Imperial College London

DrAlexanderComninos

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Clinical Senior Lecturer
 
 
 
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+44 (0)20 3313 3242a.comninos

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
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88 results found

Phylactou M, Abbara A, Al-Memar M, Kyriacou C, Pei Chia E, Nadir R, Izzie-Engbeaya C, Clarke S, Mills E, Daniels E, Huo L, Pacuszka E, Yang L, Patel B, Tan T, Bech P, Comninos A, Fourie H, Kelsey T, Bourne T, Dhillo Wet al., 2021, Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestation during the first trimester, Fertility and Sterility, Vol: 116, Pages: 809-819, ISSN: 0015-0282

ObjectiveTo compare the performance of kisspeptin and beta human chorionic gonadotropin (βhCG), both alone and in combination, as biomarkers for miscarriage throughout the first trimester.DesignProspective, nested case-control study.SettingTertiary Centre, Queen Charlotte Hospital, London, United Kingdom.Patient(s)Adult women who had miscarriages (n = 95, 173 samples) and women with healthy pregnancies (n = 265, 557 samples).Intervention(s)The participants underwent serial ultrasound scans and blood sampling for measurement of plasma kisspeptin and βhCG levels during the first trimester.Main Outcome Measure(s)The ability of plasma kisspeptin and βhCG levels to distinguish pregnancies complicated by miscarriage from healthy pregnancies unaffected by miscarriage.Result(s)Gestation-adjusted levels of circulating kisspeptin and βhCG were lower in samples from women with miscarriages than in women with healthy pregnancies by 79% and 70%, respectively. The area under the receiver-operating characteristic curve for identifying miscarriage during the first trimester was 0.874 (95% confidence interval [CI] 0.844–0.904) for kisspeptin, 0.859 (95% CI 0.820–0.899) for βhCG, and 0.916 (95% CI 0.886–0.946) for the sum of the two markers. The performance of kisspeptin in identifying miscarriage improved with increasing length of gestation, whereas that of βhCG worsened. A decision matrix incorporating kisspeptin, βhCG, and gestational age had 83% to 87% accuracy for the prediction of miscarriage.Conclusion(s)Plasma kisspeptin is a promising biomarker for miscarriage and provides additional value to βhCG alone, especially during later gestational weeks of the first trimester.

Journal article

Phylactou M, Abbara A, Al-Memar M, Daniels E, Patel B, Eng PC, Nadir R, Izzi-Engbeaya C, Clarke S, Mills E, Hunjan T, Pacuszka E, Yang L, Bech P, Tan T, Comninos A, Kelsey T, Kyriacou C, Fourie H, Bourne T, Dhillo Wet al., 2021, Changes in circulating kisspeptin levels during each trimester in women with antenatal complications, Journal of Clinical Endocrinology and Metabolism, ISSN: 0021-972X

ContextAntenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all three trimesters in women with antenatal complications.ObjectiveTo assess whether kisspeptin levels are altered in women with antenatal complications.DesignWomen with antenatal complications (n=105) and those with uncomplicated pregnancies (n=265) underwent serial ultrasound scans and blood-sampling at least once during each trimester (March 2014 to March 2017).SettingEarly Pregnancy Assessment Unit at Hammersmith Hospital, UK.ParticipantsWomen with antenatal complications: HDP (n=32), FGR (n=17), GDM (n=35) and PTB (n=11), and 10 women with multiple complications, provided 373 blood samples, and a further 265 controls provided 930 samples.Main outcomeDifferences in circulating kisspeptin levels.ResultsThird trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking and parity were increased by 30% (95%CI 16-47%; p<0.0001), and of FGR were reduced by 28% (95%CI 4-46%; p=0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (p=0.014), and lower in those affected by GDM (p=0.020), but not significantly on multivariable analysis.ConclusionWe delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

Journal article

Phylactou M, Clarke S, Patel B, Baggaley C, Jayasena C, Kelsey T, Comninos A, Dhillo W, Abbara Aet al., 2021, Clinical and biochemical discriminants between functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS), Clinical Endocrinology, Vol: 95, Pages: 239-252, ISSN: 0300-0664

BackgroundSecondary oligo/amenorrhoea occurs in 3%–5% of women of reproductive age. The two most common causes are polycystic ovary syndrome (PCOS) (2%–13%) and functional hypothalamic amenorrhoea (FHA) (1%–2%). Whilst both conditions have distinct pathophysiology and their diagnosis is supported by guidelines, in practice, differentiating these two common causes of menstrual disturbance is challenging. Moreover, both diagnoses are qualified by the need to first exclude other causes of menstrual disturbance.AimTo review clinical, biochemical and radiological parameters that could aid the clinician in distinguishing PCOS and FHA as a cause of menstrual disturbance.ResultsFHA is uncommon in women with BMI > 24 kg/m2, whereas both PCOS and FHA can occur in women with lower BMIs. AMH levels are markedly elevated in PCOS; however, milder increases may also be observed in FHA. Likewise, polycystic ovarian morphology (PCOM) is more frequently observed in FHA than in healthy women. Features that are differentially altered between PCOS and FHA include LH, androgen, insulin, AMH and SHBG levels, endometrial thickness and cortisol response to CRH. Other promising diagnostic tests with the potential to distinguish these two conditions pending further study include assessment of 5‐alpha‐reductase activity, leptin, INSL3, kisspeptin and inhibin B levels.ConclusionFurther data directly comparing the discriminatory potential of these markers to differentiate PCOS and FHA in women with secondary amenorrhoea would be of value in defining an objective probability for PCOS or FHA diagnosis.

Journal article

Comninos A, Yang L, OCallaghan J, Mills E, Wall M, Demetriou L, Wing V, Thurston L, Owen B, Abbara A, Rabiner E, Dhillo Wet al., 2021, Kisspeptin modulates gamma-aminobutyric acid levels in the human brain, Psychoneuroendocrinology, Vol: 129, Pages: 1-5, ISSN: 0306-4530

Gamma-aminobutyric acid (GABA) is a key inhibitory neurotransmitter that has been implicated in the aetiology of common mood and behavioural disorders. By employing proton magnetic resonance spectroscopy in man, we demonstrate that administration of the reproductive neuropeptide, kisspeptin, robustly decreases GABA levels in the limbic system of the human brain; specifically the anterior cingulate cortex (ACC). This finding defines a novel kisspeptin-activated GABA pathway in man, and provides important mechanistic insights into the mood and behaviour-altering effects of kisspeptin seen in rodents and humans. In addition, this work has therapeutic implications as it identifies GABA-signalling as a potential target for the escalating development of kisspeptin-based therapies for common reproductive disorders of body and mind.

Journal article

Clarke S, Phylactou M, Patel B, Mills E, Muzi B, Izzi-Engbeaya C, Choudhury S, Khoo B, Meeran K, Comninos A, Abbara A, Tan T, Dhillo Wet al., 2021, Normal adrenal and thyroid function in patients who survive COVID-19 infection, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: 2208-2220, ISSN: 0021-972X

ContextThe COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown. ObjectivesOur objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors. DesignA prospective, observational study was undertaken. SettingClinical Research Facility, Imperial College NHS Healthcare Trust. ParticipantsSeventy patients ≥ 18 years at least 3 months after diagnosis of COVID-19 were included. InterventionParticipants attended a research study visit (08:00-09:30), during which a short Synacthen test (250 µg IV bolus), and thyroid function assessments were performed.ResultsAll patients had a peak cortisol ≥450 nmol/l after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n=44) compared to those without (n=26).ConclusionsAdrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. Whilst a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19.

Journal article

Kyriacou C, Abbara A, Bobdiwala S, Fourie H, Al-Memar M, Phylactou M, Eng CP, Izzi-Engbeaya C, Mills E, Bech P, Comninos A, Huo L, Dhillo W, Bourne Tet al., 2021, Circulating kisspeptin levels in ectopic pregnancy and pregnancy of unknown location, Publisher: WILEY, Pages: 38-39, ISSN: 1470-0328

Conference paper

Mills EG, Yang L, Nielsen MF, Kassem M, Dhillo WS, Comninos ANet al., 2021, The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens., Endocr Rev

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as Primary Ovarian Insufficiency, Hypothalamic Amenorrhea, Congenital Hypogonadotropic Hypogonadism and Early Menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin releasing hormone, follicle stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly ageing population.

Journal article

Yang L, Demetriou L, Wall MB, Mills EG, Wing VC, Thurston L, Schaufelberger CN, Owen BM, Abbara A, Rabiner EA, Comninos AN, Dhillo WSet al., 2021, The Effects of Kisspeptin on Brain Response to Food Images and Psychometric Parameters of Appetite in Healthy Men, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 106, Pages: E1837-E1848, ISSN: 0021-972X

Journal article

Khoo B, Tan T, Clarke S, Mills E, Patel B, Modi M, Phylactou M, Eng PC, Thurston L, Alexander E, Meeran K, Comninos A, Abbara A, Dhillo Wet al., 2021, Thyroid function before, during and after COVID-19, Journal of Clinical Endocrinology and Metabolism, Vol: 106, Pages: e803-e811, ISSN: 0021-972X

Context: The effects of COVID-19 on the thyroid axis remain uncertain. Recent evidence has been conflicting, with both thyrotoxicosis and suppression of thyroid function reported. Objective: We aimed to detail the acute effects of COVID-19 on thyroid function and determine if these effects persisted upon recovery from COVID-19. Design: Cohort observational study. Participants and setting: Adult patients admitted to Imperial College Healthcare National Health Service Trust, London, UK with suspected COVID-19 between March 9 to April 22, 2020 were included, excluding those with pre-existing thyroid disease and those missing either free thyroxine (FT4) or TSH measurements. Of 456 patients, 334 had COVID-19 and 122 did not.Main Outcome Measures: TSH and FT4 measurements at admission, and where available, those taken in 2019 and at COVID-19 follow-up. Results: Most patients (86·6%) presenting with COVID-19 were euthyroid, with none presenting with overt thyrotoxicosis. Patients with COVID-19 had a lower admission TSH and FT4 compared to those without COVID-19. In the COVID-19 patients with matching baseline thyroid function tests from 2019 (n=185 for TSH and 104 for FT4), both TSH and FT4 were reduced at admission compared to baseline. In a complete cases analysis of COVID-19 patients with TSH measurements at follow-up, admission and baseline (n=55), TSH was seen to recover to baseline at follow-up. Conclusions: Most patients with COVID-19 present with euthyroidism. We observed mild reductions in TSH and FT4 in keeping with a non-thyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.

Journal article

Mills EG, Izzi-Engbeaya C, Abbara A, Comninos AN, Dhillo WSet al., 2020, Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour, Nature Reviews Endocrinology, Vol: 17, Pages: 97-113, ISSN: 1759-5029

The bioactive peptides galanin, spexin and kisspeptin have a common ancestral origin and their pathophysiological roles are increasingly the subject of investigation. Evidence suggests that these bioactive peptides play a role in the regulation of metabolism, pancreatic β-cell function, energy homeostasis, mood and behaviour in several species, including zebrafish, rodents and humans. Galanin signalling suppresses insulin secretion in animal models (but not in humans), is potently obesogenic and plays putative roles governing certain evolutionary behaviours and mood modulation. Spexin decreases insulin secretion and has potent anorectic, analgesic, anxiolytic and antidepressive-like effects in animal models. Kisspeptin modulates glucose-stimulated insulin secretion, food intake and/or energy expenditure in animal models and humans. Furthermore, kisspeptin is implicated in the control of reproductive behaviour in animals, modulation of human sexual and emotional brain processing, and has antidepressive and fear-suppressing effects. In addition, galanin-like peptide is a further member of the galaninergic family that plays emerging key roles in metabolism and behaviour. Therapeutic interventions targeting galanin, spexin and/or kisspeptin signalling pathways could therefore contribute to the treatment of conditions ranging from obesity to mood disorders. However, many gaps and controversies exist, which must be addressed before the therapeutic potential of these bioactive peptides can be established.

Journal article

Abbara A, Eng PC, Phylactou M, Clarke SA, Mills E, Chia G, Yang L, Izzi-Engbeaya C, Smith N, Jayasena CN, Comninos AN, Anand-Ivell R, Rademaker J, Xu C, Quinton R, Pitteloud N, Dhillo WSet al., 2020, Kisspeptin-54 accurately identifies hypothalamic GnRH neuronal dysfunction in men with congenital hypogonadotropic hypogonadism., Neuroendocrinology

BACKGROUND: Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Congenital Hypogonadotropic Hypogonadism (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration of function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. METHODS: Men with CHH (n=21) and healthy eugonadal men (n=21) received an intravenous bolus of either GnRH (100mcg), or KP54 (6.4nmol/kg), on two occasions, and were monitored for 6hrs after administration of each neuropeptide. RESULTS: Maximal LH-rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; P<0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (auROC curve KP54: 1.0, 95%CI 1.0-1.0; GnRH: 0.88, 95%CI 0.76-0.99). Indeed, all CHH men had an LH-rise <2.0 iU/L following KP54, whereas all healthy men had an LH-rise >4.0 iU/L. Anosmic men with CHH (i.e. Kallmann syndrome) had even lower LH-rises after KP54 than did normosmic men with CHH (P=0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH-rises after KP54 than other men with CHH (P=0.035). CONCLUSION: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.

Journal article

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, Vol: 130, Pages: 6739-6753, ISSN: 0021-9738

BACKGROUND. Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODS. We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTS. In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSION. Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDING. National Institute for Health Research and NIH.

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, Vol: 11, ISSN: 1664-2392

Objective: The maturation of oocytes to acquire competence for fertilization is critical to the success of in vitro fertilization (IVF) treatment. It requires LH-like exposure, provided by either human chorionic gonadotropin (hCG), or gonadotropin releasing hormone agonist (GnRHa). More recently, the hypothalamic stimulator, kisspeptin, was used to mature oocytes. Herein, we examine the relationship between the endocrine changes following these agents and oocyte maturation.Design: Retrospective cohort study.Methods: Prospectively collected hormonal data from 499 research IVF cycles triggered with either hCG, GnRHa, or kisspeptin were evaluated.Results: HCG-levels (121 iU/L) peaked at 24 h following hCG, whereas LH-levels peaked at ~4 h following GnRHa (140 iU/L), or kisspeptin (41 iU/L). HCG-levels were negatively associated with body-weight, whereas LH rises following GnRHa and kisspeptin were positively predicted by pre-trigger LH values. The odds of achieving the median mature oocyte yield for each trigger were increased by hCG/LH level. Progesterone rise during oocyte maturation occurred precipitously following each trigger and strongly predicted the number of mature oocytes retrieved. Progesterone rise was positively associated with the hCG-level following hCG trigger, but negatively with LH rise following all three triggers. The rise in progesterone per mature oocyte at 12 h was greater following GnRHa than following hCG or kisspeptin triggers.Conclusion: The endocrine response during oocyte maturation significantly differed by each trigger. Counter-intuitively, progesterone rise during oocyte maturation was negatively associated with LH rise, even when accounting for the number of mature oocytes retrieved. These data expand our understanding of the endocrine changes during oocyte maturation and inform the design of future precision-triggering protocols.

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, Cortisol concentrations and mortality from COVID-19 - Authors' reply, The Lancet Diabetes and Endocrinology, Vol: 8, Pages: 809-810, ISSN: 2213-8595

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

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

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

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

Mills EGA, O'Byrne KT, Comninos AN, 2019, Kisspeptin as a behavioral hormone, Seminars in Reproductive Medicine, Vol: 37, Pages: 56-63, ISSN: 1526-4564

Successful reproduction is dependent not only on hormonal endocrine responses but also on suitable partner selection, copulatory acts, as well as associated emotional, behavioral, and cognitive processes many of which are supported by the limbic system. The reproductive hormone kisspeptin (encoded by the KISS1/kiss1 gene) is now recognized as the key orchestrator of the reproductive axis. In addition to the hypothalamus, prominent kisspeptin neuronal populations have been identified throughout limbic and paralimbic brain regions across an assortment of species. In this review, we detail the emerging roles of kisspeptin signaling in the broader aspects of behavioral, emotional, and cognitive control. Recent studies from zebrafish through humans have provided new molecular and neural insights into the complex role of kisspeptin in interpreting olfactory and auditory cues to govern sexual partner preference, in regulating copulatory behaviors and in influencing mood and emotions. Furthermore, emerging roles for kisspeptin in facilitating memory and learning are also discussed. To this end, these findings shed new light onto the importance of kisspeptin signaling, while informing the pharmacological development of kisspeptin as a potential therapeutic strategy for individuals suffering from associated reproductive, emotional, and cognitive disorders.

Journal article

Mills EGA, O'Byrne KT, Comninos AN, 2019, The roles of the amygdala kisspeptin system, Seminars in Reproductive Medicine, Vol: 37, Pages: 64-70, ISSN: 1526-4564

The hypothalamic hormone kisspeptin (encoded by the KISS1/kiss1 gene) is the master regulator of the reproductive axis with its role in controlling gonadotrophin hormone secretion now well characterized. However, identification of kisspeptin and its cognate receptor expression within the amygdala, a key limbic brain region whose functions contribute to a broad range of physiological and behavioral processes, has heightened interest concerning kisspeptins' role in the broader aspects of reproductive physiology. In this review, we detail the important developments and key studies examining the emerging functions of this kisspeptin population. These studies provide novel advances in our understanding of the mechanisms controlling reproductive neuroendocrinology by defining the crucial role of the amygdala kisspeptin system in modulating pubertal timing, reproductive hormone secretion, and pulsatility, as well as its influence in governing-related behaviors. To this end, the role of the amygdala kisspeptin system in integrating reproductive hormone secretion with behavior sheds new light onto the potential use of kisspeptin-based therapeutics for reproductive and related psychosexual disorders.

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

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

Hunjan T, Abbara A, Patel A, 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, 35th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 447-447, ISSN: 0268-1161

Conference paper

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

Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Mohideen P, Lin VH, Stern TP, Panay N, Hunter MS, Webber LC, Dhillo WSet al., 2019, Neurokinin 3 Receptor Antagonism Rapidly Improves Vasomotor Symptoms With Sustained Duration of Action, Obstetrical & Gynecological Survey, Vol: 74, Pages: 221-222, ISSN: 0029-7828

Journal article

Izzi-Engbeaya CN, Comninos AN, Clarke S, Abbara A, Lewis M, Holmes E, Nicholson J, Tan T, Rutter G, Dhillo Wet al., 2018, The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans, Diabetes, Obesity and Metabolism, Vol: 20, Pages: 2800-2810, ISSN: 1462-8902

AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

Journal article

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