Pattern Of Pulsatile Secretion Research Articles

9318 Growth Response To Oral Growth Hormone Secretagogue LUM-201 In Children With Moderate GH Deficiency (GHD) Is Dependent On The Pattern Of Pulsatile GH Secretion Induced By LUM-201

Abstract Disclosure: A. Roslan: None. R. Roman: None. A. Avila: None. D. Said: None. I. Baier: None. E. Brincks: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P. Pitukcheewanont: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc.. M. Johnson: None. T. Garner: Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P.E. Clayton: Advisory Board Member; Self; Lumos Pharma, Inc.. Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. A. Stevens: Consulting Fee; Self; Lumos Pharma, Inc. F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc.. Background: Oral GH secretagogue, LUM-201, increases growth rates in children with moderate GHD in Phase 2 trials (OraGrowtH210 and 212) [ENDO 2023, OR21-06]. GH pulse profiles at baseline (D1) and 6 months (6M) were assessed in OraGrowtH212. This study aims to understand relationships between pulse profiles and growth response to LUM-201. Methods: The OraGrowtH212 trial is being conducted at a single site (Chile). 22 prepubertal children (M 14: F 8) with moderate GHD (peak GH level on two stimulation tests >3 and <10ng/ml), who had basal IGF-I >30ng/ml and an acute GH response to 0.8mg/kg LUM-201 of ≥5ng/ml, were randomised to receive LUM-201 1.6 or 3.2 mg/kg/day. 10min samples over 12hrs (08.00-20.00) were collected at D1 and M6 for measurement of GH concentration (ng/ml), with GH secretion rates (ng/ml/min) derived by deconvolution analysis. A univariate Spearman’s rank correlation matrix was used to screen for relationships (significant at p<0.05) between D1 characteristics, D1 height velocity, 6M annualised height velocity (AHV) and interpulse, pulsatile and total GH secretion at D1 and M6.The pattern of pulsatile GH secretion in the 12hr profile was characterised using Functional Principal Component Analysis (FPCA) - used to explore the dominant modes of variation in functional data, in this case the GH time series. Subjects were grouped into tertiles based on 6M AHV (High [mean 8.9cm/yr], Medium [7.7], and Low [6.7]), and the 12hr profiles were divided into three 4hr intervals. The interquartile range (IQR) for mean GH secretion (representing variation in amount) and principal components [PCs] (variation in pattern) for all subjects in each AHV tertile at D1 and M6 were generated. Results: All GH secretion parameters increased significantly from D1 to M6 (p<0.01). Age was negatively associated with 6m AHV (rs= -0.46), and D1 pulsatile GH secretion was positively associated with D1 AHV (rs = +0.51). However, GH secretion at D1 and M6 was not correlated with 6m AHV. In the FPCA, the difference in IQR for mean GH secretion from D1 to 6M was highest over 0-4hrs for subjects in the high and medium AHV tertiles (5- and 3.3-fold greater respectively compared to the other time intervals), while subjects with low AHV had the highest difference over 8-12hrs (42-fold greater). Using the first PC (which accounts for ∼50% of total variation), the change in IQR was highest over 0-4 and 4-8hrs in the high AHV tertile (3-fold greater compared to other time intervals), over 0-4hrs in the medium tertile (46-fold greater) and over 8-12hrs in the low tertile (3.4-fold greater). Conclusions: Oral LUM-201 stimulates significant increases in GH secretion over 6 months in children with moderate GH deficiency. Complex relationships exist between growth response and both the amount and pattern of GH secretion, with the highest growth responses to LUM-201 associated with the greatest pulsatile activity early in the profile. Presentation: 6/3/2024

TSH Pulses Finely Tune Thyroid Hormone Release and TSH Receptor Transduction.

Detection of circulating TSH is a first-line test of thyroid dysfunction, a major health problem (affecting about 5% of the population) that, if untreated, can lead to a significant deterioration of quality of life and adverse effects on multiple organ systems. Human TSH levels display both pulsatile and (nonpulsatile) basal TSH secretion patterns; however, the importance of these in regulating thyroid function and their decoding by the thyroid is unknown. Here, we developed a novel ultra-sensitive ELISA that allows precise detection of TSH secretion patterns with minute resolution in mouse models of health and disease. We characterized the patterns of ultradian TSH pulses in healthy, freely behaving mice over the day-night cycle. Challenge of the thyroid axis with primary hypothyroidism because of iodine deficiency, a major cause of thyroid dysfunction worldwide, results in alterations of TSH pulsatility. Induction in mouse models of sequential TSH pulses that mimic ultradian TSH profiles in periods of minutes were more efficient than sustained rises in basal TSH levels at increasing both thyroid follicle cAMP levels, as monitored with a genetically encoded cAMP sensor, and circulating thyroid hormone. Hence, this mouse TSH assay provides a powerful tool to decipher how ultradian TSH pulses encode thyroid outcomes and to uncover hidden parameters in the TSH-thyroid hormone set-point in health and disease.

Effects of PTH glandular and external dosing patterns on bone cell activity using a two-state receptor model-Implications for bone disease progression and treatment.

Temporal aspects of ligand specificity have been shown to play a significant role in the case of pulsatile hormone secretion, as exemplified by parathyroid hormone (PTH) binding to its receptor (PTH1R), a G-protein-coupled receptor expressed on surfaces of osteoblasts and osteocytes. The latter binding reaction regulates intracellular signalling and subsequently modulates skeletal homeostasis via bone remodelling. PTH glandular secretion patterns dictate bone cellular activity. In healthy humans, 70% of PTH is secreted in a tonic fashion, whereas 30% is secreted in low-amplitude and high-frequency bursts occurring every 10-20 min, superimposed on the tonic secretion. Changes in the PTH secretion patterns have been associated with various bone diseases. In this paper, we analyse PTH glandular secretion patterns for healthy and pathological states and their link to bone cellular responsiveness (αR). We utilise a two-state receptor ligand binding model of PTH to PTH1R together with a cellular activity function which is able to distinguish various aspects of the stimulation signal including peak dose, time of ligand exposure, and exposure period. Formulating and solving several constrained optimisation problems, we investigate the potential of pharmacological manipulation of the diseased glandular secretion and via clinical approved external PTH injections to restore healthy bone cellular responsiveness. Based on the mean experimentally reported data, our simulation results indicate cellular responsiveness in healthy subjects is sensitive to the tonic baseline stimulus and it is 28% of the computed maximum responsiveness. Simulation results for pathological cases of glucocorticoid-induced osteoporosis, hyperparathyroidism, initial and steady state hypocalcemia clamp tests indicate αR values significantly larger than the healthy baseline (1.7, 2.2, 4.9 and 1.9-times, respectively). Manipulation of the pulsatile glandular secretion pattern, while keeping the mean PTH concentration constant, allowed restoration of healthy baseline values from these catabolic bone diseases. Conversely, PTH glandular diseases that led to maximum bone cellular responsiveness below the healthy baseline value can't be restored to baseline via glandular manipulation. However, external PTH injections allowed restoration of these latter cases.

Pulsatile gonadotropin-releasing hormone: clinical applications of a physiologic paradigm

Gonadotropin-releasing hormone (GnRH) is a fundamental driver of human reproduction. A pulsatile pattern of GnRH secretion is essential to achieve pituitary stimulation, gonadotropin secretion, and normal gonadal function. Pulsatile GnRH administration is used to treat anovulation and male hypogonadotropic hypogonadism. Pulsatile GnRH ovulation induction is effective and safe because it allows to avoid ovarian hyperstimulation syndrome and reduce the occurrence of multiple pregnancies. This physiology-inspired therapeutic tool has also permitted to elucidate several pathophysiologic features of human reproductive disorders.

Transcriptional and cell type profiles of cortical brain regions showing ultradian cortisol rhythm dependent responses to emotional face stimulation

The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling – the ANXA1 gene and retrograde endocannabinoid signaling – show most significant differential expression (q = 3.99e−10) and enrichment (fold enrichment = 5.56, q = 9.09e−4). Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies.

Effect of Growth Hormone Secretagogue Receptor Deletion on Growth, Pulsatile Growth Hormone Secretion, and Meal Pattern in Male and Female Mice

Introduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5–6 weeks old) or adult (10–19 weeks old) GHS-R KO (Ghsr−/−) and WT (Ghsr+/+) male and female mice. Results: Adult Ghsr−/− male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr−/− mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr−/− females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females.

An integrate-and-fire model for pulsatility in the neuroendocrine system.

A model for pulsatility in neuroendocrine regulation is proposed which combines Goodwin-type feedback control with impulsive input from neurons located in the hypothalamus. The impulsive neural input is modeled using an integrate-and-fire mechanism; namely, inputs are generated only when the membrane potential crosses a threshold, after which it is reset to baseline. The resultant model takes the form of a functional-differential equation with continuous and impulsive components. Despite the impulsive nature of the inputs, realistic hormone profiles are generated, including ultradian and circadian rhythms, pulsatile secretory patterns, and even chaotic dynamics.

Rhythmic growth hormone secretion in physiological and pathological conditions: Lessons from rodent studies

Evolutionally conserved in all mammalians, the release of GH occurs in a rhythmic pattern, characterized by several dominant surges (pulsatile GH) with tonic low inter-pulse levels (tonic GH). Such pulsatile secretion pattern is essential for many physiological actions of GH on different tissues with defined gender dimorphism. Rhythmic release of pulsatile GH is tightly controlled by hypothalamic neurons as well as peripheral metabolic factors. Changes of GH pattern occur within a range of sophisticated physiological and pathological settings and significantly contribute to growth, ageing, survival and disease predispositions. Precise analysis of GH secretion pattern is vitally important for a comprehensive understanding of the function of GH and the components that regulate GH secretion pattern.

Electrophysiological approach to the hypothalamic GnRH pulse generator

The hypothalamic GnRH pulse generator that regulates intermittent GnRH discharge into the pituitary portal circulation and thereby modulates pulsatile secretion of LH has been recognized as a key determinant of the reproductive function in mammals. Thus, various internal, as well as external, factors first modify the electrical activity of the GnRH pulse generator, which then alters the pulsatile pattern of gonadotrophin secretion and eventually influences reproductive function. Here, we describe a procedure that has permitted long-term recording of electrophysiological manifestation of the GnRH pulse generator activity and its application to our research which uses ovariectomized and cyclic female goats as experimental models. We have successfully recorded characteristic increases in neuronal activity associated with pulsatile LH secretion from conscious goats by means of a multiple unit activity (MUA) recording technique, which is an adaptation of that developed originally for use in rhesus monkeys. The unitary relationship between periodical increases in MUA (MUA volleys) and LH pulses is well maintained under a variety of experimental conditions, providing evidence that these MUA volleys are the consequence of GnRH pulse generator activity.

Frequent Tail-tip Blood Sampling in Mice for the Assessment of Pulsatile Luteinizing Hormone Secretion.

In many endocrine systems, circulating factors or hormones are not released continuously, but are secreted as a discrete pulse in response to a releasing factor. Single-point sampling measures are inadequate to fully understand the biological significance of the secretory pattern of pulsatile hormones either under normal physiologic conditions or during conditions of dysregulation. Luteinizing hormone (LH) is synthesized by the anterior pituitary gonadotropecells and secreted in a pulsatile pattern which requires frequent collection of blood samples for pulse assessment. This has not been possible in mice until recently, due to the development of a high-sensitivity LH assay and advancement in a technique for frequent low-volume sample collection, initially described by Steyn and colleagues.1 Here we describe a protocol for the frequent peripheral blood sample collection from mice with sufficient handling acclimatization to detect pulsatile secretion of LH. The current protocol details an expanded acclimatization period that allows assessment of robust and continuous pulses of LH over multiple hours. In this protocol, the tip of the tail is clippedand blood is collected from the tail using a hand-held pipette. For assessment of pulsatile LH in gonadectomized mice, serial samples are collected every 5-6 min for 90-180 min. Importantly, the collection of blood and measurement of robust pulses of LH can be accomplished in awake, freely behaving mice, given adequate handling acclimatization and effort to minimize environmental stressors. Sufficient acclimatization can be achieved within 4-5 weeks prior to blood collection. This protocol highlights advances in the methodology to ensure collection of whole blood samples for assessment of pulsatile LH secretion patterns over multiple hours in the mouse, a powerful animal model for neuroendocrine research.

Oxytocin secretion is pulsatile in men and is related to social-emotional functioning

The hypothalamic hormone oxytocin (OXT) plays an important role in a range of physiological processes and social-emotional functioning in both sexes. In women, physiological stimuli, such as suckling and parturition, result in pulsatile release of OXT into the peripheral circulation via the posterior pituitary gland. However, data regarding OXT secretory patterns in men during a state of rest are limited. Further, the relationship between secretory dynamics of OXT and emotional measures has never been evaluated. We hypothesized a pulsatile pattern of OXT secretion in men, and explored the relationship between OXT secretory patterns and social-emotional functioning. MethodsDeconvolution analysis was performed on serum OXT levels obtained every 5min over a period of 10h in 5 healthy normal weight men. Area under the curve (AUC), average OXT values, and pulse characteristics [pulse number, inter-pulse interval, pulse height and mass (area under each pulse)] were calculated. State Adult Attachment Measure (SAAM) assessed types of human attachment. Interpersonal Support Evaluation List (ISEL) assessed perception of social support. Toronto Alexithymia Scale (TAS-20) measured the ability to express and identify one’s own emotions. ResultsMean age was 22.8±1.2years, and BMI was 21.7±0.4kg/m2 (mean±SEM). Assuming a basal secretion of zero and a half life of five to seven minutes, we demonstrated the following: OXT AUC: 5421±1331pg/ml, mean OXT level: 9.1pg/ml, mean pulse number: 22±3/10hr, mean pulse height: 1.81±0.48pg/ml, mean pulse mass: 30.34±10.29pg/ml and mean inter-pulse interval: 27±4min. The SAAM Avoidant scale correlated negatively with mean OXT pulse height (r=−0.90, p=0.04) and pulse mass (r=−0.95, p=0.01). The ISEL Belonging score correlated positively with OXT AUC (r=0.89, p=0.04) and average OXT (r=0.93, p=0.02). ISEL Appraisal score also had a positive association with mean OXT pulse height (r=0.99, p=0.0006) and pulse mass (r=0.98, p=0.003). Finally, ISEL total score had a significant correlation with average OXT values (r=0.90, p=0.04). While none of the subjects had a score in the alexithymia range, TAS-20 Difficulty describing feelings score had an inverse correlation with OXT pulse height (r=−0.96, p=0.01) and pulse mass (r=−0.99, p=0.001). TAS-20 total score also had an inverse correlation with OXT pulse height (r=−0.94, p=0.02) and pulse mass (r=−0.96, p=0.009). ConclusionWe demonstrate a pulsatile pattern of peripheral OXT secretion in healthy men at rest. Subjects with lower OXT pulse height and pulse mass had a more avoidant style of attachment, felt less supported, and expressed greater difficulty in describing their feelings. Our findings support the concept that OXT is a key mediator of social-emotional functioning. Future studies to determine causality are warranted.

Temporary undernutrition during early gestation, corpora lutea morphometrics, ovarian progesterone secretion and embryo survival in gilts.

The present study reports effects of severe undernutrition on luteal function and pregnancy in pigs. Gilts were inseminated and either fasted on Day 10 and 11 after conception (n=11) or fully fed throughout (n=10). Fasting did not affect LH or progesterone pulsatile secretion pattern on Day 11 in samples taken from blood vessels draining an ovary. Ultrasonographic measurements of the size of the corpora lutea did not show any effect of fasting either. However, fasted gilts had 10 to 30% lower systemic progesterone from Day 12 through Day 15 after conception (P<0.05). All gilts farrowed, but fasted gilts had fewer born piglets than fully fed gilts (8.8±0.8 vs 10.9±0.5 respectively; P<0.05). In conclusion, fasting during embryo elongation can compromise embryonic survival by affecting ovarian function in the days after fasting, without having an immediate effect on LH secretion and progesterone output by the ovaries.

Sequence analysis, tissue distribution and molecular physiology of the GnRH preprogonadotrophin in the South American plains vizcacha (Lagostomus maximus)

Gonadotropin-releasing hormone (GnRH) is the regulator of the hypothalamic-hypophyseal-gonadal (HHG) axis. GnRH and GAP (GnRH-associated protein) are both encoded by a single preprohormone. Different variants of GnRH have been described. In most mammals, GnRH is secreted in a pulsatile manner that stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The South-American plains vizcacha, Lagostomus maximus, is a rodent with peculiar reproductive features including natural poly-ovulation up to 800 oocytes per estrous cycle, pre-ovulatory follicle formation throughout pregnancy and an ovulatory process which takes place at mid-gestation and adds a considerable number of secondary corpora lutea. Such features should occur under a special modulation of the HHG axis, guided by GnRH. The aim of this study was to sequence hypothalamic GnRH preprogonadotrophin mRNA in the vizcacha, to compare it with evolutionarily related species and to identify its expression, distribution and pulsatile pattern of secretion. The GnRH1variant was detected and showed the highest homology with that of chinchilla, its closest evolutionarily related species. Two isoforms of transcripts were identified, carrying the same coding sequence, but different 5′ untranslated regions. This suggests a sensitive equilibrium between RNA stability and translational efficiency. A predominant hypothalamic localization and a pulsatile secretion pattern of one pulse of GnRH every hour were found. The lower homology found for GAP, also among evolutionarily related species, depicts a potentially different bioactivity.

60 YEARS OF NEUROENDOCRINOLOGY: Glucocorticoid dynamics: insights from mathematical, experimental and clinical studies.

A pulsatile pattern of secretion is a characteristic of many hormonal systems, including the glucocorticoid-producing hypothalamic-pituitary-adrenal (HPA) axis. Despite recent evidence supporting its importance for behavioral, neuroendocrine and transcriptional effects of glucocorticoids, there has been a paucity of information regarding the origin of glucocorticoid pulsatility. In this review we discuss the mechanisms regulating pulsatile dynamics of the HPA axis, and how these dynamics become disrupted in disease. Our recent mathematical, experimental and clinical studies show that glucocorticoid pulsatility can be generated and maintained by dynamic processes at the level of the pituitary-adrenal axis, and that an intra-adrenal negative feedback may contribute to these dynamics.

Cortisol secretion in response to metabolic and inflammatory challenges in dairy cows.

Cortisol in dairy cows is released in an episodic manner underlying a circadian rhythm. The involvement of cortisol in numerous adaptive processes to cope with adverse conditions such as pain and inflammation is well characterized. Recent studies described contradictory effects of nutrition and metabolism on the secretory pattern of cortisol. However, up to now, the direct effects of single metabolites during various metabolic conditions without the profound endocrine changes around parturition on the glucocorticoid secretion in dairy cows have not been described. The objective of this study was to investigate the effects of long-term (56-h) manipulated metabolic states, that is, manipulated plasma concentrations of glucose and β-hydroxybutyrate (BHBA), on the release of cortisol in midlactation dairy cows. Besides the concentration of cortisol at defined time points, its pulsatile secretory pattern was studied in combination with an acute immune challenge through an intramammary lipopolysaccharide (LPS) challenge. Twenty-five midlactation dairy cows were randomly assigned to 1 of 4 treatments (hyperinsulinemic hypoglycemic clamp [HypoG], hyperinsulinemic–euglycemic clamp [EuG], continuous infusion of BHBA [HyperB], or infusion of saline solution for the control group [Control). Different metabolic states induced by infusion treatments affected the characteristics of cortisol secretion (elevation of baseline [the HypoG and HyperB treatments] and decreased peak length [the HypoG treatment]; P < 0.05), whereas amplitude, peak interval, height, peak area, area under the curve (AUC) above the baseline cortisol concentration (AUCb), and the total AUC (AUCt) were not different between infusion treatments. The induced inflammatory response due to the intramammary LPS challenge at simultaneously maintained infusion treatments diminished the pulsatile nature of cortisol release, whereas AUCb (and AUCt, respectively) was lowest for the HypoG treatment compared with the HyperB and Control treatments (P < 0.05). This study indicates that single metabolites (glucose and BHBA) and their availability or turnover (in case of glucose) have a different impact on the regulation of cortisol secretion resulting in changes of its pulsatile release. Furthermore, cortisol release during intramammary inflammation was found to be greater in the HyperB, EuG, and Control treatments compared with the HypoG treatment (P < 0.05). This finding emphasizes the regulatory role of the current metabolic status on the cortisol release during inflammation.

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years.

At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.

Twenty-Hour Growth Hormone Secretory Profiles after Aerobic and Resistance Exercise

The pulsatile secretion pattern of growth hormone (GH) is an important parameter of GH action at peripheral tissues, and more information is needed on how exercise impacts GH secretion. This study hypothesized that both aerobic and resistance exercise would exhibit dose-response relationships with respect to exercise duration and 20-h postexercise GH secretion. Eight healthy men randomly completed five separate conditions: 1) control (no exercise; CON), 2) a moderate-duration (1-h) aerobic exercise session (MA), 3) a long-duration (2-h) aerobic exercise session (LA), 4) a moderate-duration (1-h) resistance exercise session (MR), and 5) a long-duration (2-h) resistance exercise session (LR). Exercise intensity, diet, sleep, and physical activity were strictly controlled during each condition, and blood was sampled postexercise every 20 min for 20 h, and GH secretion parameters were analyzed via cluster and deconvolution analyses. Only the 2-h aerobic exercise bout resulted in a significant amplification of GH secretion as evidenced by increases in GH burst peak amplitude (∼100%), basal GH secretion rate (∼127%), total GH basal secretion (∼120%), total pulsatile secretion (∼88%), and total GH secretion (∼89%) over the control (i.e., no exercise) condition. GH secretions for the resistance exercise conditions were not different from control. The fact that the 2-h aerobic exercise condition resulted in higher energy expenditure than the other exercise conditions could offer a partial explanation for the greater GH amplification because of the metabolic effects that GH exerts in stimulating postexercise lipolysis. We conclude that extending the duration of aerobic exercise, but not resistance exercise, from 1- to 2-h significantly amplifies GH secretion during a 20-h period.

Effects of gonadoliberin analogue triptorelin on the pituitary-testicular complex in neonatal rats.

Triptorelin, a synthetic analogue of neurohormone gonadoliberin (gonadotropin-releasing hormone, GnRH) administered daily to rats on postnatal days 5-7 suppressed the expression of GnRH receptor in the pituitary gland, but did not change functioning of the pituitary-testicular complex. Administration of triptorelin on postnatal days 12-14 (i.e. during the formation of pulsatile pattern of GnRH secretion and increasing levels of its mRNA receptor in the pituitary gland) had no effect on receptor expression, but increased the levels of luteinizing hormone mRNA in the pituitary gland and the weight of testes. At that time, blood levels of testosterone were lowered, which indicated disturbed pulsatile pattern of GnRH secretion.

Contribution of Glucocorticoids and Glucocorticoid Receptors to the Regulation of Neurodegenerative Processes

Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR) and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in neurodegenerative disorders. Patients with Alzheimer's or Parkinson's or Huntington's disease show chronically high cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However, recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity and find ways to harness their protective actions.

A Network Model of the Periodic Synchronization Process in the Dynamics of Calcium Concentration in GnRH Neurons

Mathematical neuroendocrinology is a branch of mathematical neurosciences that is specifically interested in endocrine neurons, which have the uncommon ability of secreting neurohormones into the blood. One of the most striking features of neuroendocrine networks is their ability to exhibit very slow rhythms of neurosecretion, on the order of one or several hours. A prototypical instance is that of the pulsatile secretion pattern of GnRH (gonadotropin releasing hormone), the master hormone controlling the reproductive function, whose origin remains a puzzle issue since its discovery in the seventies. In this paper, we investigate the question of GnRH neuron synchronization on a mesoscopic scale, and study how synchronized events in calcium dynamics can arise from the average electric activity of individual neurons. We use as reference seminal experiments performed on embryonic GnRH neurons from rhesus monkeys, where calcium imaging series were recorded simultaneously in tens of neurons, and which have clearly shown the occurrence of synchronized calcium peaks associated with GnRH pulses, superposed on asynchronous, yet oscillatory individual background dynamics. We design a network model by coupling 3D individual dynamics of FitzHugh–Nagumo type. Using phase-plane analysis, we constrain the model behavior so that it meets qualitative and quantitative specifications derived from the experiments, including the precise control of the frequency of the synchronization episodes. In particular, we show how the time scales of the model can be tuned to fit the individual and synchronized time scales of the experiments. Finally, we illustrate the ability of the model to reproduce additional experimental observations, such as partial recruitment of cells within the synchronization process or the occurrence of doublets of synchronization.