in reduced endometrial receptivity during the GnRH antagonist protocol remains unclear.
Methods
Endometrial tissue was collected at the time of implantation window from patients undergoing the GnRH agonist (GnRH-a) or GnRH antagonist (GnRH-ant) protocols, as well as from patients on their natural cycles. Endometrial cell apoptosis and expression levels of S100P, HOXA10, Bax, and Bcl-2 were assessed. Ishikawa cells were cultured to evaluate the effects that GnRH antagonist exposure or S100P up- or down- regulation had on apoptosis.
Results
Endometrial tissue from patients in the GnRH-ant group showed elevated apoptosis and decreased expression of the anti-apoptotic marker Bcl-2. In addition, endometrial expression of S100P was significantly reduced in the GnRH-ant group, and expression of HOXA10 was lower. Immunofluorescence colocalization analysis revealed that S100P was mainly distributed in the epithelium. In vitro experiments showed that knockdown of S100P in Ishikawa cells induced apoptosis, decreased expression of Bcl-2, while overexpression of S100P caused the opposite effects and decreased expression of Bax. Furthermore, endometrial epithelial cells exposed to GnRH antagonist expressed lower levels of S100P and Bcl-2, increased expression of Bax, and had higher rates of apoptosis. The increased apoptosis induced by GnRH antagonist treatment could be rescued by overexpression of S100P.
Conclusions
We found that GnRH antagonist treatment induced endometrial epithelial cell apoptosis by down-regulating S100P, which was detrimental to endometrial receptivity. These results further define a mechanistic role for S100P in contributing to endometrial apoptosis during GnRH antagonist treatment, and suggest that S100P is a potential clinical target to improve the success of IVF using the GnRH antagonist protocol.
... The female reproductive system was governed by peptide (gonadotropins: folliclestimulating hormone, FSH and luteinizing hormone, LH) and steroid (oestrogen, progesterone and testosterone) hormones. The peptide hormones, FSH and LH, were hydrophilic, which elicited cellular response via binding with G-protein-coupled receptors (GPCRs) and activation of the cyclic AMP (cAMP) second-messenger pathway and concurrent pathways, such as inositol trisphosphate (IP3) and diacylglycerol (DAG) [28]. The binding of either FSH or LH with GPCRs on the membrane surface caused shuffling of the α-subunit of G-protein and activation of adenyl cyclase, thereby causing cAMP to activate kinase A to phosphorylate designated proteins and elicit various cellular responses. ...
... Earlier studies of HS on gynaecological problems focused on the applications of HS as (i) an anti-fungal agent for genital tract infection [20,27,28,43], (ii) pain relief for primary dysmenorrhoea [21] and (iii) collagen-promoting actions of honey in the prevention of premature rupture of foetal membranes [22]. Although these studies were conducted on the female reproductive system, no reports were made on the effects of HS on the female hormonal levels, menstrual cycle and symptoms of menopause. ...
Phytochemical contents of honey are presumed to be beneficial to the female reproductive system (FRS). However, the biological effects of honey supplementation (HS) in vivo on the FRS remain unclear. This review aims to investigate the current literature on the effects of HS on the FRS, particularly on the sex hormone profile and reproductive organs (uterus and vagina). A systematic literature search using Scopus, MEDLINE via Ovid and Cochrane Library databases was conducted. Records were screened and identified for preclinical and clinical studies addressing the effects of HS on the FRS. Data on populations, interventions, outcomes and methodological quality were extracted. Studies were synthesised using tables and written summaries. Of the 198 identified records, six fulfilled the inclusion criteria. All six records were used for data extraction: two experimental studies using rats as the model organism and four human clinical studies of honey on female reproductive health. HS elevated the progesterone levels, restrained body weight increase, prevented uterine and vaginal atrophies in ovariectomised rats, attenuated symptoms of candidiasis and improved oxidative status in patients. Current evidence shows that short-term HS following surgical or physiological menopause exerts an oestrogenic, antioxidant and anti-inflammatory effect on the FRS. However, insufficient long-term studies preclude any definitive conclusions.
