Figure - available from: Therapeutic Advances in Endocrinology and Metabolism
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Schematic summary of gonadotropin-releasing hormone intracellular signaling. Gq-protein-mediated stimulation of phospholipase Cβ (PLCb) is the initial phase of GnRH action, which leads to the formation of inositol-3-phosphate (IP3) and diacylglycerol (DAG). The release of intracellular calcium from endoplasmic reticulum is induced by IP3 and DAG activating protein kinase C (PKC) and ERK. GnRH also activates P38 MAPK, c-Jun N-terminal kinase (JNK), and calcium–calmodulin kinase II (CaMK II). Not predominantly, but GnRH is also coupled to GaS protein which are linked to adenylate cyclase and induces rapid cAMP production, which subsequently activates protein kinase A (PKA). cAMP, cyclic adenosine monophosphate; ERK, extracellular-signal-regulated kinase; GnRH, gonadotropin-releasing hormone; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; PIP2, phosphatidylinositol biphosphate.
Source publication
Mammalian reproduction systems are largely regulated by the secretion of two gonadotropins, that is, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The main action of LH and FSH on the ovary is to stimulate secretion of estradiol and progesterone, which play an important role in the ovarian function and reproductive cycle control....
Citations
... Consequently, active calmodulin and activated PKC collaboratively facilitate the release of gonadotropins. Simultaneously, DAG amplifies the activity of Ca 2+ calmodulin, contributing to the release of gonadotropins [26]. ...
... This IP3 promotes intracellular Ca 2+ mobilization [8]. GnRH facilitates the entry of Ca 2+ into gonadotrophs through voltage-operated channels, resulting in an increased cytosolic Ca 2+ concentration primarily responsible for LH release [26]. ...
GnRH is essential for the regulation of mammalian reproductive processes. It regulates the production and release of pituitary gonadotropins, thereby influencing steroidogenesis and gametogenesis. While primarily produced in the hypothalamus, GnRH is also produced in peripheral organs, such as the gonads and placenta. GnRH analogs, including agonists and antagonists, have been synthesized for the reproductive management of animals and humans. This review focuses on the functions of hypothalamic GnRH in the reproductive processes of cattle. In addition to inducing the surge release of LH, the pulsatile secretion of GnRH stimulates the pituitary gland to release FSH and LH, thereby regulating gonadal function. Various GnRH-based products have been synthesized to increase their potency and efficacy in regulating reproductive functions. This review article describes the chemical structures of GnRH and its agonists. This discussion extends to the gene expression of GnRH in the hypothalamus, highlighting its pivotal role in regulating the reproductive process. Furthermore, GnRH is involved in regulating ovarian follicular development and luteal phase support, and estrus synchronization is involved. A comprehensive understanding of the role of GnRH and its analogs in the modulation of reproductive processes is essential for optimizing animal reproduction.
... Successful fertility in mammals is dependent on various biological processes, including oocyte maturity, ovulation, embryo formation, and implantation (1). In majority of multicellular organisms, germ cells are the origin of new organism, which transfer the genetic and epigenetic information to the next generation. ...
Primordial germ cells develop into oocytes and sperm cells. These cells are useful resources in reproductive biology and regenerative medicine. The mesenchymal stem cells (MSCs) have been examined for in vitro production of primordial germ cell-like cells. This study aimed to summarize the existing protocols for MSCs differentiation into primordial germ cell-like cells (PGLCs). In the limited identified studies, various models of mesenchymal stem cells, including those derived from adipose tissue, bone marrow, and Wharton's jelly, have been successfully differentiated into primordial germ cell-like cells. Although the protocols of specification induction are basically very similar, they have been adjusted to the mesenchymal cell type and the species of origin. The availability of MSCs has made it possible to customize conditions for their differentiation into primordial germ cell-like cells in several models, including humans. Refining germ cell-related signaling pathways during induced differentiation of MSCs will help define extension to the protocols for primordial germ cell-like cells production.
... Thus, the upregulation of TAC3 identified in blood, and yet the heifers not becoming pregnant may suggest an alteration in the hormonal and sex-steroid levels. FSH and LH signaling also regulate several pathways in ovarian granulosa cells, such as the mitogen-activated protein kinase (MAPK) pathway [42]. The MAPK pathway consists of protein kinases that regulate cell proliferation, inflammatory response, development, differentiation, and apoptosis [42]. ...
... FSH and LH signaling also regulate several pathways in ovarian granulosa cells, such as the mitogen-activated protein kinase (MAPK) pathway [42]. The MAPK pathway consists of protein kinases that regulate cell proliferation, inflammatory response, development, differentiation, and apoptosis [42]. In our study, the MAPK pathway was significantly over-represented in the NP group. ...
... The MAPK pathway allows cells to interpret external signals, specifically during EMT [49]. Furthermore, the MAPK pathway regulates extracellular signal-regulated kinase (ERK) proteins involved in the primary regulation of GnRH to stimulate the secretion of estradiol and progesterone [42]. In our study, PDGFB is negatively and differentially correlated with the hydrocinnamic acid in the NP group. ...
Reproductive failure remains a significant challenge to the beef industry. The omics technologies have provided opportunities to improve reproductive efficiency. We used a multistaged analysis from blood profiles to integrate metabolome (plasma) and transcriptome (peripheral white blood cells) in beef heifers. We used untargeted metabolomics and RNA-Seq paired data from six AI-pregnant (AI-P) and six nonpregnant (NP) Angus-Simmental crossbred heifers at artificial insemination (AI). Based on network co-expression analysis, we identified 17 and 37 hub genes in the AI-P and NP groups, respectively. Further, we identified TGM2, TMEM51, TAC3, NDRG4, and PDGFB as more connected in the NP heifers’ network. The NP gene network showed a connectivity gain due to the rewiring of major regulators. The metabolomic analysis identified 18 and 15 hub metabolites in the AI-P and NP networks. Tryptophan and allantoic acid exhibited a connectivity gain in the NP and AI-P networks, respectively. The gene–metabolite integration identified tocopherol-a as positively correlated with ENSBTAG00000009943 in the AI-P group. Conversely, tocopherol-a was negatively correlated in the NP group with EXOSC2, TRNAUIAP, and SNX12. In the NP group, α-ketoglutarate-SMG8 and putrescine-HSD17B13 were positively correlated, whereas a-ketoglutarate-ALAS2 and tryptophan-MTMR1 were negatively correlated. These multiple interactions identified novel targets and pathways underlying fertility in bovines.
... The mitogen-activated protein kinase (MAPKs), members of the serine/threonine-protein kinase family, are involved in cell proliferation, differentiation, growth, and many other physiological processes. MAPK1, also known as extracellular signal-regulated kinase 2(ERK2), plays an essential role in regulating the gonadotropin LH-β and FSH-β expression, oocyte meiotic maturation, and ovulation [27,28]. ALA induces dose-dependent activation of MAPK1 in the endothelial cells [29]. ...
Women experiencing primary ovarian insufficiency (POI) are more likely to experience infertility, and its incidence is increasing worldwide annually. Recently, the role of alpha-lipoic acid (ALA) in the treatment of POI has been reported. However, details of the potential pharmacological targets and related molecular pathways of ALA remain unclear and need to be elucidated. Thus, this study aims to elucidate the potential therapeutic target and related molecular mechanism of ALA on POI. First, the potential targets of POI and ALA related targets were downloaded from online public databases. Subsequently, the overlapped target genes between POI and ALA were acquired, and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Protein-Protein interaction (PPI) networks were performed and constructed. Finally, molecular docking was performed to verify protein-to-protein effect. A total of 152 potential therapeutic targets were identified. The biological processes of the intersecting targets were mainly involved in the cellular response to peptides, response to xenobiotic stimuli, and response to peptide hormones. The highly enriched pathways were the cAMP, PI3K/AKT, estrogen, progesterone mediated oocyte maturation, and apoptosis signaling pathways. The top ten hub targets for ALA in the treatment of POI were STAT3, STAT1, CASP3, MTOR, PTGS2, CASP8, HSP90AA1, PIK3CA, MAPK1, and ESR1. The binding between ALA and all top hub targets were verified using the molecular docking analysis. In summary, using the systematic integrated pharmacology network and bioinformatics analysis, this study illustrated that ALA participates in the treatment of POI via multiple-targets and multiple-pathways mechanisms.
... GnRH was shown to play a dual role in regulating cAMP production in cancer cells. GnRH up-regulates the intracellular concentration of cAMP by Gαs proteins and subsequently activates PKA in gonadotrophic cancers such as ovarian, endometrium, and breast cancer [93]. Interestingly, a high concentration (100 nM) of GnRH agonist inhibits cAMP production right after the initial increase through GnRH receptor [94]. ...
Neuropeptides are autocrine and paracrine signalling factors and mainly bind to G protein-coupled receptors (GPCRs) to trigger intracellular secondary messenger release including adenosine 3′, 5′-cyclic monophosphate (cAMP), thus modulating cancer progress in different kind of tumours. As one of the downstream effectors of cAMP, exchange proteins directly activated by cAMP (EPACs) play dual roles in cancer proliferation and metastasis. More evidence about the relationship between neuropeptides and EPAC pathways have been proposed for their potential role in cancer development; hence, this review focuses on the role of neuropeptide/GPCR system modulation of cAMP/EPACs pathways in cancers. The correlated downstream pathways between neuropeptides and EPACs in cancer cell proliferation, migration, and metastasis is discussed to glimmer the direction of future research.
... However, they synthesize precursor of the yolk proteins vitellogenin throughout an entire prespawning period (Mewes et al., 2002). Besides, this stage of life is assumed to be accompanied by enhanced release of gonadotropins which are known as the strong stimuli of MAPKs exerting their effects through various membrane receptors in mammals (Naor, 2009;Kahnamouyi et al., 2018) and lower vertebrate animals (Méndez et al., 2005;Yang et al., 2005). ...
The study was designed to identify the types of mitogen-activated protein kinases (MAPKs) in erythrocytes and liver tissues of river lamprey Lampetra fluviatilis and monitor the changes in protein expression levels of found enzymes on the course of prespawning starvation (from November to the end of May). Immunoreactivity of the native and phosphorylated forms of ERK1/2, JNK and p38 was examined in the cytosolic and membrane cell fractions. Both lamprey erythrocytes and liver were found to highly express ERK1/2 and JNK, whereas only trace amounts of p38 were revealed in hepatic tissues. ERK1/2 was identified in cytosolic and membrane fractions, whereas JNK and p38 were predominantly cytosolic enzymes. Total cellular amounts of ERK1/2 and phospho-ERK1/2 in both erythrocytes and liver tissues appeared to be relatively stable on the course of prespawning starvation. However, before spawning ERK1/2 translocated from cytosol to membranes, with partial decline of its cytoplasmic immunoreactivity being compensated by increases in membrane-bound pool. Immunoreactivity of cytoplasmic JNK, phospho-JNK and p38 were stable from November to March, but sharply decreased before spawning exhibiting almost negligible levels in May, which suggests the depletion of their cellular fractions. Most probably, ERK1/2 plays more important role in mediating adaptive responses of erythrocytes and liver tissues to conditions of natural starvation and maintenance of cell viability before spawning and death of animals in May.
... PI3K/mTOR/p70S6K signaling plays an important role in FSH-induced actions including proliferation, gene transcription, and protein translation (Gloaguen et al., 2011). FSH can also activate MAPK/ERK signaling in a PKA-dependent or PKA-independent manner (Donaubauer et al., 2016;Kahnamouyi et al., 2018). Our short-term in vivo data document that FSH18/21 rapidly stimulates both PI3K/AKT/p70S6K and MAPK/ERK pathways. ...
STUDY QUESTION
Does hypo-glycosylated human recombinant FSH (hFSH18/21) have greater in vivo bioactivity that drives follicle development in vivo compared to fully-glycosylated human recombinant FSH (hFSH24)?
SUMMARY ANSWER
Compared with fully-glycosylated hFSH, hypo-glycosylated hFSH has greater bioactivity, enabling greater follicular health and growth in vivo, with enhanced transcriptional activity, greater activation of receptor tyrosine kinases (RTKs) and elevated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling.
WHAT IS KNOWN ALREADY
Glycosylation of FSH is necessary for FSH to effectively activate the FSH receptor (FSHR) and promote preantral follicular growth and formation of antral follicles. In vitro studies demonstrate that compared to fully-glycosylated recombinant human FSH, hypo-glycosylated FSH has greater activity in receptor binding studies, and more effectively stimulates the PKA pathway and steroidogenesis in human granulosa cells.
STUDY DESIGN, SIZE, DURATION
This is a cross-sectional study evaluating the actions of purified recombinant human FSH glycoforms on parameters of follicular development, gene expression and cell signaling in immature postnatal day (PND) 17 female CD-1 mice. To stimulate follicle development in vivo, PND 17 female CD-1 mice (n = 8–10/group) were treated with PBS (150 µl), hFSH18/21 (1 µg/150 µl PBS) or hFSH24 (1 µg/150 µl PBS) by intraperitoneal injection (i.p.) twice daily (8:00 a.m. and 6:00 p.m.) for 2 days. Follicle numbers, serum anti-Müllerian hormone (AMH) and estradiol levels, and follicle health were quantified. PND 17 female CD-1 mice were also treated acutely (2 h) in vivo with PBS, hFSH18/21 (1 µg) or hFSH24 (1 µg) (n = 3–4/group). One ovary from each mouse was processed for RNA sequencing analysis and the other ovary processed for signal transduction analysis. An in vitro ovary culture system was used to confirm the relative signaling pathways.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The purity of different recombinant hFSH glycoforms was analyzed using an automated western blot system. Follicle numbers were determined by counting serial sections of the mouse ovary. Real-time quantitative RT-PCR, western blot and immunofluorescence staining were used to determine growth and apoptosis markers related with follicle health. RNA sequencing and bioinformatics were used to identify pathways and processes associated with gene expression profiles induced by acute FSH glycoform treatment. Analysis of RTKs was used to determine potential FSH downstream signaling pathways in vivo. Western blot and in vitro ovarian culture system were used to validate the relative signaling pathways.
MAIN RESULTS AND THE ROLE OF CHANCE
Our present study shows that both hypo- and fully-glycosylated recombinant human FSH can drive follicular growth in vivo. However, hFSH18/21 promoted development of significantly more large antral follicles compared to hFSH24 (P < 0.01). In addition, compared with hFSH24, hFSH18/21 also promoted greater indices of follicular health, as defined by lower BAX/BCL2 ratios and reduced cleaved Caspase 3. Following acute in vivo treatment with FSH glycoforms RNA-sequencing data revealed that both FSH glycoforms rapidly induced ovarian transcription in vivo, but hypo-glycosylated FSH more robustly stimulated Gαs and cAMP-mediated signaling and members of the AP-1 transcription factor complex. Moreover, hFSH18/21 treatment induced significantly greater activation of RTKs, PI3K/AKT and MAPK/ERK signaling compared to hFSH24. FSH-induced indices of follicle growth in vitro were blocked by inhibition of PI3K and MAPK.
LARGE SCALE DATA
RNA sequencing of mouse ovaries. Data will be shared upon reasonable request to the corresponding author.
LIMITATIONS, REASONS FOR CAUTION
The observations that hFSH glycoforms have different bioactivities in the present study employing a mouse model of follicle development should be verified in nonhuman primates. The gene expression studies reflect transcriptomes of whole ovaries.
WIDER IMPLICATIONS OF THE FINDINGS
Commercially prepared recombinant human FSH used for ovarian stimulation in human ART is fully-glycosylated FSH. Our findings that hypo-glycosylated hFSH has greater bioactivity enabling greater follicular health and growth without exaggerated estradiol production in vivo, demonstrate the potential for its development for application in human ART.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by NIH 1P01 AG029531, NIH 1R01 HD 092263, VA I01 BX004272, and the Olson Center for Women’s Health. JSD is the recipient of a VA Senior Research Career Scientist Award (1IK6 BX005797). This work was also partially supported by National Natural Science Foundation of China (No. 31872352). The authors declared there are no conflicts of interest.
... MAPK1, also known as extracellular signal-regulated kinase 2 (ERK2), is a downstream effector of the EGFR pathway. Activated ERK regulates the expression of LHb and FSHb, which are gonadotropin synthesis genes, and induces follicle growth and ovulation (67,68). In addition, the activation of EGFR-ERK1/2 dependent gene transcription leads to the cascade of prostaglandin E2 and p38MAPK induction, which in turn stimulates the production of EGFR ligands (AREG, EREG, and BTC) in granulosa FIGURE 7 | Distribution of the potential therapeutic targets on significantly enriched pathways. ...
Background
Diminished ovarian reserve (DOR) significantly increases the risk of female infertility and contributes to reproductive technology failure. Recently, the role of melatonin in improving ovarian reserve (OR) has attracted widespread attention. However, details on the pharmacological targets and mechanisms of melatonin-improved OR remain unclear.
Objective
A systems pharmacology strategy was proposed to elucidate the potential therapeutic mechanism of melatonin on DOR at the molecular, pathway, and network levels.
Methods
The systems pharmacological approach consisted of target identification, data integration, network construction, bioinformatics analysis, and molecular docking.
Results
From the molecular perspective, 26 potential therapeutic targets were identified. They participate in biological processes related to DOR development, such as reproductive structure development, epithelial cell proliferation, extrinsic apoptotic signaling pathway, PI3K signaling, among others. Eight hub targets (MAPK1, AKT1, EGFR, HRAS, SRC, ESR1, AR, and ALB) were identified. From the pathway level, 17 significant pathways, including the PI3K-Akt signaling pathway and the estrogen signaling pathway, were identified. In addition, the 17 signaling pathways interacted with the 26 potential therapeutic targets to form 4 functional modules. From the network point of view, by regulating five target subnetworks (aging, cell growth and death, development and regeneration, endocrine and immune systems), melatonin could exhibit anti-aging, anti-apoptosis, endocrine, and immune system regulation effects. The molecular docking results showed that melatonin bound well to all hub targets.
Conclusion
This study systematically and intuitively illustrated the possible pharmacological mechanisms of OR improvement by melatonin through anti-aging, anti-apoptosis, endocrine, and immune system regulation effects.
... Notably, melatonin still promoted FSH synthesis in ovariectomized mice ( Figure 4B), which demonstrated that melatonin accelerated the puberty onset not by ovary. Moreover, we observed that melatonin significantly enhanced the level of phosphorylated ERK1/2, a pivotal signaling pathway that controls the transcription of FSHβ in the pituitary [38]. These findings in the present study are not consistent with those in a previous study where it was reported that the most definitive endocrine characteristic of puberty is the change of GnRH release. ...
Although melatonin has been extensively studied in animal reproduction, the mechanism of melatonin in puberty remains elusive. This study was designed to explore the effect of intraperitoneal administration of melatonin on puberty onset in female mice. The injection of melatonin into postnatal days 10 mice at a dose of 15 mg/kg accelerated the puberty onset in mice. Mechanistically, there was no difference in physical growth and serum Leptin levels after melatonin administration. Meanwhile, the serum levels of reproductive hormones involved in hypothalamic-pituitary-ovarian axis, such as FSH and estrogen level in serum were increased. The mRNA levels of GnRH and GnRHr were not affected by melatonin, while the expressions of FSHβ in pituitary and Cyp19a1 in ovary were significantly up-regulated. In addition, melatonin still promoted FSH synthesis after ovariectomy. Furthermore, the enhanced activity of ERK1/2 signaling verified that the expression of FSHβ increased in pituitary. We confirmed that melatonin promoted the FSH synthesis in pituitary, thereby increased serum estrogen levels and ultimately accelerated puberty onset. However, these effects of melatonin may be pharmacological due to the high dose. This study would help us to understand the functions of melatonin in pubertal regulation comprehensively.
... Moreover, inhibition of progesterone receptor membrane component 1 (PGRMC1, also known as sigma-2 receptor) can increase the activation of adenosine 5'-monophosphate (AMP)activated protein kinase (AMPK) and promotes the levels of tuberous sclerosis complex (TSC), which causing the inactivation of mTOR and the elevated autophagic flux [41]. Combined with progesterone, PGR can activate MAPK/ERK and the transcription factor cyclic AMP response-element binding protein (CREB), thereby modulating the expression of genes required for cell proliferation, inflammatory responses, differentiation, and apoptosis [42]. ...
Menstruation occurs in few species and involves a cyclic process of proliferation, breakdown and regeneration under the control of ovarian hormones. Knowledge of normal endometrial physiology, as it pertains to the regulation of menstruation, is essential to understand disorders of menstruation. Accumulating evidence indicates that autophagy in the endometrium, under the regulation of ovarian hormones, can result in the infiltration of immune cells, which plays an indispensable role in the endometrium shedding, tissue repair and prevention of infections during menstruation. In addition, abnormal autophagy levels, together with resulting dysregulated immune system function, are associated with the pathogenesis and progression of endometriosis. Considering its potential value of autophagy as a target for the treatment of menstrual-related and endometrium-related disorders, we review the activity and function of autophagy during menstrual cycles. The role of the estrogen/progesterone-autophagy-immunity axis in endometriosis are also discussed.
