Imperial College London

ProfessorWaljitDhillo

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Professor of Endocrinology & Metabolism
 
 
 
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Contact

 

+44 (0)20 7594 3487w.dhillo Website

 
 
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Assistant

 

Ms Suzanne Wheeler +44 (0)20 7594 3487

 
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Location

 

6N6ECommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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254 results found

Abbara A, Eng P, Phylactou M, Clarke S, Richardson R, sykes C, Phumsatitpong C, Mills E, Modi M, Izzi-Engbeaya C, Papadopoulou D, Purugganan K, Jayasena C, Webber L, salim R, Owen B, Bech P, Comninos A, McArdle C, violitis M, Tsaneva-Atanasova K, Moenter S, Hanyaloglu A, Dhillo Wet al., 2020, Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders., Journal of Clinical Investigation, ISSN: 0021-9738

Journal article

Abbara A, Hunjan T, NGOC ANH Ho V, Clarke S, Comninos A, Izzi-Engbeaya C, ho T, Trew G, hramyka A, kelsey T, salim R, humaidan P, vuong L, Dhillo Wet al., 2020, Endocrine requirements for oocyte maturation following hCG, GnRH agonist and kisspeptin during IVF treatment, Frontiers in Endocrinology, ISSN: 1664-2392

Journal article

Vessey W, Saifi S, Sharma A, McDonald C, Almeida P, Figueiredo M, Minhas S, Virmani A, Dhillo WS, Ramsay JW, Jayasena CNet al., 2020, Baseline levels of seminal reactive oxygen species predict improvements in sperm function following anti-oxidant therapy in men with infertility., Clin Endocrinol (Oxf)

BACKGROUND: Poor sperm function is a major cause of infertility. There is no drug therapy to improve sperm function. Semen oxidative stress is a recently identified pathway for sperm damage. Commercial anti-oxidants such as L-carnitine and acetyl-L-carnitine (LAL) are commonly self-administered by infertile men. However, concerns have been raised whether inappropriate LAL therapy causes reductive stress-mediated sperm damage. It is imperative to investigate whether: (1) LAL improves sperm function by reducing reactive oxidative species (ROS); (2) LAL has differential effects on sperm function between men with normal and elevated ROS. METHODS: A prospective cohort study of routine clincical practice was performed in infertile men with abnormal sperm quality. Changes in sperm function and semen ROS levels following three-months of oral LAL therapy were compared between participants with baseline seminal Normal-ROS (≤10RLU/SEC/106 sperm; n=29) and High-ROS (>10 RLU/SEC/106 sperm; n=15) levels measured using an established colorimetric-luminol method. RESULTS: In Normal-ROS group, sperm function did not change following LAL therapy. In High-ROS group, LAL therapy reduced semen ROS 5-fold, increased sperm count by 50% (mean count in mill/ml: 21.5+7.2, baseline; 32.6+9.5, post-treatment, p=0.0005), and total and progressive sperm motility each by 30% (mean total sperm motility in % 29.8+5.0, baseline: 39.4+6.2, post-treatment, p=0.004; mean progressive sperm motility in % 23.1+4.6, baseline: 30.0+5.5, post-treatment, p=0.014 vs. baseline). CONCLUSIONS: We report for the first time that LAL only improves sperm quality in infertile men who have baseline high-ROS levels prior to treatment. These data have important potential implications for couples with male infertility and their clinicians.

Journal article

Abbara A, Dhillo WS, 2020, Makorin rings the kisspeptin bell to signal pubertal initiation., J Clin Invest, Vol: 130, Pages: 3957-3960

The signals maintaining quiescence of the reproductive endocrine axis during childhood before its reawakening at puberty had been enigmatic. Studies in patients with abnormal puberty have illuminated the identity of the signals; kisspeptin has emerged as a major stimulator of puberty, and makorin RING finger protein 3 (MKRN3) as an inhibitory signal that prevents premature initiation of puberty. In this issue of the JCI, Abreu et al. investigated the mechanism by which MKRN3 regulates pubertal onset. The authors found that a reduction in MKRN3 alleviated the constraint on kisspeptin-expressing neurons to allow pubertal initiation, a phenomenon observed across species, including nonhuman primates. Further, the ubiquitinase activity of MKRN3 required its RING finger domain, in order to repress the promoter activity of genes encoding kisspeptin and neurokinin B. These data advance our understanding of the regulation of kisspeptin-expressing neurons by MKRN3 to initiate puberty.

Journal article

Tan T, Khoo B, Mills EG, Phylactou M, Patel B, Eng PC, Thurston L, Muzi B, Meeran K, Prevost AT, Comninos AN, Abbara A, Dhillo WSet al., 2020, Association between high serum total cortisol concentrations and mortality from COVID-19, The Lancet Diabetes and Endocrinology, Vol: 8, Pages: 659-660, ISSN: 2213-8595

Journal article

Izzi-Engbeaya C, Mills E, Yang L, Minnion J, Tharakan G, Abbara A, Comninos A, Tan T, Dhillo Wet al., 2020, Acute effects of glucagon on reproductive hormone secretion in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 105, ISSN: 0021-972X

ContextGlucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting.ObjectiveThe objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men.DesignA single-blinded, randomized, placebo-controlled crossover study was conducted.SettingThe setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study.InterventionAn 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered.Main Outcome MeasuresLuteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured.ResultsAlthough glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P < .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration.ConclusionsAcute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based tre

Journal article

Izzi-Engbeaya C, Ma Y, Buckley NW, Ratnasabapathy R, Richardson E, Counsell JR, Fernandes-Freitas I, Norton M, Farooq G, Mirza Z, Cai M, Cheetham S, Seckl J, Murphy K, Dhillo WS, Gardiner Jet al., 2020, Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats, Molecular Metabolism, Vol: 36, Pages: 1-7, ISSN: 2212-8778

BackgroundObesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents.ObjectivesTo investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats.MethodsRecombinant adeno-associated virus bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1) respectively were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels.ResultsCompared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake.ConclusionsTherefore, ARC corticosterone, regulated by 11βHSD1, may play a role in fo

Journal article

Abbara A, Clarke S, Brewster R, Simmonard A, Eng PC, Phylactou M, Papadopoulou D, Izzi-Engbeaya C, Sam A, Wernig F, Jonauskyte E, Comninos A, Meeran K, Kelsey T, Dhillo Wet al., 2020, Pharmacodynamic response to anti-thyroid drugs in Graves’ hyperthyroidism, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392

Objective: Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole.Design: Retrospective cohort study.Methods: Participants were patients (n = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD.Results: Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4*0.97–11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity.Conclusion: We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.

Journal article

Jayasena CN, Sharma A, Abbara A, Rong L, White CJ, Hoskin SG, Khanjani S, Crawford MJ, Ramsay JW, Minhas S, Dhillo WSet al., 2020, Burdens and awareness of adverse self-reported lifestyle factors in men with sub-fertility: a cross-sectional study in 1149 men., Clinical Endocrinology, ISSN: 0300-0664

BACKGROUND: There are no current pharmacological therapies to improve sperm quality in men with sub-fertility. Reducing the exposure to lifestyle risk factor (LSF) is currently the only intervention for improving sperm quality in men with sub-fertility. No previous study has investigated what proportion of men with sub-fertility are exposed to adverse lifestyle factors. Furthermore, it is not known to what extent men with sub-fertility are aware of lifestyle factors potentially adversely impacting their fertility. METHODS: A cross-sectional anonymous questionnaire-based study on self-reported exposure and awareness of LSF was conducted in 1149 male partners of couples investigated for sub-fertility in a tertiary andrology centre in London, UK. RESULTS: Seventy-percent of men investigated for sub-fertility had ≥1 LSF, and twenty-nine-percent had ≥2 LSF. Excessive alcohol consumption was the most common LSF (40% respondents). Seventeen-percent of respondents used recreational drugs (RD) regularly, but only 32% of RD users believed RD impair male fertility. Twenty-five-percent of respondents were smokers, which is higher than the UK average (20%). Twenty-seven percent of respondents had a waist circumference (WC) >36inches (91cm), and 4% had WC >40inches (102cm). Seventy-nine-percent of respondents wanted further lifestyle education to improve their fertility. CONCLUSIONS: Our data suggest that men with sub-fertility are: (1) exposed to one or more LSF; (2) have incomplete education about how LSF may cause male sub-fertility; (3) want more education about reducing LSF. Further studies are needed to investigate the potential of enhanced education of men about LSF to treat couples with sub-fertility.

Journal article

Ma Y, Ratnasabapathy R, De Backer I, Izzi-Engbeaya C, Nguyen-Tu M-S, Cuenco J, Jones B, John C, Lam B, Rutter G, Yeo G, Dhillo W, Gardiner Jet al., 2020, Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 release, JCI insight, Vol: 5, ISSN: 2379-3708

Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1.

Journal article

Rumpler É, Skrapits K, Takács S, Göcz B, Trinh SH, Rácz G, Matolcsy A, Kozma Z, Ciofi P, Dhillo WS, Hrabovszky Eet al., 2020, Characterization of kisspeptin neurons in the human rostral hypothalamus., Neuroendocrinology

INTRODUCTION: Kisspeptin (KP) neurons in the rostral periventricular area (RP3V) of female rodents mediate positive estrogen feedback to gonadotropin-releasing hormone neurons and thus, play fundamental role in the mid-cycle luteinizing hormone (LH) surge. The RP3V is sexually dimorphic and male rodents with lower KP cell numbers are unable to mount estrogen-induced LH surges. OBJECTIVE: To find and characterize the homologous KP neurons in the human brain, we studied formalin-fixed post mortem hypothalami. METHODS: Immunohistochemical techniques were used. RESULTS: Distribution of KP neurons in the rostral hypothalamus overlapped with different subdivision of the paraventricular nucleus. Cell numbers decreased after menopause, indicating that estrogens positively regulate KP gene expression in the rostral hypothalamus in humans, similarly to several other species. Young adult women and men had similar cell numbers, as opposed to rodents having more KP neurons in the RP3V of females. Human KP neurons differed neurochemically as well from the homologous rodent cells in that they were devoid of enkephalins, galanin and tyrosine hydroxylase. Further, they did not contain known KP neuron markers of the human infundibular nucleus, neurokinin B, Substance P and cocaine- and amphetamine-regulated transcript but received afferent input from these KP neurons. CONCLUSIONS: Identification and positive estrogenic regulation of KP neurons in the human rostral hypothalamus challenge the long-held view that positive estrogen feedback may be restricted to the mediobasal part of the hypothalamus in primates and point to the need of further anatomical, molecular and functional studies of rostral hypothalamic KP neurons.

Journal article

Sharma A, Thaventhiran T, Minhas S, Dhillo WS, Jayasena CNet al., 2020, Kisspeptin and Testicular Function-Is It Necessary?, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 21

Journal article

Yang L, Demetriou L, Wall M, Mills E, Zargaran D, Sykes M, Prague J, Abbara A, Owen B, Bassett P, Rabiner E, Comninos A, Dhillo Wet al., 2020, Kisspeptin enhances brain responses to olfactory and visual cues of attraction in men, JCI insight, Vol: 5, ISSN: 2379-3708

Successful reproduction is a fundamental physiological process which relies on the integration of sensory cues of attraction with appropriate emotions and behaviors and the reproductive axis. However, the factors responsible for this integration remain largely unexplored. Using functional neuroimaging, hormonal and psychometric analyses, we demonstrate that the reproductive hormone kisspeptin enhances brain activity in response to olfactory and visual cues of attraction in men. Furthermore, the brain regions enhanced by kisspeptin correspond to areas within the olfactory and limbic systems that govern sexual behavior and perception of beauty as well as overlapping with its endogenous expression pattern. Of key functional and behavioral significance, we observed that kisspeptin was most effective in men with lower sexual quality of life scores. As such, our results reveal a previously undescribed attraction pathway in humans activated by kisspeptin, and identify kisspeptin signaling as a new therapeutic target for related reproductive and psychosexual disorders.

Journal article

Izzi-Engbeaya C, Dhillo W, Tan T, Abbara A, Comninos A, Bech P, Minnion Jet al., 2020, Effects of glucagon-like peptide-1 on the reproductive axis in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: 1-7, ISSN: 0021-972X

ContextGlucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans.ObjectiveTo investigate the effects of GLP-1 administration on the reproductive axis in humans.DesignSingle-blind, randomized, placebo-controlled crossover study.SettingClinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2).InterventionEight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion.Main Outcome MeasuresNumber of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels.ResultsThe number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01).ConclusionsIn contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Journal article

Dragan M, Nguyen M-U, Guzman S, Goertzen C, Brackstone M, Dhillo WS, Bech PR, Clarke S, Abbara A, Tuck AB, Hess DA, Pine SR, Zong W-X, Wondisford FE, Su X, Babwah AV, Bhattacharya Met al., 2020, G protein-coupled kisspeptin receptor induces metabolic reprograming and tumorigenesis in estrogen receptor-negative breast cancer, Cell Death and Disease, Vol: 11, ISSN: 2041-4889

Triple-negative breast cancer (TNBC) is a highly metastatic and deadly disease. TNBC tumors lack estrogen receptor (ERα), progesterone receptor (PR), and HER2 (ErbB2) and exhibit increased glutamine metabolism, a requirement for tumor growth. The G protein-coupled kisspeptin receptor (KISS1R) is highly expressed in patient TNBC tumors and promotes malignant transformation of breast epithelial cells. This study found that TNBC patients displayed elevated plasma kisspeptin levels compared with healthy subjects. It also provides the first evidence that in addition to promoting tumor growth and metastasis in vivo, KISS1R-induced glutamine dependence of tumors. In addition, tracer-based metabolomics analyses revealed that KISS1R promoted glutaminolysis and nucleotide biosynthesis by increasing c-Myc and glutaminase levels, key regulators of glutamine metabolism. Overall, this study establishes KISS1R as a novel regulator of TNBC metabolism and metastasis, suggesting that targeting KISS1R could have therapeutic potential in the treatment of TNBC.

Journal article

Fernandes-Freitas I, Milona A, Murphy KG, Dhillo WS, Owen Bet al., 2020, Live birth in sex-reversed XY mice lacking the nuclear receptor Dax1, Scientific Reports, Vol: 10, ISSN: 2045-2322

The nuclear hormone receptor Dax1 functions during development as a testes-determining gene. However, the phenotype of male mice lacking Dax1 is strain-dependent due to the background-specific abundance of male-determining Sry gene-transcripts. We hypothesised that inter-individual variation in Sry mRNA-abundance would result in a spectrum of phenotypes even within-strain. We found that while all XY C57BL/6J mice lacking Dax1 presented as phenotypic females, there was a marked inter-individual variability in measures of fertility. Indeed, we report rare occasions where sex-reversed mice had measures of fertility comparable to those in control females. On two occasions, these sex-reversed XY mice were able to give birth to live offspring following mating to stud-males. As such, this work documents within-strain variability in phenotypes of XY mice lacking Dax1, and reports for the first time a complete sex-reversal capable of achieving live birth in these mice.

Journal article

Prague J, Abbara A, Comninos A, Jayasena C, higham C, adaway J, keevil B, veldhuis J, Dhillo Wet al., 2020, Neurokinin 3 receptor antagonists do not increase FSH or estradiol secretion in menopausal women, Journal of the Endocrine Society, Vol: 4, ISSN: 2472-1972

Background: Neurokinin 3 receptor (NK3R) antagonism is a promising novel treatment for menopausal flashes. However, to avoid adverse hormonal effects it is clinically important to first confirm whether gonadotropin and estradiol concentrations change as a result of their administration. Methods: Single-center, randomized, double-blind, placebo-controlled, crossover trial of an oral NK3R antagonist (MLE4901) in 28 women aged 40-62yrs, experiencing >7 hot flashes/24h; some bothersome or severe (Clinicaltrials.gov NCT02668185). Weekly serum gonadotropins and estradiol levels were measured using commercially available automated immunoassays a priori. Serum estradiol was also measured post hoc using a highly sensitive direct assay by liquid chromatography tandem mass spectrometry. Hormone levels were compared by the paired sample t-tests or by the Wilcoxon matched-pairs signed rank test, as appropriate for the distribution of the data. Results: Mean (SD) serum FSH concentration was not significantly increased when taking MLE4901 (72.07 ±19.81iU/L) compared to placebo (70.03 ±19.56iU/L), p=0.26. Serumestradiol was also not significantly altered, irrespective of which assay method was used (median IQR of serum estradiol by immunoassay: placebo 36 ±3pmol/L, MLE4901 36 ± 1pmol/L, p=0.21; median serum highly sensitive estradiol: placebo 12 ± 16pmol/L, MLE4901 5 13 ± 15pmol/L, p=0.70). However, mean (SD) serum LH concentration significantly decreased with MLE4901 (27.63 ± 9.76iU/L) compared to placebo (30.26 ± 9.75iU/L), p=0.0024. Implication: NK3R antagonists do not increase serum estradiol or FSH despite their reduction in hot flashes. This is clinically significant; and highly reassuring for women who have a contraindication to conventional hormone therapy such as prior/existing breast cancer and/or thromboembolism.

Journal article

Milona A, Massafra V, Vos H, Naik J, Artigas N, Paterson HAB, Bijsmans ITGW, Willemsen ECL, Ramos Pittol JM, Miguel-Aliaga I, Bosma P, Burgering BMT, Williamson C, Vernia S, Dhillo WS, van Mil SWC, Owen BMet al., 2019, Steroidogenic control of liver metabolism through a nuclear receptor-network, Molecular Metabolism, Vol: 30, Pages: 221-229, ISSN: 2212-8778

OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown. METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1. CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

Journal article

Izzi-Engbeaya C, Jones S, Crustna Y, Machenahalli PC, Papadopoulou D, Modi M, Panayi C, Starikova J, Eng PC, Phylactou M, Mills E, Yang L, Ratnasabapathy R, Sykes M, Plumptre I, Coumbe B, Wing V, Pacuszka E, Bech P, Minnion J, Tharakan G, Tan T, Veldhuis J, Abbara A, Comninos AN, Dhillo WSet al., 2019, Effects of peptide-YY on the hypothalamic-pituitary-gonadal axis in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: 1-6, ISSN: 0021-972X

ContextCentral and peripheral administration of peptide-YY (PYY) has potent anorectic effects, and PYY analogues are under development as anti-obesity treatments. Recent animal data suggest PYY may also influence the reproductive axis, however the effects of PYY on the human reproductive system are unknown.ObjectiveTo investigate the effects of PYY administration on the reproductive axis in healthy young men.DesignSingle-blind, randomised, placebo-controlled crossover study.SettingClinical Research Facility, Imperial College Healthcare NHS Trust.ParticipantsEighteen healthy eugonadal men (mean age 24.1±0.9years, mean BMI 22.2±0.4kg/m2).InterventionEight-hour intravenous infusion of 0.4pmol/kg/min PYY3-36 or rate-matched vehicle infusion.ResultsThe number of LH pulses (mean number of LH pulses/8hours: PYY 4.4±0.3 vs vehicle 4.4±0.4, p>0.99), LH area under the curve (AUC) (PYY 1503±79IU.min/L vs vehicle 1574±86IU.min/L, p=0.36), FSH AUC (PYY 1158±513IU.min/L vs vehicle 1199±476IU.min/L, p=0.49) and testosterone AUC (PYY 10485±684IU.min/L vs vehicle 11133±803IU.min/L, p=0.24) were similar during PYY and vehicle infusions.ConclusionsAcute intravenous infusion of 0.4pmol/kg/min PYY does not affect the reproductive axis in healthy men.

Journal article

Abbara A, Eng PC, Phylactou M, Clarke SA, Tia H, Roberts R, Vimalesvaran S, Christopoulos G, Islam R, Purugganan K, Comninos AN, Trew GH, Salim R, Hramyka A, Owens L, Kelsey T, Dhillo WSet al., 2019, Anti-Mullerian Hormone (AMH) in the diagnosis of menstrual disturbance due to polycystic ovarian syndrome, Frontiers in Endocrinology, Vol: 10, Pages: 1-11, ISSN: 1664-2392

Introduction: Polycystic ovarian syndrome (PCOS) is a leading cause of female subfertility worldwide, however due to the heterogeneity of the disorder, the criteria for diagnosis remains subject to conjecture. In the present study, we evaluate the utility of serum Anti-Müllerian Hormone (AMH) in the diagnosis of menstrual disturbance due to PCOS.Method: Menstrual cycle length, serum AMH, gonadotropin and sex-hormone levels, total antral follicle count (AFC), body mass index (BMI) and ovarian morphology on ultrasound were analyzed in a cohort of 187 non-obese women, aged 18–35 years, screened for participation in a clinical trial of fertility treatment between 2013 and 2016 at a tertiary reproductive endocrine center.Results: Serum AMH was higher in women with menstrual disturbance when compared to those with regular cycles (65.6 vs. 34.8 pmol/L; P < 0.0001). The odds of menstrual disturbance was increased 28.5-fold (95% CI 3.6–227.3) in women with serum AMH >60 pmol/L, in comparison to those with an AMH < 15 pmol/L. AMH better discriminated women with menstrual disturbance (area under ROC 0.77) from those with regular menstrual cycles than AFC (area under ROC 0.67), however the combination of the two markers increased discrimination than either measure alone (0.83; 95% CI 0.77–0.89). Serum AMH was higher in women with all three cardinal features of PCOS (menstrual disturbance, hyperandrogenism, polycystic ovarian morphology) when compared to women with none of these features (65.6 vs. 14.6 pmol/L; P < 0.0001). The odds of menstrual disturbance were increased by 10.7-fold (95% CI 2.4–47.1) in women with bilateral polycystic morphology ovaries than those with normal ovarian morphology. BMI was a stronger predictor of free androgen index (FAI) than either AMH or AFC.Conclusion: Serum AMH could serve as a useful biomarker to indicate the risk of menstrual disturbance due to PCOS. Women with higher AMH levels had increased rates o

Journal article

Dimakopoulou A, Jayasena CN, Radia UK, Algefari M, Minhas S, Oliver N, Dhillo WSet al., 2019, Animal models of diabetes-related male hypogonadism, Frontiers in Endocrinology, Vol: 10, ISSN: 1664-2392

Hypogonadism is the clinical syndrome associated with low testosterone secretion in men. Hypogonadism affects ~37–57% men with diabetes mellitus (1). Male reproduction is orchestrated by the hypothalamo-pituitary-gonadal (HPG) axis, which regulates the biosynthesis of testosterone from the testes. Diabetes may cause hypogonadism through multiple mechanisms including suppression of hypothalamic gonadotrophin-releasing hormone (GnRH) secretion, or direct disruption of spermatogenesis (2). Clinical stigmata of hypogonadism include reduced libido, erectile dysfunction (ED) and reduced physical strength. This article will summarize the evidence from animal models including how diabetes affects male reproductive endocrine function and predisposes to hypogonadism.

Journal article

Prague J, voliotis M, Clarke S, Comninos A, Abbara A, Jayasena C, Roberts R, Yang L, veldhuis J, tsaneva-atanasova K, mcardle C, Dhillo Wet al., 2019, Determining the relationship between hot flushes and LH pulses in menopausal women using mathematical modelling, Journal of Clinical Endocrinology and Metabolism, Vol: 104, Pages: 3628-3636, ISSN: 0021-972X

BackgroundHypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurones regulate LH pulsatility. It is widely accepted that the menopausal hot flush (HF) consistently synchronises with the LH pulse. This suggests that the hypothalamic KNDy neurones are implicated in generating LH pulsatility and HF. Using a modern immunoassay and mathematical modelling we investigated if the HF and LH pulse was consistently synchronised in menopausal women.MethodsEleven menopausal women (51-62yrs experiencing ≥7 HF/24hrs) attended for an 8 hour study where they self-reported HF and underwent peripheral blood sampling every 10 mins. LH pulsatility was determined using two mathematical models: blinded deconvolution analysis and Bayesian spectrum analysis. The probability that the LH pulse and HF event intervals matched was estimated using the interval distributions observed in our data.ResultsNinety-six HF were self-reported, and 82 LH pulses were identified by blinded deconvolution analysis. Using both models, the probability that the two event intervals matched was low in the majority of participants (mean P=0.24 (P=1 reflects perfect association)).InterpretationOur data challenges the widely accepted dogma that HF consistently synchronise with an LH pulse, and so has clinically important therapeutic and mechanistic implications.

Journal article

Abbara A, patel A, Hunjan T, Clarke S, Chia G, Eng P, Phylactou M, Comninos A, Lavery S, Trew G, salim R, Rai R, kelsey T, Dhillo Wet al., 2019, FSH requirements for follicle growth during controlled ovarian stimulation, Frontiers in Endocrinology, Vol: 10, ISSN: 1664-2392

Introduction: Ovarian follicle growth is a key step in the success of assisted reproductive treatment, but limited data exists to directly relate follicle growth to recombinant FSH (rFSH) dose. In this study, we aim to evaluate FSH requirements for follicular growth during controlled ovarian stimulation.Method: Single centre retrospective cohort study of 1,034 IVF cycles conducted between January 2012-January 2016 at Hammersmith Hospital IVF unit, London, UK. Median follicle size after five days of stimulation with rFSH and the proportion of antral follicles recruited were analysed in women treated with rFSH alone to induce follicular growth during IVF treatment.Results: Starting rFSH dose adjusted for body weight (iU/kg) predicted serum FSH level after 5 days of rFSH (r2=0.352, p<0.0001), median follicle size after 5 days of rFSH, and the proportion of antral follicles recruited by the end of stimulation. Day 5 median follicle size predicted median follicle size on subsequent ultrasound scans (r2=0.58-0.62; p<0.0001), and hence time to oocyte maturation trigger (r2=0.22, P<0.0001). Insufficient rFSH starting dose that required >5% dose-increase was associated with increased variability in follicle size on the day of oocyte maturation trigger, and negatively impacted the number of mature oocytes retrieved.Conclusion: Weight-adjusted rFSH dose correlates with follicular growth during ovarian stimulation. Early recruitment of follicles using a sufficient dose of rFSH from the start of stimulation was associated with reduced variability in follicle size at time of oocyte maturation trigger and an increased number of mature oocytes retrieved.

Journal article

Thurston L, Abbara A, Dhillo W, 2019, Investigation and management of subfertility, Journal of Clinical Pathology, Vol: 72, Pages: 579-587, ISSN: 1472-4146

Subfertility affects one in seven couples and is defined as the inability to conceive after 1 year of regular unprotected intercourse. This article describes the initial clinical evaluation and investigation to guide diagnosis and management. The primary assessment of subfertility is to establish the presence of ovulation, normal uterine cavity and patent fallopian tubes in women, and normal semen parameters in men. Ovulation is supported by a history of regular menstrual cycles (21–35 days) and confirmed by a serum progesterone >30 nmol/L during the luteal phase of the menstrual cycle. Common causes of anovulation include polycystic ovary syndrome (PCOS), hypothalamic amenorrhoea (HA) and premature ovarian insufficiency (POI). Tubal patency is assessed by hysterosalpingography, hystero-contrast sonography, or more invasively by laparoscopy and dye test. The presence of clinical or biochemical hyperandrogenism, serum gonadotrophins (luteinising hormone/follicle stimulating hormone) / oestradiol, pelvic ultrasound to assess ovarian morphology / antral follicle count, can help establish the cause of anovulation. Ovulation can be restored in women with PCOS using letrozole (an aromatase inhibitor), clomifene citrate (an oestrogen antagonist) or exogenous gonadotrophin administration. If available, pulsatile gonadotrophin releasing hormone therapy is the preferred option for restoring ovulation in HA. Spermatogenesis can be induced in men with hypogonadotrophic hypogonadism with exogenous gonadotrophins. Unexplained subfertility can be treated with in vitro fertilisation after 2 years of trying to conceive. Involuntary childlessness is associated with significant psychological morbidity; hence, expert assessment and prompt treatment are necessary to support such couples.

Journal article

Clarke SA, Dhillo WS, 2019, Phoenixin and Its Role in Reproductive Hormone Release, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 191-196, ISSN: 1526-8004

Journal article

Dhillo WS, 2019, Kisspeptin, Neurokinin B and New Players in Reproduction Preface, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 153-153, ISSN: 1526-8004

Journal article

Behary P, Tharakan G, Alexiadou K, Johnson N, Wewer Albrechtsen NJ, Kenkre J, Cuenco J, Hope D, Anyiam O, Choudhury S, Alessimii H, Poddar A, Minnion J, Doyle C, Frost G, Le Roux C, Purkayastha S, Moorthy K, Dhillo W, Holst JJ, Ahmed AR, Prevost AT, Bloom SR, Tan TMet al., 2019, Combined GLP-1, oxyntomodulin, and peptide YY improves body weight and glycemia in obesity and prediabetes/type 2 diabetes: a randomized single-blinded placebo controlled study, Diabetes Care, Vol: 42, Pages: 1446-1453, ISSN: 0149-5992

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity. RESEARCH DESIGN AND METHODS: In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (n = 15) or saline (n = 11) infusion for 4 weeks. We also studied 21 patients who had undergone RYGB and 22 patients who followed a very low-calorie diet (VLCD) as unblinded comparators. Outcomes measured were 1) body weight, 2) fructosamine levels, 3) glucose and insulin during a mixed meal test (MMT), 4) energy expenditure (EE), 5) energy intake (EI), and 6) mean glucose and measures of glucose variability during continuous glucose monitoring. RESULTS: GOP infusion was well tolerated over the 4-week period. There was a greater weight loss (P = 0.025) with GOP (mean change -4.4 [95% CI -5.3, -3.5] kg) versus saline (-2.5 [-4.1, -0.9] kg). GOP led to a greater improvement (P = 0.0026) in fructosamine (-44.1 [-62.7, -25.5] µmol/L) versus saline (-11.7 [-18.9, -4.5] µmol/L). Despite a smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose tolerance after a mixed-meal stimulus and reduced glycemic variability compared with RYGB and VLCD. CONCLUSIONS: GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.

Journal article

Hunjan T, Abbara A, Patel A, Clarke S, Chia G, Eng PC, Phylactou M, Cominos A, Lavery S, Trew G, Salim R, Rai R, Kelsey T, Dhillo Wet al., 2019, FSH requirements for follicle growth during controlled ovarian stimulation in IVF cycles, Publisher: WILEY, Pages: 193-194, ISSN: 1470-0328

Conference paper

Dhillo WS, 2019, Kisspeptin, Neurokinin B and New Players in Reproduction Preface, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 107-107, ISSN: 1526-8004

Journal article

Modi M, Dhillo WS, 2019, Neurokinin B and Neurokinin-3 Receptor Signaling: Promising Developments in the Management of Menopausal Hot Flushes, SEMINARS IN REPRODUCTIVE MEDICINE, Vol: 37, Pages: 125-129, ISSN: 1526-8004

Journal article

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