Acciones óseas de las hormonas de la neurohipófisis / Bone actions of neuro hypophyseal hormones

La oxitocina (OXT) como la arginina-vasopresina (AVP) son dos hormonas primitivas secretadas por la hipófisis posterior. Sus receptores están mucho más ampliamente distribuidos en el organismo de lo que se pensaba originalmente, incluido el hueso. En los estudios preclínicos, la OXT ha mostrado ser anabólica para el hueso, promoviendo la osteogénesis sobre la adipogénesis y favoreciendo la actividad osteoblástica sobre la osteoclástica. Tanto los osteoblastos como los osteoclastos tienen receptores para la OXT, y los efectos de los estrógenos sobre la masa ósea en ratones está mediada por lo menos en parte por la OXT. El mecanismo preciso por el cual la activación de los receptores de oxitocina (OXTR) se traduce en un incremento de la formación ósea permanece poco claro. La AVP también podría afectar el esqueleto en forma directa. Dos de los receptores de la AVP, V1a y V2 están expresados en osteoblastos y osteoclastos. La inyección de AVP en ratones de tipo salvaje aumenta la formación osteoclastos que producen resorción y reduce los osteoblastos formadores de hueso. En forma opuesta, la exposición de precursores osteoblásticos a antagonistas de los receptores V1a o V2, incrementan la osteoblastogénesis, como también lo hace la deleción genética del receptor V1a. (AU)

Both oxytocin (OXT) and argininevasopressin (AVP) are primitive hormones secreted by the posterior pituitary gland. OXT receptors are much more widely distributed in the body than originally thought, including in bone. In preclinical studies, OXT has been shown to be anabolic for bone, promoting osteogenesis over adipogenesis and favoring osteoblastic over osteoclastic activity. Both osteoblasts and osteoclasts have receptors for OXT, and the effects of estrogen on bone mass in mice is mediated at least in part by OXT. The precise mechanism by which the activation of oxytocin receptors (OXTRs) results in an increase in bone formation remains unclear. AVP could also have direct actions on the skeleton. The two AVP receptors, V1a and V2, are expressed in osteoblasts and osteoclasts. Injection of AVP in wild-type mice increases the formation of osteoclasts increasing bone resorption, and reduces bone-forming osteoblasts. On the contrary, the exposure of osteoblastic precursors to V1a and V2 antagonists increase osteoblastogenesis, the same as the genetic deletion of the V1a receptor. (AU)

The effect of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus.

Methylenedioxymethamphetamine (MDMA, 'ecstasy'), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. Release of both oxytocin and vasopressin from isolated hypothalami obtained from male Wistar rats was determined under basal conditions and following potassium (40 mM) stimulation. The results were compared with those obtained for basal and stimulated release in the presence of MDMA or metabolites in the dose range 1 microM to 100 pM (n=5 - 8) using Student's t-test with Dunnett's correction for multiple comparisons. All compounds tested affected neurohypophysial hormone release, HMMA (4-hydroxy-3-methoxymethamphetamine) and DHA (3,4-dihydroxyamphetamine) being more active than MDMA, and DHMA (3,4-dihydroxymethamphetamine) being the least active. The effect on vasopressin release was greater than that on oxytocin. In the presence of HMMA the ratio test:control for basal release increased for vasopressin from 1.1+/-0.16 to 2.7+/-0.44 (s.e.m., P<0.05) at 10 nM and for oxytocin from 1.0+/-0.05 to 1.6+/-0.12 in the same hypothalami. For MDMA the ratio increased to 1.5+/-0.27 for vasopressin and to 1.28+/-0.04 for oxytocin for 10 nM. MDMA and its metabolites can stimulate both oxytocin and vasopressin release in vitro, the response being dose dependent for each drug with HMMA being the most potent.

Interleukin-1 beta and interleukin-6 stimulate neurohypophysial hormone release in vitro.

Interleukin-1 (IL-1) and interleukin-6 (IL-6) have been reported to stimulate the release of corticotrophin-releasing hormone (CRH) in vitro, the response being antagonized by the cyclo-oxygenase inhibitor, indomethacin. The effects of cytokines on the other major ACTH-releasing hormone, vasopressin (AVP), and the other neurohypophysial hormone, oxytocin, have been little studied, and the published data are conflicting. We have therefore used a previously validated rat hypothalamic explant model to evaluate whether IL-1 beta and IL-6 can directly activate the AVP and oxytocin neurosecretory system. In addition, we have also investigated the effects of inhibition of cyclo-oxygenase (CO) and lipoxygenase (LO) activities on the stimulated release of AVP and oxytocin by means of a series of antagonists, including a specific LO pathway inhibitor. The static rat hypothalamic incubation system used involves fresh hypothalamic explants with consecutive 20-min incubations, and estimation of AVP and oxytocin concentrations in the medium by specific and sensitive radioimmunoassays. It was found that IL-1 beta produced a dose-dependent increase in the release of AVP and oxytocin at doses of 10 and 100 U/ml (P < 0.005). Only at the higher dose of 100 U/ml was IL-6 able to increase significantly AVP and oxytocin release (P < 0.05). These stimulatory effects of IL-1 beta and IL-6 were blocked by cyclo-oxygenase inhibitors, indomethacin (28 microM) and ibuprofen (100 nM), but not by the lipoxygenase inhibitor, BW A4C (10 micrograms/ml), suggesting that prostaglandins are involved in this process.(ABSTRACT TRUNCATED AT 250 WORDS)

[Common precursors of neurohypophysial hormones and neurophysins]. / Les précurseurs communs des hormones neurohypophysaires et des neurophysines.

Neurohypophysial hormones and neurophysins are former domains of common precursors processed during the axonal transport from hypothalamus to neurohypophysis. Two neurohormones, an oxytocin-like and a vasopressin-like, and two neurophysins, termed VLDV- and MSEL-neurophysins according to residues in positions 2, 3, 6 and 7, are usually found in vertebrate species. In mammals, a non-covalent stoichiometric and reversible complex including the two neurohormones and the two neurophysins has been isolated. In contrast to other mammals investigated, the three-domain precursor of vasopressin (vasopressin, MSEL-neurophysin and copeptin) is not completely processed in guinea pig and an intermediate precursor including MSEL-neurophysin and copeptin linked by an arginine residue has been isolated and sequenced. "In vitro" processing of this intermediate through trypsin-Sepharose has revealed cleavages only in the inter-domain region, showing the role of precursor conformation in the processing. In neurosecretory granules from guinea pig, only free vasopressin and MSEL-neurophysin have been detected. In bovine foetus at the age of 3 and 7 months, only vasopressin and oxytocin in molar ratios 4 and 3, respectively, have been identified as well as adult MSEL- and VLDV-neurophysins. No vasotocin and no additional neurophysin when compared to the adult have been found. Diabetes insipidus rats from the Brattleboro strain have been examined in order to identify an abnormal vasopressin precursor. No free vasopressin and no free MSEL-neurophysin have been detected through high pressure liquid chromatography whereas oxytocin and VLDV-neurophysin have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)

The neurohypophysis: recent developments.

The hormones of the neurohypophysis, vasopressin and oxytocin, have now been shown to be synthesized as part of a prohormone complex that includes a vasopressin-neurophysin and oxytocin-neurophysin, respectively. In addition, for vasopressin, there is a glycopeptide as part of the prohormone. For each hormone the prohormone is packaged into neurosecretory granules and transported via axons to the posterior pituitary gland. In addition to this "classic" system, axons containing neurohypophyseal hormones project to the median eminence for release into portal vessels, and to other areas of the brain and spinal cord where the peptides may function as neurotransmitters rather than as hormones. As neurotransmitters, the neurohypophyseal hormones may be involved in the regulation of certain autonomic functions. Vasopressin and oxytocin are secreted into the cerebrospinal fluid where there is a diurnal rhythmic secretion of the peptides in several animal species (some species have a predominant rhythm of vasopressin and others a rhythm of oxytocin). Neurohypophyseal peptides are synthesized in some non-neuronal tissues where the function is unknown, and recently a novel peptide with similarities to oxytocin and vasotocin has been identified. The relationship of this novel peptide to the neurohypophyseal peptides is unknown. These new developments are likely to elucidate many new functions for the hormones of the neurohypophysis.

Dynamic neuronal-glial interactions in hypothalamus and pituitary: implications for control of hormone synthesis and release.

Various lines of evidence have suggested that astrocytes play a dynamic role in control of hormone synthesis and release from the CNS. The model system most studied has been the rat hypothalamo-neurohypophysial system, consisting chiefly of the supraoptic and paraventricular nuclei and their axonal terminals. Neurons of this system manufacture and secrete oxytocin and vasopressin. Electron microscopic studies have shown that certain physiological conditions (e.g., dehydration, lactation) produce increases in direct apposition among these neurosecretory cells, an effect due to withdrawal of glial processes from between the neurons. Neurohypophysial astrocytes (pituicytes) show dynamic interactions with the neurons at the level of the terminals, by engulfing them and interposing processes between the terminals and the basement membrane when hormone demand is low. Pituicyte processes retract from both areas when hormone demand is high, allowing the neuronal terminals direct access to the perivascular space. Recently, osmotic manipulations (in the physiological range) have shown that these changes can be produced in vitro in neurohypophysial explants without stimulated hormone release. Experiments on cultured adult rat pituicytes have revealed similar morphological changes in response to noradrenaline. These changes were reversed or blocked by propranolol. The increase in direct soma-somatic apposition (7-9 nm separation) of magnocellular neurons could produce a tonic rise in (K+)o which would increase protein synthesis and contribute to the raised excitability of these neurons. Also, the removal of interposed glia could allow the formation of gap junctions and specialised synapses which are known to occur between these neurons. These in turn may participate in producing the coordinated firing that maximizes hormone release. The interactions of pituicytes with the terminals in the neurohypophysis suggests that these astrocytes are also a part of the mechanism of control of hormone release.

[Primary dysmenorrhea: current insights in etiology and treatment]. / Primaire dysmenorroe: huidige inzichten in etiologie en behandeling.

PIP: Dysmenorrhea means not only uterine pain in the lower abdomen and back, but in many cases headaches, depression, perspiration, nausea, vomiting, and diarrhea, mostly during the first 12-48 hours of menstruation. Primary dysmenorrhea begins at a young age, and some investigators have stated that 50% all of women suffer from dysmenorrhea. No gynecological cure has been found. The socioeconomic consequences are substantial due to absences from school and work. It was previously believed that dysmenorrhea was caused by hormonal imbalance, but there is now evidence that it could be caused by prostaglandins in the menstrual blood. When prostaglandins are administered, the aforementioned side effects of dysmenorrhea are experienced. Since the 1960s, oral contraceptives (OCs) have been administered with success. If for some reason OCs are not advisable, there are very few effective alternatives. Dydrogesterone, a retroprogesterone derivative, does not slow down ovulation, but has to be taken for several weeks of the month just like the pill. Several inhibitors of prostaglandin synthesis are available, but naproxene is the best. It is the longest acting, requiring administration only 2 times/day. It works immediately and can be taken when needed. Because it is used only when needed, there is a minimm of side effects from long-term use. It should not be used by women under 16 years of age. Side effects of all prostaglandin synthesis inhibitors are nausea, vomiting, abdominal pain, and diarrhea. The use of calcium is also advised and warrants further study.^ieng

Analysis of the neurohypophyseal components accumulating in the supraoptic nucleus of the rat after injection of colchicine.

[35S]Cysteine has been injected into the supraoptic nuclei of normal rats and of animals given 7 micrograms colchicine into the cerebrospinal fluid to inhibit transport of neurosecretory granules. Analysis of extracts of the supraoptic nuclei 20 min or 6 h after isotope injections showed that (i) colchicine does not affect biosynthesis, i.e., incorporation of tracer into the common precursors of neurohypophyseal hormones and their associated neurophysins, and (ii) processing of precursors inside the arrested granules proceeds normally.

Biosynthesis of neurohypophysial hormones: historical and current events.

Properties of the neurohypophysial hormones and neurophysins are presented and historical events contributing to our present understanding of the biosynthesis of these molecules are reviewed. Recent findings, including cloning of mRNA and identification of putative giant precursors, are discussed in the context of precursor processing systems and possible biochemical and physiological mechanisms.