Androgen excess and diagnostic steroid biomarkers for nonclassic 21-hydroxylase deficiency without cosyntropin stimulation

in European Journal of Endocrinology
View More View Less
  • 1 Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA
  • 2 National Institutes of Health (NIH) Clinical Center, Bethesda, Maryland, USA
  • 3 School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
  • 4 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA
  • 5 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA

Correspondence should be addressed to A F Turcu; Email: aturcu@umich.edu
Restricted access

Objectives

The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess. Herein, we aimed to: (1.) compare the relative contribution of traditional and 11-oxyandrogens in N21OHD patients and (2.) identify steroids that accurately diagnose N21OHD with a single baseline blood draw.

Design

We prospectively enrolled patients who underwent a cosyntropin stimulation test for suspected N21OHD in two tertiary referral centers between January 2016 and August 2019.

Methods

Baseline sera were used to quantify 15 steroids by liquid chromatography-tandem mass spectrometry. Logistic regression modeling was implemented to select steroids that best discriminate N21OHD from controls.

Results

Of 86 participants (72 females), median age 26, 32 patients (25 females) had N21OHD. Age, sex distribution, and BMI were similar between patients with N21OHD and controls. Both testosterone and androstenedione were similar in patients with N21OHD and controls, while four 11-oxyandrogens were significantly higher in patients with N21OHD (ratios between medians: 1.7 to 2.2, P < 0.01 for all). 17α-Hydroxyprogesterone (6.5-fold), 16α-hydroxyprogesterone (4.1-fold), and 21-deoxycortisol (undetectable in 80% of the controls) were higher, while corticosterone was 3.6-fold lower in patients with N21OHD than in controls (P < 0.001). Together, baseline 17α-hydroxyprogesterone, 21-deoxycortisol, and corticosterone showed perfect discrimination between N21OHD and controls.

Conclusions

Adrenal 11-oxyandrogens are disproportionately elevated compared to conventional androgens in N21OHD. Steroid panels can accurately diagnose N21OHD in unstimulated blood tests.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 1608 1608 144
Full Text Views 165 165 9
PDF Downloads 113 113 6
  • 1

    Speiser PW, White PC. Congenital adrenal hyperplasia. New England Journal of Medicine 2003 349 776788. (https://doi.org/10.1056/NEJMra021561)

    • Search Google Scholar
    • Export Citation
  • 2

    Casteras A, De Silva P, Rumsby G, Conway GS. Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. Clinical Endocrinology 2009 70 833837. (https://doi.org/10.1111/j.1365-2265.2009.03563.x)

    • Search Google Scholar
    • Export Citation
  • 3

    Moran C, Azziz R, Carmina E, Dewailly D, Fruzzetti F, Ibanez L, Knochenhauer ES, Marcondes JA, Mendonca BB & Pignatelli D et al. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. American Journal of Obstetrics and Gynecology 2000 183 14681474. (https://doi.org/10.1067/mob.2000.108020)

    • Search Google Scholar
    • Export Citation
  • 4

    Bidet M, Bellanne-Chantelot C, Galand-Portier MB, Tardy V, Billaud L, Laborde K, Coussieu C, Morel Y, Vaury C & Golmard JL et al. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. Journal of Clinical Endocrinology and Metabolism 2009 94 15701578. (https://doi.org/10.1210/jc.2008-1582)

    • Search Google Scholar
    • Export Citation
  • 5

    Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Human Reproduction Update 2017 23 580599. (https://doi.org/10.1093/humupd/dmx014)

    • Search Google Scholar
    • Export Citation
  • 6

    Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998 101 583590. (https://doi.org/10.1542/peds.101.4.583)

    • Search Google Scholar
    • Export Citation
  • 7

    New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, Dupont B, Stoner E, Levy DJ & Pang S et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. Journal of Clinical Endocrinology and Metabolism 1983 57 320326. (https://doi.org/10.1210/jcem-57-2-320)

    • Search Google Scholar
    • Export Citation
  • 8

    Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. Journal of Clinical Endocrinology and Metabolism 1995 80 23222329. (https://doi.org/10.1210/jcem.80.8.7629224)

    • Search Google Scholar
    • Export Citation
  • 9

    Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM & Oberfield SE et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010 95 41334160. (https://doi.org/10.1210/jc.2009-2631)

    • Search Google Scholar
    • Export Citation
  • 10

    Pauwels G, Allegaert K, Regal L, Meulemans A. Risk factors for elevated levels of 17-hydroxyprogesterone during neonatal intensive care unit admission. Acta Clinica Belgica 2012 67 8893. (https://doi.org/10.2143/ACB.67.2.2062637)

    • Search Google Scholar
    • Export Citation
  • 11

    Ryckman KK, Cook DE, Berberich SL, Shchelochkov OA, Berends SK, Busch T, Dagle JM, Murray JC. Replication of clinical associations with 17-hydroxyprogesterone in preterm newborns. Journal of Pediatric Endocrinology and Metabolism 2012 25 301305. (https://doi.org/10.1515/jpem-2011-0456)

    • Search Google Scholar
    • Export Citation
  • 12

    Nordenstrom A, Wedell A, Hagenfeldt L, Marcus C, Larsson A. Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants. Pediatrics 2001 108 E68. (https://doi.org/10.1542/peds.108.4.e68)

    • Search Google Scholar
    • Export Citation
  • 13

    Olgemoller B, Roscher AA, Liebl B, Fingerhut R. Screening for congenital adrenal hyperplasia: adjustment of 17-hydroxyprogesterone cut-off values to both age and birth weight markedly improves the predictive value. Journal of Clinical Endocrinology and Metabolism 2003 88 57905794. (https://doi.org/10.1210/jc.2002-021732)

    • Search Google Scholar
    • Export Citation
  • 14

    Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR. Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertility and Sterility 1999 72 915925. (https://doi.org/10.1016/s0015-0282(99)00383-0)

    • Search Google Scholar
    • Export Citation
  • 15

    Cavarzere P, Samara-Boustani D, Flechtner I, Dechaux M, Elie C, Tardy V, Morel Y, Polak M. Transient hyper-17-hydroxyprogesteronemia: a clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia. European Journal of Endocrinology 2009 161 285292. (https://doi.org/10.1530/EJE-09-0145)

    • Search Google Scholar
    • Export Citation
  • 16

    Turcu AF, Rege J, Chomic R, Liu J, Nishimoto HK, Else T, Moraitis AG, Palapattu GS, Rainey WE, Auchus RJ. Profiles of 21-carbon steroids in 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2015 100 22832290. (https://doi.org/10.1210/jc.2015-1023)

    • Search Google Scholar
    • Export Citation
  • 17

    Costa-Barbosa FA, Carvalho VM, Nakamura OH, Bachega TA, Vieira JG, Kater CE. Zona fasciculata 21-hydroxysteroids and precursor-to-product ratios in 21-hydroxylase deficiency: further characterization of classic and non-classic patients and heterozygote carriers. Journal of Endocrinological Investigation 2011 34 587592. (https://doi.org/10.3275/7273)

    • Search Google Scholar
    • Export Citation
  • 18

    Costa-Barbosa FA, Tonetto-Fernandes VF, Carvalho VM, Nakamura OH, Moura V, Bachega TA, Vieira JG, Kater CE. Superior discriminating value of ACTH-stimulated serum 21-deoxycortisol in identifying heterozygote carriers for 21-hydroxylase deficiency. Clinical Endocrinology 2010 73 700706. (https://doi.org/10.1111/j.1365-2265.2010.03871.x)

    • Search Google Scholar
    • Export Citation
  • 19

    Milewicz A, Vecsei P, Gruszka S, Szymczak J, Bednarek-Tupikowska G, Grabinski M. Diagnosis of congenital adrenal hyperplasia based on plasma 21-deoxycortisol level determined with a specific radioimmunoassay. Materia Medica Polona: Polish Journal of Medicine and Pharmacy 1984 16 9598.

    • Search Google Scholar
    • Export Citation
  • 20

    Bloem LM, Storbeck KH, Schloms L, Swart AC. 11beta-Hydroxyandrostenedione returns to the steroid arena: biosynthesis, metabolism and function. Molecules 2013 18 1322813244. (https://doi.org/10.3390/molecules181113228)

    • Search Google Scholar
    • Export Citation
  • 21

    Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Molecular Endocrinology 2013 27 315324. (https://doi.org/10.1210/me.2012-1287)

    • Search Google Scholar
    • Export Citation
  • 22

    Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano TJ, Shields JJ, Merke DP, Rainey WE, Auchus RJ. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. European Journal of Endocrinology 2016 174 601609. (https://doi.org/10.1530/EJE-15-1181)

    • Search Google Scholar
    • Export Citation
  • 23

    Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA. Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia. Journal of Steroid Biochemistry and Molecular Biology 2018 178 221228. (https://doi.org/10.1016/j.jsbmb.2017.12.016)

    • Search Google Scholar
    • Export Citation
  • 24

    Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, Tsodikov A, Auchus RJ, Merke DP. 11-Oxygenated androgens are biomarkers of adrenal volume and testicular adrenal rest tumors in 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2017 102 27012710. (https://doi.org/10.1210/jc.2016-3989)

    • Search Google Scholar
    • Export Citation
  • 25

    Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ & Taylor AE et al. The androgen excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and Sterility 2009 91 456488. (https://doi.org/10.1016/j.fertnstert.2008.06.035)

    • Search Google Scholar
    • Export Citation
  • 26

    Nanba AT, Rege J, Ren J, Auchus RJ, Rainey WE, Turcu AF. 11-Oxygenated C19 steroids do not decline with age in women. Journal of Clinical Endocrinology and Metabolism 2019 104 26152622. (https://doi.org/10.1210/jc.2018-02527)

    • Search Google Scholar
    • Export Citation
  • 27

    Wong T, Shackleton CH, Covey TR, Ellis G. Identification of the steroids in neonatal plasma that interfere with 17 alpha-hydroxyprogesterone radioimmunoassays. Clinical Chemistry 1992 38 18301837. (https://doi.org/10.1093/clinchem/38.9.1830)

    • Search Google Scholar
    • Export Citation
  • 28

    Minutti CZ, Lacey JM, Magera MJ, Hahn SH, McCann M, Schulze A, Cheillan D, Dorche C, Chace DH & Lymp JF et al. Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2004 89 36873693. (https://doi.org/10.1210/jc.2003-032235)

    • Search Google Scholar
    • Export Citation
  • 29

    Schwarz E, Liu A, Randall H, Haslip C, Keune F, Murray M, Longo N, Pasquali M. Use of steroid profiling by UPLC-MS/MS as a second tier test in newborn screening for congenital adrenal hyperplasia: the Utah experience. Pediatric Research 2009 66 230235. (https://doi.org/10.1203/PDR.0b013e3181aa3777)

    • Search Google Scholar
    • Export Citation
  • 30

    Janzen N, Peter M, Sander S, Steuerwald U, Terhardt M, Holtkamp U, Sander J. Newborn screening for congenital adrenal hyperplasia: additional steroid profile using liquid chromatography-tandem mass spectrometry. Journal of Clinical Endocrinology and Metabolism 2007 92 25812589. (https://doi.org/10.1210/jc.2006-2890)

    • Search Google Scholar
    • Export Citation
  • 31

    Janzen N, Sander S, Terhardt M, Peter M, Sander J. Fast and direct quantification of adrenal steroids by tandem mass spectrometry in serum and dried blood spots. Journal of Chromatography: B, Analytical Technologies in the Biomedical and Life Sciences 2008 861 117122. (https://doi.org/10.1016/j.jchromb.2007.11.006)

    • Search Google Scholar
    • Export Citation
  • 32

    Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH & Oberfield SE et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2018 103 40434088. (https://doi.org/10.1210/jc.2018-01865)

    • Search Google Scholar
    • Export Citation
  • 33

    Miller WL. Congenital adrenal hyperplasia: time to replace 17OHP with 21-deoxycortisol. Hormone Research in Paediatrics 2019 91 416420. (https://doi.org/10.1159/000501396)

    • Search Google Scholar
    • Export Citation
  • 34

    Armengaud JB, Charkaluk ML, Trivin C, Tardy V, Breart G, Brauner R, Chalumeau M. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. Journal of Clinical Endocrinology and Metabolism 2009 94 28352840. (https://doi.org/10.1210/jc.2009-0314)

    • Search Google Scholar
    • Export Citation
  • 35

    Rege J, Turcu AF, Kasa-Vubu JZ, Lerario AM, Auchus GC, Auchus RJ, Smith JM, White PC, Rainey WE. 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. Journal of Clinical Endocrinology and Metabolism 2018 103 45894598. (https://doi.org/10.1210/jc.2018-00736)

    • Search Google Scholar
    • Export Citation
  • 36

    Storbeck KH, Bloem LM, Africander D, Schloms L, Swart P, Swart AC. 11beta-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? Molecular and Cellular Endocrinology 2013 377 135146. (https://doi.org/10.1016/j.mce.2013.07.006)

    • Search Google Scholar
    • Export Citation
  • 37

    Pretorius E, Africander DJ, Vlok M, Perkins MS, Quanson J, Storbeck KH. 11-Ketotestosterone and 11-Ketodihydrotestosterone in castration resistant prostate cancer: potent androgens which can no longer be ignored. PLoS ONE 2016 11 e0159867. (https://doi.org/10.1371/journal.pone.0159867)

    • Search Google Scholar
    • Export Citation
  • 38

    O'Reilly MW, Kempegowda P, Jenkinson C, Taylor AE, Quanson JL, Storbeck KH, Arlt W. 11-Oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2017 102 840848. (https://doi.org/10.1210/jc.2016-3285)

    • Search Google Scholar
    • Export Citation