Study on Therapeutic Effect and Related Mechanism of Fuyou Granule on Precocious Puberty in SD Female Rats / 中国实验方剂学杂志

Objective:To study the effect and related mechanism of Fuyou granule on danazol-induced precocious puberty model in rats. Method:Totally 21 cages of SD female rats were randomly divided into normal group， model group， Leuprorelin（0.1 g·kg^-1） and Fuyou mixture group（37.9 g·kg^-1）， and high-dose， mid-dose and low dose Fuyou granule<italic> </italic>groups（17.0，8.5，4.3 g·kg^-1）. Rats at 5 days of age were given a single subcutaneous injection of 300 μg danazol to establish the precocious puberty model. After 10 days of modeling， drug intervention was started. Vaginal opening was examined at the age of 20 days， and the gonadal development was observed by hematoxylin-eosin （HE） staining. The levels of serum luteinizing hormone （LH）， follicle-stimulating hormone （FSH） and estradiol （E₂） were determined by radioimmunoassay. The mRNA expressions of hypothalamic gonadotropin releasing hormone （GnRH）， Kiss-1， G protein-coupled receptor 54 （GPR54） were detected by Real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， and the expression of GnRH cells in the hypothalamus was detected by immunohistochemistry. Result:Compared with the normal group， the vaginal opening of the model group was significantly earlier， and the uterus and ovarian coefficients were significantly increased （<italic>P</italic><0.05）， indicating that the danazol-induced precocious puberty model was successfully established. The expression levels of GnRH， Kiss-1， and GPR54 also increased significantly （<italic>P</italic><0.05）， indicating that the danazol model can activate the HPG axis in advance， thereby inducing precocious puberty<bold>. </bold>Compared with the model group， the mid-dose Fuyou granule group significantly delayed the time of vaginal opening （<italic>P</italic><0.01）， high-dose Fuyou granule group<italic> </italic>significantly reduced uterine wall thickness and uterine coefficient （<italic>P</italic><0.05，<italic>P</italic><0.01）， mid-dose group reduced ovarian coefficient and uterine wall thickness （<italic>P</italic><0.05）. All the three dosage groups of Fuyou granule significantly reduced the content of serum hormones E₂， LH and FSH （<italic>P</italic><0.05，<italic>P</italic><0.01）， reduced the expression levels of hypothalamic GnRH， Kiss-1 and GPR54 mRNA （<italic>P</italic><0.05）， and decreased the expression of GnRH cells （<italic>P</italic><0.05）. Conclusion:Fuyou granule can achieve therapeutic precocity by regulating the Kiss-1/GPR54 system and down-regulating the expression of GnRH to inhibit the activation of the HPG axis.

KISS1 Gene Polymorphisms in Korean Girls with Central Precocious Puberty

Kisspeptin/G-protein couple receptor-54 (GPR54) system plays a key role in the activation of the gonadotropic axis at puberty. Central precocious puberty (CPP) is caused by the premature activation of hypothalamic gonadotropin-releasing hormone secretion. This study was aimed to identify KISS1 gene variations and to investigate the associations between KISS1 gene variations and CPP in Korean girls. All coding exons of KISS1 gene were sequenced in Korean girls with CPP (n = 143) and their healthy controls (n = 101). Nine polymorphisms were identified in KISS1 gene. A novel single-nucleotide polymorphism (SNP), 55648176 T/G, was identified for the first time. SNP 55648184 C/G and 55648186 -/T were detected more frequently in CPP group than in control group. SNP 55648176 T/G was detected less frequently in CPP group than in control group. Haplotype GGGC-ACCC was detected less frequently in CPP group. The genetic variations of KISS1 gene can be contributing factors of development of CPP. The association between the gene variations and CPP should be validated by further evidence obtained from large-scaled and functional studies.

KISS1 Gene Polymorphisms in Korean Girls with Central Precocious Puberty

Kisspeptin/G-protein couple receptor-54 (GPR54) system plays a key role in the activation of the gonadotropic axis at puberty. Central precocious puberty (CPP) is caused by the premature activation of hypothalamic gonadotropin-releasing hormone secretion. This study was aimed to identify KISS1 gene variations and to investigate the associations between KISS1 gene variations and CPP in Korean girls. All coding exons of KISS1 gene were sequenced in Korean girls with CPP (n = 143) and their healthy controls (n = 101). Nine polymorphisms were identified in KISS1 gene. A novel single-nucleotide polymorphism (SNP), 55648176 T/G, was identified for the first time. SNP 55648184 C/G and 55648186 -/T were detected more frequently in CPP group than in control group. SNP 55648176 T/G was detected less frequently in CPP group than in control group. Haplotype GGGC-ACCC was detected less frequently in CPP group. The genetic variations of KISS1 gene can be contributing factors of development of CPP. The association between the gene variations and CPP should be validated by further evidence obtained from large-scaled and functional studies.

Kisspeptin/G protein-coupled receptor-54 system as an essential gatekeeper of pubertal development

Puberty is the end-point of a complex series of developmental events, defined by the dynamic interaction between genetic factors and environmental cues, ultimately leading to the attainment of reproductive capacity. Kisspeptins, products of the KISS1 gene, were originally identified as metastasis suppressor peptides with the ability to bind G protein-coupled receptors (GPR54). In 2003, loss-of-function mutations of the GPR54 gene were found in patients with hypogonadotropic hypogonadism. This finding triggered study of the role of the kisspeptin/GPR54 system as an essential gatekeeper of control of reproduction and pubertal development. Kisspeptins are very potent elicitors of gonadotropin secretion, primarily through stimulation of gonadotropin-releasing hormone release. KISS1 also functions as an essential integrator for peripheral inputs, including gonadal steroids and nutritional signals, and for controlling GnRH and gonadotropin secretion. Whether the kisspeptin/GPR54 system is the trigger for puberty onset and/or it operates as integrator and effector of up-stream regulatory factors warrants further investigation.

Kisspeptin/G protein-coupled receptor-54 system as an essential gatekeeper of pubertal development

Puberty is the end-point of a complex series of developmental events, defined by the dynamic interaction between genetic factors and environmental cues, ultimately leading to the attainment of reproductive capacity. Kisspeptins, products of the KISS1 gene, were originally identified as metastasis suppressor peptides with the ability to bind G protein-coupled receptors (GPR54). In 2003, loss-of-function mutations of the GPR54 gene were found in patients with hypogonadotropic hypogonadism. This finding triggered study of the role of the kisspeptin/GPR54 system as an essential gatekeeper of control of reproduction and pubertal development. Kisspeptins are very potent elicitors of gonadotropin secretion, primarily through stimulation of gonadotropin-releasing hormone release. KISS1 also functions as an essential integrator for peripheral inputs, including gonadal steroids and nutritional signals, and for controlling GnRH and gonadotropin secretion. Whether the kisspeptin/GPR54 system is the trigger for puberty onset and/or it operates as integrator and effector of up-stream regulatory factors warrants further investigation.

The role of Kisspeptin in sexual development / 国际儿科学杂志

Activation of gonadotrophic hormone neuronstion and downstream reproductive hormones (luteinizing hormone and follicle stimulating hormone) secretion is the key event representing the onset of puberty.Hypothalamic pituitary gonad axis varies among gender,season and the stage of development.A number of hormones are involved in the control of hypothalamic pituitary gonad axis.Kisspeptins are potent secretagogues for gonadotrophic hormone,and the KISS1 gene is a target for regulation by gonadal steroids,metabolic factors,photoperiod,and season.This review focuses on Kisspeptin in the regulation of sexual development.

Serum Kisspeptin Levels in Korean Girls with Central Precocious Puberty

Central precocious puberty (CPP) is caused by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin and G-protein coupled receptor-54 system is the essential gatekeeper of the reproductive system, playing a key role in the activation of the gonadotropic axis at puberty. We aimed to determine whether serum kisspeptin may function as a marker for CPP by investigating serum kisspeptin levels in Korean girls with CPP and their prepubertal controls. Serum kisspeptin levels of Korean girls with CPP (n = 30) and age-matched healthy prepubertal controls (n = 30) were measured with a competitive enzyme immunoassay. Serum kisspeptin levels were significantly higher in CPP group than in control group (4.61 +/- 1.78 vs 2.15 +/- 1.52 pM/L, P < 0.001). Serum kisspeptin was positively correlated with peak luteinizing hormone (LH), peak/basal LH ratio and peak LH/follicular-stimulating hormone (FSH) ratio during GnRH stimulation test. CPP is supposed to be triggered by premature increase of kisspeptin. Serum kisspeptin may be used as a marker of CPP. Further studies on KISS1 gene polymorphisms leading to higher risk of premature increase of kisspeptin and upstream regulator of kisspeptin are also needed.