Hormonal and molecular characterization of calcium oxalate stone formers predicting occurrence and recurrence

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Elshal, Heba Shamshoun, Amira Awadalla, Ramy Elbaz, Asmaa E. Ahmed, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2147324/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Apr, 2023 Read the published version in Urolithiasis → Version 1 posted 8 You are reading this latest preprint version Abstract Abstract Purpose: To investigate the role of sex hormones, androgen receptors (ARs) and mi-RNA/CSF-1 in occurrence and recurrence of calcium oxalate (CaOx) renal urolithiasis. Materials and Methods: In this prospective study, 74 patients with CaOx stones; stone formers group (SFG) and 40 healthy subjects; control group were compared. SFG includes both denovo and recurrent cases. Steroid sex hormone plasma assay including testosterone, free testosterone, dihydrotestosterone, estradiol, and sex hormone binding globulin were analyzed. ARs, mi-RNA 185-5p and CSF-1 expression were compared between groups. Results: SFG showed significant higher ARs and mi-RNA 185-5p expression (3.7 ± 1.3, 1.8 ± 0.4, respectively) than control group (1 ± 0.08 and 1± 0.07, respectively) (p < 0.05). However, CSF-1 expression was significantly lower in stone formers than control group. (0.4 ± 0.19 vs 1 ± 0.1, respectively) (p < 0.05). No differences were detected between denovo and recurrent SFG regarding sex hormones, AR, mi-RNA or CSF-1 expression. Conclusion: Our data suggest the important role of AR. mi-RNA and CSF-1 signaling in human nephrolithiasis pathogenesis. Figures Figure 1 Introduction Urolithiasis represents one of the most common urologic health care problems worldwide. Estimates of calcium oxalate (CaOx) / calcium phosphate (CaPh) stones occurrence are as high as 80% of all renal stones. The underlying pathophysiology of the calcium based renal stones is complex and multifactorial with most of these stones occur in healthy individuals because of metabolic derangements which involve an imbalance between stone formers and stone inhibitors. The most common of these derangements are idiopathic hypercalciuria, hyperoxaluria and hypocitraturia.[ 1 ]. CaOx stones formation can be affected by infiltrating macrophages which include pro- inflammatory macrophages or M1 promoting crystals deposition and anti-inflammatory or M2 macrophages phagocytosing ca-oxalate stone formation directly [ 2 ]. Regarding the age and sex prevalence of renal stones; it is more common in males compared to females by about 3:1. This prevalence gap is mainly present in reproductive age between 15–49 years and lowest in postmenopausal females with low estrogen which propose that estrogen can serve as a protective hormone against urolithiasis [ 3 ] [ 4 ]. Also, androgen deprivation therapy (ADT) use in patients with Prostate cancer results in approximately one-third lower risk of subsequent renal calculi [ 5 ] which may suggest a promoting effect of male androgens on renal stones formation. This effect has been established experimentally in rats in some trials [ 6 ]. Testosterone appears to promote stone formation by suppressing osteopontin expression in the kidneys and increasing urinary oxalate excretion, this action has been found that is reversed with estrogen [ 7 ]. Another possible mechanism for promoting role of testosterone on calcium oxalate stone formation may be due to increase urinary uric acid excretion [ 3 ] and increase hepatic synthesis of glycolic acid oxidase (GAO), an enzyme essentially involved in primary hyperoxaluria [ 8 ] This action of sex hormones could be done either through alternation of serum hormone levels or expression of their receptors. It was found that androgen receptors (AR) stimulation increases miRNA-185-5p which inhibit macrophages colony stimulating factor 1 (CSF-1) result in inhibition of M2 mediated CaOx crystals phagocytosis [ 9 – 11 ]. However, this action was demonstrated only using human cell lines via invitro studies and rat models. Furthermore, higher testosterone levels were reported in renal stones patients. Considering the role of estrogen, data is sparse due to lack of assessment of the role of estrogen or absence of depictable inhibitory role of estrogen on stones formation. [ 9 – 11 ]. Also, the relation between sex hormones and calcium oxalates stones recurrence was not assessed before in any trial. Until now, there is a shortage of data regarding the association between sex hormones and the prevalence of urolithiasis and the utility of this association in clinical practice. This study was conducted looking for an association between sex hormones and calcium oxalate stone formation. Moreover, the relation between sex hormones and recurrence of calcium oxalate stones was assessed. Patients And Methods Study design and groups This is a prospective controlled study that was performed between June 2020 and June 2021 after approval of the local ethical committee. Patients who were diagnosed with calcium oxalate (Ca.ox) stones on further stone analysis either as pure Ca Ox stones or mixed stones were allocated as stone formers group (SFG) and compared against healthy subjects who were selected from same age range with no history or radiological evidence of urinary stones and considered as “control” group. Stone formers group was subdivided into: “denovo” group included patients who presented with renal stones for the first time, and they were compared against “recurrent” group who presented with previous episodes of renal stones that necessitated active intervention. Inclusion and exclusion criteria Inclusion criteria included male patients between 18–60 years who were diagnosed with renal stones and were admitted to our center for active stone intervention. Eligible subjects were asked to sign an informed consent. Exclusion criteria included patients with known hyperthyroidism, hyperparathyroidism, recurrent urinary tract infections, renal and liver diseases, intestinal malabsorption, or metabolic syndromes were excluded from the study. Also, patients with known structural or functional abnormality of the urinary tract like vesico-ureteric reflux, neuropathic bladder or pelvi-uretral junction obstruction were also excluded from the study. Intervention All patients who were diagnosed with renal stones were managed with standard percutaneous nephrolithotomy (PNL) or retrograde intrarenal surgery (RIRS) depending on stone volume, location, and surgeons’ preference. Retrieved stones were submitted for stone analysis and calcium oxalate (Ca.ox) stone formers were included. Study work-up All clinical data including history, clinical examination and routine laboratory investigation were collected. The sonographic and computerized tomographic evaluations of the kidneys and urinary tract systems and the diagnosis of renal stone were performed by the attending expert radiologists. Sample collection for laboratory and molecular analysis was done as following: 24-hour urine samples collection for determination the levels of calcium, uric acid, citrate and oxalate. Stone samples for analysis using FT-IR (Fourier Transform- Infrared) spectroscopy looking for type of stone. Blood samples were taken for evaluation the level of sex hormones and gene expression. A. Hormone analysis For hormone analysis, all samples of blood were collected, and each sample was centrifuged at 3000 g for 15 min and the separated plasma then fractionated and stored at -20C until hormone assay. Hormones in the plasma samples including testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), estradiol (E2), and sex hormone binding globulin (SHBG) were analyzed by ELISA. B. Gene expression of AR and CSF- 1 using Real-time PCR AR mRNA level were assessed by quantitative RT-qPCR method. Total RNA (0.5 µg), was isolated from the blood samples, reverse transcribed. Gene expression for Primers for the AR and CSF-1 and human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were examined by real-time qPCR, using AR primers (Applied Biosystems, Foster City, CA, USA). Gene expressions all data were normalized to GAPDH; expression of one tumor was assumed to be 1 and used as reference. The 2 − ΔΔCT method was used to calculate relative amounts of target genes. C. Gene expression of miRNA-185-5p miRNA technology ingeniously integrates a universal tailing and reverse transcription reaction specific for mature miRNA combined with state-of-the-art primer-assay design technology to enable the accurate expression level measurement of miR-2909. miRNA was extracted from plasma samples using an miRneasy Mini Kit. cDNA was synthesized from 1 µg of total miRNA. Amplification and detection was performed using real time PCR (step one plus). AR, CSF- 1 and miRNA-185-5p Study outcomes The primary outcome was to assess the association between sex hormones and occurrence of calcium oxalate renal stones. While the secondary outcome was to assess the association between these hormones and recurrence of calcium oxalate stones over time. • Statistical Analysis Continuous variables were presented as mean ± SD for normally distributed and as median and range for non-normally distributed variables. Ordinal and nominal variables were presented as frequency and percentage. Comparison between study and control groups was performed by Student’s t-test for normally distributed continuous variables and by Mann-Whitney test for asymmetric continuous variables. Chi square and Fisher exact tests was used for comparison between categorical variables. Multivariable analysis by logistic regression was done as appropriate. A P value < 0.05 was considered significant. A software SPSS was used for storage and analysis of data. Results Demographic and Perioperative Data Out of 91 male patient who were diagnosed with renal stones and underwent endoscopic treatment with PNL or RIRS between June 2020 and June 2021, 74 patients were diagnosed as Ca Ox stones and included in the study. Then, they were compared against 40 healthy subjects. After that, the 2 subgroups of SFG were compared against each other: 40 patients of denovo group and 34 patients of recurrent group as shown in study`s flow chart (Fig. 1). The mean ± SD age and BMI in SFG and control groups were (52 ± 14 and 54 ± 10, P 0.4) and (30.6 ± 7.3 and 29 ± 5.3, P 0.09) respectively. Also, patients̓ demographics and stone characteristics of denovo and recurrent stone formers group were comparable with no significant difference as shown in Table 1 . The primary outcome As shown in table 2 , The mean ± SD levels of RQ-AR, mi-RNA-185 and serum estradiol were significantly higher in SFG 3.7 ± 1.3, 1.8 ± 0.4 and 69.5 (20–300), respectively compared to control group 1 ± 0.08, 1 ± 0.07 and 34 (20–55), respectively with p < 0.001 . However, RQ-csf-1 was significantly lower in SFG than control group (0.4 ± 0.19 vs 1 ± 0.1, respectively) with p < 0.001. While serum androgens and SHBG levels did not show significant difference between 2 groups. The secondary outcome Table 2 summarizes data of SFG with comparative analysis of its 2 subgroups. Both denovo and recurrent stone formers group were comparable regarding serum androgens, estradiol levels and molecular gene expression of RQ-AR, RQ-csf-1 and Mirna 185 with p > 0.05. Table 3 summarizes 24-hours urinary metabolites among the 2 subgroups of stone formers with only urinary citrate level that showed significant higher median concentration in denovo stone formers (< 0.001). Discussion Kidney stones prevalence had markedly increased over the past two decades. According to the latest report from the National Health and Nutrition Examination Survey (NHANES 2007–2010), the prevalence of kidney stones among American adults was 8.8%: 10.6% among men and 7.1% among women [ 10 ]. Renal stones has major economic and medical burdens due to cost of treatment, sick leaves from work, risk of renal impairment and renovascular hypertension [ 12 ]. Another major problem of stone diseases is the risk of recurrence, 50% of patient with kidney stones have chance of development another episode of stone disease over 7 years [ 13 ]. CaOx stones are formed through a complex and multifactorial process including underlying genetic and metabolic abnormalities, life style pattern, obesity and hot climatic environment [ 1 ]. Recently, a strong association was found between sex hormones and kidney stones. Testosterone and dihydrotestosterone hormones were found to be a potential promoting factor in occurrence of CaOx urolithiasis, while estrogen hormone was found to be a protective against urolithiasis [ 11 ] [ 3 ]. This role was supported by age and sex prevalence of urolithiasis. It was found that kidney stones are more common 3 times in males than females and this gap is significantly decreased in postmenopausal females [ 14 ]. Also, hyperoxaluria was found to be significantly lower in castrated male rates compared to normal ones [ 15 ]. Polycystic ovary syndrome which characterized by clinical and laboratory evidence of hyperandrogenism is a known risk factor in kidney stones formation [ 16 ]. In some animal studies, administration of testosterone increases urinary oxalate excretion and enhances the formation of calcium oxalate stones [ 17 ]. This promoting effect of testosterone in urolithiasis pathogenesis is mediated through different mechanisms including increase hepatic synthesis of glycolic acid oxidase (GAO) which results in hyperoxaluria [ 8 ]. Also, testosterone was found that it inhibits renal osteopontin expression and subsequent increase renal excretion of oxalate [ 7 ]. In serum, 95% of testosterone binds sex hormone binding globulin and only 1–2% is free testosterone [ 18 ]. Free testosterone diffuses into target cells, where it binds to AR, which has the pivotal role in androgen signaling. ARs were found to be expressed in nuclei of normal distal renal tubular epithelial cells. Moreover, they were found to be up regulated in tubular epithelial cells of patients with hyperoxaluria which suggests the important role of androgen/AR axis enhancement in kidney stones formation [ 6 ]. The molecular mechanisms of action of ARs in pathogenesis of hyperoxaluria and CaOx stones formation were demonstrated in 2 animal trials on mice [ 9 , 19 ]. First, on physiological basis, there are Types of intrarenal macrophages: M1 macrophages which induce kidney epithelial injury and inflammation and not phagocytose CaOx crystals and M 2 macrophages which promote phagocytosis of CaOx crystals. In this trial, they found that CSF- 1 is mainly secreted from renal tubular epithelium and play an important role in M2 macrophages proliferation and in extension suppression of hyperoxaluria. However, they found that AR increase miRNA expression which inhibit CSF-1 resulting in M2 macrophages inhibition and promoting hyperoxaluria. In the second trial [ 19 ], they found that AR could directly up-regulate hepatic glycolate oxidase and kidney epithelial NADPH oxidase subunit p22-PHOX at the transcriptional level. This up-regulation might then increase oxalate biosynthesis and oxidative stress that resulted in induction of kidney tubular injury. Targeting AR with the AR degradation enhancer dimethyl curcumin (ASC-J9) led to suppression of CaOx crystal formation. However, these results were demonstrated only in animal studies. Only one trial assessed the levels of ARs in human patients with CaOx stones [ 6 ]. This study included 68 participants, 37 male patients with CaOx/CaPh stones and 31 healthy controls. ARs were detected by immunohistochemistry in nuclei of normal distal renal tubular epithelial cells. Moreover, they were found to be up regulated in tubular epithelial cells of patients with hyperoxaluria which suggests the important role of androgen/AR axis enhancement in kidney stones formation. However, this study has some limitations of being small sample size and the detailed mechanism of ARs could not yet be fully elucidated. From clinical point of view, knowing that the risk of recurrence of stone formation is about 50% [ 13 ], there was a need for a trial looking after molecular and genetic differences and if they have a role in stone recurrence. This might have clinical impact on attempts to reduce stone recurrence. To the best of our knowledge, this prospective trial is the first one to compare the difference in sex hormones between denovo and recurrent stone formers and, the first one to study the relation between AR and genetic expression of miRNA and CSF-1 in stone former patients. Moreover, it includes a sample size larger than any other previous study. In the current study, AR and miRNA were significantly higher and CSF-1 was significantly lower in SFG compared to control group. These results go in parallel with the previous result of [ 9 ] animal studies. However, no difference between both groups was observed regarding blood androgen level. Interestingly plasma estradiol level was higher among SFG in the current study, yet this could be explained by the higher rate of conversion of testosterone to estradiol in the testosterone metabolic pathway. However, this higher level did not seem strong enough to exert stone inhibiting effect in males. [ 10 ] Nevertheless, denovo and recurrent stone formers were not different regarding all studied parameters. Further studies are warranted to look for the clinical utility of those findings. In conclusion, CaOx renal stones was found to positively correlated with genetic expression of AR and miRNA and it inversely related with CSF-1. However, renal CaOx stones` recurrence was not associated with changes in sex hormone levels nor its related molecular pathway. References Xu H, Zisman AL, Coe FL, Worcester EM. Kidney stones: an update on current pharmacological management and future directions. Expert opinion on pharmacotherapy. 2013: 14 :435-47 Taguchi K, Okada A, Hamamoto S, et al. Proinflammatory and metabolic changes facilitate renal crystal deposition in an obese mouse model of metabolic syndrome. The Journal of urology. 2015: 194 :1787-96 Shakhssalim N, Roohi Gilani K, Parvin M, et al. An assessment of parathyroid hormone, calcitonin, 1, 25 (OH) 2 vitamin D3, estradiol and testosterone in men with active calcium stone disease and evaluation of its biochemical risk factors. Urological research. 2011: 39 :1-7 Alelign T, Petros B. Kidney stone disease: an update on current concepts. Advances in urology. 2018: 2018 Lin C-Y, Liu J-M, Wu C-T, Hsu R-J, Hsu W-L. Decreased Risk of Renal Calculi in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer. International Journal of Environmental Research and Public Health. 2020: 17 :1762 Li J-Y, Zhou T, Gao X, et al. Testosterone and androgen receptor in human nephrolithiasis. The Journal of urology. 2010: 184 :2360-3 YAGISAWA T, ITO F, OSAKA Y, AMANO H, KOBAYASHI C, TOMA H. The influence of sex hormones on renal osteopontin expression and urinary constituents in experimental urolithiasis. The Journal of urology. 2001: 166 :1078-82 Soundararajan P, Mahesh R, Ramesh T, Begum VH. Effect of Aerva lanata on calcium oxalate urolithiasis in rats. 2006: Zhu W, Zhao Z, Chou F, et al. Loss of the androgen receptor suppresses intrarenal calcium oxalate crystals deposition via altering macrophage recruitment/M2 polarization with change of the miR-185-5p/CSF-1 signals. Cell death & disease. 2019: 10 :1-19 Naghii MR, Babaei M, Hedayati M. Androgens involvement in the pathogenesis of renal stones formation. PLoS One. 2014: 9 :e93790 Gupta K, Gill GS, Mahajan R. Possible role of elevated serum testosterone in pathogenesis of renal stone formation. International Journal of Applied and Basic Medical Research. 2016: 6 :241 Rule AD, Bergstralh EJ, Melton LJ, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clinical Journal of the American Society of Nephrology. 2009: 4 :804-11 Sutherland J, Parks J, Coe F. Recurrence after a single renal stone in a community practice. Mineral and electrolyte metabolism. 1985: 11 :267-9 Curhan GC. Epidemiology of stone disease. Urologic Clinics of North America. 2007: 34 :287-93 Lee Y-H, Huang W-C, Chiang H, Chen M-T, Huang J-K, Chang LS. Determinant role of testosterone in the pathogenesis of urolithiasis in rats. The Journal of urology. 1992: 147 :1134-8 Kaygusuz I, Karatas OF, Kafali H, Cimentepe E, Unal D. Is polycystic ovarian syndrome a risk factor for urolithiasis? Urolithiasis. 2013: 41 :361-2 Fan J, Chandhoke P, Grampsas S. Role of sex hormones in experimental calcium oxalate nephrolithiasis. Journal of the American Society of Nephrology: JASN. 1999: 10 :S376-80 Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. The Journal of Clinical Endocrinology & Metabolism. 1981: 53 :58-68 Liang L, Li L, Tian J, et al. Androgen receptor enhances kidney stone-CaOx crystal formation via modulation of oxalate biosynthesis & oxidative stress. Molecular Endocrinology. 2014: 28 :1291-303 Tables Table 1: Baseline demographic characteristics of denovo and recurrent stone formers groups. Variable : Denovo group N:40 Recurrent group N:34 P value Patients’ characteristics Age (years) Mean± SD 51 ± 10 53 ± 8 0.3* BMI (kg/m2) Mean± SD 30.1 ± 5.3 28 ± 8.3 0.07* DM: NO (%) 4 (10%) 7 (20.6) 0.3# Urinary tract characteristics Urine PH Mean ±SD 5.7 ± 0.7 5.4 ± 0.7 0.02* S Cr Median (range) 0.9 (0.6-4) 1 (0.4-3) 0.1** Stone characteristics Stone density Mean ±SD 1015 ± 306 1021 ± 266 0.9* Stone diameter Median (range) 13 (4-30) 14 (1-40) 0.7** Stone length Median (range) 16 (2-40) 15 (1.6-42) 0.7** Stone side NO (%) RT LT Bilateral 15 (37.5) 21 (52.5) 4 (10) 11 (32.4) 17 (50) 6 (17.6) 0.6# *Independent sample t test, ** Man-Whitney U test, # Chi square test S Cr : serum creatinine, BMI : body mass index Table (2): Comparison of hormonal and molecular characteristics of SFG (with its 2 subgroups) and control group Variable Stone formers group N: 74 Control group N:40 P1 P2 Denovo N:40 Recurrent N:34 Total N:74 Testosterone (2.62-16 ng/ml) . Median (range) 7 (1.5 -17.5) 4.5 (1-20) 5.3 (13.3-20) 7 (1.4-16) 0.8** 0.6** Free Testosterone (10-40pg/ml) Mean ± SD 24 ± 11 23.5 ± 11 24 ± 11 24.7 ± 7 0.7* 0.8* DHT (52-90 ng/dl): Mean ± SD 40 ± 15 41 ± 15 40.6 ± 15 37.5 ± 10 0.2* 0.7* SHBG (10-71 nmol/l) Mean ± SD 37 ± 9 39 ± 9 37.8 ± 9 37.7 ± 9 0.9* 0.5* Estradiol (up to 56 pg/ml) Median (range) 65 (20-226) 73 (20-300) 69.5 (20-300) 34 (20-55) <0.001** 0.8** RQ-AR Mean ±SD 3.8 ± 1.3 3.5 ± 1.4 3.7 ± 1.3 1± 8 <0.001* 0.5* RQ-csf-1 Mean ±SD 0.5 ± 0.19 0.4 ± 0.19 0.4 ± 0.19 1 ± 0.1 <0.001* 0.6* Mirna 185 Mean ±SD 1.8 ± 0.3 1.9 ± 0.4 1.8 ± 0.4 1± 0.07 <0.001* 0.4* *Independent sample t test, ** Man-Whitney U test, SHBG; sex hormone binding globulin , DHT; dihydrotestosterone . P1: Total stone formers group Vs control group P2: Denovo Vs control group Table 3: comparison of metabolic work up between denovo and recurrent stone formers group: Variable : Denovo group N: 40 Recurrent group N: 34 P value 24 hrs urinary Ca Median (range) 327 (125-3511) 410 (123-710) 0.3** 24 hrs urinary uric acid Median (range) 240 (122-921) 254 (201-698) 0.2** 24 hrs urinary Oxalate Median (range) 55 (22-80) 47 (41-84) 0.2** 24 hrs urinary Citrate Median (range) 354 (30-651) 526 (236-652) <0.001** Hypercalciuria NO (%) 37 (92.5) 32 (94.1) 0.7# Hyperuricosuria NO (%) 2 (5) 0 0.2# Hyperoxaluria NO (%) 31 (77.5) 22 (64.7) 0.2# Hypocitraturia NO (%) 14 (35) 5 (15.2) 0.05# ** Man-Whitney U test, # Chi square test Reference range ; hypercalciuria; >200 mg/day, hyperuricosuria; >750 mg/day, hyperoxaluria; >45 mg/day and hypocitraturia; <320 mg/day Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Apr, 2023 Read the published version in Urolithiasis → Version 1 posted Editorial decision: Major revision 21 Feb, 2023 Reviews received at journal 20 Dec, 2022 Reviewers agreed at journal 20 Dec, 2022 Reviewers agreed at journal 20 Nov, 2022 Reviewers invited by journal 13 Oct, 2022 Editor assigned by journal 10 Oct, 2022 Submission checks completed at journal 10 Oct, 2022 First submitted to journal 09 Oct, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2147324","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":143000388,"identity":"e4a2183d-3dde-456b-9eac-4f04c3107628","order_by":0,"name":"Ahmed M. 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Estimates of calcium oxalate (CaOx) / calcium phosphate (CaPh) stones occurrence are as high as 80% of all renal stones. The underlying pathophysiology of the calcium based renal stones is complex and multifactorial with most of these stones occur in healthy individuals because of metabolic derangements which involve an imbalance between stone formers and stone inhibitors. The most common of these derangements are idiopathic hypercalciuria, hyperoxaluria and hypocitraturia.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCaOx stones formation can be affected by infiltrating macrophages which include pro- inflammatory macrophages or M1 promoting crystals deposition and anti-inflammatory or M2 macrophages phagocytosing ca-oxalate stone formation directly [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding the age and sex prevalence of renal stones; it is more common in males compared to females by about 3:1. This prevalence gap is mainly present in reproductive age between 15\u0026ndash;49 years and lowest in postmenopausal females with low estrogen which propose that estrogen can serve as a protective hormone against urolithiasis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlso, androgen deprivation therapy (ADT) use in patients with Prostate cancer results in approximately one-third lower risk of subsequent renal calculi [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] which may suggest a promoting effect of male androgens on renal stones formation. This effect has been established experimentally in rats in some trials [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTestosterone appears to promote stone formation by suppressing osteopontin expression in the kidneys and increasing urinary oxalate excretion, this action has been found that is reversed with estrogen [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Another possible mechanism for promoting role of testosterone on calcium oxalate stone formation may be due to increase urinary uric acid excretion [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and increase hepatic synthesis of glycolic acid oxidase (GAO), an enzyme essentially involved in primary hyperoxaluria [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThis action of sex hormones could be done either through alternation of serum hormone levels or expression of their receptors. It was found that androgen receptors (AR) stimulation increases miRNA-185-5p which inhibit macrophages colony stimulating factor 1 (CSF-1) result in inhibition of M2 mediated CaOx crystals phagocytosis [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, this action was demonstrated only using human cell lines via invitro studies and rat models. Furthermore, higher testosterone levels were reported in renal stones patients. Considering the role of estrogen, data is sparse due to lack of assessment of the role of estrogen or absence of depictable inhibitory role of estrogen on stones formation. [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Also, the relation between sex hormones and calcium oxalates stones recurrence was not assessed before in any trial.\u003c/p\u003e \u003cp\u003eUntil now, there is a shortage of data regarding the association between sex hormones and the prevalence of urolithiasis and the utility of this association in clinical practice. This study was conducted looking for an association between sex hormones and calcium oxalate stone formation. Moreover, the relation between sex hormones and recurrence of calcium oxalate stones was assessed.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudy design and groups\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e This is a prospective controlled study that was performed between June 2020 and June 2021 after approval of the local ethical committee.\u003c/p\u003e \u003cp\u003ePatients who were diagnosed with calcium oxalate (Ca.ox) stones on further stone analysis either as pure Ca Ox stones or mixed stones were allocated as stone formers group \u003cb\u003e(SFG)\u003c/b\u003e and compared against healthy subjects who were selected from same age range with no history or radiological evidence of urinary stones and considered as \u003cb\u003e\u0026ldquo;control\u0026rdquo;\u003c/b\u003e group.\u003c/p\u003e \u003cp\u003eStone formers group was subdivided into: \u003cb\u003e\u0026ldquo;denovo\u0026rdquo;\u003c/b\u003e group included patients who presented with renal stones for the first time, and they were compared against \u003cb\u003e\u0026ldquo;recurrent\u0026rdquo;\u003c/b\u003e group who presented with previous episodes of renal stones that necessitated active intervention.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eInclusion and exclusion criteria\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eInclusion criteria included male patients between 18\u0026ndash;60 years who were diagnosed with renal stones and were admitted to our center for active stone intervention. Eligible subjects were asked to sign an informed consent.\u003c/p\u003e \u003cp\u003eExclusion criteria included patients with known hyperthyroidism, hyperparathyroidism, recurrent urinary tract infections, renal and liver diseases, intestinal malabsorption, or metabolic syndromes were excluded from the study. Also, patients with known structural or functional abnormality of the urinary tract like vesico-ureteric reflux, neuropathic bladder or pelvi-uretral junction obstruction were also excluded from the study.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAll patients who were diagnosed with renal stones were managed with standard percutaneous nephrolithotomy (PNL) or retrograde intrarenal surgery (RIRS) depending on stone volume, location, and surgeons\u0026rsquo; preference. Retrieved stones were submitted for stone analysis and calcium oxalate (Ca.ox) stone formers were included.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudy work-up\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAll clinical data including history, clinical examination and routine laboratory investigation were collected. The sonographic and computerized tomographic evaluations of the kidneys and urinary tract systems and the diagnosis of renal stone were performed by the attending expert radiologists.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSample collection for laboratory and molecular analysis was done as following:\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003e24-hour urine\u003c/span\u003e samples collection for determination the levels of calcium, uric acid, citrate and oxalate.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eStone\u003c/span\u003e samples for analysis using FT-IR (Fourier Transform- Infrared) spectroscopy looking for type of stone.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eBlood samples\u003c/span\u003e were taken for evaluation the level of sex hormones and gene expression.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eA. Hormone analysis\u003c/h2\u003e \u003cp\u003eFor hormone analysis, all samples of blood were collected, and each sample was centrifuged at 3000 g for 15 min and the separated plasma then fractionated and stored at -20C until hormone assay. Hormones in the plasma samples including testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), estradiol (E2), and sex hormone binding globulin (SHBG) were analyzed by ELISA.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eB. Gene expression of AR and CSF- 1 using Real-time PCR\u003c/h2\u003e \u003cp\u003eAR mRNA level were assessed by quantitative RT-qPCR method. Total RNA (0.5 \u0026micro;g), was isolated from the blood samples, reverse transcribed. Gene expression for Primers for the AR and CSF-1 and human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were examined by real-time qPCR, using AR primers (Applied Biosystems, Foster City, CA, USA). Gene expressions all data were normalized to GAPDH; expression of one tumor was assumed to be 1 and used as reference. The 2\u0026thinsp;\u0026minus;\u0026thinsp;ΔΔCT method was used to calculate relative amounts of target genes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eC. Gene expression of miRNA-185-5p\u003c/h2\u003e \u003cp\u003emiRNA technology ingeniously integrates a universal tailing and reverse transcription reaction specific for mature miRNA combined with state-of-the-art primer-assay design technology to enable the accurate expression level measurement of miR-2909.\u003c/p\u003e \u003cp\u003emiRNA was extracted from plasma samples using an miRneasy Mini Kit. cDNA was synthesized from 1 \u0026micro;g of total miRNA. Amplification and detection was performed using real time PCR (step one plus).\u003c/p\u003e \u003cp\u003eAR, CSF- 1 and miRNA-185-5p\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudy outcomes\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe primary outcome was to assess the association between sex hormones and occurrence of calcium oxalate renal stones.\u003c/p\u003e \u003cp\u003eWhile the secondary outcome was to assess the association between these hormones and recurrence of calcium oxalate stones over time.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e\u0026bull; Statistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD for normally distributed and as median and range for non-normally distributed variables. Ordinal and nominal variables were presented as frequency and percentage. Comparison between study and control groups was performed by Student\u0026rsquo;s t-test for normally distributed continuous variables and by Mann-Whitney test for asymmetric continuous variables. Chi square and Fisher exact tests was used for comparison between categorical variables. Multivariable analysis by logistic regression was done as appropriate. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. A software SPSS was used for storage and analysis of data.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eDemographic and Perioperative Data\u003c/h2\u003e\n \u003cp\u003eOut of 91 male patient who were diagnosed with renal stones and underwent endoscopic treatment with PNL or RIRS between June 2020 and June 2021, 74 patients were diagnosed as Ca Ox stones and included in the study. Then, they were compared against 40 healthy subjects.\u003c/p\u003e\n \u003cp\u003eAfter that, the 2 subgroups of SFG were compared against each other: 40 patients of denovo group and 34 patients of recurrent group as shown in study`s flow chart (Fig.\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003eThe mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD age and BMI in SFG and control groups were (52\u0026thinsp;\u0026plusmn;\u0026thinsp;14 and 54\u0026thinsp;\u0026plusmn;\u0026thinsp;10, P 0.4) and (30.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 and 29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3, P 0.09) respectively. Also, patients̓ demographics and stone characteristics of denovo and recurrent stone formers group were comparable with no significant difference as shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003eThe primary outcome\u003c/h2\u003e\n \u003cp\u003eAs shown in \u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003etable 2\u003c/span\u003e, The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD levels of RQ-AR, mi-RNA-185 and serum estradiol were significantly higher in SFG 3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3, 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 and 69.5 (20\u0026ndash;300), respectively compared to control group 1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08, 1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 and 34 (20\u0026ndash;55), respectively with \u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/em\u003e.\u003c/p\u003e\n \u003cp\u003eHowever, RQ-csf-1 was significantly lower in SFG than control group (0.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 vs 1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1, respectively) with \u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/em\u003e While serum androgens and SHBG levels did not show significant difference between 2 groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003eThe secondary outcome\u003c/h2\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eTable\u0026nbsp;2\u003c/span\u003e summarizes data of SFG with comparative analysis of its 2 subgroups. Both denovo and recurrent stone formers group were comparable regarding serum androgens, estradiol levels and molecular gene expression of RQ-AR, RQ-csf-1 and Mirna 185 with \u003cem\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05.\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes 24-hours urinary metabolites among the 2 subgroups of stone formers with only urinary citrate level that showed significant higher median concentration in denovo stone formers (\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eKidney stones prevalence had markedly increased over the past two decades. According to the latest report from the National Health and Nutrition Examination Survey (NHANES 2007\u0026ndash;2010), the prevalence of kidney stones among American adults was 8.8%: 10.6% among men and 7.1% among women [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRenal stones has major economic and medical burdens due to cost of treatment, sick leaves from work, risk of renal impairment and renovascular hypertension [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Another major problem of stone diseases is the risk of recurrence, 50% of patient with kidney stones have chance of development another episode of stone disease over 7 years [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCaOx stones are formed through a complex and multifactorial process including underlying genetic and metabolic abnormalities, life style pattern, obesity and hot climatic environment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Recently, a strong association was found between sex hormones and kidney stones. Testosterone and dihydrotestosterone hormones were found to be a potential promoting factor in occurrence of CaOx urolithiasis, while estrogen hormone was found to be a protective against urolithiasis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis role was supported by age and sex prevalence of urolithiasis. It was found that kidney stones are more common 3 times in males than females and this gap is significantly decreased in postmenopausal females [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Also, hyperoxaluria was found to be significantly lower in castrated male rates compared to normal ones [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Polycystic ovary syndrome which characterized by clinical and laboratory evidence of hyperandrogenism is a known risk factor in kidney stones formation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In some animal studies, administration of testosterone increases urinary oxalate excretion and enhances the formation of calcium oxalate stones [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis promoting effect of testosterone in urolithiasis pathogenesis is mediated through different mechanisms including increase hepatic synthesis of glycolic acid oxidase (GAO) which results in hyperoxaluria [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Also, testosterone was found that it inhibits renal osteopontin expression and subsequent increase renal excretion of oxalate [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In serum, 95% of testosterone binds sex hormone binding globulin and only 1\u0026ndash;2% is free testosterone [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Free testosterone diffuses into target cells, where it binds to AR, which has the pivotal role in androgen signaling.\u003c/p\u003e \u003cp\u003eARs were found to be expressed in nuclei of normal distal renal tubular epithelial cells. Moreover, they were found to be up regulated in tubular epithelial cells of patients with hyperoxaluria which suggests the important role of androgen/AR axis enhancement in kidney stones formation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe molecular mechanisms of action of ARs in pathogenesis of hyperoxaluria and CaOx stones formation were demonstrated in 2 animal trials on mice [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFirst, on physiological basis, there are Types of intrarenal macrophages: M1 macrophages which induce kidney epithelial injury and inflammation and not phagocytose CaOx crystals and M 2 macrophages which promote phagocytosis of CaOx crystals.\u003c/p\u003e \u003cp\u003eIn this trial, they found that CSF- 1 is mainly secreted from renal tubular epithelium and play an important role in M2 macrophages proliferation and in extension suppression of hyperoxaluria.\u003c/p\u003e \u003cp\u003eHowever, they found that AR increase miRNA expression which inhibit CSF-1 resulting in M2 macrophages inhibition and promoting hyperoxaluria.\u003c/p\u003e \u003cp\u003eIn the second trial [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], they found that AR could directly up-regulate hepatic glycolate oxidase and kidney epithelial NADPH oxidase subunit p22-PHOX at the transcriptional level. This up-regulation might then increase oxalate biosynthesis and oxidative stress that resulted in induction of kidney tubular injury. Targeting AR with the AR degradation enhancer dimethyl curcumin (ASC-J9) led to suppression of CaOx crystal formation. However, these results were demonstrated only in animal studies.\u003c/p\u003e \u003cp\u003eOnly one trial assessed the levels of ARs in human patients with CaOx stones [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This study included 68 participants, 37 male patients with CaOx/CaPh stones and 31 healthy controls. ARs were detected by immunohistochemistry in nuclei of normal distal renal tubular epithelial cells. Moreover, they were found to be up regulated in tubular epithelial cells of patients with hyperoxaluria which suggests the important role of androgen/AR axis enhancement in kidney stones formation. However, this study has some limitations of being small sample size and the detailed mechanism of ARs could not yet be fully elucidated.\u003c/p\u003e \u003cp\u003eFrom clinical point of view, knowing that the risk of recurrence of stone formation is about 50% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], there was a need for a trial looking after molecular and genetic differences and if they have a role in stone recurrence. This might have clinical impact on attempts to reduce stone recurrence.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this prospective trial is the first one to compare the difference in sex hormones between denovo and recurrent stone formers and, the first one to study the relation between AR and genetic expression of miRNA and CSF-1 in stone former patients. Moreover, it includes a sample size larger than any other previous study.\u003c/p\u003e \u003cp\u003eIn the current study, AR and miRNA were significantly higher and CSF-1 was significantly lower in SFG compared to control group. These results go in parallel with the previous result of [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] animal studies. However, no difference between both groups was observed regarding blood androgen level. Interestingly plasma estradiol level was higher among SFG in the current study, yet this could be explained by the higher rate of conversion of testosterone to estradiol in the testosterone metabolic pathway. However, this higher level did not seem strong enough to exert stone inhibiting effect in males. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eNevertheless, denovo and recurrent stone formers were not different regarding all studied parameters. Further studies are warranted to look for the clinical utility of those findings.\u003c/p\u003e \u003cp\u003eIn conclusion, CaOx renal stones was found to positively correlated with genetic expression of AR and miRNA and it inversely related with CSF-1. However, renal CaOx stones` recurrence was not associated with changes in sex hormone levels nor its related molecular pathway.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eXu H, Zisman AL, Coe FL, Worcester EM. Kidney stones: an update on current pharmacological management and future directions. Expert opinion on pharmacotherapy. 2013: \u003cstrong\u003e14\u003c/strong\u003e:435-47\u003c/li\u003e\n \u003cli\u003eTaguchi K, Okada A, Hamamoto S, et al. Proinflammatory and metabolic changes facilitate renal crystal deposition in an obese mouse model of metabolic syndrome. 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Androgens involvement in the pathogenesis of renal stones formation. PLoS One. 2014: \u003cstrong\u003e9\u003c/strong\u003e:e93790\u003c/li\u003e\n \u003cli\u003eGupta K, Gill GS, Mahajan R. Possible role of elevated serum testosterone in pathogenesis of renal stone formation. International Journal of Applied and Basic Medical Research. 2016: \u003cstrong\u003e6\u003c/strong\u003e:241\u003c/li\u003e\n \u003cli\u003eRule AD, Bergstralh EJ, Melton LJ, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clinical Journal of the American Society of Nephrology. 2009: \u003cstrong\u003e4\u003c/strong\u003e:804-11\u003c/li\u003e\n \u003cli\u003eSutherland J, Parks J, Coe F. Recurrence after a single renal stone in a community practice. Mineral and electrolyte metabolism. 1985: \u003cstrong\u003e11\u003c/strong\u003e:267-9\u003c/li\u003e\n \u003cli\u003eCurhan GC. Epidemiology of stone disease. Urologic Clinics of North America. 2007: \u003cstrong\u003e34\u003c/strong\u003e:287-93\u003c/li\u003e\n \u003cli\u003eLee Y-H, Huang W-C, Chiang H, Chen M-T, Huang J-K, Chang LS. Determinant role of testosterone in the pathogenesis of urolithiasis in rats. The Journal of urology. 1992: \u003cstrong\u003e147\u003c/strong\u003e:1134-8\u003c/li\u003e\n \u003cli\u003eKaygusuz I, Karatas OF, Kafali H, Cimentepe E, Unal D. Is polycystic ovarian syndrome a risk factor for urolithiasis? Urolithiasis. 2013: \u003cstrong\u003e41\u003c/strong\u003e:361-2\u003c/li\u003e\n \u003cli\u003eFan J, Chandhoke P, Grampsas S. Role of sex hormones in experimental calcium oxalate nephrolithiasis. Journal of the American Society of Nephrology: JASN. 1999: \u003cstrong\u003e10\u003c/strong\u003e:S376-80\u003c/li\u003e\n \u003cli\u003eDunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 1981: \u003cstrong\u003e53\u003c/strong\u003e:58-68\u003c/li\u003e\n \u003cli\u003eLiang L, Li L, Tian J, et al. Androgen receptor enhances kidney stone-CaOx crystal formation via modulation of oxalate biosynthesis \u0026amp; oxidative stress. Molecular Endocrinology. 2014: \u003cstrong\u003e28\u003c/strong\u003e:1291-303\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Baseline demographic characteristics of denovo and recurrent stone formers groups.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"668\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; Denovo group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; N:40 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;Recurrent group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; N:34\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;P value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients\u0026rsquo; characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e (years) \u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Mean\u0026plusmn; SD\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e51 \u0026plusmn; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e53 \u0026plusmn; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.3*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u0026nbsp;\u003c/strong\u003e(kg/m2) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cem\u003eMean\u0026plusmn; SD\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e30.1 \u0026plusmn; 5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e28 \u0026plusmn; 8.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.07*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDM: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cem\u003e\u0026nbsp;NO (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e4 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.3#\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Urinary tract characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrine PH \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e5.7 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e5.4 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.02*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eS Cr \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cem\u003eMedian (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e0.9 (0.6-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e1 (0.4-3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.1**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eStone characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStone density \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e1015 \u0026plusmn; 306\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e1021 \u0026plusmn; 266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.9*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStone diameter \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cem\u003eMedian (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e13 (4-30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e14 (1-40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.7**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStone length \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cem\u003eMedian (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e16 (2-40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e15 (1.6-42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e0.7**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.714499252615845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStone side \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cem\u003eNO (%)\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eRT\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eLT\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eBilateral\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.51420029895366%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (37.5)\u003c/p\u003e\n \u003cp\u003e21 (52.5)\u003c/p\u003e\n \u003cp\u003e4 \u0026nbsp; (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.318385650224215%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (32.4)\u003c/p\u003e\n \u003cp\u003e17 (50)\u003c/p\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.452914798206278%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.6#\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e*Independent sample t test, ** Man-Whitney U test, # Chi square test\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eS Cr\u003c/strong\u003e : serum creatinine, \u003cstrong\u003eBMI\u003c/strong\u003e: body mass index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTable (2): Comparison of hormonal and molecular characteristics of SFG (with its 2 subgroups) and control group\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"left\" dir=\"ltr\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"762\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"37.79527559055118%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Stone formers group\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; N: 74\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;Control group\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; N:40\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;P1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;P2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"31.25%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDenovo\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cem\u003eN:40\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"35.416666666666664%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; Recurrent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cem\u003eN:34 \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"33.333333333333336%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;Total\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cem\u003eN:74\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTestosterone (2.62-16 ng/ml)\u003c/strong\u003e.\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMedian (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e7 (1.5 -17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e4.5 (1-20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e5.3 (13.3-20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e7 (1.4-16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.8**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.6**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFree Testosterone (10-40pg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e24 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e23.5 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e24 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e24.7 \u0026plusmn; 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.7*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.8*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDHT (52-90 ng/dl):\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e40 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e41 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e40.6 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e37.5 \u0026plusmn; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.2*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.7*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSHBG (10-71 nmol/l)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn; SD\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e37 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e39 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e37.8 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e37.7 \u0026plusmn; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.9*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e0.5*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eEstradiol (up to 56 pg/ml)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMedian (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e65 (20-226)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e73 (20-300)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e69.5 (20-300)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e34 (20-55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.8**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRQ-AR\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3.8 \u0026plusmn; 1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;3.5 \u0026plusmn; 1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;3.7 \u0026plusmn; 1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e1\u0026plusmn; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026lt;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 0.5*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRQ-csf-1\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.5 \u0026plusmn; 0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.4 \u0026plusmn; 0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0.4 \u0026plusmn; 0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; 1 \u0026plusmn; 0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u0026lt;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 0.6*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"27.559055118110237%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMirna 185 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cem\u003eMean\u0026nbsp;\u003c/em\u003e\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.811023622047244%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 1.8 \u0026plusmn; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.385826771653543%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 1.9 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.598425196850394%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1.8 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.173228346456693%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1\u0026plusmn; 0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.023622047244094%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026lt;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.448818897637794%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.4*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" width=\"100%\"\u003e\n \u003cp dir=\"LTR\"\u003e*Independent sample t test, ** Man-Whitney U test, \u003cstrong\u003eSHBG;\u0026nbsp;\u003c/strong\u003esex hormone binding globulin\u003cstrong\u003e, DHT;\u0026nbsp;\u003c/strong\u003edihydrotestosterone\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; P1:\u0026nbsp;\u003c/strong\u003eTotal stone formers group Vs control group\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp; P2:\u0026nbsp;\u003c/strong\u003eDenovo Vs control group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003cstrong\u003eTable 3: comparison of metabolic work up between denovo and recurrent stone formers group:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"685\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDenovo group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eN: 40\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecurrent group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eN: 34\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 hrs urinary Ca\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Median (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e327 (125-3511)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e410 (123-710)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.3**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 hrs urinary uric acid\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Median (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e240 (122-921)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e254 (201-698)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.2**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 hrs urinary Oxalate\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Median (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e55 (22-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e47 (41-84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.2**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 hrs urinary Citrate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Median (range)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e354 (30-651)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e526 (236-652)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypercalciuria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cem\u003eNO (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e37 (92.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e32 (94.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.7#\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperuricosuria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cem\u003eNO (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.2#\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperoxaluria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;NO (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e31 (77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e22 (64.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.2#\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"38.68613138686131%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypocitraturia\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; NO (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.021897810218977%\"\u003e\n \u003cp\u003e14 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.525547445255473%\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.766423357664234%\"\u003e\n \u003cp\u003e0.05#\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003e** Man-Whitney U test, # Chi square test\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eReference range\u003c/strong\u003e; hypercalciuria; \u0026gt;200\u0026nbsp;mg/day, hyperuricosuria; \u0026gt;750\u0026nbsp;mg/day, hyperoxaluria; \u0026gt;45\u0026nbsp;mg/day and hypocitraturia; \u0026lt;320 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"urolithiasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ures","sideBox":"Learn more about [Urolithiasis](http://link.springer.com/journal/240)","snPcode":"240","submissionUrl":"https://submission.nature.com/new-submission/240/3","title":"Urolithiasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2147324/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2147324/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Abstract\nPurpose:\nTo investigate the role of sex hormones, androgen receptors (ARs) and mi-RNA/CSF-1 in occurrence and recurrence of calcium oxalate (CaOx) renal urolithiasis.\nMaterials and Methods:\nIn this prospective study, 74 patients with CaOx stones; stone formers group (SFG) and 40 healthy subjects; control group were compared. SFG includes both denovo and recurrent cases.\nSteroid sex hormone plasma assay including testosterone, free testosterone, dihydrotestosterone, estradiol, and sex hormone binding globulin were analyzed. ARs, mi-RNA 185-5p and CSF-1 expression were compared between groups.\nResults:\nSFG showed significant higher ARs and mi-RNA 185-5p expression (3.7 ± 1.3, 1.8 ± 0.4, respectively) than control group (1 ± 0.08 and 1± 0.07, respectively) (p \u003c 0.05).\nHowever, CSF-1 expression was significantly lower in stone formers than control group. (0.4 ± 0.19 vs 1 ± 0.1, respectively) (p \u003c 0.05). No differences were detected between denovo and recurrent SFG regarding sex hormones, AR, mi-RNA or CSF-1 expression.\nConclusion:\nOur data suggest the important role of AR. mi-RNA and CSF-1 signaling\nin human nephrolithiasis pathogenesis.","manuscriptTitle":"Hormonal and molecular characterization of calcium oxalate stone formers predicting occurrence and recurrence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-13 18:27:04","doi":"10.21203/rs.3.rs-2147324/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-02-21T16:41:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-12-20T21:00:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"99a61752-3ae8-4187-b2c3-ee96fe0a6d6a","date":"2022-12-20T19:35:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c44f2397-76da-4bfb-8f71-96e28df8e736","date":"2022-11-20T14:55:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-10-13T14:18:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-10-10T07:36:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-10-10T07:36:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Urolithiasis","date":"2022-10-09T09:37:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"urolithiasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ures","sideBox":"Learn more about [Urolithiasis](http://link.springer.com/journal/240)","snPcode":"240","submissionUrl":"https://submission.nature.com/new-submission/240/3","title":"Urolithiasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"37b47659-2e35-4302-99d5-6f5a4fe651c6","owner":[],"postedDate":"October 13th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T21:09:19+00:00","versionOfRecord":{"articleIdentity":"rs-2147324","link":"https://doi.org/10.1007/s00240-023-01440-8","journal":{"identity":"urolithiasis","isVorOnly":false,"title":"Urolithiasis"},"publishedOn":"2023-04-24 20:35:40","publishedOnDateReadable":"April 24th, 2023"},"versionCreatedAt":"2022-10-13 18:27:04","video":"","vorDoi":"10.1007/s00240-023-01440-8","vorDoiUrl":"https://doi.org/10.1007/s00240-023-01440-8","workflowStages":[]},"version":"v1","identity":"rs-2147324","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2147324","identity":"rs-2147324","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}