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

Al Wattar BH, Teh JJ, Clarke S, Abbara A, Morman R, Wilcox A, Talaulikar Vet al., 2024, Healthcare and research priorities for women with polycystic ovary syndrome in the UK National Health Service: A modified Delphi method, Clinical Endocrinology, Vol: 100, Pages: 459-465, ISSN: 0300-0664

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a chronic lifelong condition affecting up to 20% of women worldwide. There is limited input from affected women to guide the provision of healthcare services and future research needs. Our objective was to scope the healthcare and research priorities of women with PCOS in the United Kingdom. DESIGN: A three-staged modified Delphi method, consisting of two questionnaires and a consensus meeting involving lay representatives and healthcare professionals. PATIENTS AND MEASUREMENTS: Lay patient representatives of women with PCOS. Participants were asked to identify and rank healthcare and research priorities for their importance. RESULTS: Six hundred and twenty-four lay participants took part in our Delphi method. Over 98% were diagnosed with PCOS (614/624, 98.4%). More than half experienced difficulties to receive a PCOS diagnosis (375/624, 60%), and the majority found it difficult to access specialised PCOS health services in the NHS (594/624, 95%). The top two healthcare priorities included better education for health professionals on the diagnosis and management of PCOS (238/273, 87.1%) and the need to set up specialist PCOS services (234/273, 85.7%). The top two research priorities focused on identifying better treatments for irregular periods (233/273, 85.3%) followed by better tests for early PCOS diagnosis (230/273, 84.2%). CONCLUSIONS: We identified 13 healthcare and 14 research priorities that reflect the current health needs of women with PCOS in the United Kingdom. Adopting these priorities in future healthcare and research planning will help to optimise the health of women with PCOS and increase patient satisfaction.

Journal article

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., 2024, Obesity-related hypogonadism in women, Endocrine Reviews, Vol: 45, Pages: 171-189, 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

Hanassab S, Abbara A, Yeung AC, Voliotis M, Tsaneva-Atanasova K, Kelsey TW, Trew GH, Nelson SM, Heinis T, Dhillo WSet al., 2024, The prospect of artificial intelligence to personalize assisted reproductive technology, npj Digital Medicine, Vol: 7, Pages: 1-19, ISSN: 2398-6352

Infertility affects 1-in-6 couples, with repeated intensive cycles of assisted reproductive technology (ART) required by many to achieve a desired live birth. In ART, typically, clinicians and laboratory staff consider patient characteristics, previous treatment responses, and ongoing monitoring to determine treatment decisions. However, the reproducibility, weighting, and interpretation of these characteristics are contentious, and highly operator-dependent, resulting in considerable reliance on clinical experience. Artificial intelligence (AI) is ideally suited to handle, process, and analyze large, dynamic, temporal datasets with multiple intermediary outcomes that are generated during an ART cycle. Here, we review how AI has demonstrated potential for optimization and personalization of key steps in a reproducible manner, including: drug selection and dosing, cycle monitoring, induction of oocyte maturation, and selection of the most competent gametes and embryos, to improve the overall efficacy and safety of ART.

Journal article

Garg A, Zielinska AP, Yeung AC, Abdelmalak R, Chen R, Hossain A, Israni A, Nelson SM, Babwah AV, Dhillo WS, Abbara Aet al., 2024, Luteal phase support in assisted reproductive technology., Nat Rev Endocrinol, Vol: 20, Pages: 149-167

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.

Journal article

Voliotis M, Abbara A, Prague JK, Veldhuis JD, Dhillo WS, Tsaneva-Atanasova Ket al., 2024, HormoneBayes: A novel Bayesian framework for the analysis of pulsatile hormone dynamics., PLoS Comput Biol, Vol: 20

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e.g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no open-access, graphical interface software for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the widely used deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driv

Journal article

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

Abbara A, Ufer M, Voors-Pette C, Berman L, Ezzati M, Wu R, Lee T-Y, Arjona Ferreira JC, Migoya E, Dhillo WSet al., 2024, Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from two randomized, placebo-controlled clinical trials, Fertility and Sterility, Vol: 121, Pages: 95-106, ISSN: 0015-0282

Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 (KP54) can induce oocyte maturation during in vitro fertilization treatment, including in women at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported.ObjectiveTo determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (Phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (Phase-2a trial).DesignTwo randomized, placebo-controlled, parallel group, dose-finding trials.SettingClinical trials unit, Netherlands.ParticipantsHealthy women aged 18-35 years, either without (Phase-1; n=24), or with ovarian stimulation (Phase-2a; n=75).InterventionsPhase-1: Single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 μg) or placebo, (n=6 per dose).Phase-2a: Single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 μg; n=16-17 per dose), triptorelin 0.2 mg (n=5; active comparator), or placebo (n=5).Main Objectives and Outcome MeasuresPhase-1: Safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones).Phase-2a: Safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); time to ovulation assessed by transvaginal ultrasound.ResultsIn both trials, MVT-602 was safe and well-tolerated across the entire dose-range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours.In the Phase-2a trial, LH concentrations increased dose-dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3μg MVT-602

Journal article

Koysombat K, McGown P, Nyunt S, Abbara A, Dhillo WSet al., 2024, New advances in menopause symptom management, Best Practice and Research: Clinical Endocrinology and Metabolism, Vol: 38, Pages: 1-17, ISSN: 1521-690X

Vasomotor symptoms (VMS) are characteristic of menopause experienced by over 75% of postmenopausal women with significant health and socioeconomic implications. Although the average duration of symptoms is seven years, 10% of women experience symptoms for more than a decade. Although menopausal hormone therapy (MHT) remains an efficacious and cost-effective treatment, its use may not be suitable in all women, such as those at an increased risk of breast cancer or gynaecological malignancy. The neurokinin B (NKB) signaling pathway, together with its intricate connection to the median preoptic nucleus (MnPO), has been postulated to provide integrated reproductive and thermoregulatory responses, with a central role in mediating postmenopausal VMS. This review describes the physiological hypothalamo-pituitary-ovary (HPO) axis, and subsequently the neuroendocrine changes that occur with menopause using evidence derived from animal and human studies. Finally, data from the latest clinical trials using novel therapeutic agents that antagonise NKB signaling are reviewed.

Journal article

Grant B, Campbell J, Pradeep A, Burns AD, Bassett P, Abbara A, Saket P, Minhas S, Dhillo WS, McVeigh J, Bhasin S, Jayasena CNet al., 2023, Factors predicting normalization of reproductive hormones after cessation of anabolic-androgenic steroids in men: a single center retrospective study., Eur J Endocrinol, Vol: 189, Pages: 601-610

OBJECTIVE: Symptomatic hypogonadism discourages men from stopping anabolic-androgenic steroids (AAS). Some men illicitly take drugs temporarily stimulating endogenous testosterone following AAS cessation (post-cycle therapy; PCT) to lessen hypogonadal symptoms. We investigated whether prior PCT use was associated with the normalization of reproductive hormones following AAS cessation. METHODS: Retrospective analysis of 641 men attending a clinic between 2015-2022 for a single, nonfasting, random blood test <36 months following AAS cessation, with or without PCT. Normalized reproductive hormones (ie, a combination of reference range serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels) were the surrogate marker of biochemical recovery. RESULTS: Normalization of reproductive hormones was achieved in 48.2% of men. PCT use was associated with faster biochemical recovery (13.0 (IQR8.0-19.0) weeks, PCT; 26.0 (IQR10.5-52) weeks, no-PCT; P < .001). Odds of biochemical recovery during multivariable analysis were: (1) higher with PCT (OR3.80) vs no-PCT (P = .001), in men stopping AAS ≤3 months previously; (2) reduced when 2 (OR0.55), 3 (OR0.46), or 4 (OR0.25) AAS were administered vs 1 drug (P = .009); (3) lower with AAS >6 vs ≤3 months previously (OR0.34, P = .01); (4) higher with last reported AAS >3 months (OR 5.68) vs ≤3 months (P = .001). PCT use was not associated with biochemical recovery in men stopping AAS >3 months previously. CONCLUSION: Without evidence-based withdrawal protocols, men commonly try avoiding post-AAS hypogonadism with PCT, which is illicit, ill-defined, and not recommended. Only half of men had complete biochemical testicular recovery after stopping AAS. The surprising association of self-reported PCT use with short-term biochemical recovery from AAS-induced hypogonadism warrants further investigation.

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

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, Bhattacharya M, 2023, The versatile kisspeptin: advances in cancer, metabolism, and reproduction, FRONTIERS IN ENDOCRINOLOGY, Vol: 14, ISSN: 1664-2392

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

Koysombat K, Dhillo WS, Abbara A, 2023, Assessing hypothalamic pituitary gonadal function in reproductive disorders, Clinical Science, Vol: 137, Pages: 863-879, ISSN: 0143-5221

Reproductive conditions secondary to disorders of the hypothalamic–pituitary–gonadal (HPG) axis are common and are associated with important health implications and considerable psychosocial impact. Basal and dynamic tests enable interrogation of individual components of the HPG axis, facilitating diagnosis and understanding of the pathophysiology of reproductive disorders. Onset of puberty is controlled by hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal function. To date, a dynamic test of hypothalamic function is not yet available. Therefore, accurate differentiation of pubertal disorders such as constitutional delay of growth and puberty (CDGP) and congenital hypogonadotrophic hypogonadism (CHH) as causes of delayed puberty is challenging due to similar clinical presentations and hormonal profiles. Likewise, although the two commonest reproductive disorders in women, polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhoea (FHA) have disparate hypothalamic function, oligo/amenorrhoea frequently poses a diagnostic conundrum owing to the overlap in the criteria used to define both conditions. This review aims to describe pubertal and reproductive disorders secondary to pathologies affecting the HPG axis. Challenges encountered in clinical practice in differentiating pubertal and reproductive conditions are reviewed in conjunction with the utility of baseline and dynamic endocrine tests to interrogate specific components of the HPG axis. We also highlight putative hypothalamic, pituitary, and gonadal markers in development that could improve the diagnosis of patients presenting with disorders of puberty or reproduction.

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 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

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

Koysombat K, Abbara A, Dhillo WS, 2023, Current pharmacotherapy and future directions for neuroendocrine causes of female infertility, EXPERT OPINION ON PHARMACOTHERAPY, Vol: 24, Pages: 37-47, ISSN: 1465-6566

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

Voliotis M, Hanassab S, Abbara A, Heinis T, Dhillo WS, Tsaneva-Atanasova Ket al., 2022, Quantitative approaches in clinical reproductive endocrinology, Current Opinion in Endocrine and Metabolic Research, Vol: 27, ISSN: 2451-9650

Understanding the human hypothalamic-pituitary-gonadal (HPG) axis presents a major challenge for medical science. Dysregulation of the HPG axis is linked to infertility and a thorough understanding of its dynamic behaviour is necessary to both aid diagnosis and to identify the most appropriate hormonal interventions. Here, we review how quantitative models are being used in the context of clinical reproductive endocrinology to: 1. analyse the secretory patterns of reproductive hormones; 2. evaluate the effect of drugs in fertility treatment; 3. aid in the personalization of assisted reproductive technology (ART). In this review, we demonstrate that quantitative models are indispensable tools enabling us to describe the complex dynamic behaviour of the reproductive axis, refine the treatment of fertility disorders, and predict clinical intervention outcomes.

Journal article

Tsoutsouki J, Abbara A, Dhillo W, 2022, Novel therapeutic avenues for kisspeptin, CURRENT OPINION IN PHARMACOLOGY, Vol: 67, ISSN: 1471-4892

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

Stevenson H, Bartram S, Charalambides MM, Murthy S, Petitt T, Pradeep A, Vineall O, Abaraonye I, Lancaster A, Koysombat K, Patel B, Abbara Aet al., 2022, Kisspeptin-neuron control of LH pulsatility and ovulation, Frontiers in Endocrinology, Vol: 13, ISSN: 1664-2392

Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action via oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated via upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed ‘Kisspeptin-Neurokinin B-Dynorphin’ (KNDy) neurons. ARC KP-neurons function as the ‘GnRH pulse generator’ to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.

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

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