Egészségügy | Endokrinológia » Thozhukat Sathyapalan - Novel and traditional biomarkers for the diagnosis and risk stratification for women with polycystic ovary syndrome

University of Warwick Coventry CV4 7AL, UK A Thesis Submitted for the Degree of PhD at the University of Warwick Permanent WRAP URL: http://wrap.warwickacuk/193425 Copyright and reuse: This thesis is made available online and is protected by original copyright. Please scroll down to view the document itself. Please refer to the repository record for this item for information to help you to cite it. Our policy information is available from the repository home page. For more information, please contact the WRAP Team at: wrap@warwick.acuk Warwick Research Publications (WRAP) Novel and traditional biomarkers for the diagnosis and risk stratification for women with polycystic ovary syndrome by Thozhukat Sathyapalan MBBS, MD, FRCP Thesis submitted for the degree of Doctor of Philosophy (by Published Work) in Medical Sciences Warwick Medical School University of Warwick December 2024 1 Table of Contents TABLES.3 FIGURES.4 ABBREVIATIONS.5 ACKNOWLEDGEMENTS.6 DECLARATION.7

ABSTRACT.8 INTRODUCTION.9 AETIOLOGY OF PCOS.9 DIAGNOSIS OF PCOS.10 Table 1.12 Table 2.13 POLYCYSTIC OVARIES.14 ANTI-MULLERIAN HORMONE (AMH).14 AMH AND POLYCYSTIC OVARIES.15 ANDROGENS.15 SALIVARY ANDROGENS.15 TANDEM MASS SPECTROMETRY.16 PCOS AND METABOLIC SYNDROME.16 HULL PCOS BIOBANK.17 Table 3: Comparison of anthropometric and hormonal parameters of the women recruited to Hull PCOS biobank.18 THESIS OVERVIEW.19 PUBLICATION 1.19 PUBLICATION 2.22 PUBLICATION 3.25 PUBLICATION 4.27 Table 4 : Demographic characteristics of the discovery cohort (PCOS audit) and replication cohort (PCOS biobank).30 Figure 1a and 1b: PCOS clusters in PCOS audit and PCOS biobank.32 PUBLICATION 5.34 SUMMARY DISCUSSION.36 CONCLUSION AND FUTURE DIRECTIONS.38 REFERENCES.39 PUBLISHED WORK TILL DATE.42 DECLARATION OF CONTRIBUTORS.78 2 TABLES Table 1 – Diagnostic criteria for PCOS Table 2 – PCOS phenotypes Table 3 - Comparison of anthropometric and hormonal parameters of the women (Hull PCOS biobank). Table

4 - Demographic characteristics of the discovery cohort (PCOS audit) and replication cohort (PCOS biobank) 3 FIGURES Figure 1a and 1b: PCOS clusters in PCOS audit and PCOS biobank 4 ABBREVIATIONS 7OHP – 17 hydroxy progesterone AMH – Anti-Müllerian hormone ASRM - American Society for Reproductive Medicine BMI – Body Mass Index CAH – Congenital Adrenal Hyperplasia DHEAS – Dehydroepiandrosterone DHT – Dihydrotestosterone ESHRE - European Society of Human Reproduction and Embryology FAI – Free Androgen Index FSH – Follicle Stimulating Hormone HOMA-IR – Homeostasis model of assessment – insulin resistance LC-MS/MS - liquid chromatography-mass spectrometry LH – Luteinising hormone NIH/NICHD - National Institutes of Health/National Institute of Child Health and Human Development PCO – Polycystic ovaries PCOS – Polycystic ovary syndrome Sal A – Salivary androstenedione Sal T – Salivary testosterone SHBG- Sex Hormone Binding Globulin siMS - Metabolic

syndrome score 5 ACKNOWLEDGEMENTS I thank my wife Esther Selvey and my extended family for their tireless support and encouragement. I thank all collaborators and co-authors of the work presented in this thesis for their invaluable contribution. I thank Prof Stephen Atkin and Prof Eric Kilpatrick for their constructive suggestions Finally, I thank Professor Harpal S Randeva for supervising this thesis. 6 DECLARATION This thesis is submitted to the University of Warwick in support of an application for the degree of Doctor of Philosophy. It has been composed by Thozhukat Sathyapalan under the supervision of Professor Harpal S Randeva and has not been submitted in any previous application for any degree. The work presented was carried out by Thozhukat Sathyapalan. Thozhukat Sathyapalan 1st October 2024 7 ABSTRACT This thesis explores the diagnostic challenges and heterogeneity of Polycystic Ovary Syndrome (PCOS), a prevalent endocrine disorder affecting women of

reproductive age. Traditional diagnostic criteria for the condition, such as the Rotterdam Consensus Criteria, do not adequately address the diversity of metabolic and hormonal manifestations present in women with PCOS. This research aims to refine diagnostic accuracy and management by integrating novel biomarkers and developing a risk stratification model. First, this thesis investigates the efficacy of Anti-Müllerian Hormone (AMH) as a biomarker for PCOS. AMH, reflective of antral follicle count, provides a more convenient diagnostic tool than traditional ultrasound, offering enhanced diagnostic reliability. Additionally, the research evaluates the utility of salivary androgens, particularly testosterone and androstenedione, measured using advanced liquid chromatography- mass spectrometry/mass spectrometry (LCMS/MS) techniques to assess their role in diagnosing PCOS. This approach simplifies the testing process, potentially enabling broader screening and more precise monitoring of

treatment efficacy. Further, the thesis employs statistical analyses to segment the PCOS population into distinct subgroups based on hormonal and metabolic profiles, aiming to tailor treatment approaches to individual risk profiles. This supported the development of a novel four-variable risk prediction and stratification model derived from a well-characterised biobank cohort. This model incorporates clinical and biochemical parameters to effectively assess and stratify metabolic risk. Overall, this work contributes to a better understanding of the complex pathology of PCOS and supports the implementation of personalised treatment strategies. The findings have the potential to significantly improve diagnostic and management protocols and enhance the quality of life for women with PCOS. 8 Introduction The global prevalence of PCOS ranges from 6% to 21%, depending on the diagnostic criteria used, ethnicity, and region (1). In 2017, there were approximately 155 million new cases of

PCOS among women of reproductive age worldwide (2). About 17% of PCOS cases in 2017 were in women aged 21-30 years, highlighting the prevalence in younger women of reproductive age (3). It is a complex condition with reproductive, metabolic, and psychological consequences (4). PCOS presents heterogeneously, with symptoms such as irregular menstrual cycles, hirsutism, subfertility, and an increased risk of cardiometabolic issues, including type 2 diabetes, cardiovascular disease, and endometrial cancer (5). Recent studies have shown that nearly 50% of PCOS patients have obesity, 31.1% have impaired glucose regulation, 75% have type 2 diabetes (T2D) and women with PCOS have a 3.3 times higher risk of impaired glucose tolerance (IGT) and a 2.9 times higher risk of T2D compared to healthy individuals (6) It is also linked to a higher likelihood of pregnancy-related complications, including gestational diabetes, hypertensive disorders, miscarriage, preterm delivery, and low birth weight

(7). It also has a wider societal implication and high economic cost. The condition has significant societal implications, with the economic burden, including diagnosis and long-term health issues, estimated at 4.3 billion US dollars annually as of 2020 (8) Aetiology of PCOS While precise aetiology remains to be fully elucidated, current evidence strongly supports PCOS as a complex multigenic disorder with significant epigenetic and environmental influences rather than a simple genetic condition or purely ovarian disorder (4). Based on the latest research, the genetic component of polycystic ovary syndrome (PCOS) demonstrates a significant hereditary nature, with studies indicating familial clustering, higher concordance in monozygotic twins compared to dizygotic twins, and an estimated 70% heritability, suggesting a strong genetic basis (9). Rather than being caused by a single gene mutation, PCOS is now understood to be a complex trait with an oligogenic basis involving multiple

genes (10). While some studies have suggested an autosomal dominant inheritance, current evidence points to a more complex inheritance pattern (10). The syndrome exhibits significant clinical heterogeneity, leading to the identification of distinct phenotypes, including "reproductive" and "metabolic" subtypes (10). Genome-wide association studies (GWAS) have identified several candidate genes and loci associated with PCOS, such as THADA, LHCGR, DENND1A, and INSR (9). There is also growing evidence for epigenetic influences, including 9 potential in-utero exposure to higher levels of androgens and anti-Müllerian hormone (AMH) (11). Environmental factors, such as diet, lifestyle, and obesity, play a significant role in the expression and severity of PCOS symptoms, interacting with genetic predisposition (10). Overall, PCOS is now recognised as a complex disorder with this interplay between genetic predisposition, epigenetic modifications, and environmental

factors, emphasising its multifactorial nature and moving beyond earlier simplistic models of inheritance (11). Diagnosis of PCOS Although PCOS was first identified by American gynaecologists Stein and Leventhal in 1935, based on a study involving seven women (28), its heterogeneous presentation and diagnostic complexity still often lead to delays in diagnosis and treatment (12). In the United States, the 1990 National Institute of Health (NIH) Conference on PCOS suggested that diagnostic criteria should include evidence of hyperandrogenism (either clinical or biochemical) and ovulatory dysfunction, provided there are no indications of non-classic congenital adrenal hyperplasia (CAH) or other disorders such as Cushing's syndrome, thyroid dysfunction, hyperprolactinaemia, and acromegaly. The inclusion of polycystic ovarian morphology was not considered essential. However, precise definitions for ovulatory dysfunction, hirsutism, or hyperandrogenism were not provided (13). (Table 1)

This definition of PCOS identified three principal phenotypes as below: 1. Women with hirsutism, hyperandrogenemia, and oligo-ovulation. 2. Women with hirsutism and oligo-ovulation. 3. Women with hyperandrogenemia and oligo-ovulation. Based on the latest research and guidelines, there have been significant updates to the diagnostic criteria for PCOS since the 1990 NIH Conference as follows: 1. Rotterdam Criteria (2003): The Rotterdam Consensus Workshop in 2003 (14) expanded the diagnostic criteria, requiring two out of three of the following: Polycystic ovaries: 12 or more follicles in each ovary, each measuring 2-9 mm in diameter, and/or ovarian volume >10ml. One polycystic ovary is sufficient for diagnosis Oligo-/anovulation: clinically diagnosed as oligo-/amenorrhea, defined by menstrual cycles longer than 35 days or fewer than ten menstruations per year. 10 Hyperandrogenism: clinical or biochemical. This broadened the definition and increased the diagnosed prevalence

of PCOS. 2. Androgen Excess and PCOS Society Criteria (2006) (15): In 2006, the Androgen Excess and PCOS Society established specific criteria for diagnosing Polycystic Ovary Syndrome (PCOS), emphasising the importance of androgen excess as a fundamental marker for the condition. According to these criteria, a diagnosis of PCOS requires the presence of hyperandrogenism (clinical or biochemical) and either ovulatory dysfunction or polycystic ovaries, provided other androgen-excess disorders and related conditions are excluded. This approach shifts the focus towards a more androgen-centric perspective in the identification and management of PCOS. 3. NIH Evidence-Based Methodology Workshop (2012): (Table 2) Recommended maintaining the broader Rotterdam criteria but specifying PCOS phenotypes for research purposes. 4. International Evidence-Based Guideline (2018, updated 2023)(16): - Reaffirmed the Rotterdam criteria as the international standard for PCOS diagnosis. - Introduced

significant updates, particularly regarding polycystic ovarian morphology (PCOM) assessment: - Elevated anti-Müllerian hormone (AMH) levels are now accepted as an alternative to ultrasound for assessing PCOM in adult women. - Updated ultrasound criteria: ≥20 follicles per ovary and/or ovarian volume ≥10 mL on either ovary. 11 TABLE 1 Diagnostic crirteria for PCOS NIH/NICHD Rotterdam Criteria 2003 Androgen Excess PCOS International (ASRM/ESHRE) Society 2006 Evidence-Based Guideline 2023 Includes all of the following:   Includes 2 of the following:  Clinical or/and Menstrual biochemical dysfunction hyperandrogenism Clinical or/and  biochemical hyperandrogenis m Includes 2 of the following: following:  Anovulation / Oligoovulation  Includes all of the Polycystic ovaries  Clinical or/and  Clinical or/and biochemical biochemical hyperandrogenism hyperandrogenism Polycystic ovaries  Anovulation / Oligo- and/or

ovarian ovulation dysfunction Polycystic ovaries or AMH Abbreviations: ASRM/ESHRE (American Society for Reproductive Medicine/European Society for Human Reproduction and Embryology NIH/NICHD (National Institutes of Health/National Institute of Child Health and Human Disease); Adapted from Endocrine Practice (17) AMH – anti-Mullerian hormone The NIH has revised the criteria and suggested using broader ASRM/ESHRE 2003 diagnostic criteria. In addition, they included a detailed description of PCOS phenotypes (18) They have classified women with PCOS women into four phenotypes, as in Table 2. 12 TABLE 2 PCOS Phenotypes Phenotype A HA + OD + PCOM Phenotype B HA + OD Phenotype C HA + PCOM Phenotype D OD + PCOM Abbreviations: HA (Hyperandrogenism), OD (Ovarian dysfunction), PCOM (Polycystic ovarian morphology) Adapted from Lizneva et al. (19) Classifying women with PCOS based on their phenotype offers several practical advantages. Firstly, it can help identify those at

higher risk of metabolic dysfunction where women with phenotypes associated with hyperandrogenism are at a higher metabolic risk than normoandrogenic phenotype (20). Secondly, it assists researchers in categorising study outcomes according to specific PCOS phenotypes, which can enhance the understanding of the variable results observed in trials conducted within the same population. (15) The clinical definition of hyperandrogenism encompasses hirsutism, acne, and androgenic alopecia. However, assessing hirsutism can be complex due to racial variations (21,22) Cosmetic treatments may remove visible signs of hirsutism, and although standardised scoring methods like the Ferriman-Gallwey score exist, they are seldom used clinically (23). The Rotterdam Consensus did not clearly delineate clinical hyperandrogenism, and defining biochemical hyperandrogenism remains problematic. Recent research has demonstrated that the modern immunoassay methods typically employed in routine clinical settings

do not reliably measure testosterone levels in women (24). There is also an absence of established normative ranges for androgens, and it is advisable to make adjustments based on factors such as age and BMI. Besides testosterone, other androgens like dehydroepiandrosterone sulphate (DHEAS) and androstenedione should also be taken into account. The Rotterdam consensus on the definition of PCOS did not specify clinical hyperandrogenism and the definition of biochemical hyperandrogenism also presents challenges. It is also evident that PCOS is a diagnosis of exclusion rather than being based on a single criterion. 13 The Rotterdam criteria expanded the definition of PCOS beyond the NIH criteria by introducing two additional phenotypes: 1) women with PCO, hirsutism or hyperandrogenaemia, and regular ovulation, and 2) women with PCO, oligo-ovulation, and normal androgen levels (25). Polycystic ovaries The follicle number per ovary (FNPO) is deemed the most reliable

ultrasound marker for identifying polycystic ovarian morphology (PCOM) in adults. Other effective markers include the follicle number per cross-section (FNPS) and ovarian volume (OV). The diagnosis of PCOM hinges on the presence of an excessive number of follicles (FNPO, FNPS) and/or an enlarged ovarian size. Specifically, an FNPO of 20 or more in at least one ovary is utilised as a diagnostic criterion for PCOM in adults. Transvaginal ultrasound is optimal as abdominal ultrasound may be inaccurate due to obesity. When older imaging technology is employed, or the image quality does not permit accurate follicle counting, an ovarian volume (OV) of 10 ml or more or an FNPS of 10 or more in at least one ovary can serve as acceptable thresholds for diagnosing PCOM. It is essential to regularly update these thresholds to align with advancements in ultrasound technology and to establish age-specific cut-off values for PCOM. Three-dimensional ultrasonography provides a novel approach for

diagnosing PCOS, offering precise visualisation of ovarian morphology and potentially increasing diagnostic accuracy. Nevertheless, ultrasound requires a radiologist and may be subject to variability between operators (16). Anti-Mullerian hormone (AMH) Anti-Müllerian hormone (AMH), part of the transforming growth factor β family, derives its name from its role in male sexual differentiation, specifically its involvement in the regression of the Müllerian ducts. In women, AMH is secreted by antral and small antral follicles in the ovaries. It is crucial for the initial recruitment of follicles, their growth regulation, and the ultimate maturation of follicles during the development process. Research indicates that serum AMH levels are significantly higher in women with PCOS, typically being 2 to 4 times greater than those in women without the condition (26). A prominent clinical characteristic of PCOS is numerous small follicles exhibiting arrested growth and development, a

phenomenon likely linked to these elevated AMH levels. 14 AMH and polycystic ovaries Serum Anti-Müllerian Hormone (AMH) is produced by small antral follicles visible on ultrasound scans. Despite advancements in ultrasound technology, evaluating polycystic ovarian morphology for PCOS diagnosis can be inconsistent, especially in obese women where trans-abdominal follicle counting presents challenges. Under these circumstances, serum AMH levels could provide a useful, more objective, alternative for diagnosing PCOS. Androgens Biochemical hyperandrogenemia is a crucial criterion for diagnosing PCOS, identified when levels of total testosterone or free androgens surpass the normal range. In PCOS, hyperandrogenism originates from both ovarian and adrenal sources. Low levels of sex hormone-binding globulin (SHBG) in affected women lead to increased free androgen levels, intensifying hyperandrogenism. This issue is further compounded in overweight and obese women due to obesity-related

hyperinsulinemia, which further reduces SHBG production. The primary circulating androgens in women, ranked by serum concentration, are dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT). Testosterone and DHT are primarily responsible for androgenic effects, as other androgens must convert into these forms to be active. Only 1-2% of circulating testosterone is unbound and biologically active, with the majority of androgens bound to carrier proteins such as SHBG and albumin (27). Consequently, the free androgen index (FAI), calculated as (Total Testosterone/SHBG) × 100, is crucial for assessing androgenic potential and effects. The FAI is considered a more accurate indicator of androgen excess, given the challenges associated with precisely measuring free testosterone levels (28). Salivary androgens In diagnosing PCOS, assessing free or bioavailable testosterone often proves more effective for

detecting hyperandrogenemia than measuring total testosterone alone. However, methods for measuring free testosterone, such as equilibrium dialysis, are complex, labour-intensive, and costly. To overcome this, various formulas, including the 'free androgen index' described above, have been developed to estimate free testosterone by combining serum testosterone and sex hormone-binding globulin (SHBG) levels. 15 Research has established a strong correlation between salivary testosterone (salT) and serumfree testosterone measured by equilibrium dialysis in both men and women. Nonetheless, salT cannot be directly compared to serum-free testosterone because the binding of testosterone to saliva proteins significantly affects the lower salT levels observed in women (29). Utilising saliva sampling with liquid chromatography-mass spectrometry (LC-MS/MS) could offer an effective method for assessing bioavailable testosterone in women with PCOS. This approach may enhance the

diagnosis, research, screening, and treatment monitoring of the condition. Moreover, saliva samples are generally more patient-friendly than venipuncture, potentially reducing the necessity for clinic visits, particularly when multiple samples are required for clinical monitoring or research purposes. Tandem mass spectrometry Steroid hormone levels were traditionally measured using immunoassays with different detection mechanisms, such as chemiluminescence (30). Immunoassays are quick, easily automated, safe, and now largely devoid of radiation hazards, with detection levels reaching ng/mL. However, as these rely on antigen-antibody reactions, nonspecific binding is common, often leading to an overestimation of androgen concentrations and resulting in reduced specificity and sensitivity (31). Increasing evidence indicates that liquid chromatography-mass spectrometry (LC-MS/MS) provides greater precision compared to immunoassays, especially for the low testosterone concentrations

usually found in females (32). LC-MS/MS methods tend to exhibit higher precision and are particularly effective when testosterone levels are low (32). They offer superior specificity and sensitivity for measuring analytes, making them highly effective for assessing low levels of female androgens such as testosterone and androstenedione. Given the importance of accurate androgen measurement for diagnosing PCOS and other conditions, an increasing number of laboratories are transitioning to LC-MS/MS for testosterone detection. PCOS and metabolic syndrome Over half of women with PCOS are obese, and many also display hyperinsulinaemia and insulin resistance, irrespective of their weight, when compared to women without PCOS (33). The prevalence of metabolic syndrome in women with PCOS is estimated to be as high as 30% (34-37). This syndrome includes a cluster of cardiovascular risk factors such as central obesity, dyslipidaemia, impaired fasting glucose, and elevated blood pressure, and is

particularly prevalent among women with PCOS (34-37). The exact relationship between obesity and 16 PCOS remains unclear. Yet, obesity is frequently observed in women with this condition and is believed to worsen the numerous metabolic and reproductive challenges associated with it (38). Between 40-85% of individuals with PCOS are either overweight or obese compared to agematched healthy controls, and they typically exhibit a higher waist-to-hip ratio. Additionally, 50-70% of women with PCOS have an android fat distribution, regardless of their BMI, increasing their risk of metabolic disorders such as impaired glucose tolerance, insulin resistance, type 2 diabetes, hypertension, dyslipidaemia, and abnormal platelet activity (38). Hull PCOS biobank I have established a biobank at Hull University Teaching Hospitals NHS Trust for women diagnosed with polycystic ovary syndrome (PCOS) and control subjects (Table 3). All participants provided written informed consent, and the study was

approved by the Newcastle & North Tyneside Ethics Committee (ISRCTN70196169). The diagnosis of PCOS was based on the Rotterdam consensus criteria, which include clinical and/or biochemical evidence of hyperandrogenism (Ferriman-Gallwey score >8 or free androgen index >4), self-reported oligomenorrhoea (cycle length >35 days and ≤9 periods per year) or amenorrhoea (absence of menses for ≥3 months), and the presence of polycystic ovaries on transvaginal ultrasound (≥12 antral follicles in at least one ovary or ovarian volume ≥10 cm³). Exclusion criteria for PCOS participants included non-classical 21-hydroxylase deficiency, hyperprolactinaemia, Cushing's disease, and androgen-secreting tumours, all confirmed by appropriate tests. Control participants were healthy Caucasian women with regular menstrual cycles, no clinical or biochemical hyperandrogenism, no significant medical history, and not taking any medications, including oral contraceptives or

over-the-counter drugs. All participants underwent a 75 g oral glucose tolerance test to exclude impaired glucose tolerance and type 2 diabetes. Measurements of height, weight, waist circumference, and body mass index (BMI) were taken according to WHO guidelines. All study procedures and assays were conducted in compliance with relevant guidelines and regulations. The following studies were primarily conducted on women recruited from this biobank. 17 T A B L E 3: C O M P A R I S O N O F A N T H R O P O M E T R I C A N D H O R M O N A L P A R A M E T E R S O F T H E W O M E N R E C R U I T E D T O H U L L PCOS BIOBANK. Parameters Age (years) BMI (kg/m2) Waist Circumference (cm) Hip Circumference (cm) AMH (pmol/L) Salivary testosterone (pmol/L) Total Testosterone (nmol/L) Salivary Androstenedione (pmol/L) Androstenedione (nmol/L) SHBG (nmol/L) FAI (%) FSH (IU/L) LH (IU/L) Baseline Glucose (mmol/L) 2 Hour Glucose (mmol/L) Insulin (μIU/ml) HOMA-IR Controls (n=65) Median IQR 31.0

11.0 25.0 6.1 78.0 14.8 100.0 16.0 18.1 24.8 13.1 10.0 1.0 0.5 142.89 95.00 7.40 5.90 45.0 31.8 2.2 1.9 5.6 3.6 4.3 5.4 4.5 0.6 4.9 1.3 6.0 3.8 1.2 0.8 PCOS (n=105) Median IQR 27.0 11.0 33.0 10.2 101.0 21.0 117.0 19.5 40.0 42.7 18.5 15.0 1.3 0.9 165.76 118.00 40.31 7.90 27.0 19.0 4.5 5.3 4.9 2.8 6.1 5.5 4.7 0.5 5.6 1.8 13.7 11.4 2.9 2.4 p-value 0.010* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* 0.099 0.009* 0.001* <0.001* <0.001* <0.001* BMI – Body Mass Index; AMH- anti Mullarian hormone; SHBG- sex hormone binding globulin; FAI – Free Androgen Index; FSH – Follicle Stimulating Hormone, LH – Leutenising hormone; HOMA-IR – Homeostasis model of assessment – insulin resistance To convert values for glucose to milligrams per deciliter, divide by 0.056 To convert values for insulin to picomoles per litre, multiply by 6. To convert values for testosterone to nanograms per deciliter, divide by 0.03467 To

convert values for SHBG to micrograms per deciliter, divide by 34.7 18 Thesis overview Publication 1 Sathyapalan T, Al-Qaissi A, ES, Dargham SR, Atkin SL. Anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2018;88(2):258-262. As the first author of this paper, I conducted the literature search, drafted the protocol, gained regulatory approval and recruited for the study, collated the data, performed the analysis, drafted the first version and revised it following critical review by co-authors. Subsequently I revised it following comments from peer reviewers and approved the final version for submission. Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders affecting women of reproductive age, estimated to impact 6-20%. Diagnosis relies on criteria set by the Rotterdam Consensus Criteria, Androgen Excess Society, or NIH and involves the exclusion of other similar conditions. Diagnosing PCOS has been

challenging due to its symptomatic similarity to other disorders, making a precise, reliable diagnostic marker invaluable. Recent studies suggest that the measurement of Anti-Müllerian hormone (AMH), produced by granulosa cells from pre-antral and small antral follicles, could enhance the diagnostic process. Elevated AMH levels are thought to reflect the increased count of these follicles typical in PCOS sufferers and might be an excellent marker for the antral follicle pool size. The role of AMH in diagnosing PCOS is of particular interest because it might offer a more consistent and less invasive alternative to ultrasound, the current standard, which suffers from operator dependency. This study aimed to assess AMH's utility in diagnosing PCOS within a cohort that strictly met all three Rotterdam criteria, potentially supplementing or refining the existing diagnostic frameworks. In this cross-sectional study, 105 women with PCOS and 65 controls, all Caucasian, were enrolled from

a local biobank. All participants underwent comprehensive screening to ensure no other concurrent illnesses, including non-classical 21-hydroxylase deficiency and Cushing's disease. The diagnosis was confirmed via clinical and biochemical evidence of hyperandrogenism, oligomenorrhoea or amenorrhoea, and polycystic ovaries on ultrasound. The analysis involved evaluating the utility of AMH levels in diagnosing PCOS and understanding its relationship with metabolic and androgen profiles. Two diagnostic thresholds 19 for AMH were considered based on the sensitivity and specificity derived from the control group's 95th percentile. Women diagnosed with PCOS were notably younger than controls, with average ages of 27.7 versus 30.2 years, respectively Measurements such as BMI, waist, and hip circumferences were significantly higher among the PCOS group, confirming the association of PCOS with higher body adiposity. As expected, the hormonal profiles showed significantly higher

levels of serum testosterone and FAI in the PCOS group. Insulin resistance, indicated by higher HOMA-IR scores and glucose levels post-OGTT, were also markedly greater in the PCOS group, reflecting the metabolic disturbances associated with the condition. At the 46 pmol/L AMH threshold, 16 of 102 PCOS women (15.7%) who did not exhibit elevated androgen levels tested positive for AMH, suggesting its potential in diagnosing PCOS independently from traditional markers. This threshold demonstrated a sensitivity of 41% and a specificity of 86%. Lowering the AMH threshold to 35 pmol/L increased sensitivity to 55% and maintained a specificity of 79%. This threshold identified 23 of 102 PCOS women (225%) who lacked elevated traditional androgen markers. Interestingly, AMH levels did not correlate with markers of insulin resistance such as HOMAIR or CRP in either group, suggesting that AMH's diagnostic value in PCOS is specific to ovarian function rather than metabolic dysfunction.

However, AMH did show a correlation with serum testosterone and FAI levels in the control group, underscoring its linkage with androgen levels. The study confirmed that higher AMH levels are strongly associated with PCOS, with the hormone identifying an additional 16-22% of PCOS cases depending on the threshold used. This finding supports the potential of AMH not only as a standalone diagnostic marker but also as a complementary tool alongside current criteria, especially in ambiguous cases. While the research provided strong evidence supporting the measurement of AMH in diagnosing PCOS, limitations included its narrow demographic focus, which might limit the generalisability of the findings to broader populations. The study suggests further research across diverse populations and incorporating other PCOS phenotypes to fully ascertain AMH's efficacy and reliability as a diagnostic marker. 20 In conclusion, AMH measurement presents a promising tool in the biochemical

assessment of PCOS, with the potential to improve diagnosis significantly. It could identify additional women with PCOS who might otherwise remain undiagnosed with traditional methods, especially in cases where androgen levels are not elevated. This enhancement in diagnostic capability could lead to better-targeted treatments and management strategies, improving outcomes for those affected by this condition. 21 Publication 2 The role of salivary testosterone measurement using tandem mass spectrometry in polycystic ovary syndrome Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Adaway J, Keevil B, Atkin SL. Salivary testosterone measurement in women with and without polycystic ovary syndrome. Sci Rep. 2017;7(1):3589§ As the first author of this paper, I took the lead role in the literature search and design of the study. I conceptualised the structure of the paper, including figures and tables, drafted it, and revised it following critical review by the co-authors. I

critically reviewed the draft versions of the paper and approved the final version for submission. The central defect in PCOS women is often considered to be androgen excess, frequently influenced by factors such as obesity and insulin resistance. Consequently, androgen measurements play a pivotal role in the diagnosis of PCOS. Recent advancements have made liquid chromatography-tandem mass spectrometry (LCMS/MS) more accessible in clinical practice. Its high specificity and sensitivity make it particularly suitable for measuring the low concentrations of androgens like testosterone and androstenedione in females. For diagnosing PCOS, assessing free or bioavailable testosterone, which gives a closer estimate of biologically active testosterone than total testosterone alone, is considered superior. However, direct measurement can be laborious and expensive, leading to the use of various formulae like the 'free androgen index' (FAI) to estimate free testosterone using more

routinely measured serum testosterone and sex hormone-binding globulin (SHBG). Studies have shown a high correlation between salivary testosterone (salT) and serum-free testosterone measured by equilibrium dialysis in both genders. However, salT is not directly comparable to serum-free testosterone due to testosterone binding to saliva proteins. Saliva might offer a more direct assessment of bioavailable testosterone, especially when combined with LC-MS/MS measurements, and could be particularly useful for diagnosing PCOS, aiding in population screening and treatment monitoring. This study explored whether salivary testosterone and androstenedione (salA) measurements could serve as diagnostic tools for PCOS either alone or alongside existing tests. 22 The study involved 110 well-characterised women with PCOS and 65 control women without PCOS, all of whom were Caucasian from the Hull PCOS biobank. Participants underwent a comprehensive screening to rule out other conditions and

confirm the PCOS diagnosis based on the Rotterdam consensus criteria, which include clinical and/or biochemical evidence of hyperandrogenism, oligomenorrhoea or amenorrhoea, and polycystic ovaries on ultrasound. Saliva and blood samples were collected and analysed using LC-MS/MS. Salivary samples were handled using the "passive drool" technique to minimise contamination and were stored at -80°C until analysis. Analytes in saliva were measured for testosterone and androstenedione, with recovery rates and precision within acceptable ranges. The results revealed significant differences in various anthropometric and hormonal parameters between the PCOS and control groups. Women with PCOS were younger and had higher BMI, waist, and hip circumferences. They also showed greater insulin resistance, evidenced by higher HOMA-IR values and 2-hour glucose levels post-OGTT. Androgen levels, including salT and salA, were markedly elevated in PCOS women compared to controls. While salT did

not show a significant linear correlation with FAI or serum testosterone, salA displayed a modest correlation with serum androstenedione. The diagnostic effectiveness of androgen measurements was evaluated using receiver operator curves (ROC). The thresholds established for salT, serum testosterone, and FAI were based on the 95th percentile of control values. The area under the ROC curves indicated that FAI and salT were more predictive of PCOS than serum testosterone. Multivariable logistic regression adjusting for age and BMI suggested that salT was a more reliable predictor than FAI or serum testosterone. The combination of raised salT or FAI identified all PCOS women in the study, highlighting their potential utility in PCOS diagnosis. This study highlights the potential of salT, measured alongside FAI, as a valuable tool for diagnosing PCOS. The findings support the integration of salT measurement into routine clinical practice, especially in cases where there is diagnostic

uncertainty about PCOS. Further studies are needed to confirm these findings in a broader population and to explore the heterogeneity of PCOS, considering different androgen measures and ethnic groups. 23 This comprehensive examination and presentation of the results aim to clarify the role and effectiveness of salivary androgens in diagnosing PCOS, providing a basis for further research and potential changes in clinical practice. 24 Publication 3 Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Keevil B, Atkin SL. Salivary and serum androgens with anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. Sci Rep 2018;8(1):3795 As the first author of this paper, I took the lead role in the literature search and design of the study. I conceptualised the structure of the paper, including figures and tables, drafted it, and revised it following critical review by the co-authors. I critically reviewed the draft versions of the paper and approved the

final version for submission. Anti-Müllerian hormone (AMH), produced in granulosa cells from pre-antral and small antral follicles, correlates highly with antral follicle count, which is often elevated in PCOS, leading to higher serum AMH levels. AMH measurement might enhance PCOS diagnosis, with studies suggesting a serum AMH cut-off of 35 pmol/L yielding a sensitivity of 79.4% and a specificity of 82.8%, as found in the first publication This study investigated whether AMH, in conjunction with elevated androgen levels, could aid in diagnosing PCOS in a well-defined cohort of women meeting all three Rotterdam criteria. The cross-sectional study involved 105 women diagnosed with PCOS and 65 control women, all Caucasian, from Hull PCOS biobank. All participants underwent thorough screening to exclude other conditions and confirmed PCOS diagnosis based on clinical and biochemical evidence of hyperandrogenism, oligomenorrhea or amenorrhea, and polycystic ovaries on ultrasound. Blood

samples were collected and analysed using LC/MS/MS for serum testosterone (T) and androstenedione (A), and sex hormone binding globulin (SHBG) was measured by an immunometric assay. The free androgen index (FAI) was calculated, and serum insulin levels were determined by a competitive chemiluminescent immunoassay. Plasma glucose levels were measured, and insulin resistance was calculated using the homeostatic model of assessment (HOMA) method. AMH levels were measured using an automated immunoassay Saliva samples were collected using a "passive drool" technique to minimise assay interference, and salivary testosterone and androstenedione were measured by LC-MS/MS. The study adhered to strict sample collection and handling guidelines to ensure reliability. In this cohort, PCOS patients exhibited significantly higher insulin levels, insulin resistance (HOMA-IR), and glucose levels two hours post-oral glucose tolerance test (OGTT) compared 25 to controls, which are

consistent indicators of the metabolic syndrome often associated with PCOS. Specifically, the median insulin resistance score in PCOS patients was notably higher than in the control group, emphasising the metabolic complications associated with the disorder. Analysis of hormonal levels showed that serum testosterone, FAI, androstenedione, and salivary testosterone were all significantly elevated in the PCOS group compared to controls. The sensitivity and specificity of AMH for diagnosing PCOS were calculated at 55% and 78%, respectively, with a positive predictive value of 80% and a negative predictive value of 52%. When combining AMH with either serum testosterone or FAI, the specificity reached 100%, with a positive predictive value of 100%, underscoring the robustness of these biomarkers in confirming PCOS in this cohort. The diagnostic performance of these combined markers was particularly striking, indicating that elevated AMH levels when accompanied by high FAI or testosterone

levels, provided a definitive diagnosis of PCOS. Conversely, the combination of AMH below 35 pmol/L with normal androgen levels accurately excluded PCOS, demonstrating these markers' utility in clinical settings. Statistical analysis reinforced these findings, showing that the combination of AMH with elevated androgens such as T, FAI, or salivary androstenedione offered a comprehensive tool for diagnosing PCOS, with varying degrees of sensitivity and specificity depending on the androgen marker used. The study underscores the importance of AMH in conjunction with androgen levels for diagnosing PCOS, particularly in patients who meet the full criteria under the Rotterdam consensus. It suggests that AMH, along with FAI or T, could significantly aid in the diagnostic process, providing a more definitive approach to identifying PCOS, especially in cases with diagnostic uncertainty. The combination of these biomarkers showed a high specificity and positive predictive value, suggesting

their potential as reliable indicators for PCOS. Further research is needed to validate these findings in a larger and more diverse cohort and to explore the role of AMH and androgens in different PCOS phenotypes across various ethnicities. This would help in standardising diagnostic criteria and refining the use of biomarkers for a more accurate diagnosis of PCOS, potentially leading to better-targeted treatments and management strategies improving outcomes for women with PCOS. 26 Publication 4 Deshmukh H, Akbar S, Bhaiji A, Saeed Y, Shah N, Adeleke K, Papageorgiou M, Atkin SL, Sathyapalan T. Assessing the androgenic and metabolic heterogeneity in polycystic ovary syndrome using cluster analysis. Clin Endocrinol (Oxf) 2023; 98:400-406 As a senior and corresponding author for this paper, I conceived the study hypothesis, developed the research protocol with support from more research team members, advised on the statistical analysis required, supervised the team and produced the

manuscript. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. This condition is associated with a high prevalence of metabolic syndrome, which significantly increases the risk of developing cardiovascular diseases, type 2 diabetes, certain cancers, sleep apnoea, and psychological issues. Women with PCOS exhibit considerable clinical and biochemical heterogeneity and, to date, clear predictors of metabolic syndrome in this group have not been definitively established. Recent studies have highlighted the potential of using hormonal parameters, including the emerging marker Anti-Müllerian Hormone (AMH) and androstenedione, to better understand the metabolic heterogeneity within PCOS. These studies, however, have generally not incorporated these markers into their clustering algorithms. This study aims to determine if routine hormonal measurements in PCOS can identify subgroups of women who are at an increased risk of metabolic

syndrome. The study involved a discovery cohort from a PCOS audit at Hull University Teaching Hospitals NHS Trust and a replication cohort from the Hull PCOS Biobank study (Table 4). Both cohorts consisted of women diagnosed with PCOS based on at least two of the Rotterdam consensus criteria. All procedures adhered to the Declaration of Helsinki and local regulations, with approval from relevant ethics committees. Participants' BMI, waist and hip circumferences, and various hormonal levels, including AMH, testosterone, androstenedione, and SHBG, were meticulously measured. Based on these hormonal parameters, cluster analysis was employed to identify subgroups within the PCOS population. We used siMS (metabolic syndrome) Score, a simple method for quantifying metabolic syndrome (39). SiMS score was calculated by using the formula: [2*waist circumference 27 (cm) /height (cm)) + (baseline glucose [in nmol.L]/56) + (triglycerides [in mmol/L]/17) + (systolic BP/130) - (HDL [in

mmol/L]/1.28)] Statistical analyses were conducted to evaluate the hormonal and metabolic data across different subgroups identified within the PCOS cohorts. Initial univariate comparative analyses involved the non-parametric Mann-Whitney tests to assess differences in baseline demographics, clinical characteristics, and androgen levels between the identified PCOS clusters. An iterative imputation method, missForest, was used to handle missing data. This nonparametric method builds a random forest model for each variable and uses the model to predict missing values based on observed data. This approach was particularly useful given the absence of missing androgen data in the validation cohort and minimal missing data in the PCOS audit cohort. For the cluster analysis, the K-means clustering algorithm, an unsupervised machine learning method, was utilised to partition the data into groups based on similarities in eight routinely measured hormonal parameters: Free androgen index (FAI),

Sex hormone-binding globulin (SHBG), Dehydroepiandrosterone sulphate (DHEAS), Androstenedione, Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), Anti-Müllerian Hormone (AMH), and 17hydroxyprogesterone (17-OHP). To validate the adequacy of the clusters, the Jaccard coefficient was used, which measures the similarity between pairs of data sets by comparing members that are shared between the sets relative to members present in at least one set. A Jaccard coefficient greater than 060 indicates moderate cluster adequacy, while a coefficient above 0.75 suggests excellent adequacy The validation cohort demonstrated a Jaccard coefficient of 0.63, indicating moderate cluster stability. In this study, we identified two subtypes of PCOS based on routinely measured hormonal parameters. We show that a smaller subgroup of women with PCOS with higher LH, FAI and androstenedione have a higher siMS; however, this was not statistically significant in this study. We also showed that higher

androstenedione and FAI levels are independently associated with a higher risk of siMS, while higher levels of DHEAS level are associated with lower siMS. 28 This study underscores the complexity of PCOS and its association with metabolic syndrome. Women with PCOS demonstrated an androgenic heterogeneity, which can influence metabolic outcomes in this population. Specifically, a subset of women with PCOS had higher LH and androgen levels and appeared to be at higher risk for metabolic syndrome. This study also showed some beneficial effects of higher DHEAS levels on siMS in women with PCOS. Further research is required to validate these findings in a larger, more diverse population and to explore the implications for managing PCOS with a precision medicine approach. Understanding the hormonal underpinnings of metabolic syndrome in PCOS will help in developing more effective, individualised treatment plans that could significantly improve outcomes for women with PCOS. 29 T A B

L E 4 : D E M O G R A P H I C C H A R A C T E R I S T I C S O F T H E D I S C O V E R Y C O H O R T (PCOS A U D I T ) A N D R E P L I C A T I O N C O H O R T (PCOS B I O B A N K ) Parameters Discovery cohort (PCOS audit) n=199 Replication cohort (PCOS Biobank) n=111 Age (years) 28.7 (±644) 27.7 (603) SBP mmgHg 130 (±13.8) 121 (14.2) DBP mmHg 82.3 (±992) 76.5 (109) BMI (kg/m2) 37.2 (±817) 33.9 (751) Waist circumference (cm) 110 (17.9) 101 (16.0) FAI (%) 6.46 (374) 6.16 (541) SHBG (nmol/l) 28.4 (190) 33.3 (202) TSH (mU/l) 1.51 (0710) 2.13 (115) DHEAS (µmol/l) 7.77 (367) 6.11 (283) Androstenedione (nmol/l) 5.06 (228) 11.4 (610) LH (IU/L) 10.0 (992) 7.51 (537) FSH (IU/L) 6.29 (288) 4.97 (248) 17OHP (nmol/l) 2.07 (171) 5.69 (402) AMH (nmol/l) 37.3 (237) 45.9 (283) Table 4 shows the demographic and clinical characteristics of the study cohorts. 30 BMI – Body Mass Index; AMH- antiMullarian hormone; SHBG- sex hormone binding globulin;

FAI – Free Androgen Index; FSH – Follicle Stimulating Hormone, LH – Leutenising hormone; HOMA-IR – Homeostasis model of assessment – insulin 31 F I G U R E 1 A A N D 1 B : PCOS C L U S T E R S I N PCOS A U D I T A N D PCOS B I O B A N K 32 The smaller cluster in the discovery cohort had significantly higher levels of LH (7.26 IU/L vs 161 IU/L, P<0001), FAI (521 vs 922, P<0.001), androstenedione (393 vs 756 nmol/l, P<0001) and 17-OHP (159 nmol/l vs 312 nmol/l P<0001) These were replicated in the smaller cluster in the replication cohort with statistically significantly higher levels of LH ( 6.03 IU/L vs 105 IU/L P<0.001), FAI (421 vs 101, P<0001), androstenedione ( 92 nmol/l vs 158 nmol/l P<0001) and 17-OHP ( 52 nmol/l vs 658 nmol/l P<0.001) LH – Leutenising hormone; FAI – Free Androgen Index 17-OHP – 17hydroxy progesterone. 33 Publication 5 Deshmukh H, Papageorgiou M, Kilpatrick ES, Atkin SL, Sathyapalan T. Development of a novel

risk prediction and risk stratification score for polycystic ovary syndrome. Clin Endocrinol (Oxf). 2019;90(1):162-169 As senior and corresponding author for this paper, I conceived the study hypothesis, developed the research protocol with support from more research team members, advised on the statistical analysis required, supervised the team and produced the manuscript. Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders. The diagnosis of PCOS can be complex due to the spectrum of clinical features and metabolic abnormalities presented by affected patients. Current diagnostic criteria are based on the National Institute of Health (NIH), ESHRE/ASRM Rotterdam consensus criteria, and the Androgen Excess and PCOS Society (AE PCOS). These criteria include biochemical hyperandrogenism, assessed through various assays and indices like the free androgen index (FAI), which has its limitations, especially when sex hormone-binding globulin (SHBG) levels are low.

Given the variability in clinical presentations and the limitations of current diagnostic markers, there is a significant need for a reliable risk prediction and stratification tool that can encompass the entire disease spectrum of PCOS. This study aimed to utilise relevant biochemical markers and quantifiable clinical features to develop a simple risk score to assist in the diagnosis, predict the severity, and stratify the risk in women with PCOS. The study involved women diagnosed with PCOS and control women who were meticulously screened to rule out other conditions such as non-classical 21-hydroxylase deficiency and Cushing's disease in Hull PCOS biobank. All variables were initially log-transformed for the statistical analysis to address non-normal distribution. Missing values were imputed using the non-parametric missForest method, which employs a random forest algorithm to predict missing data with observed values. MannWhitney tests were used on the imputed datasets to

compare androgen levels between PCOS cases and controls. 34 To develop a robust predictive model, logistic regression with Firth's bias-adjusted estimates was employed to correct for small sample size bias and strong associations with outcomes. This method improves the efficiency of the score function by introducing a bias correction term that diminishes as sample size increases. Model selection involved including all potentially relevant predictors in a full model and using backward elimination to identify the most significant predictors based on penalised likelihood ratios. The analysis highlighted significant differences between women with PCOS and controls in terms of BMI, waist circumference, and levels of hyperandrogenic markers. Notably, women with PCOS had higher levels of AMH and 17-OHP, among others. The logistic regression model identified four variables independently associated with PCOS: FAI, 17-OHP, AMH, and waist circumference. These factors were robust across

various selection methods, including backward elimination and forward selection, indicating their strong association with PCOS. Model validation was performed using bootstrapping techniques to assess the stability and reliability of the model. Over 1000 bootstrap samples, the model showed little optimism, suggesting good generalizability. The model's discrimination ability was high, with an area under the curve (AUC) of 0.91, indicating excellent predictive performance In this publication, we have developed a simple model consisting of FAI, 17-OHP, AMH and waist circumference for risk prediction and risk stratification in PCOS. By integrating comprehensive biochemical and anthropometric measurements, the model provides a nuanced tool that not only aids in diagnosing PCOS but also helps in assessing the severity and stratifying the risk of metabolic complications associated with the disorder. Further research is necessary to validate these findings in a larger, more ethnically

diverse population. Moreover, extending this model to incorporate additional predictors and testing its applicability across different clinical settings will enhance its utility, making it a valuable tool in clinical practice. This study underscores the complexity of PCOS and highlights the potential of a multifaceted approach to its diagnosis and management. By offering a straightforward and effective risk scoring system, it opens new avenues for targeted interventions that could significantly improve outcomes for women with PCOS. 35 Summary discussion Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. In addition to its implications for fertility, PCOS has also been linked to poor metabolic outcomes. The traditional Rotterdam Consensus Criteria for diagnosis do not reflect the heterogeneity of risk factors in PCOS. To understand this, I have established a PCOS biobank in Hull, UK, with 110 well-characterised women

with PCOS and 65 women without PCOS and the following studies are based on this cohort. The collection of five studies offers an exploration into the diagnostic complexities and management strategies of Polycystic Ovary Syndrome (PCOS), a prevalent endocrine disorder affecting a significant proportion of women of reproductive age. Each study introduces innovative diagnostic approaches and underscores the importance of a multifaceted strategy in understanding and managing PCOS effectively. The first study assesses the efficacy of Anti-Müllerian Hormone (AMH) as a diagnostic marker. AMH, which is secreted by ovarian follicles, is notably elevated in women with PCOS and correlates with the antral follicle count. This hormone offers a less invasive and more consistent diagnostic alternative to ultrasound, which is subject to variability depending on the operator. The study advocates for incorporating AMH measurements into diagnostic frameworks to enhance accuracy, especially in ambiguous

cases. It was found that an elevated AMH is fourfold more likely to be associated with a diagnosis of PCOS. In the latest International Evidence-Based Guideline (2018, updated 2023) (16) AMH is suggested as an alternative to ultrasound findings of polycystic ovaries. Another diagnostic criterion is the presence of biochemical hyperandrogenaemia. Traditionally, serum androgen levels are used for diagnosis. The second publication explores the potential of salivary testosterone, measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), as a diagnostic marker for PCOS. Highlighting the noninvasiveness and practicality of this method, it presents a simplified approach to the diagnostic process, enabling easier screening and monitoring of the disorder. Salivary testosterone provides a direct assessment of bioavailable testosterone, crucial for diagnosing PCOS, making it particularly useful in clinical settings. It was found that salivary testosterone appeared to be at least

as predictive as the free androgen index (FAI) in the diagnosis of PCOS and is useful to assess hyperandrogenaemia, particularly in cases where there is diagnostic uncertainty. 36 In the next study (publication 3) in the Hull PCOS biobank, we examined whether AMH would complement traditional serum and salivary androgens in PCOS. We found that a raised AMH > 35 pmol/L and a raised FAI are very specific for a diagnosis. I then examined the metabolic heterogeneity in PCOS using the biobank as the discovery cohort (publication 4). It employed cluster analysis to investigate the heterogeneity within the PCOS population by identifying subgroups based on hormonal and metabolic profiles. It was found that higher levels of testosterone and androstenedione were associated with a higher metabolic syndrome score, and higher dehydroepiandrosterone (DHEAS) was associated with a lower score. This stratification allows for the development of tailored treatment strategies, potentially improving

clinical outcomes by aligning therapeutic approaches with individual hormonal profiles. A novel risk prediction and metabolic risk stratification score for PCOS was developed from the PCOS biobank cohort (publication 5). This is a simple four-variable model that captures the underlying clinical and metabolic abnormalities in PCOS, which can be used for metabolic risk stratification in PCOS. This score is derived from a comprehensive evaluation of women with PCOS and controls, focusing on variables such as BMI, waist and hip measurements, and levels of hormones like AMH and testosterone. The score utilises a four-variable model that encapsulates the clinical and metabolic abnormalities commonly observed in PCOS, offering a tool for metabolic risk stratification. This comprehensive series of novel studies has substantially contributed to diagnosing and understanding the metabolic risks in women with PCOS. In line with this work, AMH has now been recommended by the international guideline

on the diagnosis and management of PCOS as an alternative to ultrasound scans of ovaries. Similarly, salivary steroid hormone assays are becoming increasingly acknowledged as an alternative to serum hormonal measurements. I have used state-of-the-art assays such as tandem mass spectrometry for analysing these steroid hormones. Taking the research a step further, I have delved into the intricacies of metabolic risk in women with PCOS. This endeavour has yielded a novel risk stratification score, a significant advancement in understanding and addressing the heterogeneity of metabolic risks associated with PCOS. 37 Conclusion and Future Directions These studies collectively highlight the need for advanced diagnostic tools and personalised management plans to tackle the complexities of PCOS effectively. An integrated approach is recommended that leverages both biochemical markers and clinical assessments to improve diagnostic accuracy and optimise treatment strategies. Future research

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S, Detre K, Weimer K, Kuller L. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol. 1995;15(7):821-826 Barber TM, Hanson P, Weickert MO, Franks S. Obesity and Polycystic Ovary Syndrome: Implications for Pathogenesis and Novel Management Strategies. Clin Med Insights Reprod Health. 2019;13:1179558119874042 Soldatovic I, Vukovic R, Culafic D, Gajic M, Dimitrijevic-Sreckovic V. siMS Score: Simple Method for Quantifying Metabolic Syndrome. PLoS One 2016;11(1):e0146143 41 Published work till date 1. Deshmukh H, Ssemmondo E, Adeleke K, Mongolu S, Aye M, Orme S, Flanagan D, Abraham P, Higham C, Sathyapalan T, Group UKARS. Time to first remission and survival in patients with acromegaly: Evidence from the UK Acromegaly Register Study (UKAR). Clin Endocrinol (Oxf). 2024;101(3):274-281 2. Amini H, Meskarpour-Amiri M, Hosseini MS, Farjami M, Ashtari S, Vahedian-Azimi A, Sathyapalan T, Sahebkar A. Correlation between socio-demographic

characteristics, metabolic control factors and personality traits with self-perceived health status in patients with diabetes: A cross-sectional study. J Diabetes Metab Disord 2024;23(1):797-808 3. Nandakumar M, Das P, Sathyapalan T, Butler AE, Atkin SL. A Cross-Sectional Exploratory Study of Cardiovascular Risk Biomarkers in Non-Obese Women with and without Polycystic Ovary Syndrome: Association with Vitamin D. Int J Mol Sci 2024;25(12) 4. Butler AE, Sathyapalan T, Das P, Brennan E, Atkin SL. Association of Vitamin D with Perfluorinated Alkyl Acids in Women with and without Non-Obese Polycystic Ovary Syndrome. Biomedicines 2024;12(6) 5. Nandakumar M, Sathyapalan T, Atkin SL, Butler AE. Effect of Hypoglycemia and Rebound Hyperglycemia on Proteomic Cardiovascular Risk Biomarkers. Biomedicines 2024;12(6). 6. Nosrati-Oskouie M, Salavatizadeh M, Sadat Aghili-Moghaddam N, Sathyapalan T, Kesharwani P, Tarighat-Esfanjani A, Sahebkar A. Folate-Modified Curcumin-Loaded Nanoparticles for

Overcoming Delivery Challenges in Cancer Treatment: A Narrative Review. Curr Pharm Biotechnol. 2024 7. Aalami AH, Abdeahad H, Aalami F, Sathyapalan T, Sahebkar A. Investigating angiogenin/ribonuclease 5 as a diagnostic biomarker for bladder cancer: In-depth analysis from a systematic review and meta-analysis. Clin Biochem 2024;130:110780 8. Butler AE, Lubbad W, Akbar S, Kilpatrick ES, Sathyapalan T, Atkin SL. A CrossSectional Study of Glomerular Hyperfiltration in Polycystic Ovary Syndrome Int J Mol Sci 2024;25(9). 9. Abdalla Ahmed MA, Ssemmondo E, Mark-Wagstaff C, Sathyapalan T. Advancements in the management of obesity: a review of current evidence and emerging therapies. Expert Rev Endocrinol Metab 2024;19(3):257-268 10. Abdalla MA, Shah N, Deshmukh H, Sahebkar A, Ostlundh L, Al-Rifai RH, Atkin SL, Sathyapalan T. The Effect of Thiazolidinediones in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Adv Ther 2024;41(6):21682195 42

11. Butler AE, Moin ASM, Sathyapalan T, Atkin SL. A Cross-Sectional Study of Protein Changes Associated with Dementia in Non-Obese Weight Matched Women with and without Polycystic Ovary Syndrome. Int J Mol Sci 2024;25(4) 12. Butler AE, Moin ASM, Sathyapalan T, Atkin SL. A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome. Int J Mol Sci 2024;25(2). 13. Ssemmondo E, Deshmukh H, Wilmot EG, Adeleke KA, Shah N, Walton C, Barnes D, Ryder REJ, Sathyapalan T. Effect of intermittently scanned continuous glucose monitoring in people with diabetes with a psychosocial indication for initiation. Diabetes Obes Metab 2024;26(4):1340-1345. 14. Deshmukh H, Adeleke K, Wilmot EG, Folwell A, Barnes D, Walker N, Saunders S, Ssemmondo E, Walton C, Patmore J, Ryder REJ, Sathyapalan T. Clinical features of type 1 diabetes in older adults and the impact of intermittently scanned continuous glucose monitoring: An Association of British Clinical Diabetologists (ABCD)

study. Diabetes Obes Metab. 2024;26(4):1333-1339 15. Batten L, Sathyapalan T, Palmer TM. Molecular Mechanisms Linking Diabetes with Increased Risk of Thrombosis. Int J Mol Sci 2023;24(24) 16. Ghazvini A, Vahedian-Azimi A, Abdoli M, Rahimibashar F, Panahi Y, Sathyapalan T, Sahebkar A. Effects of Iranian herbal Zofa((R)) syrup for the management of clinical symptoms in patients with COVID-19: A randomized clinical trial. Avicenna J Phytomed 2023;13(5):500-512. 17. Mirhafez SR, Zarifian A, Movahedi A, Ferns GA, Sathyapalan T, Ghayour-Mobarhan M, Sahebkar A. Determinants of serum cytokines in a population sample of healthy subjects from Iran. Arch Med Sci Atheroscler Dis 2023;8:e89-e95 18. Brennan E, Butler AE, Nandakumar M, Thompson K, Sathyapalan T, Atkin SL. Relationship between endocrine disrupting chemicals (phthalate metabolites, triclosan and bisphenols) and vitamin D in female subjects: An exploratory pilot study. Chemosphere 2024;349:140894. 19. Butler AE, Brennan E, Drage DS,

Sathyapalan T, Atkin SL. Exploration of the correlation of serum polychlorinated biphenyl levels with luteal phase hormonal parameters and infertility in women with or without polycystic ovary syndrome. Front Endocrinol (Lausanne). 2023;14:1270949 20. Brennan E, Butler AE, Drage DS, Sathyapalan T, Atkin SL. Serum polychlorinated biphenyl levels and circulating miRNAs in non-obese women with and without polycystic ovary syndrome. Front Endocrinol (Lausanne) 2023;14:1233484 43 21. Deshmukh H, Papageorgiou M, Wells L, Akbar S, Strudwick T, Deshmukh K, Vitale SG, Rigby A, Vince RV, Reid M, Sathyapalan T. The Effect of a Very-Low-Calorie Diet (VLCD) vs. a Moderate Energy Deficit Diet in Obese Women with Polycystic Ovary Syndrome (PCOS)-A Randomised Controlled Trial. Nutrients 2023;15(18) 22. Mark-Wagstaff C, Deshmukh H, Wilmot EG, Walker N, Barnes D, Parfitt V, Saunders S, Gregory R, Choudhary P, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Intermittently scanned continuous glucose

monitoring and hypoglycaemia awareness in drivers with diabetes: Insights from the Association of British Clinical Diabetologists Nationwide audit. Diabetes Obes Metab 2024;26(1):46-53 23. Niknejad A, Hosseini Y, Najafi Arab Z, Razavi SM, Momtaz S, Sathyapalan T, Majeed M, Jamialahmadi T, Abdolghaffari AH, Sahebkar A. Pharmacological activities of turmerones. Curr Med Chem 2023 24. Butler AE, Moin ASM, Sathyapalan T, Atkin SL. Complement Dysregulation in Obese Versus Nonobese Polycystic Ovary Syndrome Patients. Cells 2023;12(15) 25. Ashraf Ganjooei N, Jamialahmadi T, Nematy M, Shah NZ, Jangjoo S, Emami N, Jangjoo A, Faridnia R, Alidadi M, Sathyapalan T, Sahebkar A. Association between Thyroid Hormones and Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis in Obese Individuals Undergoing Bariatric Surgery. Middle East J Dig Dis 2022;14(4):410-421 26. Nandakumar M, Sathyapalan T, Butler AE, Atkin SL. Oxidative Stress Markers and Heat Shock Proteins in Non-Obese Women

with Polycystic Ovary Syndrome Are Not Elevated and Show No Correlation with Vitamin D. Biomedicines 2023;11(7) 27. Ehteshami A, Shirban F, Bagherniya M, Sathyapalan T, Jamialahmadi T, Sahebkar A. The association between high-density lipoproteins and periodontitis. Curr Med Chem 2023 28. Ahmadzadeh AM, Pourali G, Mirheidari SB, Shirazinia M, Hamedi M, Mehri A, Amirbeik H, Saghebdoust S, Tayarani-Najaran Z, Sathyapalan T, Forouzanfar F, Sahebkar A. Medicinal Plants for the Treatment of Neuropathic Pain: A Review of Randomized Controlled Trials. Curr Pharm Biotechnol 2024;25(5):534-562 29. Butler AE, Brennan E, Drage DS, Sathyapalan T, Atkin SL. Association of flame retardants, polybrominated diethyl ethers (PBDEs), with vitamin D in female subjects. Chemosphere. 2023;338:139488 30. Shirani M, Talebi S, Shojaei M, Askari G, Bagherniya M, Guest PC, Sathyapalan T, Sahebkar A. Spices and Biomarkers of COVID-19: A Mechanistic and Therapeutic Perspective. Adv Exp Med Biol 2023;1412:375-395

31. Kouhpeikar H, Khazir Z, Naghipour A, Tabasi HK, Khezri MT, Abdollai M, Ayar A, Jamialahmadi T, Sathyapalan T, Abbasifard M, Sahebkar A. Red Cell Distribution Width as a 44 Prognostic Indicator for Mortality and ICU Admission in Patients with COVID-19. Adv Exp Med Biol. 2023;1412:225-235 32. Butler AE, Brennan E, Drage DS, Sathyapalan T, Atkin SL. Association of polychlorinated biphenyls with vitamin D in female subjects. Environ Res 2023;233:116465 33. Saghafi N, Mahmoudi M, Momtazi-Borojeni AA, Mirzaeian S, Tavasolian F, Sathyapalan T, Abdollahi E, Sahebkar A. Severity of COVID-19 in Pregnant Women: A Review on the Potential Role of Regulatory T Cells. Curr Med Chem 2024;31(26):4199-4212 34. Brennan E, Butler AE, Nandakumar M, Drage DS, Sathyapalan T, Atkin SL. Association between Organochlorine Pesticides and Vitamin D in Female Subjects. Biomedicines. 2023;11(5) 35. Butler AE, Moin ASM, Reiner Z, Sathyapalan T, Jamialahmadi T, Sahebkar A, Atkin SL. High density

lipoprotein-associated proteins in non-obese women with and without polycystic ovary syndrome. Front Endocrinol (Lausanne) 2023;14:1117761 36. Khayatan D, Razavi SM, Arab ZN, Hosseini Y, Niknejad A, Momtaz S, Abdolghaffari AH, Sathyapalan T, Jamialahmadi T, Kesharwani P, Sahebkar A. Superoxide dismutase: a key target for the neuroprotective effects of curcumin. Mol Cell Biochem 2024;479(3):693-705. 37. Forouzanfar F, Pourbagher-Shahri AM, Vafaee F, Sathyapalan T, Sahebkar A. Phytochemicals as substances that affect astrogliosis and their implications for the management of neurodegenerative diseases. Curr Med Chem 2023 38. Abolfazli S, Ebrahimi N, Morabi E, Asgari Yazdi MA, Zengin G, Sathyapalan T, Jamialahmadi T, Sahebkar A. Hydrogen Sulfide: Physiological Roles and Therapeutic Implications against COVID-19. Curr Med Chem 2024;31(21):3132-3148 39. Deshmukh H, Sathyapalan T. No causal association between anti-Mullerian hormone (AMH) levels and polycystic ovary syndrome (PCOS)-a

Mendelian randomization analysis. Endocrine. 2023;81(2):388-389 40. Hamedani SG, Pourmasoumi M, Askari G, Bagherniya M, Sathyapalan T, Sahebkar A. An Investigation into the Effects of Chemical, Pharmaceutical, and Herbal Compounds on Neuroglobin: A Literature Review. Curr Med Chem 2024;31(20):2944-2954 41. Jamialahmadi T, Bo S, Abbasifard M, Sathyapalan T, Jangjoo A, Moallem SA, Almahmeed W, Ashari S, Johnston TP, Sahebkar A. Association of C-reactive protein with histological, elastographic, and sonographic indices of non-alcoholic fatty liver disease in individuals with severe obesity. J Health Popul Nutr 2023;42(1):30 42. Aminifar E, Tavakkol Afshari HS, Sathyapalan T, Abbasifard M, Sahebkar A. The pleiotropic effects of statins in rheumatoid arthritis. J Pharm Pharmacol 2023;75(7):910-920 45 43. Deshmukh H, Adeleke KA, Ssemmondo E, Wilmot EG, Shah N, Pieri B, Gregory R, Kilvert A, Lumb A, Christian P, Barnes D, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Ethnic disparities

in people accessing FreeStyle Libre in the United Kingdom: Insights from the Association of British Clinical Diabetologists audit. Diabet Med 2023;40(8):e15095 44. Butler AE, Moin ASM, Reiner Z, Sathyapalan T, Jamialahmadi T, Sahebkar A, Atkin SL. HDL-Associated Proteins in Subjects with Polycystic Ovary Syndrome: A Proteomic Study. Cells 2023;12(6) 45. Bandara T, Deshmukh HA, Abdalla M, Sathyapalan T. Metabolic and Endocrine Complications of Long-COVID-19: A Review. Exp Clin Endocrinol Diabetes 2023;131(6):367-374. 46. Moin ASM, Sathyapalan T, Butler AE, Atkin SL. Coagulation factor dysregulation in polycystic ovary syndrome is an epiphenomenon of obesity. Clin Endocrinol (Oxf) 2023;98(6):796-802. 47. Shah N, Deshmukh H, Wilmot EG, Patmore J, Christian P, Barnes DJ, Walton C, Ryder REJ, Sathyapalan T. The long-term impact of glucose monitoring with the FreeStyle Libre on glycaemic control and hypoglycaemia awareness in people with type 1 diabetes: Insights from the Association of

British Clinical Diabetologists national audit. Diabet Med 2023;40(6):e15070. 48. Babaie F, Omraninava M, Gorabi AM, Khosrojerdi A, Aslani S, Yazdchi A, Torkamandi S, Mikaeili H, Sathyapalan T, Sahebkar A. Etiopathogenesis of Psoriasis from Genetic Perspective: An updated Review. Curr Genomics 2022;23(3):163-174 49. Sardou HS, Vosough PR, Abbaspour M, Akhgari A, Sathyapalan T, Sahebkar A. A review on curcumin colon-targeted oral drug delivery systems for the treatment of inflammatory bowel disease. Inflammopharmacology 2023;31(3):1095-1105 50. Chamani S, Moossavi M, Naghizadeh A, Abbasifard M, Kesharwani P, Sathyapalan T, Sahebkar A. Modulatory properties of curcumin in cancer: A narrative review on the role of interferons. Phytother Res 2023;37(3):1003-1014 51. Yaribeygi H, Maleki M, Sathyapalan T, Rizzo M, Sahebkar A. Cognitive Benefits of Sodium-Glucose Co-Transporters-2 Inhibitors in the Diabetic Milieu. Curr Med Chem 2024;31(2):138-151. 52. Heidari H, Bagherniya M, Majeed M,

Sathyapalan T, Jamialahmadi T, Sahebkar A. Curcumin-piperine co-supplementation and human health: A comprehensive review of preclinical and clinical studies. Phytother Res 2023;37(4):1462-1487 53. Moin ASM, Sathyapalan T, Butler AE, Atkin SL. Classical and alternate complement factor overexpression in non-obese weight matched women with polycystic ovary syndrome does not correlate with vitamin D. Front Endocrinol (Lausanne) 2022;13:935750 46 54. Jangjoo S, Emami N, Sahranavard M, Shah NZ, Alidadi M, Baratzadeh F, Sathyapalan T, Eid AH, Jangjoo A, Jamialahmadi T, Sahebkar A. Diagnostic Value of Noninvasive Liver Function Tests in Liver Fibrosis and Changes in These Parameters Postmetabolic Surgery Obes Surg 2023;33(2):548-554 55. Ajjan RA, Heller SR, Everett CC, Vargas-Palacios A, Higham R, Sharples L, Gorog DA, Rogers A, Reynolds C, Fernandez C, Rodrigues P, Sathyapalan T, Storey RF, Stocken DD. Multicenter Randomized Trial of Intermittently Scanned Continuous Glucose Monitoring

Versus Self-Monitoring of Blood Glucose in Individuals With Type 2 Diabetes and RecentOnset Acute Myocardial Infarction: Results of the LIBERATES Trial. Diabetes Care 2023;46(2):441-449. 56. Ramanjaneya M, Bettahi I, Pawar K, Halabi NM, Moin ASM, Sathyapalan T, AbouSamra AB, Atkin SL, Butler AE. MicroRNA Changes Up to 24 h following Induced Hypoglycemia in Type 2 Diabetes. Int J Mol Sci 2022;23(23) 57. Deshmukh H, Akbar S, Bhaiji A, Saeed Y, Shah N, Adeleke K, Papageorgiou M, Atkin S, Sathyapalan T. Assessing the androgenic and metabolic heterogeneity in polycystic ovary syndrome using cluster analysis. Clin Endocrinol (Oxf) 2023;98(3):400-406 58. Deshmukh H, Adeleke KA, Wilmot E, Shah N, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Ethnic disparities in people accessing FreeStyle Libre in the UK: insights from the Association of British Clinical Diabetologists audit. Future Healthc J 2022;9(Suppl 2):11 59. Butler AE, Cunningham TK, Ramachandran V, Diboun I, Halama A, Sathyapalan T,

Najafi-Shoushtari SH, Atkin SL. Association of microRNAs With Embryo Development and Fertilization in Women Undergoing Subfertility Treatments: A Pilot Study. Front Reprod Health. 2021;3:719326 60. Butler AE, Moin ASM, Sathyapalan T, Atkin SL. Components of the Complement Cascade Differ in Polycystic Ovary Syndrome. Int J Mol Sci 2022;23(20) 61. Abdalla MA, Shah N, Deshmukh H, Sahebkar A, Ostlundh L, Al-Rifai RH, Atkin SL, Sathyapalan T. Impact of metformin on the clinical and metabolic parameters of women with polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials. Ther Adv Endocrinol Metab 2022;13:20420188221127142 62. Moin ASM, Sathyapalan T, Atkin SL, Butler AE. The severity and duration of Hypoglycemia affect platelet-derived protein responses in Caucasians. Cardiovasc Diabetol 2022;21(1):202. 63. Mohamadian M, Parsamanesh N, Chiti H, Sathyapalan T, Sahebkar A. Protective effects of curcumin on ischemia/reperfusion injury. Phytother Res

2022;36(12):4299-4324 64. Mahdi Seyedzadeh Sani S, Sahranavard M, Jannati Yazdanabad M, Seddigh Shamsi M, Elyasi S, Hooshang Mohammadpour A, Sathyapalan T, Arasteh O, Ghavami V, Sahebkar 47 A. The effect of concomitant use of Colony-Stimulating factors on bleomycin pulmonary toxicity - A systematic review and meta-analysis. Int Immunopharmacol 2022;112:109227 65. Moin ASM, Sathyapalan T, Atkin SL, Butler AE. Inflammatory Markers in NonObese Women with Polycystic Ovary Syndrome Are Not Elevated and Show No Correlation with Vitamin D Metabolites. Nutrients 2022;14(17) 66. Sadeghalbanaei L, Shirban F, Bagherniya M, Sathyapalan T, Sahebkar A. The Role of High-density Lipoprotein in Oral and Dental Diseases. Curr Med Chem 2023;30(20):22262246 67. Deshmukh H, Wilmot E, Pieri B, Choudhary P, Shah N, Gregory R, Kilvert A, Lumb A, Christian P, Barnes D, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Time in range following flash glucose monitoring: Relationship with glycaemic control,

diabetes-related distress and resource utilisation in the Association of British Clinical Diabetologists national audit. Diabet Med 2022;39(11):e14942 68. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Renal Effects of Empagliflozin in Patients with Type 2 Diabetes Mellitus. Curr Med Chem 2023;30(25):2850-2863. 69. Ramanjaneya M, Priyanka R, Bensila M, Jerobin J, Pawar K, Sathyapalan T, AbouSamra AB, Halabi NM, Moin ASM, Atkin SL, Butler AE. MiRNA and associated inflammatory changes from baseline to hypoglycemia in type 2 diabetes. Front Endocrinol (Lausanne). 2022;13:917041 70. Vitale SG, Fulghesu AM, Mikus M, Watrowski R, D'Alterio MN, Lin LT, Shah M, Reyes-Munoz E, Sathyapalan T, Angioni S. The Translational Role of miRNA in Polycystic Ovary Syndrome: From Bench to Bedside-A Systematic Literature Review. Biomedicines 2022;10(8). 71. Sadeghi M, Dehnavi S, Shohan M, Jamialahmadi T, Sathyapalan T, Sahebkar A. Potential Role of SUMO and SUMOylation in the

Pathogenesis of Diabetes Mellitus. Curr Med Chem. 2023;30(14):1623-1637 72. Pieri B, Deshmukh H, Wilmot EG, Choudhary P, Shah N, Gregory R, Barnes D, Saunders S, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Impaired awareness of hypoglycaemia: Prevalence and associated factors before and after FreeStyle Libre use in the Association of British Clinical Diabetologists audit. Diabetes Obes Metab 2023;25(1):302305 73. Diego-Taboada A, Sathyapalan T, Courts F, Lorch M, Almutairi F, Burke BP, Harris K, Kruusmagi M, Walther T, Booth J, Boa AN, Archibald SJ, Thompson C, Atkin SL, Mackenzie G. Spore exines increase vitamin D clinical bioavailability by mucoadhesion and bile triggered release. J Control Release 2022;350:244-255 48 74. Brennan E, Kumar N, Drage DS, Cunningham TK, Sathyapalan T, Mueller JF, Atkin SL. A case-control study of polychlorinated biphenyl association with metabolic and hormonal outcomes in polycystic ovary syndrome. J Environ Sci Health C Toxicol Carcinog

2022;40(1):86-105. 75. Saberianpour S, Abolbashari S, Modaghegh MHS, Karimian MS, Eid AH, Sathyapalan T, Sahebkar A. Therapeutic effects of statins on osteoarthritis: A review J Cell Biochem. 2022;123(8):1285-1297 76. Arab ZN, Khayatan D, Razavi SM, Zare K, Kheradkhah E, Momtaz S, Ferretti G, Bacchetti T, Sathyapalan T, Emami SA, Abdolghaffari AH, Sahebkar A. Phytochemicals as Modulators of Paraoxonase-1 in Health and Diseases. Antioxidants (Basel) 2022;11(7) 77. Vitale SG, Watrowski R, Barra F, D'Alterio MN, Carugno J, Sathyapalan T, Kahramanoglu I, Reyes-Munoz E, Lin LT, Urman B, Ferrero S, Angioni S. Abnormal Uterine Bleeding in Perimenopausal Women: The Role of Hysteroscopy and Its Impact on Quality of Life and Sexuality. Diagnostics (Basel) 2022;12(5) 78. Javid H, Karimi-Shahri M, Khorramdel M, Mashhad AS, Tabrizi AT, Sathyapalan T, Afshari AR, Sahebkar A. Probiotics as an Adjuvant for Management of Gastrointestinal Cancers through their Anti-inflammatory Effects: A

Mechanistic Review. Curr Med Chem 2023;30(4):390-406. 79. Macnamara AF, Bird K, Rigby A, Sathyapalan T, Hepburn D. High-fidelity simulation and virtual reality: an evaluation of medical students' experiences. BMJ Simul Technol Enhanc Learn. 2021;7(6):528-535 80. Abdalla MA, Shah N, Deshmukh H, Sahebkar A, Ostlundh L, Al-Rifai RH, Atkin SL, Sathyapalan T. Impact of pharmacological interventions on biochemical hyperandrogenemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials. Arch Gynecol Obstet 2023;307(5):1347-1376 81. Arab A, Karimi E, Bagherniya M, Sathyapalan T, Sahebkar A. The Effect of Probiotic and Synbiotic Consumption on the Most Prevalent Chemotherapy-related Complications: A Systematic Review of Current Literature. Curr Med Chem 2022;29(33):5462-5473 82. Nandakumar M, Moin ASM, Ramanjaneya M, Qaissi AA, Sathyapalan T, Atkin SL, Butler AE. Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor

protein response. Diabetes Obes Metab 2022;24(8):1483-1497 83. Yale JF, Bodholdt U, Catarig AM, Catrina S, Clark A, Ekberg NR, Erhan U, Holmes P, Knudsen ST, Liutkus J, Sathyapalan T, Schultes B, Rudofsky G. Real-world use of onceweekly semaglutide in patients with type 2 diabetes: pooled analysis of data from four SURE studies by baseline characteristic subgroups. BMJ Open Diabetes Res Care 2022;10(2) 49 84. Blissett R, Blissett D, Levrat-Guillen F, Deshmukh H, Wilmot EG, Ryder REJ, Walton C, Sathyapalan T. FreeStyle Libre Flash Glucose Monitoring system for people with type 1 diabetes in the UK: a budget impact analysis. BMJ Open Diabetes Res Care 2022;10(2) 85. Moin ASM, Sathyapalan T, Atkin SL, Butler AE. Diagnostic and Prognostic Protein Biomarkers of beta-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization. Metabolites 2022;12(3) 86. Mesgari M, Aalami AH, Sathyapalan T, Sahebkar A. A Comprehensive Review of the Development of Carbohydrate

Macromolecules and Copper Oxide Nanocomposite Films in Food Nanopackaging. Bioinorg Chem Appl 2022;2022:7557825 87. Sahebkar A, Sathyapalan T, Guest PC, Barreto GE. Identification of difluorinated curcumin molecular targets linked to traumatic brain injury pathophysiology. Biomed Pharmacother. 2022;148:112770 88. Perros P, Basu A, Boelaert K, Dayan C, Vaidya B, Williams GR, Lazarus JH, Hickey J, Drake WM, Crown A, Orme SM, Johnson A, Ray DW, Leese GP, Jones TH, Abraham P, Grossman A, Rees A, Razvi S, Gibb FW, Moran C, Madathil A, Zarkovic MP, Plummer Z, Jarvis S, Falinska A, Velusamy A, Sanderson V, Pariani N, Atkin SL, Syed AA, Sathyapalan T, Nag S, Gilbert J, Gleeson H, Levy MJ, Johnston C, Sturrock N, Bennett S, Mishra B, Malik I, Karavitaki N. Postradioiodine Graves' management: The PRAGMA study Clin Endocrinol (Oxf). 2022;97(5):664-675 89. Jamialahmadi T, Nematy M, Abdalla M, Jangjoo A, Goshayeshi L, Kroh M, Moallem SA, Abbasifard M, Sathyapalan T, Sahebkar A. The Predictive

Role of Parathyroid Hormone for Nonalcoholic Fatty Liver Disease following Bariatric Surgery. J Nutr Metab 2022;2022:7319742. 90. Ramanjaneya M, Abdalhakam I, Bettahi I, Bensila M, Jerobin J, Aye MM, Alkasem M, Sathyapalan T, Atkin SL, Abou-Samra AB. Effect of Moderate Aerobic Exercise on Complement Activation Pathways in Polycystic Ovary Syndrome Women. Front Endocrinol (Lausanne). 2021;12:740703 91. Akbari A, Rafiee M, Sathyapalan T, Sahebkar A. Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis. J Diabetes Res 2022;2022:7520632 92. Bibak B, Shakeri F, Keshavarzi Z, Mollazadeh H, Javid H, Jalili-Nik M, Sathyapalan T, Afshari AR, Sahebkar A. Anticancer Mechanisms of Berberine: A Good Choice for Glioblastoma Multiforme Therapy. Curr Med Chem 2022;29(26):4507-4528 93. Saghafi N, Rezaee SA, Momtazi-Borojeni AA, Tavasolian F, Sathyapalan T, Abdollahi E, Sahebkar A. The therapeutic potential of regulatory T

cells in reducing cardiovascular complications in patients with severe COVID-19. Life Sci 2022;294:120392 50 94. Shakeri F, Bibak B, Safdari MR, Keshavarzi Z, Jamialahmadi T, Sathyapalan T, Sahebkar A. Cellular and Molecular Mechanisms of Curcumin in Thyroid Gland Disorders Curr Med Chem. 2022;29(16):2878-2890 95. Moutabian H, Ghahramani-Asl R, Mortezazadeh T, Laripour R, Narmani A, Zamani H, Ataei G, Bagheri H, Farhood B, Sathyapalan T, Sahebkar A. The cardioprotective effects of nano-curcumin against doxorubicin-induced cardiotoxicity: A systematic review. Biofactors 2022;48(3):597-610. 96. Bagherniya M, Mahdavi A, Abbasi E, Iranshahy M, Sathyapalan T, Sahebkar A. The effects of phytochemicals and herbal bio-active compounds on tumour necrosis factor-alpha in overweight and obese individuals: a clinical review. Inflammopharmacology 2022;30(1):91110 97. Yaribeygi H, Ashrafizadeh M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Naturally Occurring SGLT2 Inhibitors: A Review. Adv Exp

Med Biol 2021;1328:523-530 98. Radbakhsh S, Momtazi-Borojeni AA, Mahmoudi A, Sarborji MR, Jamialahmadi T, Sathyapalan T, Sahebkar A. Investigation of the Effects of Trehalose on Glycemic Indices in Streptozotocin-Induced Diabetic Rats. Adv Exp Med Biol 2021;1328:481-488 99. Ashrafizadeh M, Ahmadi Z, Yaribeygi H, Sathyapalan T, Jamialahmadi T, Sahebkar A. Antitumor and Protective Effects of Melatonin: The Potential Roles of MicroRNAs Adv Exp Med Biol. 2021;1328:463-471 100. Yaribeygi H, Sathyapalan T, Jamialahmadi T, Sahebkar A Natural Insulin Sensitizers for the Management of Diabetes Mellitus: A Review of Possible Molecular Mechanisms. Adv Exp Med Biol. 2021;1328:401-410 101. Panahi Y, Roozbahani M, Pirhadi S, Aghamollaei H, Nejat F, Naderi M, Serahati S, Jadidi K, Sathyapalan T, Jamialahmadi T, Sahebkar A. Safety and Efficacy of Oral Supplementation of Lentil (Lens culinaris Medic) in Dry Eye Patients. Adv Exp Med Biol 2021;1328:377-384. 102. Ashrafizadeh M, Ahmadi Z, Yaribeygi H,

Sathyapalan T, Jamialahmadi T, Sahebkar A. The Effects of Ginsenosides on the Nrf2 Signaling Pathway Adv Exp Med Biol 2021;1328:307-322. 103. Safdari MR, Shakeri F, Mohammadi A, Bibak B, Alesheikh P, Jamialahmadi T, Sathyapalan T, Sahebkar A. Role of Herbal Medicines in the Management of Brain Injury Adv Exp Med Biol. 2021;1328:287-305 104. Yaribeygi H, Maleki M, Mohammadi MT, Sathyapalan T, Jamialahmadi T, Sahebkar A. Crocin Improves Diabetes-Induced Oxidative Stress via Downregulating the Nox-4 in Myocardium of Diabetic Rats. Adv Exp Med Biol 2021;1328:275-285 51 105. Yousefsani BS, Dadmehr M, Shirani K, Jamshidi A, Sathyapalan T, Sahebkar A Health Benefits of Turmeric and Curcumin Against Food Contaminants. Adv Exp Med Biol 2021;1328:171-197. 106. Hedayati-Moghadam M, Hosseinian S, Paseban M, Shabgah AG, Gholizadeh J, Jamialahmadi T, Sathyapalan T, Sahebkar A. The Role of Chemokines in Cardiovascular Diseases and the Therapeutic Effect of Curcumin on CXCL8 and CCL2 as

Pathological Chemokines in Atherosclerosis. Adv Exp Med Biol 2021;1328:155-170 107. Motlagh PE, Novin AG, Ghahari F, Nikzad A, Khoshandam M, Mardani S, Khanbabaei H, Farsinejad A, Sathyapalan T, Sahebkar A, Pourghadamyari H. Evaluation of the Effect of Crocin on Doxorubicin-Induced Cardiotoxicity. Adv Exp Med Biol 2021;1328:143153 108. Fakheran O, Khademi A, Bagherniya M, Sathyapalan T, Sahebkar A The Effects of Nutraceuticals and Bioactive Natural Compounds on Chronic Periodontitis: A Clinical Review. Adv Exp Med Biol. 2021;1328:59-80 109. Atazadegan MA, Bagherniya M, Fakheran O, Sathyapalan T, Sahebkar A The Effect of Herbal Medicine and Natural Bioactive Compounds on Plasma Adiponectin: A Clinical Review. Adv Exp Med Biol 2021;1328:37-57 110. Moin ASM, Nandakumar M, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Potential Biomarkers to Predict Acute Ischemic Stroke in Type 2 Diabetes. Front Mol Biosci 2021;8:744459. 111. Abdalla MA, Shah N, Deshmukh H, Sahebkar A, Ostlundh L,

Al-Rifai RH, Atkin SL, Sathyapalan T. Impact of pharmacological interventions on anthropometric indices in women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials. Clin Endocrinol (Oxf) 2022;96(6):758-780 112. Deshmukh H, Shah N, Papageorgiou M, Abdalla MA, Lhaf F, Aye M, Sathyapalan T Genetic risk for the polycystic ovary syndrome, bone mineral density and fractures in women and men: A UK Biobank Mendelian randomisation study. Bone 2022;155:116285 113. Moin ASM, Nandakumar M, Kahal H, Sathyapalan T, Atkin SL, Butler AE Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia. Cells 2021;10(11) 114. Moin ASM, Nandakumar M, Diboun I, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE. Hypoglycemia-induced changes in complement pathways in type 2 diabetes Atheroscler Plus. 2021;46:35-45 115. Abdalla MA, Shah N, Deshmukh H, Sahebkar A, Ostlundh L, Al-Rifai RH, Atkin SL,

Sathyapalan T. Effect of pharmacological interventions on lipid profiles and C-reactive protein 52 in polycystic ovary syndrome: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 2022;96(4):443-459. 116. Lashgari NA, Roudsari NM, Momtaz S, Sathyapalan T, Abdolghaffari AH, Sahebkar A. The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease J Neuroimmunol. 2021;361:577758 117. Abdalla MA, Shah N, Deshmukh H, Sahebkar A, Ostlundh L, Al-Rifai RH, Atkin SL, Sathyapalan T. Impact of pharmacological interventions on insulin resistance in women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials. Clin Endocrinol (Oxf) 2022;96(3):371-394 118. Safarzadeh S, Shirban F, Bagherniya M, Sathyapalan T, Sahebkar A The effects of herbal medicines on cancer therapy-induced oral mucositis: A literature review. Phytother Res 2022;36(1):243-265. 119. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T,

Sahebkar A Pathophysiology of Physical Inactivity-Dependent Insulin Resistance: A Theoretical Mechanistic Review Emphasizing Clinical Evidence. J Diabetes Res 2021;2021:7796727 120. Moosavian SA, Sathyapalan T, Jamialahmadi T, Sahebkar A The Emerging Role of Nanomedicine in the Management of Nonalcoholic Fatty Liver Disease: A State-of-the-Art Review. Bioinorg Chem Appl 2021;2021:4041415 121. Simental-Mendia LE, Shah N, Sathyapalan T, Majeed M, Orekhov AN, Jamialahmadi T, Sahebkar A. Effect of Curcumin on Glycaemic and Lipid Parameters in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Reprod Sci. 2022;29(11):3124-3133 122. Butler AE, Al-Qaissi A, Sathyapalan T, Atkin SL Angiopoietin-1: an early biomarker of diabetic nephropathy? J Transl Med. 2021;19(1):427 123. Butler AE, Moin ASM, Sathyapalan T, Atkin SL Vitamin D association with the renin angiotensin system in polycystic ovary syndrome. J Steroid Biochem Mol Biol 2021;214:105965.

124. Pashirzad M, Sathyapalan T, Sahebkar A Clinical Importance of Wnt5a in the Pathogenesis of Colorectal Cancer. J Oncol 2021;2021:3136508 125. Shah N, Abdalla MA, Deshmukh H, Sathyapalan T Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab 2021;12:20420188211042145 126. Gorabi AM, Abbasifard M, Imani D, Aslani S, Razi B, Alizadeh S, BagheriHosseinabadi Z, Sathyapalan T, Sahebkar A Effect of curcumin on C-reactive protein as a 53 biomarker of systemic inflammation: An updated meta-analysis of randomized controlled trials. Phytother Res 2022;36(1):85-97 127. Koushki K, Keshavarz Shahbaz S, Keshavarz M, Bezsonov EE, Sathyapalan T, Sahebkar A. Gold Nanoparticles: Multifaceted Roles in the Management of Autoimmune Disorders. Biomolecules 2021;11(9) 128. Holmes P, Bell HE, Bozkurt K, Catarig AM, Clark A, Machell A, Sathyapalan T Real-World Use of Once-Weekly

Semaglutide in Type 2 Diabetes: Results from the SURE UK Multicentre, Prospective, Observational Study. Diabetes Ther 2021;12(11):2891-2905 129. Deshmukh H, Wilmot EG, Choudhary P, Narendran P, Shah N, Barnes D, Kamruddin S, Banatwalla R, Christian P, Saunders S, Lumb A, Herring R, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Impaired Awareness of Hypoglycemia and Severe Hypoglycemia in Drivers With Diabetes: Insights From the Association of British Clinical Diabetologists Nationwide Audit. Diabetes Care 2021;44(11):e190-e191 130. Hatamipour M, Hadizadeh F, Jaafari MR, Khashyarmanesh Z, Sathyapalan T, Sahebkar A. Anti-Proliferative Potential of Fluorinated Curcumin Analogues: Experimental and Computational Analysis and Review of the Literature. Curr Med Chem 2022;29(8):14591471 131. Alikiaii B, Heidari Z, Bagherniya M, Askari G, Sathyapalan T, Sahebkar A The Effect of Statins on C-Reactive Protein in Stroke Patients: A Systematic Review of Clinical Trials. Mediators Inflamm

2021;2021:7104934 132. Gorabi AM, Aslani S, Imani D, Razi B, Sathyapalan T, Sahebkar A Effect of resveratrol on C-reactive protein: An updated meta-analysis of randomized controlled trials. Phytother Res. 2021;35(12):6754-6767 133. Shah NZ, Malik S, Sathyapalan T, Mohammed K Refractory hypokalaemia and hypertension with metabolic alkalosis: an acute presentation of Cushing's disease secondary to a pituitary macroadenoma. BMJ Case Rep 2021;14(8) 134. Shahbaz SK, Koushki K, Sathyapalan T, Majeed M, Sahebkar A PLGA-Based Curcumin Delivery System: An Interesting Therapeutic Approach in the Treatment of Alzheimer's Disease. Curr Neuropharmacol 2022;20(2):309-323 135. Atkin AS, Moin ASM, Nandakumar M, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE. Impact of severe hypoglycemia on the heat shock and related protein response Sci Rep 2021;11(1):17057. 136. Gholami L, Ivari JR, Nasab NK, Oskuee RK, Sathyapalan T, Sahebkar A Recent Advances in Lung Cancer Therapy Based on

Nanomaterials: A Review. Curr Med Chem 2023;30(3):335-355. 54 137. Gorabi AM, Kiaie N, Aslani S, Sathyapalan T, Jamialahmadi T, Sahebkar A Implications on the Therapeutic Potential of Statins via Modulation of Autophagy. Oxid Med Cell Longev. 2021;2021:9599608 138. Bagherniya M, Askari G, Alikiaii B, Abbasi S, Soleimani D, Sathyapalan T, Jamialahmadi T, Sahebkar A. Curcumin for the Treatment of Prostate Diseases: A Systematic Review of Controlled Clinical Trials. Adv Exp Med Biol 2021;1291:345-362 139. Bagherniya M, Soleimani D, Rouhani MH, Askari G, Sathyapalan T, Sahebkar A The Use of Curcumin for the Treatment of Renal Disorders: A Systematic Review of Randomized Controlled Trials. Adv Exp Med Biol 2021;1291:327-343 140. Shokri-Mashhadi N, Bagherniya M, Askari G, Sathyapalan T, Sahebkar A A Systematic Review of the Clinical Use of Curcumin for the Treatment of Osteoarthritis. Adv Exp Med Biol. 2021;1291:265-282 141. Bagherniya M, Darand M, Askari G, Guest PC, Sathyapalan T,

Sahebkar A The Clinical Use of Curcumin for the Treatment of Rheumatoid Arthritis: A Systematic Review of Clinical Trials. Adv Exp Med Biol 2021;1291:251-263 142. Fakheran O, Khademi A, Bagherniya M, Dehghannejad M, Sathyapalan T, Sahebkar A. Antibacterial Activity of Curcumin Against Periodontal Pathogens: A Systematic Review Adv Exp Med Biol. 2021;1291:239-249 143. Gharibpour F, Fakheran O, Parvaneh A, Shirban F, Bagherniya M, Sathyapalan T, Sahebkar A. The Clinical Use of Curcumin for the Treatment of Recurrent Aphthous Stomatitis: A Systematic Review of Clinical Trials. Adv Exp Med Biol 2021;1291:229-238 144. Ehteshami A, Shirban F, Gharibpour F, Bagherniya M, Sathyapalan T, Sahebkar A Does Curcumin Have an Anticaries Effect? A Systematic Review of In Vitro Studies. Adv Exp Med Biol. 2021;1291:213-227 145. Shirban F, Gharibpour F, Ehteshami A, Bagherniya M, Sathyapalan T, Sahebkar A The Effects of Curcumin in the Treatment of Gingivitis: A Systematic Review of Clinical Trials. Adv

Exp Med Biol 2021;1291:179-211 146. Rafiee S, Bagherniya M, Askari G, Sathyapalan T, Jamialahmadi T, Sahebkar A The Effect of Curcumin in Improving Lipid Profile in Patients with Cardiovascular Risk Factors: A Systematic Review of Clinical Trials. Adv Exp Med Biol 2021;1291:165-177 147. Mahdavi A, Moradi S, Askari G, Iraj B, Sathyapalan T, Guest PC, Bagherniya M, Sahebkar A. Effect of Curcumin on Glycemic Control in Patients with Type 2 Diabetes: A Systematic Review of Randomized Clinical Trials. Adv Exp Med Biol 2021;1291:139-149 55 148. Safari Z, Bagherniya M, Askari G, Sathyapalan T, Sahebkar A The Effect of Curcumin Supplemsentation on Anthropometric Indices in Overweight and Obese Individuals: A Systematic Review of Randomized Controlled Trials. Adv Exp Med Biol 2021;1291:121137 149. Yaribeygi H, Farrokhi FR, Abdalla MA, Sathyapalan T, Banach M, Jamialahmadi T, Sahebkar A. The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood

Pressure and Cardiovascular Complications in Diabetes. J Diabetes Res 2021;2021:6518221 150. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection? Front Endocrinol (Lausanne). 2021;12:665134 151. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Type 2 Diabetes Coagulopathy Proteins May Conflict With Biomarkers Reflective of COVID-19 Severity. Front Endocrinol (Lausanne). 2021;12:658304 152. Marsden AJ, Riley DRJ, Birkett S, Rodriguez-Barucg Q, Guinn BA, Carroll S, Ingle L, Sathyapalan T, Beltran-Alvarez P. Love is in the hair: arginine methylation of human hair proteins as novel cardiovascular biomarkers. Amino Acids 2022;54(4):591-600 153. Deshmukh H, Wilmot EG, Gregory R, Barnes D, Narendran P, Saunders S, Furlong N, Kamaruddin S, Banatwalla R, Herring R, Kilvert A, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Predictors of diabetes-related distress

before and after FreeStyle Libre-1 use: Lessons from the Association of British Clinical Diabetologists nationwide study. Diabetes Obes Metab. 2021;23(10):2261-2268 154. Li JV, Ashrafian H, Sarafian M, Homola D, Rushton L, Barker G, Cabrera PM, Lewis MR, Darzi A, Lin E, Gletsu-Miller NA, Atkin SL, Sathyapalan T, Gooderham NJ, Nicholson JK, Marchesi JR, Athanasiou T, Holmes E. Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype. Microbiome 2021;9(1):139. 155. Amini L, Chekini R, Nateghi MR, Haghani H, Jamialahmadi T, Sathyapalan T, Sahebkar A. The Effect of Combined Vitamin C and Vitamin E Supplementation on Oxidative Stress Markers in Women with Endometriosis: A Randomized, Triple-Blind PlaceboControlled Clinical Trial. Pain Res Manag 2021;2021:5529741 156. Abdalla MA, Deshmukh H, Mohammed I, Atkin S, Reid M, Sathyapalan T The Effect of Free Androgen Index on the Quality of Life of Women With Polycystic Ovary Syndrome: A

Cross-Sectional Study. Front Physiol 2021;12:652559 56 157. Moin ASM, Sathyapalan T, Butler AE, Atkin SL Vitamin D association with coagulation factors in polycystic ovary syndrome is dependent upon body mass index. J Transl Med. 2021;19(1):239 158. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A Antioxidative Potentials of Incretin-Based Medications: A Review of Molecular Mechanisms. Oxid Med Cell Longev. 2021;2021:9959320 159. Jamialahmadi T, Nematy M, Jangjoo A, Goshayeshi L, Abdalla MA, Akhlaghi S, Sathyapalan T, Sahebkar A. The predictive role of parathyroid hormone for non-alcoholic fatty liver disease based on invasive and non-invasive findings in candidates of bariatric surgery. Eat Weight Disord. 2022;27(2):693-700 160. Aalami AH, Abdeahad H, Mesgari M, Sathyapalan T, Sahebkar A Urinary Angiogenin as a Marker for Bladder Cancer: A Meta-Analysis. Biomed Res Int 2021;2021:5557309. 161. Ashrafizadeh M, Ahmadi Z, Yaribeygi H, Sathyapalan T, Sahebkar A

Astaxanthin and Nrf2 Signaling Pathway: A Novel Target for New Therapeutic Approaches. Mini Rev Med Chem. 2022;22(2):312-321 162. Gorabi AM, Razi B, Aslani S, Abbasifard M, Imani D, Sathyapalan T, Sahebkar A Effect of curcumin on proinflammatory cytokines: A meta-analysis of randomized controlled trials. Cytokine 2021;143:155541 163. Moin ASM, Kahal H, Al-Qaissi A, Kumar N, Sathyapalan T, Atkin SL, Butler AE Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia. BMJ Open Diabetes Res Care 2021;9(1) 164. Atkin AS, Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Plasma heat shock protein response to euglycemia in type 2 diabetes. BMJ Open Diabetes Res Care 2021;9(1). 165. Jerobin J, Ramanjaneya M, Bettahi I, Parammal R, Siveen KS, Alkasem M, Aye M, Sathyapalan T, Skarulis M, Atkin SL, Abou-Samra AB. Regulation of circulating CTRP-2/CTRP-9 and GDF-8/GDF-15 by intralipids and insulin in healthy control and polycystic ovary syndrome

women following chronic exercise training. Lipids Health Dis 2021;20(1):34. 166. Gharibpour F, Shirban F, Bagherniya M, Nosouhian M, Sathyapalan T, Sahebkar A The Effects of Nutraceuticals and Herbal Medicine on Candida albicans in Oral Candidiasis: A Comprehensive Review. Adv Exp Med Biol 2021;1308:225-248 167. Mirhafez SR, Azimi-Nezhad M, Dehabeh M, Hariri M, Naderan RD, Movahedi A, Abdalla M, Sathyapalan T, Sahebkar A. The Effect of Curcumin Phytosome on the Treatment 57 of Patients with Non-alcoholic Fatty Liver Disease: A Double-Blind, Randomized, PlaceboControlled Trial. Adv Exp Med Biol 2021;1308:25-35 168. Amini A, Khadivar P, Ahmadnia A, Alipour M, Majeed M, Jamialahmadi T, Sathyapalan T, Sahebkar A. Role of Curcumin in Regulating Long Noncoding RNA Expression in Cancer. Adv Exp Med Biol 2021;1308:13-23 169. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Platelet ProteinRelated Abnormalities in Response to Acute Hypoglycemia in Type 2 Diabetes Front Endocrinol

(Lausanne). 2021;12:651009 170. Nosrati-Oskouie M, Aghili-Moghaddam NS, Sathyapalan T, Sahebkar A Impact of curcumin on fatty acid metabolism. Phytother Res 2021;35(9):4748-4762 171. Amiri A, Barreto G, Sathyapalan T, Sahebkar A siRNA Therapeutics: Future Promise for Neurodegenerative Diseases. Curr Neuropharmacol 2021;19(11):1896-1911 172. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Glucose excursions in type 2 diabetes modulate amyloid-related proteins associated with dementia. J Transl Med 2021;19(1):131. 173. Moin ASM, Sathyapalan T, Diboun I, Atkin SL, Butler AE Identification of macrophage activation-related biomarkers in obese type 2 diabetes that may be indicative of enhanced respiratory risk in COVID-19. Sci Rep 2021;11(1):6428 174. Karimi L, Makvandi S, Vahedian-Azimi A, Sathyapalan T, Sahebkar A Effect of COVID-19 on Mortality of Pregnant and Postpartum Women: A Systematic Review and MetaAnalysis. J Pregnancy 2021;2021:8870129 175. Atabati H, Yazdanpanah E,

Mortazavi H, Bajestani SG, Raoofi A, Esmaeili SA, Khaledi A, Saburi E, Afshari JT, Sathyapalan T, Moghaddam AS, Sahebkar A. Immunoregulatory Effects of Tolerogenic Probiotics in Multiple Sclerosis. Adv Exp Med Biol 2021;1286:87-105. 176. Moin ASM, Sathyapalan T, Atkin SL, Butler AE Correction to: COVID-19 biomarkers for severity mapped to polycystic ovary syndrome. J Transl Med 2021;19(1):106 177. Moin ASM, Sathyapalan T, Butler AE, Atkin SL Vitamin D Association With Macrophage-Derived Cytokines in Polycystic Ovary Syndrome: An Enhanced Risk of COVID-19 Infection? Front Endocrinol (Lausanne). 2021;12:638621 178. Moin ASM, Sathyapalan T, Diboun I, Elrayess MA, Butler AE, Atkin SL Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome. Sci Rep 2021;11(1):5320. 58 179. Moayed MS, Rahimi-Bashar F, Vahedian-Azimi A, Sathyapalan T, Guest PC, Jamialahmadi T, Sahebkar A. Cardiac Injury in COVID-19: A Systematic Review Adv Exp Med Biol.

2021;1321:325-333 180. Moayed MS, Vahedian-Azimi A, Mirmomeni G, Rahimi-Bashar F, Goharimoghadam K, Pourhoseingholi MA, Abbasi-Farajzadeh M, Babaei M, Sathyapalan T, Guest PC, Sahebkar A. A Survey of Psychological Distress Among the Community in the COVID-19 Epidemic: A Cross-Sectional Study. Adv Exp Med Biol 2021;1321:253-260 181. Moayed MS, Vahedian-Azimi A, Mirmomeni G, Rahimi-Bashar F, Goharimoghadam K, Pourhoseingholi MA, Abbasi-Farajzadeh M, Khatibzadeh A, Sathyapalan T, Guest PC, Sahebkar A. Coronavirus (COVID-19)-Associated Psychological Distress Among Medical Students in Iran. Adv Exp Med Biol 2021;1321:245-251 182. Moayed MS, Vahedian-Azimi A, Mirmomeni G, Rahimi-Bashar F, Goharimoghadam K, Pourhoseingholi MA, Abbasi-Farajzadeh M, Hekmat M, Sathyapalan T, Guest PC, Sahebkar A. Survey of Immediate Psychological Distress Levels Among Healthcare Workers in the COVID-19 Epidemic: A Cross-Sectional Study. Adv Exp Med Biol 2021;1321:237-243 183. Moayed MS, Vahedian-Azimi A,

Mirmomeni G, Rahimi-Bashar F, Goharimoghadam K, Pourhoseingholi MA, Abbasi-Farajzadeh M, Hekmat M, Sathyapalan T, Guest PC, Sahebkar A. Depression, Anxiety, and Stress Among Patients with COVID-19: A CrossSectional Study Adv Exp Med Biol 2021;1321:229-236 184. Tavasolian F, Hatam GR, Mosawi SH, Saadi MI, Abdollahi E, Jamialahmadi T, Sathyapalan T, Sahebkar A. The Immune Response and Effectiveness of COVID-19 Therapies Adv Exp Med Biol. 2021;1321:115-126 185. Moin ASM, Nandakumar M, Sathyapalan T, Atkin SL, Butler AE Biomarkers of COVID-19 severity may not serve patients with polycystic ovary syndrome. J Transl Med 2021;19(1):63. 186. Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T The potential role of incretinbased therapies for polycystic ovary syndrome: a narrative review of the current evidence Ther Adv Endocrinol Metab. 2021;12:2042018821989238 187. Hosseini SA, Zahedipour F, Sathyapalan T, Jamialahmadi T, Sahebkar A Pulmonary fibrosis: Therapeutic and mechanistic insights into the

role of phytochemicals. Biofactors 2021;47(3):250-269. 188. Moin ASM, Sathyapalan T, Atkin SL, Butler AE The relationship of soluble neuropilin-1 to severe COVID-19 risk factors in polycystic ovary syndrome. Metabol Open 2021;9:100079. 59 189. Gorabi AM, Ghanbari M, Sathyapalan T, Jamialahmadi T, Sahebkar A Implications of microRNAs in the Pathogenesis of Atherosclerosis and Prospects for Therapy. Curr Drug Targets. 2021;22(15):1738-1749 190. Navashenaq JG, Shabgah AG, Hedayati-Moghadam M, Ariaee N, Mohammadi H, Hemmatzadeh M, Azhdari S, Jamialahmadi T, Sathyapalan T, Sahebkar A. The role of myeloid-derived suppressor cells in rheumatoid arthritis: An update. Life Sci 2021;269:119083. 191. Afshari AR, Motamed-Sanaye A, Sabri H, Soltani A, Karkon-Shayan S, Radvar S, Javid H, Mollazadeh H, Sathyapalan T, Sahebkar A. Neurokinin-1 Receptor (NK-1R) Antagonists: Potential Targets in the Treatment of Glioblastoma Multiforme. Curr Med Chem 2021;28(24):4877-4892. 192. Moin ASM, Al-Qaissi

A, Sathyapalan T, Atkin SL, Butler AE Mapping of type 2 diabetes proteins to COVID-19 biomarkers: A proteomic analysis. Metabol Open 2021;9:100074. 193. Moin ASM, Sathyapalan T, Atkin SL, Butler AE COVID-19 biomarkers for severity mapped to polycystic ovary syndrome. J Transl Med 2020;18(1):490 194. Yaribeygi H, Sathyapalan T, Jamialahmadi T, Sahebkar A The Impact of Diabetes Mellitus in COVID-19: A Mechanistic Review of Molecular Interactions. J Diabetes Res 2020;2020:5436832. 195. Tavasolian F, Hosseini AZ, Rashidi M, Soudi S, Abdollahi E, Momtazi-Borojeni AA, Sathyapalan T, Sahebkar A. The Impact of Immune Cell-derived Exosomes on Immune Response Initiation and Immune System Function. Curr Pharm Des 2021;27(2):197-205 196. Mohammadi S, Abdollahi E, Nezamnia M, Esmaeili SA, Tavasolian F, Sathyapalan T, Sahebkar A. Adoptive transfer of Tregs: A novel strategy for cell-based immunotherapy in spontaneous abortion: Lessons from experimental models. Int Immunopharmacol 2021;90:107195.

197. Brown O, Costanzo P, Clark AL, Condorelli G, Cleland JGF, Sathyapalan T, Hepburn D, Kilpatrick ES, Atkin SL. Relationship between a single measurement at baseline of body mass index, glycated hemoglobin, and the risk of mortality and cardiovascular morbidity in type 2 diabetes mellitus. Cardiovasc Endocrinol Metab 2020;9(4):177-182 198. Afshari AR, Jalili-Nik M, Abbasinezhad-Moud F, Javid H, Karimi M, Mollazadeh H, Jamialahmadi T, Sathyapalan T, Sahebkar A. Anti-tumor Effects of Curcuminoids in Glioblastoma Multiforme: An Updated Literature Review. Curr Med Chem 2021;28(39):8116-8138. 60 199. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Do biomarkers of COVID-19 severity simply reflect a stress response in type 2 diabetes: Biomarker response to hypoglycemia. Metabolism 2021;114:154417 200. Alikiaii B, Bagherniya M, Askari G, Sathyapalan T, Sahebkar A Evaluation of the effect of curcumin on pneumonia: A systematic review of preclinical studies. Phytother Res

2021;35(4):1939-1952. 201. Butler AE, Abouseif A, Dargham SR, Sathyapalan T, Atkin SL Metabolic comparison of polycystic ovarian syndrome and control women in Middle Eastern and UK Caucasian populations. Sci Rep 2020;10(1):18895 202. Butler AE, Ramachandran V, Cunningham TK, David R, Gooderham NJ, Benurwar M, Dargham SR, Hayat S, Sathyapalan T, Najafi-Shoushtari SH, Atkin SL. Increased MicroRNA Levels in Women With Polycystic Ovarian Syndrome but Without Insulin Resistance: A Pilot Prospective Study. Front Endocrinol (Lausanne) 2020;11:571357 203. Ramanjaneya M, Bensila M, Bettahi I, Jerobin J, Samra TA, Aye MM, Alkasem M, Siveen KS, Sathyapalan T, Skarulis M, Atkin SL, Abou-Samra AB. Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women. Front Endocrinol (Lausanne) 2020;11:568500 204. Everett CC, Reynolds C, Fernandez C, Stocken DD, Sharples LD, Sathyapalan T, Heller S, Storey RF, Ajjan RA.

Rationale and design of the LIBERATES trial: Protocol for a randomised controlled trial of flash glucose monitoring for optimisation of glycaemia in individuals with type 2 diabetes and recent myocardial infarction. Diab Vasc Dis Res 2020;17(5):1479164120957934. 205. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Hypoglycaemia in type 2 diabetes exacerbates amyloid-related proteins associated with dementia. Diabetes Obes Metab. 2021;23(2):338-349 206. Danta CC, Boa AN, Bhandari S, Sathyapalan T, Xu SZ Recent advances in drug discovery for diabetic kidney disease. Expert Opin Drug Discov 2021;16(4):447-461 207. Draicchio F, van Vliet S, Ancu O, Paluska SA, Wilund KR, Mickute M, Sathyapalan T, Renshaw D, Watt P, Sylow L, Burd NA, Mackenzie RW. Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients. J Physiol. 2020;598(24):5701-5716 208. Moin ASM, Sathyapalan T, Atkin SL, Butler AE Pro-fibrotic M2 macrophage

markers may increase the risk for COVID19 in type 2 diabetes with obesity. Metabolism 2020;112:154374. 61 209. Deshmukh H, Papageorgiou M, Aye M, England J, Abdalla M, Sathyapalan T Hyperthyroidism and bone mineral density: Dissecting the causal association with Mendelian randomization analysis. Clin Endocrinol (Oxf) 2021;94(1):119-127 210. Chattopadhyay S, George A, John J, Sathyapalan T Postload glucose spike but not fasting glucose determines prognosis after myocardial infarction in patients without known or newly diagnosed diabetes. J Diabetes 2021;13(3):191-199 211. Butler AE, Ramachandran V, Sathyapalan T, David R, Gooderham NJ, Benurwar M, Dargham SR, Hayat S, Hani Najafi-Shoushtari S, Atkin SL. Corrigendum: microRNA Expression in Women With and Without Polycystic Ovarian Syndrome Matched for Body Mass Index. Front Endocrinol (Lausanne) 2020;11:515 212. Moin ASM, Sathyapalan T, Atkin SL, Butler AE Renin-Angiotensin System overactivation in polycystic ovary syndrome, a risk

for SARS-CoV-2 infection? Metabol Open. 2020;7:100052. 213. Butler AE, Hayat S, Dargham SR, Malek JA, Abdullah SA, Mahmoud YA, Sathyapalan T, Atkin SL. Long non-coding RNA expression in non-obese women with polycystic ovary syndrome and weight-matched controls. Reprod Biomed Online 2020;41(4):579-583. 214. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A Obesity and Insulin Resistance: A Review of Molecular Interactions. Curr Mol Med 2021;21(3):182-193 215. Chattopadhyay S, George A, John J, Sathyapalan T Two-Hour Post-Load Plasma Glucose, a Biomarker to Improve the GRACE Score in Patients without Known Diabetes. Cardiology. 2020;145(9):553-561 216. Gorabi AM, Kiaie N, Sathyapalan T, Al-Rasadi K, Jamialahmadi T, Sahebkar A The Role of MicroRNAs in Regulating Cytokines and Growth Factors in Coronary Artery Disease: The Ins and Outs. J Immunol Res 2020;2020:5193036 217. Abdalla M, Deshmukh H, Atkin SL, Sathyapalan T miRNAs as a novel clinical biomarker and therapeutic

targets in polycystic ovary syndrome (PCOS): A review. Life Sci 2020;259:118174. 218. Pourtaji A, Jahani V, Sahebkar A, Sathyapalan T, Mohammadpour AH Application of Erythropoietin in Chronic Heart Failure Treatment. Mini Rev Med Chem 2020;20(20):2080-2089. 219. Heiat M, Hashemi-Aghdam MR, Heiat F, Rastegar Shariat Panahi M, Aghamollaei H, Moosazadeh Moghaddam M, Sathyapalan T, Ranjbar R, Sahebkar A. Integrative role of traditional and modern technologies to combat COVID-19. Expert Rev Anti Infect Ther 2021;19(1):23-33. 62 220. Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2020;11:2042018820938305 221. Deshmukh H, Wilmot EG, Gregory R, Barnes D, Narendran P, Saunders S, Furlong N, Kamaruddin S, Banatwalla R, Herring R, Kilvert A, Patmore J, Walton C, Ryder REJ, Sathyapalan T. Effect of Flash Glucose Monitoring on Glycemic Control, Hypoglycemia,

Diabetes-Related Distress, and Resource Utilization in the Association of British Clinical Diabetologists (ABCD) Nationwide Audit. Diabetes Care 2020;43(9):2153-2160 222. Moin ASM, Al-Qaissi A, Sathyapalan T, Atkin SL, Butler AE Renin-Angiotensin System Overactivation in Type 2 Diabetes: A Risk for SARS-CoV-2 Infection? Diabetes Care. 2020;43(10):e131-e133. 223. Bahrami A, Sathyapalan T, Moallem SA, Sahebkar A Counteracting arsenic toxicity: Curcumin to the rescue? J Hazard Mater. 2020;400:123160 224. Kahal H, Halama A, Aburima A, Bhagwat AM, Butler AE, Graumann J, Suhre K, Sathyapalan T, Atkin SL. Author Correction: Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects. Sci Rep 2020;10(1):10233 225. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A Incretin-based therapies and renin-angiotensin system: Looking for new therapeutic potentials in the diabetic milieu. Life Sci 2020;256:117916 226. Ghazanfarpour M,

Sathyapalan T, Banach M, Jamialahmadi T, Sahebkar A Prophylactic aspirin for preventing pre-eclampsia and its complications: An overview of metaanalyses. Drug Discov Today 2020;25(8):1487-1501 227. Kouhpeikar H, Delbari Z, Sathyapalan T, Simental-Mendia LE, Jamialahmadi T, Sahebkar A. The Effect of Statins through Mast Cells in the Pathophysiology of Atherosclerosis: a Review. Curr Atheroscler Rep 2020;22(5):19 228. Javed Z, Papageorgiou M, Madden LA, Rigby AS, Kilpatrick ES, Atkin SL, Sathyapalan T. The effects of empagliflozin vs metformin on endothelial microparticles in overweight/obese women with polycystic ovary syndrome. Endocr Connect 2020;9(6):563569 229. Omidkhoda N, Vakilian F, Mohammadpour AH, Sathyapalan T, Sahebkar A Aldosterone and Mineralocorticoid Receptor Antagonists on Pulmonary Hypertension and Right Ventricular Failure: A Review. Curr Pharm Des 2020;26(31):3862-3870 63 230. Deshmukh H, Aylward LL, Rose M, Fernandes A, Sedman P, Thatcher NJ, Atkin SL,

Sathyapalan T. Association of endocrine active environmental compounds with body mass index and weight loss following bariatric surgery. Clin Endocrinol (Oxf) 2020;93(3):280-287 231. Zahedipour F, Hosseini SA, Sathyapalan T, Majeed M, Jamialahmadi T, Al-Rasadi K, Banach M, Sahebkar A. Potential effects of curcumin in the treatment of COVID-19 infection Phytother Res. 2020;34(11):2911-2920 232. Butler AE, Ramachandran V, Sathyapalan T, David R, Gooderham NJ, Benurwar M, Dargham SR, Hayat S, Hani Najafi-Shoushtari S, Atkin SL. microRNA Expression in Women With and Without Polycystic Ovarian Syndrome Matched for Body Mass Index. Front Endocrinol (Lausanne). 2020;11:206 233. Forouzanfar F, Forouzanfar A, Sathyapalan T, Orafai HM, Sahebkar A Curcumin for the Management of Periodontal Diseases: A Review. Curr Pharm Des 2020;26(34):4277-4284 234. Bahrami A, Sathyapalan T, Sahebkar A The Role of Interleukin-18 in the Development and Progression of Atherosclerosis. Curr Med Chem

2021;28(9):1757-1774 235. Babatabar Darzi H, Vahedian-Azimi A, Ghasemi S, Ebadi A, Sathyapalan T, Sahebkar A. The effect of aromatherapy with rose and lavender on anxiety, surgical site pain, and extubation time after open-heart surgery: A double-center randomized controlled trial. Phytother Res. 2020;34(10):2675-2684 236. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A Molecular Mechanisms by Which Imeglimin Improves Glucose Homeostasis. J Diabetes Res 2020;2020:8768954. 237. Yaribeygi H, Sathyapalan T, Atkin SL, Sahebkar A Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus. Oxid Med Cell Longev 2020;2020:8609213 238. Kahal H, Halama A, Aburima A, Bhagwat AM, Butler AE, Graumann J, Suhre K, Sathyapalan T, Atkin SL. Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects. Sci Rep 2020;10(1):4750 239. Arasteh O, Nomani H, Baharara H, Sadjadi SA, Mohammadpour AH, Ghavami V, Sathyapalan T, Sahebkar A.

Antipsychotic Drugs and Risk of Developing Venous Thromboembolism and Pulmonary Embolism: A Systematic Review and Meta-Analysis. Curr Vasc Pharmacol. 2020;18(6):632-643 240. Korani M, Korani S, Zendehdel E, Jaafari MR, Sathyapalan T, Sahebkar A Utilization of Lipid-based Nanoparticles to Improve the Therapeutic Benefits of Bortezomib. Anticancer Agents Med Chem. 2020;20(6):643-650 241. Radbakhsh S, Sathyapalan T, Banach M, Sahebkar A Incretins and microRNAs: Interactions and physiological relevance. Pharmacol Res 2020;153:104662 64 242. Ashrafizadeh M, Ahmadi Z, Samarghandian S, Mohammadinejad R, Yaribeygi H, Sathyapalan T, Sahebkar A. MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress. Life Sci 2020;244:117329. 243. Yaribeygi H, Maleki M, Sathyapalan T, Iranpanah H, Orafai HM, Jamialahmadi T, Sahebkar A. The molecular mechanisms by which vitamin D improve glucose homeostasis: A mechanistic review. Life

Sci 2020;244:117305 244. Chattopadhyay S, George A, John J, Sathyapalan T Newly diagnosed abnormal glucose tolerance determines post-MI prognosis in patients with hospital related hyperglycaemia but without known diabetes. J Diabetes Complications 2020;34(4):107518 245. Yaribeygi H, Ashrafizadeh M, Henney NC, Sathyapalan T, Jamialahmadi T, Sahebkar A. Neuromodulatory effects of anti-diabetes medications: A mechanistic review Pharmacol Res. 2020;152:104611 246. Bagheri H, Ghasemi F, Barreto GE, Sathyapalan T, Jamialahmadi T, Sahebkar A The effects of statins on microglial cells to protect against neurodegenerative disorders: A mechanistic review. Biofactors 2020;46(3):309-325 247. Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A Antiinflammatory potentials of incretin-based therapies used in the management of diabetes Life Sci. 2020;241:117152 248. Jones HS, Papageorgiou M, Gordon A, Ehtesham, Javed Z, Wells LK, Greetham S, Doyle B, Hayes N, Rigby A, Atkin SL, Courts FL,

Sathyapalan T. Physiologically relevant screening of polyphenol-rich commercial preparations for bioactivity in vascular endothelial cells and application to healthy volunteers: A viable workflow and a cautionary tale. Biochem Pharmacol. 2020;173:113754 249. Ganie MA, Sahar T, Rashid A, Wani IA, Nisar S, Sathyapalan T, Vishnubhatla S, Ramakrishnan L, Parvez T, Geer I. Comparative Evaluation of Biomarkers of Inflammation Among Indian Women With Polycystic Ovary Syndrome (PCOS) Consuming Vegetarian vs. Non-vegetarian Diet. Front Endocrinol (Lausanne) 2019;10:699 250. Leese HJ, Sathyapalan T, Allgar V, Brison DR, Sturmey R Going to extremes: the Goldilocks/Lagom principle and data distribution. BMJ Open 2019;9(11):e027767 251. Yaribeygi H, Sathyapalan T, Maleki M, Jamialahmadi T, Sahebkar A Molecular mechanisms by which SGLT2 inhibitors can induce insulin sensitivity in diabetic milieu: A mechanistic review. Life Sci 2020;240:117090 252. Butler AE, Ramachandran V, Hayat S, Dargham SR,

Cunningham TK, Benurwar M, Sathyapalan T, Najafi-Shoushtari SH, Atkin SL. Expression of microRNA in follicular fluid in women with and without PCOS. Sci Rep 2019;9(1):16306 65 253. Gorabi AM, Hajighasemi S, Sathyapalan T, Sahebkar A Cell transfer-based immunotherapies in cancer: A review. IUBMB Life 2020;72(4):790-800 254. Yaribeygi H, Maleki M, Sathyapalan T, Sahebkar A The effect of C-peptide on diabetic nephropathy: A review of molecular mechanisms. Life Sci 2019;237:116950 255. Bagheri H, Ghasemi F, Barreto GE, Rafiee R, Sathyapalan T, Sahebkar A Effects of curcumin on mitochondria in neurodegenerative diseases. Biofactors 2020;46(1):5-20 256. Gorabi AM, Hajighasemi S, Kiaie N, Rosano GMC, Sathyapalan T, Al-Rasadi K, Sahebkar A. Anti-fibrotic effects of curcumin and some of its analogues in the heart Heart Fail Rev. 2020;25(5):731-743 257. La Rosa VL, Ciebiera M, Lin LT, Fan S, Buttice S, Sathyapalan T, Jedra R, Lordelo P, Favilli A. Treatment of genitourinary syndrome of

menopause: the potential effects of intravaginal ultralow-concentration oestriol and intravaginal dehydroepiandrosterone on quality of life and sexual function. Prz Menopauzalny 2019;18(2):116-122 258. Butler AE, Hayat S, Dargham SR, Malek JA, Abdulla SA, Mohamoud YA, Suhre K, Sathyapalan T, Atkin SL. Alterations in long noncoding RNAs in women with and without polycystic ovarian syndrome. Clin Endocrinol (Oxf) 2019;91(6):793-797 259. Al-Qaissi A, Alqarni S, Javed Z, Atkin SL, Sathyapalan T, Vince RV, Madden LA The CD105:CD106 microparticle ratio is CD106 dominant in polycystic ovary syndrome compared to type 2 diabetes and healthy subjects. Endocrine 2019;66(2):220-225 260. Korani S, Korani M, Sathyapalan T, Sahebkar A Therapeutic effects of Crocin in autoimmune diseases: A review. Biofactors 2019;45(6):835-843 261. Kahkhaie KR, Mirhosseini A, Aliabadi A, Mohammadi A, Mousavi MJ, Haftcheshmeh SM, Sathyapalan T, Sahebkar A. Correction to: Curcumin: a modulator of inflammatory signaling

pathways in the immune system. Inflammopharmacology 2019;27(5):901. 262. Yaribeygi H, Sathyapalan T, Sahebkar A Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity. Life Sci 2019;234:116776 263. Bibak B, Shakeri F, Barreto GE, Keshavarzi Z, Sathyapalan T, Sahebkar A A review of the pharmacological and therapeutic effects of auraptene. Biofactors 2019;45(6):867-879 264. Drage DS, Heffernan AL, Cunningham TK, Aylward LL, Mueller JF, Sathyapalan T, Atkin SL. Serum measures of hexabromocyclododecane (HBCDD) and polybrominated diphenyl ethers (PBDEs) in reproductive-aged women in the United Kingdom. Environ Res 2019;177:108631. 265. Jervis W, Shah N, Mongolu SK, Sathyapalan T Severe proximal myopathy secondary to Hashimoto's thyroiditis. BMJ Case Rep 2019;12(7) 66 266. Reyes-Munoz E, Guardo FD, Ciebiera M, Kahramanoglu I, Sathyapalan T, Lin LT, Shah M, Karaman E, Fan S, Zito G, Noventa M. Diet and Nutritional Interventions with the Special Role of

Myo-Inositol in Gestational Diabetes Mellitus Management. An EvidenceBased Critical Appraisal Curr Pharm Des 2019;25(22):2467-2473 267. Sathyapalan T, Hobkirk JP, Javed Z, Carroll S, Coady AM, Pemberton P, Smith A, Cianflone K, Atkin SL. The Effect of Atorvastatin (and Subsequent Metformin) on Adipose Tissue Acylation-Stimulatory-Protein Concentration and Inflammatory Biomarkers in Overweight/Obese Women With Polycystic Ovary Syndrome. Front Endocrinol (Lausanne) 2019;10:394. 268. Papageorgiou M, Kerschan-Schindl K, Sathyapalan T, Pietschmann P Is Weight Loss Harmful for Skeletal Health in Obese Older Adults? Gerontology. 2020;66(1):2-14 269. Yaribeygi H, Yaribeygi A, Sathyapalan T, Sahebkar A Molecular mechanisms of trehalose in modulating glucose homeostasis in diabetes. Diabetes Metab Syndr 2019;13(3):2214-2218. 270. Keshavarzi Z, Shakeri F, Barreto GE, Bibak B, Sathyapalan T, Sahebkar A Medicinal plants in traumatic brain injury: Neuroprotective mechanisms revisited. Biofactors

2019;45(4):517-535. 271. Mosenzon O, Blicher TM, Rosenlund S, Eriksson JW, Heller S, Hels OH, Pratley R, Sathyapalan T, Desouza C, Investigators P. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol 2019;7(7):515-527 272. Yaribeygi H, Lhaf F, Sathyapalan T, Sahebkar A Effects of novel antidiabetes agents on apoptotic processes in diabetes and malignancy: Implications for lowering tissue damage. Life Sci. 2019;231:116538 273. Alkandari A, Ashrafian H, Sathyapalan T, Darzi A, Holmes E, Athanasiou T, Atkin SL, Gooderham NJ. Bariatric Surgery Modulates Urinary Levels of MicroRNAs Involved in the Regulation of Renal Function. Front Endocrinol (Lausanne) 2019;10:319 274. Konya J, Sathyapalan T, Kilpatrick ES, Atkin SL The Effects of Soy Protein and Cocoa With or Without Isoflavones on Glycemic Control in Type 2 Diabetes. A Double-Blind, Randomized,

Placebo-Controlled Study. Front Endocrinol (Lausanne) 2019;10:296 275. Kahkhaie KR, Mirhosseini A, Aliabadi A, Mohammadi A, Mousavi MJ, Haftcheshmeh SM, Sathyapalan T, Sahebkar A. Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmacology 2019;27(5):885-900 276. Ramanjaneya M, Jerobin J, Bettahi I, Bensila M, Aye M, Siveen KS, Sathyapalan T, Skarulis M, Abou-Samra AB, Atkin SL. Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects. Clin Endocrinol (Oxf) 2019;91(2):278-287 67 277. Rahimi K, Ahmadi A, Hassanzadeh K, Soleimani Z, Sathyapalan T, Mohammadi A, Sahebkar A. Targeting the balance of T helper cell responses by curcumin in inflammatory and autoimmune states. Autoimmun Rev 2019;18(7):738-748 278. Chattopadhyay S, George A, John J, Sathyapalan T Pre-diabetes mellitus newly diagnosed after myocardial infarction adversely affects prognosis in patients without known diabetes. Diab Vasc Dis Res

2019;16(6):489-497 279. Swart AC, Johannes ID, Sathyapalan T, Atkin SL The Effect of Soy Isoflavones on Steroid Metabolism. Front Endocrinol (Lausanne) 2019;10:229 280. Tabeshpour J, Banaeeyeh S, Eisvand F, Sathyapalan T, Hashemzaei M, Sahebkar A Effects of curcumin on ion channels and pumps: A review. IUBMB Life 2019;71(7):812-820 281. Dawson AJ, Sathyapalan T, Vince R, Coady AM, Ajjan RA, Kilpatrick ES, Atkin SL The Effect of Exenatide on Cardiovascular Risk Markers in Women With Polycystic Ovary Syndrome. Front Endocrinol (Lausanne) 2019;10:189 282. Rezaei H, Khadempar S, Farahani N, Hosseingholi EZ, Hayat SMG, Sathyapalan T, Sahebkar AH. Harnessing CRISPR/Cas9 technology in cardiovascular disease Trends Cardiovasc Med. 2020;30(2):93-101 283. Paseban M, Mohebbati R, Niazmand S, Sathyapalan T, Sahebkar A Comparison of the Neuroprotective Effects of Aspirin, Atorvastatin, Captopril and Metformin in Diabetes Mellitus. Biomolecules 2019;9(4) 284. Javed Z, Papageorgiou M, Deshmukh H,

Rigby AS, Qamar U, Abbas J, Khan AY, Kilpatrick ES, Atkin SL, Sathyapalan T. Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study. Clin Endocrinol (Oxf) 2019;90(6):805-813. 285. Otun J, Sahebkar A, Ostlundh L, Atkin SL, Sathyapalan T Systematic Review and Meta-analysis on the Effect of Soy on Thyroid Function. Sci Rep 2019;9(1):3964 286. Alalami H, Sathyapalan T, Atkin SL Cardiovascular profile of pharmacological agents used for the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab 2019;10:2042018818805674. 287. Cunningham TK, Allgar V, Dargham SR, Kilpatrick E, Sathyapalan T, Maguiness S, Mokhtar Rudin HR, Abdul Ghani NM, Latiff A, Atkin SL. Association of Vitamin D Metabolites With Embryo Development and Fertilization in Women With and Without PCOS Undergoing Subfertility Treatment. Front Endocrinol (Lausanne) 2019;10:13 288. Javed Z, Papageorgiou M, Deshmukh H, Kilpatrick ES, Mann V, Corless L, Abouda G, Rigby

AS, Atkin SL, Sathyapalan T. A Randomized, Controlled Trial of Vitamin D 68 Supplementation on Cardiovascular Risk Factors, Hormones, and Liver Markers in Women with Polycystic Ovary Syndrome. Nutrients 2019;11(1) 289. Halama A, Kahal H, Bhagwat AM, Zierer J, Sathyapalan T, Graumann J, Suhre K, Atkin SL. Metabolic and proteomic signatures of hypoglycaemia in type 2 diabetes Diabetes Obes Metab. 2019;21(4):909-919 290. Sathyapalan T, Kohrle J, Rijntjes E, Rigby AS, Dargham SR, Kilpatrick ES, Atkin SL. The Effect of High Dose Isoflavone Supplementation on Serum Reverse T(3) in Euthyroid Men With Type 2 Diabetes and Post-menopausal Women. Front Endocrinol (Lausanne) 2018;9:698. 291. Papageorgiou M, Sathyapalan T, Schutte R Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women. J Cachexia Sarcopenia Muscle 2019;10(1):131-139. 292. Deshmukh H, Papageorgiou M, Kilpatrick ES, Atkin SL, Sathyapalan T Development of a novel risk prediction and risk

stratification score for polycystic ovary syndrome. Clin Endocrinol (Oxf) 2019;90(1):162-169 293. Al-Qaissi A, Papageorgiou M, Javed Z, Heise T, Rigby AS, Garrett AT, Hepburn D, Kilpatrick ES, Atkin SL, Sathyapalan T. Environmental effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes mellitus. Diabetes Obes Metab. 2019;21(3):569-574 294. Reyes-Munoz E, Sathyapalan T, Rossetti P, Shah M, Long M, Buscema M, Valenti G, La Rosa VL, Cianci S, Vitale SG. Polycystic Ovary Syndrome: Implication for Drug Metabolism on Assisted Reproductive Techniques-A Literature Review. Adv Ther 2018;35(11):1805-1815. 295. Al-Qaissi A, Papageorgiou M, Deshmukh H, Madden LA, Rigby A, Kilpatrick ES, Atkin SL, Sathyapalan T. Effects of acute insulin-induced hypoglycaemia on endothelial microparticles in adults with and without type 2 diabetes. Diabetes Obes Metab 2019;21(3):533-540. 296. Sathyapalan T, Dawson AJ, Rigby AS, Thatcher NJ, Kilpatrick ES,

Atkin SL The Effect of Phytoestrogen on Thyroid in Subclinical Hypothyroidism: Randomized, Double Blind, Crossover Study. Front Endocrinol (Lausanne) 2018;9:531 297. Papageorgiou M, Wells L, Williams C, White KLM, De Santis B, Liu Y, Debegnach F, Miano B, Moretti G, Greetham S, Brera C, Atkin SL, Hardie LJ, Sathyapalan T. Occurrence of deoxynivalenol in an elderly cohort in the UK: a biomonitoring approach. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2018;35(10):2032-2044 298. Heffernan AL, Cunningham TK, Drage DS, Aylward LL, Thompson K, Vijayasarathy S, Mueller JF, Atkin SL, Sathyapalan T. Perfluorinated alkyl acids in the serum 69 and follicular fluid of UK women with and without polycystic ovarian syndrome undergoing fertility treatment and associations with hormonal and metabolic parameters. Int J Hyg Environ Health. 2018;221(7):1068-1075 299. Konya J, Spurgeon BEJ, Al Qaissi A, Sathyapalan T, Ajjan R, Madden L, Naseem KM, Garrett AT, Kilpatrick E, Atkin SL.

Corrigendum: The Effect of a Simulated Commercial Flight Environment With Hypoxia and Low Humidity on Clotting, Platelet, and Endothelial Function in Participants With Type 2 Diabetes - A Cross-Over Study. Front Endocrinol (Lausanne). 2018;9:301 300. Alkandari A, Ashrafian H, Sathyapalan T, Sedman P, Darzi A, Holmes E, Athanasiou T, Atkin SL, Gooderham NJ. Improved physiology and metabolic flux after Roux-en-Y gastric bypass is associated with temporal changes in the circulating microRNAome: a longitudinal study in humans. BMC Obes 2018;5:20 301. Kahal H, Aburima A, Spurgeon B, Wraith KS, Rigby AS, Sathyapalan T, Kilpatrick ES, Naseem KM, Atkin SL. Platelet function following induced hypoglycaemia in type 2 diabetes. Diabetes Metab 2018;44(5):431-436 302. Sathyapalan T, Aye M, Rigby AS, Thatcher NJ, Dargham SR, Kilpatrick ES, Atkin SL. Soy isoflavones improve cardiovascular disease risk markers in women during the early menopause. Nutr Metab Cardiovasc Dis 2018;28(7):691-697 303.

Chattopadhyay S, George A, John J, Sathyapalan T Adjustment of the GRACE score by 2-hour post-load glucose improves prediction of long-term major adverse cardiac events in acute coronary syndrome in patients without known diabetes. Eur Heart J 2018;39(29):27402745 304. Gonzalez S, Sathyapalan T, Javed Z, Atkin SL Effects of Growth Hormone Replacement on Peripheral Muscle and Exercise Capacity in Severe Growth Hormone Deficiency. Front Endocrinol (Lausanne) 2018;9:56 305. Chattopadhyay S, George A, John J, Sathyapalan T Correction to: Two-hour postchallenge glucose is a better predictor of adverse outcome after myocardial infarction than fasting or admission glucose in patients without diabetes. Acta Diabetol 2018;55(5):459 306. Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Keevil B, Atkin SL Salivary and serum androgens with anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. Sci Rep 2018;8(1):3795 307. Konya J, Spurgeon BEJ, Al Qaissi A,

Sathyapalan T, Ajjan R, Madden L, Naseem KM, Garrett AT, Kilpatrick E, Atkin SL. The Effect of a Simulated Commercial Flight Environment with Hypoxia and Low Humidity on Clotting, Platelet, and Endothelial Function in Participants with Type 2 Diabetes - A Cross-over Study. Front Endocrinol (Lausanne) 2018;9:26. 70 308. Chattopadhyay S, George A, John J, Sathyapalan T Two-hour post-challenge glucose is a better predictor of adverse outcome after myocardial infarction than fasting or admission glucose in patients without diabetes. Acta Diabetol 2018;55(5):449-458 309. Papageorgiou M, Wells L, Williams C, White K, De Santis B, Liu Y, Debegnach F, Miano B, Moretti G, Greetham S, Brera C, Atkin SL, Hardie LJ, Sathyapalan T. Assessment of Urinary Deoxynivalenol Biomarkers in UK Children and Adolescents. Toxins (Basel) 2018;10(2). 310. Sathyapalan T, Javed Z, Rigby AS, Kilpatrick ES, Atkin SL Soy Protein Improves Cardiovascular Risk in Subclinical Hypothyroidism: A Randomized

Double-Blinded Crossover Study. J Endocr Soc 2017;1(5):423-430 311. Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Atkin SL Anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2018;88(2):258-262. 312. Sathyapalan T, Aye M, Rigby AS, Fraser WD, Kilpatrick ES, Atkin SL Effect of soy on bone turn-over markers in men with type 2 diabetes and hypogonadism - a randomised controlled study. Sci Rep 2017;7(1):15366 313. O'Doherty AF, Jones HS, Sathyapalan T, Ingle L, Carroll S The Effects of Acute Interval Exercise and Strawberry Intake on Postprandial Lipemia. Med Sci Sports Exerc 2017;49(11):2315-2323. 314. Sathyapalan T, Coady AM, Kilpatrick ES, Atkin SL The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome. Endocr Connect 2017;6(8):811-816. 315. Gonzalez S, Windram JD, Sathyapalan T, Javed Z, Clark AL, Atkin SL Effects of human recombinant growth hormone on exercise capacity,

cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency. J Int Med Res 2017;45(6):1708-1719. 316. Sathyapalan T, Dickerson EH, Maguiness SM, Robinson J, Dakroury YHZ, Atkin SL Androstenedione and testosterone levels correlate with in vitro fertilization rates in insulinresistant women. BMJ Open Diabetes Res Care 2017;5(1):e000387 317. Dawson AJ, Kilpatrick ES, Coady AM, Elshewehy AMM, Dakroury Y, Ahmed L, Atkin SL, Sathyapalan T. Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss. BMC Endocr Disord. 2017;17(1):41 318. Wells L, Hardie L, Williams C, White K, Liu Y, De Santis B, Debegnach F, Moretti G, Greetham S, Brera C, Papageorgiou M, Thatcher NJ, Rigby A, Atkin SL, Sathyapalan T. Deoxynivalenol Biomarkers in the Urine of UK Vegetarians. Toxins (Basel) 2017;9(7) 71 319. Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Adaway J, Keevil B, Atkin SL. Salivary

testosterone measurement in women with and without polycystic ovary syndrome Sci Rep. 2017;7(1):3589 320. Cho LW, Sathyapalan T, Kilpatrick ES, Keevil BG, Miller AG, Coady AM, Ahmed L, Atkin SL. Androsterone glucuronide to dehydroepiandrosterone sulphate ratio is discriminatory for obese Caucasian women with polycystic ovary syndrome. BMC Endocr Disord. 2017;17(1):26 321. Sathyapalan T, Rigby AS, Bhasin S, Thatcher NJ, Kilpatrick ES, Atkin SL. Effect of Soy in Men With Type 2 Diabetes Mellitus and Subclinical Hypogonadism: A Randomized Controlled Study. J Clin Endocrinol Metab 2017;102(2):425433 322. Wells L, Hardie L, Williams C, White K, Liu Y, De Santis B, Debegnach F, Moretti G, Greetham S, Brera C, Rigby A, Atkin S, Sathyapalan T. Determination of Deoxynivalenol in the Urine of Pregnant Women in the UK. Toxins (Basel) 2016;8(11) 323. O'Doherty AF, Sathyapalan T, Rigby AS, Ingle L, Carroll S The repeatability of the abbreviated (4-h) Oral Fat Tolerance Test and influence of

prior acute aerobic exercise. Eur J Nutr. 2018;57(1):309-318 324. Simintiras CA, Frohlich T, Sathyapalan T, Arnold GJ, Ulbrich SE, Leese HJ, Sturmey RG. Modelling oviduct fluid formation in vitro Reproduction 2016 325. Sathyapalan T, Javed Z, Kilpatrick ES, Coady AM, Atkin SL Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017;86(3):384-387 326. Greetham S, Goodwin S, Wells L, Whitham C, Jones H, Rigby A, Sathyapalan T, Reid M, Atkin S. Pilot Investigation of a Virtual Gastric Band Hypnotherapy Intervention Int J Clin Exp Hypn. 2016;64(4):419-433 327. Sathyapalan T, Aye M, Rigby AS, Fraser WD, Thatcher NJ, Kilpatrick ES, Atkin SL Soy Reduces Bone Turnover Markers in Women During Early Menopause: A Randomized Controlled Trial. J Bone Miner Res 2017;32(1):157-164 328. Sathyapalan T, Dakroury Y, Ahmed L, Elshewehy AM, Kilpatrick ES, Coady AM, Atkin SL.

Endocannabinoid receptor blockade increases hepatocyte growth factor and reduces insulin levels in obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2016;85(4):671-673. 329. Javed Z, Sathyapalan T Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab 2016;7(1):12-23 72 330. Javed Z, Qamar U, Sathyapalan T Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives. Indian J Endocrinol Metab. 2015;19(6):753-763 331. Javed Z, Qamar U, Sathyapalan T The role of kisspeptin signalling in the hypothalamic-pituitary-gonadal axis--current perspective. Endokrynol Pol 2015;66(6):534547 332. Sathyapalan T, David R, Gooderham NJ, Atkin SL Increased expression of circulating miRNA-93 in women with polycystic ovary syndrome may represent a novel, noninvasive biomarker for diagnosis. Sci Rep 2015;5:16890 333. George A, Bhatia RT, Buchanan GL, Whiteside

A, Moisey RS, Beer SF, Chattopadhyay S, Sathyapalan T, John J. Impaired Glucose Tolerance or Newly Diagnosed Diabetes Mellitus Diagnosed during Admission Adversely Affects Prognosis after Myocardial Infarction: An Observational Study. PLoS One 2015;10(11):e0142045 334. Sathyapalan T, Thatcher NJ, Hammersley R, Rigby AS, Courts FL, Pechlivanis A, Gooderham NJ, Holmes E, le Roux CW, Atkin SL. Aspartame sensitivity? A double blind randomised crossover study. PLoS One 2015;10(3):e0116212 335. Mellor DD, Sathyapalan T, Kilpatrick ES, Atkin SL Diabetes and chocolate: friend or foe? J Agric Food Chem. 2015;63(45):9910-9918 336. Sathyapalan T, Atkin SL, Kilpatrick ES LDL cholesterol variability in patients with Type 2 diabetes taking atorvastatin and simvastatin: a comparison of two formulae for LDL-C estimation. Ann Clin Biochem 2015;52(Pt 1):180-182 337. Dawson AJ, Sathyapalan T, Sedman P, Ajjan R, Kilpatrick ES, Atkin SL Insulin resistance and cardiovascular risk marker evaluation in morbid

obesity 12 months after bariatric surgery compared to weight-matched controls. Obes Surg 2014;24(3):349-358 338. Kamalanathan S, Sahoo JP, Sathyapalan T Pregnancy in polycystic ovary syndrome Indian J Endocrinol Metab. 2013;17(1):37-43 339. Dawson AJ, Sathyapalan T, Smithson JA, Vince RV, Coady AM, Ajjan R, Kilpatrick ES, Atkin SL. A comparison of cardiovascular risk indices in patients with polycystic ovary syndrome with and without coexisting nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 2014;80(6):843-849. 340. Dawson AJ, Sathyapalan T, Atkin SL, Kilpatrick ES Biological variation of cardiovascular risk factors in patients with diabetes. Diabet Med 2013;30(10):1172-1180 73 341. Sathyapalan T, Shepherd J, Atkin SL, Kilpatrick ES The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study. Diabetes Obes Metab 2013;15(8):767-769 342. Sathyapalan T, Shepherd J, Coady

AM, Kilpatrick ES, Atkin SL Atorvastatin reduces malondialdehyde concentrations in patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2012;97(11):3951-3955 343. Sathyapalan T, Dixit S Radiotherapy-induced hypopituitarism: a review Expert Rev Anticancer Ther. 2012;12(5):669-683 344. Shor D, Sathyapalan T, Atkin SL, Thatcher NJ Does equol production determine soy endocrine effects? Eur J Nutr. 2012;51(4):389-398 345. Sathyapalan T, Atkin SL Recent advances in cardiovascular aspects of polycystic ovary syndrome. Eur J Endocrinol 2012;166(4):575-583 346. Dickerson EH, Sathyapalan T, Knight R, Maguiness SM, Killick SR, Robinson J, Atkin SL. Endocrine disruptor & nutritional effects of heavy metals in ovarian hyperstimulation. J Assist Reprod Genet 2011;28(12):1223-1228 347. Sathyapalan T, Smith KA, Coady AM, Kilpatrick ES, Atkin SL Atorvastatin therapy decreases androstenedione and dehydroepiandrosterone sulphate concentrations in patients with polycystic ovary syndrome:

randomized controlled study. Ann Clin Biochem 2012;49(Pt 1):80-85. 348. Kahal H, Aye M, Rigby AS, Sathyapalan T, England RJ, Atkin SL The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism. Clin Endocrinol (Oxf) 2012;76(2):196-200 349. Sathyapalan T, Aye MM, Atkin SL. Postural hypotension BMJ 2011;342:d3128 350. Thong KY, Jose B, Blann AD, Cull ML, Mills AP, Sathyapalan T, Walton C, Ryder REJ. Response at 3 months to insulin dose decisions made at exenatide initiation in the Association of British Clinical Diabetologists (ABCD) nationwide exenatide audit. Diabetes Res Clin Pract. 2011;93(2):e87-e91 351. Wakil A, Sathyapalan T, Atkin SL Pituitary hypophysitis and gulf war syndrome: a case series and hypothesis. Clin Endocrinol (Oxf) 2011;75(2):272-274 352. Sathyapalan T, Atkin SL Is there a role for immune and anti-in-flammatory therapy in type 2 diabetes? Minerva Endocrinol.

2011;36(2):147-156 353. Thong KY, Jose B, Sukumar N, Cull ML, Mills AP, Sathyapalan T, Shafiq W, Rigby AS, Walton C, Ryder RE, Contributors ANEA. Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit*. Diabetes Obes Metab 2011;13(8):703-710 74 354. Sathyapalan T, Manuchehri AM, Thatcher NJ, Rigby AS, Chapman T, Kilpatrick ES, Atkin SL. The effect of soy phytoestrogen supplementation on thyroid status and cardiovascular risk markers in patients with subclinical hypothyroidism: a randomized, doubleblind, crossover study. J Clin Endocrinol Metab 2011;96(5):1442-1449 355. Kahal H, Atkin SL, Sathyapalan T Pharmacological treatment of obesity in patients with polycystic ovary syndrome. J Obes 2011;2011:402052 356. Dawson AJ, Mellor DD, Sathyapalan T, Kilpatrick ES, Atkin SL Metformin may maintain weight loss in obese patients with dysglycaemia initially treated with rimonabant. Diabet

Med. 2011;28(1):124-125 357. Sathyapalan T, Beckett S, Rigby AS, Mellor DD, Atkin SL High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome. Nutr J 2010;9:55. 358. Mellor DD, Sathyapalan T, Kilpatrick ES, Beckett S, Atkin SL High-cocoa polyphenol-rich chocolate improves HDL cholesterol in Type 2 diabetes patients. Diabet Med 2010;27(11):1318-1321. 359. Sathyapalan T, Shepherd J, Arnett C, Coady AM, Kilpatrick ES, Atkin SL Atorvastatin increases 25-hydroxy vitamin D concentrations in patients with polycystic ovary syndrome. Clin Chem 2010;56(11):1696-1700 360. Sathyapalan T, Atkin SL, Kilpatrick ES Disparate effects of atorvastatin compared with simvastatin on C-reactive protein concentrations in patients with type 2 diabetes. Diabetes Care. 2010;33(9):1948-1950 361. Sathyapalan T, Atkin SL, Kilpatrick ES Low density lipoprotein-cholesterol variability in patients with type 2 diabetes taking atorvastatin compared to simvastatin:

justification for direct measurement? Diabetes Obes Metab. 2010;12(6):540-544 362. Sathyapalan T, Atkin SL Mediators of inflammation in polycystic ovary syndrome in relation to adiposity. Mediators Inflamm 2010;2010:758656 363. Sathyapalan T, Manuchehri AM, Rigby AS, Atkin SL Subclinical hypothyroidism is associated with reduced all-cause mortality in patients with type 2 diabetes. Diabetes Care 2010;33(3):e37. 364. Sathyapalan T, Atkin SL Evidence for statin therapy in polycystic ovary syndrome Ther Adv Endocrinol Metab. 2010;1(1):15-22 365. Sathyapalan T, Mellor D, Atkin SL Obesity and gestational diabetes Semin Fetal Neonatal Med. 2010;15(2):89-93 75 366. Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL Atorvastatin pretreatment augments the effect of metformin in patients with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf). 2010;72(4):566-568 367. Sathyapalan T, Gonzalez S, Atkin SL Effect of long-term, high-dose estrogen treatment on prolactin levels: a retrospective

analysis. Climacteric 2009;12(5):427-430 368. Sathyapalan T, Cho L, Kilpatrick ES, Le Roux CW, Coady AM, Atkin SL Effect of rimonabant and metformin on glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 in obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2010;72(3):423-425. 369. Sathyapalan T, Atkin SL. Investigating hirsutism BMJ 2009;338:b912 370. Sathyapalan T, Cho LW, Kilpatrick ES, Coady AM, Atkin SL Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2009;70(1):124-128 371. Sathyapalan T, Atkin SL, Kilpatrick ES Variability of lipids in patients with Type 2 diabetes taking statin treatment: implications for target setting. Diabet Med 2008;25(8):909915 372. Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J

Clin Endocrinol Metab. 2009;94(1):103-108 373. Sathyapalan T, Cho LW, Kilpatrick ES, Coady AM, Atkin SL A comparison between rimonabant and metformin in reducing biochemical hyperandrogenaemia and insulin resistance in patients with polycystic ovary syndrome (PCOS): a randomized open-label parallel study. Clin Endocrinol (Oxf). 2008;69(6):931-935 374. Manuchehri AM, Sathyapalan T, Jayagopal V, Kilpatrick ES, Ghatei MA, Bloom SR, Atkin SL. Alterations in thyroid status do not affect plasma peptide YY (PYY) and ghrelin concentrations. Clin Endocrinol (Oxf) 2008;68(5):836-838 375. Manuchehri AM, Sathyapalan T, Lowry M, Turnbull LW, Rowland-Hill C, Atkin SL Effect of dopamine agonists on prolactinomas and normal pituitary assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Pituitary 2007;10(3):261-266 376. Sathyapalan T, Lowry M, Turnbull LW, Rowland-Hill C, Atkin SL Mechanism of action of octreotide in acromegalic tumours in vivo using dynamic contrast-enhanced

magnetic resonance imaging. Pituitary 2007;10(3):233-236 377. Mistry D, Maung KH, Manuchehri AM, Sathyapalan T, Atkin S, England J Key developments in endocrinology. Practitioner 2005;249(1673):541, 543-547, 549 passim 76 77 DECLARATION OF CONTRIBUTORS Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Atkin SL. Anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2018;88(2):258-262 Thozhukat Sathyapalan conducted the literature search, drafted the protocol, gained regulatory approval and recruited for the study. He worked with co-authors to collate the data, conducted the analysis, drafted the first version and revised it following critical review by co-authors. Subsequently he revised it following comments from peer reviewers and approved the final version for submission. Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Adaway J, Keevil B, Atkin SL. Salivary testosterone measurement in women with and without

polycystic ovary syndrome. Sci Rep 2017;7(1):3589 Thozhukat Sathyapalan conducted the literature search, drafted the protocol, gained regulatory approval and recruited for the study. He worked with co-authors to collate the data, conducted the analysis, drafted the first version and revised it following critical review by co-authors. Subsequently he revised it following comments from peer reviewers and approved the final version for submission. Sathyapalan T, Al-Qaissi A, Kilpatrick ES, Dargham SR, Keevil B, Atkin SL. Salivary and serum androgens with anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. Sci Rep 2018;8(1):3795 Thozhukat Sathyapalan conducted the literature search, drafted the protocol, gained regulatory approval and recruited for the study. He worked with co-authors to collate the data, conducted the analysis, drafted the first version and revised it following critical review by co-authors. Subsequently he revised it following comments

from peer reviewers and approved the final version for submission. Deshmukh H, Akbar S, Bhaiji A, Saeed Y, Shah N, Adeleke K, Papageorgiou M, Atkin SL, Sathyapalan T. Assessing the androgenic and metabolic heterogeneity in polycystic ovary syndrome using cluster analysis. Clin Endocrinol (Oxf) 2023; 98:400-406 Thozhukat Sathuyapalan guided the literature search as senior author, gained the regulatory approvals, drafted the protocol and completed the GafREC ethical approval process. He worked with co-authors to collate the data, helped conduct the analysis of the results and interpretation of the data. He revised it following critical review by co-authors Subsequently he revised it following comments from peer reviewers and approved the final version for submission. 78 Deshmukh H, Papageorgiou M, Kilpatrick ES, Atkin SL, Sathyapalan T. Development of a novel risk prediction and risk stratification score for polycystic ovary syndrome. Clin Endocrinol (Oxf). 2019;90(1):162-169

Thozhukat Sathuyapalan guided the literature search as senior author, gained the regulatory approvals, drafted the protocol and completed the GafREC ethical approval process. He worked with co-authors to collate the data, helped conduct the analysis of the results and interpretation of the data. He revised it following critical review by co-authors Subsequently he revised it following comments from peer reviewers and approved the final version for submission. Declaration of contributions We undersigned agree with the assignment of contributorship outlined above. Authors Deshmukh H Al-Qaissi A Akbar S Adeleke K 79 Shah N Adaway J Keevil B Kilpatrick ES Atkin SL *I contacted the remaining authors multiple times by email asking for confirmation of co-authorship but did not hear back. As I was the first or last or corresponding author in all publications, I assume they will not have any concerns as all authors signed an authorship form for each journal our papers were

published into. 80