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Screening for 21-hydroxylase–deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study
Open accessAbstract
Objective To prospectively establish the specificity, sensitivity, and positive predictive value (PPV) of a basal 17-hydroxyprogesterone (17-HP) level for the screening of 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) among hyperandrogenic women.Design Prospective observational trial.Setting Tertiary care academic medical centers.Patient(s) Eight healthy controls, 20 patients with NCAH, and 284 consecutively seen patients with hyperandrogenism.Intervention(s) All controls and patients with NCAH, and select patients with hyperandrogenism, underwent acute ACTH (1-24) stimulation.Main outcome measure(s) Specificity was determined by measuring 17-HP every other day during one menstrual cycle in 8 healthy women with normal ovulation (107 samples). Sensitivity was determined by measuring 17-HP between 7 and 9 A.M. and 3 and 5 P.M. on the same day in 20 patients with genetically confirmed NCAH. The PPV was determined by prospectively measuring 17-HP in 284 consecutively seen hyperandrogenic women at their initial evaluation. The diagnosis of NCAH was established by a stimulated 17-HP level of >10 ng/mL.Result(s) Among controls, 17-HP levels of <2, <3, and <4 ng/mL all had a specificity of 100% when obtained in the follicular phase; when obtained in the luteal phase, they had specificities of 53%, 82%, and 82%, respectively. Among patients with NCAH, 17-HP levels of >2, >3, and >4 ng/mL had sensitivities of 100%, 90%, and 90%, respectively, for the detection of the disorder when obtained in the morning, and sensitivities of 95%, 90%, and 85%, respectively, when obtained in the afternoon. Among the 284 consecutively seen hyperandrogenic women, the PPVs of the first and second 17-HP levels were 7.3% and 19% for a cutoff level of >2 ng/mL, 13% and 43% for a cutoff level of >3 ng/mL, and 33% and 40% for a cutoff level of >4 ng/mL, respectively.Conclusion(s) A basal 17-HP level is a useful screening tool for NCAH. A cutoff level of 4 ng/mL has maximum specificity and PPV, with little loss in sensitivity if testing is performed in the morning and during the follicular phase. However, a lower cutoff level (e.g., 2 or 3 ng/mL) is preferable if testing is performed at odd hours of the day, as is common in many practices, and maximum sensitivity is desired.
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In the citing paper
“In NC forms, 17-OHP may be only mildly elevated, often requiring ACTH stimulation for confirmation (8).”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [8]
In the citing paper
“The most frequent differential diagnosis is between PCOS and nonclassic forms of congenital adrenal hyperplasia (NCAH) because the phenotypic features are very similar [97,98]”
From The Diagnosis of Polycystic Ovary Syndrome during Adolescence (2015) · cites this paper as [98]
In the citing paper
“The discrepancy between the results of this study and those suggesting baseline 17-OHP values O2 ng/ml (O6 nmol/l) as predictor of the disease may rely on the limited number of affected individuals analyzed in the latter studies (10,22), that might have underestimated the percentage of patients with values below the threshold.”
From Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche (2011) · cites this paper as [10]
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Self-citation
Metadata
- Authors
- Azziz, R., Hincapie, L. A., Knochenhauer, E. S., Dewailly, D., Fox, L., & Boots, L. R.
- Affiliations
- Centre Hospitalier Universitaire de Lille (FR)
- Corresponding author
- Azziz, Ricardo
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 1999-11
- Volume
- 72
- Issue
- 5
- Pages
- 915-925
- ISSN
- 0015-0282 (ISSN-L)
- OpenAlex
- W2146453639
- Cited by
- 244
- References
- 46
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 8 · 2020: 5 · 2019: 10 · 2018: 7 · 2017: 4 · 2016: 12 · 2015: 18 · 2014: 7 · 2013: 9 · 2012: 6
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Fertility and Sterility (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD029364, R01-HD29364)
- 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, hyperandrogenism, 17-hydroxyprogesterone, screening, diagnostic accuracy, ACTH stimulation test, menstrual cycle phases, luteal phase, positive predictive value, sensitivity and specificity, ovulatory women
- MeSH terms
- Adrenal Glands, Adrenal Hyperplasia, Congenital, Basal Metabolism, Female, Humans, Mass Screening, Predictive Value of Tests, Prospective Studies, Sensitivity and Specificity, Case-Control Studies, 17-alpha-Hydroxyprogesterone
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