Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.143
Filtrar
1.
Int J Gynaecol Obstet ; 148(1): 59-64, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31569274

RESUMO

OBJECTIVE: To compare the effect of gonadotropin-releasing hormone (GnRH) agonist microdose flare-up and GnRH agonist flare-up protocols among women with poor ovarian reserve undergoing intracytoplasmic sperm injection (ICSI) cycles. METHODS: Randomized controlled trial study among 131 women with poor ovarian reserve who underwent ICSI cycles at a single center in Tehran, Iran, between September 2008 and May 2014. Eligible women were randomly assigned to either the microdose flare-up (n=66) or flare-up (n=65) protocol. The primary outcome measure was live birth rate. RESULTS: Both groups were comparable in cycle cancellation, mean number of dominant follicles, retrieved oocytes, and metaphase II oocytes. Number of stimulation days (P=032) and endometrial thickness (P=0.001) were significantly higher, and gonadotropin dose was non-significantly higher (P=0.075) in the microdose flare-up group than in the flare-up group. No difference in clinical pregnancy, implantation, or abortion rate was observed between the two protocols. Live birth was higher in the microdose flare-up group than in the flare-up group (P=0.036). CONCLUSION: The microdose flare-up protocol seemed to be superior to the flare-up protocol, but it required a higher dose of gonadotropins and a longer duration of stimulation. Further prospective clinical trials of the microdose flare-up protocol are recommended. CLINICALTRIALS.GOV: NCT01006954.


Assuntos
Hormônio Liberador de Gonadotropina/agonistas , Antagonistas de Hormônios/administração & dosagem , Indução da Ovulação/métodos , Injeções de Esperma Intracitoplásmicas/métodos , Adulto , Coeficiente de Natalidade , Relação Dose-Resposta a Droga , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Antagonistas de Hormônios/farmacologia , Humanos , Irã (Geográfico) , Nascimento Vivo , Recuperação de Oócitos/estatística & dados numéricos , Gravidez
2.
Histochem Cell Biol ; 152(6): 423-437, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630211

RESUMO

Wide application of gonadotropin-releasing hormone (GnRH) agonists and antagonists for clinical purposes determines their effects on ovarian signaling pathways. Our study aimed to determine the localization, expression levels of Wnt signaling members in the pubertal and adult mouse ovary and the impact of GnRH antagonist cetrorelix on these signaling members. 0.5 mg/kg of cetrorelix was injected to 3-and 6-week-old mice for 2 weeks. At the end of injection, ovaries from 5 (5Ce)- to 8-week (8Ce)-old mice were embedded in paraffin for immunohistochemistry and homogenized for western blot to compare with control (5C-8C) and sham groups (5S-8S). WNT2 and WNT4 showed higher expression in thecal and stromal cells in adult mouse ovaries and only WNT4 expression was affected by cetrorelix. FZD1 was localized mainly in oocytes of pubertal ovaries and granulosa cells and oocytes of adult ovaries. FZD1 was reduced by cetrorelix in pubertal ovaries. FZD4 was abundantly localized in thecal and stromal cells of all groups and protein level was not affected by cetrorelix. LRP-6 was expressed mainly in oocytes and stromal cells of pubertal, oocytes of adult ovaries and its expression was reduced by cetrorelix in adult ovaries. CTNNB1 intensity in granulosa cells was the lowest in pubertal and the highest in adult ovaries and its expression was decreased by cetrorelix in adult ovaries. Cetrorelix affected the expression of specific members of the Wnt signaling depending on the developmental stage of mice, pointing out its possible interaction with gonadotropins during pubertal and adult stages.


Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/farmacologia , Oócitos/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/química , Camundongos , Camundongos Endogâmicos BALB C , Oócitos/metabolismo , Puberdade/metabolismo
3.
Nurs Womens Health ; 23(4): 366-369, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31276630

RESUMO

Endometriosis, which is the growth of endometrial tissue outside of the uterus, is estimated to affect up to 10% of reproductive-age women. Symptoms associated with endometriosis include dysmenorrhea, chronic pelvic pain, and dyspareunia. In July 2018, the U.S. Food and Drug Administration approved elagolix (Orilissa, AbbVie, North Chicago, IL) as an oral treatment for endometriosis-related pain. This medication is a gonadotropin-releasing hormone receptor antagonist that works by suppressing levels of hormones, including estrogen and progesterone. This helps decrease inflammation and the proliferation of endometrial tissue. In this column, I provide an overview of elagolix and discuss contraindications, adverse effects, and practice implications for nurses who work with women affected by endometriosis.


Assuntos
Dor Abdominal/tratamento farmacológico , Endometriose/tratamento farmacológico , Hidrocarbonetos Fluorados/uso terapêutico , Pirimidinas/uso terapêutico , Dor Abdominal/etiologia , Dor Abdominal/fisiopatologia , Adulto , Tratamento Farmacológico/métodos , Dismenorreia/complicações , Dismenorreia/tratamento farmacológico , Endometriose/fisiopatologia , Feminino , Antagonistas de Hormônios/farmacologia , Antagonistas de Hormônios/uso terapêutico , Humanos , Hidrocarbonetos Fluorados/farmacologia , Pirimidinas/farmacologia
4.
Reprod Biol ; 19(2): 179-188, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31151754

RESUMO

Corpus luteum (CL) is an endocrine tissue involved in regulation of reproductive cycle and early pregnancy establishment. In the present study DEAD-box helicase-5 (Ddx5), a member of the DEAD box family of RNA helicases was investigated for its expression, regulation and function in CL of Wistar rats. Ddx5 was expressed in adult rat CL. Primary cell culture from supra-ovulated ovaries were established for in vitro studies. Addition of luteinizing hormone (LH; 100 ng/ml), a luteotrophic factor in primary cell culture, decreased Ddx5 RNA expression (foldchange:0.6 ±â€¯0.075) while prostaglandin alpha (PGF2α; 1µM), a luteolytic factor caused an increase (foldchange:2.4 ±â€¯0.4) compared to control group. Under in vivo conditions, the administration of PGF2α or gonadotropin-releasing hormone antagonist; cetrorelix (CET) caused luteolysis as well as an increase in the protein level of Ddx5 (foldchange:1.9 ±â€¯0.27 and 1.4 ±â€¯0.09 viz.; p < 0.05) in CL of adult rats. LH was administered post CET treatment which suppressed Ddx5 protein expression (foldchange:0.8 ±â€¯0.16; p < 0.05) compared to CET treated group. Further, it was observed that the expression of Ddx5 was upregulated (foldchange:1.5 ±â€¯0.23; p < 0.05) in CL during late pregnancy compared to mid pregnancy concomitant to luteolysis in adult rats. Overall, the results suggest for the first time that Ddx5 is expressed in rat CL and regulated by luteolytic and luteotrophic factors in an inverse fashion. Further, the data significantly correlates ddx5 expression to CL regression suggesting involvement of ddx5 in luteolysis. These results suggest a significant role of Ddx5 in female reproduction biology and warrant in depth examination of the function of Ddx5 in CL.


Assuntos
Cloprostenol/farmacologia , Corpo Lúteo/metabolismo , RNA Helicases DEAD-box/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Animais , Gonadotropina Coriônica/farmacologia , RNA Helicases DEAD-box/genética , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Luteolíticos/farmacologia , Gravidez , Ratos , Ratos Wistar
5.
Neuroscience ; 411: 255-269, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31163207

RESUMO

Repeated stress induces systemic elevations in glucocorticoid levels. Stress is also associated with alterations in central nervous system astrocytes and oligodendrocytes that involve connexins and myelin proteins. Corticosteroid elevation seems a major factor in stress-induced neuropathology. Changes in astrocyte connexins and myelin components may be important mediators for the neurological effects of corticosteroid elevations. Two primary cell culture models, myelination culture from rat embryonic spinal cord (SC) or cerebral cortex (CC) consisting of neurons and glial cells (oligodendrocytes, microglia and astrocytes), and mixed astrocyte-and-oligodendrocyte culture prepared from postnatal rat CC, were used in this study. Cell cultures were treated with either vehicle, corticosterone (CORT) with or without glucocorticoid receptor antagonist mifepristone, or dexamethasone (DEX) during the period of in vitro myelination. Immunoreactivity of astrocyte connexin 43 (Cx43) and oligodendrocyte myelin basic protein (MBP), or the myelination index (co-localization of MBP and phosphorylated neurofilament) was determined by double immunofluorescent labeling. Oligodendrocyte morphology was evaluated by Sholl analysis. Prolonged exposure to CORT or DEX induced dose-dependent reduction of the myelination index, and of immunostaining for MBP and Cx43 in SC and CC myelination cultures, which was prevented by mifepristone. In glial cultures single CORT or DEX exposure caused shrinkage and simplification of/' MBP- or CNPase-positive oligodendrocyte processes. The results support that concurrent effects of glucocorticoids on myelination and astrocyte Cx43 immunoreactivity are mediated by glucocorticoid receptors and may partially account for the involvement of CNS glia in the pathological effects of prolonged stress.


Assuntos
Conexina 43/metabolismo , Dexametasona/farmacologia , Mifepristona/farmacologia , Bainha de Mielina/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Glucocorticoides/farmacologia , Antagonistas de Hormônios/farmacologia , Bainha de Mielina/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Ratos , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
6.
Drug Des Devel Ther ; 13: 1855-1863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239640

RESUMO

Purpose: The two major ovarian-stimulation protocols for in vitro fertilization are gonadotropin-releasing hormone agonist (GnRH-a) protocol or GnRH antagonist (GnRH-ant) protocol; however, comparisons of their relative efficacy remain controversial. Additionally, conflicting data exist regarding their effects on endometrial receptivity. Thus, this study investigated how GnRH-a and GnRH-ant treatments alter the endometrium during the mid-secretory phase. Patients and methods: We compared proteomic profiles across human endometrium tissues of mid-secretory phase from normal control humans (n=5), patients treated with GnRH-a (n=5), and patients treated with GnRH-ant (n=5). Results: We identified 2088 proteins, with 362 that exhibited significantly different expression. Fuzzy c-means clustering (FCM) using the M Fuzz algorithm analysis showed that the same 87 proteins changed significantly in both the GnRH-a and GnRH-ant groups compared with those in the control. Moreover, Gene Ontology (GO) analysis showed that, of these 87, downregulated proteins were associated with energy metabolism and upregulated proteins were linked to cytoskeleton maintenance. Upregulated proteins involved in complement-mediated immunity were present in 151 proteins that exhibited significantly different expression in the GnRH-ant group only. Conclusion: We demonstrated that comparative proteomic analysis is useful for accessing endometrial receptivity, which seemed more strongly impaired by GnRH-ant than GnRH-a treatments. Our findings also revealed that energy metabolism and immunity response may be the key biological mechanisms underlying human endometrial receptivity.


Assuntos
Endométrio/efeitos dos fármacos , Doenças das Tubas Uterinas/tratamento farmacológico , Hormônio Liberador de Gonadotropina , Antagonistas de Hormônios/farmacologia , Proteômica , Adulto , Algoritmos , Análise por Conglomerados , Endométrio/patologia , Doenças das Tubas Uterinas/patologia , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos
7.
Br Poult Sci ; 60(4): 395-403, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132872

RESUMO

1. In this study, geese (Anas cygnoides) embryonic pituitary cells were cultured in vitro to determine if glucocorticoids could induce growth hormone (GH) expression and to investigate the molecular mechanisms involved in this process. 2. On embryonic day 15 (e15) and e20 the pituitary cells were treated with corticosterone (CORT), membrane impermeable bovine serum albumin-conjugate corticosterone (CORT-BSA), dexamethasone (DEX), and a glucocorticoid receptor (GR) antagonist (RU486) to detect responsiveness of somatotrophs to glucocorticoids. 3. Treatment with CORT, CORT-BSA, and DEX for as little as 6 h increased the percentage of GH-positive cells (P < 0.01) and increased GH mRNA expression (P < 0.01) in e15 goose pituitary cells compared to the control. CORT significantly increased the level of GH protein secreted from cultured e15 goose embryonic pituitary cells, and CORT-BSA increased GH secretion from e20 goose embryonic pituitary cells. 4. A significant increase was observed in the glucocorticoid receptor in GR transcription levels (P < 0.01) with CORT, CORT-BSA, and DEX treatment. Furthermore, the CORT-stimulated GH mRNA expression was completely negated by pre-treatment with RU486. 5. These findings demonstrate that glucocorticoids can stimulate somatotroph differentiation in vitro, as characterised by enhanced GH protein secretion andmRNA expression in cultured geese embryonic pituitary cells. The membrane GR was involved in pituitary somatotroph differentiation induced by glucocorticoids during the embryonic development of geese.


Assuntos
Diferenciação Celular/fisiologia , Corticosterona/farmacologia , Cortisona/farmacologia , Dexametasona/farmacologia , Gansos/fisiologia , Receptores de Glucocorticoides/metabolismo , Soroalbumina Bovina/farmacologia , Somatotrofos/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/fisiologia , Gansos/genética , Antagonistas de Hormônios/farmacologia , Mifepristona/farmacologia , Hipófise/fisiologia , RNA Mensageiro/metabolismo
8.
BMC Cancer ; 19(1): 376, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31014286

RESUMO

BACKGROUND: Previous work in our laboratory demonstrated that antiprogestin mifepristone impairs the growth and adhesion of highly metastatic cancer cells, and causes changes in their cellular morphology. In this study, we further assess the anti-metastatic properties of mifepristone, by studying whether cytostatic doses of the drug can inhibit the migration and invasion of various cancer cell lines using a double fluorescence cytochemical labeling approach. METHODS: Cell lines representing cancers of the ovary (SKOV-3), breast (MDA-MB-231), glia (U87MG), or prostate (LNCaP) were treated with cytostatic concentrations of mifepristone. Wound healing and Boyden chamber assays were utilized to study cellular migration. To study cellular invasion, the Boyden chamber assay was prepared by adding a layer of extracellular matrix over the polycarbonate membrane. We enhanced the assays with the addition of double fluorescence cytochemical staining for fibrillar actin (F-actin) and DNA to observe the patterns of cytoskeletal distribution and nuclear positioning while cells migrate and invade. RESULTS: When exposed to cytostatic concentrations of mifepristone, all cancer cells lines demonstrated a decrease in both migration and invasion capacities measured using standard approaches. Double fluorescence cytochemical labeling validated that mifepristone-treated cancer cells exhibit reduced migration and invasion, and allowed to unveil a distinct migration pattern among the different cell lines, different arrays of nuclear localization during migration, and apparent redistribution of F-actin to the nucleus. CONCLUSION: This study reports that antiprogestin mifepristone inhibits migration and invasion of highly metastatic cancer cell lines, and that double fluorescence cytochemical labeling increases the value of well-known approaches to study cell movement.


Assuntos
Movimento Celular , Proliferação de Células , Fluorescência , Antagonistas de Hormônios/farmacologia , Mifepristona/farmacologia , Neoplasias/patologia , Humanos , Invasividade Neoplásica , Neoplasias/tratamento farmacológico , Células Tumorais Cultivadas , Cicatrização
9.
J Biomed Sci ; 26(1): 26, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898126

RESUMO

BACKGROUND: Traumatic experience may lead to various psychological sequelae including the unforgettable trauma-associated memory as seen in posttraumatic stress disorder (PTSD), with a mechanism of impaired fear extinction due to biological imbalance among hypothalamic-pituitary-adrenal (HPA) axis and fear circuit areas such as medial prefrontal cortex (mPFC), hippocampus, and amygdala. Recently the impaired sociability seen in PTSD patients received great attention and the involvement of oxytocin (OXT) mediation is worth being investigated. This study examined whether the trauma-altered prosocial behavior can be modulated by OXT manipulation and its relationship with corticotropin-releasing hormone (CRH) signaling. METHODS: Male rats previously exposed to a single prolonged stress (SPS) were evaluated for their performance in social choice test (SCT) and novel object recognition test (NORT) following the introduction of intranasal oxytocin (OXT) and OXT receptor antagonist atosiban (ASB). OXT receptors (OXTR) and CRH receptors (CRHR1, CRHR2) were quantified in both protein and mRNA levels in medial prefrontal cortex (mPFC), hippocampus, and amygdala. RESULTS: SPS reduced inclination of rats staying at the sociable place with performing less prosocial contacts. OXT can amend the deficit but this effect was blocked by ASB. Expression of OXTR became reduced following SPS in mPFC and amygdala, the latter exhibited higher therapeutic specificity to OXT. Expression of CRHR1 appeared more sensitive than CRHR2 to SPS, higher CRHR1 protein levels were found in mPFC and amygdala. CONCLUSION: Psychological trauma-impaired sociability is highly associated with OXT signaling pathway. Intranasal OXT restored both the SPS-impaired prosocial contacts and the SPS-reduced OXTR expressions in mPFC and amygdala. OXT may have therapeutic potential to treat PTSD patients with impaired social behaviors.


Assuntos
Expressão Gênica/efeitos dos fármacos , Ocitocina/farmacologia , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Ocitocina/genética , Comportamento Social , Transtornos de Estresse Pós-Traumáticos/genética , Administração Intranasal , Animais , Antagonistas de Hormônios/farmacologia , Humanos , Masculino , Ocitócicos/administração & dosagem , Ocitócicos/farmacologia , Ocitocina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Ocitocina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Vasotocina/análogos & derivados , Vasotocina/farmacologia
10.
Taiwan J Obstet Gynecol ; 58(2): 234-238, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30910145

RESUMO

OBJECTIVE: To evaluate the effect of the GnRH antagonist on gonadotropin ovulation induction in women with PCOS. MATERIALS AND METHODS: A total of 175 intrauterine insemination (IUI) cycles in women with polycystic ovary syndrome (PCOS) were included in the study. Women in the control group (n = 87) underwent controlled ovarian stimulation (COS) with recombinant follicle stimulating hormone (r-FSH) only, while women in the study group (n = 88) were administered r-FSH plus cetrorelix. RESULTS: As expected, the mean value of luteinizing hormone and progesterone, on the day of human chorionic gonadotropin administration were statistically significantly lower in patients receiving GnRH antagonist than the control group (p = 0.002). Premature luteinization occurred in only one of the patients in the GnRH antagonist group (1.1%) and in 15 of the 88 cycles in the control group (17.2%), showing a significant difference between the two groups (P = 0.001). The clinical pregnancy rate per cycle was higher in GnRH-antagonist group compared to the control group but the difference did not reach to a statistical significance (25% vs 14.9%, P = 0.096). CONCLUSIONS: Adding GnRH-antagonist in COS/IUI cycles in women with PCOS resulted in a lower incidence of premature luteinization but did not improve pregnancy rates. However, owing to some benefits, antagonist therapy could be considered as a reasonable alternative to IVF in order to reduce PCOS patients'emotional distress.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/análogos & derivados , Antagonistas de Hormônios/administração & dosagem , Inseminação Artificial/métodos , Indução da Ovulação/métodos , Adulto , Estudos de Casos e Controles , Feminino , Hormônio Foliculoestimulante/administração & dosagem , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Humanos , Infertilidade Feminina/etiologia , Hormônio Luteinizante Subunidade beta/sangue , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Gravidez , Taxa de Gravidez , Progesterona/sangue , Estudos Retrospectivos , Adulto Jovem
11.
Horm Behav ; 110: 46-55, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836063

RESUMO

Parental care plays an important role in individual survival and development in mammals. Many studies have focused on the mechanisms underlying maternal behavior. However, the underlying neural mechanisms of paternal behavior are less understood. Using monogamous mandarin voles (Microtus mandarinus), the present study found that fathers initiated more paternal behavior and the virgin male showed more infanticide. Moreover fathers had shorter latency to approach a pup at the postnatal day (PND) 10 than PND1, PND20 than nonfathers. Fathers had a shorter latency to take care of unfamiliar pups than nonfathers. They had higher levels of paternal behavior at PND 10 than PND1 and PND20 toward the mandarin vole pups. Fathers had a significantly higher serum concentration of oxytocin (OT) than virgin males. Both RT-PCR and Western blot results indicated that the levels of the oxytocin receptor (OTR) in the medial preoptic area (MPOA) of fathers were significantly higher than in virgin males, but the levels of vasopressin 1a receptor (V1AR) mRNA and protein expression in the MPOA did not show significant differences. Microinjection of an oxytocin receptor antagonist into the MPOA significantly reduced the total duration of paternal behavior and increased the latency to approach the pup and initiate paternal behavior. Our results indicated that OT plays a key role in the modulation of paternal behavior via the MPOA.


Assuntos
Arvicolinae/fisiologia , Comportamento de Nidação/efeitos dos fármacos , Ocitocina/farmacologia , Comportamento Paterno/efeitos dos fármacos , Área Pré-Óptica/efeitos dos fármacos , Animais , Arvicolinae/metabolismo , Pai , Feminino , Antagonistas de Hormônios/farmacologia , Masculino , Ocitocina/metabolismo , Área Pré-Óptica/metabolismo , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo
12.
J Clin Endocrinol Metab ; 104(5): 1637-1644, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476255

RESUMO

CONTEXT: A paradoxical GH response to oral glucose (OG) is often found in acromegaly. However, the clinical characteristics of patients with acromegaly and a paradoxical GH response to OG (OG responders) remain unclear. OBJECTIVE: The aim of the present study was to define the clinical characteristics of OG responders with acromegaly. DESIGN: Retrospective study. SETTING: Hospitalized care at Osaka University Hospital. PATIENTS AND METHODS: Of 63 patients with acromegaly admitted to our hospital from January 2006 to January 2017, 19 were classified as OG responders and 44 as nonresponders. The clinical characteristics of these groups were compared. RESULTS: Before surgery, OG responders had substantially greater IGF-1 SD scores than nonresponders (P < 0.05), although no difference was found in basal GH levels between the two groups (P = 0.46). Regarding glucose metabolism, 120-minute plasma glucose and immunoreactive insulin after OG administration and hemoglobin A1c were significantly greater in OG responders than in nonresponders (P < 0.01, P < 0.05, P < 0.05, respectively). GH levels during octreotide or bromocriptine testing were decreased more significantly in OG responders than in nonresponders (P < 0.05, P < 0.05, respectively). The proportion of pituitary tumors with hypointensity on T2-weighted MRI was significantly greater in OG responders than in nonresponders (P < 0.05). The difference in IGF-1 and parameters of glucose metabolism described disappeared between the two groups after surgery. CONCLUSIONS: The paradoxical GH response reflected the clinical characteristics, especially IGF-I level, glucose metabolism, and drug efficacy in acromegaly. A paradoxical GH response, in addition to the nadir GH levels, to OG load is potentially useful for evaluation of the clinical characteristics of acromegaly.


Assuntos
Acromegalia/tratamento farmacológico , Glucose/administração & dosagem , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Hipofisárias/tratamento farmacológico , Acromegalia/metabolismo , Acromegalia/patologia , Adulto , Biomarcadores/análise , Bromocriptina/farmacologia , Estudos de Casos e Controles , Feminino , Seguimentos , Fármacos Gastrointestinais/farmacologia , Glucose/metabolismo , Antagonistas de Hormônios/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/farmacologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prognóstico , Estudos Retrospectivos
13.
Behav Brain Res ; 360: 146-157, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30500430

RESUMO

Somatic and motivational symptoms accompanying opiate withdrawal are considered one of the major reasons for relapse to opiate-seeking and opiate-taking behaviors. These symptoms are accompanied by the activation of stress-related processes including hypothalamic-pituitary-adrenal axis activity and noradrenergic (NA) signaling. In particular, the NA system plays an important role in the expression of somatic signs of opiate withdrawal, whereas glucocorticoid (GR) and mineralocorticoid receptors (MR) are activated during opiate abstinence. The purpose of our study was to examine the roles of α1-, α2-, and ß-adrenoceptors (ARs) as well as GR and MR, in the formation and expression of physiological and motivational symptoms of morphine withdrawal. We showed that systemic pretreatment with the selective α1-AR antagonist prazosin (0-1 mg/kg), the selective α2-AR antagonist RX821002 (0-2 mg/kg), the selective ß-adrenergic antagonist, propranolol (0-10 mg/kg), or the selective MR antagonist spironolactone (0-50 mg/kg), but not the selective GR antagonist mifepristone (0-40 mg/kg), decreased somatic symptoms of naloxone-precipitated morphine withdrawal in mice chronically treated with morphine. In contrast, only propranolol pretreatment attenuated the dysphoric affective state accompanying naloxone-precipitated morphine withdrawal as assessed in the conditioned place aversion (N-CPA) paradigm. Together, our results demonstrate the important roles of noradrenergic receptors in the modulation of somatic, but not motivational/affective, symptoms of morphine withdrawal. In addition MR but not GR regulates the expression of only somatic symptoms of morphine withdrawal.


Assuntos
Transtornos do Humor/etiologia , Morfina/toxicidade , Receptores Adrenérgicos/metabolismo , Receptores de Esteroides/metabolismo , Distúrbios Somatossensoriais/etiologia , Síndrome de Abstinência a Substâncias/complicações , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas de Hormônios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mifepristona/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes , Uso Off-Label , Prazosina/farmacologia , Propranolol/farmacologia , Síndrome de Abstinência a Substâncias/psicologia
14.
Thyroid ; 29(1): 111-123, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30351237

RESUMO

BACKGROUND: The thyrotropin receptor (TSHR) is the target for autoimmune thyroid stimulating antibodies (TSAb) triggering hyperthyroidism. Whereas elevated thyroid hormone synthesis by the thyroid in Graves' disease can be treated by antithyroid agents, for the pathogenic activation of TSHR in retro-orbital fibroblasts of the eye, leading to Graves' orbitopathy (GO), no causal TSHR directed therapy is available. METHODS: Due to the therapeutic gap for severe GO, TSHR inhibitors were identified by high-throughput screening in Chinese hamster ovary cells expressing the TSHR. Stereo-selective synthesis of the screening hits led to the molecule S37, which contains seven chiral centers. Enantiomeric separation of the molecule S37 resulted in the enantiopure molecule S37a-a micro-molar antagonist of thyrotropin-induced cyclic adenosine monophosphate accumulation in HEK 293 cells expressing the TSHR. RESULTS: The unique rigid bent shape of molecule S37a may mediate the observed high TSHR selectivity. Most importantly, the closely related follitropin and lutropin receptors were not affected by this compound. S37a not only inhibits the TSHR activation by thyrotropin itself but also activation by monoclonal TSAb M22 (human), KSAb1 (murine), and the allosteric small-molecule agonist C2. Disease-related ex vivo studies in HEK 293 cells expressing the TSHR showed that S37a also inhibits cyclic adenosine monophosphate formation by oligoclonal TSAb, which are highly enriched in GO patients' sera. Initial in vivo pharmacokinetic studies revealed no toxicity of S37a and a remarkable 53% oral bioavailability in mice. CONCLUSION: In summary, a novel highly selective inhibitor for the TSHR is presented, which has promising potential for further development for the treatment of GO.


Assuntos
Oftalmopatia de Graves/tratamento farmacológico , Antagonistas de Hormônios/farmacologia , Receptores da Tireotropina/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Fibroblastos/efeitos dos fármacos , Células HEK293 , Antagonistas de Hormônios/uso terapêutico , Humanos , Transdução de Sinais/efeitos dos fármacos
15.
J Endocrinol Invest ; 42(6): 639-652, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30370446

RESUMO

PURPOSE: Prolactinoma is the most commonly seen secretory tumor of pituitary glands, which accounts for approximately up to 40% of total pituitary adenomas. Due to its high drug resistance, dopamine agonist, such as bromocriptine, has limited effect on the treatment of patients with prolactinoma. Recent discoveries have revealed that multiple miRNAs were involved in regulating drug resistance. In this research, we explored the relationship between miR-145-5p expression as well as bromocriptine sensitivity both in vitro and in vivo. METHODS: To study the role of miR-145-5p in drug resistance of prolactinoma, the expression levels of miR-145-5p in bromocriptine-resistant prolactinoma cell line MMQ/BRC and its parental cell line MMQ cells, 24 bromocriptine-resistant as well as eight sensitive clinical samples were measured by qRT-PCR. Moreover, CCK8, flow cytometry and immunofluorescence were performed to identify the biological characteristics of MMQ/BRC and MMQ. TPT1 was predicted as a direct target gene of miR-145-5p by bioinformatic methods. In addition, qRT-PCR, western blot and immunohistochemistry were used to detect the expression level of TPT1 in clinical specimens and cell lines. Xenograft mouse model was constructed to analyze whether miR-145-5p could reverse bromocriptine resistance in prolactinoma in vivo. RESULTS: In our study, bromocriptine-resistant prolactinoma clinical samples and cell line had decreased miR-145-5p levels and expressed high levels of TPT1 compared with their sensitive counterparts. Bioinformatic methods and our preliminary dual luciferase reporter assay were utilized to elucidate that TPT1 was a direct target gene of miR-145-5p. Furthermore, introducing miR-145-5p mimic into MMQ cells led to a decrease of IC50 along with upregulation of TPT1; nevertheless, transfecting the corresponding inhibitor into MMQ cells resulted in an upregulation of IC50 as well as reduction of TPT1. CONCLUSIONS: Collectively, our findings elucidated the role of miR-145-5p as an important regulator of drug resistance in prolactinoma by controlling TPT1, and implicated the potential application of miR-145-5p in cancer therapy as well.


Assuntos
Biomarcadores Tumorais/metabolismo , Bromocriptina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Adolescente , Adulto , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Regulação para Baixo , Feminino , Antagonistas de Hormônios/farmacologia , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prognóstico , Prolactinoma/genética , Prolactinoma/metabolismo , Prolactinoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
16.
Acta Obstet Gynecol Scand ; 98(2): 250-261, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30325501

RESUMO

INTRODUCTION: Women with hereditary mutation in breast cancer-associated genes (BRCA1-/2- ) have a higher lifetime risk of developing ovarian cancer. Here, we aimed to investigate the effect of mifepristone, a selective progesterone receptor modulator of ovarian mesenchymal stem/stromal cells (MSC) from BRCA1-/2- carriers. MATERIAL AND METHODS: Ovarian BRCA1-/2- MSC were positively selected using the markers CD90, CD73 and CD105 from nine healthy women. The effect of dose response and combination treatment with mifepristone and analogs of progesterone- or glucocorticoid-receptors were investigated on BRCA1-/2- MSC in vitro using a panel of markers for proliferation (ki67, BrdU, CDK2, p21CIP ), apoptosis (BAX, BCL2, CASPASE3), tumor suppression (TP53, PTEN) and cell survival (PI3KCA, MAPK3, mTOR). RESULTS: The dose response with mifepristone treatment suggested an optimal effect with 10 µm mifepristone, exhibiting >90% viability and significantly reducing growth signaling markers (TP53 and MAPK3). Furthermore, combined treatment with progesterone plus mifepristone (PG+MIFE) gave an enhanced anti-proliferative effect in comparison with hydrocortisone plus mifepristone (HC+MIFE) by significantly reducing markers of proliferation (BrdU+ and Ki67 expression) and tumor suppressors (PTEN, TP53), and increasing the percentage of pro-apoptotic cells. Consequently, accumulation of p21CIP together with reduced levels of CDK2 confirms growth inhibition by reversibly arresting cell-cycle progression at the G1-S phase, not by inducing apoptosis. CONCLUSIONS: Our study showed an anti-proliferative effect on ovarian BRCA1-/2- MSC on in vitro combined treatment with mifepristone and progesterone. These findings suggest that mifepristone or other selective progesterone receptor modulators could be developed as a preventive treatment and postpone early use of prophylactic salpingo-oophorectomy as well as reduce the risk of ovarian cancer.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Proliferação de Células/efeitos dos fármacos , Células-Tronco Mesenquimais , Mifepristona/farmacologia , Ovário , Células Estromais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Antagonistas de Hormônios/farmacocinética , Antagonistas de Hormônios/farmacologia , Humanos , Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/fisiologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Células Estromais/patologia , Células Estromais/fisiologia , Células Tumorais Cultivadas
17.
J Endocrinol Invest ; 42(4): 443-451, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30171531

RESUMO

PURPOSE: Somatostatin analogs (SSAs) are considered one of the most effective medical treatments for patients with growth hormone-secreting pituitary adenomas (GH-PAs). The postoperative electron microscopy (EM) pathological subtype and SSTR2 expression in the tumor are the most established predictors of patient response to SSA therapy. The aim of this study was to evaluate how will magnetic resonance spectroscopy (MRS) measurements before surgery predict the EM pathological subtypes and SSTR2 expression of tumors, and thereby serve as an indicator for the therapeutic sensitivity to SSAs of patients with GH-PAs. METHODS: Eighteen patients with GH pituitary macroadenomas who underwent transsphenoidal surgery were included in this retrospective study. The preoperative MRS data and T2 signal intensity were obtained from patients by 1.5 T MR spectroscopy of the sellar mass. The EM pathological subtypes of tumors were determined after surgery through examination of cell granulations. The expressions of somatostatin receptor 2 (SSTR2), SSTR5, P21, P27, and Ki-67 were evaluated by immunohistochemistry. RESULTS: The MRS parameters that were found to significantly predict the EM pathological subtypes of tumors, as calculated by the receiver operating characteristic curve, were the choline (Ch) value at 3140.5 MR units (sensitivity 69.2%, specificity 100%) and the choline/creatine (Ch/Cr) ratio at 1.27 (sensitivity 92.3%, specificity 100%). Further, the Ch/Cr ratio, but not other MRS data, was shown to negatively correlate with the expression of SSTR2 (P = 0.02). The Ch/Cr ratio was also found to positively correlate with the Ki-67 value (P < 0.05) and T2 signal (P < 0.05), but not with other factors that were examined in this study. Moreover, the Ch/Cr ratio could predict the EM pathological subtypes of tumors with an accuracy of 83.3% (5/6) for patients with an isointense T2 signal. CONCLUSION: The Ch/Cr ratio by MRS could effectively predict the tumor subtype and was significantly correlated with the expression of SSTR2, which was consistent with other predictors. It was also able to distinguish the patients with isointense T2 signals. Our results provide a potentially new and non-invasive method to predict the response to SSAs in patients with GH pituitary macroadenomas.


Assuntos
Adenoma/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Antagonistas de Hormônios/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Cuidados Pré-Operatórios , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adenoma/cirurgia , Adulto , Idoso , Biomarcadores/análise , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
18.
Physiol Behav ; 198: 96-101, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30342057

RESUMO

Central oxytocin is implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, oxytocin acts centrally to regulate gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system (CNS). Little is, however, known about a role of central oxytocin in visceral sensation. The present study was therefore performed to clarify whether oxytocin in the CNS may be involved in visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered oxytocin increased the threshold volume of colonic distension-induced AWR while intraperitoneal injection of oxytocin did not alter the threshold volume. Pretreatment with subcutaneous injection of naloxone hydrochloride, a peripheral and central opioid antagonist, blocked the oxytocin-induced visceral antinociception while neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, sulpiride, a dopamine D2 receptor antagonist, DPCPX, an adenosine A1 receptor antagonist, AM251, a cannabinoid 1 receptor antagonist nor AM630, a cannabinoid 2 receptor antagonist blocked the antinociception. Intracisternally administered oxytocin antagonist, L368,899 significantly blocked the intracisternal orexin-A-induced visceral antinociception. These results suggest that oxytocin specifically acts in the CNS to enhance antinociceptive response to colonic distension through the central opioid system. The oxytocin signaling may mediate the central orexin-induced visceral antinociception.


Assuntos
Analgésicos/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Ocitocina/farmacologia , Reflexo/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/farmacologia , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas de Hormônios/farmacologia , Indóis/farmacologia , Masculino , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/antagonistas & inibidores , Sulpirida/farmacologia , Xantinas/farmacologia
19.
J Clin Endocrinol Metab ; 104(3): 915-924, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30346538

RESUMO

Background: The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression. Aim: To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment. Methods: We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS). Results: The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9). Conclusions: In a cohort of patients partially responsive to SRLs, the IGF-I-lowering effects of PAS-LAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.


Assuntos
Acromegalia/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Antagonistas de Hormônios/farmacologia , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/patologia , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do Tratamento
20.
J Sex Med ; 15(12): 1698-1706, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527053

RESUMO

INTRODUCTION: Few treatments are available for men with premature ejaculation (PE); oxytocin (OT) receptor antagonism in the central nervous system (CNS) is a potential new approach. AIM: To determine if cligosiban selectively inhibits human OT receptors, penetrates the CNS, shows pharmacology in the CNS, and effects ejaculatory physiology in pre-clinical systems. METHODS: Experiments complied with United Kingdom legislation and were subject to local ethical review. In vitro potency and selectivity of cligosiban was assessed using recombinant and native OT receptor systems including both neuronal and non-neuronal cell types. Selectivity was determined over neighboring V1A, V1B, and V2 vasopressin receptors using a combination of recombinant and native vasopressin receptor assay systems. To determine an effect on central OT receptors and on ejaculation, cligosiban was evaluated in 2 anesthetized rat models-the electromyography model of ejaculatory physiology and a model of OT-mediated CNS neuronal firing. The CNS penetration of cligosiban was also determined by measuring cerebrospinal fluid and plasma drug concentrations following an intravenous (IV) infusion in rats. MAIN OUTCOME MEASURE: These were functional measures of pharmacology in vitro, in cell lines and tissues, and in vivo in rats. RESULTS: Cligosiban is a potent OT receptor antagonist, with a base dissociation constant of 5.7 nmol/L against native human uterine smooth muscle cell OT receptors. Cligosiban displays similar antagonistic potency against human recombinant and rat native OT receptors, including neuronal OT receptors. Cligosiban demonstrates >100-fold selectivity over human V1A, V1B, and V2 vasopressin receptors. In the electromyography model, cligosiban (0.9 mg/kg, IV bolus) reduced the bulbospongiosum burst pattern and contraction amplitude associated with ejaculation. In the anesthetized CNS neuronal firing model, the same dosing regimen of cligosiban (0.9 mg/kg IV bolus) modulated the OT-mediated response in the nucleus tractus solitarius. After systemic dosing to rats, cligosiban showed good CNS penetration. CLINICAL IMPLICATIONS: As the first highly selective and centrally penetrant OT receptor antagonist, cligosiban represents a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. STRENGTH & LIMITATIONS: The pharmacology and selectivity of cligosiban is determined using functional assays in recombinant cell lines, native cell lines, and tissue. Functional outcomes in in vivo systems are linked to CNS measures of pharmacology. The translation of the animal models of ejaculation to PE in man is unproven. CONCLUSION: Cligosiban, a potent, selective OT receptor antagonist, demonstrated CNS penetration and pharmacology and, using the same dosing regimen, inhibited apomorphine-induced ejaculation in rats. Cligosiban is a promising compound to test the clinical hypothesis that antagonism of central OT receptors may be of therapeutic benefit in the treatment of PE. Wayman C, Russell R, Tang K, et al. Cligosiban, A Novel Brain Penetrant Selective Oxytocin Receptor Antagonist, Inhibits Ejaculatory Physiology in Rodents. J Sex Med 2018;15:1698-1706.


Assuntos
Ejaculação/efeitos dos fármacos , Ocitocina/farmacologia , Ejaculação Precoce/tratamento farmacológico , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Vasopressinas/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Antagonistas de Hormônios/farmacologia , Humanos , Masculino , Ratos , Roedores , Reino Unido
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA