193 results found
Abbara A, Clarke S, Islam R, et al., 2018, Reply: Clinical trial registry alone is not adequate: on the perception of possible endpoint switching and P-hacking., Hum Reprod, Vol: 33, Pages: 342-344
Algeffari M, Jayasena CN, MacKeith P, et al., 2018, Testosterone therapy for sexual dysfunction in men with Type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials, DIABETIC MEDICINE, Vol: 35, Pages: 195-202, ISSN: 0742-3071
Cassatella D, Howard S, Acierno J, et al., 2018, Congenital Hypogonadotropic Hypogonadism and Constitutional Delay of Growth and Puberty Have Distinct Genetic Architectures., Eur J Endocrinol
OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated with CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. METHODS: Exome sequencing data was used to identify rare variants in known genes in CHH (n=116), CDGP (n=72), and control cohorts (n=36,874 ExAC and n=405 CoLaus). RESULTS: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, p=7.6x10-11) or controls (18%, p=5.5x10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, p=0.002) and controls (2%, p=6.4x10-7). CONCLUSIONS: Our data suggests that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.
Owens LA, Abbara A, Lerner A, et al., 2018, The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function., Hum Reprod, Vol: 33, Pages: 292-302
STUDY QUESTION: What are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation? SUMMARY ANSWER: The use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS. WHAT IS KNOWN ALREADY: hCG is the most widely used trigger of oocyte maturation, but is associated with an increased risk of OHSS. The use of GnRH agonists to trigger oocyte maturation is a safer alternative to hCG. More recently, kisspeptin-54 has emerged as a novel therapeutic option that safely triggers oocyte maturation even in women at high risk of OHSS. Kisspeptin indirectly stimulates gonadotropin secretion by acting on hypothalamic GnRH neurons. Kisspeptin and its receptor are also expressed in the human ovary, but there is limited data on the direct action of kisspeptin on the ovary. STUDY DESIGN SIZE, DURATION: Forty-eight women undergoing IVF treatment for infertility consented to kisspeptin-54 triggering and/or granulosa cell collection and were included in the study. Twelve women received hCG, 12 received GnRH agonist and 24 received kisspeptin-54 to trigger oocyte maturation. In the kisspeptin-54 group, 12 received one injection of kisseptin-54 (9.6 nmol/kg) and 12 received two injections of kisspeptin-54 at a 10 h interval (9.6 nmol/kg × 2). PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was aspirated and pooled from follicles during the retrieval of oocytes for IVF/ICSI. GL
Takács S, Bardóczi Z, Skrapits K, et al., 2018, Post mortem single-cell labeling with DiI and immunoelectron microscopy unveil the fine structure of kisspeptin neurons in humans., Brain Struct Funct
Kisspeptin (KP) synthesizing neurons of the hypothalamic infundibular region are critically involved in the central regulation of fertility; these cells regulate pulsatile gonadotropin-releasing hormone (GnRH) secretion and mediate sex steroid feedback signals to GnRH neurons. Fine structural analysis of the human KP system is complicated by the use of post mortem tissues. To gain better insight into the neuroanatomy of the somato-dendritic cellular compartment, we introduced the diolistic labeling of immunohistochemically identified KP neurons using a gene gun loaded with the lipophilic dye, DiI. Confocal microscopic studies of primary dendrites in 100-µm-thick tissue sections established that 79.3% of KP cells were bipolar, 14.1% were tripolar, and 6.6% were unipolar. Primary dendrites branched sparsely, contained numerous appendages (9.1 ± 1.1 spines/100 µm dendrite), and received rich innervation from GABAergic, glutamatergic, and KP-containing terminals. KP neuron synaptology was analyzed with immunoelectron microscopy on perfusion-fixed specimens. KP axons established frequent contacts and classical synapses on unlabeled, and on KP-immunoreactive somata, dendrites, and spines. Synapses were asymmetric and the presynaptic structures contained round and regular synaptic vesicles, in addition to dense-core granules. Although immunofluorescent studies failed to detect vesicular glutamate transporter isoforms in KP axons, ultrastructural characteristics of synaptic terminals suggested use of glutamatergic, in addition to peptidergic, neurotransmission. In summary, immunofluorescent and DiI labeling of KP neurons in thick hypothalamic sections and immunoelectron microscopic studies of KP-immunoreactive neurons in brains perfusion-fixed shortly post mortem allowed us to identify previously unexplored fine structural features of KP neurons in the mediobasal hypothalamus of humans.
d'Anglemont de Tassigny X, Jayasena CN, Murphy KG, et al., 2018, Correction: Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo., PLoS One, Vol: 13
[This corrects the article DOI: 10.1371/journal.pone.0176821.].
Abbara A, Clarke S, Islam R, et al., 2017, A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial, HUMAN REPRODUCTION, Vol: 32, Pages: 1915-1924, ISSN: 0268-1161
Bhatt PS, Dhillo WS, Salem V, 2017, Human brown adipose tissue - function and therapeutic potential in metabolic disease, CURRENT OPINION IN PHARMACOLOGY, Vol: 37, Pages: 1-9, ISSN: 1471-4892
Comninos AN, Dhillo WS, 2017, Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing., Neuroendocrinology
<br>The emergence of kisspeptin as a crucial regulator of the hypothalamo-pituitary-gonadal (HPG) axis over the last 14 years has answered many questions as to the control of reproductive hormone secretion from the hypothalamus. More recently the role of kisspeptin outside the HPG axis has received increasing attention in the hope of delineating the pathways linking various sensory and social behaviours to reproduction. These studies, in a range of species from zebrafish to humans, have identified a role for kisspeptin in behavioural networks related to reproduction including olfaction, audition, fear, anxiety, mood and sexual arousal. The available evidence suggests that extrahypothalamic kisspeptin signalling encourages positive aspects of emotional and sexual brain processing in a presumed drive towards reproduction and ultimately maintenance of the species at a population level. In this review, we examine these studies, which collectively propose that kisspeptin may integrate sexual and emotional brain processing with the control of the HPG axis.<br>.
Comninos AN, Wall MB, Demetriou L, et al., 2017, Kisspeptin modulates sexual and emotional brain processing in humans, JOURNAL OF CLINICAL INVESTIGATION, Vol: 127, Pages: 709-719, ISSN: 0021-9738
Hameed S, Patterson M, Dhillo WS, et al., 2017, Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight, CELL REPORTS, Vol: 19, Pages: 2202-2209, ISSN: 2211-1247
Katugampola H, King PJ, Chatterjee S, et al., 2017, Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 102, Pages: 3349-3359, ISSN: 0021-972X
Law JM, Morris DE, Izzi-Engbeaya C, et al., 2017, Thermal imaging is a non-invasive alternative to PET-CT for measurement of brown adipose tissue activity in humans., J Nucl Med
Background: Obesity and its metabolic consequences are a major cause of morbidity and mortality. Brown adipose tissue (BAT) utilises glucose and free fatty acids to produce heat, thereby increasing energy expenditure. Effective evaluation of human BAT stimulators is constrained by current standard BAT assessment methods as positron emission tomography-computed tomography (PET-CT) requires exposure to high doses of ionising radiation. Infrared thermography (IRT) is a potential non-invasive, safe alternative, although direct corroboration with PET-CT has not previously been established. Methods: IRT and 18F-FDG PET-CT data from 8 healthy male participants subjected to water jacket cooling were directly compared. Thermal images (TIs) were geometrically transformed to overlay PET-CT-derived maximum intensity projection (MIP) images from each subject and the areas of greatest intensity of temperature and glucose-uptake within the supraclavicular regions compared. Relationships between supraclavicular temperatures from IRT (TSCR) and the maximum rate of glucose uptake (MR(gluc)) from PET-CT were determined. Results: Glucose uptake on MR(gluc)MIP was positively correlated with change in TSCR relative to a reference region (r2 = 0.721; P = 0.008). Spatial overlap between areas of maximal MR(gluc)MIP and maximal TSCR was 29.5±5.1%. Prolonged cooling to 60 minutes was associated with further TSCR rise compared with cooling to 10 minutes. Conclusion: The supraclavicular hotspot identified on IRT closely corresponds to the area of maximal uptake on PET-CT-derived MR(gluc)MIP images. Greater increases in relative TSCR were associated with raised glucose uptake. IRT should now be considered a suitable method for measuring BAT activation, especially in populations where PET-CT is not feasible, practical or repeatable. This work is licensed under a Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/.
Prague JK, Dhillo WS, 2017, Neurokinin 3 receptor antagonism - the magic bullet for hot flushes?, CLIMACTERIC, Vol: 20, Pages: 505-509, ISSN: 1369-7137
Prague JK, Dhillo WS, 2017, Treating hot flushes with a neurokinin 3 receptor antagonist, ONCOTARGET, Vol: 8, Pages: 106153-106154, ISSN: 1949-2553
Prague JK, Roberts RE, Comninos AN, et al., 2017, Neurokinin 3 receptor antagonism is a highly effective, novel treatment for menopausal hot flushes with rapid onset: a phase 2, randomised, double-blind, placebo-controlled trial, 28th Annual Meeting of the North-American-Menopause-Society, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1429-1430, ISSN: 1072-3714
Prague JK, Roberts RE, Comninos AN, et al., 2017, Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial, LANCET, Vol: 389, Pages: 1809-1820, ISSN: 0140-6736
Vimalesvaran S, Narayanaswamy S, Yang L, et al., 2017, Using kisspeptin to assess GnRH function in an unusual case of primary amenorrhoea., Endocrinol Diabetes Metab Case Rep, Vol: 2017, ISSN: 2052-0573
SUMMARY: Primary amenorrhoea is defined as the failure to commence menstruation by the age of 15 years, in the presence of normal secondary sexual development. The potential causes of primary amenorrhoea extend from structural to chromosomal abnormalities. Polycystic ovarian syndrome (PCOS) is a common cause of secondary amenorrhoea but an uncommon cause of primary amenorrhoea. An early and prompt diagnosis of PCOS is important, as up to 30% of these women are predisposed to glucose intolerance and obesity, with the subgroup of women presenting with primary amenorrhoea and PCOS displaying a higher incidence of metabolic dysfunction. We describe a case of an 18-year-old female presenting with primary amenorrhoea of unknown aetiology. Although initial investigations did not demonstrate clinical or biochemical hyperandrogenism or any radiological evidence of polycystic ovaries, a raised luteinising hormone (LH) suggested a diagnosis of PCOS. If PCOS was the correct diagnosis, then one would expect intact hypothalamic GnRH and pituitary gonadotropin release. We used the novel hormone kisspeptin to confirm intact hypothalamic GnRH release and a GnRH stimulation test to confirm intact pituitary gonadotroph function. This case highlights that kisspeptin is a potential unique tool to test GnRH function in patients presenting with reproductive disorders. LEARNING POINTS: Polycystic ovarian syndrome (PCOS) can present with primary amenorrhoea, and therefore, should be considered in the differential diagnosis.PCOS is a heterogeneous condition that may present in lean women with few or absent signs of hyperandrogenism.GnRH stimulation tests are useful in evaluating pituitary function; however, to date, we do not have a viable test of GnRH function. Kisspeptin has the potential to form a novel diagnostic tool for assessing hypothalamic GnRH function by monitoring gonadotropin response as a surrogate marker of GnRH release.Confirmation of intact GnRH function helps consolidate a
Wernig F, Jayasena CN, Dhillo WS, 2017, Carcinoid syndrome and neuroendocrine tumours, Medicine (United Kingdom), Vol: 45, Pages: 543-546, ISSN: 1357-3039
© 2017 Neuroendocrine tumours (NETs) arise from the gastrointestinal tract, pancreas, bronchi or other rare primary sites and comprise a variety of different tumour types. Carcinoid tumours are the most common. NETs can be associated with a variety of clinical syndromes. For instance, classic symptoms of carcinoid syndrome, such as flushing and diarrhoea, occur because of the release of hormones, including serotonin, tachykinins and peptide hormones. However, most NETs are non-secretory in nature and are detected incidentally or through compression of surrounding structures. Liver metastasis has usually already occurred at the time of diagnosis. Surgery can be curative if disease is entirely localized. Injections of somatostatin analogues such as octreotide are the mainstay of non-surgical treatment for NETs. Surgical debulking and embolization techniques are useful to reduce tumour bulk in patients who remain symptomatic despite medical treatment. Peptide receptor radionucleotide therapy using radiolabelled somatostatin analogues has recently been shown to prolong progression-free survival. Furthermore, several novel agents, such as everolimus, have emerged in the treatment of patients with metastatic disease. This article aims to summarize the pathophysiology and clinical features of NETs, with a focus on carcinoid syndrome. It also discusses recent advances in clinical management of NETs.
de Tassigny XD, Jayasena C, Murphy KG, et al., 2017, Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo, PLOS ONE, Vol: 12, ISSN: 1932-6203
Comninos AN, Anastasovska J, Sahuri-Arisoylu M, et al., 2016, Kisspeptin signaling in the amygdala modulates reproductive hormone secretion, BRAIN STRUCTURE & FUNCTION, Vol: 221, Pages: 2035-2047, ISSN: 1863-2653
Hickson M, Moss C, Dhillo WS, et al., 2016, Increased peptide YY blood concentrations, not decreased acyl-ghrelin, are associated with reduced hunger and food intake in healthy older women: Preliminary evidence, APPETITE, Vol: 105, Pages: 320-327, ISSN: 0195-6663
Jayasena CN, Abbara A, Comninos AN, et al., 2016, Novel circulating placental markers prokineticin-1, soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor and association with late miscarriage, HUMAN REPRODUCTION, Vol: 31, Pages: 2681-2688, ISSN: 0268-1161
Narayanaswamy S, Jayasena CN, Ng N, et al., 2016, Subcutaneous infusion of kisspeptin-54 stimulates gonadotrophin release in women and the response correlates with basal oestradiol levels, CLINICAL ENDOCRINOLOGY, Vol: 84, Pages: 939-945, ISSN: 0300-0664
Narayanaswamy S, Prague JK, Jayasena CN, et al., 2016, Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 101, Pages: 3429-3436, ISSN: 0021-972X
Polyviou T, MacDougall K, Chambers ES, et al., 2016, Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 44, Pages: 662-672, ISSN: 0269-2813
Salem V, Izzi-Engbeaya C, Coello C, et al., 2016, Glucagon increases energy expenditure independently of brown adipose tissue activation in humans, DIABETES OBESITY & METABOLISM, Vol: 18, Pages: 72-81, ISSN: 1462-8902
Abbara A, Jayasena CN, Christopoulos G, et al., 2015, Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 100, Pages: 3322-3331, ISSN: 0021-972X
Chambers ES, Viardot A, Psichas A, et al., 2015, Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults, GUT, Vol: 64, Pages: 1744-1754, ISSN: 0017-5749
Chambers ES, Viardot A, Psichas A, et al., 2015, Effects of elevating colonic propionate on liver fat content in overweight adults with non-alcoholic fatty liver disease: a pilot study, PROCEEDINGS OF THE NUTRITION SOCIETY, Vol: 74, Pages: E30-E30, ISSN: 0029-6651
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