Current medical treatment of uterine fibroids

Uterine fibroids (leiomyomas or myomas), benign monoclonal tumors, are the most common benign tumors in women. Heavy or prolonged menstrual bleeding, abnormal uterine bleeding, resultant anemia, pelvic pain, infertility, and/or recurrent pregnancy loss are generally associated with uterine fibroids. Although curative treatment of this tumor relies on surgical therapies, medical treatments are considered the first-line treatment to preserve fertility and avoid or delay surgery. The aim of this review is to provide available and emerging medical treatment options for symptomatic uterine fibroids. Literature review and consensus of expert opinion. Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow-up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Treatment options for symptomatic uterine fibroids — include medical, surgical, and radiologically guided interventions. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Currently, gonadotrophin-releasing hormone (GnRH) agonists and selective progesterone receptor modulators (SPRMs) are the most effective medical therapies, with the most evidence to support their reduction of fibroid volume and symptomatic improvement in menstrual bleeding. The choice of treatment depends on the patient's personal treatment goals, as well as efficacy and need for repeated interventions.

Effect of threat stress on expression of GnRH receptor in stomach of Sprague-Dawley (SD) rats / 临床检验杂志

Objective To study the localizations and the quantity of GnRH receptor in stomach of Sprague-Dawley (SD) rats under stress.Methods The model of stress SD rats was established by fear. Then, stomachs were taken from the rats in acute stress group (2h-12h), chronic stress group (1d-4w) and the control group respectively.The localizations and the quantity of GnRH receptor in stomachs were detected using immunohistochemistry and Western blotting.Results The results of immunohistochemistry showed that immunoreactivity of GnRH receptor was displayed in the gastric parietal cells and the epithelial cells of the gastric pits in stomachs of rats in all groups. The immunoreactive materials were distributed in membrane and cytoplasm of all positive cells, but not in nuclei. Meanwhile, the results of Western blotting showed that the number of GnRH receptor decreased significantly when SD rats were in stress from 2h to 2w (P

Detection of the Gonadotropin Releasing Hormone (GnRH) and Its Receptor in Cancer Cell HT-1197 and HT-1376, and Effect of GnRH on Cancer Cell Cycle / 대한비뇨기과학회지

Gonadotropin releasing hormone (GnRH) is believed to be pivotal hormone in hypothalamo-pituitary gonadal axis and the hypothalamus is believed as the exclusive organ producing GnRH and pituitary is for GnRH re ceptor until recently. Some reported the exptra-hypothalamic GnRH or extra-pituitary GnRH receptors from decades ago. The aims of this study are to confirm the existence of the GnRH receptor in bladder epithelial cancer cell, HT-1197 and HT-1376, and evaluated the possible role of the GnRH on cell cycle. The GnRH and GnRH receptor were detected by immunohistochemical staining and the effect of GnRH on cell cycle change in both cell line were studied by fluorescence activated cell sorter (FACS). The control cells were cultured at media supplemented with normal serum, and experimental group were cultured at media supplemented with charcoal stripped serum (CSS) which excluding peptide hormones except exogenous GnRH with different concentration. The GnRHs and GnRH receptors were detected at both cell lines and the cell cycle analysis showed that there were little difference in proportion of cell cycle among examined 10,000 cells in both cell lines, neither control nor experimental groups. This study shows that the GnRHs and GnRH receptors exist in bladder cancer cells and GnRH did not influence on the cell cycle progression. With this study, we suppose that the bladder cancer cells produce the GnRH and GnRH receptors and the role of the GnRF produced from the bladder cancer cells might be the autocrine rather than endo-or paracrine factor.

Regulation of gonadotropin releasing hormone receptor mRNA expression in cultured rat granulosa cells

The homologous regulation of pituitary Gonadotropin Releasing Hormone Receptor (GnRH-R) mRNA expression by GnRH has been well demonstrated. However, the regulation of the ovarian GnRH-R is poorly understood. The present study was performed to demonstrate the presence of GnRH transcripts in addition to GnRH-R mRNA and the regulation of GnRH-R mRNA expression in the granulosa cells isolated from small antral follicles. The GnRH and GnRH-R mRNA levels were determined by a competitive reverse transcription-polymerase chain reaction (RT-PCR). The granulosa cells were obtained from immature rats implanted with diethylstilbestrol for 3 days. When GnRH transcript expression was examined in isolated granulosa cells by RT-PCR, the PCR products showed two bands. The larger band contained intronic sequences and the smaller band was a fully processed GnRH gene transcript identical to hypothalamic GnRH. This suggests that authentic GnRH gene transcripts are expressed in ovarian granulosa cells and may act on the granulosa cells in a paracrine or autocrine manner. Since GnRH action in the granulosa cells is mediated by specific GnRH-R, it is of interest to examine whether GnRH-R is synthesized in the granulosa cells. When the granulosa cells were cultured in media only, GnRH-R mRNA levels increased abruptly within 3 h and gradually decreased thereafter during the 24 h culture period. However, GnRH itself did not alter the GnRH-R mRNA expression levels in cultured granulosa cells. Interestingly, treatment with FSH decreased the GnRH-R mRNA levels in a dose-dependent manner. A time-course analysis revealed that the GnRH-R mRNA levels were significantly lower up to 9 h after FSH treatment, and returned to the basal level between 12 h-24 h. Activation of adenylate cyclase with forskolin also decreased the GnRH-R mRNA levels. It is therefore concluded that in the granulosa cells of the small antral follicles GnRH-R mRNA expression was not homologously regulated by GnRH, while FSH may negatively regulate GnRH-R mRNA expression in the granulosa cells possibly through a cAMP-protein kinase A pathway.

KAL Gene and GnRH Receptor Gene Analysis in Patients with Kallmann's Syndrome / 대한내분비학회지

BACKGROUND: Kallmann's syndrome is related to the defect in migration of olfactory neuron and GnRH neuron from the olfactory placode to the brain and it represents hypogonadism with anosmia or hyposmia. There are 3 modes of transmission in Kallmann's syndrome: X-linked, autosomal recessive and autosomal dominant. X-linked form is the most common. KAL gene is responsible for the X-linked form of Kallmann's syndrome and it had been localized to Xp22.3. The intron-exon organization had been determined and KAL gene mutation had also been identified in familial Kallmann's syndrome and it is very rare and shows heterogeneity. Furthermore, in the sporadic cases, KAL gene mutation is more rare. METHODS: In order to investigate the KAL gene mutation and the regulation of the gene expression in Kallmann's syndrome, we examined genomic DNA of 35 patients with sporadic Kallmann's syndrome. In the exon 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 of KAL gene and 1, 2, 3 of GnRH receptor gene, the mutations were analyzed by PCR-based DNA sequencing. RESULTS: In our study, the mutation of KAL gene and GnRH receptor gene was not identified in the studied exons that were known as preferable sites of the mutation. CONCLUSION: The mutation of KAL gene and GnRH receptor gene is rare, and it might be needed to investigate mutations in other genes or in other part of the KAL gene such as intron or promoter region.

Effects of Toluene, Xylene and Trichloroethylene on the Regulation of GnRH, GnRH Receptor and Pit-1 Gene Expression in Male Rat Hypothalamus and Pituitary / 대한산업의학회지

The workplace exposure of chemicals has steadily increased, therefore the concern for subsequent effect on reproductive outcome has been an important issue in occupational medicine. In previous studies, higher rates of spontaneous abortion, reduced fertility and menstrual disorder among women, and an impairment of sperm quantity and quality among men have been associated with a wide variety of chemical agents. This study was conducted to evaluate the effects of toluene, xylene and trichloroethylene (TCE) injection on the mRNA levels of GnRH, GnRH receptor and Pit-1 genes in male rats hypothalamus and pituitary and the effects on the plasma levels of FSH, LH, prolactin and testosterone. Sprague-Dawley male rats were divided into five groups of five each according to concentration of toluene, xylene and TCE. The rats were injected subcutaneously to 0, 50, 100, 200, 400 mg/kg body weight/day of toluene, xylene and TCE, respectively for 6 days. Rat brains were excised and hypothalamus and pituitary were separated. Reverse transcription-polymerase chain reaction (RT-PCR) and RNase protection assay (RPA) were used to evaluate the GnRH, GnRH receptor and Pit-1 mRNA levels. Plasma concentrations of FSH, LH, prolactin and testosterone were assayed by radioimulunoassay (RIA). The results were as follows; 1. GnRH, GnRH receptor and Pit-1 mRNA levels in toluene and xylene injected groups, and GnRH receptor mRNA levels in TCE injected group were lowered dose-dependently. Especially, GnRH receptor and Pit-1 mRNA levels in 200 mg/kg of toluene injected group, and GnRH, GnRH receptor and Pit-1 mRNA levels in 400 mg/kg of toluene injected group were significantly lowed than control group (p<0.05). GnRH receptor and Pit-1 mRNA levels in 400 mg/kg of xylene injected group, and GnRH receptor mRNA levels in 400 mg/kg of TCE injected group were significantly lower than control group (p<0.05). 2. The plasma levels of prolactin and testosterone in 400 mg/kg of toluene injected group, and LH in 100, 200 and 400 mg/kg of xylene injected group, and testosterone in 400 mg/kg of TCE injected group were significantly lower than control group (p<0.05). In conclusion, we speculated that toluene and xylene affected reproductive system secondarily through hypothalamus-pituitary axis, and TCE affected directly through steroidogenesis. And we recomended that further study for assessment of the reproductive toxiclty of mixed organic solvent exposures should be conducted.

Expression of GnRH-receptor mRNA in the Placenta during Pregnancy / 대한산부인과학회잡지

OBJECTIVE: Our previous study demonstrated that the placental GnRH and GnRH mRNA did not parallel the time course of hCG secretion, though it is thought to be one of the potential paracrine regulators of hCG secretion from the trophoblasts. The present study was designed to examine the potential variation in GnRH-receptor mRNA expression in the placenta, which may account for the GnRH-mediated action of hCG secretion during pregnancy. METHODS: Human placentas in firt, second, and third trimester of normal pregnancy were obtained. These placentas were fixed with 4% paraformaldehyde and embedded in OCT compound, and sectioned by cryostat. For in situ hybridization, S labeled RNA probes were used and followed by autoradiography. RESULTS: The GnRH-receptor mRNA signals were present in both cytotrophoblast and syncytiotrophoblast cell layers. Signal intensities varied with gestational ages and were abundant at 6-7 weeks, peaked at 9-12weeks, declined at 14 and 24 weeks, and were barely detectable at term. The present study demonstrates that GnRH-receptor mRNA exhibits changes paralleling the time course of hCG secretion during pregnancy CONCLUSION: These data provide mechanistic understanding that the paracrine/autocrine regulation of hCG secretion by placental GnRH is mediated through an increase followed by a decline in GnRH-receptor mRNA expression from the first trimester to term placenta.

Expression of GnRH and GnRH-receptor mRNAs in the Human Placenta / 체질인류학회지

Placental GnRH is one of the potential paracrine regulator of hCG secretion from the trophoblasts during pregnancy. However, this paracrine function is not clearly confirmed. The present study was designed to evaluate the possible correlation between the synthesis and cellular distribution of GnRH and GnRH -receptor in the placental villi. 6 to 40 weeks termed twenty five human placental tissues were used in this study. GnRH and GnRH -receptor mRNAs were localized in the placenta by in situ hybridization using the corresponding cRNA probes. GnRH mRNA was present in all cell types of placenta including cytotrophoblasts, syncytiotrophoblasts and stromal cells. The GnRH -receptor mRNA signals were localized in both cytotrophoblasts and syncytiotrophoblasts. The GnRH -receptor mRNA signals were also localized in some stromal cells at the full term placenta. GnRH mRNA signals were detected abundantly at 6 ~7 weeks and the intensities were remarkably increased with the following gestational ages. GnRH -receptor mRNA signals were detected at 6 ~7 weeks, peaked at 9 ~10 weeks, declined at 23 ~24 weeks and focally expressed at full term placenta. The present study demonstrates that GnRH mRNA is expressed in all cell types of the placenta, however GnRH -receptor mRNA is expressed only in the cytoptrophblasts and syncytiotrophoblasts and exhibits parallel change with the time course of hCG secretion during pregnancy. These data provide a morphological understanding that placental GnRH has a paracrine/autocrine role through its receptor from 6 ~7 weeks gestation to term placenta.

AMPLIFICATION SEQUENCE ANALYSIS OF GnRH RECEPTOR GENE IN RAT SUBMAXILLARY GLAND / 解剖学报

Objective\ To study whether gonadotropin releasing hormone receptor (GnRHR)mRNA exist in rat submaxillary gland and it's gene sequence. Methods\ The total RNA isolated from rat submaxillary gland was amplified by RT\|PCR, the PCR products were identified by sequencing with Sanger's method. Results\ The specific amplified band of GnRHR mRNA was detected through agarose gel electrophoresis and gene sequence is identical to the sequence of GnRHR which has been reported in rat pituitary. Conclusion\ GnRHR can be produced by submaxillary and response for modulating biological function of submaxillary.\;