{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T23:23:55Z","timestamp":1770333835690,"version":"3.49.0"},"reference-count":42,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1997,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A deficiency of 21-hydroxylase activity is one of the most commonly inherited genetic disorders in man, with heterozygosity for CYP21 mutations affecting approximately 1 in 60 of the non-Jewish Caucasian population. We have hypothesized that heterozygosity for CYP21 mutations in women increases their risk of developing clinically evident hyperandrogenism, and that this risk is related to the severity of the mutation of CYP21 and\/or the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation. To test these hypotheses, we studied 38 obligate carriers for 21-hydroxylase deficiency (i.e. mothers of children with congenital adrenal hyperplasia or nonclassic congenital adreanl hyperplasia), comparing them to 27 weight-, parity-, and age-matched controls. Premenopausal carriers, not receiving hormonal treatment (n = 27), had higher mean total and free testosterone [T; 2.02 \u00b1 0.55 vs. 1.56 \u00b1 0.65 nmol\/L (P &amp;lt; 0.007) and 0.018 \u00b1 0.007 vs. 0.012 \u00b1 0.006 nmol\/L (P &amp;lt; 0.007), respectively] and lower mean sex hormone-binding globulin (214 \u00b1 62 vs. 277 \u00b1 129 nmol\/L; P &amp;lt; 0.03) levels compared to controls. There was no difference in the mean basal levels of dehydroepiandrosterone sulfate, androstenedione (A4), or 17-OHP between carriers and controls. As expected, carriers exhibited higher stimulated and net increment 17-OHP levels than controls [21.1 \u00b1 27.1 vs. 6.2\u00b1 3.1 nmol\/L (P &amp;lt; 0.01) and 19.0 \u00b1 26.5 vs. 4.4 \u00b1 2.8 nmol\/L (P &amp;lt; 0.009), respectively]. However, no difference was observed in the response of A4 to ACTH-(1\u201324) stimulation. Of the 27 carriers studied biochemically, 2 (7.4%) had a stimulated 17-OHP value between 30.3\u201360.6 nmol\/L, and 1 (3.7%) had a 17-OHP level above 60.6 nmol\/L, suggestive of nonclassic adrenal hyperplasia. Of all carriers studied genetically (n = 36), 50.0% (18 of 36) had 1, 33% (12 of 36) had 2, and 16.7% (6 of 36) had 3 or more mutations. In 27.8% (10 of 36) of carriers, the mutations were contiguous, consistent with a large gene conversion. All 38 carriers were examined for historical and physical features of hyperandrogenism. Hirsutism was defined as a Ferriman-Gallwey score of 6 or more, menstrual\/ovulatory dysfunction as a history of menstrual cycles of more than 35-day, and hyperandrogenemia as total or free T, A4, and\/or dehydroepiandrosterone sulfate levels above the upper 95th percentile of control values. Further, defining functional androgen excess (FAE) as the presence of at least 2 of the 3 hyperandrogenic features, 4 of 38 (10.5%) of carriers appeared to be affected (95% confidence interval, 2.9\u201324.8%). Assuming an expected prevalence rate of FAE in the general population of 5\u201320%, the frequency of FAE among our carriers was not significantly higher than expected.<\/jats:p>\n               <jats:p>In conclusion, heterozygosity for CYP21 mutations does not appear to increase the risk of clinically evident hyperandrogenism, although carrying the defect was associated with higher mean and free T levels. Finally, due to the low frequency of androgen excess in our heterozygote population, we were unable to correlate the severity of the CYP21 mutation and\/or the 17-OHP response to ACTH stimulation with the presence of the phenotype.<\/jats:p>","DOI":"10.1210\/jcem.82.2.3759","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:00:51Z","timestamp":1389200451000},"page":"479-485","source":"Crossref","is-referenced-by-count":6,"title":["Carriers of 21-Hydroxylase Deficiency Are Not at Increased Risk for Hyperandrogenism*"],"prefix":"10.1210","volume":"82","author":[{"given":"E. S.","family":"Knochenhauer","sequence":"first","affiliation":[{"name":"Departments of Obstetrics and Gynecology (E.S.K., B.A.C.-M., R.A.), Birmingham, Alabama 35233"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Cortet-Rudelli","sequence":"additional","affiliation":[{"name":"the Department d\u2019Endocrinologie, Metabolismes, Nutrition, et Reproduction, Centre Hospitalier Regional et Universitaire de Lille (C.C.-R., D.D., R.A.), Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. D.","family":"Cunnigham","sequence":"additional","affiliation":[{"name":"Pediatrics (R.D.C.), University of Alabama, Birmingham, Alabama 35233"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. A.","family":"Conway-Myers","sequence":"additional","affiliation":[{"name":"Departments of Obstetrics and Gynecology (E.S.K., B.A.C.-M., R.A.), Birmingham, Alabama 35233"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Dewailly","sequence":"additional","affiliation":[{"name":"the Department d\u2019Endocrinologie, Metabolismes, Nutrition, et Reproduction, Centre Hospitalier Regional et Universitaire de Lille (C.C.-R., D.D., R.A.), Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Azziz","sequence":"additional","affiliation":[{"name":"Departments of Obstetrics and Gynecology (E.S.K., B.A.C.-M., R.A.), Birmingham, Alabama 35233"},{"name":"Medicine (R.A.), Birmingham, Alabama 35233"},{"name":"the Department d\u2019Endocrinologie, Metabolismes, Nutrition, et Reproduction, Centre Hospitalier Regional et Universitaire de Lille (C.C.-R., D.D., R.A.), Lille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071619400764500_R1","first-page":"650","article-title":"High frequency of nonclassical steroid 21-hydroxylase deficiency.","volume":"37","author":"Speiser","year":"1985","journal-title":"Am J Hum Genet"},{"key":"2020071619400764500_R2","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/0002-9378(95)90021-7","article-title":"Molecular abnormalities of the 21-hydroxylase gene in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation.","volume":"172","author":"Azziz","year":"1995","journal-title":"Am J Obstet Gynecol"},{"key":"2020071619400764500_R3","first-page":"810","article-title":"Nonclassic adrenal hyperplasia: current concepts [Clinical Review 56].","volume":"78","author":"Azziz","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R4","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1056\/NEJM198507253130404","article-title":"Late-onset adrenal hyperplasia in hirsutism.","volume":"313","author":"Kuttenn","year":"1985","journal-title":"N Engl J Med"},{"key":"2020071619400764500_R5","first-page":"241","article-title":"Genetics, diagnosis, and management of 21-hydroxylase deficiency [Clinical Review 54].","volume":"78","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R6","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1172\/JCI115897","article-title":"Disease expression and molecular genotyping in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.","volume":"90","author":"Speiser","year":"1992","journal-title":"J Clin Invest"},{"key":"2020071619400764500_R7","doi-asserted-by":"crossref","first-page":"7232","DOI":"10.1073\/pnas.89.15.7232","article-title":"Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations.","volume":"89","author":"Wedell","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071619400764500_R8","first-page":"6","article-title":"Genetic basis of endocrine disease 2: congenital adrenal hyperplasia due to 21-hydroxylase deficiency.","volume":"74","author":"White","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R9","first-page":"615","article-title":"Concordance of 21-hydroxylase gene ratio, human leukocyte antigen haplotyping and adrenal testing results in a family with late-onset adrenal hyperplasia.","volume":"38","author":"Wells","year":"1993","journal-title":"J Reprod Med"},{"key":"2020071619400764500_R10","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1210\/jcem-57-2-320","article-title":"Genotyping steroid 21-hydroxylase deficiency: hormonal reference data.","volume":"57","author":"New","year":"1983","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R11","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/0140-6736(90)91185-D","article-title":"Improved test to identify heterozygotes for congenital adrenal hyperplasia without index case examination.","volume":"335","author":"Peter","year":"1990","journal-title":"Lancet"},{"key":"2020071619400764500_R12","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S0022-3476(77)80560-X","article-title":"The detection of the heterozygous carrier for congenital virilizing adrenal hyperplasia.","volume":"90","author":"Gutai","year":"1977","journal-title":"J Pediatr"},{"key":"2020071619400764500_R13","first-page":"495","article-title":"Test for heterozygosity of congenital adrenal hyperplasia.","volume":"88","author":"Knorr","year":"1976","journal-title":"Acta Endocrinol (Copenh)"},{"key":"2020071619400764500_R14","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/S0022-3476(77)80561-1","article-title":"Identification of heterozygote carriers of congenital adrenal hyperplasia by radioimmunoassay of serum 17-OH progesterone.","volume":"90","author":"Krensky","year":"1977","journal-title":"J Pediatr"},{"key":"2020071619400764500_R15","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1530\/acta.0.0910109","article-title":"Comparison of two tests for heterozygosity in congenital adrenal hyperplasia (CAH).","volume":"91","author":"Weil","year":"1979","journal-title":"Acta Endocrinol (Copenh)"},{"key":"2020071619400764500_R16","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1210\/jcem-41-2-415","article-title":"Evidence for partial 21-hydroxylase deficiency among heterozygote carriers of congenital adrenal hyperplasia.","volume":"41","author":"Lee","year":"1975","journal-title":"J Clin Endocrinol 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(Copenh)"},{"key":"2020071619400764500_R20","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1210\/jcem-57-5-1061","article-title":"Impaired mineralocorticoid hormone responses to adrenocorticotropin stimulation: additional characterization of heterozygosity for the 21-hydroxylase deficiency type of congenital adrenal hyperplasia.","volume":"57","author":"Pardini","year":"1983","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R21","year":"1991"},{"key":"2020071619400764500_R22","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S0002-9378(12)90840-6","article-title":"3\u03b2-Hydroxysteroid dehydrogenase deficiency in hyperandrogenism.","volume":"168","author":"Azziz","year":"1993","journal-title":"Am J Obstet Gynecol"},{"key":"2020071619400764500_R23","first-page":"239","volume":"17","year":"1992"},{"key":"2020071619400764500_R24","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1210\/jcem-70-5-1273","article-title":"Acute adrenocorticotropin-(1\u201324) (ACTH) adrenal stimulation in eumenorrheic women: reproducibility and effect of ACTH dose, subject weight and sampling time.","volume":"70","author":"Azziz","year":"1990","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R25","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1210\/jcem-73-6-1327","article-title":"Abnormalities of 21-hydroxylase gene ratio and adrenal steroidogenesis in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to acute adrenal stimulation.","volume":"73","author":"Azziz","year":"1991","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R26","first-page":"1635","article-title":"Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene.","volume":"80","author":"Wilson","year":"1995","journal-title":"J Clin Endocrinol 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Steril"},{"key":"2020071619400764500_R31","doi-asserted-by":"crossref","first-page":"4436","DOI":"10.1073\/pnas.85.12.4436","article-title":"Characterization of frequent deletions causing steroid 21-hydroxylase deficiency.","volume":"85","author":"White","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071619400764500_R32"},{"key":"2020071619400764500_R33","author":"Zawadzki","year":"1992"},{"key":"2020071619400764500_R34","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1210\/jcem-21-11-1440","article-title":"Clinical assessment of body hair growth in women.","volume":"21","author":"Ferrimen","year":"1961","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R35","first-page":"57","article-title":"The association of obesity with infertility and related menstrual abnormalities in women.","volume":"3","author":"Hartz","year":"1979","journal-title":"Int J Obes"},{"key":"2020071619400764500_R36","first-page":"410","article-title":"The prevalence of hirsutism in young women.","volume":"1","year":"1964","journal-title":"Lancet"},{"key":"2020071619400764500_R37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1365-2265.1992.tb02296.x","article-title":"How common are polycystic ovaries in normal women and what is their significance for the fertility of the population.","volume":"37","author":"Clayton","year":"1992","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071619400764500_R38","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/j.1479-828X.1994.tb01041.x","article-title":"The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women.","volume":"34","author":"Farquhar","year":"1994","journal-title":"Aust NZ Obstet Gynecol"},{"key":"2020071619400764500_R39","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/S0140-6736(88)91612-1","article-title":"Polycystic ovaries\u2013a common finding in normal women.","volume":"1","author":"Polson","year":"1988","journal-title":"Lancet"},{"key":"2020071619400764500_R40","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0015-0282(16)45429-4","article-title":"Polycystic ovarian disease.","volume":"35","year":"1981","journal-title":"Fertil Steril"},{"key":"2020071619400764500_R41","first-page":"1421","article-title":"Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency.","volume":"75","author":"Speiser","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619400764500_R42","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/BF00201668","article-title":"Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency by allele-specific hybridization and Southern blot.","volume":"93","author":"Speiser","year":"1994","journal-title":"Hum Genet"}],"container-title":["The Journal of Clinical Endocrinology &amp; 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