MiR-664-2 impacts pubertal development in a precocious-puberty rat model through targeting the NMDA receptor-1†

2019 ◽  
Vol 100 (6) ◽  
pp. 1536-1548 ◽  
Author(s):  
Minda Ju ◽  
Liu Yang ◽  
Jing Zhu ◽  
Zhejun Chen ◽  
Mizhen Zhang ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Bioinformatics Analysis ◽  
Pubertal Development ◽  
Follicle Stimulating Hormone ◽  
Gonadotropin Releasing Hormone ◽  
Untranslated Regions ◽  
Vaginal Opening ◽  
Protein Levels ◽  
Pulsatile Gnrh ◽  
Puberty Onset

Abstract Precocious puberty (PP) commonly results from premature activation of the hypothalamic–pituitary–gonadal axis (HPGA). Gonadotropin-releasing hormone (GnRH) is the initial trigger for HPGA activation and plays an important role in puberty onset. N-methyl-D-aspartate (NMDA) can promote pulsatile GnRH secretion and accelerates puberty onset. However, the mechanism of N-methyl-D-aspartate receptors (NMDARs) in PP pathogenesis remains obscure. We found that serum GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen (E2) levels, hypothalamic NMDAR1, and GnRH mRNA expression peaked at the vaginal opening (VO) day. Next, the hypothalamic NMDAR1 mRNA and protein levels in rats treated with danazol, a chemical commonly effecting on the reproductive system, were significantly increased at the VO day (postnatal day 24) compared to controls, accompanied by enhanced serum GnRH, LH, FSH, and E2 levels. Further, microRNA-664-2 (miR-664-2) was selected after bioinformatics analysis and approved in primary hypothalamic neurons, which binds to the 3′-untranslated regions of NMDAR1. Consistently, the miR-664-2 expression in hypothalamus of the Danazol group was decreased compared to Vehicle. Our results suggested that attenuated miR-664-2 might participate in PP pathogenesis through enhancing the NMDAR1 signaling.

scholarly journals Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects

2004 ◽  
pp. U89-U94 ◽  
Author(s):  
HA Delemarre-van de Waal
Keyword(s):  
Pulse Generator ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Releasing Hormone ◽  
Delayed Puberty ◽  
Releasing Hormone ◽  
Testicular Growth ◽  
Pulsatile Gnrh ◽  
Portable Pump

BACKGROUND: Puberty is the result of reactivation of the gonadotropin releasing hormone (GnRH) pulse generator resulting in an increasing release of GnRH by the hypothalamus, which stimulates the gonadotropic cells of the pituitary to synthesize and secrete LH and FSH. Hypogonadotropic hypogonadism (HH) is often the result of GnRH deficiency. The clinical picture is characterized by the absence of pubertal development and infertility. It is difficult to differentiate HH from delayed puberty since low gonadotropin and low testosterone levels are found in both conditions. We hypothesized that long-term GnRH administration may differentiate between the two conditions by a difference in the increase of gonadotropins, the idea being that in normal delayed puberty the pituitary of the patient has been primed with GnRH during the fetal and early postnatal period. PATIENTS: Seventeen adolescents suspected of having hypogonadotropic hypogonadism were treated with pulsatile GnRH for 7 days. At the present time, the diagnosis of these patients is known and the results of the long-term GnRH stimulation have been evaluated according to the present diagnosis. RESULTS: The results show that the increase in gonadotropins following GnRH treatment is similar in both conditions. Therefore, at a prepubertal age a normal delayed puberty cannot be distinguished from hypogonadotropic hypogonadism using long-term GnRH stimulation. Long-term pulsatile GnRH treatment is a physiological therapy for the induction of puberty. Unlike testosterone it has the advantage of stimulation of testicular growth and fertility, as well as virilization, in males. We have treated 68 male patients with HH with pulsatile GnRH. The results show testicular growth and virilization in all the patients and spermatogenesis in 58 patients. Wearing a portable pump is cumbersome. However, the patients were very motivated and adapted very easily to this inconvenience. When spermatogenesis had developed, GnRH treatment was changed to human chorionic gonadotropin (hCG) administration 1-2 times per week intramuscularly or subcutaneously. During hCG therapy spermatogenesis was maintained or even improved. At least ten patients fathered children. CONCLUSION: Pulsatile GnRH cannot distinguish between a normal delayed puberty and a hypothalamic defect in still prepubertal patients. Pulsatile GnRH offers an appropriate way to initiate testicular growth including virilization and fertility in males with hypogonadotropic hypogonadism.

scholarly journals Study on the mechanism of sarsasapogenin in treating precocious puberty by regulating HPG axis

2020 ◽  
Author(s):  
KaiLi Hu ◽  
Wenyan Sun ◽  
Yu Li ◽  
Bo Zhang ◽  
Meng Zhang ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Uterine Wall ◽  
Gonadotropin Releasing Hormone ◽  
Group Model ◽  
Vaginal Opening ◽  
Sprague Dawley ◽  
Serum Hormones ◽  
Hpg Axis ◽  
Releasing Hormone ◽  
Fertility Drugs

Abstract Background Precocious puberty is a common endocrine disorder in children,and its pathogenic factor is early initiation of hypothalamic-pituitary-gonadal (HPG) axis. Sarsasapogenin is the main component of traditional Chinese medicine Zhimu, which has anti-fertility effect. There is already evidence that anti-fertility drugs may be resistant to precocity by regulating the HPG axis. Therefore, we speculated that sarsasapogenin might also has the effect. In order to test this hypothesis, this study determined the effect and mechanism of sarsasapogenin on precocious puberty by establishing a danazol-induced precocious puberty model. Methods Female Sprague-Dawley rats were divided into normal(N)group, model (M) group, leuprolide (L) group and sarsasapogenin (Sar) group. Rats at 5 days of age were given a single subcutaneous injection of 300 microgram of danazol dissolved in 25 microliter vehicle of ethylene glycol-ethanol (1:1, v/v), to establish the precocious puberty model. After 10 days of modeling, drug intervention was started. Vaginal opening was started at the age of 20 days, and then vaginal cell smears were examined. The development of uterus and ovary was observed by hematoxylin and eosin (HE) staining. The levels of Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) were determined by radioimmunoassay. The expressions of hypothalamic gonadotropin releasing hormone (GnRH), Kiss-1, G protein-coupled receptor 54 (GPR54) and pituitary gonadotropin releasing hormone receptor (GnRH-R) were detected by RT-PCR. Results The day of vaginal opening was significantly advanced in the M than that in the N group. Compared with the M group, the Sar and L groups could significantly delay the opening time of vaginal (P < 0.001,P < 0.05,respectively). The Sar group could significantly decrease uterine and ovarian coefficients, and reduce uterine wall thickness (P < 0.05, respectively). In terms of serum hormones (LH, FSH, E2), the M group was significantly higher than the N group (P < 0.001,respectively). Moreover, the Sar group can significantly down-regulate the levels of serum hormones (P < 0.001, P < 0.01, P < 0.01,respectively). Also, the expression of GnRH, GnRH-R, Kiss-1 mRNA were significantly decreased in the Sar group compared with that in the M group (P < 0.01, P < 0.05, P < 0.001, respectively). Conclusions The results showed that sarsasapogenin had the effect of treating precocious puberty, and its mechanism might be to down-regulate the expression of GnRH and GnRH-R mRNA through the Kiss-/GPR54 system, thus delaying the initiation of HPG axis.

scholarly journals MiR-505-3p is a Repressor of the Puberty Onset in Female Mice miR-505-3p and the puberty onset

2018 ◽  
Author(s):  
Yuxun Zhou ◽  
Li Tong ◽  
Maochun Wang ◽  
Xueying Chang ◽  
Sijia Wang ◽  
...  
Keyword(s):  
Sexual Maturation ◽  
Positional Cloning ◽  
Target Gene ◽  
Pubertal Development ◽  
Ectopic Expression ◽  
Reproductive Capacity ◽  
Vaginal Opening ◽  
Female Mice ◽  
Puberty Onset ◽  
The Impact

AbstractPuberty onset is a complex trait regulated by multiple genetic and environmental factors. In this study, we narrowed a puberty related QTL down to a 1.7 Mb region on chromosome X in female mice and inferred miR-505-3p as the functional gene.We conducted ectopic expression of miR-505-3p in the hypothalamus of prepubertal female mice through lentivirus-mediated orthotopic injection. The impact of miR-505-3p on female puberty was evaluated by the measurement of pubertal events and histological analysis. The results showed that female mice with overexpression of miR-505-3p in the hypothalamus manifested later puberty onset timing both in vaginal opening and ovary maturation, followed by weaker fertility lying in the longer interval time between mating and delivery, higher abortion rate and smaller litter size. We also constructed miR-505-3p knockout mice by CRISPR/Cas9 technology. MiR-505-3p knockout female mice showed earlier vaginal opening timing, higher serum gonadotrophin and higher expression of puberty-related gene, as well as its target gene Srsf1 in the hypothalamus than their wild type littermates.Srsf1 was proved to be the target gene of miR-505-3p that played the major role in this process. The results of RIP-seq (RNA Immunoprecipitation-sequencing) showed that SF2, the protein product of Srsf1 gene, mainly bound to ribosome protein (RP) mRNAs in GT1-7 cells. The collective evidence implied that miR-505-3p/SRSF1/RP could play a role in the sexual maturation regulation of mammals.Author summaryThe puberty onset in mammals is a vital biological process that signals the acquisition of reproductive capacity. The initiation of puberty is triggered by the activation of hypothalamic pulsatile GnRH surge. The dysregulation of pubertal development shows relevance to later health risks of type 2 diabetes, cardiovascular disease, breast cancer and other health disorders. Recent progress indicates that a lot of genes play a role in the excitatory or inhibitory regulation of GnRH release. However, the detailed pathway of pubertal timing remains unclear. Our previous studies isolated an X-linked QTL that was associated with the timing of puberty in mice. In this study, we proved that miR-505-3p was a female puberty onset regulator based on data from positional cloning, ectopic expression and knockout mouse models. We also assigned Srsf1 as the functional target gene of miR-505-3p underlying this process. The results of RIP-seq showed that SF2, the protein of Srsf1 gene, preferential bound to ribosome protein (RP) mRNAs in GT1-7 cells. We propose that miR-505-3p/SF2/RP could play a role in the sexual maturation regulation of mammals.

scholarly journals Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Luhong Wang ◽  
Charlotte Vanacker ◽  
Laura L Burger ◽  
Tammy Barnes ◽  
Yatrik M Shah ◽  
...  
Keyword(s):  
Gonadotropin Releasing Hormone ◽  
Genetic Dissection ◽  
Glutamatergic Transmission ◽  
Female Reproduction ◽  
Positive Feedbacks ◽  
Pulsatile Gnrh ◽  
Lh Release ◽  
Puberty Onset ◽  
Reproductive Cycles ◽  
The Brain

The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedbacks are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest that activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.

scholarly journals Toward More Targeted and Cost-Effective Gonadotropin-Releasing Hormone Analog Treatment in Girls with Central Precocious Puberty

2018 ◽  
Vol 90 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Paul B. Kaplowitz ◽  
Philippe F. Backeljauw ◽  
David B. Allen
Keyword(s):  
Precocious Puberty ◽  
Cost Effective ◽  
Central Precocious Puberty ◽  
Gonadotropin Releasing Hormone ◽  
Healthy Children ◽  
Defined Benefit ◽  
Early Puberty ◽  
Releasing Hormone ◽  
Early Maturation ◽  
Puberty Onset

The use of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of central precocious puberty (CPP), especially in girls, has increased rapidly in recent years. In the context of a secular trend towards earlier puberty onset, many girls now treated for CPP are healthy children experiencing puberty onset within the early end of the normal range. Justifications for GnRHa treatment include the preservation of adult height (AH) potential and the alleviation of presumed distress of early maturation and menarche. With a case of a family requesting treatment for an 8-year-old girl in early puberty as a background, studies of the effect of untreated CPP and of GnRHa treatment of CPP on AH are reviewed. In addition, the limited evidence relating CPP to significant psychological distress – in part due to early menses, and for the amelioration of such distress by GnRHa treatment – is discussed. Taken together, current information suggests that for girls with mildly early onset of puberty (ages 7–9 years), an informed assent discussion with the family should include the consideration of reassurance and observation for many girls who might otherwise receive 2–4 years of GnRHa treatment for a poorly defined benefit and at a cost of at least $20–30,000 per year.

scholarly journals Frequency-Dependent Regulation of Follicle-Stimulating Hormone β by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors

2009 ◽  
Vol 30 (4) ◽  
pp. 1028-1040 ◽  
Author(s):  
Nick A. Ciccone ◽  
Shuyun Xu ◽  
Charlemagne T. Lacza ◽  
Rona S. Carroll ◽  
Ursula B. Kaiser
Keyword(s):  
Molecular Mechanisms ◽  
Follicle Stimulating Hormone ◽  
Critical Role ◽  
Reproductive Function ◽  
Gonadotropin Releasing Hormone ◽  
Stimulatory Action ◽  
Frequency Dependent ◽  
Releasing Hormone ◽  
Pulsatile Gnrh ◽  
Stimulating Hormone

ABSTRACT Oscillatory synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), under the control of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH), is essential for normal reproductive development and fertility. The molecular mechanisms by which various patterns of pulsatile GnRH regulate gonadotrope responsiveness remain poorly understood. In contrast to the α and LHβ subunit genes, FSHβ subunit transcription is preferentially stimulated at low rather than high frequencies of pulsatile GnRH. In this study, mutation of a cyclic AMP response element (CRE) within the FSHβ promoter resulted in the loss of preferential GnRH stimulation at low pulse frequencies. We hypothesized that high GnRH pulse frequencies might stimulate a transcriptional repressor(s) to attenuate the action of CRE binding protein (CREB) and show that inducible cAMP early repressor (ICER) fulfills such a role. ICER was not detected under basal conditions, but pulsatile GnRH stimulated ICER to a greater extent at high than at low pulse frequencies. ICER binds to the FSHβ CRE site to reduce CREB occupation and abrogates both maximal GnRH stimulation and GnRH pulse frequency-dependent effects on FSHβ transcription. These data suggest that ICER production antagonizes the stimulatory action of CREB to attenuate FSHβ transcription at high GnRH pulse frequencies, thereby playing a critical role in regulating cyclic reproductive function.

scholarly journals Downregulation of TTF1 in the rat hypothalamic ARC or AVPV nucleus inhibits Kiss1 and GnRH expression, leading to puberty delay

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shaolian Zang ◽  
Xiaoqin Yin ◽  
Pin Li
Keyword(s):  
Pubertal Development ◽  
Gonad Development ◽  
Gene Promoter ◽  
Female Rats ◽  
Luciferase Reporter ◽  
Vaginal Opening ◽  
Early Puberty ◽  
Puberty Onset

Abstract Background TTF1 is a transcription factor that is expressed in the hypothalamus after birth and plays crucial roles in pubertal development. TTF1 may regulate the expression of the Kiss1 gene, which may drive puberty onset in the hypothalamic arcuate (ARC) and anterior ventral paraventricular (AVPV) nuclei. Methods A dual-luciferase reporter assay was used to detect binding between TTF1 and the Kiss1 gene promoter. To investigate the effects of TTF1, we modified TTF1 expression in cell lines and in the ARC or AVPV nucleus of 21-day-old female rats via lentivirus infection. TTF1 and other puberty onset-related genes were detected by qRT-PCR and western blot analyses. Results The in vitro data indicated that TTF1 knockdown (KD) significantly reduced Kiss1 and GnRH expression. Overexpression (OE) of TTF1 promoted Kiss1 expression. In vivo, the expression of Kiss1 and GnRH decreased significantly in the rats with hypothalamic ARC- or AVPV-specific TTF1 KD. The TTF1-KD rats showed vaginal opening delay. H&E staining revealed that the corpus luteum was obviously reduced at the early puberty and adult stages in the rats with ARC- or AVPV-specific TTF1 KD. Conclusion TTF1 bound to the promoter of the Kiss1 gene and enhanced its expression. For 21-day-old female rats, decreased TTF1 in the hypothalamic ARC or AVPV nucleus resulted in delayed vaginal opening and ovarian abnormalities. These observations suggested that TTF1 regulates puberty onset by promoting the expression of Kiss1 and plays an important role in gonad development.

The effect of GnRH stimulation on AMH regulation in central precocious puberty and isolated premature thelarche

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Nursel Muratoglu Sahin ◽  
H. Nursun Ozcan ◽  
Aslihan Arasli Yilmaz ◽  
Senay Savas Erdeve ◽  
Semra Cetinkaya ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Pubertal Development ◽  
Follicle Stimulating Hormone ◽  
Central Precocious Puberty ◽  
Complex Interaction ◽  
Breast Development ◽  
Premature Thelarche ◽  
Blood Samples ◽  
Isolated Premature Thelarche ◽  
First Time

Abstract Objectives There is a complex interaction between the anti-müllerian hormone (AMH) and hypothalamic–pituitary–gonadal axis. However, the effect of gonadotropin-releasing hormone (GnRH) stimulation on AMH levels is not clearly known. In the study, we aimed to evaluate the effect of GnRH stimulation on AMH levels in central precocious puberty (CPP) and isolated premature thelarche (PT) groups. Methods Sixty-three girls with breast development before the age of 8 were enrolled in the study. GnRH test was performed on all subjects. Blood samples for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and AMH levels were taken at basal, 40th, and 90th minute of GnRH test. Subjects were grouped as CPP and PT group. Results After GnRH stimulation, AMH levels increased significantly at the 40th minute and the stimulating effect of GnRH on AMH continued till the 90th minute (p: 0.0001). There was a positive correlation between basal and 90th-minute AMH levels (r: 479, p: 0.0001). The highest FSH, LH, and AMH times were significantly different after the GnRH stimulation (p: 0.001, p: 0.001, and p: 0.007). Although the CPP group had a lower basal AMH level than the PT group’s basal AMH level; AMH response to GnRH stimulation was not different (p>0.05). Conclusions In our study, which examined the effect of GnRH stimulation on AMH levels in early pubertal development disorders for the first time, GnRH stimulated AMH secretion rapidly, correlated with basal AMH. Basal AMH levels were lower in patients with CPP than in those with PT; however, the effect of GnRH stimulation on AMH levels was similar in both groups.

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