11-Oxygenated Androgens are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency
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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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The inverse correlation of 11KT and testosterone in men with classic 21OHD supports their origin from independent sources in well-controlled men.
“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]
The Results (Interhormonal correlations; page unavailable) report an inverse correlation between 11-ketotestosterone and testosterone in males at Tanner stage 5. The Discussion interprets the findings as suggesting that 11-ketotestosterone relies predominantly on adrenal precursors, distinct from testosterone’s association with LH. The paper does not establish that this correlation specifically holds in well-controlled men. (LLM, conf=0.86)
Experimental — accuracy not yet measured11-oxyandrogens were found to correlate with parameters of poor 21OHD control.
“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]
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.
“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]
PregS has been found to be associated with clinical surrogates of poor 21OHD control.
“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]
Increased 11-oxygenated androgen levels in CAH derive primarily from the adrenals and correlate with poor long-term disease control and disease-specific comorbidities.
“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]
In CAH cohorts, increased adrenal volume correlates with suboptimal disease control (elevated adrenal androgens) and with comorbidities including adverse cardiovascular profile, hypogonadism and oligomenorrhoea.
“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 CAH, 21-deoxycortisol and 11-oxysteroids may give more direct evidence of adrenal androgen precursor production than traditional markers.
“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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MANAGEMENT OF ENDOCRINE DISEASE: Gonadal dysfunction in congenital adrenal hyperplasia
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Gonadal function in adult male patients with congenital adrenal hyperplasia
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Newborn Screening for Congenital Adrenal Hyperplasia: Review of Factors Affecting Screening Accuracy
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Self-citationThe clinical and biochemical significance of 11-oxygenated androgens in human health and disease
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Disorders of Sex Development of Adrenal Origin
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Revisiting Classical 3β-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases
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The Rise, Fall, and Resurrection of 11-Oxygenated Androgens in Human Physiology and Disease
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Self-citationThe Adrenal Cortex and its Disorders
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Nonclassic Congenital Adrenal Hyperplasia
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Circadian Rhythms of 11-Oxygenated C19 Steroids and 5-Steroid Sulfates in Healthy Men
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Self-citationThe Adrenal Cortex and Its Disorders
Miller, W. L., Flück, C. E., Breault, D. T., & Feldman, B. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-62520-3.00014-2 · Cited by 14 · see citing works
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Davis, S. R., Turcu, A. F., Robinson, P. J., & Bell, R. J. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2018-00412 · Cited by 10 · see citing works
Self-citationCongenital adrenal hyperplasia: New biomarkers and adult treatments
Dreves, B., Reznik, Y., & Tabarin, A. (2023) · Annales d Endocrinologie · doi:10.1016/j.ando.2023.01.008 · Cited by 10 · see citing works
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Self-citationMonitoring treatment in pediatric patients with 21-hydroxylase deficiency
Itonaga, T., & Hasegawa, Y. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1102741 · Cited by 10 · see citing works
Transcriptional comparison of testicular adrenal rest tumors with fetal and adult tissues
Schröder, M. A. M., Sweep, F. C. G. J., van Herwaarden, A. E., Mitchell, R. T., Eliveld, J., van Pelt, A. M. M., Rowan, A. E., Korbie, D. J., Stikkelbroeck, N. M. M. L., der Grinten, H. L. C., et al. (2022) · European Journal of Endocrinology · doi:10.1530/eje-22-0143 · Cited by 10 · see citing works
11-Oxygenated Androgen Metabolite Concentrations Are Affected by Pubertal Progression and Obesity
Breslow, E., Taylor, A., Chan, C. L., Severn, C., Pyle, L., Torchen, L. C., Sisk, R. K., Legro, R. S., Turcu, A. F., Auchus, R. J., et al. (2022) · Hormone Research in Paediatrics · doi:10.1159/000528341 · Cited by 9 · see citing works
Self-citationLongitudinal Characterization and Sonographic Staging of Testicular Adrenal Rest Tumors
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Prenatal and Pregnancy Management of Congenital Adrenal Hyperplasia
Nowotny, H. F., Tschaidse, L., Auer, M. K., & Reisch, N. (2024) · Clinical Endocrinology · doi:10.1111/cen.15131 · Cited by 10 · see citing works
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Congenital adrenal hyperplasia is a very rare cause of adrenal incidentalomas in Sweden
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11-Oxyandrogens from the viewpoint of pediatric endocrinology
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Adrenal gland involvement in 11-ketotestosterone production analyzed using LC-MS/MS
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The Landscape of Androgens in Cushing’s Syndrome
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Pregnancy in Congenital Adrenal Hyperplasia
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Self-citationMultiple 17-OHP Cutoff Co-Variates Fail to Improve 21-Hydroxylase Deficiency Screening Accuracy
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Diversity of Androgens; Comparison of Their Significance and Characteristics in Vertebrate Species
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- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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