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  1. Neuroendocrine Regulation of Hydromineral Homeostasis
    Mecawi Ade S, Ruginsk SG, Elias LL, Varanda WA, Antunes-Rodrigues J
    Compr Physiol, 2015 Jul 1;5(3):1465-516.
    PMID: 26140725 DOI: 10.1002/cphy.c140031
    Since the crucial evolutionary change from an aqueous to a terrestrial environment, all living organisms address the primordial task of equilibrating the ingestion/production of water and electrolytes (primarily sodium) with their excretion. In mammals, the final route for the excretion of these elements is mainly through the kidneys, which can eliminate concentrated or diluted urine according to the requirements. Despite their primary role in homeostasis, the kidneys are not able to recover water and solutes lost through other systems. Therefore, the selective stimulation or inhibition of motivational and locomotor behavior becomes essential to initiate the search and acquisition of water and/or sodium from the environment. Indeed, imbalances affecting the osmolality and volume of body fluids are dramatic challenges to the maintenance of hydromineral homeostasis. In addition to behavioral changes, which are integrated in the central nervous system, most of the systemic responses recruited to restore hydroelectrolytic balance are accomplished by coordinated actions of the cardiovascular, autonomic and endocrine systems, which determine the appropriate renal responses. The activation of sequential and redundant mechanisms (involving local and systemic factors) produces accurate and self-limited effector responses. From a physiological point of view, understanding the mechanisms underlying water and sodium balance is intriguing and of great interest for the biomedical sciences. Therefore, the present review will address the biophysical, evolutionary and historical perspectives concerning the integrative neuroendocrine control of hydromineral balance, focusing on the major neural and endocrine systems implicated in the control of water and sodium balance.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/metabolism*; Hypothalamo-Hypophyseal System/physiology
  2. Fulltext Seasonal adaptations of the hypothalamo-neurohypophyseal system of the dromedary camel
    Alim FZD, Romanova EV, Tay YL, Rahman AYBA, Chan KG, Hong KW, et al.
    PLoS One, 2019;14(6):e0216679.
    PMID: 31211771 DOI: 10.1371/journal.pone.0216679
    The "ship" of the Arabian and North African deserts, the one-humped dromedary camel (Camelus dromedarius) has a remarkable capacity to survive in conditions of extreme heat without needing to drink water. One of the ways that this is achieved is through the actions of the antidiuretic hormone arginine vasopressin (AVP), which is made in a specialised part of the brain called the hypothalamo-neurohypophyseal system (HNS), but exerts its effects at the level of the kidney to provoke water conservation. Interestingly, our electron microscopy studies have shown that the ultrastructure of the dromedary HNS changes according to season, suggesting that in the arid conditions of summer the HNS is in an activated state, in preparation for the likely prospect of water deprivation. Based on our dromedary genome sequence, we have carried out an RNAseq analysis of the dromedary HNS in summer and winter. Amongst the 171 transcripts found to be significantly differentially regulated (>2 fold change, p value <0.05) there is a significant over-representation of neuropeptide encoding genes, including that encoding AVP, the expression of which appeared to increase in summer. Identification of neuropeptides in the HNS and analysis of neuropeptide profiles in extracts from individual camels using mass spectrometry indicates that overall AVP peptide levels decreased in the HNS during summer compared to winter, perhaps due to increased release during periods of dehydration in the dry season.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/metabolism; Hypothalamo-Hypophyseal System/physiology*; Hypothalamo-Hypophyseal System/ultrastructure
  3. Fulltext Parity and housing effects on the behavioural and hypothalamic-pituitary-adrenal axis responses of pregnant ewes
    Yusof NNM, Rutherford KMD, Jarvis S, Valente L, Dwyer CM
    Animal, 2023 Nov;17(11):101006.
    PMID: 37897868 DOI: 10.1016/j.animal.2023.101006
    It is common in many countries for sheep to be housed during winter from mid-gestation until lambing to protect ewes and lambs from adverse conditions and improve late gestation nutritional management. Keeping ewes indoors, however, has its own challenges as the animals may be mixed with unfamiliar conspecifics, have limited floor and feeding space, experience changes to their diet and increased handling by humans. Therefore, the objective of this study was to investigate the effect of variation in housing management (space allowance and social stability) on the behaviour and hypothalamic-pituitary-adrenal (HPA) axis responses of pregnant ewes from mid-to-late gestation (weeks 11-18 of pregnancy). Seventy-seven ewes (41 primiparous, 36 multiparous) were divided into two groups: 'Control' and 'Restricted space and mixed' (RS-Mix), where RS-Mix ewes were allocated half the amount of space (1.27 vs 2.5 m2 for RS-Mix and Control, respectively) and feedface (concentrate feeder space) allowance (36 vs 71 cm per ewe) given to the Control group and were also subjected to two social mixing events. Aggressive behaviour at the feedface and time spent standing, lying, walking, feeding and ruminating were recorded and faecal samples were collected for assessment of faecal glucocorticoid metabolite (FGM) concentrations. Higher aggression was observed in RS-Mix ewes during the first week of observation (P = 0.044), which gradually declined to the same level as Control ewes by the end of the study (P = 0.045). RS-Mix ewes were significantly less likely to be able to freely join the feedface compared to Controls (P = 0.022). No other significant treatment effects on aggressive behaviour or FGM during gestation were found. RS-Mix ewes displayed significantly higher ruminating behaviour at week 18 of gestation compared to Control ewes (P 
    Matched MeSH terms: Hypothalamo-Hypophyseal System*
  4. Fulltext Cortisol on Circadian Rhythm and Its Effect on Cardiovascular System
    Mohd Azmi NAS, Juliana N, Azmani S, Mohd Effendy N, Abu IF, Mohd Fahmi Teng NI, et al.
    Int J Environ Res Public Health, 2021 01 14;18(2).
    PMID: 33466883 DOI: 10.3390/ijerph18020676
    The synthesis and secretion of cortisol are controlled by the hypothalamic-pituitary-adrenal axis. Cortisol exhibits a proper 24-h circadian rhythm that affects the brain, the autonomic nervous system, the heart, and the vasculature that prepares the cardiovascular system for optimal function during these anticipated behavioral cycles. A literature search was conducted using databases such as Google Scholar, PubMed, and Scopus. Relevant search terms included "circadian rhythm and cardiovascular", "cortisol", "cortisol and acute coronary syndrome", "cortisol and arrhythmias", "cortisol and sudden cardiac death", "cortisol and stroke", and "cardioprotective agents". A total of 120 articles were obtained on the basis of the above search. Lower levels of cortisol were seen at the beginning of sleep, while there was a rise towards the end of sleep, with the highest level reached at the moment the individual wakes up. In the present review, we discuss the role of 11β-hydroxysteroid dehydrogenase (11β-HSD1), which is a novel molecular target of interest for treating metabolic syndrome and type-2 diabetes mellitus. 11β-HSD1 is the major determinant of cortisol excess, and its inhibition alleviates metabolic abnormalities. The present review highlights the role of cortisol, which controls the circadian rhythm, and describes its effect on the cardiovascular system. The review provides a platform for future potential cardioprotective therapeutic agents.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/metabolism
  5. Fulltext Exploring the Role and Potential of Probiotics in the Field of Mental Health: Major Depressive Disorder
    Johnson D, Thurairajasingam S, Letchumanan V, Chan KG, Lee LH
    Nutrients, 2021 May 20;13(5).
    PMID: 34065187 DOI: 10.3390/nu13051728
    The field of probiotic has been exponentially expanding over the recent decades with a more therapeutic-centered research. Probiotics mediated microbiota modulation within the microbiota-gut-brain axis (MGBA) have been proven to be beneficial in various health domains through pre-clinical and clinical studies. In the context of mental health, although probiotic research is still in its infancy stage, the promising role and potential of probiotics in various mental disorders demonstrated via in-vivo and in-vitro studies have laid a strong foundation for translating preclinical models to humans. The exploration of the therapeutic role and potential of probiotics in major depressive disorder (MDD) is an extremely noteworthy field of research. The possible etio-pathological mechanisms of depression involving inflammation, neurotransmitters, the hypothalamic-pituitary-adrenal (HPA) axis and epigenetic mechanisms potentially benefit from probiotic intervention. Probiotics, both as an adjunct to antidepressants or a stand-alone intervention, have a beneficial role and potential in mitigating anti-depressive effects, and confers some advantages compared to conventional treatments of depression using anti-depressants.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/microbiology
  6. A randomized controlled trial on the efficacy of resistant dextrin, as functional food, in women with type 2 diabetes: Targeting the hypothalamic-pituitary-adrenal axis and immune system
    Farhangi MA, Javid AZ, Sarmadi B, Karimi P, Dehghan P
    Clin Nutr, 2018 08;37(4):1216-1223.
    PMID: 28669666 DOI: 10.1016/j.clnu.2017.06.005
    OBJECTIVE: The aim of this trial was to determine the efficacy of a resistant dextrin on immune-mediated inflammation and hypothalamic-pituitary-adrenal axis in women with type 2 diabetes mellitus (T2DM).

    METHODS: Females (n = 55) with T2DM were randomly allocated into intervention group (n = 30) and control group (n = 25), in which they received 10 g/d of Nutriose®06 (a resistant dextrin) or maltodextrin for 8 weeks, respectively. Fasting blood samples were taken to measure immune system related parameters like white blood cell count, CD4, CD8, interferon-γ (IFNγ), interleukins (IL12, IL4, IL10), cortisol, tryptophan (TRP), ACTH (Adrenocorticotropic hormone), Kynurenine (KYN) and plasma lipopolysaccharide (LPS) at the beginning and end of trial. Mental health was assessed using general health questionnaire (GHQ) and depression, anxiety and stress scale (DASS).

    RESULTS: Resistant dextrin caused a significant decrease in levels of cortisol, KYN, KYN/TRP ratio, IFNγ, IL12, IFNγ/IL10 ratio, LPS, and a significant increase in the monocyte, GHQ, DASS, CD8, IL10, IL4 in the intervention group as compared with baseline. A significant decrease in the level of LPS (-6.20 EU/mL, -17.8%), IFNγ (-0.6 pg/ml, -26.8%), cortisol (-2.6 μg/dl, -20.9%), IFNγ/IL10 ratio (0.01, 10%), GHQ (-5.1, -12.5%), DASS (-10.4, -38.4%), KYN/TRP ratio (6.8, 29.1%), and a significant increase in levels of CD8 (6.4%, 6.1%) and IL10 (2.6 pg/ml, 21.6%) in the intervention group as compared with the control group (P  0.05).

    CONCLUSION: Supplementation of Nutriose®06 may have beneficial effects on mental health and the immune system response in women with T2DM.

    Matched MeSH terms: Hypothalamo-Hypophyseal System/physiology
  7. The effect of Eurycoma Longifolia on the regulation of reproductive hormones in young males
    Chan KQ, Stewart C, Chester N, Hamzah SH, Yusof A
    Andrologia, 2021 May;53(4):e14001.
    PMID: 33559971 DOI: 10.1111/and.14001
    Eurycoma longifolia supplementation increases testosterone levels in humans via activation of the hypothalamic-pituitary-gonadal axis and/or the hypothalamic-pituitary-adrenal axis mainly in older adults and nonhealthy populations. This study aimed to assess the impact of Eurycoma longifolia on the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes in healthy young males since this might promote functional testosterone prowess. Thirty-two males (24.4 ± 4.7 years; 1.74 ± 0.07 m; 73.7 ± 8.4 kg) in a placebo-controlled, double-blind, matched-paired study received 600 mg/day Eurycoma longifolia or placebo for two weeks. Blood analysis using repeated measures analysis of variance showed significant interaction and time effects for testosterone (F1,30  = 9.04, p = .005), free testosterone (F1,30  = 7.13, p = .012) and estradiol (F1,30  = 8.07, p = .008) levels in favour of the treatment group, while luteinising hormone, follicle-stimulating hormone and sexual hormone-binding globulin did not. The lack of changes in luteinising hormone and follicle-stimulating hormone levels suggests that a lesser role played by Eurycoma longifolia in activating the hypothalamic-pituitary-gonadal axis in the young adults. The raised testosterone level may be due to a greater rate of hormone production via the hypothalamic-pituitary-adrenal axis. The supplementation of Eurycoma longifolia for two weeks demonstrates steroidogenic effects on young men were dose-related. Consequently, the raised testosterone following Eurycoma longifolia supplementations could benefit muscle and strength gain in young adults.
    Matched MeSH terms: Hypothalamo-Hypophyseal System
  8. Acute serotonergic treatment changes the relation between anxiety and HPA-axis functioning and periaqueductal gray activation
    Hestermann D, Temel Y, Blokland A, Lim LW
    Behav Brain Res, 2014 Oct 15;273:155-65.
    PMID: 25043730 DOI: 10.1016/j.bbr.2014.07.003
    Serotonergic (5-HT) drugs are widely used in the clinical management of mood and anxiety disorders. However, it is reported that acute 5-HT treatment elicits anxiogenic-like behavior. Interestingly, the periaqueductal gray (PAG), a midbrain structure which regulates anxiety behavior - has robust 5-HT fibers and reciprocal connections with the hypothalamic-pituitary-adrenal (HPA) axis. Although the HPA axis and the 5-HT system are well investigated, the relationship between the stress hormones induced by 5-HT drug treatment and the PAG neural correlates of the behavior remain largely unknown. In this study, the effects of acute and chronic treatments with buspirone (BUSP) and escitalopram (ESCIT) on anxiety-related behaviors were tested in an open-field (OF). The treatment effects on PAG c-Fos immunoreactivity (c-Fos-ir) and corticosterone (CORT) concentration were measured in order to determine the neural-endocrine correlates of anxiety-related behaviors and drug treatments. Our results demonstrate that acute BUSP and ESCIT treatments induced anxiogenic behaviors with elevation of CORT compared to the baseline. A decrease of c-Fos-ir was found in the dorsomedial PAG region of both the treatment groups. Correlation analysis showed that the CORT were not associated with the OF anxiogenic behavior and PAG c-Fos-ir. No significant differences were found in behaviors and CORT after chronic treatment. In conclusion, acute BUSP and ESCIT treatments elicited anxiogenic response with activation of the HPA axis and reduction of c-Fos-ir in the dorsomedial PAG. Although no correlation was found between the stress hormone and the PAG c-Fos-ir, this does not imply the lack of cause-and-effect relationship between neuroendocrine effects and PAG function in anxiety responses. These correlation studies suggest that the regulation of 5-HT system was probably disrupted by acute 5-HT treatment.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/drug effects*
  9. Fulltext Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen
    Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ahmad AH
    ScientificWorldJournal, 2014;2014:310821.
    PMID: 24550703 DOI: 10.1155/2014/310821
    A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF) expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 17 β -estradiol (E2) on the depressive-like behaviour, stress hormones, and BDNF concentration in stressed ovariectomised (OVX) rats. The animals were divided into six groups: (i) nonstressed sham-operated control, (ii) stressed sham-operated control, (iii) nonstressed OVX, (iv) stressed OVX, (v) stressed OVX treated with E2 (20  μg daily, sc), and (vi) stressed OVX treated with Tualang honey (0.2 g/kg body weight daily, orally). Two months after surgery, the animals were subjected to social instability stress procedure followed by forced swimming test. Struggling time, immobility time, and swimming time were scored. Serum adrenocorticotropic hormone (ACTH) and corticosterone levels, and the BDNF concentration were determined using commercially available ELISA kits. Stressed OVX rats displayed increased depressive-like behaviour with significantly increased serum ACTH and corticosterone levels, while the BDNF concentration was significantly decreased compared to other experimental groups. These changes were notably reversed by both E2 and Tualang honey. In conclusion, both Tualang honey and E2 mediate antidepressive-like effects in stressed OVX rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis and enhancement of the BDNF concentration.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/physiology*
  10. Fulltext Neonatal feed restriction modulates circulating levels of corticosterone and expression of glucocorticoid receptor and heat shock protein 70 in aged Japanese quail exposed to acute heat stress
    Soleimani AF, Zulkifli I, Omar AR, Raha AR
    Poult Sci, 2011 Jul;90(7):1427-34.
    PMID: 21673157 DOI: 10.3382/ps.2011-01403
    This study aimed to determine the effect of neonatal feed restriction on plasma corticosterone concentration (CORT), hippocampal glucocorticoid receptor (GR) expression, and heat shock protein (Hsp) 70 expression in aged male Japanese quail subjected to acute heat stress. Equal numbers of chicks were subjected to either ad libitum feeding (AL) or 60% feed restriction on d 4, 5, and 6 (FR). At 21 (young) and 270 (aged) d of age, birds were exposed to 43 ± 1°C for 1 h. Blood and hippocampus samples were collected to determine CORT and Hsp 70 and GR expressions before heat stress and following 1 h of heat stress, 1 h of post-heat stress recovery, and 2 h of post-heat stress recovery. With the use of real-time PCR and enzyme immunoassay, we examined the hippocampal expression of GR and Hsp 70 and CORT. The GR expression of the young birds increased following heat stress and remained consistent throughout the period of recovery. Conversely, no significant changes were noted on GR expression of aged birds. Although both young and aged birds had similar CORT before and during heat stress, the latter exhibited greater values following 1 and 2 h of recovery. Within the young group, feeding regimens had no significant effect on Hsp 70 expression. However, neonatal feed restriction improved Hsp 70 expression in aged birds. Neonatal feed restriction, compared with the AL group, resulted in higher CORT on d 21 but the converse was noted on d 270. Neonatal feed restriction appears to set a robust reactive hypothalamo-pituitary-adrenal response allowing the development of adaptive, healthy, and resilient phenotypes in aged quail as measured by a higher hippocampal Hsp 70 expression along with lower CORT.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/physiology
  11. High prevalence of thyroid function test abnormalities in chronic schizophrenia
    Othman SS, Abdul Kadir K, Hassan J, Hong GK, Singh BB, Raman N
    Aust N Z J Psychiatry, 1994 Dec;28(4):620-4.
    PMID: 7794205
    The thyroid status of 249 patients with chronic schizophrenia (males = 136, females = 113) with a median age of 36 years (range: 16 to 58 years) and a median duration of hospitalisation of 10 years (range: 1 to 30 years) was assessed. Thyroid antibodies (TAb) were found in 51 patients (20%). In female patients, 32 (28%) were TAb positive compared to 13% (n = 152, p = 0.01) in healthy female blood donors. In male patients, the prevalence of TAb was 14% compared to 7% (n = 449, p = 0.01) in healthy male blood donors. Of the 183 patients who had thyroid hormone measurements, 60% had normal test, 5% had elevated TSH and 17% had low TSH. The T4, FT41 and FT31 were significantly lower in those with low or high TSH (p < 0.001) compared to those with normal TSH. Of the 143 patients with normal TSH, 33 (23%) had low T3. In conclusion, there is a spectrum of thyroid function test abnormalities in chronic schizophrenia; this may be related to an abnormality in the central regulation of the hypothalamo-pituitary thyroid axis as well as at the peripheral level. However the association between chronic schizophrenia and the presence of thyroid antibodies, and the clinical relevance of these biochemical abnormalities, are still not clear.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/physiopathology
  12. Discovering the Potentials of Medicinal Mushrooms in Combating Depression - A Review
    Lew SY, Teoh SL, Lim SH, Lim LW, Wong KH
    Mini Rev Med Chem, 2020;20(15):1518-1531.
    PMID: 32452327 DOI: 10.2174/1389557520666200526125534
    Depression is the most common form of mental illness and the major cause of disability worldwide. Symptoms of depression, including feelings of intense sadness and hopelessness, may occur after a specific event or in response to a gradual decline in health and functional status, often associated with aging. Current therapies for treating these symptoms include antidepressant drugs, counseling and behavioral therapy. However, antidepressant drugs are associated with mild to severe adverse effects, which has prompted the need for better treatment options. Medicinal mushrooms are valuable sources of food and medicine and are increasingly being used as supplements or as alternative medicines in standard healthcare. Numerous studies have provided insights into the neuroprotective effects of medicinal mushrooms, which are attributed to their antioxidant, anti-neuroinflammatory, cholinesterase inhibitory and neuroprotective properties. In this review, we comprehensively examine the role of these medicinal mushrooms in the treatment of depression. However, to apply these natural products in clinical settings, the therapeutic agent needs to be properly evaluated, including the active ingredients, the presence of synergistic effects, efficient extraction methods, and stabilization of the active ingredients for delivery into the body as well as crossing the blood-brain barrier.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/drug effects
  13. Fulltext Tualang honey exerts antioxidant and antidepressant-like effects in stress-exposed rats
    Khairunnuur Fairuz Azman, Rahimah Zakaria, Che Badariah Abdul Aziz, Zahiruddin Othman
    Malaysian Journal of Applied Sciences, 2019;4(1):15-25.
    MyJurnal
    Recent evidence has exhibited dietary influence on the manifestation of depressive-like behaviour induced by stressor tasks. The present study examined the effects of Tualang honey supplement administered with the goal of preventing or attenuating the occurrence of depressive-like behaviour in male rats subjected to noise stress. Forty-eight adult male rats were randomly divided into the following groups: i) nonstressed with placebo, ii) nonstressed with honey, iii) stressed with placebo, and iv) stressed with honey. Tualang honey (200 mg/kg body weight) was administered for 28 days. Stressed rats were subjected to loud noise 100 dB(A) 4 hours daily for 14 days. Forced swimming test was performed to evaluate depressive-like behaviour. Stressed control rats displayed significant increase in depressive-like behaviour, serum adrenocorticotropic hormone (ACTH), corticosterone, and brain oxidative stress markers levels, with significant decrease in antioxidant enzymes activities and total antioxidant status. Honey supplementation successfully counteracted the stress effects whereby the honey treated rats exhibited significant decrease in depressive-like behaviour and levels of ACTH, corticosterone, and oxidative stress markers, with significant increase in antioxidant enzymes activities and total antioxidant status. In conclusion, Tualang honey mediated antidepressant-like effects in stressed rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis through its antioxidant properties.
    Matched MeSH terms: Hypothalamo-Hypophyseal System
  14. Fulltext Sleep and Obesity
    Ding C, Lim LL, Xu L, Kong APS
    J Obes Metab Syndr, 2018 Mar 30;27(1):4-24.
    PMID: 31089536 DOI: 10.7570/jomes.2018.27.1.4
    Rising global prevalence and incidence of obesity lead to increased cardiovascular-renal complications and cancers. Epidemiological studies reported a worldwide trend towards suboptimal sleep duration and poor sleep quality in parallel with this obesity epidemic. From rodents and human models, it is highly plausible that abnormalities in sleep, both quantity and quality, impact negatively on energy metabolism. While excess dietary intake and physical inactivity are the known drivers of the obesity epidemic, promotion of healthy sleep habits has emerged as a new target to combat obesity. In this light, present review focuses on the existing literature examining the relationship between sleep physiology and energy homeostasis. Notably, sleep dysregulation perturbs the metabolic milieu via alterations in hormones such as leptin and ghrelin, eating behavior, neuroendocrine and autonomic nervous systems. In addition, shift work and trans-meridian air travel may exert a negative influence on the hypothalamic-pituitary-adrenal axis and trigger circadian misalignment, leading to impaired glucose tolerance and increased fat accumulation. Amassing evidence has also suggested that uncoupling of the circadian clock can increase the risk of adverse metabolic health. Given the importance of sleep in maintaining energy homeostasis and that it is potentially modifiable, promoting good sleep hygiene may create new avenues for obesity prevention and treatment.
    Matched MeSH terms: Hypothalamo-Hypophyseal System
  15. Fulltext Osmoregulation requires brain expression of the renal Na-K-2Cl cotransporter NKCC2
    Konopacka A, Qiu J, Yao ST, Greenwood MP, Greenwood M, Lancaster T, et al.
    J Neurosci, 2015 Apr 01;35(13):5144-55.
    PMID: 25834041 DOI: 10.1523/JNEUROSCI.4121-14.2015
    The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABA-mediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/cytology; Hypothalamo-Hypophyseal System/drug effects; Hypothalamo-Hypophyseal System/metabolism*
  16. Hypothalamic pituitary dysfunction amongst nasopharyngeal cancer survivors
    Ratnasingam J, Karim N, Paramasivam SS, Ibrahim L, Lim LL, Tan AT, et al.
    Pituitary, 2015 Aug;18(4):448-55.
    PMID: 25134488 DOI: 10.1007/s11102-014-0593-6
    PURPOSE: Radiation fields for nasopharyngeal cancer (NPC) include the base of skull, which places the hypothalamus and pituitary at risk of damage. We aimed to establish the prevalence, pattern and severity of hypothalamic pituitary (HP) dysfunction amongst NPC survivors.

    METHODS: We studied 50 patients (31 males) with mean age 57 ± 12.2 years who had treatment for NPC between 3 and 21 years (median 8 years) without pre-existing HP disorder from other causes. All patients had a baseline cortisol, fT4, TSH, LH, FSH, oestradiol/testosterone, prolactin and renal function. All patients underwent dynamic testing with insulin tolerance test to assess the somatotroph and corticotroph axes. Baseline blood measurements were used to assess thyrotroph, gonadotroph and lactotroph function.

    RESULTS: Hypopituitarism was present in 82% of patients, 30% single axis, 28% two axes, 18% three axes and 6% four axes deficiencies. Somatotroph deficiency was most common (78%) while corticotroph, gonadotroph and thyrotroph deficiencies were noted in 40% (4 complete/16 partial), 22 and 4% of the patients respectively. Hyperprolactinaemia was present in 30% of patients. The development of HP dysfunction was significantly associated with the time elapsed from irradiation, OR 2.5 (1.2, 5.3), p = 0.02, for every 2 years post treatment. The use of concurrent chemo-irradiation (CCRT) compared to those who had radiotherapy alone was also significantly associated with HP dysfunction, OR 14.5 (2.4, 87.7), p < 0.01.

    CONCLUSION: Despite low awareness and detection rates, HP dysfunction post-NPC irradiation is common. Use of CCRT may augment time related pituitary damage. As these endocrinopathies result in significant morbidity and mortality we recommend periodic assessment of pituitary function amongst NPC survivors.

    Matched MeSH terms: Hypothalamo-Hypophyseal System*
  17. Fulltext 5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats
    Brunton PJ, Donadio MV, Yao ST, Greenwood M, Seckl JR, Murphy D, et al.
    J Neurosci, 2015 Jan 14;35(2):666-77.
    PMID: 25589761 DOI: 10.1523/JNEUROSCI.5104-13.2015
    Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β; IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3β-androstanediol (3β-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.
    Matched MeSH terms: Hypothalamo-Hypophyseal System/drug effects*; Hypothalamo-Hypophyseal System/growth & development
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