RESUMEN
The pituitary gland is a small endocrine gland located below the hypothalamus. This gland releases several important hormones and controls the function of many other endocrine system glands to release hormones. Fish pituitary hormonal cells are controlled by neuroendocrine and sex steroid feedback. To study the complex pituitary function in vivo, we established an in vitro pituitary spheroid assay and evaluated its suitability for monitoring the annual reproductive physiological conditions in Takifugu rubripes, also known as torafugu, is one of the most economically important species distributed in the northwestern part of the Pacific Ocean, in the western part of the East China Sea, and in more northern areas near Hokkaido, Japan. Fish pituitary spheroids can be easily constructed in liquid or solid plates. The culture medium (L-15) made the aggregation faster than MEM (Hank's). A Rho-kinase inhibitor (Y-27632, 10 µM) and/or fish serum (2.5 %) also promoted spheroid formation. Laser confocal microscopy analysis of spheroids cultured with annual serum of both sexes revealed that luteinizing hormone (LH) synthesis has the highest peak in the final maturation stage (3 years old, May) in accordance with the highest serum sex steroid levels; in contrast, follicle stimulating hormone (FSH) synthesis has no correlation with the dose of serum or nutrients. Similarly, 3D cell propagation assays using female serum showed that total pituitary cells displayed the highest proliferation at puberty onset (2 years old, October) before half a year of the spawning season. These results indicate that pituitary spheroids are useful in vitro models for monitoring the reproductive physiological status of fish in vivo and may be applicable to the in vitro screening of environmental chemicals and bioactive compounds affecting reproductive efficiency in aquaculture.
Asunto(s)
Hipófisis , Maduración Sexual , Animales , Masculino , Femenino , Hormona Luteinizante , Hormona Folículo Estimulante , Sistema Endocrino , Hormonas Esteroides Gonadales , Esteroides , Hormona Liberadora de Gonadotropina/fisiologíaRESUMEN
Pulsatile gonadotropin-releasing hormone (GnRH) release is critical for reproduction. Disruptions to GnRH secretion patterns may contribute to polycystic ovary syndrome (PCOS). Prenatally androgenized (PNA) female mice recapitulate many neuroendocrine abnormalities observed in PCOS patients. PNA and development induce changes in spontaneous GnRH neuron firing rate, response to synaptic input, and the afterhyperpolarization potential of the action potential. We hypothesized potassium currents are altered by PNA treatment and/or development. Whole-cell patch-clamp recordings were made of transient and residual potassium currents of GnRH neurons in brain slices from 3-week-old and adult control and PNA females. At 3 weeks of age, PNA treatment increased transient current density versus controls. Development and PNA altered voltage-dependent activation and inactivation of the transient current. In controls, transient current activation and inactivation were depolarized at 3 weeks of age versus in adulthood. In GnRH neurons from 3-week-old mice, transient current activation and inactivation were more depolarized in control than PNA mice. Development and PNA treatment interacted to shift the time-dependence of inactivation and recovery from inactivation. Notably, in cells from adult PNA females, recovery was prolonged compared to all other groups. Activation of the residual current occurred at more depolarized membrane potentials in 3-week-old than adult controls. PNA depolarized activation of the residual current in adults. These findings demonstrate the properties of GnRH neuron potassium currents change during typical development, potentially contributing to puberty, and further suggest PNA treatment may both alter some typical developmental changes and induce additional modifications, which together may underlie aspects of the PNA phenotype. There was not any clinical trial involved in this work.
Asunto(s)
Síndrome del Ovario Poliquístico , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Humanos , Ratones , Embarazo , Andrógenos/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Ratones Transgénicos , Neuronas/fisiología , VirilismoRESUMEN
The unintended exposure of humans and animals to isothiazolinones has led to an increasing concern regarding their health hazards. Isothiazolinones were previously found to disrupt reproductive endocrine homeostasis. However, the long-term reproductive toxicity and underlying mechanism remain unclear. In this study, life-cycle exposure of medaka to dichlorocthylisothiazolinone (DCOIT), a representative isothiazolinone, significantly stimulated the gonadotropin releasing hormone receptor (GnRHR)-mediated synthesis of follicle stimulating hormone and luteinizing hormone in the brain. Chem-Seq and proteome analyses revealed disturbances in the G-protein-coupled receptor, MAPK, and Ca2+ signaling cascades by DCOIT. The G protein αi subunit was identified as the binding target of DCOIT. Gαi bound by DCOIT had an enhanced affinity for the mitochondrial calcium uniporter, consequently changing Ca2+ subcellular compartmentalization. Stimulation of Ca2+ release from the endoplasmic reticulum and blockage of Ca2+ uptake into the mitochondria resulted in a considerably higher cytoplasmic Ca2+ concentration, which then activated the phosphorylation of MEK and ERK to dysregulate hormone synthesis. Overall, by comprehensively integrating in vivo, ex vivo, in silico, and in vitro evidence, this study proposes a new mode of endocrine disrupting toxicity based on isothiazolinones, which is expected to aid the risk assessment of the chemical library and favor the mechanism-driven design of safer alternatives.
Asunto(s)
Receptores Acoplados a Proteínas G , Transducción de Señal , Humanos , Animales , Transducción de Señal/fisiología , Reproducción , Hormona Liberadora de Gonadotropina/fisiologíaRESUMEN
BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases. METHODS: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE-/- mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms. RESULTS: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist-treated mice, blocking of short FSH surge by anti-FSHß antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist-treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3ß (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3ß/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist-induced endothelial inflammation and atherosclerosis in mice. CONCLUSIONS: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Neoplasias de la Próstata , Animales , Masculino , Ratones , Antagonistas de Andrógenos/efectos adversos , Andrógenos/deficiencia , Aterosclerosis/patología , Endotelio/metabolismo , Hormona Folículo Estimulante/genética , Hormona Folículo Estimulante/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Inflamación/etiología , Monocitos/metabolismo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , TestosteronaRESUMEN
Spanning from bench to bedside, the history of normal and precocious puberty is characterized by a series of remarkable advances that have illuminated reproductive physiology and profoundly impacted clinical care. Early recognition of the hypothalamic and pituitary control of ovarian and testicular function led to the identification of GnRH as the key driver of pubertal onset. Decades later, discovery of the kisspeptin system further refined our understanding of human reproductive neuroendocrinology. Development of long-acting analogs of GnRH revolutionized the treatment of precocious puberty worldwide and ushered in the current era of an ever-expanding therapeutic armamentarium. Identification of monogenic etiologies of precocious puberty has further illustrated the exquisite complexity that comprises neurosecretory modulation of the hypothalamic GnRH neuron and may well lead to exciting novel targeted therapies.
Asunto(s)
Hormona Liberadora de Gonadotropina , Pubertad Precoz , Pubertad , Humanos , Hormona Liberadora de Gonadotropina/fisiología , Neuroendocrinología , Neuronas/fisiología , Pubertad/fisiología , Pubertad Precoz/tratamiento farmacológicoRESUMEN
A hormone enhances cognition in mouse models of Alzheimer's disease and Down syndrome.
Asunto(s)
Enfermedad de Alzheimer , Cognición , Síndrome de Down , Hormona Liberadora de Gonadotropina , Enfermedad de Alzheimer/psicología , Enfermedad de Alzheimer/terapia , Animales , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Síndrome de Down/psicología , Síndrome de Down/terapia , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/fisiología , RatonesRESUMEN
At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.
Asunto(s)
Cognición , Disfunción Cognitiva , Síndrome de Down , Hormona Liberadora de Gonadotropina , Trastornos del Olfato , Adulto , Animales , Cognición/efectos de los fármacos , Cognición/fisiología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/psicología , Femenino , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Trastornos del Olfato/tratamiento farmacológico , Trastornos del Olfato/etiología , Transmisión Sináptica/efectos de los fármacos , Adulto JovenRESUMEN
Reproductive endocrine disorders are common comorbidities of temporal lobe epilepsy (TLE). Our previous studies using the intrahippocampal kainic acid (IHKA) mouse model of TLE demonstrated that many females show prolonged estrous cycles and hypothalamic gonadotropin-releasing hormone (GnRH) neurons exhibit elevated firing during diestrus. However, it is unknown whether the degree of change in GnRH neuron activity is dependent on epilepsy severity. Here, we used 24/7 in vivo electroencephalography (EEG) and in vitro electrophysiological recordings in acute brain slices to assess GnRH neuron firing in relation to chronic seizure burden in diestrous female mice at two months after IHKA injection. We found that percentage of time in seizure activity in the 24 h prior to slice preparation is an accurate proxy of overall seizure burden. Firing rates of GnRH neurons from EEG-recorded IHKA mice were increased in comparison to controls, but no relationships were found between GnRH neuron firing and seizure burden measured in vivo. The independence of GnRH neuron firing rate in relation to seizure burden was unaffected by GnRH neuron soma location or estrous cycle length. Furthermore, GnRH neuron firing rates were not yet different from control values when measured 1 month after injection, when epileptogenesis is already complete in IHKA mice. These findings indicate that the severity of epilepsy and the degree of downstream disruption to GnRH neuron activity are independent, suggesting that susceptibility to reproductive endocrine comorbidities is driven by other risk factors.
Asunto(s)
Epilepsia del Lóbulo Temporal , Hormona Liberadora de Gonadotropina , Animales , Femenino , Hormona Liberadora de Gonadotropina/fisiología , Ratones , Ratones Transgénicos , Neuronas/fisiología , ConvulsionesRESUMEN
Gonadotropin-releasing-hormone (GnRH) neurons sitting within the hypothalamus control the production of gametes and sex steroids by the gonads, therefore ensuring survival of species. As orchestrators of reproductive function, GnRH neurons integrate information from external and internal cues. This occurs through an extensively studied neuronal network known as the "GnRH neuronal network." However, the brain is not simply composed of neurons. Evidence suggests a role for glial cells in controlling GnRH neuron activity, secretion and fertility outcomes, although numerous questions remain. Glial cells have historically been seen as support cells for neurons. This idea has been challenged by the discovery that some neurological diseases originate from glial dysfunction. The prevalence of infertility disorders is increasing worldwide, with one in four couples being affected; therefore, it remains essential to understand the mechanisms by which the brain controls fertility. The "GnRH glial network" could be a major player in infertility disorders and represent a potential therapeutic target. In polycystic ovary syndrome (PCOS), the most common infertility disorder of reproductive aged women worldwide, the brain is considered a prime suspect. Recent studies have demonstrated pathological neuronal wiring of the "GnRH neuronal network" in PCOS-like animal models. However, the role of the "GnRH glial network" remains to be elucidated. In this review, I aim to propose glial cells as unusual suspects in infertility disorders such as PCOS. In the first part, I state our current knowledge about the role of glia in the regulation of GnRH neurons and fertility. In the second part, based on our recent findings, I discuss how glial cells could be implicated in PCOS pathology.
Asunto(s)
Infertilidad , Síndrome del Ovario Poliquístico , Adulto , Animales , Femenino , Fertilidad , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Neuroglía/patologíaRESUMEN
As gonadotropin-releasing hormone (GnRH) is expressed in the thymus, its direct action on thymic cells, including thymic involution, has been suggested. Annexin A5 (ANXA5), a biomarker of GnRH, was used to determine whether GnRH affects the thymus of male rats. Immunohistochemistry showed positive reactions for ANXA5 in large medullary epithelial cells at 30 days of age, and the expression continued until 180 days of age. Organ culture of thymus pieces was performed to examine the direct action of a GnRH agonist (GnRHa) on the expression of Anxa5 and Gnrh mRNA. Thymus tissues obtained from male rats (40-60 days old) were cut into small pieces (2-3 mm3) and incubated for 3 hr with the GnRHa. The expression levels of Anxa5 and Gnrh mRNA were augmented by the GnRHa. Immunohistochemistry of these tissue fragments showed that ANXA5 expression was enhanced, especially in medullary epithelial cells. These results revealed that GnRH synthesis in the thymus could affect thymic epithelial cells after puberty.
Asunto(s)
Hormona Liberadora de Gonadotropina , Animales , Anexina A5/genética , Anexina A5/metabolismo , Hormona Liberadora de Gonadotropina/fisiología , Masculino , ARN Mensajero/metabolismo , RatasRESUMEN
Vasoactive intestinal peptide (Vip) regulates luteinizing hormone (LH) release through the direct regulation of gonadotropin-releasing hormone (GnRH) neurons at the level of the brain in female rodents. However, little is known regarding the roles of Vip in teleost reproduction. Although GnRH is critical for fertility through the regulation of LH secretion in vertebrates, the exact role of the hypophysiotropic GnRH (GnRH3) in zebrafish is unclear since GnRH3 null fish are reproductively fertile. This phenomenon raises the possibility of a redundant regulatory pathway(s) for LH secretion in zebrafish. Here, we demonstrate that VipA (homologues of mammalian Vip) both inhibits and induces LH secretion in zebrafish. Despite the observation that VipA axons may reach the pituitary proximal pars distalis including LH cells, pituitary incubation with VipA in vitro, and intraperitoneal injection of VipA, did not induce LH secretion and lhß mRNA expression in sexually mature females, respectively. On the other hand, intracerebroventricular administration of VipA augmented plasma LH levels in both wild-type and gnrh3-/- females at 1 hour posttreatment, with no observed changes in pituitary GnRH2 and GnRH3 contents and gnrh3 mRNA levels in the brains. While VipA's manner of inhibition of LH secretion has yet to be explored, the stimulation seems to occur via a different pathway than GnRH3, dopamine, and 17ß-estradiol in regulating LH secretion. The results indicate that VipA induces LH release possibly by acting with or through a non-GnRH factor(s), providing proof for the existence of functional redundancy of LH release in sexually mature female zebrafish.
Asunto(s)
Hormona Liberadora de Gonadotropina/fisiología , Hormona Luteinizante/metabolismo , Hipófisis/metabolismo , Ácido Pirrolidona Carboxílico/análogos & derivados , Péptido Intestinal Vasoactivo/fisiología , Pez Cebra , Animales , Anticuerpos/farmacología , Química Encefálica , Femenino , Técnicas de Inactivación de Genes , Hormona Liberadora de Gonadotropina/análisis , Hormona Liberadora de Gonadotropina/genética , Hormona Luteinizante/sangre , Hormona Luteinizante de Subunidad beta/genética , Hipófisis/química , Ácido Pirrolidona Carboxílico/análisis , ARN Mensajero/análisis , Péptido Intestinal Vasoactivo/administración & dosificación , Péptido Intestinal Vasoactivo/genéticaRESUMEN
Mathematical modelling is an indispensable tool in modern biosciences, enabling quantitative analysis and integration of biological data, transparent formulation of our understanding of complex biological systems, and efficient experimental design based on model predictions. This review article provides an overview of the impact that mathematical models had on GnRH research. Indeed, over the last 20 years mathematical modelling has been used to describe and explore the physiology of the GnRH neuron, the mechanisms underlying GnRH pulsatile secretion, and GnRH signalling to the pituitary. Importantly, these models have contributed to GnRH research via novel hypotheses and predictions regarding the bursting behaviour of the GnRH neuron, the role of kisspeptin neurons in the emergence of pulsatile GnRH dynamics, and the decoding of GnRH signals by biochemical signalling networks. We envisage that with the advent of novel experimental technologies, mathematical modelling will have an even greater role to play in our endeavour to understand the complex spatiotemporal dynamics underlying the reproductive neuroendocrine system.
Asunto(s)
Hormona Liberadora de Gonadotropina , Kisspeptinas , Hormona Liberadora de Gonadotropina/fisiología , Kisspeptinas/fisiología , Modelos Teóricos , Neuronas/fisiología , Reproducción/fisiologíaRESUMEN
Gonadotropin-releasing hormone (GnRH) regulates gonadal function via its stimulatory effects on gonadotropin production by pituitary gonadotrope cells. GnRH is released from the hypothalamus in pulses and GnRH pulse frequency differentially regulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis and secretion. The GnRH receptor (GnRHR) is a G protein-coupled receptor that canonically activates Gαâq/11-dependent signaling on ligand binding. However, the receptor can also couple to Gαâs and in vitro data suggest that toggling between different G proteins may contribute to GnRH pulse frequency decoding. For example, as we show here, knockdown of Gαâs impairs GnRH-stimulated FSH synthesis at low- but not high-pulse frequency in a model gonadotrope-derived cell line. We next used a Cre-lox conditional knockout approach to interrogate the relative roles of Gαâq/11 and Gαâs proteins in gonadotrope function in mice. Gonadotrope-specific Gαâq/11 knockouts exhibit hypogonadotropic hypogonadism and infertility, akin to the phenotypes seen in GnRH- or GnRHR-deficient mice. In contrast, under standard conditions, gonadotrope-specific Gαâs knockouts produce gonadotropins at normal levels and are fertile. However, the LH surge amplitude is blunted in Gαâs knockout females and postgonadectomy increases in FSH and LH are reduced both in males and females. These data suggest that GnRH may signal principally via Gαâq/11 to stimulate gonadotropin production, but that Gαâs plays important roles in gonadotrope function in vivo when GnRH secretion is enhanced.
Asunto(s)
Cromograninas/fisiología , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/fisiología , Subunidades alfa de la Proteína de Unión al GTP Gs/fisiología , Gonadotrofos/metabolismo , Gonadotropinas/metabolismo , Animales , Castración , Línea Celular , Cromograninas/genética , Femenino , Fertilidad/genética , Fertilidad/fisiología , Hormona Folículo Estimulante de Subunidad beta/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Regulación de la Expresión Génica/fisiología , Hormona Liberadora de Gonadotropina/fisiología , Gonadotropinas/genética , Células HEK293 , Humanos , Hormona Luteinizante/genética , Hormona Luteinizante/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores LHRH/genética , Receptores LHRH/fisiología , Maduración Sexual , Transducción de Señal/fisiologíaRESUMEN
The field of fish gonadotropin-releasing hormones (GnRHs) is also celebrating its 50th anniversary this year. This review provides a chronological history of fish GnRH biology over the past five decades. It demonstrates how discoveries in fish regarding GnRH and GnRH receptor multiplicity, dynamic interactions between GnRH neurons, and additional neuroendocrine factors acting alongside GnRH, amongst others, have driven a paradigm shift in our understanding of GnRH systems and functions in vertebrates, including mammals. The role of technological innovations in enabling scientific discoveries is portrayed, as well as how fundamental research in fish GnRH led to translational outcomes in aquaculture. The interchange between fish and mammalian GnRH research is discussed, as is the value and utility of using fish models for advancing GnRH biology. Current challenges and future perspectives are presented, with the hope of expanding the dialogue and collaborations within the neuroendocrinology scientific community at large, capitalizing on diversifying model animals and the use of comparative strategies.
Asunto(s)
Hormona Liberadora de Gonadotropina , Neuroendocrinología , Animales , Hormona Liberadora de Gonadotropina/fisiología , Gonadotropinas , Mamíferos , Sistemas NeurosecretoresRESUMEN
Animals properly perform sexual behaviors by using multiple sensory cues. However, neural mechanisms integrating multiple sensory cues and regulating motivation for sexual behaviors remain unclear. Here, we focused on peptidergic neurons, terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons, which receive inputs from various sensory systems and co-express neuropeptide FF (NPFF) in addition to GnRH. Our behavioral analyses using knockout medaka of GnRH (gnrh3) and/or NPFF (npff) demonstrated that some sexual behavioral repertoires were delayed, not disrupted, in gnrh3 and npff single knockout males, while the double knockout appeared to alleviate the significant defects that were observed in single knockouts. We also found anatomical evidence to show that both neuropeptides modulate the sexual behavior-controlling brain areas. Furthermore, we demonstrated that NPFF activates neurons in the preoptic area via indirect pathway, which is considered to induce the increase in motivation for male sexual behaviors. Considering these results, we propose a novel mechanism by which co-existing peptides of the TN-GnRH neurons, NPFF, and GnRH3 coordinately modulate certain neuronal circuit for the control of behavioral motivation. Our results may go a long way toward understanding the functional significance of peptidergic neuromodulation in response to sensory information from the external environments.
Asunto(s)
Hormona Liberadora de Gonadotropina/fisiología , Oligopéptidos/fisiología , Oryzias , Ácido Pirrolidona Carboxílico/análogos & derivados , Conducta Sexual Animal/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Encéfalo/metabolismo , Química Encefálica , Femenino , Técnicas de Inactivación de Genes , Hormona Liberadora de Gonadotropina/análisis , Hormona Liberadora de Gonadotropina/genética , Masculino , Neuronas/química , Neuronas/fisiología , Oligopéptidos/análisis , Oligopéptidos/genética , Filogenia , Ácido Pirrolidona Carboxílico/análisis , Alineación de SecuenciaRESUMEN
The specific role of gonadotropin-releasing hormone (GnRH) on brain sexual differentiation remains unclear. To investigate whether gonadotropin and, in turn, testosterone (T) secretion is regulated by GnRH during the critical period for brain differentiation in sheep fetuses, we attempted to selectively suppress pituitary-testicular activation during midgestation with the long-acting GnRH antagonist degarelix. Fetuses received subcutaneous injections of the antagonist or vehicle on day 62 of gestation. After 2 to 3 weeks we examined consequences of the intervention on baseline and GnRH-stimulated plasma luteinizing hormone (LH) and T levels. In addition, we measured the effect of degarelix-treatment on messenger RNA (mRNA) expression for the pituitary gonadotropins and key gonadal steroidogenic enzymes. Baseline and GnRH-stimulated plasma LH levels were significantly suppressed in degarelix-treated male and female fetuses compared to control values. Similarly, T concentrations were suppressed in degarelix-treated males. The percentage of LHß-immunoreactive cells colocalizing c-fos was significantly reduced by degarelix treatment indicating that pituitary sensitivity was inhibited. Degarelix treatment also led to the significant suppression of mRNA expression coding for the pituitary gonadotropin subunits and for the gonadal enzymes involved in androgen synthesis. These findings demonstrate that pharmacologic inhibition of GnRH early in gestation results in suppression of LH secretion and deficits in the plasma T levels of male lamb fetuses. We conclude that GnRH signaling plays a pivotal role for regulating T exposure during the critical period of sheep gestation when the brain is masculinized. Thus, disturbance to gonadotropin secretion during this phase of gestation could have long-term consequence on adult sexual behaviors and fertility.
Asunto(s)
Edad Gestacional , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Gonadotropinas Hipofisarias/metabolismo , Oligopéptidos/administración & dosificación , Adenohipófisis/embriología , Ovinos/embriología , Animales , Encéfalo/embriología , Femenino , Sangre Fetal/química , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/fisiología , Gonadotropinas Hipofisarias/genética , Inyecciones Subcutáneas/veterinaria , Hormona Luteinizante/sangre , Masculino , Ovario/química , Ovario/embriología , Adenohipófisis/química , Adenohipófisis/efectos de los fármacos , Embarazo , ARN Mensajero/análisis , Diferenciación Sexual/fisiología , Testículo/química , Testículo/embriología , Testosterona/sangreRESUMEN
To this day, the identity of gonadotropin-releasing hormone (GnRH) progenitors remains unclear. However, the visualization of different developmental markers in subsets of GnRH neurons during early embryonic stages raised the possibility of at least two GnRH subpopulations. This observation led directly to a second question. Does visualization of different developmental markers in subsets of GnRH neurons reflect functional heterogeneity? This question remains unanswered, but as we learn more about the GnRH system, functional GnRH subpopulations become critically important to understanding GnRH function. This review addresses the development of the neuroendocrine GnRH system, specifically the heterogeneity of the GnRH neuroendocrine population.
Asunto(s)
Hormona Liberadora de Gonadotropina , Células Neuroendocrinas , Hormona Liberadora de Gonadotropina/fisiología , Neuronas/fisiología , Sistemas NeurosecretoresRESUMEN
In vertebrates, gonadotropin-releasing hormone (GnRH) peptide is the central mediator of reproduction. Homologous peptides have previously also been identified in molluscan species. However, emerging evidence suggests that these molecules might serve diverse regulatory functions and proposes to consider them as corazonin (CRZ). We previously isolated the full-length cDNA of the invGnRH/CRZ peptide (termed ly-GnRH/CRZ) in the well-established invertebrate model species, the great pond snail Lymnaea stagnalis; however, its predicted functions remain to be verified. In this study, we first confirmed the presence of the deduced active peptide from the central nervous system of L. stagnalis. Further, we performed in vivo and in vitro studies to explore the functions of ly-GnRH/CRZ. Injection of sexually mature specimens with synthetic active peptide had an inhibitory effect on locomotion and an acceleratory effect on egg-laying, but had no effect on feeding. The previously predicted modulatory effect of ly-GnRH/CRZ was supported by its identified co-localization with serotonin on the surface of the heart atria. Lastly, we demonstrated not only the presence of ly-GnRH/CRZ in the penial complex but also that ly-GnRH/CRZ-containing neurons project to the efferent penis nerve, suggesting ly-GnRH/CRZ may directly modulate the motor output of this peripheral tissue. Overall, our findings strongly support that ly-GnRH/CRZ is a multifunctional neuropeptide. These results contribute to the understanding of the GnRH superfamily and, more broadly, disciplines such as comparative endocrinology and neurobiology.
Asunto(s)
Lymnaea/fisiología , Neuropéptidos/fisiología , Animales , Evolución Biológica , Sistema Nervioso Central/metabolismo , Conducta Alimentaria , Hormona Liberadora de Gonadotropina/química , Hormona Liberadora de Gonadotropina/fisiología , Locomoción , Lymnaea/química , Neuropéptidos/química , OviparidadRESUMEN
Gonadotropin-releasing hormone agonist (GnRHa) for final oocyte maturation, along with vitrification of all usable embryos followed by transfer in a subsequent frozen-thawed cycle, is the most effective strategy to avoid ovarian hyperstimulation syndrome (OHSS). However, less is known about the ovulation induction triggers effect on early embryo development and blastocyst formation. This study is a secondary analysis of a multicenter, randomized controlled trial, with the aim to compare embryo development in normo-ovulatory women, randomized to GnRHa or human chorionic gonadotropin (hCG) trigger. In all, 4056 retrieved oocytes were observed, 1998 from the GnRHa group (216 women) and 2058 from the hCG group (218 women). A number of retrieved oocytes, mature and fertilized oocytes, and high-quality embryos and blastocysts were similar between the groups. A sub-analysis in 250 women enrolled at the main trial site including 2073 oocytes was conducted to compare embryo morphokinetics and cleavage patterns with EmbryoScope time-lapse system. In total, 1013 oocytes were retrieved from the GnRHa group (124 women) and 1060 oocytes were retrieved from the hCG group (126 women). Morphokinetic parameters and cleavage patterns were comparable between the groups. However, embryos derived from the GnRHa group were less likely to perform rolling during their development than the embryos from the hCG trigger group (OR = 0.41 (95%CI 0.25; 0.67), p-value 0.0003). The comparable results on embryo development and utilization rates between the GnRHa and hCG triggers is of clinical relevance to professionals and infertile patients, when GnRHa trigger and freeze-all is performed to avoid OHSS development. ClinicalTrials.gov Identifier: NCT02746562.
Asunto(s)
Blastocisto/efectos de los fármacos , Gonadotropina Coriónica/farmacología , Técnicas de Cultivo de Embriones/métodos , Desarrollo Embrionario/efectos de los fármacos , Hormona Liberadora de Gonadotropina/agonistas , Ovulación/efectos de los fármacos , Adulto , Blastocisto/fisiología , Desarrollo Embrionario/fisiología , Femenino , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Ovulación/fisiología , Inducción de la Ovulación/métodos , EmbarazoRESUMEN
Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as primary ovarian insufficiency, hypothalamic amenorrhea, congenital hypogonadotropic hypogonadism, and early menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin, and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly aging population.