scholarly journals Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling

2019 ◽  
Vol 104 (10) ◽  
pp. 4304-4318 ◽  
Author(s):  
Margaret F Lippincott ◽  
Silvia León ◽  
Yee-Ming Chan ◽  
Chrysanthi Fergani ◽  
Rajae Talbi ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Medical Center ◽  
Academic Medical Center ◽  
Pulse Frequency ◽  
Pulse Generation ◽  
Loss Of Function ◽  
Neurokinin B ◽  
Gene Encoding ◽  
Reproductive Endocrine ◽  
Pulse Characteristics

Abstract Context Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. Objective To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. Design Case/control. Setting Academic medical center. Participants Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. Interventions Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. Main Outcome Measures LH pulse characteristics. Results Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. Conclusion The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.

scholarly journals Kisspeptin, Neurokinin B, and Dynorphin Act in the Arcuate Nucleus to Control Activity of the GnRH Pulse Generator in Ewes

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4259-4269 ◽  
Author(s):  
Robert L. Goodman ◽  
Stanley M. Hileman ◽  
Casey C Nestor ◽  
Katrina L. Porter ◽  
John M. Connors ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Pulse Frequency ◽  
Afferent Input ◽  
Pulse Generation ◽  
Orphanin Fq ◽  
Neurokinin B ◽  
Control Activity ◽  
Kndy Neurons ◽  
Lh Secretion

Recent work has led to the hypothesis that kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the arcuate nucleus play a key role in GnRH pulse generation, with kisspeptin driving GnRH release and neurokinin B (NKB) and dynorphin acting as start and stop signals, respectively. In this study, we tested this hypothesis by determining the actions, if any, of four neurotransmitters found in KNDy neurons (kisspeptin, NKB, dynorphin, and glutamate) on episodic LH secretion using local administration of agonists and antagonists to receptors for these transmitters in ovariectomized ewes. We also obtained evidence that GnRH-containing afferents contact KNDy neurons, so we tested the role of two components of these afferents: GnRH and orphanin-FQ. Microimplants of a Kiss1r antagonist briefly inhibited LH pulses and microinjections of 2 nmol of this antagonist produced a modest transitory decrease in LH pulse frequency. An antagonist to the NKB receptor also decreased LH pulse frequency, whereas NKB and an antagonist to the receptor for dynorphin both increased pulse frequency. In contrast, antagonists to GnRH receptors, orphanin-FQ receptors, and the N-methyl-D-aspartate glutamate receptor had no effect on episodic LH secretion. We thus conclude that the KNDy neuropeptides act in the arcuate nucleus to control episodic GnRH secretion in the ewe, but afferent input from GnRH neurons to this area does not. These data support the proposed roles for NKB and dynorphin within the KNDy neural network and raise the possibility that kisspeptin contributes to the control of GnRH pulse frequency in addition to its established role as an output signal from KNDy neurons that drives GnRH pulses.

scholarly journals Suppression of the GnRH Pulse Generator by Neurokinin B Involves a κ-Opioid Receptor-Dependent Mechanism

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4894-4904 ◽  
Author(s):  
P. Grachev ◽  
X. F. Li ◽  
J. S. Kinsey-Jones ◽  
A. L. di Domenico ◽  
R. P. Millar ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pulse Generator ◽  
Pulse Frequency ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Neurokinin B ◽  
Kndy Neurons ◽  
Lh Secretion ◽  
Dose Dependent

Abstract Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First, we investigated the effect of intra-ARC administration of the selective NK3R agonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17β-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion in response to senktide in rats pretreated with nor-binaltorphimine, a selective KOR antagonist. We show that nor-binaltorphimine blocks the senktide-induced suppression of pulsatile LH secretion but does not affect LH pulse frequency per se. In order to address the effects of acute activation of ARC NK3R, we quantified (using quantitative RT-PCR) changes in mRNA levels of KNDy-associated genes in hypothalamic micropunches following intra-ARC administration of senktide. Senktide down-regulated expression of genes encoding GnRH and GPR54 (GNRH1 and Kiss1r, respectively), but did not affect the expression of Kiss1 (which encodes kisspeptin). We conclude that NKB suppresses the GnRH pulse generator in a KOR-dependent fashion and regulates gene expression in GnRH neurons.

scholarly journals Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay

2020 ◽  
Vol 105 (8) ◽  
pp. e2717-e2725 ◽  
Author(s):  
Yee-Ming Chan ◽  
Margaret F Lippincott ◽  
Priscila Sales Barroso ◽  
Cielo Alleyn ◽  
Jill Brodsky ◽  
...  
Keyword(s):  
Medical Center ◽  
Academic Medical Center ◽  
Inhibin B ◽  
Endocrine Function ◽  
Delayed Puberty ◽  
Pubertal Delay ◽  
Gnrh Release ◽  
Stimulation Tests ◽  
Reproductive Endocrine ◽  
Outcomes For Children

Abstract Context The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis. Objective We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay. Design, Setting, and Participants We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty. Intervention and Outcome Measures Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.

Pulsatile thyrotropin and prolactin secretion in a patient with a mixed thyrotropin- and prolactin-secreting pituitary adenoma

1994 ◽  
Vol 130 (2) ◽  
pp. 113-120 ◽  
Author(s):  
Ria Adriaanse ◽  
Georg Brabant ◽  
Erik Endert ◽  
Frederique J Bemelman ◽  
Wilmar M Wiersinga
Keyword(s):  
Pituitary Adenoma ◽  
Medical Center ◽  
Academic Medical Center ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Prolactin Secretion ◽  
Before And After ◽  
Temporal Coupling ◽  
Nocturnal Increase ◽  
The Mean

Adriaanse R, Brabant G, Endert E, Bemelman FJ, Wiersinga WM. Pulsatile thyrotropin and prolactin secretion in a patient with mixed thyrotropin- and prolactin-secreting pituitary adenoma. Eur J Endocrinol 1994;130:113–20. ISSN 0804–4643 The circadian and pulsatile thyrotropin (TSH) and prolactin (PRL) release was investigated in a patient with slight hyperthyroidism due to a mixed TSH- and PRL-secreting pituitary adenoma. Blood was withdrawn every 10 min for 24 h (before and after medical treatment); pulse characteristics were analyzed by Desade and Cluster programs (values as mean±sd). The inappropriately high mean 24-h TSH concentration of 3.55 ±0.31 mU/l was associated with a higher mean 24-h TSH pulse amplitude but unaltered mean 24-h TSH pulse frequency relative to healthy controls. The nocturnal TSH surge (absolute surge 0.5 mU/l, relative surge 16%) was low, related to a loss of the usual nocturnal increase of TSH pulse amplitude and TSH pulse frequency. Chronic treatment with octreotide resulted in a modest clinical and biochemical improvement of the hyperthyroid state; addition of bromocriptine at a later stage had no further beneficial effect. At the end of the follow-up period the mean 24-h TSH paradoxically had increased to 5.33 ±0.81 mU/l. The nocturnal TSH surge also increased (absolute surge 1.9 mU/l, relative surge 42%), but circadian changes in TSH pulsatility remained absent. In the untreated period the increased mean 24-h PRL concentration of 234 ± 24 μg/l was associated with an increased mean 24-h PRL amplitude, whereas the 24-h PRL pulse frequency (N = 4) was lower relative to controls. No circadian PRL rhythm was present. After octreotide and bromocriptine treatment the mean 24-h PRL concentration and mean 24-h PRL pulse amplitude were unchanged, but a clear nocturnal increase of PRL now was observed. Analysis of the temporal coupling between TSH and PRL release by bivariate autoregressive modeling revealed significant cross-correlations in all three periods investigated (coefficients in the range 0.34–0.76, median 0.52; p<0.01) between TSH and PRL concentrations with a lag time of 10–20 min. We conclude that pulsatile TSH and PRL release in this mixed TSH- and PRL-secreting pituitary adenoma was autonomous in nature. The observed dampening of the nocturnal increase of TSH and PRL is putatively related to a lack of TRH receptors in these tumors. The observed co-secretion of TSH and PRL suggests synthesis of both hormones by the same cell. R Adriaanse, Department of Endocrinology F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Risk Factors for Wire Fracture or Tethering in Deep Brain Stimulation: A 15-Year Experience

2020 ◽  
Author(s):  
Charles E Mackel ◽  
Efstathios Papavassiliou ◽  
Ron L Alterman
Keyword(s):  
Deep Brain Stimulation ◽  
Fracture Risk ◽  
Brain Stimulation ◽  
Pulse Generator ◽  
Medical Center ◽  
Academic Medical Center ◽  
Rank Test ◽  
Lead Wire ◽  
Consecutive Series ◽  
Deep Brain

Abstract BACKGROUND In deep brain stimulation (DBS), tunneled lead and extension wires connect the implantable pulse generator to the subcortical electrode, but circuit discontinuity and wire revision compromise a significant portion of treatments. OBJECTIVE To identify factors predisposing to fracture or tethering of the lead or extension wire in patients undergoing DBS. METHOD Retrospective review of wire-related complications was performed in a consecutive series of patients treated with DBS at a tertiary academic medical center over 15 yr. RESULTS A total of 275 patients had 513 extension wires implanted or revised. There were 258 extensions of 40 cm implanted with a postauricular connector (50.3%), 229 extensions of 60 cm with a parietal connector (44.6%), and 26 extensions 40 cm with a parietal connector (5.1%). In total, 26 lead or extension wires (5.1%) were replaced for fracture. Fracture rates for 60 cm extensions with a parietal connector, 40 cm wires with a postauricular connector, and 40 cm extensions with a parietal connector were 0.2, 1.4, and 12.9 fractures per 100 wire-years, significantly different on log-rank test. Total 16 (89%) 40 cm extension wires with a postauricular connector had fracture implicating the lead wire. Tethering occurred only in patients with 60 cm extensions with parietal connectors (1.14 tetherings per 100 wire-years). Reoperation rate correlated with younger age, dystonia, and target in the GPI. CONCLUSION The 40 cm extensions with parietal connectors have the highest fracture risk and should be avoided. Postauricular connectors risk lead wire fracture and should be employed cautiously. The 60 cm parietal wires may reduce fracture risk but increase tethering risk.

scholarly journals Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System

2014 ◽  
Vol 99 (3) ◽  
pp. 861-870 ◽  
Author(s):  
Valerie F. Sidhoum ◽  
Yee-Ming Chan ◽  
Margaret F. Lippincott ◽  
Ravikumar Balasubramanian ◽  
Richard Quinton ◽  
...  
Keyword(s):  
Medical Center ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Academic Medical Center ◽  
Brain Magnetic Resonance Imaging ◽  
Magnetic Resonance Imaging Scan ◽  
Event Analysis ◽  
Neurokinin B ◽  
Olfactory Bulbs ◽  
History Of

Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieves activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. Objective: The objective of this study was to determine the natural history of reversal and to identify associated phenotypes and genotypes. Design, Setting, and Subjects: This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center. Main Outcome Measures: History of spontaneous fertility, regular menses, testicular growth, or normalization of serum sex steroids, LH secretory profiles, brain imaging findings, and sequences of 14 genes associated with IHH were reviewed. Results: Of 308 patients with IHH, 44 underwent reversal. Time-to-event analysis estimated a lifetime incidence of reversal of 22%. There were no differences in the rates of cryptorchidism, micropenis, or partial pubertal development in patients with reversal vs IHH patients without reversal. Fifteen patients with reversal (30%) had Kallmann syndrome (IHH and anosmia); one had undetectable olfactory bulbs on a brain magnetic resonance imaging scan. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared with a cohort of IHH patients without reversal (10% vs 3%, P = .044), had comparable frequencies of mutations in FGFR1, PROKR2, and GNRHR, and had no mutations in KAL1. Five men did not sustain their reversal and again developed hypogonadotropism. Conclusions: Reversal of IHH may be more widespread than previously appreciated and occurs across a broad range of genotypes and phenotypes. Enrichment for mutations that disrupt neurokinin B signaling in patients who reversed indicates that, despite the importance of this signaling pathway for normal pubertal timing, its function is dispensable later in life. The occurrence of reversal in a patient with no olfactory bulbs demonstrates that these structures are not essential for normal reproductive function. Patients with IHH require lifelong monitoring for reversal and, if reversal occurs, subsequent relapse also may occur.

scholarly journals Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations

2020 ◽  
Vol 105 (10) ◽  
pp. 3190-3202 ◽  
Author(s):  
Patrick C Hanley ◽  
Harsh S Kanwar ◽  
Corine Martineau ◽  
Michael A Levine
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Extended Family ◽  
Medical Center ◽  
Academic Medical Center ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Wild Type ◽  
Z Scores

Abstract Background NPR2 encodes atrial natriuretic peptide receptor B (ANPRB), a regulator of skeletal growth. Biallelic loss-of-function mutations in NPR2 result in acromesomelic dysplasia Maroteaux type (AMDM; OMIM 602875), while heterozygous mutations may account for 2% to 6% of idiopathic short stature (ISS). Objective Describe the physical proportions and growth characteristics of an extended family with novel NPR2 mutations including members with AMDM, ISS, or normal stature. Design and Participants We performed whole exome sequencing in 2 healthy parents and 2 children with AMDM. Detailed genotyping and phenotyping were performed on members of a multigenerational family in an academic medical center. We expressed mutant proteins in mammalian cells and characterized expression and function. Results The sisters with AMDM were compound heterozygotes for missense mutations in the NPR2 gene, a novel p.P93S (maternal) and the previously reported p.R989L (paternal). Both mutant ANPRB proteins were normally expressed in HEK293T cells and exhibited dominant negative effects on wild-type ANPRB catalytic activity. Heterozygous relatives had proportionate short stature (height z-scores −2.06 ± 0.97, median ± SD) compared with their wild-type siblings (−1.37 ± 0.59). Height z-scores progressively and significantly decreased as NPR2-heterozygous children matured, while remaining constant in their wild-type siblings. Conclusions Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature with by increasing loss of height potential with age.

scholarly journals Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction

2021 ◽  
Vol 12 ◽  
Author(s):  
Yoshihisa Uenoyama ◽  
Mayuko Nagae ◽  
Hitomi Tsuchida ◽  
Naoko Inoue ◽  
Hiroko Tsukamura
Keyword(s):  
Pulse Generator ◽  
Pulse Generation ◽  
G Protein Coupled Receptors ◽  
Historical Background ◽  
Dynorphin A ◽  
Neurokinin B ◽  
The Past ◽  
Kndy Neurons ◽  
G Protein Coupled

Increasing evidence accumulated during the past two decades has demonstrated that the then-novel kisspeptin, which was discovered in 2001, the known neuropeptides neurokinin B and dynorphin A, which were discovered in 1983 and 1979, respectively, and their G-protein-coupled receptors, serve as key molecules that control reproduction in mammals. The present review provides a brief historical background and a summary of our recent understanding of the roles of hypothalamic neurons expressing kisspeptin, neurokinin B, and dynorphin A, referred to as KNDy neurons, in the central mechanism underlying gonadotropin-releasing hormone (GnRH) pulse generation and subsequent tonic gonadotropin release that controls mammalian reproduction.

scholarly journals Mathematical modelling elucidates core mechanisms underpinning GnRH pulse generation

2018 ◽  
Author(s):  
Margaritis Voliotis ◽  
Xiao Feng Li ◽  
Ross De Burgh ◽  
Geffen Lass ◽  
Stafford L Lightman ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Pulse Generator ◽  
Low Frequency ◽  
Pulse Frequency ◽  
Pulse Generation ◽  
Frequency Model ◽  
Pulsatile Release ◽  
Basal Activity ◽  
Theoretical Evidence

SummaryFertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons co-expressing kisspeptin, neurokoinin-B and dynorphin that drives the pulsatile release of GnRH. How this neural network generates and controls the appropriate ultradian frequency essential for gametogenesis and ovulation is unknown. Here, we present a mathematical model of the GnRH pulse generator with theoretical evidence and in vivo experimental data showing that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low frequency optogenetic stimulation of the neural construct. Further increases in basal activity markedly increase pulse frequency. Model predictions that such behaviors are concomitant of non-linear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our mathematical model sheds light on the long-elusive GnRH pulse generator offering new horizons for fertility regulation.

Does the KNDy Model for the Control of Gonadotropin-Releasing Hormone Pulses Apply to Monkeys and Humans?

2019 ◽  
Vol 37 (02) ◽  
pp. 071-083 ◽  
Author(s):  
Michael N. Lehman ◽  
Wen He ◽  
Lique M. Coolen ◽  
Jon E. Levine ◽  
Robert L. Goodman
Keyword(s):  
Nonhuman Primates ◽  
Pulse Generator ◽  
Functional Organization ◽  
Current Knowledge ◽  
Pulse Generation ◽  
Gonadotropin Releasing Hormone ◽  
Neurokinin B ◽  
Releasing Hormone ◽  
Hormone Pulses ◽  
Kndy Neurons

AbstractThere is now considerable evidence supporting the role of a subpopulation of neurons in the arcuate nucleus of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (abbreviated as KNDy neurons) as the long sought-after gonadotropin-releasing hormone (GnRH) pulse generator. The “KNDy hypothesis” of pulse generation has largely been based on findings in rodents and ruminants, and there is considerably less information about the anatomical and functional organization of the KNDy subpopulation in the primate hypothalamus. In this review, we focus on the applicability of this hypothesis, and the roles of kisspeptin, neurokinin B, and dynorphin in reproduction, to humans and nonhuman primates, reviewing available data and pointing out important gaps in our current knowledge. With recent application of drugs that target KNDy peptides and their receptors to therapeutic treatments for reproductive disorders, it is imperative we fully understand the primate KNDy network and its role in the control of GnRH secretion, as well as species differences in this system that may exist between humans, nonhuman primates, and other mammals.

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