Imperial College London

DrAliAbbara

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Senior Lecturer in Diabetes and Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 4843ali.abbara Website

 
 
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Location

 

6N6Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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128 results found

Garg A, Patel B, Abbara A, Dhillo WSet al., 2022, Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS), CLINICAL ENDOCRINOLOGY, Vol: 97, Pages: 156-164, ISSN: 0300-0664

Journal article

Abbara A, 2022, Editorial for clinical endocrinology special issue on polycystic ovary syndrome (PCOS), CLINICAL ENDOCRINOLOGY, Vol: 97, Pages: 155-155, ISSN: 0300-0664

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

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

Guzman S, Dragan M, Kwon H, de Oliveira V, Rao S, Bhatt V, Kalemba KM, Shah A, Rustgi VK, Wang H, Bech PR, Abbara A, Izzi-Engbeaya C, Manousou P, Guo JY, Guo GL, Radovick S, Dhillo WS, Wondisford FE, Babwah AV, Bhattacharya Met al., 2022, Targeting hepatic kisspeptin receptor ameliorates non-alcoholic fatty liver disease in a mouse model., Journal of Clinical Investigation, Vol: 132, Pages: 1-20, ISSN: 0021-9738

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes and metabolic syndrome. A hallmark feature of NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism which can progress to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here we have identified that activation of the kisspeptin receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high fat diet-fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In NAFLD patients and in HFD-fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.

Journal article

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

Clarke SA, Abbara A, Dhillo WS, Clarke SA, Abbara A, Dhillo WSet al., 2022, Impact of COVID-19 on the Endocrine System: A Mini-review, ENDOCRINOLOGY, Vol: 163, ISSN: 0013-7227

Journal article

Abbara A, Al-Memar M, Phylactou M, Daniels E, Patel B, Eng PC, Nadir R, Izzi-Engbeaya C, Clarke SA, Mills EG, Hunjan T, Pacuszka E, Yang L, Bech P, Tan T, Comninos AN, Kelsey TW, Kyriacou C, Fourie H, Bourne T, Dhillo WSet al., 2022, Changes in Circulating Kisspeptin Levels During Each Trimester in Women With Antenatal Complications., J Clin Endocrinol Metab, Vol: 107, Pages: e71-e83

CONTEXT: Antenatal 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 3 trimesters in women with antenatal complications. OBJECTIVE: We aimed to assess whether kisspeptin levels are altered in women with antenatal complications. METHODS: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. RESULTS: Third-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 with GDM (P = 0.020), but not significantly on multivariable analysis. CONCLUSION: We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

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

Johnson H, Piggin M, Abbara A, Izzi-Engbeaya C, Scholtz S, Webber L, Jayasena C, Tan Tet al., 2021, Insight Report: Metabolic medicine and endocrinology online public involvement session on weight and fertility

Summary report on the views of members of the public on the proposed research on weight and fertility by the Metabolic Medicine and Endocrinology Theme of the Imperial Biomedical Research Centre.

Report

Guzman S, Dragan M, Kwon H, Bhatt V, Shah A, Rustgi VK, Dhillo WS, Bech PR, Abbara A, Izzi-Engbeaya C, Wang H, Guo GL, Guo JY, Wondisford FE, Babwah AV, Bhattacharya Met al., 2021, KISSPEPTIN RECEPTOR: NEW TARGET TO TREAT NONALCOHOLIC FATTY LIVER DISEASE, Publisher: WILEY, Pages: 1074A-1075A, ISSN: 0270-9139

Conference paper

Abou Sherif S, Newman R, Haboosh S, Al-Sharefi A, Papanikolaou N, Dimakopoulou A, Webber LJ, Abbara A, Franks S, Dhillo WS, Jayasena CNet al., 2021, Investigating the potential of clinical and biochemical markers to differentiate between functional hypothalamic amenorrhoea and polycystic ovarian syndrome: A retrospective observational study, CLINICAL ENDOCRINOLOGY, Vol: 95, Pages: 618-627, ISSN: 0300-0664

Journal article

Abbara A, Dhillo WS, Abbara A, Dhillo WSet al., 2021, Targeting Elevated GnRH Pulsatility to Treat Polycystic Ovary Syndrome, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 106, Pages: E4275-E4277, ISSN: 0021-972X

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 W, Abbara Aet 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, 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

Abbara A, Clarke SA, Dhillo WS, 2021, Clinical Potential of Kisspeptin in Reproductive Health, TRENDS IN MOLECULAR MEDICINE, Vol: 27, Pages: 807-823, ISSN: 1471-4914

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

Yang L, Demetriou L, Wall MB, Mills EG, Wing VC, Thurston L, Schaufelberger CN, Owen BM, Abbara A, Rabiner EA, Comninos AN, Dhillo WS, 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

Abbara A, Phylactou M, Dhillo WS, Abbara A, Phylactou M, Dhillo WSet al., 2021, Commentary on "Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men" Comment, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 106, Pages: E1028-E1030, ISSN: 0021-972X

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 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

Izzi-Engbeaya C, Abbara A, Cass A, Dhillo Wet al., 2020, Using Aptamers as a Novel Method for Determining GnRH/LH Pulsatility, International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067

Aptamers are a novel technology enabling the continuous measurement of analytes in blood and other body compartments, without the need for repeated sampling and the associated reagent costs of traditional antibody-based methodologies. Aptamers are short single-stranded synthetic RNA or DNA that recognise and bind to specific targets. The conformational changes that can occur upon aptamer–ligand binding are transformed into chemical, fluorescent, colour changes and other readouts. Aptamers have been developed to detect and measure a variety of targets in vitro and in vivo. Gonadotropin-releasing hormone (GnRH) is a pulsatile hypothalamic hormone that is essential for normal fertility but difficult to measure in the peripheral circulation. However, pulsatile GnRH release results in pulsatile luteinizing hormone (LH) release from the pituitary gland. As such, LH pulsatility is the clinical gold standard method to determine GnRH pulsatility in humans. Aptamers have recently been shown to successfully bind to and measure GnRH and LH, and this review will focus on this specific area. However, due to the adaptability of aptamers, and their suitability for incorporation into portable devices, aptamer-based technology is likely to be used more widely in the future.

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

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