Browsing by Author "Ivovic, Miomira (6507747450)"

Maintaining body homeostasis is a prerequisite for normal reproductive function, which is vital for the survival of the species and an important process of natural selection. Body weight is an independent regulator of the hypothalamic–pituitary–gonadal axis activity. © 2016, International Society of Gynecological Endocrinology.

Climacterium is the phase in women’s life beginning with the first menopausal symptom and cycle irregularities and ending 1 year after the last menstruation. Endocrinological, biological and clinical changes become apparent at that time. © 2016, International Society of Gynecological Endocrinology.

More empathized approach is required and is obligatory to women with premature ovarian insufficiency (POI) interested for pregnancy. In order to improve fertility rate in POI patients our suggestions would be: (1) To decrease FSH value to 10–15 IU/L by increasing estrogen. Oocyte donation can be suggested after a minimum of six month interval from FSH between 10–15 IU/L and when no dominant follicles are found. (2) To perform oral glucose tolerance test (OGTT). Insulin sensitizing agents has to be included, when indicated, 3–6 month before pregnancy. (3) TSH has to be 1–2.5 mM/L during 3–6 months before pregnancy. (4) Tests for thrombophyllia (Leiden V, FII, MTHFR, PAI) have to be obligatory. They are less expensive than those repeated in vitro fertilizations. Therapy has to be included according to the indications. (5) In order to regulate disturbed immune response in POI patients with endometriosis oral contraceptive therapy is needed for atleast six months prior to the pregnancy. (5) Encourage the patients and advice them about healthy life style and eating habits. (6) Add other drugs, when they are indicated. Complex interplay between endocrine, immunological, haematological, and psychological factors are very often underdetected in POI patients. It is very important to find out the real time for oocyte donation after correcting all the disturbances, improving endometrium receptivity and reaching women’s acceptable psychological status. Untreated disturbances induce cardiovascular diseases, diabetes mellitus, thyroid diseases, coagulopathioes etc. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

More empathized approach is required and is obligatory to women with premature ovarian insufficiency (POI) interested for pregnancy. In order to improve fertility rate in POI patients our suggestions would be: (1) To decrease FSH value to 10–15 IU/L by increasing estrogen. Oocyte donation can be suggested after a minimum of six month interval from FSH between 10–15 IU/L and when no dominant follicles are found. (2) To perform oral glucose tolerance test (OGTT). Insulin sensitizing agents has to be included, when indicated, 3–6 month before pregnancy. (3) TSH has to be 1–2.5 mM/L during 3–6 months before pregnancy. (4) Tests for thrombophyllia (Leiden V, FII, MTHFR, PAI) have to be obligatory. They are less expensive than those repeated in vitro fertilizations. Therapy has to be included according to the indications. (5) In order to regulate disturbed immune response in POI patients with endometriosis oral contraceptive therapy is needed for atleast six months prior to the pregnancy. (5) Encourage the patients and advice them about healthy life style and eating habits. (6) Add other drugs, when they are indicated. Complex interplay between endocrine, immunological, haematological, and psychological factors are very often underdetected in POI patients. It is very important to find out the real time for oocyte donation after correcting all the disturbances, improving endometrium receptivity and reaching women’s acceptable psychological status. Untreated disturbances induce cardiovascular diseases, diabetes mellitus, thyroid diseases, coagulopathioes etc. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Objective To identify whether variants found in a large Han Chinese cohort - 8q22.3 SNPs rs3847153 and rs3108910; and one SNP each in HK3 (rs2278493), ESR1 (rs2234693) and BRSK1 (rs12611091) - are associated with premature ovarian failure (POF) in a different ethnic group (Serbian). Design Case-control genetic association study in 197 Serbian POF cases and 552 matched controls. Results None of the SNPs found associated with POF in Chinese cohort were found to be associated in the Serbian sample. Conclusions In contrast to Han Chinese, no association was found between POF in Serbian women and any of the four tested loci: 8q22.3, HK3, ESR1 and BRSK1. This indicates that ethnically distinct populations may show differences in gene-regulating pathways and genes causing POF. © 2013 Elsevier Ireland Ltd.

Objective To identify whether variants found in a large Han Chinese cohort - 8q22.3 SNPs rs3847153 and rs3108910; and one SNP each in HK3 (rs2278493), ESR1 (rs2234693) and BRSK1 (rs12611091) - are associated with premature ovarian failure (POF) in a different ethnic group (Serbian). Design Case-control genetic association study in 197 Serbian POF cases and 552 matched controls. Results None of the SNPs found associated with POF in Chinese cohort were found to be associated in the Serbian sample. Conclusions In contrast to Han Chinese, no association was found between POF in Serbian women and any of the four tested loci: 8q22.3, HK3, ESR1 and BRSK1. This indicates that ethnically distinct populations may show differences in gene-regulating pathways and genes causing POF. © 2013 Elsevier Ireland Ltd.

It is well known that hypertension can be primary or secondary. However, among secondary causes of hypertension, gender-specific hypertension is one lately recognized. © 2016, International Society of Gynecological Endocrinology.

In the ancient Rome, average life duration was 23 years; in Sweden at the end of the eighteenth century, 36.6 years for women and 33.7 for men; and in many European countries at the beginning of the twenty-first century, life expectancy was 72 and 76 years, respectively. The menopause (period in women’s life 1 year after the last menstruation until the end of life) and involutive hypoandrogenism in males (testosterone below 12 nmol/L and typical symptoms) are characterized by decrease of gonadal steroids and initiating of cardiovascular diseases (CVD). Rahman [1] found that women who entered early menopause (40–45 years) had 40% increase of heart disease. Meta-analysis confirmed these data (Table 16.1). © 2018, International Society of Gynecological Endocrinology.

To improve our understanding of hyperostosis frontalis interna (HFI), we investigated whether HFI was accompanied by changes in the postcranial skeleton. Based on head CT scan analyses, 103 postmenopausal women were divided into controls without HFI and those with HFI, in whom we measured the thickness of frontal, occipital, and parietal bones. Women in the study underwent dual energy x-ray absorptiometry to analyze the bone density of the hip and vertebral region and external geometry of the proximal femora. Additionally, all of the women completed a questionnaire about symptoms and conditions that could be related to HFI. Women with HFI had a significantly higher prevalence of headaches, neurological and psychiatric disorders, and a significantly lower prevalence of having given birth. Increased bone thickness and altered bone structure in women with HFI was localized only on the skull, particularly on the frontal bone, probably due to specific properties of its underlying dura. Bone loss in the postcranial skeleton showed the same pattern in postmenopausal women with HFI as in those without HFI. Recording of HFI in medical records can be helpful in distinguishing whether reported disorders occur as a consequence of HFI or are related to other diseases, but does not appear helpful in identifying women at risk of bone loss. © 2016 Taylor & Francis.

In this paper we examined age-related and sexspecific deterioration in bone strength of the proximal femur reflected in mechanical properties from dual energy X-ray absorptiometry (DXA)-based hip structural analysis (HSA) on a cadaveric sample from the Balkans. Cadaveric studies permit more precise measurement of HSA parameters and allow further analyses by micromorphometric methods. DXA and HSA analysis was performed on a total of 138 cadaveric proximal femora (63 female, 75 male, age range 20-101 years) from Belgrade. HSA parameters are reported for three standard regions of the proximal femur (narrow neck, intertrochanteric, and shaft). Major agerelated findings include an increase in the radius of gyration (first reported in this study), a decline in the cross-sectional area (CSA), a shift in the centroid towards the medial cortex, higher buckling ratios and lower section moduli. Whereas age appears to affect mostly the neck region in men, weakening is also evident in the intertrochanteric region in women, particularly after the age of 80. Aging femoral neck declines in bending strength and increases in buckling susceptibility. The reduced bone mass tends to be distributed farther from the centroidal axis (increase in radius of gyration with decline in CSA). Bone mass is preferentially lost from the lateral part of the cross-section shifting the centroid towards the medial cortex which may increase fragility of the lateral part during fall impact. Results of this study contribute to the epidemiologic data on gender differences and age trends in aging male and female femora. © The Japanese Society for Bone and Mineral Research and Springer 2011.

In this paper we examined age-related and sexspecific deterioration in bone strength of the proximal femur reflected in mechanical properties from dual energy X-ray absorptiometry (DXA)-based hip structural analysis (HSA) on a cadaveric sample from the Balkans. Cadaveric studies permit more precise measurement of HSA parameters and allow further analyses by micromorphometric methods. DXA and HSA analysis was performed on a total of 138 cadaveric proximal femora (63 female, 75 male, age range 20-101 years) from Belgrade. HSA parameters are reported for three standard regions of the proximal femur (narrow neck, intertrochanteric, and shaft). Major agerelated findings include an increase in the radius of gyration (first reported in this study), a decline in the cross-sectional area (CSA), a shift in the centroid towards the medial cortex, higher buckling ratios and lower section moduli. Whereas age appears to affect mostly the neck region in men, weakening is also evident in the intertrochanteric region in women, particularly after the age of 80. Aging femoral neck declines in bending strength and increases in buckling susceptibility. The reduced bone mass tends to be distributed farther from the centroidal axis (increase in radius of gyration with decline in CSA). Bone mass is preferentially lost from the lateral part of the cross-section shifting the centroid towards the medial cortex which may increase fragility of the lateral part during fall impact. Results of this study contribute to the epidemiologic data on gender differences and age trends in aging male and female femora. © The Japanese Society for Bone and Mineral Research and Springer 2011.

Although increased hip fracture risk is noted in patients with alcoholic liver disease (ALD), their femoral microstructural and mechanical properties were not investigated previously. The present study aimed to analyze the associations between subregional deteriorations in femoral mechano-structural properties and clinical imaging findings to explain increased femoral fracture risk among ALD patients. This study analyzed proximal femora of 33 male cadaveric donors, divided into ALD (n = 13, 57 ± 13 years) and age-matched control group (n = 20, 54 ± 13 years). After pathohistological verification of ALD stage, DXA and HSA measurements of the proximal femora were performed, followed by micro-CT and Vickers microindentation of the superolateral neck, inferomedial neck, and intertrochanteric region. Bone mineral density and cross sectional area of the femoral neck were deteriorated in ALD donors, compared with healthy controls (p < 0.05). Significant ALD-induced degradation of trabecular and cortical microstructure and Vickers microhardness reduction were noted in the analyzed femoral regions (p < 0.05). Still, the most prominent ALD-induced mechano-structural deterioration was noted in intertrochanteric region. Additionally, more severe bone alterations were observed in individuals with an irreversible stage of ALD, alcoholic liver cirrhosis (ALC), than in those with an initial ALD stage, fatty liver disease. Observed osteodensitometric and mechano-structural changes illuminate the basis for increased femoral fracture risk in ALD patients. Additionally, our data suggest bone strength reduction that may result in increased susceptibility to intertrochanteric femoral fracture in men with ALD. Thus, femoral fracture risk assessment should be advised for all ALD patients, especially in those with ALC. © 2021 Elsevier Inc.

Although increased hip fracture risk is noted in patients with alcoholic liver disease (ALD), their femoral microstructural and mechanical properties were not investigated previously. The present study aimed to analyze the associations between subregional deteriorations in femoral mechano-structural properties and clinical imaging findings to explain increased femoral fracture risk among ALD patients. This study analyzed proximal femora of 33 male cadaveric donors, divided into ALD (n = 13, 57 ± 13 years) and age-matched control group (n = 20, 54 ± 13 years). After pathohistological verification of ALD stage, DXA and HSA measurements of the proximal femora were performed, followed by micro-CT and Vickers microindentation of the superolateral neck, inferomedial neck, and intertrochanteric region. Bone mineral density and cross sectional area of the femoral neck were deteriorated in ALD donors, compared with healthy controls (p < 0.05). Significant ALD-induced degradation of trabecular and cortical microstructure and Vickers microhardness reduction were noted in the analyzed femoral regions (p < 0.05). Still, the most prominent ALD-induced mechano-structural deterioration was noted in intertrochanteric region. Additionally, more severe bone alterations were observed in individuals with an irreversible stage of ALD, alcoholic liver cirrhosis (ALC), than in those with an initial ALD stage, fatty liver disease. Observed osteodensitometric and mechano-structural changes illuminate the basis for increased femoral fracture risk in ALD patients. Additionally, our data suggest bone strength reduction that may result in increased susceptibility to intertrochanteric femoral fracture in men with ALD. Thus, femoral fracture risk assessment should be advised for all ALD patients, especially in those with ALC. © 2021 Elsevier Inc.

Aim: to test effects of estradiol (E2) 1 mg and drospirenone (DRSP) 2 mg in treatment of normal weight menopausal women with typical menopausal symptoms, hyperinsulinism, and grade I hypertension. Material and methods: The participants were 133 menopausal women, mean age 51.82 ± 3.25 years, body mass index (BMI) 24.9 ± 2.6 kg/m2, waist/hip 0.80 ± 0.05, amenorrhoeic period 2.12 ± 2.10 years. All patients were treated with E2 1 mg and DRSP 2 mg during 12 months period. Blood samples were taken at 8 am before and during 12 months of therapy for: glycemia, lipids, hormonal analysis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, testosterone (T), prolactin (PRL), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Oral glucose tolerance test (OGTT) was performed with 75 g glucose in order to assess insulin secretion. All had grade I hypertension 24 h blood pressure monitoring was performed before and after 12 months of therapy. Results: E2/DRSP significantly decreased total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (ApoB), and increased high-density lipoprotein cholesterol (HDL) and apolipoprotein A (ApoA). Insulin area under the curve (AUC) significantly decreased (6586.1 ± 4194.2 vs. 5315.3 ± 2895.0, p <.05) and homeostatic model assessment (HOMA) (3.53 ± 2.18 vs. 3.0 ± 1.8, p <.05). FSH, LH decreased, E2 increased significantly. Of 24 h day blood pressure decreased significantly. Conclusions: E2/DRSP represents suitable therapy for hyperinsulinemic, grade I hypertensive menopausal women with typical symptoms and normal weight. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Aim: to test effects of estradiol (E2) 1 mg and drospirenone (DRSP) 2 mg in treatment of normal weight menopausal women with typical menopausal symptoms, hyperinsulinism, and grade I hypertension. Material and methods: The participants were 133 menopausal women, mean age 51.82 ± 3.25 years, body mass index (BMI) 24.9 ± 2.6 kg/m2, waist/hip 0.80 ± 0.05, amenorrhoeic period 2.12 ± 2.10 years. All patients were treated with E2 1 mg and DRSP 2 mg during 12 months period. Blood samples were taken at 8 am before and during 12 months of therapy for: glycemia, lipids, hormonal analysis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, testosterone (T), prolactin (PRL), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Oral glucose tolerance test (OGTT) was performed with 75 g glucose in order to assess insulin secretion. All had grade I hypertension 24 h blood pressure monitoring was performed before and after 12 months of therapy. Results: E2/DRSP significantly decreased total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (ApoB), and increased high-density lipoprotein cholesterol (HDL) and apolipoprotein A (ApoA). Insulin area under the curve (AUC) significantly decreased (6586.1 ± 4194.2 vs. 5315.3 ± 2895.0, p <.05) and homeostatic model assessment (HOMA) (3.53 ± 2.18 vs. 3.0 ± 1.8, p <.05). FSH, LH decreased, E2 increased significantly. Of 24 h day blood pressure decreased significantly. Conclusions: E2/DRSP represents suitable therapy for hyperinsulinemic, grade I hypertensive menopausal women with typical symptoms and normal weight. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Genetic and environmental factors influence the quality of life and well-being. Breaking of adaptive mechanisms, induced by stressors, triggers diseases. Premature ovarian insufficiency (POI) is characterized by oligo/amenorrhea, high gonadotropin, and low estradiol levels in women younger than 40 years of age. Known etiological factors inducing POI include chromosomal abnormalities, enzyme changes, autoimmune diseases, FSH receptor gene polymorphism, inhibin B mutation, infectious disease, adnexectomy, radiotherapy, uterine artery embolization, etc. Unknown factors include stressors, inflammation, telomerase shortening, biological clock acceleration, etc. Early POI symptoms, significantly decreasing the quality of life, are hot flushes, irritability, anxiety, depression, mood swings, loss of concentration, insomnia, loss of libido, etc. Late complications include cardiovascular diseases, osteoporosis, metabolic syndrome, cognitive changes, Alzheimer’s disease, urogenital dysfunction, decreased fertility rate, etc. Diagnosis is confirmed by FSH >40 IU/L (or 25 IU/L), estradiol <50 pmol/L, and oligo/amenorrhea in women younger than 40 years of age. Also, suggested analyses are AMH, inhibin B, prolactin, dehydroepiandrosterone sulfate (DHEAS), free testosterone, free thyroxin (fT4), thyroid-stimulating hormone (TSH), cortisol, vitamin D, and oral glucose tolerance test (OGTT). Visualization methods include ultrasound examination of uterus, ovaries, and breasts and osteodensitometry. In untreated POI patients, mortality rate is increased. Therapy with estroprogestogens, and all other insufficient hormones (testosterone, fT4, DHEAS, vitamin D, etc.), has to be initiated immediately and continued without age limits, depending on individual needs, in order to achieve the best quality of life. © 2023, International Society of Gynecological Endocrinology.

Main regulators of breast metabolism are estradiol, progesterone, prolactin, growth hormone, and insulin-like growth factor 1 (IGF-1) [1]. They control cell function, proliferation, and differentiation activating intracellular signaling cascade (Erk, Akt, JNK, and Ark/Stat) of breast tissue [2]. Estrogen receptor (ER) expression in the breast is stable and differs relatively little in correlation with reproductive status, menstrual cycle phase, or exogenous hormones [3]. Estrogens have apocrine, paracrine, and intercrine effects. Receptors for estradiol are present in fibroblast, epithelial cells, adipocytes, and stromal tissue. Intramammary concentration of estradiol is 20 times higher compared to the level in the blood. Estradiol increases number of progesterone receptors, epithelial proliferation in the luteal phase, galactophore differentiation, connective tissue development, and growth hormone. © 2021, International Society of Gynecological Endocrinology.

Objective To investigate whether gene variants of SOHLH1 exist in Chinese and Serbian patients with primary ovarian insufficiency (POI). Design Case-control genetic study. Setting University hospitals. Patient(s) A total of 364 Han Chinese and 197 Serbian women with nonsyndromic POI and ethnically matched controls. Intervention(s) None. Main Outcome Measure(s) SOHLH1 gene sequencing. Result(s) We found 10 novel heterozygous variants in our cohorts of 561 women with POI but none in the 600 ethnically matched controls. Statistical and bioinformatic analyses indicated that three of the eight variants in Chinese POI cases are potentially disease causing. They comprise two missense variants (p.Ser317Phe and p.Glu376Lys) that might each change activity of the SOHLH1 protein as a transcription factor and one variant (c.∗118C>T) located in the 3′ untranslated region of the SOHLH1 gene, which might generate a new binding site for the microRNA hsa-miR-888-5p. Of the two variants in the Serbian POI cases, both were synonymous, and no missense variant was identified. The allele frequencies of some known single-nucleotide polymorphisms were statistically significantly different between patients and controls in both the Chinese and Serbian groups. Conclusion(s) Our results suggest that SOHLH1 may be regarded as a new candidate gene for POI. © 2015 American Society for Reproductive Medicine.

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. Findings: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2–23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9–82·0] vs 64·0% [61·4–66.4]) while maintaining sensitivity (99·0% [94·4–100·0] vs 100·0% [96·3–100·0]; PPV 19·7%, 16·3–23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6–41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2–84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4–100·0). Interpretation: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. Funding: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. Findings: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2–23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9–82·0] vs 64·0% [61·4–66.4]) while maintaining sensitivity (99·0% [94·4–100·0] vs 100·0% [96·3–100·0]; PPV 19·7%, 16·3–23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6–41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2–84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4–100·0). Interpretation: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. Funding: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license