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11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency
Open accessAbstract
Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11β-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = -0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.
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“similar to our previous studies (12, 17), supporting their origin from independent sources in well-controlled men.”
From 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency (2021) · cites this paper as [17]
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“11-oxyandrogens were found to correlate with parameters of poor 21OHD control (11, 17).”
From 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency (2021) · cites this paper as [17]
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“11KT and its precursors are associated with clinical indicators of poor 21OHD control, including large adrenal volume, presence of testicular adrenal rest tumor in males, and irregular menses in females (17).”
From 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency (2021) · cites this paper as [17]
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“PregS has also been found to be associated with clinical surrogates of poor 21OHD control (17).”
From 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency (2021) · cites this paper as [17]
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“In these patients, these increased levels derive primarily from the adrenals and high levels correlate well with poor long-term disease control and disease-specific comorbidities (for example, increased adrenal volume, testicular tumours of adrenal-like tissue termed testicular adrenal rest tumours (TART), menstrual irregularity or hirsutism)51.”
From Management challenges and therapeutic advances in congenital adrenal hyperplasia (2022) · cites this paper as [51]
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“CAH cohort studies demonstrate that increased adrenal volume is correlated with suboptimal disease control, based on elevated adrenal androgens, and other comorbidities, including adverse cardiovascular profile, hypogonadism and oligomenorrhoea51,94,95.”
From Management challenges and therapeutic advances in congenital adrenal hyperplasia (2022) · cites this paper as [51]
In the citing paper
“More recently, it has been found that metabolites such as 21-deoxycortisol and 11-oxysteroids may provide more direct evidence of adrenal androgen precursor production in CAH (218, 219).”
From Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline (2018) · cites this paper as [219]
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Metadata
- Authors
- Turcu, A. F., Mallappa, A., Elman, M. S., Avila, N. A., Marko, J., Rao, H., Tsodikov, A., Auchus, R. J., & Merke, D. P.
- Affiliations
- University of Michigan (US)
- National Institutes of Health (US)
- Veterans Health Administration (US)
- Corresponding author
- Merke, Deborah P
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2017-05-01
- Volume
- 102
- Issue
- 8
- Pages
- 2701-2710
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5546849
- OpenAlex
- W2610763596
- Cited by
- 107
- References
- 55
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 12 · 2021: 15 · 2020: 12 · 2019: 10 · 2018: 12 · 2017: 3
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM086596)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK109116, P30DK089503)
- Michigan Nutrition Obesity Research Center, Medical School, University of Michigan
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- 21-hydroxylase deficiency, 11-oxygenated androgens, adrenal volume, testicular adrenal rest tumor, adrenal incidentaloma, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, 11-ketotestosterone, pregnenolone sulfate, menstrual disorders, hirsutism, steroid biomarkers, glucocorticoid therapy
- MeSH terms
- Adolescent, Adrenal Glands, Adrenal Hyperplasia, Congenital, Adrenal Rest Tumor, Adult, Age Determination by Skeleton, Aged, Androgens, Androstenedione, Androstenes, Child, Child, Preschool, Cortodoxone, Cross-Sectional Studies, Female, Hirsutism, Humans, 17-alpha-Hydroxypregnenolone, Hydroxytestosterones, Male, Menstruation Disturbances, Middle Aged, Organ Size, Pregnenolone, Testicular Neoplasms, Testosterone, Young Adult
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