The value of 11-oxygenated androgens in the diagnosis and treatment of 21-hydroxylase deficiency

The value of 11-oxygenated androgens in the diagnosis and treatment of 21-hydroxylase deficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The value of 11-oxygenated androgens in the diagnosis and treatment of 21-hydroxylase deficiency Tian Lan, Wen Ruan, Kaibi Chen, Meng Yang, Xiaohong Chen, Hui Yao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6484008/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background In 21-hydroxylase deficiency (21-OHD), traditional androgens like testosterone (T), androstenedione (A4), and dihydrotestosterone (DHT) are commonly used for monitoring disease. However, these biomarkers alone cannot fully explain the clinical hyperandrogenism observed in patients. Recent studies suggest that 11-oxygenated androgens also contribute to androgen-related symptoms. Objective This study aimed to assess the role of 11-oxygenated androgens in diagnosing and managing 21-OHD in children. Methods This study collected 67 patients of 21-OHD in Wuhan Children's Hospital from February 2021 to February 2022. The control group was 67 healthy children. 21-OHD children were divided into well-controlled and suboptimally-controlled groups. The clinical characteristics of 21-OHD children were recorded. The concentrations of 17-hydroxyprogesterone (17-OHP), A4, T, progesterone (PROG), 11 ketotestosterone (11KT), and 11β-hydroxyandrostenedione (11OHA4) in the two groups of children were detected. The diagnostic value of 11-oxygen androgens for 21-OHD and the follow-up value of efficacy judgment were explored. Results (1) The 11KT concentration of 21-OHD children was significantly higher than that of the healthy control group (P<0.001). (2) There was a positive correlation between 11-oxygen androgens and 17-OHP, A4, T, and PROG in 21-OHD children. (3) The concentrations of 11KT, PROG, A4, 17-OHP, and T in 21-OHD suboptimally-controlled group children were significantly higher than those in the well-controlled group (P<0.05). (4) 11KT has a high monitoring valuefor the control effect (ROC curve AU value 0.712). Conclusion 11KT is expected to become a new biomarker for the auxiliary diagnosis and monitoring the therapy of 21-OHD children. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Adrenal gland diseases Health sciences/Medical research/Paediatric research 21-hydroxylase deficiency 11-oxygenated androgens Clinical efficacy evaluation Follow-up Figures Figure 1 1 INTRODUCTION 21-hydroxylase deficiency (21-OHD) accounts for more than 95% of congenital adrenal hyperplasia (CAH). The incidence rate of newborns is 1/18,000 to 1/14,000(Speiser et al.,2018). Currently, there is still controversy about the follow-up detection biomarkers for 21-OHD patients. In China, 21-OHD is mainly diagnosed and evaluated by detecting 17-hydroxyprogesterone (17-OHP), androstenedione (A4), and testosterone (T)(Turcu & Rege et al.,2020). Excessive adrenal-derived androgens causes advancement of bone age, and short stature in adulthood; female external genitalia pseudohermaphroditism; peripheral precocious puberty, hirsutism, acne, irregular menstruation, testicular residual tumor, infertility, etc. Early diagnosis and adequate control of 21-OHD can improve the life quality of children to the greatest extent. However, the serum 17-OHP level of 21-OHD patients fluctuates greatly, and it can only return to normal when using supraphysiological doses of glucocorticoids(Charmandari et al.,2001;Krone et al.,2000). In addition, the mature gonads also produce A4 and T. After puberty, these two biomarkers will be confused to evaluate curative effects. Therefore, the conventional androgen biomarkers for the assessment of 21-OHD are limited(Krone et al.,2000;Pretorius et al.,2017;Turcu et al.,2016). 11β-hydroxyandrostenedione (11OHA4) and 11-hydroxydroxytestoterone (11OHT) are only originate from the adrenal glands. Since they contain an oxygen atom at carbon 11, they are named 11-oxygenated androgens. They have the advantages of single origin and relatively stable circulating concentrations with age change(Rege et al.,2014;Turcu & Rege et al.,2020). 11-oxygenated androgens mainly includes 11OHA4, 11OHT, 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT). Among them, the content of 11OHA4 is the highest, and 11KT has the highest androgenic activity(Turcu & Rege et al.,2020). Although 11-oxyandrogens have been discovered by humans for decades, little exploration has been made into their significance in human physiology and diseases. This study aims to analyze the follow-up value of 11-oxyandrogens in the diagnosis and therapeutic efficiency judgment of children with 21-OHD. 2 MATERIALS AND METHODS 2.1 Research Object This study included 67 children with 21-OHD who were diagnosed in Wuhan Children's Hospital from February 2021 to February 2022 and had long-term regular follow-up for more than 1 year. The children's clinical manifestations, laboratory examinations and genetic tests all met the diagnostic criteria for 21-OHD published by The American Endocrine Society in 2018(Speiser et al.,2018). The control group consisted of 67 healthy children undergoing physical examinations with matched ages and genders. This study was approved by the Ethics Committee of Wuhan Children's Hospital (2022R081-E01), and the families of the enrolled children had all signed informed consent forms. All methods were performed in accordance with the relevant guidelines and regulations. The complete dataset analyzed in this study is included in this article and its supplementary materials. 2.2 Follow-up Observation The enrolled children were followed up once every 3 months. The observation items included: (1) Record height, weight, and the development of secondary sexual characteristics; (2) Record whether there was a history of adrenal crisis; (3) Collect 2 mL of venous blood before taking medicine at 8–9 am in the early morning and place it in an inert separation gel coagulation tube. After centrifugation, it was stored at -4°C. Detect the concentrations of 17-OHP, A4, T, PROG, 11OHA4, and 11KT using ultra-high performance liquid chromatography-tandem mass spectrometry; (4) Perform bone age film examination every six months. Male children completed testicular color ultrasound to rule out testicular residual tumor. 2.3 Assessment Methods Bone age (BA) was evaluated by the designated professionals using the Greulich-Pyle (G-P) atlas method(Prokop-Piotrkowska et al.,2021). The height standard deviation score (HtSDS) of the children was calculated with reference to the physical development measurement table in the Research and Application of Growth Standards for Chinese children and adolescents aged 0–18 Years(Li Hui et al.,2009). The HtSDS according to the chronological age (CA) was expressed as HtSDSca. HtSDSca=(height-the reference value of the average height of children of the same age and gender)/the standard deviation of the reference value of the average height of children of the same age and gender. Bone age progression (△BA/△CA) = the increment of bone age/the increment of age within the observation time. 2.4 Treatment Response Groups in 21-OHD 2.4.1 Patients who met all of the following criteria were classified into the well-controlled groupADDIN: (1) The child has no deepening of skin pigmentation and no newly-emerged or progressive virilization signs (acne, hirsutism, clitoral or penile enlargement); (2) There is no manifestation of hypercortisolism; c. Residual testicular tumor, adrenal crisis or central precocious puberty has not occurred; (3) The linear growth rate is normal, with ΔHtSDSca/year being (-0.3 ~ + 0.3); (4) The bone age progression rate is normal, with ΔBA/ΔCA < 1.25. 2.4.2 Patients who failed to meet any one of these criteria were classified into the suboptimally-controlled group. 2.5 Statistical Analysis Statistical analysis was performed using SPSS 26.0 software. The Kolmogorov-Smirnov method was used to test the normality of the data. Count data were expressed as percentages, and non-normal measurement data were expressed as "median and interquartile range (P25, P75)". Two-factor analysis was performed using the bivariate Sperman method. Inter-group comparisons were performed using the two-sample rank sum test (Mann-Whitney U test) and the chi-square test. The receiver operating characteristic curve (ROC curve) was used to calculate the cut-off value of the suboptimally-controlled group for the evaluation of diagnostic effects. The Youden index = sensitivity + specificity-1. P < 0.05 was statistically significant. 3 RESULTS 3.1 General Conditions There was no statistically significant difference in age (P = 0.260) (Table 1 ) and gender (P = 0.487) (Table 2 ) between 67 children with 21-OHD and 67 healthy control children. Table 1 Age and steroid levels in 21-OHD vs control children[M(P25, P75)] Clinical presentation 21-OHD(n = 67) Healthy controls(n = 67) Z P Age(year) 7.83(4.67,10.25) 9.25(6.33,10.25) -1.13 0.26 11OHA4(ng/ml) 1.21(0.50,2.41) 1.29(0.93,1.76) -0.48 0.63 11KT(ng/ml) 0.91(0.36,1.81) 0.41(0.26,0.56) -4.1 < 0.001 PROG(ng/ml) 0.33(0.11,1.26) 0.05(0.05,0.06) -7.53 0.001 A4(ng/ml) 0.65(0.15,1.779) 0.30(0.13,0.55) -3.57 0.001 17-OHP(ng/ml) 6.20(4.30,52.56) 0.236 (0.12,0.41) -8.72 0.001 T(ng/ml) 0.10(0.05,0.60) 0.05(0.05,0.10) -1.85 0.06 21-OHD 21-hydroxylase deficiency, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone Table 2 Gender-specific analysis between children with 21-OHD and healthy Controls 21-OHD(n = 67) Healthy controls(n = 67) χ² value P M 40(59.70%) 35 (52.24%) 0.76 0.49 F 27 (40.30%) 32 (47.76%) 21-OHD 21-hydroxylase deficiency, M male, F female 3.2 Comparison of Hormone Levels between Children with 21-OHD and the Healthy Control Group Among the 6 adrenal steroid hormones included in this study, the levels of 4 hormones (11KT, PROG, A4, 17-OHP) in children with 21-OHD were significantly higher than those in the healthy control group, while the levels of the remaining 2 hormones (11OHA4, T) showed no significant difference (Table 1 ). 3.3 Correlation Analysis of Adrenocortical Steroid Hormone Concentrations A comparison of the correlations among 11KT, 11OHA4, 17-OHP, A4, T, and PROG in children with 21-OHD. The results showed that 11OHA4 and 11KT were significantly positively correlated with 17-OHP, A4, T, and PROG (Table 3 ). Table 3 Correlation Analysis of Adrenocortical Steroid Hormone Concentrations in 21-OHD r PROG A4 17-OHP T 11OHA4 0.27* 0.54* 0.36* 0.46* 11KT 0.59* 0.80* 0.72* 0.7 17-OHP 0.87* 0.73* - 0.70* r Pearson's r * Significant at p < 0.05 (two-tailed) 21-OHD 21-hydroxylase deficiency, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone 3.4 Comparison of 21-OHD Outcomes Between Well-Controlled and Suboptimally-controlled Groups 67 children with 21-OHD were divided into a well-controlled group and a s uboptimally-controlled group according to the treatment effect. The dosage of hydrocortisone in both groups of children was 10-15mg/m 2 , and there was no significant statistical difference in the hydrocortisone dose. The bone age progression (△BA/△CA) in the suboptimally-controlled group was significantly faster than that in the well-controlled group. The levels of 11KT, PROG, A4, 17-OHP and T in the suboptimally-controlled group were all significantly higher than those in the well-controlled group (Table 4 ), but there was no significant difference in the 11OHA4 level. The growth rate SDS (△HtSDSca/year) did not differ between the two groups. Table 4 Group Comparisons: Well- vs Suboptimally- Controlled 21-OHD [M(P25,P75)] Clinical presentation Well-controlled group(n = 35) Suboptimally-controlled group(n = 32) Z P △BA/△CA 1.00(0.40,1.00) 1.00(0.80,1.50) -2.14 0.03 Growth velocity SDS 0.012(-0.08,0.20) 0.130(-0.53,0.84) -0.48 0.63 HC(mg/m2) 11.98(11.36,12.93) 12.50(11.7,13.19) -1.21 0.23 11OHA4(ng/ml) 0.835(0.40,2.47) 1.545(0.82,2.38) -1.66 0.10 11KT(ng/ml) 0.604(0.226,1.222) 1.625(0.72,2.65) -2.98 0.00 PROG(ng/ml) 0.241(0.08,0.57) 0.874(0.25,1.95) -2.39 0.02 A4(ng/ml) 0.487(0.05,1.34) 1.197(0.59,2.82) -2.77 0.01 17-OHP(ng/ml) 9.033(0.84,16.20) 38.471(19.17,74.90) -3.40 0.00 T(ng/ml) 0.050(0.03,0.34) 0.156(0.05,1.03) -2.16 0.03 21-OHD 21-hydroxylase deficiency, BA bone age, CA chronological age, SDS standard deviation score, HC hydrocortisone, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone 3.5 Diagnostic Accuracy of Adrenal Steroids for Identifying Suboptimally Controlled 21-OHD The results of the ROC curve for the diagnosis of suboptimal controlled 21-OHD by adrenal steroid hormones (Table 5 ) showed that serum 17-OHP(Fig. 1 , A)and 11KT(Fig. 1 , B) had the highest diagnostic value for poor control, followed by A4(Fig. 1 , C), PROG(Fig. 1 , D), T(Fig. 1 , E), and 11OHA4(Fig. 1 , F) in turn. Moreover, the specificity of 11KT was higher than that of 17-OHP. Table 5 ROC Curve analysis of adrenal steroid hormones for diagnosing suboptimal control in 21-OHD Hormone AUC SE P Optimal cut-off value Sensitivity Specificity Cut-off 17-OHP 0.74 0.07 <0.001 0.56 0.84 0.71 14.87 11KT 0.71 0.06 0 0.39 0.59 0.8 1.23 A4 0.7 0.07 0 0.41 0.78 0.63 0.59 PROG 0.67 0.07 0.01 0.36 0.56 0.8 0.74 T 0.65 0.07 0.02 0.26 0.69 0.57 0.07 11OHA4 0.62 0.07 0.09 0.32 0.75 0.57 0.9 21-OHD 21-hydroxylase deficiency, AUC area under the curve, SE standard error, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone 4 DISCUSSION 11-oxygenated androgens are mainly derived from the adrenal glands, including four types: 11OHA4, 11OHT, 11KA and 11KT(Turcu & Rege et al.,2020). The synthesis of 11oxygenated androgens starts from dehydroepiandrosterone and is converted into A4 and T respectively through the actions of two enzymes, 3β-hydroxysteroid dehydrogenase Type 2 and 17β-hydroxysteroid dehydrogenase Type 3. Subsequently, A4 and T are respectively converted into 11OHA4 and 11OHT under the action of 11β-hydroxylase. 11OHA4 and 11OHT, produced by the adrenal gland, which can be oxidized into 11KA and 11KT respectively by type 2 11β-hydroxysteroid dehydrogenase in peripheral tissues. 11β-hydroxylase is mainly highly expressed in the zona fasciculata and zona reticularis of the adrenal gland(Rege et al.,2014), and its content in the gonads is negligible(Rege et al.,2019), so 11-oxygenated androgens can be regarded as adrenal specific hormones. In the adrenal gland, dehydroepiandrosterone and dehydroepiandrosterone sulfate are the androgens with the highest content, but they have the least biologic activity. The biologic activities of A4 and 11OHA4 are also relatively low. T and 11KT are both have a relatively strong ability to induce the expression of androgen receptor target genes, there biologic activity is similar, and the activity of 11OHT is relatively weak(Rege et al.,2018). 11-Oxygenated androgens are relatively stable with age change(Nanba et al.,2019;Turcu et al.,2016). Among the four 11-oxygenated androgens, the content of 11OHA4 is the highest(Turcu et al.,2016), and the activity of 11KT is the highest(Turcu & Rege et al.,2020). Therefore, 11KT is the best representative index for studying 11oxyandrogens. When 21-hydroxylase is deficient, the synthesis of glucocorticoids and mineralocorticoids is blocked, which promotes the feedback increase of adrenocorticotropic hormone, causing excessive 17-OHP to be further converted into sex hormones, making downstream A4 and T increase, and the production of 11-oxygenated androgens also increases. At present, there are still disputes over the diagnostic and follow-up detection indicators for patients with 21-OHD. The results of traditional androgen detection are not in good agreement with its clinical manifestations of hyperandrogenism. In terms of diagnosis, this study compared the levels of six steroid hormones between children with 21-OHD and the healthy control group. It was found that the levels of 11KT, 17-OHP, A4 and PROG in children with 21-OHD were significantly higher than those in the healthy control group, while there was no statistical difference in the levels of 11OHA4 and T between the two groups. This suggests that 11KT has a certain value in the diagnosis of 21-OHD. Compared with 11OHA4, 11KT in children with 21-OHD has a stronger correlation with traditional biomarkers such as 17-OHP, A4, T and PROG. 11KT is expected to become a new biomarker for the auxiliary diagnosis of 21-OHD. The results of this study are consistent with the conclusion of Turcu AF(Turcu & El-Maouche et al.,2020;Turcu et al.,2017). The results of this study showed that both 11KT and 17-OHP can be used as biomarkers for evaluating the efficacy of regular follow-up in children with 21-OHD, while 11OHA4 has limited ability to distinguish the disease control status. When 17-OHP is 14.87ng/ml, it has the highest sensitivity for evaluating suboptimally controlled and can effectively identify patients with insufficient drug dosage. When 11KT is 1.23ng/ml, it has the highest specificity for evaluating suboptimally controlled and can reduce the risk of omission. However, the diagnostic performance of a single biomarker is limited, and the AUC of both 11KT and 17-OHP has not reached the relatively ideal sensitivity and specificity (0.9). Thus, in clinical applications, it is recommended to combine these two hormones and conduct a comprehensive evaluation in combination with other indicators and clinical manifestations to achieve more accurate diagnosis and efficacy evaluation. 11-Oxygenated androgens (such as 11KT, 11OHA4) are adrenal-derived hormones and are of great value in the diagnosis and efficacy evaluation of 21-OHD. 11KT is the most bioactive hormone among 11-oxygenated androgens. Its level is significantly increased in children with 21-OHD, and it has a strong correlation with traditional markers (such as 17-OHP, A4, T). Especially, it has a high specificity (11KT > 1.23 ng/ml) when evaluating suboptimally controlled and can effectively reduce the risk of missed diagnosis. However, although 11OHA4 has a high content, its androgenic activity is weak and its ability to distinguish the disease control state is limited. The diagnostic performance of a single index (such as 11KT or 17-OHP) is insufficient (the AUC of both is < 0.9). Therefore, in clinical applications, it is recommended to use 11KT and 17-OHP in combination and conduct a comprehensive evaluation in combination with other steroid hormones and the clinical manifestations of children, so as to improve the accuracy of diagnosis and efficacy monitoring. 11KT is expected to become a supplement to 17-OHP and provide a new biomarker for the diagnosis and follow-up of 21-OHD. This study has certain limitations. The sample size is small and the incidence of rare diseases is low; the clinical efficacy lags behind biochemical control, and it is not scientific enough to use clinical assessment as the gold standard for well controlled or suboptimally controlled, for example, hirsutism improvement may take 6–12 months(Martin et al.,2018). In addition, clinical assessment may be subjective. In the future, it is necessary to expand the sample size and design rigorous prospective studies to improve the results and obtain more comprehensive and reliable conclusions. Declarations ETHICS STATEMENT The studies involving human participants were reviewed and approved by Medical Ethics Committee of Wuhan Children’s Hospital (2022R081-E01). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. DATA AVAILABILITY STATEMENT The complete dataset analyzed in this study is included in this article and its supplementary materials. AUTHOR CONTRIBUTIONS HY conceived this study. TL, WR, KC MYand XC cared the patient and collected the clinical data of the patient. TL and WR interpreted data and contributed to the manuscript. YH supervised the study. All authors read and approved the final manuscript. FUNDING This research was funded by Wuhan Knowledge Innovation Program (Grant number: 22022020801020570) and China Children's Growth and Development Academic Exchange Special Fund (Z-2019-41-2303). We are grateful for the patient and her family. ACKNOWLEDGMENTS We are grateful for the patient and her family. CONFLICT OF INTEREST The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Charmandari, E., Matthews, D. R., Johnston, A., Brook, C. G., Hindmarsh, P. C. (2001). Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: Is current replacement therapy satisfactory? [Journal Article]. J Clin Endocrinol Metab . 86(10), 4679-4685. doi: 10.1210/jcem.86.10.7972 Jha, S., Turcu, A. F., Sinaii, N., Brookner, B., Auchus, R. J., and Merke, D. P. 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F., Rege, J., Auchus, R. J., Rainey, W. E. (2020). 11-Oxygenated androgens in health and disease. [Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review]. Nat. Rev. Endocrinol. 16(5), 284-296. doi: 10.1038/s41574-020-0336-x Li Hui, Ji Chengye, Zong Xinnan, Zhang Yaqin. (2009). [Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years]. Chinese Journal of Pediatrics. 47(7), 487-492. doi: 10.3760/cma.j.issn.0578-1310.2009.07.003 Xiao Huiwen, Ma Huamei, Su Zhe, Du Minlian, Li Yanhong and Chen Hongshan, et al. (2012). [Determination of serum steroids in monitoring therapy of congenital adrenal hyperplasia]. Chinese Journal of Pediatrics. 50(4), 301-307. doi: 10.3760/cma.j.issn.0578-1310.2012.04.016 Additional Declarations No competing interests reported. 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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-6484008","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":452108177,"identity":"1cfdacaf-a8c0-4012-864d-e19a97588531","order_by":0,"name":"Tian Lan","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tian","middleName":"","lastName":"Lan","suffix":""},{"id":452108178,"identity":"3f814ede-6222-4589-8247-3a514b6d0322","order_by":1,"name":"Wen Ruan","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Ruan","suffix":""},{"id":452108179,"identity":"4e433f44-6b79-49c5-8caa-2ca0d08e9fc3","order_by":2,"name":"Kaibi Chen","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kaibi","middleName":"","lastName":"Chen","suffix":""},{"id":452108180,"identity":"64522d99-27cd-445a-8e70-2d3504aa7320","order_by":3,"name":"Meng Yang","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"Yang","suffix":""},{"id":452108181,"identity":"61662ea8-e44b-4cff-ae89-c032af0f8195","order_by":4,"name":"Xiaohong Chen","email":"","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaohong","middleName":"","lastName":"Chen","suffix":""},{"id":452108182,"identity":"145b8a1d-cf3b-453a-b68b-7aaf92bddc94","order_by":5,"name":"Hui Yao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYHACNgYGAwkefobDBxgSSNBiISfZeCyBFC0MFcYGh88YEKfe4PjhY495CiQSG46d+fzh4Q47Bv72bvyWGZxJSzfmMZBIbOw5u00i8Uwyg8SZsxvwazmQYyYN0tIscXYbQ2IbMzAocgloOf8GoqVN/s3jD4lt9URouQGxxZiH4QwDUONhwlokbzxLk5xjICEnwXDMDKjlOA9Bv/CdTz4m8eZPHY/9gcOPP/5sq5bjb+/Fr0XhAJoAD17lICDfQFDJKBgFo2AUjHgAAJJMSP3DcqkJAAAAAElFTkSuQmCC","orcid":"","institution":"Wuhan Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hui","middleName":"","lastName":"Yao","suffix":""}],"badges":[],"createdAt":"2025-04-19 10:08:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6484008/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6484008/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82349590,"identity":"7c5392cb-0666-4e3d-8923-e7477d146209","added_by":"auto","created_at":"2025-05-09 10:47:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":142180,"visible":true,"origin":"","legend":"\u003cp\u003eROC analysis of adrenal steroids in diagnosing suboptimal 21-OHD control.\u003c/p\u003e\n\u003cp\u003eROC receiver operating characteristic, 21-OHD 21-hydroxylase deficiency, 17-OHP 17-hydroxyprogesterone, 11KT, 11 ketotestosterone, A4 androstenedione, PROG progesterone, T testosterone, 11OHA4, 11 hydroxyandrostenedione\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6484008/v1/31fd6d0c4e32a99e9d3684f3.png"},{"id":90274851,"identity":"a819f5db-81c8-4e2d-95eb-0f4642bdc3f8","added_by":"auto","created_at":"2025-09-01 02:16:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":902807,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6484008/v1/ab81949f-9a2e-4f1f-ae66-8d227ca86ba5.pdf"},{"id":82349586,"identity":"99440ab8-0fe0-442a-a0ba-02e8ed2d80d6","added_by":"auto","created_at":"2025-05-09 10:47:33","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":65793,"visible":true,"origin":"","legend":"","description":"","filename":"CAH11.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6484008/v1/be43609fc143a2878d3e7198.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The value of 11-oxygenated androgens in the diagnosis and treatment of 21-hydroxylase deficiency","fulltext":[{"header":"1 INTRODUCTION","content":"\u003cp\u003e21-hydroxylase deficiency (21-OHD) accounts for more than 95% of congenital adrenal hyperplasia (CAH). The incidence rate of newborns is 1/18,000 to 1/14,000(Speiser et al.,2018). Currently, there is still controversy about the follow-up detection biomarkers for 21-OHD patients. In China, 21-OHD is mainly diagnosed and evaluated by detecting 17-hydroxyprogesterone (17-OHP), androstenedione (A4), and testosterone (T)(Turcu \u0026amp; Rege et al.,2020). Excessive adrenal-derived androgens causes advancement of bone age, and short stature in adulthood; female external genitalia pseudohermaphroditism; peripheral precocious puberty, hirsutism, acne, irregular menstruation, testicular residual tumor, infertility, etc. Early diagnosis and adequate control of 21-OHD can improve the life quality of children to the greatest extent. However, the serum 17-OHP level of 21-OHD patients fluctuates greatly, and it can only return to normal when using supraphysiological doses of glucocorticoids(Charmandari et al.,2001;Krone et al.,2000). In addition, the mature gonads also produce A4 and T. After puberty, these two biomarkers will be confused to evaluate curative effects. Therefore, the conventional androgen biomarkers for the assessment of 21-OHD are limited(Krone et al.,2000;Pretorius et al.,2017;Turcu et al.,2016). 11β-hydroxyandrostenedione (11OHA4) and 11-hydroxydroxytestoterone (11OHT) are only originate from the adrenal glands. Since they contain an oxygen atom at carbon 11, they are named 11-oxygenated androgens. They have the advantages of single origin and relatively stable circulating concentrations with age change(Rege et al.,2014;Turcu \u0026amp; Rege et al.,2020). 11-oxygenated androgens mainly includes 11OHA4, 11OHT, 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT). Among them, the content of 11OHA4 is the highest, and 11KT has the highest androgenic activity(Turcu \u0026amp; Rege et al.,2020). Although 11-oxyandrogens have been discovered by humans for decades, little exploration has been made into their significance in human physiology and diseases. This study aims to analyze the follow-up value of 11-oxyandrogens in the diagnosis and therapeutic efficiency judgment of children with 21-OHD.\u003c/p\u003e"},{"header":"2 MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Research Object\u003c/h2\u003e\n \u003cp\u003eThis study included 67 children with 21-OHD who were diagnosed in Wuhan Children\u0026apos;s Hospital from February 2021 to February 2022 and had long-term regular follow-up for more than 1 year. The children\u0026apos;s clinical manifestations, laboratory examinations and genetic tests all met the diagnostic criteria for 21-OHD published by The American Endocrine Society in 2018(Speiser et al.,2018). The control group consisted of 67 healthy children undergoing physical examinations with matched ages and genders. This study was approved by the Ethics Committee of Wuhan Children\u0026apos;s Hospital (2022R081-E01), and the families of the enrolled children had all signed informed consent forms. All methods were performed in accordance with the relevant guidelines and regulations. The complete dataset analyzed in this study is included in this article and its supplementary materials.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Follow-up Observation\u003c/h2\u003e\n \u003cp\u003eThe enrolled children were followed up once every 3 months. The observation items included: (1) Record height, weight, and the development of secondary sexual characteristics; (2) Record whether there was a history of adrenal crisis; (3) Collect 2 mL of venous blood before taking medicine at 8\u0026ndash;9 am in the early morning and place it in an inert separation gel coagulation tube. After centrifugation, it was stored at -4\u0026deg;C. Detect the concentrations of 17-OHP, A4, T, PROG, 11OHA4, and 11KT using ultra-high performance liquid chromatography-tandem mass spectrometry; (4) Perform bone age film examination every six months. Male children completed testicular color ultrasound to rule out testicular residual tumor.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Assessment Methods\u003c/h2\u003e\n \u003cp\u003eBone age (BA) was evaluated by the designated professionals using the Greulich-Pyle (G-P) atlas method(Prokop-Piotrkowska et al.,2021).\u003c/p\u003e\n \u003cp\u003eThe height standard deviation score (HtSDS) of the children was calculated with reference to the physical development measurement table in the Research and Application of Growth Standards for Chinese children and adolescents aged 0\u0026ndash;18 Years(Li Hui et al.,2009). The HtSDS according to the chronological age (CA) was expressed as HtSDSca. HtSDSca=(height-the reference value of the average height of children of the same age and gender)/the standard deviation of the reference value of the average height of children of the same age and gender.\u003c/p\u003e\n \u003cp\u003eBone age progression (△BA/△CA)\u0026thinsp;=\u0026thinsp;the increment of bone age/the increment of age within the observation time.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 Treatment Response Groups in 21-OHD\u003c/h2\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003e2.4.1\u003c/strong\u003e Patients who met all of the following criteria were classified into the well-controlled groupADDIN: (1) The child has no deepening of skin pigmentation and no newly-emerged or progressive virilization signs (acne, hirsutism, clitoral or penile enlargement); (2) There is no manifestation of hypercortisolism; c. Residual testicular tumor, adrenal crisis or central precocious puberty has not occurred; (3) The linear growth rate is normal, with \u0026Delta;HtSDSca/year being (-0.3\u0026thinsp;~\u0026thinsp;+\u0026thinsp;0.3); (4) The bone age progression rate is normal, with \u0026Delta;BA/\u0026Delta;CA\u0026thinsp;\u0026lt;\u0026thinsp;1.25.\u003c/p\u003e\n \u003c/span\u003e \u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003e2.4.2\u003c/strong\u003e Patients who failed to meet any one of these criteria were classified into the suboptimally-controlled group.\u003c/p\u003e\n \u003c/span\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e\n \u003cp\u003eStatistical analysis was performed using SPSS 26.0 software. The Kolmogorov-Smirnov method was used to test the normality of the data. Count data were expressed as percentages, and non-normal measurement data were expressed as \u0026quot;median and interquartile range (P25, P75)\u0026quot;. Two-factor analysis was performed using the bivariate Sperman method. Inter-group comparisons were performed using the two-sample rank sum test (Mann-Whitney U test) and the chi-square test. The receiver operating characteristic curve (ROC curve) was used to calculate the cut-off value of the suboptimally-controlled group for the evaluation of diagnostic effects. The Youden index\u0026thinsp;=\u0026thinsp;sensitivity\u0026thinsp;+\u0026thinsp;specificity-1. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 General Conditions\u003c/h2\u003e \u003cp\u003eThere was no statistically significant difference in age (P\u0026thinsp;=\u0026thinsp;0.260) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and gender (P\u0026thinsp;=\u0026thinsp;0.487) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) between 67 children with 21-OHD and 67 healthy control children.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAge and steroid levels in 21-OHD vs control children[M(P25, P75)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21-OHD(n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthy controls(n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.83(4.67,10.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.25(6.33,10.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11OHA4(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.21(0.50,2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.29(0.93,1.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11KT(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.91(0.36,1.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.41(0.26,0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROG(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.33(0.11,1.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.05(0.05,0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-7.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA4(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.65(0.15,1.779)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.30(0.13,0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17-OHP(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.20(4.30,52.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.236 (0.12,0.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-8.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.10(0.05,0.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.05(0.05,0.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e21-OHD 21-hydroxylase deficiency, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGender-specific analysis between children with 21-OHD and healthy Controls\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21-OHD(n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHealthy controls(n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eχ\u0026sup2; value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40(59.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (52.24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (40.30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32 (47.76%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e21-OHD 21-hydroxylase deficiency, M male, F female\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Comparison of Hormone Levels between Children with 21-OHD and the Healthy Control Group\u003c/h2\u003e \u003cp\u003eAmong the 6 adrenal steroid hormones included in this study, the levels of 4 hormones (11KT, PROG, A4, 17-OHP) in children with 21-OHD were significantly higher than those in the healthy control group, while the levels of the remaining 2 hormones (11OHA4, T) showed no significant difference (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Correlation Analysis of Adrenocortical Steroid Hormone Concentrations\u003c/h2\u003e \u003cp\u003eA comparison of the correlations among 11KT, 11OHA4, 17-OHP, A4, T, and PROG in children with 21-OHD. The results showed that 11OHA4 and 11KT were significantly positively correlated with 17-OHP, A4, T, and PROG (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation Analysis of Adrenocortical Steroid Hormone Concentrations in 21-OHD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePROG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17-OHP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11OHA4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.27*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.54*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.36*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.46*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11KT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.59*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.80*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17-OHP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.87*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.73*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.70*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003er Pearson's r\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* Significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (two-tailed)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e21-OHD 21-hydroxylase deficiency, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Comparison of 21-OHD Outcomes Between Well-Controlled and Suboptimally-controlled Groups\u003c/h2\u003e \u003cp\u003e67 children with 21-OHD were divided into a well-controlled group and a \u003cb\u003es\u003c/b\u003euboptimally-controlled group according to the treatment effect. The dosage of hydrocortisone in both groups of children was 10-15mg/m\u003csup\u003e2\u003c/sup\u003e, and there was no significant statistical difference in the hydrocortisone dose. The bone age progression (△BA/△CA) in the suboptimally-controlled group was significantly faster than that in the well-controlled group. The levels of 11KT, PROG, A4, 17-OHP and T in the suboptimally-controlled group were all significantly higher than those in the well-controlled group (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), but there was no significant difference in the 11OHA4 level. The growth rate SDS (△HtSDSca/year) did not differ between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGroup Comparisons: Well- vs Suboptimally- Controlled 21-OHD [M(P25,P75)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWell-controlled group(n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSuboptimally-controlled group(n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e△BA/△CA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00(0.40,1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00(0.80,1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth velocity\u003c/p\u003e \u003cp\u003eSDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.012(-0.08,0.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.130(-0.53,0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHC(mg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.98(11.36,12.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.50(11.7,13.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11OHA4(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.835(0.40,2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.545(0.82,2.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11KT(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.604(0.226,1.222)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.625(0.72,2.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROG(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.241(0.08,0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.874(0.25,1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA4(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.487(0.05,1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.197(0.59,2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17-OHP(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.033(0.84,16.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38.471(19.17,74.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.050(0.03,0.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.156(0.05,1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e21-OHD 21-hydroxylase deficiency, BA bone age, CA chronological age, SDS standard deviation score, HC hydrocortisone, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Diagnostic Accuracy of Adrenal Steroids for Identifying Suboptimally Controlled 21-OHD\u003c/h2\u003e \u003cp\u003eThe results of the ROC curve for the diagnosis of suboptimal controlled 21-OHD by adrenal steroid hormones (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) showed that serum 17-OHP(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, A)and 11KT(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, B) had the highest diagnostic value for poor control, followed by A4(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, C), PROG(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, D), T(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, E), and 11OHA4(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, F) in turn. Moreover, the specificity of 11KT was higher than that of 17-OHP.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eROC Curve analysis of adrenal steroid hormones for diagnosing suboptimal control in 21-OHD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAUC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOptimal cut-off value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSpecificity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCut-off\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17-OHP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e14.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11KT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11OHA4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e21-OHD 21-hydroxylase deficiency, AUC area under the curve, SE standard error, 11OHA4, 11 hydroxyandrostenedione, 11KT, 11 ketotestosterone, PROG progesterone, A4 androstenedione, 17-OHP 17-hydroxyprogesterone, T testosterone\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 DISCUSSION","content":"\u003cp\u003e11-oxygenated androgens are mainly derived from the adrenal glands, including four types: 11OHA4, 11OHT, 11KA and 11KT(Turcu \u0026amp; Rege et al.,2020). The synthesis of 11oxygenated androgens starts from dehydroepiandrosterone and is converted into A4 and T respectively through the actions of two enzymes, 3β-hydroxysteroid dehydrogenase Type 2 and 17β-hydroxysteroid dehydrogenase Type 3. Subsequently, A4 and T are respectively converted into 11OHA4 and 11OHT under the action of 11β-hydroxylase.\u003c/p\u003e \u003cp\u003e11OHA4 and 11OHT, produced by the adrenal gland, which can be oxidized into 11KA and 11KT respectively by type 2 11β-hydroxysteroid dehydrogenase in peripheral tissues. 11β-hydroxylase is mainly highly expressed in the zona fasciculata and zona reticularis of the adrenal gland(Rege et al.,2014), and its content in the gonads is negligible(Rege et al.,2019), so 11-oxygenated androgens can be regarded as adrenal specific hormones. In the adrenal gland, dehydroepiandrosterone and dehydroepiandrosterone sulfate are the androgens with the highest content, but they have the least biologic activity. The biologic activities of A4 and 11OHA4 are also relatively low. T and 11KT are both have a relatively strong ability to induce the expression of androgen receptor target genes, there biologic activity is similar, and the activity of 11OHT is relatively weak(Rege et al.,2018).\u003c/p\u003e \u003cp\u003e11-Oxygenated androgens are relatively stable with age change(Nanba et al.,2019;Turcu et al.,2016). Among the four 11-oxygenated androgens, the content of 11OHA4 is the highest(Turcu et al.,2016), and the activity of 11KT is the highest(Turcu \u0026amp; Rege et al.,2020). Therefore, 11KT is the best representative index for studying 11oxyandrogens. When 21-hydroxylase is deficient, the synthesis of glucocorticoids and mineralocorticoids is blocked, which promotes the feedback increase of adrenocorticotropic hormone, causing excessive 17-OHP to be further converted into sex hormones, making downstream A4 and T increase, and the production of 11-oxygenated androgens also increases.\u003c/p\u003e \u003cp\u003eAt present, there are still disputes over the diagnostic and follow-up detection indicators for patients with 21-OHD. The results of traditional androgen detection are not in good agreement with its clinical manifestations of hyperandrogenism. In terms of diagnosis, this study compared the levels of six steroid hormones between children with 21-OHD and the healthy control group. It was found that the levels of 11KT, 17-OHP, A4 and PROG in children with 21-OHD were significantly higher than those in the healthy control group, while there was no statistical difference in the levels of 11OHA4 and T between the two groups. This suggests that 11KT has a certain value in the diagnosis of 21-OHD. Compared with 11OHA4, 11KT in children with 21-OHD has a stronger correlation with traditional biomarkers such as 17-OHP, A4, T and PROG. 11KT is expected to become a new biomarker for the auxiliary diagnosis of 21-OHD. The results of this study are consistent with the conclusion of Turcu AF(Turcu \u0026amp; El-Maouche et al.,2020;Turcu et al.,2017).\u003c/p\u003e \u003cp\u003eThe results of this study showed that both 11KT and 17-OHP can be used as biomarkers for evaluating the efficacy of regular follow-up in children with 21-OHD, while 11OHA4 has limited ability to distinguish the disease control status. When 17-OHP is 14.87ng/ml, it has the highest sensitivity for evaluating suboptimally controlled and can effectively identify patients with insufficient drug dosage. When 11KT is 1.23ng/ml, it has the highest specificity for evaluating suboptimally controlled and can reduce the risk of omission. However, the diagnostic performance of a single biomarker is limited, and the AUC of both 11KT and 17-OHP has not reached the relatively ideal sensitivity and specificity (0.9). Thus, in clinical applications, it is recommended to combine these two hormones and conduct a comprehensive evaluation in combination with other indicators and clinical manifestations to achieve more accurate diagnosis and efficacy evaluation.\u003c/p\u003e \u003cp\u003e11-Oxygenated androgens (such as 11KT, 11OHA4) are adrenal-derived hormones and are of great value in the diagnosis and efficacy evaluation of 21-OHD. 11KT is the most bioactive hormone among 11-oxygenated androgens. Its level is significantly increased in children with 21-OHD, and it has a strong correlation with traditional markers (such as 17-OHP, A4, T). Especially, it has a high specificity (11KT\u0026thinsp;\u0026gt;\u0026thinsp;1.23 ng/ml) when evaluating suboptimally controlled and can effectively reduce the risk of missed diagnosis. However, although 11OHA4 has a high content, its androgenic activity is weak and its ability to distinguish the disease control state is limited. The diagnostic performance of a single index (such as 11KT or 17-OHP) is insufficient (the AUC of both is \u0026lt;\u0026thinsp;0.9). Therefore, in clinical applications, it is recommended to use 11KT and 17-OHP in combination and conduct a comprehensive evaluation in combination with other steroid hormones and the clinical manifestations of children, so as to improve the accuracy of diagnosis and efficacy monitoring. 11KT is expected to become a supplement to 17-OHP and provide a new biomarker for the diagnosis and follow-up of 21-OHD.\u003c/p\u003e \u003cp\u003eThis study has certain limitations. The sample size is small and the incidence of rare diseases is low; the clinical efficacy lags behind biochemical control, and it is not scientific enough to use clinical assessment as the gold standard for well controlled or suboptimally controlled, for example, hirsutism improvement may take 6\u0026ndash;12 months(Martin et al.,2018). In addition, clinical assessment may be subjective. In the future, it is necessary to expand the sample size and design rigorous prospective studies to improve the results and obtain more comprehensive and reliable conclusions.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by Medical Ethics Committee of Wuhan Children\u0026rsquo;s Hospital (2022R081-E01). Written informed consent to participate in this study was provided by the participants\u0026rsquo; legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe complete dataset analyzed in this study is included in this article and its supplementary materials.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHY conceived this study. TL, WR, KC MYand XC cared the patient and collected the clinical data of the patient. TL and WR interpreted data and contributed to the manuscript. YH supervised the study. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by Wuhan Knowledge Innovation Program (Grant number: 22022020801020570) and China Children\u0026apos;s Growth and Development Academic Exchange Special Fund (Z-2019-41-2303). We are grateful for the patient and her family.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful for the patient and her family. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCharmandari, E., Matthews, D. R., Johnston, A., Brook, C. G., Hindmarsh, P. C. (2001). Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase \u0026nbsp;deficiency: Is current replacement therapy satisfactory? 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Evaluation and treatment of hirsutism in premenopausal women: An endocrine society clinical practice guideline. [Journal Article; Practice Guideline; Research Support, Non-U.S. Gov\u0026apos;t]. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e. 103(4), 1233-1257. doi: 10.1210/jc.2018-00241\u003c/li\u003e\n \u003cli\u003eNanba, A. T., Rege, J., Ren, J., Auchus, R. J., Rainey, W. E., and Turcu, A. F. (2019). 11-Oxygenated c19 steroids do not decline with age in women. [Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov\u0026apos;t]. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e. 104(7), 2615-2622. doi: 10.1210/jc.2018-02527\u003c/li\u003e\n \u003cli\u003ePretorius, E., Arlt, W., Storbeck, K. (2017). A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids. [Journal Article; Research Support, Non-U.S. Gov\u0026apos;t; Review]. \u003cem\u003eMol. Cell. 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Transcriptome profiling reveals differentially expressed transcripts between the \u0026nbsp;human adrenal zona fasciculata and zona reticularis. [Journal Article; Research Support, N.I.H., Extramural]. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e. 99(3), E518-E527. doi: 10.1210/jc.2013-3198\u003c/li\u003e\n \u003cli\u003eRege, J., Nakamura, Y., Wang, T., Merchen, T. D., Sasano, H., and Rainey, W. E. (2014). Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis. [Journal Article; Research Support, N.I.H., Extramural]. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e. 99(3), E518-E527. doi: 10.1210/jc.2013-3198\u003c/li\u003e\n \u003cli\u003eRege, J., Turcu, A. F., Kasa-Vubu, J. Z., Lerario, A. M., Auchus, G. C., and Auchus, R. J., et al. (2018). 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. 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Chinese Journal of Pediatrics. 50(4), 301-307. doi: 10.3760/cma.j.issn.0578-1310.2012.04.016\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"21-hydroxylase deficiency, 11-oxygenated androgens, Clinical efficacy evaluation, Follow-up","lastPublishedDoi":"10.21203/rs.3.rs-6484008/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6484008/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eIn 21-hydroxylase deficiency (21-OHD), traditional androgens like testosterone (T), androstenedione (A4), and dihydrotestosterone (DHT) are commonly used for monitoring disease. However, these biomarkers alone cannot fully explain the clinical hyperandrogenism observed in patients. Recent studies suggest that 11-oxygenated androgens also contribute to androgen-related symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective \u003c/strong\u003eThis study aimed to assess the role of 11-oxygenated androgens in diagnosing and managing 21-OHD in children.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis study collected 67 patients of 21-OHD in Wuhan Children's Hospital from February 2021 to February 2022. The control group was 67 healthy children. 21-OHD children were divided into well-controlled and suboptimally-controlled groups. The clinical characteristics of 21-OHD children were recorded. The concentrations of 17-hydroxyprogesterone (17-OHP), A4, T, progesterone (PROG), 11 ketotestosterone (11KT), and 11β-hydroxyandrostenedione (11OHA4) in the two groups of children were detected. The diagnostic value of 11-oxygen androgens for 21-OHD and the follow-up value of efficacy judgment were explored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003e(1) The 11KT concentration of 21-OHD children was significantly higher than that of the healthy control group (P\u0026lt;0.001). (2) There was a positive correlation between 11-oxygen androgens and 17-OHP, A4, T, and PROG in 21-OHD children. (3) The concentrations of 11KT, PROG, A4, 17-OHP, and T in 21-OHD suboptimally-controlled group children were significantly higher than those in the well-controlled group (P\u0026lt;0.05). (4) 11KT has a high monitoring valuefor the control effect (ROC curve AU value 0.712).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003e11KT is expected to become a new biomarker for the auxiliary diagnosis and monitoring the therapy of 21-OHD children.\u003c/p\u003e","manuscriptTitle":"The value of 11-oxygenated androgens in the diagnosis and treatment of 21-hydroxylase deficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 10:47:28","doi":"10.21203/rs.3.rs-6484008/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e49123e8-ab1b-4778-9367-b92645cc6456","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48081912,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Adrenal gland diseases"},{"id":48081913,"name":"Health sciences/Medical research/Paediatric research"}],"tags":[],"updatedAt":"2025-09-01T02:08:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 10:47:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6484008","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6484008","identity":"rs-6484008","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}