Prevention of Premature Ovulation by Administration of Gonadotropin Releasing Hormone Antagonist the day After Ovulation Triggering in Diminished Ovarian Reserve Patients / Prevenção da ovulação prematura por meio da administração de antagonismo de liberação de gonadotropismo no dia seguinte à ovulação

Abstract Objective The aim of the present retrospective study was to investigate the effectiveness of single-dose gonadotropin releasing hormone (GnRH) antagonist administration, the day after human chorionic gonadotropin (hCG) triggering for final oocyte maturation, on the prevention of premature luteinization in patients with diminished ovarian reserve in in-vitro fertilization (IVF) cycles. The secondary objective of the study was to search the effect of this protocol on pregnancy outcomes. Methods This is a retrospective study including 267 infertile patients who have single antral follicle seen with ultrasonography on the 2nd or 3rd day of the menstrual cycle before starting IVF treatment. We randomized patients into two groups. The case group comprised patients who had single-dose GnRH antagonist injection the day after hCG triggering formed, and the patients who had the standard treatment regime formed the control group. In both groups, the oocytes were collected 36 hours after hCG injection. Results The premature ovulation rate was significantly low in the case group compared with the control group (6.86 versus 20.6% per scheduled cycle) (p=0.022). Also, the oocyte retrieval rate (93.14 versus 67.87% per scheduled cycle) (p=0.013), the oocyte maturity rate (79.42 versus 47.87%) (p=0.041), the fertilization rate (65.68 versus 34.54%) (p=0.018), and the embryo transfer rate per scheduled cycle (44.11 versus 18.78%) (p=0.003) were higher in the GnRH antagonist group than in the control group. Conclusion The administration of GnRH antagonist the day after hCG trigger in IVF treatments of patients with diminished ovarian reserve enabled a significant decrease in the rate of premature ovulation but had no effect on live birth rate.

Resumo Objetivo O objetivo do presente estudo retrospectivo foi investigar a eficácia da administração do antagonista do hormônio liberador da gonadotrofina (GnRH) em dose única no dia seguinte ao desencadeamento da gonadotrofina coriônica humana (hCG) para a maturação final do oócito, na prevenção da luteinização prematura em pacientes com diminuição do ovário reserva em ciclos de fertilização in vitro (FIV). O objetivo secundário do estudo foi pesquisar o efeito deste protocolo nos resultados da gravidez. Métodos Trata-se de um estudo retrospectivo incluindo 267 pacientes inférteis que apresentam um único folículo antral visto por ultrassonografia no 2° ou 3° dia do ciclo menstrual antes de iniciar o tratamento de FIV. Nós randomizamos os pacientes em dois grupos. Os pacientes que receberam injeção de antagonista de GnRH em dose única no dia seguinte ao desencadeamento do hCG formaram o grupo caso, e os pacientes que receberam o regime de tratamento padrão formaram o grupo controle. Em ambos os grupos, os oócitos foram coletados 36 horas após a injeção de hCG. Resultados A taxa de ovulação prematura foi significativamente baixa no grupo caso em comparação com o grupo controle (6,86 versus 20,6% por ciclo programado) (p=0,022). Além disso, a taxa de recuperação de oócitos (93,14 versus 67,87% por ciclo programado) (p=0,013), a taxa de maturidade do oócito (79,42 versus 47,87%) (p=0,041), a taxa de fertilização (65,68 versus 34,54%) (p=0,018) e a taxa de transferência de embriões por ciclo programado (44,11 versus 18,78%) (p=0,003) foram maiores no grupo antagonista de GnRH do que no grupo controle. Conclusão A administração de antagonista de GnRH, no dia seguinte ao desencadeamento de hCG em tratamentos de FIV de pacientes com reserva ovariana diminuída permitiu uma redução significativa na taxa de ovulação precoce,mas não teve efeito na taxa de nascidos vivos.

Methylphenidate and Central Precocious Puberty: A Probable Side Effect among Seven Children with the Attention Deficit Hyperactivity Disorder

Methylphenidate (MPH) is the most preferred drug for treatment of the attention deficit hyperactivity disorder (ADHD). Here, we aimed to discuss the possible effects and mechanisms of MPH on precocious puberty (PP) via a case series with seven children who had normal body mass index. In this case series we evaluated seven children with ADHD, who had received MPH for at least 6 months (0.5 mg/kg/dose three times a day, maximum 60 mg) and admitted to Department of Pediatric Endocrinology with PP symptoms. The mean age was 8.16 years. Basal hormonal levels (luteinizing hormone [LH], follicle stimulating hormone, and estrogen/testosterone) were within normal range. Results of LH-releasing hormone stimulation tests demonstrated central pubertal responses. Glutamine, dopamine and noradrenaline are most important excitatory neurotransmitters that have a role at the beginning of puberty. The effect of MPH, cumulating dopamine and noradrenaline in the synaptic gap could be associated with the acceleration of puberty with the excitatory effect of dopamine’s gonadotropin-releasing hormone (GnRH) release, excitatory effect of noradrenaline’s GnRH release and the disappearance of GnRH receptor expression suppressor effect on prolactin disinhibitory effect.

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.

Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism / Nova mutação no receptor do hormônio liberador de gonadotrofinas (GNRHR) em um paciente com hipogonadismo hipogonadotrófico isolado normósmico

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4.

Relatamos uma nova mutação no gene GNRHR em um homem com hipogonadismo hipogonadotrófico isolado normósmico (HHIn). A região codificadora do gene GNRHR foi amplificada e sequenciada. Três variantes p.[Asn10Lys;Gln11Lys]; [Tyr283His] foram identificadas no GNRHR em um homem com HHIn esporádico. As três variantes estavam ausentes no grupo controle (130 adultos normais). A segregação familiar mostrou que as variantes previamente descritas p.[Asn10Lys;Gln11Lys] se localizavam no mesmo alelo, em heterozigose composta com a nova variante p.Tyr283His. As mutações p.[Asn10Lys;Gln11Lys] são sabidamente inativadoras. A variante p.Tyr283His afeta um resíduo bem conservado, e a análise in silico sugeriu que essa é uma mutação deletéria. Descrevemos uma mutação inédita no gene GNRHR em um paciente com HHIn nIHH. A ausência da variante no grupo controle, a conservação entre as espécies, a análise in silico e a segregação familiar sugerem que a p.Tyr283His é uma mutação inativadora, identificada em heterozigose composta com as mutações p.[Asn10Lys;Gln11Lys]. Arq Bras Endocrinol Metab. 2012;56(8):540-4.

In vitro anti-tumor effect of methotrexate modified by peptide / 药学学报

This study is to investigate the anti-tumor effect in vitro of methotrexate modified by LH-RH peptide (LH-RH-MTX). LH-RH receptors highly expressing MCF-7 human breast carcinoma cell line and lowly expressing K562 human erythroleukemia cell line were served as the tested cells. The cell proliferation inhibition rates of LH-RH-MTX were detected by MTT colorimetric assay. The effects of LH-RH-MTX on the cell cycle and apoptosis rates were detected by flow cytometry. The inhibition rate of LH-RH-MTX on MCF-7 cells was much higher than that on K562 cells, and the inhibition rate of LH-RH-MTX on MCF-7 cells was much higher than that of free MTX at the same concentration. The inhibition rate of LH-RH-MTX on rat bone marrow mononuclear cells was less than that of free MTX. The number of MCF-7 cells in S phase increased after administration of LH-RH-MTX. The apoptosis rate of LH-RH-MTX group significantly increased compared with that of the control group and MTX group. The relative expression of LHRHR mRNA of LH-RH-MTX group markedly decreased compared with that of the control group and MTX group. LH-RH-MTX is realizable to reduce drug side effects, increase the therapeutic index and achieve tumor-targeted therapy.

Manejo de las terapias hormonales para el tratamiento del cáncer de próstata avanzado hormonodependiente: evaluación fármaco: económica del tratamiento con Degarelix û Firmagon frente a Triptorelina genérica / Management of hormonal therapy for the treatment of advanced hormone-dependent prostate cancer: A pharmacoeconomics assessment of the use of Degarelix û Firmagon compared to generic triptorelin

Objetivo: Evaluación farmacoeconómica de dos tratamientos con drogas de distinto mecanismo de acción: Degarelix y triptorelina en el manejo de pacientes con cáncer de próstata avanzado hormonodependiente. Material y método: Se realizó una revisión de la literatura sobre el tratamiento estándar de estos pacientes, efectos tempranos y tardíos de las terapias existentes y además una valoración de Costo Integral del Tratamiento usando el tarifario de Essalud. Resultados: El Costo Integral del Tratamiento, es S/ 10 793 para un paciente que usa Degarelix y S/ 12 251 para un paciente que usa triptorelina genérica; es decir, la terapia con el antagonista de la GnRH genera un ahorro de S/ 1 458 por paciente. Conclusiones: Este ahorro representa S/ 1 008 017 para el total de pacientes con cáncer de próstata avanzado hormonodependiente que se atienden en Essalud, a nivel nacional, con la ventaja adicional que Degarelix no genera costos adicionales por complicaciones producto del efecto Flare.

Objective: This is a pharmacoeconomic evaluation of two therapy schedules using drugs with different modes of action: Degarelix and triptorelin in the treatment of patients with advanced hormone-dependent prostate cancer. Methods: We reviewed the literature on the standard treatment for these patients, early and late effects of existing therapies, and we also performed a valuation using the Comprehensive Cost Treatment EsSalud (Peruvian Social Security) rates. Results:The Comprehensive Cost Treatment is S/. 10 793 for a patient using Degarelix and S/. 12 251 for a patient using generic triptorelin, so the therapy with the GnRH antagonist generates S/. 1 458 savings per patient. Conclusions: This represents S/. 1,008,017 savings for all patients with advanced hormone-dependent prostate who attend to EsSalud, with the added advantage that there are no extra costs with the use of Degarelix because of the absence of complications due to any flare effect.

Participation of the endoplasmic reticulum protein chaperone thio-oxidoreductase in gonadotropin-releasing hormone receptor expression at the plasma membrane

Chaperone members of the protein disulfide isomerase family can catalyze the thiol-disulfide exchange reaction with pairs of cysteines. There are 14 protein disulfide isomerase family members, but the ability to catalyze a thiol disulfide exchange reaction has not been demonstrated for all of them. Human endoplasmic reticulum protein chaperone thio-oxidoreductase (ERp18) shows partial oxidative activity as a protein disulfide isomerase. The aim of the present study was to evaluate the participation of ERp18 in gonadotropin-releasing hormone receptor (GnRHR) expression at the plasma membrane. Cos-7 cells were cultured, plated, and transfected with 25 ng (unless indicated) wild-type human GnRHR (hGnRHR) or mutant GnRHR (Cys14Ala and Cys200Ala) and pcDNA3.1 without insert (empty vector) or ERp18 cDNA (75 ng/well), pre-loaded for 18 h with 1 µCi myo-[2-3H(N)]-inositol in 0.25 mL DMEM and treated for 2 h with buserelin. We observed a decrease in maximal inositol phosphate (IP) production in response to buserelin in the cells co-transfected with hGnRHR, and a decrease from 20 to 75 ng of ERp18 compared with cells co-transfected with hGnRHR and empty vector. The decrease in maximal IP was proportional to the amount of ERp18 DNA over the range examined. Mutants (Cys14Ala and Cys200Ala) that could not form the Cys14-Cys200 bridge essential for plasma membrane routing of the hGnRHR did not modify maximal IP production when they were co-transfected with ERp18. These results suggest that ERp18 has a reduction role on disulfide bonds in wild-type hGnRHR folding.

Endocrine disorders in patients with sickle cell anemia

Red blood cell transfusions are a therapeutic mainstay in Sickle Cell Disease [SCD] and repeated transfusions can result in iron overload. Endocrine dysfunction is the most common and earliest organ toxicity seen in subjects with chronic iron-induced cellular oxidative damage. The aim of the present work is to investigate some of the endocrine functional disorders in patients with SCD. The present study consisted of 30 patients with SCD [proved by hemoglobin electrophoresis from the start of the condition] recruited from the Medical Department of King Fahd Hospital-Hofuf, Eastern Province-Saudi Arabia. Most of the patients had a history of repeated blood transfusions [5 times/year]. Patients were classified into two groups. Group 1 [15 males] and Group 2 [15 females] with mean age for both sex [28.6 +/- 5.4 years]. Thirty age and sex matched normal subjects were, also, included in the study as a control group. Plasma level of testosterone for group 1 and male control group, FSH and LH for group 2 and female control group. Complete blood count, biochemistry, iron profile, as well as thyroid function tests were assessed for both group 1 and 2 and control group. A total of 30 patients with SCD were recruited in the study [15 males and 15 females] with mean age 28.6 +/- 5.4 years. They were compared to a control group of 30 healthy subjects and showed no significant difference between group 1 and the control group regarding the level of testosterone [5.03 +/- 3.37 Vs 6.95 +/- 1.69; respectively, p0.0S]. Also the plasma level of testosterone showed insignificant correlation with the serum iron level among groupi [r=-O.18.p=0.5]. A significant lower level in T4 was detected in group 1 compared to the control group [5.17 +/- 3.41 Vs. 11.01 +/- 1.44; respectively, p=0.001]. There was insignificant correlation between testosterone level in group 1 and the T4 level in the same group [r=-0.Ol, p=0.89]. On the other hand, no significant correlation was detected between group 1 and control group as regard TSH level [p=0.3]. Female patients with SCD [group 2] have a significant lower level of LH than the control group [72 +/- 5.44 Vs. 16.2 +/- 2.74; respectively, p=0.001]. The present study revealed that there was no significant difference between the level of FSH among group 2 and the control group [6.19 +/- 3, 60 Vs. 6.4 +/- 1.3; respectively, p=0.05], as regard the correlation between the LH level and the serum iron among group 2, there was no significant correlation [r=-0.35, p=0.18]. Also group 2 showed significant lower level of the T4 than the control group [6.5 8 +/- 6.3 Vs 11.64 +/- 1.05; respectively, p=0.001]. On the other hand no significant correlation was found between patients in group 2 and control group as regard TSH level p=0.3]. There was no significant correlation between the level of T4 and the serum iron level in both group 1 and group 2 [p=0.5]. The present study had demonstrated that SCD had a depressant effect on the hormone LH in female patients with SCD, and T4 in both males anti females with SCD irrespective of the serum iron level

Occupational exposure to cadmium and relation to male infertility

Cadmium is a new class of endocrine disruptors with a wide range of effects on mammalian reproduction. To determine the association between occupational exposure to cadmium and male fertility. Blood cadmium and lead levels were estimated by atomic absorption spectrophotometry in 30 infertile male welders and 30 healthy age matched, fertile, male welders as controls. FSH, LH and testosterone were estimated and semen analysis was done. The age ranged between 27-45 years. The infertile welders show significantly higher blood cadmium levels [42.7 +/- 1.7 micro g/dl] compared to the fertile group [11.3 +/- 4.1 micro g/dl, p <0.01] while serum testosterone and FSH are significantly lower among the infertile welders compared to controls [p < 0.05]. In addition, blood cadmium but not blood lead level has a significant inverse correlation, with serum testosterone and FSH [r=-0.37, -0.39, respectively, p < 0.05]. Oligozoospermia and abnormal forms is present in 56.7% and 43.3% of the infertile welders, respectively. Smokers have significantly higher blood cadmium compared to non smokers [p <0.01]. Smoking index has insignificant correlation with FSH, LH and testosterone but shows a significant positive correlation with blood cadmium [p <0.05] but not blood lead level. Blood cadmium is an independent predictor of infertility among the studied population Chronic exposure to cadmium can affect endocrine function of reproduction in males at the level of hypothalamus, pituitary and the testes together with its effects on spermatogenesis. Smoking can potentiate the effects of cadmium on the male reproductive system

Historical background and review of drugs and methods used for induction of ovulation. Part 1

Infertility is distressing life crises for many couples. Of the 15% of childless couples around the world approximately 15-25% is due to ovulating disturbances. Ovulation induction [01] therefore strives to redress ovulation problems by replicating the natural physiology of the cyclic ovarian function, with the goal of achieving ovulation of single or more mature follicles. Since the first ever successful induction of ovulation using extract of human cadaver pituitary glands in 1958, there have been substantial advances in the management of anovulatory infertility and an improved insight into the physiology of the micro environments of ovulation. Progressively, the need for new and effective methods for ovulation induction became more intense particularly with the introduction of In Vitro Fertilization procedures in clinical practice. During the last five decades, a large inventory of hormonal therapies for 01 and many management protocols have been presented, but more importantly was the new understanding of the varieties of ovarian dysfunctions and the pathophysiology of ovulation failure. The objective of this mini review article is to inform the readers about the current practical approaches in management of ovulation induction addressing the costs, risks, and critical evaluation of their effectiveness

Gestação sem intercorrências com mioma uterino volumoso tratado previamente com agonista do hormônio liberador das gonadotrofinas / Uneventful pregnancy with large uterine leiomyomata previously treated with gonadotrophin realease hormone agonist

Introdução. Os miomas uterinos, principalmente os submucosos, estão associados a infertilidade e intercorrências durante a gestação. A miomectomia é um procedimento comumente utilizado em mulheres com miomas, que desejam engravidar. O uso clínico dos análogos de hormônio liberador das gonadotrofinas antes da cirurgia tem por objetivo reduzir as dimensões do tumor e o sangramento durante o procedimento. Relato do caso. Mulher, 26 anos de idade, G1P1C0A0, com infertilidade secundária, hiperpolimenorréia, dor em hipogástrio e volume do útero aumentado por miomas, principalmente à custa de volumoso mioma submucoso e intramural que comprometia boa parte da cavidade do útero e obstruía as trompas. A paciente manifestou desejo de gestação. Optou-se então por miomectomia, mas durante o ato cirúrgico o procedimento não foi realizado em conseqüência da grande dimensão dos tumores. Apesar de possibilidade remota de gestação, foi introduzido o tratamento com análogo do hormônio liberador das gonadotrofinas para, em seguida, se tentar novamente a miomectomia. Entretanto, ocorreu gestação espontânea logo depois da conclusão do tratamento. A gestação cursou sem más intercorrências maternas ou fetais, e o parto ocorreu com 39 semanas de gestação. Conclusão. O tratamento com o análogo permitiu redução no volume do útero, retorno da fertilidade e gestação espontânea com evolução satisfatória. Portanto, em situações como essa, em que a cirurgia radical parece ser a única escolha, o tratamento com o análogo do hormônio liberador das gonadotrofinas pode ser a opção.

Introduction. Uterine leiomyomata, mainly the submucous, are associated to infertility and events during pregnancy. Myomectomy is a common procedure in women who want to get pregnant. Clinical use of the gonadotrophin release hormone analogues previously to surgery has an objective of reducing tumor size as well as the intraoperative bleeding.Case report. Woman, 26 years old, one previous normal pregnancy, with secondary infertility, hyperpolimenorrhea, hypogastric pain and enlarged uterus with myomas, mainly a big submucous and intramural myoma affecting most of the uterus cavity and obstructing the fallopian tubes. The patient declared her wish to get pregnant again. The option was, then, to myomectomy, but such procedure was not possible due to the intraoperative findings of many highly enlarged tumors. Even with small chances of pregnancy, treatment with a gonadotrophin release hormone analogue was initiated, so that myomectomy could be tried again latter. Nevertheless, spontaneous pregnancy occurred right after the end of the hormonal treatment. The pregnancy presented no abnormal maternal or child events, and delivery came up at the 39th week. Conclusion. The treatment with gonadotrophin release hormone analogue allowed reduction of tumor size, fertility recovery and spontaneous pregnancy with satisfactory evolution. In cases when radical surgery may appear as the only choice, the treatment with gonadotrophin release hormone analogues may be an option.

Advances in the study of small peptides in targeted drug delivery system / 药学学报

Recently various peptide receptors which displayed the highest binding affinity and specificity with their peptide ligands by ligand-receptor have been exploited to develop drug delivery system which can directionally deliver drug to targeted cell. It is significant to study and applicate, including targeted drug delivery system mediated by bombesin receptor, somatostatin receptor, SynB3 receptor, LH-RH receptor and other peptide receptor, et al. Several small peptide fragments were selected as carriers radicals combining doxorubicin, 2-pyrrolino-DOX, methotrexate, cis-platinum, and camptothecin to form hybrid cytotoxic analogs. These highly potent cytotoxic analogs have been designed as targeted anti-tumor agents for the treatment and study of various cancers that possess receptors for the carrier peptide.

Cyclophosphamide-induced rat ovarian damage and expression of gonadotropin-releasing hormone receptor in the damaged ovaries / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate ovarian follicular damage induced by chemotherapeutic agents and gonadotropin- releasing hormone receptor (GnRHR) expression in the damaged ovaries in rats.</p><p><b>METHODS</b>Two groups of adult SD rats were subjected to intraperitoneal injection of a single-dose cyclophosphamide and saline, respectively, and 8 weeks later, the ovaries were taken for observing the ovarian damages. The distribution of GnRHR was detected with immunohistochemistry, and RT-PCR was used to determine the expression of GnRHR mRNA in the rat ovaries.</p><p><b>RESULTS</b>Massive primordial follicular loss occurred in the ovaries of rats exposed to cyclophosphamide with also evident stromal ovarian blood vessel damages and focal fibrosis. Both the protein and mRNA expressions of GnRHR were detected in normal rat ovaries, but in rats exposed to cyclophosphamide, the expressions were significantly lowered in the ovaries (P<0.05).</p><p><b>CONCLUSION</b>Low-level GnRHR expressions in the ovaries of rats with cyclophosphamide exposure suggest microenvironment disturbances in the damaged rat ovaries in advanced stage of chemotherapy.</p>

Gonadotropin Releasing Hormone (GnRH) and GnRH Receptor in Normal Bladder Epithelia and Their Role in Bladder Epithelial Proliferation / 대한비뇨기과학회지

PURPOSE: To confirm the production of extra-hypothalamic gonadotropin releasing hormone (GnRH) and GnRH receptor in bladder mucosal epithelia, and a potential role of GnRH on the bladder, normal human bladder tissues, and primary cultured dog bladder mucosal epithelia were studied. MATERIALS AND METHODS: For this study, normal human bladder tissue from 4 patients and primary cultured normal bladder mucosal epithelial cells from 2 dogs were used. For localization of extra-hypothalamic GnRH and the extra-pituitary GnRH receptor, in situ hybridization and immunohistochemical staining were done. To evaluate the roles of exogenous GnRH in bladder mucosal cells, the culture media were supplemented with charcoal stripped serum and 4 different concentrations of GnRH (0, 10(-3), 10(-5) and 10(-7)M). The effect of exogenous GnRH was evaluated using a hemocytometer and fluorescence activated cell sorter (FACS). RESULTS: GnRH and GnRH receptors, and their mRNA signals were localized in most of the both human bladder mucosal epithelia and dog bladder mucosal epithelia, but not in a few cells. There were no significant GnRH effects on cellular proliferation and cell cycle changes (p<0.05). CONCLISIONS: Bladder mucosal epithelium produces GnRH and GnRH receptors, but they do not effect either the proliferation or cell cycle changes. Although the exact function of extra-hypothalamic bladder GnRH is unknown, GnRH and GnRH receptors would be assumed to have unknown autocrine or paracrine relationships with each other.

Biologia de neurônios hipotalâmicos produtores do hormônio liberador das gonadotrofinas: novas informações sobre o uso das células imortalizadas secretoras desse hormônio / Biology of hypothalamic neurons producing gonadotropin releasing hormone (GnRH): new information on the use of immortalized cells secreting GnRH

O estudo dos neurônios que produzem o hormônio liberador das gonadotrofinas (GnRH), hormônio hipotalámico que estimula a secreção, das gonadotrofinas hipofisárias, tem recebido vigoroso impulso com a disponibilidade das células imortalizadas, que especificamente sintetizam e secretam o hormônio em questão. Duas são as linhas celulares obtidas por tumorigênese induzida em camundongos transgênicos: 1) as células GT1 (com os seus subclones GT1-1, GT1-3, GT1-7) e 2) as células GN (com os seus subclones GN10, GN11, NLT). As células GT1 foram derivadas de um tumor hipotalâmico. Pode-se constatar que elas são dotadas de propriedades dos neurônios maduros secretores de GnRH, que completaram o seu trajeto da sua sede de origem, o placóide olfatório, até a sua sede definitiva, o hipotálamo, e já perderam a capacidade de mover-se. Por essas características, as células GT1 são utilizadas sobretudo para o estudo das propriedades secretórias dos neurônios que produzem o GnRH e para identificar os sinais que ali chegam. Pode-se assim evidenciar uma série de receptores, que, ativados pelos seus ligantes (neurotransmissores, hormônios, fatores de crescimento), modulam a síntese e a secreção do GnRH. As células GN foram retiradas de um tumor do bulbo olfatório, portanto, elas são consideradas mais semelhantes aos neurônios imaturos secretores de GnRH que ainda estão desenvolvendo o processo de migração do placóide olfatório até o hipotálamo. Desse modo, tais células são utilizadas sobretudo para identificar e caracterizar os fatores que possam influenciar os processos de migração dos neurônios que produzem o GnRH. Em particular, pode-se constatar que a motilidade dos neurônios secretores desse hormônio é estimulada pela anosmina, a proteína codificada pelo gene KAL1, que, nas suas formas mutantes, ocasiona o hipogonadismo hipogonadotrófico conhecido como a síndrome de Kallmann, por alguns fatores de crescimento (fator de crescimento de fibroblasto, fator de crescimento...

The study of the neurons secreting the gonadotropin releasing hormone (GnRH), the hypothalamic hormone stimulating the release of pituitary gonadotropins, has been potentiated by the development of immortalized cells that specifically synthetize and secrete GnRH. Two cell lines have been obtained by targeted tumorigenesis in transgenic mice: 1) the GT1 cells (with GT1-1, GT1-3 and GT1-7 subclones), and 2) the GN cells (with the GN10, GN11 and NLT subclones). GT1 cells have been obtained from a hypothalamic tumor and exhibit the properties of fully mature GnRH secreting neurons after they reached their final destination in the hypothalamus starting from the olfactory placode. Because of their characteristics GT1 cells have been mainly utilized to investigate the secretory properties of GnRH neurons and to identify the inputs modulating their activity. By this way a consistent number of receptors responding to specific ligands (neurotransmitters, hormones, growth factors) controlling GnRH synthesis and secretion has been identified. GN cells have been derived from a tumor of the olfactory bulb and are considered to replicate the properties of immature GnRH secreting neurons still retaining the capacity of moving. Consequently these cells are used to identify and characterize the factors influencing the migratory process of GnRH neurons from the olfactory placode to the hypothalamus. It has been found that factors stimulating GnRH neuron motility include anosmin, the protein encoded by the KAL1 gene, whose mutations lead to the form of hypogonadotropic hypogonadism known as Kallmann’s syndrome, growth factors such as fibroblast growth factor, hepatocyte growth factor, vascular endothelial growth factor, and cytoskeleton associated proteins (stathmin). On the contrary GABA agonists and glucocorticoids depress GN cells motility. As a whole the findings reported in this review seem particularly important to provide further information on the central...

A Familial Case of Idiopathic Hypogonadotropic Hypogonadism Occurred in a Boy and His Sister / 대한소아내분비학회지

Isolated gonadotropin deficiency can be idiopathic or a part of X-linked Kallmann syndrome associated with anosmia. There have been several trials to reveal the genetic mutations that affect gonadotropin secretion, and approximately 10% of sporadic patients have mutations in either gonadotropin releasing hormone receptor (GnRHR) or KAL1 gene. Here we report one familial cases of idiopathic hypogonadotropic hypogonadism occurred in a boy and his elder sister. They presented with delayed puberty and hypoplastic gonads, but normal sense of smell. We performed GnRHR and KAL1 mutation analysis, but could not find any mutation.

Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

Similar to women with Polycystic Ovary Syndrome (PCOS), female sheep treated prenatally with testosterone (T-females) are hypergonadotropic, exhibit neuroendocrine defects, multifollicular ovarian morphology, hyperinsulinemia and cycle defects. Hypergonadotropism and multifollicular morphology may in part be due to developmentally regulated increase in pituitary responsiveness to GnRH and may culminate in increased ovarian estradiol production. In this study, we utilized a GnRH agonist, leuprolide, to determine the developmental impact of prenatal testosterone exposure on pituitary-gonadal function and to establish if prenatal exposure produces changes in the reproductive axis similar to those described for women with PCOS. Eight control and eight T-females were injected intravenously with 0.1 mg of leuprolide acetate per kilogram of body weight at 5, 10 and 20 weeks of age. Blood samples were collected by means of an indwelling jugular vein catheter at 0, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours after leuprolide. Area under the curve (AUC) of LH response to leuprolide increased progressively between the three ages studied (P<0.05). AUC of LH in T-females was higher than in control females of the same age at 5 and 10 weeks of age (P<0.05), but similar at 20 weeks of age. AUC of estradiol response was lower at 10 but higher at 20 weeks of age in T-females compared to controls of the same age (P<0.05). Our findings suggest that prenatal T treatment alters the pituitary and ovarian responsiveness in a manner comparable to that observed in women with PCOS.

Tratamento endócrino adjuvante do câncer de mama / Adjuvant endocrine treatment in breast cancer

Os autores apresentam revisão da literatura acerca dos procedimentos utilizados na terapêutica endócrina adjuvante do câncer de mama, com o propósito de obter melhores taxas de intervalo livre da doença e da sobrevida global. Inicialmente, analisam estudos epidemiológicos, que evidenciam o papel dos estrógenos endógenos na patogenia e na proliferação da neoplasia,assim como a importância da presença de receptores de estrógenos...

Effect of Chinese herbal medicine for nourishing yin and purging fire on mRNA expressions of gonadotropin-releasing hormone and its receptor in precocious puberty model rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To probe the mechanism of Chinese herbal medicine (CHM) for nourishing Yin and purging Fire on the expressions of gonadotropin-release hormone (GnRH) and its mRNA expression in hypothalamus and GnRH receptor mRNA in pituitary in danazol induced precocious puberty model rats.</p><p><b>METHODS</b>Rats were divided into the normal group, the model group, the blank control group and the CHM group. Rats, except that in the normal group, were subcutaneously administered danazol 300 micrograms at 5 days of age individually and CHM was fed to rats in the CHM group from 15 days of age, in the meantime, normal saline was fed to rats in the blank control group. Expression of GnRH in hypothalamus was observed by immunohistochemical method and expressions of GnRH mRNA in hypothalamus and GnRH receptor mRNA in pituitary were determined by RT-PCR.</p><p><b>RESULTS</b>Compared with rats in the normal groups, the vaginal opening and the onset of first estrus were ahead of time, the number of GnRH immunoreactive positive cells decreased and the expressions of GnRH mRNA in hypothalamus and GnRH receptor mRNA in pituitary up-regulated in the model rats and blank control rats. Compared with the model and the blank control groups, in CHM group, all the above-mentioned abnormally changed parameters improved significantly after treatment.</p><p><b>CONCLUSION</b>CHM for nourishing Yin and purging Fire may inhibit the abnormal hyperfunction of hypothalamus-pituitary-ovary axis in precocious puberty rat induced by danazol via reducing the synthesis and release of GnRH, and lowering the responsibility of pituitary cells to GnRH. This may be the primary mechanism of CHM in effectively treating the true precocious puberty.</p>

The distribution of androgen receptor and its coexistence with gonadotropin releasing hormone receptor in rat submaxillary / 中华男科学杂志

<p><b>OBJECTIVES</b>To study the coexistence of androgen receptor(AR) and GnRH receptor(GnRHR), and further identify that submaxillary is a target organ of androgen and GnRH in SD Rat.</p><p><b>METHODS</b>Sequential deparaffinized sections of SD rat submaxillary were immunostained with SABC method. The first antibodies were rabbit anti-rat GnRH idiotypic antibodies and mouse anti-rat androgen receptor antibodies.</p><p><b>RESULTS</b>AR immunoreactive cells were found in glandular epithelial cells of serous acinus and epithelial cells in all gland ducts. While the distribution of GnRHR coincides with that of AR. The immunoreactive substances were distributed in cytoplasm of all positive cells with negative nuclei.</p><p><b>CONCLUSIONS</b>The results showed that AR existed in submaxillary and was widely distributed in glandular epithelial cells with distributive pattern similar to those of GnRHR. It suggests that submaxillary is a target organ of androgen, responsible for modulating biological function of submaxillary.</p>