BackgroundGonadotropins induce follicular development that leads to ovulation and luteinization. In women, the level of gonadotropins, along with the expression of their receptors, changes dynamically throughout the menstrual cycle. This study aimed to clarify the mechanisms underlying these phenomena.MethodsThe literature was reviewed, including that published by the authors.Main findings (Results)Follicle‐stimulating hormone receptor expression in the granulosa cells was induced by androgens that were derived from growth differentiation factor‐9‐stimulated theca cells. In the theca cells, luteinizing hormone receptor (LHR) expression was noted from their appearance. In the granulosa cells, follicle‐stimulating hormone (FSH) stimulation was essential for LHR expression. However, FSH alone was not sufficient to respond to the luteinizing hormone (LH) surge for oocyte maturation, ovulation, and subsequent luteinization. To achieve these stages, various local factors that were derived from the granulosa and theca cells in response to FSH and LH stimulation had to work synergistically in an autocrine/paracrine manner to strongly induce LHR expression. Following the LH surge, the LHR expression decreased markedly; miRNAs were involved in this transient LHR downregulation. Following ovulation, LHR expression drastically increased again toward luteinization.ConclusionThe expression of gonadotropin receptors is controlled by sophisticated and complicated systems; a breakdown of this system could lead to ovulation disorders.
Several inflammatory cytokines regulate ovarian function. TNF-α is produced in granulosa cells under physiological conditions and has a reciprocal action on follicle development. In contrast, in pelvic inflammatory diseases, TNF-α is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-α on the expression of LH receptor (LHR) in immature rat granulosa cells. TNF-α suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. By using a luciferase assay, the construct containing base pairs -1389 to -1 of the rat Lhcgr promoter revealed that TNF-α decreased FSH-induced promoter activity. In response to TNF-α, nuclear factor (NF)-κB p65 was translocated to the nucleus, and the suppressive effect of TNF-α on LHR mRNA expression was abrogated by an NF-κB inhibitor. In a chromatin immunoprecipitation assay, TNF-α induced the association of NF-κB p65 with the rat Lhcgr transcriptional promoter region. NF-κB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-α-induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-κB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-α action on the regulation of LHR.
IL-6 is produced in granulosa cells under normal physiological conditions, including during ovulation. However, the roles of IL-6 in ovarian function, including regulation of LH receptor (LHR) expression in granulosa cells, have not been explored in detail. The aim of this study was to identify the mechanism underlying the effect of IL-6 on LHR expression in the granulosa cells of female Wistar rats. Our results indicated that IL-6 clearly enhanced the FSH-induced LHR mRNA expression in a dose-dependent manner and did not stimulate cAMP accumulation by itself. The membrane protein level of LHR, assessed by a binding assay, was increased by FSH and was further enhanced by association with IL-6. Results of the luciferase assay, using promoter constructs of LHR 281 bp upstream of the translational start site, revealed that IL-6 increased the promoter activity induced by FSH, but this effect was not observed with treatment by IL-6 alone. This ability of IL-6 to enhance FSH-induced LHR mRNA expression was blocked by the Janus tyrosine kinase (JAK) pathway inhibitor, but not by the ERK1/2 inhibitor. Thus, we speculated that this IL-6 activity might be mediated by the JAK/signal transducer and activator of transcription pathway. In addition, IL-6 augmented FSH-induced IL-6 receptor α mRNA expression and FSH elevated IL-6 production in granulosa cells, which indicates that IL-6 may positively regulate paracrine and autocrine actions in granulosa cells. These results suggest that IL-6 up-regulates FSH-induced LHR production by increasing mRNA transcription, and JAK/signal transducer and activator of transcription 3 signaling is required for up-regulation by IL-6 in granulosa cells.
The incidence of cervical intraepithelial neoplasia(CIN) among reproductive-aged women has increased in Japan. Cervical conization is commonly applied for local cervical treatment to preserve fertility. The Shimodaira-Taniguchi (S-T) conization procedure is widely used in Japan. S-T conization uses a high-frequency current and a triangular probe with a linear excision electrode to remove cervical tissue as a single informative specimen. However, alternative of an electrosurgical scalpel (ES) has the advantage of adjusting the surgical margin to the transformation zone in order to preserve the maximum amount of healthy cervical tissue with good hemostasis. The aim of this study is to retrospectively analyze data regarding surgical margin status, perioperative adverse events, cervical stenosis, and preterm birth between S-T and ES.Between January 2009 and December 2014, the medical records of 1166 patients who were diagnosed as CIN II, III, or stage 1a1 cervical cancer and who were treated with conization in 7 hospitals in Gunma Prefecture, Japan were enrolled for this retrospective study. The clinicopathological data was analyzed to statistically compare outcome between S-T and ES conization.There was no difference for age or post-operative follow-up period between ES and S-T treatments. However, positive surgical margins were significantly less frequent in patients who were treated with S-T than in those treated with ES, resulting in a reduced incidence of re-treatment for S-T in comparison with ES patients. In perioperative adverse events, S-T had more patients who were administered antibiotics. The incidence of preterm delivery and cervical stenosis did not differ significantly between the groups.We demonstrate here that S-T is an alternative procedure for cervical conization with a low risk of recurrence and acceptably low rate of adverse events such as cervical stenosis and preterm delivery. The results of this study can provide useful information for future management of patient with cervical intraepithelial neoplasia.
Retinoic acid (RA) is a metabolite of vitamin A and has important roles in development, differentiation, and reproduction. Activin has been shown to regulate the RA pathway and affect granulosa cell (GC) proliferation, suggesting that RA is important for early follicle development. However, little is known about the effects of RA on GC functions, particularly steroidogenesis, during the early follicle stage. The aim of this study was to investigate the effects of all-trans-RA (atRA) on progesterone production in immature rat GCs cultured without gonadotropin. Our results demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein (StAR) and cytochrome P450scc (Cyp11a1) mRNAs, but not 3β-hydroxysteroid dehydrogenase mRNA in immature rat GCs. Additionally, analysis of the mechanisms through which atRA upregulated StAR and Cyp11a1 mRNAs revealed that atRA enhanced intracellular cAMP accumulation and phosphorylation of cAMP response-element binding protein (CREB). In addition, H-89, an inhibitor of protein kinase A (PKA), abolished the stimulatory effects of atRA, indicating that atRA enhanced progesterone synthesis through cAMP/PKA signaling. In conclusion, our data demonstrated that atRA has a crucial role in progesterone synthesis in rat GCs during the early follicle stage.
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