Negative Feedback Phase Research Articles

A novel negative feedback phase locked loop-based reference current generation technique for shunt active power filter

The use of nonlinear devices introduces current and voltage harmonics into power distribution networks. The presence of harmonics, an undesirable power quality issue, causes transformer overheating, malfunctioning of sensitive loads, power losses, and significantly reduced distribution system efficiency. Therefore, harmonics mitigation in power systems has become absolutely essential and is widely addressed, utilizing shunt active power filters (SAPFs) around the globe. The performance of SAPF in generating adequate compensating current depends on the working of three control loops used for the purpose of reference current generation, dc-link voltage control, and switching pulse generation. The existing approaches for reference current generation suffer from inherent complexity and the inability to extract positive sequence signals required for obtaining synchronizing angle during source disturbance conditions. Therefore, this paper proposes a novel negative feedback phase-locked loop-based modified synchronous reference frame technique to overcome the drawback of the existing approaches. The effectiveness of the proposed approach is investigated under ideal and non-ideal grid voltage conditions with different load perturbations. The proposed control strategy is first tested using a number of simulation-based experiments and, thereafter, validated using OPAL-RT 4510 real-time digital simulator. Compared to other existing approaches, the proposed technique has offered improved results in terms of reduced total harmonics distortion.

Belief reversals as phase transitions and economic fragility: a complexity theory of financial cycles with reflexive agents.

This paper aims to contribute to the analysis of expectations and belief reversals in a evolutionary and complexity economics framework. It formulates its analysis in terms of the concept of reflexivity, drawing on the ideas regarding reflexivity in financial markets of George Soros, and lays out a model of how a financial cycle expresses a systematic pattern of interacting feedback effects. The paper develops this analysis as a complex interaction between sets of heterogeneous expectations derived from the behavior of reflexive economic agents. Positive and negative feedback phases in a cycle are distinguished and associated with boom and bust stages of that cycle. A central role is played by agents’ beliefs and judgments underlying their expectations, and how those beliefs and judgments in uncertain circumstances are changeable and subject to abrupt reversals which can manifest themselves in “Minsky moments.” The paper argues that agents’ belief reversals result from their misconceptions about causal processes in booms and upswings, a misconception that reflects their tendency to think causally in terms of negative feedback patterns rather than positive ones.

A Complexity Theory of Financial Cycles With Reflexive Agents

This paper aims to contribute to the analysis of expectations and belief reversals in an evolutionary and complexity economics framework. It formulates its analysis in terms of the concept of reflexivity, drawing on the ideas regarding reflexivity in financial markets of George Soros, and lays out a model of how a financial cycle expresses a systematic pattern of interacting feedback effects. The paper develops this analysis as a complex interaction between sets of heterogeneous expectations derived from the behavior of reflexive economic agents. Positive and negative feedback phases in a cycle are distinguished and associated with boom and bust stages of that cycle. A central role is played by agents’ beliefs and judgments underlying their expectations, and how those beliefs and judgments in uncertain circumstances are changeable and subject to abrupt reversals which can manifest themselves in ‘Minsky moments.’ The paper argues that agents’ belief reversals result follow their misconception about causal processes in booms and upswings, a misconception that reflects their tendency to think causally in terms of negative feedback patterns rather than positive ones.

Feedback-Based, System-Level Properties of Vertebrate-Microbial Interactions

BackgroundImproved characterization of infectious disease dynamics is required. To that end, three-dimensional (3D) data analysis of feedback-like processes may be considered.MethodsTo detect infectious disease data patterns, a systems biology (SB) and evolutionary biology (EB) approach was evaluated, which utilizes leukocyte data structures designed to diminish data variability and enhance discrimination. Using data collected from one avian and two mammalian (human and bovine) species infected with viral, parasite, or bacterial agents (both sensitive and resistant to antimicrobials), four data structures were explored: (i) counts or percentages of a single leukocyte type, such as lymphocytes, neutrophils, or macrophages (the classic approach), and three levels of the SB/EB approach, which assessed (ii) 2D, (iii) 3D, and (iv) multi-dimensional (rotating 3D) host-microbial interactions.ResultsIn all studies, no classic data structure discriminated disease-positive (D+, or observations in which a microbe was isolated) from disease-negative (D–, or microbial-negative) groups: D+ and D– data distributions overlapped. In contrast, multi-dimensional analysis of indicators designed to possess desirable features, such as a single line of observations, displayed a continuous, circular data structure, whose abrupt inflections facilitated partitioning into subsets statistically significantly different from one another. In all studies, the 3D, SB/EB approach distinguished three (steady, positive, and negative) feedback phases, in which D– data characterized the steady state phase, and D+ data were found in the positive and negative phases. In humans, spatial patterns revealed false-negative observations and three malaria-positive data classes. In both humans and bovines, methicillin-resistant Staphylococcus aureus (MRSA) infections were discriminated from non-MRSA infections.ConclusionsMore information can be extracted, from the same data, provided that data are structured, their 3D relationships are considered, and well-conserved (feedback-like) functions are estimated. Patterns emerging from such structures may distinguish well-conserved from recently developed host-microbial interactions. Applications include diagnosis, error detection, and modeling.

Corticosterone pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis activity via multiple actions that vary with time, site of action and de novo protein synthesis

Glucocorticoid regulation of the hypothalamic-pituitary-adrenal (HPA) axis is believed to depend on multiple actions operative within discrete time domains. However, the underlying cellular and molecular mechanisms for those glucocorticoid actions remain undetermined. Moreover, there is absence of in vivo studies examining whether there are multiple glucocorticoid effects on HPA axis-related function within an intermediate feedback time frame (1-3 h after glucocorticoid elevation), and whether those effects depend on de novo protein synthesis. We examined in rats the effects of protein synthesis inhibition on HPA axis response to restraint (15 min) after 1 and 3 h phasic corticosterone (CORT) pretreatment. We measured HPA axis hormones (ACTH and CORT) and gene expression in the paraventricular nucleus (c-fos and crh genes), as well as gene expression in the anterior and intermediate pituitaries (c-fos and pomc genes). Both CORT pretreatment intervals produced inhibition of stress-induced ACTH secretion, but no inhibition was observed in the presence of protein synthesis inhibition. CORT pretreatment produced inhibitory effects on stress-induced gene expression that varied for each gene depending on the anatomical site, pretreatment time, and protein synthesis dependency. Taken together, the ACTH and gene expression patterns support the presence of multiple independent glucocorticoid actions initiated during the intermediate glucocorticoid negative feedback phase. Moreover, we conclude that those effects are exerted predominantly on the intrinsic anatomical elements of the HPA axis, and some of those effects depend on CORT induction of the expression of one or more regulatory gene products.

Differential response to estrogen challenge test in women with and without premenstrual dysphoria

This study tested the hypothesis that brain sensitivity to normal fluctuations in gonadal hormones is increased in women with premenstrual dysphoria. For this purpose, the effect of a common gonadal hormonal challenge on the sensitivity of the brain was investigated in 13 women with premenstrual dysphoria and 12 asymptomatic controls. The estrogen challenge test, comprising estradiolbenzoate 0.04 mg/kg, was given as an intramuscular gluteal injection between 0700 and 1000h on day 3 or 4 of the menstrual cycle; blood was sampled at 0, 0.6, 6.5, 24, 32, 48, 56, 72, 96, 120, and 144h and analyzed for estradiol, FSH and LH. Serum estradiol levels after the injection and the corresponding FSH responses were similar between the study groups; however, the LH responses were significantly different. Women with premenstrual dysphoria had a relatively stronger negative feedback response (p=0.014) up to the point of nadir LH levels (maximal negative feedback), but displayed higher LH levels at the nadir (p=0.01), more LH surge-like reactions (p=0.047), and a 50% higher area under the curve (AUC) for LH (p=0.03) than controls. The LH response in women with premenstrual dysphoria was related to the VAS-rated symptoms; the negative increment (AOC) correlated to luteal phase "bloating" (r(s)=0.73; p=0.0069) whereas the AUC of LH correlated to "irritability" (r(s)=0.58; p=0.040). A significant interaction term between study group and changes in LH during the negative feedback phase (32-0h), with regard to luteal phase "irritability" was found (test for interaction p=0.005). For the premenstrual dysphoria group, ratings of "depressed mood"were related to baseline FSH levels (r(s)=0.60; p=0.034), and to the AUC of FSH during the negative feedback phase (r(s)=0.58; p=0.043). Women with premenstrual dysphoria displayed a gonadotrophin response to estradiol challenge that differed from that of controls, and was correlated to symptom severity.

Suppression subtractive hybridization and microarray identification of estrogen-regulated hypothalamic genes.

The gonadal steroid estrogen is a pleiotropic hormone that has multiple effects on numerous cellular functions. One of estrogen's major targets is the brain, where the steroid not only affects growth, differentiation, and survival of neurons, but also regulates cell excitability. Because estrogen modulates multiple, overlapping signaling pathways, it has been difficult to scrutinize the transcriptional activity of the steroid. Therefore, we still lack a global picture of how different genes interact and are regulated by estrogen. Herein we report the use of suppression subtractive hybridization followed by custom microarray analysis of thousands of genes that are differentially expressed during the negative feedback phase of the female reproductive cycle. We have found a number of key transcripts that are regulated by estrogen and contribute to the alteration in synaptic transmission and hence excitability of hypothalamic neurons (e.g., GABA neurons). These include gec-1, GABA(B)R2, PI3 kinase subunit p55gamma, and a number of proteins containing pleckstrin homology domains that are critical for plasma membrane targeting. Studies are underway to refine our analysis to individual nuclei and individual cells. However, what has emerged from this highly sensitive microarray analysis is that estrogen affects neuronal plasticity in hypothalamic neurons not only by transcription of new membrane proteins (e.g., receptors and channels), but also by altering expression of downstream signaling molecules and proteins involved in neurosecretory pathways.

Distribution, Neuronal Colocalization, and 17β-E2 Modulation of Small Conductance Calcium-Activated K+ Channel (SK3) mRNA in the Guinea Pig Brain

Molecular cloning has revealed the existence of three distinct small conductance (SK1-3) Ca(2+)-activated K(+) channels. Because SK channels underlie the afterhyperpolarization (AHP) that is critical for sculpturing phasic firing in hypothalamic neurons, we investigated the distribution of these channels in the female guinea pig. Both SK1 and SK3 cDNA fragments were cloned using PCR, and ribonuclease protection assay as well as in situ hybridization analysis illustrated that the SK3 channel was the predominant subtype expressed in the guinea pig hypothalamus. Combined in situ hybridization and fluorescence immunocytochemistry revealed that SK3 mRNA was expressed in GnRH, dopamine, and vasopressin neurons, and all of these neurons exhibited an AHP current. Moreover, SK3 mRNA was found in other brain areas, including the septum, bed nucleus, amygdala, thalamus, midbrain, and hippocampus. Using quantitative ribonuclease protection assay, the rank order of SK3 mRNA expression was septum >or= midbrain > rostral thalamus >or= rostral basal hypothalamus >or= caudal thalamus >or= preoptic area >> caudal basal hypothalamus >or= hippocampus. Moreover, 17beta-E2 treatment, which reduces plasma LH during the negative feedback phase, significantly increased SK3 mRNA levels in the rostral basal hypothalamus (P < 0.05; n = 6). Therefore, these findings suggest that estrogen increases the mRNA expression of SK3 channels, which may represent a mechanism by which estrogen regulates hypothalamic neuronal excitability during negative feedback.

Distribution, Neuronal Colocalization, and 17 -E2 Modulation of Small Conductance Calcium-Activated K+ Channel (SK3) mRNA in the Guinea Pig Brain

Molecular cloning has revealed the existence of three distinct small conductance (SK1–3) Ca2+-activated K+ channels. Because SK channels underlie the afterhyperpolarization (AHP) that is critical for sculpturing phasic firing in hypothalamic neurons, we investigated the distribution of these channels in the female guinea pig. Both SK1 and SK3 cDNA fragments were cloned using PCR, and ribonuclease protection assay as well as in situ hybridization analysis illustrated that the SK3 channel was the predominant subtype expressed in the guinea pig hypothalamus. Combined in situ hybridization and fluorescence immunocytochemistry revealed that SK3 mRNA was expressed in GnRH, dopamine, and vasopressin neurons, and all of these neurons exhibited an AHP current. Moreover, SK3 mRNA was found in other brain areas, including the septum, bed nucleus, amygdala, thalamus, midbrain, and hippocampus. Using quantitative ribonuclease protection assay, the rank order of SK3 mRNA expression was septum ≥ midbrain > rostral thalamus ≥ rostral basal hypothalamus ≥ caudal thalamus ≥ preoptic area ≫ caudal basal hypothalamus ≥ hippocampus. Moreover, 17β-E2 treatment, which reduces plasma LH during the negative feedback phase, significantly increased SK3 mRNA levels in the rostral basal hypothalamus (P < 0.05; n = 6). Therefore, these findings suggest that estrogen increases the mRNA expression of SK3 channels, which may represent a mechanism by which estrogen regulates hypothalamic neuronal excitability during negative feedback.

Estrogen Biphasically Modifies Hypothalamic GABAergic Function Concomitantly with Negative and Positive Control of Luteinizing Hormone Release

The principal role of estrogen is its control of the female ovulatory cycle via negative and positive feedback on gonadotropin secretion. However, a detailed, cohesive picture of how the steroid specifically regulates the excitability of hypothalamic neurons involved in the central control of gonadotropin secretion is still emerging. Here, we used an ovariectomized female guinea pig model to test the hypothesis that estrogen acts on GABAergic neurons in the preoptic area (POA) to elicit a biphasic profile of luteinizing hormone (LH) secretion. Intracellular electrophysiological recordings revealed that estradiol benzoate (EB; 25 microgram, s.c.) decreased the hyperpolarizing response of GABAergic neurons to the GABA(B) receptor agonist baclofen 24 hr after treatment. This effect of GABA(B) receptor stimulation in unidentified POA neurons was still depressed 42 hr after EB administration. By the use of a ribonuclease protection assay, however, EB reduced glutamic acid decarboxylase mRNA expression 42 hr but not 24 hr after its administration. Thus, estrogen attenuated the autoinhibition of GABAergic POA neurons during the initial LH suppressive (i.e., negative feedback) phase and subsequently reduced GABAergic function during the LH surge (i.e., positive feedback). These studies demonstrate that the effects of estrogen on hypothalamic GABAergic neurons coincide with the inhibitory and stimulatory actions, respectively, of the steroid on LH secretion. Furthermore, the data provide novel insights into the mechanism by which estrogen regulates hypothalamic GABAergic neurons, which are critical for the biphasic modulation of LH release observed over the course of the female ovulatory cycle.

Concentration and Distribution of Neuropeptide Y, Galanin, β‐endorphin, Vasoactive Intestinal Peptide and Gonadotrophin‐Releasing Hormone in the Hypothalamus of Gilts during Oestrogen‐Induced Surge Secretion of Luteinizing Hormone

ContentsThe relationship of neuropeptide Y (NPY), galanin (GAL), β‐endorphin (β‐END) and vasoactive intestinal peptide (VIP) to GnRH neurons were determined during the estradiol‐induced LH surge. In experiment 1, 16 ovariectomized (OVX) gilts received 15 μg estradiol benzoate (EB)/kg BW at 0800 h and were slaughtered at either 24 h (n = 5), 48 h (n = 6) or 72 h (n = 5) later and five were injected with corn oil vehicle (0 h controls). Concentrations of neuropeptides were determined in tissue extracts by RIA. In experiment 2, nine OVX gilts were injected with EB as in experiment 1 and killed at either 24, 48 or 72 h (n = 3) later and three were not injected with EB (0 h controls). Frozen sections were processed to localize neuropeptides. In experiment 1, all measured neuropeptides were highest in pituitary stalk median eminence (SME). The GnRH concentration was not different at any time point in medial basal hypothalamus (MBH), preoptic area (POA) or SME. The NPY content in MBH was lower at 24, 48 and 72 h after EB than at 0 h (p &lt; 0.001), and lower in SME at 48 and 72 h than at 24 h (p &lt; 0.05) and 0 h (p &lt; 0.01), respectively. Concentration of GAL in SME was four times higher at 72 h than at 0, 24 or 48 h (p &lt; 0.001). The VIP concentration increased in POA (p &lt; 0.05) and MBH (p &lt; 0.001) at 24 h and 72 h (p &lt; 0.05). Concentration of VIP in SME was lower at 24 and 48 h than at 0 h (p &lt; 0.05) and increased to more than twice (p &lt; 0.05) by 72 h. Concentrations of β‐END were not different at any time point in POA and MBH but the highest content of β‐END in SME occurred at 24 h (p &lt; 0.001). In experiment 2 a moderate number of GnRH‐immunoreactive (IR) fibres were found in the periventricular area of the POA and in organum vasculosum of the laminae terminalis (OVLT). The GnRH‐IR fibres formed networks in the external and internal layer of the median eminence (ME). At 24 h, GnRH‐IR neurons and fibres in the POA and ME were more numerous and noticeable differences were found in the arcuate nucleus (ARC) and ventromedial nucleus (NVM). At 48 and 72 h, numbers of IR neurons and fibres were higher in the ARC and NVM, but no changes occurred in the POA and ME. The ARC contained a moderate number of NPY‐IR fibres, but less numerous small cell bodies. Only a few NPY‐IR perikarya and fibres were in the NVM and fibre density was similar at all times after EB injection. VIP‐IR fibres were scarcely distributed mostly in the posterior POA and the internal layer of ME. The number of VIP‐IR fibres was similar at all time points and regions. A moderate number of varicose β‐END fibres supplied the POA, and they were especially dense near the OVLT, but the cell bodies were moderate in number and did not show strong immunoreactivity. In ME, ARC and NVM, the number of β‐END immunoreactive structures was greater at 24 and 48 h than at 0 h. The number of β‐END‐IR nerve fibres in POA was higher at 72 h than at 0 h. Levels of all neuropeptides studied were similar in the POA and MBH and content of NPY, GAL and β‐END was very high in the SME of the pig forebrain. The dynamic changes of NPY, GAL, VIP and β‐END content in pig hypothalamus during the oestrogen‐induced negative and positive feedback phases of LH secretion indicate their potential role in modulating GnRH release from the median eminence.

Short distance ultrasonic distance meter

A short distance ultrasonic distance meter is disclosed with provisions to reduce the ill-effects of ringing when measurements are of obstacles closer than about ten inches. In one embodiment an opposite phase ultrasonic wave is introduced by a circuit (245) and in another embodiment a strain sensor (232) introduces negative feedback to effect cancellation of ringing (147). Finally, in a third embodiment, both the negative feedback and opposite phase methods are employed for optimal results.

Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey.

Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time. The enhancement of LH release is approximately 50%, regardless of the amount of the NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels of SP, indicating that blockade of SP receptors leads to an increased release of SP. Collectively, these results further substantiate the link which exists between the ovarian steroid 17beta-estradiol and SP systems. Also, for the first time, these results demonstrate an inhibitory involvement of the human NK1 receptor in the 17beta-estradiol-induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.

Activation of the hypothalamo-anterior pituitary corticotropin-releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey.

The present work describes time-dependent changes in the content of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and beta-endorphin (beta-EP) in the hypothalamus (HT) and anterior pituitary (AP) and in the concentration of ACTH and beta-EP in the plasma during the 17 beta estradiol (E2) benzoate (E2B)-induced luteinizing hormone (LH) surge in ovariectomized cynomolgus monkeys. Monkeys were euthanized at 0, 30, 48, 72, and 96 hr post-E2B. HT and AP were rapidly dissected, extracted in 2 N acetic acid containing 1 mM phenylmethane sulfonyl fluoride at 4 degrees C, and centrifuged at 18,000g for 30 min. Peptide concentrations were measured in the supernatant by specific radioimmunoassays (RIAs). In the HT, there were significant (P < 0.05) decreases in ACTH and beta-EP content by 30 hr post-E2B and a significant (P < 0.05) decrease in HT CRH content 48 hr post-E2B. Thereafter, CRH, ACTH, and beta-EP content increased up to 72 hr post-E2B. In the AP, there was an almost linear decrease in the CRH content through 48 hr post-E2B followed by a marked 20-fold (P < 0.01) increase in the AP CRH content at 72 hr post-E2B, which corresponds to the time of the descending arm of the LH surge. The patterns of ACTH and beta-EP content were very similar in the AP, while that of CRH differed markedly. In contrast, in the HT CRH, ACTH, and beta-EP profiles were very similar. Significant (P < 0.05) increases in circulating levels of ACTH, beta-EP, and cortisol were evident at 30 hr (all 3 hormones), 48 hr (beta-EP and cortisol), and 72 hr (cortisol) post-E2B, which corresponds with the time of decreased hypothalamic content of CRH, ACTH, and beta-EP. These results suggest that there maybe a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and positive feedback phases of the E2B-induced LH surge in the ovariectomized monkey.

Opioid involvement in LH release during the negative feedback effects of oestradiol and progesterone in dairy cows

To create a clearly defined and uniform feedback phase of oestradiol, 1 mg oestradiol benzoate (OE2) was injected i.m. either 15-43 days post partum in 7 cows (Expt 1), or 12 h after prostaglandin oestrus synchronization of 4 cyclic cows (Expt 2 and 3). An endogenous opioid peptide (EOP) antagonist (250 mg naloxone), an EOP agonist (300 mg morphine), or a combination of the two was given in Expt 1, 2 and 3 respectively as a single i.v. injection in cows 16-18 h after OE2, i.e. in the negative feedback phase and before the expected onset of an induced luteinizing hormone (LH) surge. Blood samples were collected every 15 min for 1 h before and 2 h after each treatment. In Expt 1, naloxone failed to increase LH release when given during the negative feedback phase, but caused excessive release in one cow in which the LH surge had just begun. In all cows in Expt 2, morphine suppressed LH release (P less than 0.05). In Expt 3, naloxone prevented the suppressive effects of morphine for the first hour after treatment; a transient rise in LH occurred in one cow in which treatment was given 1 h before the start of the LH surge. In Expt 4, 250 mg naloxone was injected i.v. into 4 cows that had a plasma progesterone concentration of 1.5-3.1 ng mL-1 in the luteal phase of the oestrous cycle: naloxone failed to increase LH concentrations. It is concluded that LH can be further suppressed by opiates given to cows during the negative feedback phase of oestradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

Biphasic response in the secretion of gonadotrophin-releasing hormone in ovariectomized ewes injected with oestradiol.

In ovariectomized ewes, an injection of oestrogen initially inhibits the tonic secretion of LH, and then induces a large release of LH similar to the preovulatory surge in intact ewes. The pattern of hypothalamic secretion of gonadotrophin-releasing hormone (GnRH) into the pituitary portal blood during this biphasic response to oestrogen was investigated in conscious, unrestrained, ovariectomized adult Ile-de-France ewes during the breeding season. The ewes were ovariectomized and implanted with cannulae for portal blood collection on the same day. Seven days later, portal and peripheral blood samples were collected simultaneously every 5 min for 25 h. The ewes were injected with oestradiol-17 beta (25 micrograms i.v. and 25 micrograms i.m.) 6.25 h after the start of sampling. GnRH and LH were measured by radioimmunoassay in portal and jugular plasma samples respectively. A clear pulsatile pattern of LH secretion was observed before the oestradiol injection in all the ewes, followed by the typical biphasic decrease (negative feedback) and increase (positive feedback) in mean concentrations. The sampling period was divided, for analysis, into pretreatment, negative feedback and positive feedback phases. Before injection with oestradiol, the GnRH pulses were clearly defined in portal blood and were always synchronized with LH pulses in the peripheral circulation. The frequency was 5.9 +/- 0.6 pulses/6 h (mean +/- S.E.M.), and the amplitude was 31.6 +/- 7.6 pmol/l. During negative feedback, both the frequency (4.2 +/- 0.5 pulses/6 h, P less than 0.01) and amplitude (15.2 +/- 4.6 pmol/l, P less than 0.05) of the GnRH pulses decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Negative feedback as an obligatory antecedent to the estradiol-induced luteinizing hormone surge in ovariectomized pigs.

In ovariectomized pigs, estradiol treatment induces a preovulatory-like luteinizing hormone (LH) surge, but only after serum LH concentrations are suppressed for 48 h. This inhibition of LH release is attributable in large part to inhibition of gonadotropin-releasing hormone (GnRH) release. The present report examines the dependency of the estradiol-induced LH surge on this preceding phase of negative feedback. Ten ovariectomized gilts were given an i.m. injection of estradiol benzoate (10 micrograms/kg BW). Beginning at the time of estradiol treatment, 5 of these gilts received 1-microgram GnRH pulses i.v. every 45 min for 48 h, i.e. during the period of negative feedback. The remaining 5 control gilts received comparable infusions of vehicle. Estradiol induced the characteristic biphasic LH response in control gilts. On the other hand, the inhibitory LH response to estradiol was prevented and the ensuing LH surge was blocked in 4 of the 5 gilts given GnRH pulses during the negative feedback phase. These results indicate that suppressing release of GnRH and/or LH is an important antecedent to full expression of the LH surge in ovariectomized pigs. Assimilation of this observation with the existing literature provides novel insights into the neuroendocrine control of LH secretion in castrated and ovary-intact gilts.

Blockade of the oestrogen-induced LH surge in the ovariectomized common marmoset (Callithrix jacchus) by an LHRH antagonist

Six long-term ovariectomized adult marmoset monkeys were treated at 0 h with 35 micrograms oestradiol benzoate s.c. to induce an LH surge. They were also treated with detirelix (an LHRH antagonist) at 0 h, 12 h and 24 h (Exp. 1), or at 0 h and 24 h (Exp. 2) at a dose of 300 micrograms/kg s.c., or received the detirelix vehicle alone at 0 h, 12 h and 24 h (Exp. 3). All animals received the three treatments, with at least 4 weeks between experiments. Blood samples were collected at 0 h and at 6-12 h intervals for 72 h after oestradiol for the determination of plasma LH by bioassay. In control animals, oestrogen treatment resulted in a decline in plasma LH from 30.0 +/- 5.8 at 0 h to 12.8 +/- 2.6 ng/ml at 6 h (negative feedback), followed by a positive feedback surge, reaching a maximum of 148.0 +/- 34.6 ng/ml at 24 h. Values then declined to pretreatment levels by 56 h. In contrast, antagonist-treated animals showed complete abolition of the expected increase at 24 h, the low levels of the negative feedback phase being maintained for 36-72 h. These results show that hypothalamic LHRH release is essential during the oestrogen-induced LH surge, and that a direct oestrogen-induced component at the pituitary level is not expressed in the absence of LHRH in the marmoset.

Responses of luteinizing hormone (LH) and follicle-stimulating hormone levels to exogenous gonadotropin-releasing hormone during the estrogen-induced LH surge in the ovariectomized rhesus monkey

Experiments were performed to study the responsiveness of the pituitary to gonadotropin-releasing hormone (GnRH) during the dynamic changes in gonadotropin secretion associated with the estrogen-induced luteinizing hormone (LH) surge in the ovariectomized (OVX) rhesus monkey. Silastic capsules filled with estradiol-17-beta were implanted subcutaneously in ovariectomized rhesus monkeys, resulting in an initial lowering of circulating LH and follicle-stimulating hormone (FSH) concentrations followed by an LH-FSH surge. GnRH was injected intravenously just before estrogen implantation, during the negative feedback response and during the rising, the peak, and the declining phases of the LH surge. The LH and FSH responses during the negative feedback phase were as large as those before estrogen treatment (control responses). During the rising phase of the LH surge, the acute response to GnRH injection did not differ significantly from the control response, but the responses 60 and 120 min after injection were somewhat increased. During the declining phase of the LH surge, the pituitary was not responsive to exogenous GnRH, although LH probably continued to be secreted at this time since the LH surge decreased more slowly than predicted by the normal rate of disappearance of LH in the monkey. We conclude that an increased duration of response to GnRH may be an important part of the mechanism by which estrogen induces the LH surge, but we do not see evidence of increased sensitivity of the pituitary to GnRH as an acute releasing factor at that time.

Short loop feedback control of the estrogen-induced luteinizing hormone surge in pigs.

This study examines whether hCG will block the estradiol-induced LH surge in ovariectomized gilts. Twenty post-puberal cross-bred gilts were ovariectomized at 6-7 months of age. Approximately 2 months later, the experiment was conducted, and all gilts were given estradiol benzoate (EB; 10 micrograms/kg, im) at 0 h. Controls (n = 6) received im saline 24 and 48 h after EB. Two groups of gilts received 2000 IU hCG im, at 24 h (hCG24; n = 5) or 48 h (hCG48; n = 5) after EB. The fourth group (n = 4) received hCG at 48 h and was then given iv a LHRH agonist (des-Gly10, [D-Ala6]LHRH ethylamide) in 100-ng boluses hourly from 54-96 h after EB. Blood samples for determination of LH and FSH were collected every 6 h from 0-96 h. In controls, EB alone suppressed LH from 3.9 +/- 1.9 ng/ml at 0 h to 1.0 +/- 0.2 during 6-48 h (negative feedback), but LH then increased to 4.5 +/- 0.5 between 54 and 96 h (positive feedback), with the peak of the surge (6.7 +/- 1.6) occurring at 72 h. Treatment with hCG did not alter LH during the negative feedback phase (1.1 +/- 0.1 and 1.0 +/- 0.1 for hCG24 and hCG48, respectively). However, there was no LH surge in gilts given hCG at 24 or 48 h (2.4 +/- 0.2 and 2.2 +/- 0.1 form 54-96 h; P less than 0.05). Hourly injections of the LHRH agonist evoked a surge in LH (8.3 +/- 1.3) and maintained elevated LH (4.5 +/- 0.6) between 54 and 96 h, similar (P greater than 0.05) to values for controls. Generally, FSH in gilts given hCG followed the same pattern as LH secretion during the negative feedback stage; however, due to randomization, means for the period from 0-48 h for gilts treated with hCG 24 or 48 h after EB were lower (P less than 0.05) than for controls or gilts given LHRH agonist (62.2 +/- 2.8 and 63.0 +/- 2.7 vs. 79.3 +/- 3.2 and 93.3 +/- 4.2 ng/ml, respectively). During the positive feedback phase (54-96 h), FSH was lower in gilts given hCG (hCG24, 63.4 +/- 2.3; hCG48, 67.3 +/- 2.0) than in controls (86.0 +/- 4.0), but in gilts given LHRH agonist, FSH was higher (1001.1 +/- 7.7) than in controls.(ABSTRACT TRUNCATED AT 400 WORDS)