Imperial College London

ProfessorAlexanderComninos

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Professor of Practice (Endocrinology)
 
 
 
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Contact

 

+44 (0)20 3313 3242a.comninos

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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118 results found

Abbara A, Adams S, Phylactou M, Izzi-Engbeaya C, Mills EG, Thurston L, Koysombat K, Hanassab S, Heinis T, M-M Tan T, Tsaneva-Atanasova K, Comninos AN, Voliotis M, Dhillo WSet al., 2024, Quantifying the variability in the assessment of reproductive hormone levels, Fertility and Sterility, Vol: 121, Pages: 334-345, ISSN: 0015-0282

OBJECTIVE: To quantify how representative a single measure of reproductive hormone is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. DESIGN: Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. SUBJECTS: Overall, 266 individuals including healthy men and women (n=142), and those with reproductive disorders/states (n=124) [11 with functional hypothalamic amenorrhoea (FHA), 6 with polycystic ovary syndrome (PCOS), 62 women and 32 men with hypoactive sexual desire disorder (HSDD), and 13 post-menopausal women] were included in the analysis. INTERVENTIONS: Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones due to pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. MAIN OUTCOME MEASURES: The ability of a single measure of reproductive hormone to quantify the variability in reproductive hormones due to pulsatile secretion, diurnal variation, and nutrient-intake. RESULTS: The initial morning value of reproductive hormones was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: LH 18.4%, FSH 9.7%, testosterone 9.2%, and estradiol 2.1%). LH was the most variable (CV 28%), followed by sex-steroids (testosterone 12%, estradiol 13%), whereas FSH was the least variable reproductive hormone (CV 8%). In healthy men, testosterone fell between 9am and 5pm by 14.9% (95% CI 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2=0.53, p<0.0001). Testosterone was reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), or after an oral glucose load (6.0%), or an intravenous gluco

Journal article

Hanassab S, Abbara A, Kelsey TW, Yeung ACY, Hramyka A, Alhamwi T, Salim R, Comninos AN, Trew GH, Nelson SM, Heinis T, Dhillo WSet al., 2023, OPTIMIZING OOCYTE YIELD: UNVEILING THE IDEAL FOLLICLE SIZES ON THE DAY OF TRIGGER USING INTERPRETABLE MACHINE LEARNING, 79th Scientific Congress of the American-Society-for-Reproductive-Medicine (ASRM), Publisher: ELSEVIER SCIENCE INC, Pages: E34-E35, ISSN: 0015-0282

Conference paper

Eng PC, Phylactou M, Qayum A, Woods C, Lee H, Aziz S, Moore B, Miras AD, Comninos AN, Tan T, Franks S, Dhillo WS, Abbara Aet al., 2023, Obesity-related hypogonadism in women, Endocrine Reviews, ISSN: 0079-9963

Obesity-related hypogonadotropic hypogonadism is a well-characterized condition in men (termed male obesity-related secondary hypogonadism; MOSH); however, an equivalent condition has not been as clearly described in women. The prevalence of polycystic ovary syndrome (PCOS) is known to increase with obesity, but PCOS is more typically characterized by increased gonadotropin-releasing hormone (GnRH) (and by proxy luteinizing hormone; LH) pulsatility, rather than by the reduced gonadotropin levels observed in MOSH. Notably, LH levels and LH pulse amplitude are reduced with obesity, both in women with and without PCOS, suggesting that an obesity-related secondary hypogonadism may also exist in women akin to MOSH in men. Herein, we examine the evidence for the existence of a putative non-PCOS “female obesity-related secondary hypogonadism” (FOSH). We précis possible underlying mechanisms for the occurrence of hypogonadism in this context and consider how such mechanisms differ from MOSH in men, and from PCOS in women without obesity. In this review, we consider relevant etiological factors that are altered in obesity and that could impact on GnRH pulsatility to ascertain whether they could contribute to obesity-related secondary hypogonadism including: anti-Müllerian hormone, androgen, insulin, fatty acid, adiponectin, and leptin. More precise phenotyping of hypogonadism in women with obesity could provide further validation for non-PCOS FOSH and preface the ability to define/investigate such a condition.

Journal article

Izzi-Engbeaya C, Patel B, Mills E, Phylactou M, Clarke S, Comninos A, Abbara A, Tan T, Dhillo Wet al., 2023, The effects of kisspeptin on food intake in women with overweight or obesity, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 25, Pages: 2393-2397, ISSN: 1462-8902

Journal article

Patel B, Koysombat K, Mills EG, Tsoutsouki J, Comninos AN, Abbara A, Dhillo WSet al., 2023, The Emerging Therapeutic Potential of Kisspeptin and Neurokinin B, ENDOCRINE REVIEWS, ISSN: 0163-769X

Journal article

Abbara A, Phylactou M, Eng PC, Clarke S, Pham T, Ho TM, Ng KY, Mills E, Purugganan K, Hunjan T, Salim R, Comninos A, Vuong L, Dhillo WSet al., 2023, Endocrine responses to triptorelin in healthy women, women with polycystic ovary syndrome and hypothalamic amenorrhea, Journal of Clinical Endocrinology and Metabolism, Vol: 108, Pages: 1666-1675, ISSN: 0021-972X

ContextLimited data exist regarding whether the endocrine response to the gonadotropin-releasing hormone receptor agonist (GnRHa) triptorelin differs in women with polycystic ovary syndrome (PCOS) compared with healthy women or those with hypothalamic amenorrhea (HA).ObjectiveWe compared the gonadotropin response to triptorelin in healthy women, women with PCOS, or those with HA without ovarian stimulation, and in women with or without polycystic ovaries undergoing oocyte donation cycles after ovarian stimulation.MethodsThe change in serum gonadotropin levels was determined in (1) a prospective single-blinded placebo-controlled study to determine the endocrine profile of triptorelin (0.2 mg) or saline-placebo in healthy women, women with PCOS, and those with HA, without ovarian stimulation; and (2) a retrospective analysis from a dose-finding randomized controlled trial of triptorelin (0.2-0.4 mg) in oocyte donation cycles after ovarian stimulation.ResultsIn Study 1, triptorelin induced an increase in serum luteinizing hormone (LH) of similar amplitude in all women (mean peak LH: healthy, 52.3; PCOS, 46.2; HA, 41.3 IU/L). The AUC of change in serum follicle-stimulating hormone (FSH) was attenuated in women with PCOS compared with healthy women and women with HA (median AUC of change in serum FSH: PCOS, 127.2; healthy, 253.8; HA, 326.7 IU.h/L; P = 0.0005). In Study 2, FSH levels 4 hours after triptorelin were reduced in women with at least one polycystic morphology ovary (n = 60) vs normal morphology ovaries (n = 91) (34.0 vs 42.3 IU/L; P = 0.0003). Serum anti-Müllerian hormone (AMH) was negatively associated with the increase in FSH after triptorelin, both with and without ovarian stimulation.ConclusionFSH response to triptorelin was attenuated in women with polycystic ovaries, both with and without ovarian stimulation, and was negatively related to AMH levels.

Journal article

Hanassab S, Abbara A, Alhamwi T, Comninos A, Salim R, Trew G, Nelson S, Kelsey T, Heinis T, Dhillo Wet al., 2023, P-623 Using machine learning to determine follicle sizes on the day of trigger most likely to yield oocytes, Human Reproduction, Vol: 38, Pages: 1-2, ISSN: 0268-1161

Study questionWhich follicle sizes on the day of trigger (DoT) are most likely to yield oocytes after different IVF treatment protocols and trigger types?Summary answerFollicles sized 11-19mm on DoT are most likely to yield oocytes in both 'long' and 'short' protocols after using either hCG or GnRH agonist triggers.What is known alreadyOn the DoT, both follicles that are too small, or too large, are less likely to yield oocytes, but the precise range of follicle sizes that are most contributory to oocyte yield remains uncertain. Knowledge of this optimal follicle size range can aid in selecting the DoT and in quantifying the efficacy of the trigger by benchmarking the expected number of oocytes to be retrieved. Machine learning can aid in the analysis of large complex datasets and thus could be used to determine the follicle sizes on the DoT that are most predictive of the number of oocytes retrieved.Study design, size, durationWe applied machine learning techniques to data from 8030 patients aged under 35 years who underwent autologous fresh IVF and ICSI cycles between 2011-2021 in a single IVF clinic. The DoT was determined by 2-3 leading follicles reaching ≥ 18mm in size. Follicle sizes from ultrasound scans performed on the DoT (n = 3056), a day prior to DoT (n = 2839), or two days prior to DoT (n = 2135), were evaluated in relation to the number of oocytes retrieved.Participants/materials, setting, methodsA two-stage random forest pipeline was developed, with the number of follicles of a certain size on DoT as input, and the number of oocytes retrieved as output. First, a variable preselection model to determine the most contributory follicle sizes. Second, a model to identify the optimal range of follicle sizes to yield oocytes. Both models were trained and cross-validated with fixed hyperparameters. The pipeline was run for each protocol and trigger type independently.Main results and the role of chanceThe machine

Journal article

Mills EG, Abbara A, Dhillo WS, Comninos ANet al., 2023, Effects of distinct Polycystic Ovary Syndrome phenotypes on bone health, Frontiers in Endocrinology, Vol: 14, ISSN: 1664-2392

Polycystic Ovary Syndrome (PCOS) is a highly prevalent and heterogenous endocrinopathy affecting 5-18% of women. Although its cardinal features include androgen excess, ovulatory dysfunction, and/or polycystic ovarian morphology, women often display related metabolic manifestations, including hyperinsulinaemia, insulin resistance, and obesity. Emerging data reveal that the hormonal alterations associated with PCOS also impact bone metabolism. However, inconsistent evidence exists as to whether PCOS is a bone-protective or bone-hindering disorder with an accumulating body of clinical data indicating that hyperandrogenism, hyperinsulinaemia, insulin resistance, and obesity may have a relative protective influence on bone, whereas chronic low-grade inflammation and vitamin D deficiency may adversely affect bone health. Herein, we provide a comprehensive assessment of the endocrine and metabolic manifestations associated with PCOS and their relative effects on bone metabolism. We focus principally on clinical studies in women investigating their contribution to the alterations in bone turnover markers, bone mineral density, and ultimately fracture risk in PCOS. A thorough understanding in this regard will indicate whether women with PCOS require enhanced surveillance of bone health in routine clinical practice.

Journal article

Phylactou M, Comninos A, salih A, labib M, chia eng P, Clarke S, Moore P, Tan T, Cegla J, Dhillo W, Abbara Aet al., 2023, Derivation and comparison of formulae for the adjustment of total calcium, Frontiers in Endocrinology, Vol: 14, Pages: 1-10, ISSN: 1664-2392

Background: Free ionized calcium (Ca2+) is the biologically active component of total calcium (TCa) and hence responsible for its biological action. TCa is routinely adjusted for albumin using several formulae (e.g. James, Orell, Payne and Berry) to more closely reflect Ca2+. Here, we derive a novel formula to estimate Ca2+ and compare its performance to established formulae.Methods: Cohort for prediction of Ca2+: 2806 serum samples (TCa) taken contemporaneously with blood gas samples (Ca2+) at Imperial College Healthcare NHS Trust were used to derive formulae to estimate Ca2+ using multivariable linear regression. Cohort for prediction of PTH: Performance of novel and existing formulae to predict PTH in 5510 patients was determined by Spearman correlation.Results: Ca2+ prediction Cohort: Adjusted calcium (r2 = 0.269) was less strongly associated with Ca2+, than TCa (r2 = 0.314). Prediction of Ca2+ from a newly derived formula incorporating TCa, potassium, albumin, and hematocrit had an improved r2 of 0.327, whereas inclusion of all available parameters increased the r2 further to 0.364. Of the established formulae, James performed best in predicting Ca2+ (r2 = 0.27). PTH prediction cohort: Berry resulted in higher whereas Orell in lower adjusted calcium levels. Prediction of PTH was strongest in the setting of hypercalcemia, with James having the highest Spearman correlation coefficient (+0.496) similar to including all parameters (+0.499).Conclusion: Adjustment of calcium for albumin using established formulae does not always outperform unadjusted TCa in the reflection of Ca2+. Further prospective studies are needed to optimise adjustment of TCa and to establish bounds for validity.

Journal article

Mills E, Ertl N, Wall M, Thurston L, Yang L, Suladze S, Hunjan T, Phylactou M, Patel B, Muzi B, Ettehad D, Bassett P, Howard J, Rabiner E, Bech P, Abbara A, Goldmeier D, Comninos A, Dhillo Wet al., 2023, Effects of kisspeptin on sexual brain processing and penile tumescence in men with hypoactive sexual desire disorder: a randomized clinical trial, Jama Network Open, Vol: 6, Pages: 1-16, ISSN: 2574-3805

Importance The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.Objective To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.Design, Setting, and Participants This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.Interventions Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.Main Outcomes and Measures Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level–dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.Results Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass i

Journal article

Clarke SA, Phylactou M, Patel B, Mills EG, Muzi B, ChiomaIzziEngbeaya, Choudhury S, Khoo B, Meeran K, Comninos AN, Abbara A, Tan T, Dhillo WSet al., 2023, Letter to the Editor of Clinical Endocrinology: Assessment of adrenal function in patients who survive COVID‐19, Clinical Endocrinology, Vol: 98, Pages: 270-272, ISSN: 0300-0664

It is widely recognised that the effects of COVID-19 extend beyond the respiratory system. Moreover, there are an estimated 1.3 million people living with Long COVID (symptoms persisting beyond 12 weeks after infection) in the UK alone.

Journal article

Abbara A, Patel B, Parekh I, Garg A, Jayasena C, Comninos A, Dhillo Wet al., 2022, Ovarian Hyperstimulation Syndrome (OHSS) requiring Intensive Care Unit (ICU) admission between 1996-2020 in England, Wales, and Northern Ireland, Frontiers in Endocrinology, Vol: 13, ISSN: 1664-2392

Introduction: Ovarian Hyperstimulation Syndrome (OHSS) is a life-threatening iatrogenic complication of In vitro fertilisation (IVF). This study aimed to quantify rates of Ovarian Hyperstimulation Syndrome (OHSS) requiring intensive care unit (ICU) admission and assess whether trends have changed between 1996-2020 commensurate with the introduction of safer IVF practices.Methods: Data regarding Intensive Care Unit (ICU) admission across England, Wales and Northern Ireland was gathered retrospectively from the Intensive Care National Audit and Research Centre (ICNARC) database. 38,957 female patients aged between 18-55 years were admitted to ICU for OHSS or related conditions between 1996-2020. The primary outcome was the rate of OHSS requiring ICU admission expressed as a proportion of the number of fresh IVF cycles conducted in that year according to Human Fertility and Embryology Authority (HFEA) records. Baseline characteristics (for example, age, ethnicity, BMI), biochemical parameters (such as renal function, serum electrolytes), length of ICU stay and duration and need for organ support, were also compared between ICU patients with ‘confirmed OHSS’ and those ‘without OHSS’.Results: There were 238 cases of ‘confirmed OHSS’ requiring ICU admission recorded between 1996-2020. Rates of OHSS requiring ICU admission declined over the study period (P=0.006); the annual rate of severe OHSS requiring intensive care admission halved when comparing those occurring between 1996-2007 and 2008-2020 (OR=0.37, 95% CI 0.37-0.45; P<0.0001). Patients spent a mean of 3.5 days in the ICU, with 86.3% of patients with ‘confirmed OHSS’ requiring at least 2 days of higher level (i.e., level 2 or 3) care. Patients with ‘confirmed OHSS’ required a shorter duration of renal, advanced cardiovascular, and advanced respiratory support than patients ‘without OHSS’ (P<0.0001 for all comparisons). There was no signif

Journal article

Abbara A, Koysombat K, Phylactou M, Eng PC, Clarke S, Comninos AN, Yang L, Izzi-Engbeaya C, Hanassab S, Smith N, Jayasena C, Xu C, Quinton R, Pitteloud N, Binder G, Anand-Ivell R, Ivell R, Dhillo Wet al., 2022, Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men, Frontiers in Endocrinology, Vol: 13, ISSN: 1664-2392

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with “red flag” features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa).Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH.Materials and methods: Retrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adult men who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured.Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB.Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54.Results: Median INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p<0.0001). However, INSL3 more accurately differentiated CHH in adult men than in boys with delayed puberty (auROC with 95% CI in adult men: 100%, 100-100%; boys with delayed puberty: 86.7%, 77.7-95.7%).Median INB was higher in boys with CDGP than CHH (182 vs 59 pg/ml; p<0.0001). Likewise, in adult men, median INB was higher in eugonadal men than CHH (170 vs 36.5 pg/ml; p<0.0001). INB performed better than INSL3 in differentiating

Journal article

Thurston L, Hunjan T, Ertl N, Wall M, Mills E, Suladze S, Patel B, Alexander E, Muzi B, Bassett P, Rabiner E, Bech P, Goldmeier D, Abbara A, Comninos A, Dhillo Wet al., 2022, Effects of kisspeptin administration in women with hypoactive sexual desire disorder: a randomized clinical trial, Jama Network Open, Vol: 5, Pages: 1-14, ISSN: 2574-3805

Importance: The absence or deficiency of sexual desire leading to distress or interpersonal difficultydefines ‘hypoactive sexual desire disorder’ (HSDD). Despite being the most common female sexualhealth complaint worldwide, current treatment options for HSDD are limited in their safety andeffectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonalaxis with additional emerging roles in sexual and emotional behavior, however, its effects in womenwith HSDD are unknown.Objective: To test the hypothesis that kisspeptin enhances sexual and attraction brain processing inwomen with HSDD.Design: A randomized, double-blind, two-way crossover, placebo-controlled clinical trial. Functionalneuroimaging, psychometric and hormonal analyses were employed to investigate the effects ofkisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facialattraction (face images of varying attractiveness).Setting: The trial was conducted in a university research setting from October 2020 to April 2021. Datawere analyzed from May to December 2021.Participants: 32 premenopausal women with HSDD for at least 6 months’ duration.Interventions: 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rateplacebo infusion.Main Outcome and Measures: Blood oxygen level–dependent responses across the whole brain andregions of interest during kisspeptin vs placebo administration, in response to erotic and facialattraction stimuli.Results: Of the 40 participants who were randomized, 32 women completed both kisspeptin andplacebo visits, and the mean (SEM) age was 29.2 (1.2) years. Kisspeptin administration resulted inmodulations in sexual and facial attraction brain processing (all P<.05). Furthermore, positivecorrelations were observed between kisspeptin-enhanced hippocampal activity in response to eroticvideos, and baseline distress relating to sexual function (P<.01). In additio

Journal article

Bawor M, Sairam S, Rozewicz R, Viegas S, Comninos AN, Abbara Aet al., 2022, Rhabdomyolysis after COVID-19 infection: a case report and review of the literature, Viruses, Vol: 14, Pages: 1-10, ISSN: 1999-4915

Rhabdomyolysis is a condition in which muscle breaks down potentially leading to renal dysfunc-tion, and often occurs secondary to a precipitating factor. Viral or bacterial infections are common precipitants for initiating rhabdomyolysis. Recently, healthcare systems across the world have been challenged by a pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing ‘coronavirus disease 2019’ (COVID-19) disease. SARS-CoV-2 infection is recognized to cause respiratory and cardiovascular compromise, thromboembolic events, and acute kidney injury (AKI), however it is not known whether it can precipitate rhabdomyolysis, with only a limited number of cases of SARS-CoV-2 infection preceding rhabdomyolysis reported to date. Here, we report the case of a 64-year old woman who developed rhabdomyolysis shortly after SARS-CoV-2 infection and COVID-19. She initially presented with muscular pain, a creatine kinase level of 119,301 IU/L, and a mild rise in her creatinine level to 92 µmol/L, but successfully recovered with intravenous fluid support. We also review the literature to summarise previously reported cases of rhabdomyolysis precipitated by SARS-CoV-2, highlighting the need to consider this diagnosis in patients presenting with SARS-CoV-2 and myalgia.

Journal article

Thurston L, Hunjan T, Mills E, Wall M, Ertl N, Phylactou M, Muzi B, Patel B, Alexander E, Suladze S, Modi M, Eng P, Bassett P, Abbara A, Goldmeier D, Comninos A, Dhillo Wet al., 2022, Melanocortin 4 receptor agonism enhances sexual brain processing in women with hypoactive sexual desire disorder, Journal of Clinical Investigation, Vol: 132, Pages: 1-12, ISSN: 0021-9738

BACKGROUND. Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODS. Using psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTS. MC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSION. These data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATION. ClinicalTrials.gov NCT04179734.FUNDING. This is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (C

Journal article

Sharma B, Koysombat K, Dhillo W, Abbara Aet al., 2022, Use of kisspeptin to trigger oocyte maturation during in vitro fertilisation (IVF) treatment, Frontiers in Endocrinology, Vol: 13, Pages: 1-9, ISSN: 1664-2392

Infertility is a major global health issue and is associated with significant psychological distress for afflicted couples. In vitrofertilisation (IVF) utilises supra-physiological doses of stimulatory hormones to induce the growth of multiple ovarian follicles toenable surgical retrieval of several oocytes for subsequent fertilisation and implantation into the maternal endometrium. Thesupra-physiological degree of ovarian stimulation can lead to potential risks during IVF treatment, including ovarianhyperstimulation syndrome (OHSS) and multiple pregnancy.The choice of oocyte maturation trigger, such as human chorionic gonadotrophin (hCG) or gonadotrophin releasing hormoneagonist (GnRHa), can impact both the efficacy of IVF treatment with a bearing on luteal phase hormonal dynamics and thus thedegree of luteal phase support required to maintain optimal pregnancy rates, as well as on safety of treatment with particularrespect to the risk of OHSS. Kisspeptin regulates gonadotrophin releasing hormone (GnRH) release and is therefore a key regulatorof the hypothalamo-pituitary-gonadal (HPG) axis. Kisspeptin has been shown to be requisite for the occurrence of the physiologicalovulatory luteinising hormone (LH) surge. In this review, we discuss the potential use of kisspeptin as a novel trigger of oocytematuration.

Journal article

Tsoutsouki J, Patel B, Dhillo W, Abbara Aet al., 2022, Kisspeptin in the prediction of pregnancy complications, Frontiers in Endocrinology, Vol: 13, ISSN: 1664-2392

Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin’s role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).

Journal article

Todorov G, Brook S, Quah Qin Xian N, Von Widekind S, Freudenthal B, Comninos Aet al., 2022, Comparison of fracture risk calculators in elderly fallers: a hospital-based cross-sectional study, BMJ Open, Vol: 12, ISSN: 2044-6055

Objective: Elderly patients presenting with falls are known to carry an extremely high risk of future fragility fractures. Current osteoporosis guidelines recommend using fracture risk calculators such as FRAX, QFracture or Garvan to guide management. However, they differ considerably in their inputs and may therefore provide contrasting risk estimations in certain individuals. In this study, we compared these risk calculators in a high-risk cohort of elderly patients admitted to hospital with falls.Design: Hospital-based cross-sectional study.Setting: Secondary care, London, United KingdomParticipants: Data from 120 consecutive elderly falls patients presenting to a single hospital over 4 months were collected. 10-year major and hip fracture risks were calculated using FRAX, QFracture and Garvan. 1-year major and hip fracture risks from QFracture were assessed against prospective incidence of fracture.Results: Median 10-year major fracture risk was: FRAX 19.5%, QFracture 26.0%, Garvan 32.5%. Median 10-year hip fracture risk was: FRAX 9.6%, QFracture 21.2%, Garvan 6.5%. Correlation between FRAX-QFracture was r=0.672 for major, r=0.676 for hip fracture (both p<0.0001); FRAX-Garvan r=0.778 (p<0.0001) for major, r=0.128 (p=0.206) for hip fracture; QFracture-Garvan r=0.658 (p<0.0001) for major, r=0.318 (p<0.001) for hip fracture. QFracture 1-year predicted major and hip fracture rates were 1.8% and 1.2% respectively, compared to actual rates of 2.1% and 0%respectively.Conclusions: Although strong correlations between calculators were observed in the study cohort, there were differences of up to 13% between risks. QFracture captured several elderly-specific inputs not considered by other calculators and so projected higher fracture risk than the other calculators. QFracture provided 1-year fracture risks that were comparable with the prospective observed fracture incidence in the cohort. This study has important clinical implications for the use of fracture

Journal article

Behary P, Comninos A, 2022, Bone perspectives in functional hypothalamic amenorrhoea: an update and future avenues, Frontiers in Endocrinology, Vol: 13, ISSN: 1664-2392

One of the most important and potentially long-lasting detrimental consequences of Functional Hypothalamic Amenorrhoea (FHA) ison skeletal homeostasis. Beyond oestrogen deficiency, FHA is associated with a cascade of additional neuro-endocrine and metabolicalterations, some adaptive, but which combine to disrupt skeletal homeostasis. Ultimately, this leads to a two-fold increased riskof fractures in women with FHA compared to healthy eumenorrhoeic women. Although the cornerstone of management ofFHA-related bone loss remains recovery of menses via restoration of metabolic/psychological balance, there is rapidly developingevidence for hormonal manipulations (with a particular emphasis on route of administration) and other pharmacologicaltreatments that can protect or improve skeletal homeostasis in FHA. In this mini-review, we provide an update on thepathophysiology, clinical management and future avenues in the field from a bone perspective.

Journal article

Mills E, Yang L, Abbara A, Dhillo W, Comninos Aet al., 2022, Current perspectives on kisspeptins role in behaviour, Frontiers in Endocrinology, Vol: 13, ISSN: 1664-2392

The neuropeptide kisspeptin is now well-established as the master regulator of the mammalian reproductive axis. Beyond the hypothalamus, kisspeptin and its cognate receptor are also extensively distributed in extra-hypothalamic brain regions. An expanding pool of animal and human data demonstrates that kisspeptin sits within an extensive neuroanatomical and functional framework through which it can integrate a range of internal and external cues with appropriate neuroendocrine and behavioural responses. In keeping with this, recent studies reveal wide-reaching effects of kisspeptin on key behaviours such as olfactory-mediated partner preference, sexual motivation, copulatory behaviour, bonding, mood, and emotions. In this review, we provide a comprehensive update on the current animal and human literature highlighting the far-reaching behaviour and mood-altering roles of kisspeptin. A comprehensive understanding of this important area in kisspeptin biology is key to the escalating development of kisspeptin-based therapies for common reproductive and related psychological and psychosexual disorders.

Journal article

Hunjan T, Thurston L, Ertl N, Wall M, Mills E, Suladze S, Patel B, Alexander E, Muzi B, Rabiner E, Bech P, Goldmeier D, Abbara A, Comninos A, Dhillo Wet al., 2022, Kisspeptin modulates sexual brain processing in women with low sexual desire, Publisher: WILEY, Pages: 200-200, ISSN: 1470-0328

Conference paper

Hunjan T, Thurston L, Mills E, Wall M, Ertl N, Phylactou M, Muzi B, Patel B, Alexander E, Suladze S, Modi M, Eng P, Bassett P, Abbara A, Goldmeier D, Comninos A, Dhillo Wet al., 2022, MELANOCORTIN-4 RECEPTOR AGONISM MODULATES SEXUAL BRAIN PROCESSING IN WOMEN WITH LOW SEXUAL DESIRE, Publisher: ELSEVIER SCI LTD, Pages: S123-S123, ISSN: 1743-6095

Conference paper

Comninos AN, Hansen MS, Courtney A, Choudhury S, Yang L, Mills EG, Phylactou M, Busbridge M, Khir M, Thaventhiran T, Bech P, Tan T, Abbara A, Frost M, Dhillo WSet al., 2022, Acute effects of kisspeptin administration on bone metabolism in healthy men, Journal of Clinical Endocrinology and Metabolism, Vol: 107, ISSN: 0021-972X

CONTEXT: Osteoporosis results from disturbances in bone formation and resorption. Recent non-human data suggests that the reproductive hormone, kisspeptin, directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. OBJECTIVE: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. DESIGN: In vitro study: Mono- and co-cultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, two-way crossover clinical study in twenty-six men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. PARTICIPANTS: In vitro study: Twelve male blood donors and eight patients undergoing hip replacement surgery. Clinical Study: Twenty-six healthy eugonadal men (age 26.8±5.8 years). INTERVENTION: Kisspeptin (versus placebo). MAIN OUTCOME MEASURES: Changes in bone parameters and turnover markers. RESULTS: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P=0.0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P<0.0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P=0.021) and 24.3% maximal increase in carboxylated osteocalcin levels (P=0.014). CONCLUSIONS: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex-steroid levels. Kisspeptin could therefore have clinical thera

Journal article

Clarke S, Phylactou M, Patel B, Mills E, Muzi B, Izzi-Engbeaya C, khoo B, Meeran M, Comninos A, Abbara A, Tan T, Oliver N, Dhillo Wet al., 2022, Preserved C-peptide in survivors of COVID-19: post-hoc analysis, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 570-574, ISSN: 1462-8902

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., 2022, Changes in circulating kisspeptin levels during each trimester in women with antenatal complications, Journal of Clinical Endocrinology and Metabolism, Vol: 107, Pages: e71-e83, 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

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, ENDOCRINE REVIEWS, Vol: 42, Pages: 691-719, ISSN: 0163-769X

Journal article

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 (vol 42, pg 691, 2021), ENDOCRINE REVIEWS, Vol: 42, Pages: 872-872, ISSN: 0163-769X

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., 2021, Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism, NEUROENDOCRINOLOGY, Vol: 111, Pages: 1176-1186, ISSN: 0028-3835

Journal article

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

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