Publications by authors named "Waljit S Dhillo"

167 Publications

Impact of COVID-19 on the Endocrine System - a mini-review.

Endocrinology 2021 Sep 20. Epub 2021 Sep 20.

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

The Corona Virus Disease 2019 (COVID-19) pandemic continues to exert a significant impact on global healthcare systems, causing devastating mortality and morbidity. As time passes and our understanding of this novel respiratory virus deepens, it is increasingly clear that its effects extend beyond that of the respiratory system. The coronavirus responsible for COVID-19, SARS-CoV-2, obtains cellular access through the angiotensin converting enzyme 2 (ACE2) receptor in a process requiring the transmembrane serine protease 2 (TMPRSS2) protein. Both ACE2 and TMPRSS2 are widely expressed in many endocrine glands. This, along with several case reports of thyroid and pituitary disruption in patients with COVID-19, has resulted in significant interest in its impact on the endocrine system. Indeed, as mortality is abated by the increasing availability of effective vaccines, there is increasing focus on the long-term effects on health in COVID-19 survivors. This review summarises data investigating the effects of COVID-19 on each of the endocrine axes to guide appropriate investigations and optimal management.
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http://dx.doi.org/10.1210/endocr/bqab203DOI Listing
September 2021

Changes in circulating kisspeptin levels during each trimester in women with antenatal complications.

J Clin Endocrinol Metab 2021 Aug 24. Epub 2021 Aug 24.

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, UK.

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 three trimesters in women with antenatal complications.

Objective: To assess whether kisspeptin levels are altered in women with antenatal complications.

Design: Women 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).

Setting: Early Pregnancy Assessment Unit at Hammersmith Hospital, UK.

Participants: Women 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 Outcome: Differences in circulating kisspeptin levels.

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 affected by 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.
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http://dx.doi.org/10.1210/clinem/dgab617DOI Listing
August 2021

Investigating the potential of clinical and biochemical markers to differentiate between functional hypothalamic amenorrhoea and polycystic ovarian syndrome: A retrospective observational study.

Clin Endocrinol (Oxf) 2021 Oct 9;95(4):618-627. Epub 2021 Aug 9.

Section of Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, London, UK.

Objectives: Functional hypothalamic amenorrhoea (FHA) is a common cause of amenorrhoea, but diagnosis can be challenging. The aim of this study was to investigate the clinical and biochemical features of FHA, compared to that of polycystic ovarian syndrome (PCOS) and assess the diagnostic performance of the different parameters for differentiating the two conditions.

Design And Patients: This was a retrospective observational study. We analysed clinical and biochemical parameters of women diagnosed with FHA and PCOS following specialist assessment at the reproductive endocrine gynaecology clinic, St Mary's Hospital.

Results: Compared with PCOS, women with FHA had significantly lower body mass index (BMI; 20.1 ± 2.9 vs. 31.1 ± 7.8 kg/m ; p< .0001) and a thinner endometrium (3.75 ± 2.23 vs. 6.82 ± 3.32 mm; p< .0001). Women with FHA had significantly lower luteinising hormone (LH; 3.46 ± 7.31 vs. 8.79 ± 4.98 IU/L; p< .0001), and lower LH to follicle-stimulating hormone (FSH) ratio, estradiol, thyroid-stimulating hormone, free thyroxine and prolactin levels; there was no significant difference in FSH levels. BMI had the greatest predictive performance for FHA (area under the curve [AUC]: 0.93; p< .001), followed by estradiol (AUC: 0.89; p< .001), LH (AUC: 0.88; p< .001) and LH:FSH ratio (AUC: 0.86; p< .001).

Conclusions: Our data provides quantification for diagnostic accuracy of clinical parameters to differentiate FHA from PCOS, namely low BMI, estradiol, LH and LH:FSH ratio. These data could help clinicians more reliably diagnose FHA in women with secondary amenorrhoea.
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http://dx.doi.org/10.1111/cen.14571DOI Listing
October 2021

Clinical Potential of Kisspeptin in Reproductive Health.

Trends Mol Med 2021 08 29;27(8):807-823. Epub 2021 Jun 29.

Department of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 ONN, UK. Electronic address:

Kisspeptins are a family of hypothalamic neuropeptides that are essential for the regulation of reproductive physiology. Their importance in reproductive health became apparent in 2003, when loss-of-function variants in the gene encoding the kisspeptin receptor were reported to result in isolated congenital hypogonadotropic hypogonadism (CHH). It has since been ascertained that hypothalamic kisspeptin neurons regulate gonadotropin-releasing hormone (GnRH) secretion to thus stimulate the remainder of the reproductive endocrine axis. In this review, we discuss genetic variants that affect kisspeptin receptor signaling, summarize data on KISS1R agonists, and posit possible clinical uses of native and synthetic kisspeptin receptor agonists for the investigation and treatment of reproductive disorders.
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http://dx.doi.org/10.1016/j.molmed.2021.05.008DOI Listing
August 2021

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study.

Diabetes Care 2021 Aug 22;44(8):1842-1851. Epub 2021 Jun 22.

Department of Digestion, Metabolism and Reproduction, Imperial College London, London, U.K.

Objective: Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference.

Research Design And Methods: Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups.

Results: We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: ) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; ) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and ) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD.

Conclusions: Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.
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http://dx.doi.org/10.2337/dc20-2641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385466PMC
August 2021

Targeting elevated GnRH pulsatility to treat Polycystic Ovary Syndrome.

J Clin Endocrinol Metab 2021 Jun 12. Epub 2021 Jun 12.

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, UK.

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http://dx.doi.org/10.1210/clinem/dgab422DOI Listing
June 2021

Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestational age during the first trimester.

Fertil Steril 2021 09 27;116(3):809-819. Epub 2021 May 27.

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom. Electronic address:

Objective: To compare the performance of kisspeptin and beta human chorionic gonadotropin (βhCG), both alone and in combination, as biomarkers for miscarriage throughout the first trimester.

Design: Prospective, nested case-control study.

Setting: Tertiary 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.
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http://dx.doi.org/10.1016/j.fertnstert.2021.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445632PMC
September 2021

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Front Endocrinol (Lausanne) 2021 11;12:654600. Epub 2021 May 11.

Department of Endocrinology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center.

Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded.

Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement.

Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.
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http://dx.doi.org/10.3389/fendo.2021.654600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147556PMC
May 2021

Normal Adrenal and Thyroid Function in Patients Who Survive COVID-19 Infection.

J Clin Endocrinol Metab 2021 07;106(8):2208-2220

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, UK.

Context: The 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.

Objective: Our objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors.

Methods: A prospective, observational study was undertaken at the Clinical Research Facility, Imperial College NHS Healthcare Trust, including 70 patients ≥18 years of age, at least 3 months after diagnosis of COVID-19. Participants attended a research study visit (8:00-9:30 am), during which a short Synacthen test (250 µg IV bolus) and thyroid function assessments were performed.

Results: All 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).

Conclusion: Adrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. While 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.
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http://dx.doi.org/10.1210/clinem/dgab349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194556PMC
July 2021

Emerging roles for kisspeptin in metabolism.

J Physiol 2021 May 11. Epub 2021 May 11.

Section of Endocrinology & Investigative Medicine, Imperial College London, London, UK.

Kisspeptin, a neuropeptide hormone, has been firmly established as a key regulator of the hypothalamic-pituitary-gonadal axis and mammalian reproductive behaviour. In recent years, a growing body of evidence has emerged suggesting a role for kisspeptin in regulating metabolic processes. This data suggest that kisspeptin exerts its metabolic effects indirectly via gonadal hormones and/or directly via the kisspeptin receptor in the brain, pancreas and brown adipose tissue. Kisspeptin receptor knockout studies indicate that kisspeptin may play sexually dimorphic roles in the physiological regulation of energy expenditure, food intake and body weight. Some, but not all, in vitro work demonstrates positive effects on glucose-stimulated insulin secretion, which is more marked at higher kisspeptin concentrations. Acute and chronic in vivo rodent, non-human primate and human studies reveal enhancement of glucose-stimulated insulin secretion in response to pharmacological doses of kisspeptin. Although significant progress has been made in elucidating the metabolic effects of kisspeptin, further mechanistic work and translational studies are required to address unanswered questions and establish the metabolic effects of kisspeptin in diverse human populations (including women, people with obesity and people with diabetes).
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http://dx.doi.org/10.1113/JP281712DOI Listing
May 2021

Kisspeptin modulates gamma-aminobutyric acid levels in the human brain.

Psychoneuroendocrinology 2021 Jul 26;129:105244. Epub 2021 Apr 26.

Division of Diabetes, Endocrinology & Metabolism, Imperial College London, UK; Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243259PMC
July 2021

The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens.

Endocr Rev 2021 Apr 26. Epub 2021 Apr 26.

Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as Primary Ovarian Insufficiency, Hypothalamic Amenorrhea, Congenital Hypogonadotropic Hypogonadism and Early Menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin releasing hormone, follicle stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly ageing population.
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http://dx.doi.org/10.1210/endrev/bnab015DOI Listing
April 2021

Representing the Metabolome with High Fidelity: Range and Response as Quality Control Factors in LC-MS-Based Global Profiling.

Anal Chem 2021 02 15;93(4):1924-1933. Epub 2021 Jan 15.

National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom.

Liquid chromatography-mass spectrometry (LC-MS) is a powerful and widely used technique for measuring the abundance of chemical species in living systems. Its sensitivity, analytical specificity, and direct applicability to biofluids and tissue extracts impart great promise for the discovery and mechanistic characterization of biomarker panels for disease detection, health monitoring, patient stratification, and treatment personalization. Global metabolic profiling applications yield complex data sets consisting of multiple feature measurements for each chemical species observed. While this multiplicity can be useful in deriving enhanced analytical specificity and chemical identities from LC-MS data, data set inflation and quantitative imprecision among related features is problematic for statistical analyses and interpretation. This Perspective provides a critical evaluation of global profiling data fidelity with respect to measurement linearity and the quantitative response variation observed among components of the spectra. These elements of data quality are widely overlooked in untargeted metabolomics yet essential for the generation of data that accurately reflect the metabolome. Advanced feature filtering informed by linear range estimation and analyte response factor assessment is advocated as an attainable means of controlling LC-MS data quality in global profiling studies and exemplified herein at both the feature and data set level.
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http://dx.doi.org/10.1021/acs.analchem.0c03848DOI Listing
February 2021

Clinical and biochemical discriminants between functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS).

Clin Endocrinol (Oxf) 2021 Aug 19;95(2):239-252. Epub 2021 Jan 19.

Section of Endocrinology and Investigative Medicine, Hammersmith Hospital, Imperial College London, London, UK.

Background: Secondary 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.

Aim: To review clinical, biochemical and radiological parameters that could aid the clinician in distinguishing PCOS and FHA as a cause of menstrual disturbance.

Results: FHA is uncommon in women with BMI > 24 kg/m , 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.

Conclusion: Further 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.
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http://dx.doi.org/10.1111/cen.14402DOI Listing
August 2021

Male infertility due to testicular disorders.

J Clin Endocrinol Metab 2021 01;106(2):e442-e459

Section of Endocrinology and Investigative Medicine, Imperial College London, UK.

Context: Male infertility is defined as the inability to conceive following 1 year of regular unprotected intercourse. It is the causative factor in 50% of couples and a leading indication for assisted reproductive techniques (ART). Testicular failure is the most common cause of male infertility, yet the least studied to date.

Evidence Acquisition: The review is an evidence-based summary of male infertility due to testicular failure with a focus on etiology, clinical assessment, and current management approaches. PubMed-searched articles and relevant clinical guidelines were reviewed in detail.

Evidence Synthesis/results: Spermatogenesis is under multiple levels of regulation and novel molecular diagnostic tests of sperm function (reactive oxidative species and DNA fragmentation) have since been developed, and albeit currently remain as research tools. Several genetic, environmental, and lifestyle factors provoking testicular failure have been elucidated during the last decade; nevertheless, 40% of cases are idiopathic, with novel monogenic genes linked in the etiopathogenesis. Microsurgical testicular sperm extraction (micro-TESE) and hormonal stimulation with gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors are recently developed therapeutic approaches for men with the most severe form of testicular failure, nonobstructive azoospermia. However, high-quality clinical trials data is currently lacking.

Conclusions: Male infertility due to testicular failure has traditionally been viewed as unmodifiable. In the absence of effective pharmacological therapies, delivery of lifestyle advice is a potentially important treatment option. Future research efforts are needed to determine unidentified factors causative in "idiopathic" male infertility and long-term follow-up studies of babies conceived through ART.
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http://dx.doi.org/10.1210/clinem/dgaa781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823320PMC
January 2021

Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour.

Nat Rev Endocrinol 2021 02 3;17(2):97-113. Epub 2020 Dec 3.

Section of Endocrinology and Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1038/s41574-020-00438-1DOI Listing
February 2021

Kisspeptin-54 accurately identifies hypothalamic GnRH neuronal dysfunction in men with congenital hypogonadotropic hypogonadism.

Neuroendocrinology 2020 Nov 23. Epub 2020 Nov 23.

Background: Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Congenital Hypogonadotropic Hypogonadism (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration of function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH.

Methods: Men with CHH (n=21) and healthy eugonadal men (n=21) received an intravenous bolus of either GnRH (100mcg), or KP54 (6.4nmol/kg), on two occasions, and were monitored for 6hrs after administration of each neuropeptide.

Results: Maximal LH-rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; P<0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (auROC curve KP54: 1.0, 95%CI 1.0-1.0; GnRH: 0.88, 95%CI 0.76-0.99). Indeed, all CHH men had an LH-rise <2.0 iU/L following KP54, whereas all healthy men had an LH-rise >4.0 iU/L. Anosmic men with CHH (i.e. Kallmann syndrome) had even lower LH-rises after KP54 than did normosmic men with CHH (P=0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH-rises after KP54 than other men with CHH (P=0.035).

Conclusion: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.
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http://dx.doi.org/10.1159/000513248DOI Listing
November 2020

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders.

J Clin Invest 2020 12;130(12):6739-6753

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.

BACKGROUNDKisspeptin 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.METHODSWe 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.RESULTSIn 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).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.
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http://dx.doi.org/10.1172/JCI139681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685751PMC
December 2020

Thyroid Function Before, During, and After COVID-19.

J Clin Endocrinol Metab 2021 01;106(2):e803-e811

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

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 on recovery from COVID-19.

Design: A cohort observational study was conducted.

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 preexisting thyroid disease and those missing either free thyroxine (FT4) or thyrotropin (TSH) measurements. Of 456 patients, 334 had COVID-19 and 122 did not.

Main Outcome Measures: TSH and FT4 measurements were recorded at admission, and where available, 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), TSH and FT4 both were reduced at admission compared to baseline. In a complete case 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 nonthyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.
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http://dx.doi.org/10.1210/clinem/dgaa830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823247PMC
January 2021

Endocrine Requirements for Oocyte Maturation Following hCG, GnRH Agonist, and Kisspeptin During IVF Treatment.

Front Endocrinol (Lausanne) 2020 6;11:537205. Epub 2020 Oct 6.

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Objective: The maturation of oocytes to acquire competence for fertilization is critical to the success of 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.
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http://dx.doi.org/10.3389/fendo.2020.537205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573298PMC
May 2021

Commentary on "Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men".

J Clin Endocrinol Metab 2021 01;106(2):e1028-e1030

Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, UK.

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http://dx.doi.org/10.1210/clinem/dgaa783DOI Listing
January 2021

The Effects of Kisspeptin on Brain Response to Food Images and Psychometric Parameters of Appetite in Healthy Men.

J Clin Endocrinol Metab 2021 03;106(4):e1837-e1848

Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.

Context: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans.

Objective: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men.

Design: A double-blinded, randomized, placebo-controlled, crossover study was conducted.

Participants: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2).

Intervention: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes.

Main Outcome Measures: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle.

Results: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle.

Conclusions: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism.
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http://dx.doi.org/10.1210/clinem/dgaa746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993584PMC
March 2021

Using Aptamers as a Novel Method for Determining GnRH/LH Pulsatility.

Int J Mol Sci 2020 Oct 7;21(19). Epub 2020 Oct 7.

Section of Endocrinology and Investigative Medicine, Imperial College London, London W12 0NN, UK.

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.
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http://dx.doi.org/10.3390/ijms21197394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582658PMC
October 2020

Cortisol concentrations and mortality from COVID-19 - Authors' reply.

Lancet Diabetes Endocrinol 2020 10;8(10):809-810

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; Department of Endocrinology, Imperial College Healthcare National Health Service Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30306-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492064PMC
October 2020

Baseline levels of seminal reactive oxygen species predict improvements in sperm function following antioxidant therapy in men with infertility.

Clin Endocrinol (Oxf) 2021 01 12;94(1):102-110. Epub 2020 Oct 12.

Department of Andrology, Hammersmith Hospital, London, UK.

Background: Poor sperm function is a major cause of infertility. There is no drug therapy to improve sperm function. Semen oxidative stress is a recently identified pathway for sperm damage. Commercial antioxidants such as L-carnitine and acetyl-L-carnitine (LAL) are commonly self-administered by infertile men. However, concerns have been raised whether inappropriate LAL therapy causes reductive stress-mediated sperm damage. It is imperative to investigate whether: (1) LAL improves sperm function by reducing reactive oxidative species (ROS); (2) LAL has differential effects on sperm function between men with normal and elevated ROS.

Methods: A prospective cohort study of routine clinical practice was performed in infertile men with abnormal sperm quality. Changes in sperm function and semen ROS levels following three months of oral LAL therapy were compared between participants with baseline seminal normal ROS (≤10RLU/SEC/10 sperm; n = 29) and High ROS (>10 RLU/SEC/10 sperm; n = 15) levels measured using an established colorimetric-luminol method.

Results: In normal ROS group, sperm function did not change following LAL therapy. In high ROS group, LAL therapy reduced semen ROS fivefold, increased sperm count by 50% (mean count in mill/ml: 21.5 + 7.2, baseline; 32.6 + 9.5, post-treatment, P = .0005), and total and progressive sperm motility each by 30% (mean total sperm motility in % 29.8 + 5.0, baseline: 39.4 + 6.2, post-treatment, P = .004; mean progressive sperm motility in % 23.1 + 4.6, baseline: 30.0 + 5.5, post-treatment, P = .014 vs. baseline).

Conclusions: We report for the first time that LAL only improves sperm quality in infertile men who have baseline high-ROS levels prior to treatment. These data have important potential implications for couples with male infertility and their clinicians.
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http://dx.doi.org/10.1111/cen.14328DOI Listing
January 2021

Makorin rings the kisspeptin bell to signal pubertal initiation.

J Clin Invest 2020 08;130(8):3957-3960

The signals maintaining quiescence of the reproductive endocrine axis during childhood before its reawakening at puberty had been enigmatic. Studies in patients with abnormal puberty have illuminated the identity of the signals; kisspeptin has emerged as a major stimulator of puberty, and makorin RING finger protein 3 (MKRN3) as an inhibitory signal that prevents premature initiation of puberty. In this issue of the JCI, Abreu et al. investigated the mechanism by which MKRN3 regulates pubertal onset. The authors found that a reduction in MKRN3 alleviated the constraint on kisspeptin-expressing neurons to allow pubertal initiation, a phenomenon observed across species, including nonhuman primates. Further, the ubiquitinase activity of MKRN3 required its RING finger domain, in order to repress the promoter activity of genes encoding kisspeptin and neurokinin B. These data advance our understanding of the regulation of kisspeptin-expressing neurons by MKRN3 to initiate puberty.
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http://dx.doi.org/10.1172/JCI139586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410055PMC
August 2020

Association between high serum total cortisol concentrations and mortality from COVID-19.

Lancet Diabetes Endocrinol 2020 08 18;8(8):659-660. Epub 2020 Jun 18.

Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; Department of Endocrinology, Imperial College Healthcare National Health Service Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302794PMC
August 2020

Pharmacodynamic Response to Anti-thyroid Drugs in Graves' Hyperthyroidism.

Front Endocrinol (Lausanne) 2020 12;11:286. Epub 2020 May 12.

Section of Endocrinology and Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, United Kingdom.

Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole. Retrospective cohort study. Participants were patients ( = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD. Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres ( < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT40.97-11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose ( < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity. We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.
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http://dx.doi.org/10.3389/fendo.2020.00286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236601PMC
May 2021

Burdens and awareness of adverse self-reported lifestyle factors in men with sub-fertility: A cross-sectional study in 1149 men.

Clin Endocrinol (Oxf) 2020 09 19;93(3):312-321. Epub 2020 May 19.

Section of Investigative Medicine, Imperial College, London, UK.

Background: There are no current pharmacological therapies to improve sperm quality in men with sub-fertility. Reducing the exposure to lifestyle risk factor (LSF) is currently the only intervention for improving sperm quality in men with sub-fertility. No previous study has investigated what proportion of men with sub-fertility are exposed to adverse lifestyle factors. Furthermore, it is not known to what extent men with sub-fertility are aware of lifestyle factors potentially adversely impacting their fertility.

Methods: A cross-sectional anonymous questionnaire-based study on self-reported exposure and awareness of LSF was conducted in 1149 male partners of couples investigated for sub-fertility in a tertiary andrology centre in London, UK.

Results: Seventy per cent of men investigated for sub-fertility had ≥1 LSF, and twenty-nine per cent had ≥2 LSF. Excessive alcohol consumption was the most common LSF (40% respondents). Seventeen per cent of respondents used recreational drugs (RD) regularly, but only 32% of RD users believed RD impair male fertility. Twenty-five per cent of respondents were smokers, which is higher than the UK average (20%). Twenty-seven per cent of respondents had a waist circumference (WC) >36 inches (91 cm), and 4% had WC >40 inches (102 cm). Seventy-nine per cent of respondents wanted further lifestyle education to improve their fertility.

Conclusions: Our data suggest that men with sub-fertility are as follows: (a) exposed to one or more LSF; (b) have incomplete education about how LSF may cause male sub-fertility; (c) want more education about reducing LSF. Further studies are needed to investigate the potential of enhanced education of men about LSF to treat couples with sub-fertility.
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http://dx.doi.org/10.1111/cen.14213DOI Listing
September 2020

Kisspeptin and Testicular Function-Is it Necessary?

Int J Mol Sci 2020 Apr 22;21(8). Epub 2020 Apr 22.

Section of Investigative Medicine, Imperial College, 6th Floor, Commonwealth Building, Hammersmith Hospital, 150 Du Cane Road, London W12 0NN, UK.

The role of kisspeptin in stimulating hypothalamic GnRH is undisputed. However, the role of kisspeptin signaling in testicular function is less clear. The testes are essential for male reproduction through their functions of spermatogenesis and steroidogenesis. Our review focused on the current literature investigating the distribution, regulation and effects of kisspeptin and its receptor (KISS1/KISS1R) within the testes of species studied to date. There is substantial evidence of localised KISS1/KISS1R expression and peptide distribution in the testes. However, variability is observed in the testicular cell types expressing KISS1/KISS1R. Evidence is presented for modulation of steroidogenesis and sperm function by kisspeptin signaling. However, the physiological importance of such effects, and whether these are paracrine or endocrine manifestations, remain unclear.
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http://dx.doi.org/10.3390/ijms21082958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216047PMC
April 2020
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