Melatonin plays an important role in the control of diurnal rhythm in animals (reviewed by Brzezinski et al., 1997 ). The melatonin action is mediated by a G protein-coupled receptor. Reppert et al.(1995) cloned a second G protein-coupled melatonin receptor from humans and designated it the Mel(1b) melatonin receptor.
NCBI Summary:
This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane protein that is a G-protein coupled, 7-transmembrane receptor. It is found primarily in the retina and brain although this detection requires RT-PCR. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Cellular localization
Plasma membrane, SNP
Comment
candidate123
Ovarian function
Follicle development, Antral follicle growth, Steroid metabolism, Luteinization, Oocyte maturation, Early embryo development
Comment
Higher melatonin in the follicle fluid and MT2 expression in the granulosa cells contribute to the OHSS occurrence. Li Y et al. (2019) Ovarian hyperstimulation syndrome (OHSS) is a common and severe complication for patients undergoing IVF/ICSI-ET. Melatonin widely participates in the regulation of female reproductive endocrine activity. However, whether melatonin participates in the progression of OHSS is largely unknown. This study aims to identify the predictive value of follicular fluid (FF) melatonin for OHSS establishment and the underlying mechanism. All participants of this case-control study were enrolled at the Reproductive Medicine Center located in the First Affiliated Hospital of Zhengzhou University in China from January to October in 2017. Quantitative real-time PCR and western blot were used to examine the mRNA and protein levels. Primary granulosa cells were extracted and cultured for in vitro studies. Melatonin concentration was measured by ELISA. Logistic analysis and receiver-operating characteristic (ROC) curves were used to evaluate the predicting value of melatonin on OHSS occurrence. The expression level of melatonin receptor 2 (MT2), P450 aromatase cytochrome (aromatase), vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS) mRNA in human primary granulosa cells. The concentration of melatonin in FF. The predicting value of melatonin on OHSS and the cut-off value of the prediction. FF melatonin concentrations were significantly higher in patients with OHSS compared to non-OHSS group (35.94 ± 10.18 ng/mL vs 23.93 ± 10.94 ng/mL, p<0.001). The expression of MT2 mRNA (p = 0.0459) and protein in granulosa cells was also significantly higher in the OHSS group. When using a cut-off level of 27.52 ng/ml, the sensitivity and specificity of FF melatonin to predict OHSS was 84.6 and 74.0%, respectively (p < 0.0001). We also found that melatonin could up-regulates aromatase mRNA, VEGF mRNA expression and down-regulates iNOS mRNA expression in the granulosa cells. OHSS patients have higher melatonin in the FF as well as higher MT2 expression in the granulosa cells. The melatonin in FF might be used as an effective predictor for the occurrence of OHSS.//////////////////
Webley et al.(1988) reported that melatonin treatment stimulated progesterone secretion by cultured human granulosa cells and, like adrenaline, this stimulation was prevented by propranolol. Their results suggest that adrenaline and melatonin may have a physiological role in modulating luteal function and that melatonin may act by a beta-adrenergic-related mechanism. Tamura et al. (1988) reported that melatonin directly suppresses steroid production by preovulatory follicles in the cyclic hamster. Schaeffer et al. (1997) reported that melatonin regulates the release of insulin-like growth factor-I, oxytocin and progesterone by cultured human granulosa cells. Brzezinski et al., 1997. reported that, in human granulosa lutein cells, treatment with melatonin had no effect on basal progesterone or 17 beta-estradiol production. The addition of melatonin to the hCG-treated granulosa lutein cells significantly potentiated the stimulatory effect of hCG on progesterone production.
Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Wang SJ et al. Melatonin and its receptors have been detected in the ovary of many species, and mediate ovarian functions. The present study was designed to investigate the expression and subcellar location of melatonin receptors in bovine granulosa cells (GCs), using reverse transcription (RT) polymerase chain reaction, Western blot, and immunofluorescence analyses. Furthermore, expression level of melatonin receptors mRNA (real-time polymerase chain reaction) after treatment with various concentrations of melatonin, as well as its effects on cell apoptosis, proliferation, and steroidogenesis (by flow cytometry and RIA), were determined. In bovine GCs, melatonin receptors MT1 and MT2 were differentially located at the cell membrane, the cytoplasm, and nuclear membranes. The expression of MT1 and MT2 mRNA was regulated differently by melatonin in time- and dose-dependent manners. Exogenous melatonin suppressed cell apoptosis (P < 0.05) but not proliferation (P > 0.05). After 72 h, the apoptotic rate was significantly inhibited in all treatment groups. Meanwhile, melatonin supplementation stimulated progesterone production, but inhibited estradiol biosynthesis, in a time-dependent manner. Progesterone production was highest (P < 0.05) at 72 h. Estradiol concentrations were almost unaffected (P > 0.05) at 24 h, but were decreased (P < 0.05) at 48 h. In conclusion, exogenous melatonin acts via receptors and has important roles in regulation of development and function of bovine GCs.
Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis. Adriaens I et al. Chemo and/or radiotherapy applied to young cancer patients most often have severe effects upon female fertility. Today, few options are available to protect ovarian function in females. However, these options are either ineffective, belong to the field of experimental research or/and are not applicable to all patients. Drugs that could protect the oocyte and its surrounding feeder cells from damage can be of great importance. Melatonin, being an important indirect antioxidant and a powerful direct free radical scavenger could be such a reagent. This paper reports the direct effects of different melatonin concentrations (range: 1nM to 2mM) on folliculogenesis and oogenesis of in vitro cultured mouse ovarian follicles. Early secondary mouse follicles were cultured in vitro for 12 days under different melatonin regimes. Every fourth day, survival rates were scored, follicles were morphologically evaluated and medium was collected for steroid analyses. On day 12, in vitro ovulation was induced by hCG/EGF. Eighteen hours later, oocytes were measured, oocyte maturation was evaluated and normality of spindle and chromosomes ascertained. Results obtained in this study indicated that 2mM melatonin is toxic. One mM negatively influenced oocyte maturation capacity. In the presence of 100muM melatonin, androstenedione and progesterone were increased whereas estradiol was not influenced. Lower melatonin concentrations had no effect on the evaluated parameters. These data indicate an effect of melatonin on theca cell steroidogenesis. For prophylactic use, a dose of 10muM could be suitable to reduce oxidative stress in cultured follicles.
Melatonin exists in porcine follicular fluid and improves in vitro maturation and parthenogenetic development of porcine oocytes. Shi JM et al. This study focused on the effect of melatonin on in vitro maturation of porcine oocytes and their parthenogenetic embryonic development. Melatonin was measured in porcine follicular fluid of follicles of different sizes in the same ovary. Melatonin exists in follicular fluid, and the concentration is approximately 10(-11) m. Its concentration decreased as the diameter of follicle increased, which suggests an effect of melatonin on oocyte maturation. Therefore, immature oocytes were cultured in vitro in maturation medium supplemented with melatonin (10(-11), 10(-9), 10(-7), 10(-5) and 10(-3) m) or without melatonin. The oocytes at maturation stage were collected and activated. The parthenogenetic embryos were cultured and observed in medium supplemented with or without melatonin. Fresh immature oocytes without melatonin treatment were used as control. When only maturation medium was supplemented with 10(-9) m melatonin, the cleavage rate, blastocyst rate and the cell number of blastocyst (70 +/- 4.5%, 28 +/- 2.4% and 50 +/- 6.5%) were significantly higher (P < 0.05) than that of controls; when only culture medium was supplemented with melatonin, the highest cleavage rate, blastocyst rate and the cell number of blastocyst was observed at 10(-7) m melatonin, which were significantly higher than that of controls (P < 0.05). The best results (cleavage rates 79 +/- 8.4%, blastocyst rates 35 +/- 6.7%) were obtained when both the maturation and culture medium were supplemented with 10(-9) m melatonin respectively (P < 0.05). In conclusion, exogenous melatonin at the proper concentration may improve the in vitro maturation of porcine oocytes and their parthenogenetic embryonic development. Further research is needed to identify the effect of melatonin on in vitro and in vivo oocyte maturation and embryo development in porcine.
Expression regulated by
Comment
Ovarian localization
Granulosa, Luteal cells
Comment
Expression of functional melatonin MT(1) receptors in equine luteal cells: in vitro effects of melatonin on progesterone secretion. Pedreros M et al. In the present study, we analysed the molecular mechanism(s) by which melatonin directly affects ovarian function in the mare. In Experiment 1, follicles and corpora lutea (CL) were collected from slaughterhouse ovaries and analysed for melatonin (MT(1)) receptor mRNA and protein. In Experiment 2, CL were collected from slaughterhouse ovaries and cultured in Dulbecco's modified Eagle's medium-F12 medium (control medium) supplemented with 50ngmL(-1) equine chorionic gonadotrophin (eCG), 1nM-1?M melatonin, 1?M forskolin or 1?M luzindole. Explants were cultured for 3h in the presence of these drugs. Conditioned media were analysed for progesterone production; luteal cells were analysed for cholesterol side-chain cleavage enzyme (P450scc), a steroidogenic enzyme that converts cholesterol into pregnenolone. Both MT(1) receptor mRNA and protein were expressed in follicles and CL. Melatonin inhibited both the eCG- and forskolin-stimulated production of progesterone, as well as the forskolin-stimulated expression of P450scc, in equine luteal cells and the effect was dose-dependent. The inhibitory effect of melatonin was blocked by luzindole, a non-selective melatonin MT(1) and MT(2) receptor antagonist. The data support the presence of functional melatonin receptors in luteal cells and a regulatory role for melatonin in the endocrine function of the equine CL.
Yie et al. 1995 found putative melatonin binding sites in the membrane fraction of gonadotropin-stimulated human granulosa cells using the melatonin analogue 2-125I-iodomelatonin (125I-IML). Saturation studies and Scatchard analysis revealed the presence of a major binding site with a Kd of 99 pM. In competition studies, the rank order of potency of indoles for inhibition of 125I-IML binding at these sites was typical of melatonin receptors: 2-iodomelatonin > melatonin > N-acetylserotonin > 5-methoxytryptamine > serotonin. Culture of cells for 7 days in vitro increased receptor density but not the affinity. Niles LP, et al. studied melatonin receptor mRNA expression in human granulosa cells. RT-PCR studies revealed the presence of the mt1 (Mel1alpha) melatonin receptor subtype in ten single or pooled HG cell samples
which were obtained from 14 patients. In contrast, expression of MT2 ( Mel1b) mRNA was observed in only two of these HG samples. DNA sequencing of the mt1 PCR product confirmed its identity with the reported human mt1 melatonin receptor. The expression of mt1 and MT2 receptor mRNA in HG cells and the reported presence of melatonin in human follicular fluid indicate a potentially important role for this hormone in regulating human ovarian and reproductive function.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Common genetic variation in MTNR1B is associated with serum testosterone, glucose tolerance, and insulin secretion in polycystic ovary syndrome patients. Wang L et al. Melatonin plays an important role in many aspects of the human reproductive process. Our results first strongly suggest that MTNR1B mediating some functions of melatonin contributes to the phenotypic expression of polycystic ovary syndrome, which provide a new insight into the role of MTNR1B gene in the pathophysiology of the disease.
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Association of rs10830963 and rs10830962 SNPs in the melatonin receptor (MTNR1B) gene among Han Chinese women with polycystic ovary syndrome. Li C et al. The aim of the present study was to determine whether or not the melatonin receptor (MTNR1B) gene polymorphisms are associated with a predisposition for polycystic ovary syndrome (PCOS) . The single nucleotide polymorphisms (SNPs), rs10830963 and rs10830962, in the MTNR1B gene were detected in 526 patients with PCOS and 547 healthy Chinese Han women. The association between MTNR1B gene variants and plasma glucose and insulin levels during oral glucose tolerance test (OGTT), and hormone levels was investigated. The frequencies of three genotypes and two allelotypes of the SNP, rs10830963, differed significantly between women with PCOS and healthy controls (p<0.001 and p<0.001, respectively). The SNP, rs10830963, was significantly associated with higher fasting plasma glucose concentrations(p<0.001) and increased the area under the curve (AUC) of plasma glucose levels during the OGTT(p<0.001), as well as increased homeostasis model assessment of insulin resistance (HOMA-IR; p=0.027). No significant differences were observed in the genotypes and allele distributions of rs10830962 polymorphisms between the PCOS and control groups (p=0.311 and p=0.178, respectively). There was no significant difference in the clinical and metabolic characteristics in women with PCOS with different genotypes in the SNP, rs10830962 (All p>0.005). The present study suggest that the SNP, rs10830963, in the MTNR1B gene is not only associated with susceptibility to PCOS, but also contributes to the PCOS phenotype.