11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency

Adina F Turcu, Ashwini Mallappa, Meredith S Elman, Nilo A Avila, Jamie Marko, Hamsini Rao, Alexander Tsodikov, Richard J Auchus, Deborah P Merke, Adina F Turcu, Ashwini Mallappa, Meredith S Elman, Nilo A Avila, Jamie Marko, Hamsini Rao, Alexander Tsodikov, Richard J Auchus, Deborah P Merke

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00250159.

Copyright © 2017 Endocrine Society

Figures

Figure 1.
Figure 1.
Interhormonal correlation matrix (lower panel shows P values). AdiolS, androst-5-ene-3β,17β-diol-3-sulfate;16/17OHP, DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate.
Figure 2.
Figure 2.
Correlations between 11ketoT and T in boys in Tanner stages 1 and 2 (upper graph), males in Tanner stage 5 (middle graph), and females of all ages (lower graph).

References

    1. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349(8):776–788.
    1. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125–2136.
    1. Reisch N, Scherr M, Flade L, Bidlingmaier M, Schwarz HP, Müller-Lisse U, Reincke M, Quinkler M, Beuschlein F. Total adrenal volume but not testicular adrenal rest tumor volume is associated with hormonal control in patients with 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2010;95(5):2065–2072.
    1. Jaresch S, Kornely E, Kley HK, Schlaghecke R. Adrenal incidentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1992;74(3):685–689.
    1. Nermoen I, Rørvik J, Holmedal SH, Hykkerud DL, Fougner KJ, Svartberg J, Husebye ES, Løvås K. High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 2011;75(6):753–759.
    1. Stikkelbroeck NM, Otten BJ, Pasic A, Jager GJ, Sweep CG, Noordam K, Hermus AR. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86(12):5721–5728.
    1. Claahsen-van der Grinten HL, Sweep FC, Blickman JG, Hermus AR, Otten BJ. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol. 2007;157(3):339–344.
    1. Falhammar H, Nyström HF, Ekström U, Granberg S, Wedell A, Thorén M. Fertility, sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia. Eur J Endocrinol. 2012;166(3):441–449.
    1. Bouvattier C, Esterle L, Renoult-Pierre P, de la Perrière AB, Illouz F, Kerlan V, Pascal-Vigneron V, Drui D, Christin-Maitre S, Galland F, Brue T, Reznik Y, Schillo F, Pinsard D, Piguel X, Chabrier G, Decoudier B, Emy P, Tauveron I, Raffin-Sanson ML, Bertherat J, Kuhn JM, Caron P, Cartigny M, Chabre O, Dewailly D, Morel Y, Touraine P, Tardy-Guidollet V, Young J. Clinical outcome, hormonal status, gonadotrope axis, and testicular function in 219 adult men born with classic 21-hydroxylase deficiency. A French national survey. J Clin Endocrinol Metab. 2015;100(6):2303–2313.
    1. Delfino M, Elia J, Imbrogno N, Argese N, Mazzilli R, Toscano V, Mazzilli F. Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. J Ultrasound Med. 2012;31(3):383–388.
    1. Zaarour MG, Atallah DM, Trak-Smayra VE, Halaby GH. Bilateral ovary adrenal rest tumor in a congenital adrenal hyperplasia following adrenalectomy. Endocr Pract. 2014;20(4):e69–e74.
    1. Tiosano D, Vlodavsky E, Filmar S, Weiner Z, Goldsher D, Bar-Shalom R. Ovarian adrenal rest tumor in a congenital adrenal hyperplasia patient with adrenocorticotropin hypersecretion following adrenalectomy. Horm Res Paediatr. 2010;74(3):223–228.
    1. Stikkelbroeck NM, Hermus AR, Schouten D, Suliman HM, Jager GJ, Braat DD, Otten BJ. Prevalence of ovarian adrenal rest tumours and polycystic ovaries in females with congenital adrenal hyperplasia: results of ultrasonography and MR imaging. Eur Radiol. 2004;14(10):1802–1806.
    1. Crocker MK, Barak S, Millo CM, Beall SA, Niyyati M, Chang R, Avila NA, Van Ryzin C, Segars J, Quezado M, Merke DP. Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012;97(11):E2084–E2089.
    1. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC; Endocrine Society . Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133–4160.
    1. 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. Eur J Endocrinol. 2016;174(5):601–609.
    1. 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. J Clin Endocrinol Metab. 2015;100(6):2283–2290.
    1. Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA. The urinary steroidome of treated children with classic 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2017;165(Pt B):396–406.
    1. Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM, Merke DP. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012;97(12):4429–4438.
    1. Weise M, Eisenhofer G, Merke DP. Pubertal and gender-related changes in the sympathoadrenal system in healthy children. J Clin Endocrinol Metab. 2002;87(11):5038–5043.
    1. Nella AA, Mallappa A, Perritt AF, Gounden V, Kumar P, Sinaii N, Daley LA, Ling A, Liu CY, Soldin SJ, Merke DP. A phase 2 study of continuous subcutaneous hydrocortisone infusion in adults with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2016;101(12):4690–4698.
    1. Peng HM, Im SC, Pearl NM, Turcu AF, Rege J, Waskell L, Auchus RJ. Cytochrome b5 activates the 17,20-lyase activity of human cytochrome P450 17A1 by increasing the coupling of NADPH consumption to androgen production. Biochemistry. 2016;55(31):4356–4365.
    1. Greulich WWPS. Radiographic Skeletal Development of the Hand and Wrist. Stanford: Stanford University Press; 1985.
    1. Chrysostomou PP, Lodish MB, Turkbey EB, Papadakis GZ, Stratakis CA. Use of 3-dimensional volumetric modeling of adrenal gland size in patients with primary pigmented nodular adrenocortical disease. Horm Metab Res. 2016;48(4):242–246.
    1. Geraghty EM, Boone JM, McGahan JP, Jain K. Normal organ volume assessment from abdominal CT. Abdom Imaging. 2004;29(4):482–490.
    1. 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. Clin Endocrinol (Oxf). 2010;73(6):700–706.
    1. Milewicz A, Vecsei P, Gruszka S, Szymczak J, Bednarek-Tupikowska G, Grabiński M. Diagnosis of congenital adrenal hyperplasia based on plasma 21-deoxycortisol level determined with a specific radioimmunoassay. Mater Med Pol. 1984;16(2-4):95–98.
    1. Rege J, Nakamura Y, Wang T, Merchen TD, Sasano H, Rainey WE. Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis. J Clin Endocrinol Metab. 2014;99(3):E518–E527.
    1. Kamrath C, Hochberg Z, Hartmann MF, Remer T, Wudy SA. Increased activation of the alternative “backdoor” pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis. J Clin Endocrinol Metab. 2012;97(3):E367–E375.
    1. Claahsen-van der Grinten HL, Otten BJ, Sweep FC, Span PN, Ross HA, Meuleman EJ, Hermus AR. Testicular tumors in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency show functional features of adrenocortical tissue. J Clin Endocrinol Metab. 2007;92(9):3674–3680.
    1. Bercovici JP, Fiet J, Gibault L, Volant A, Abalain JH, Floch HH, Sonnet E, Fournier G. Testicular adrenal rest tumours in salt wasting congenital adrenal hyperplasia (in vivo and in vitro studies). J Steroid Biochem Mol Biol. 2005;93(1):67–72.
    1. Franco-Saenz R, Antonipillai I, Tan SY, McCorquodale M, Kropp K, Mulrow PJ. Cortisol production by testicular tumors in a patient with congenital adrenal hyperplasia (21-hydroxylase deficiency). J Clin Endocrinol Metab. 1981;53(1):85–90.
    1. Clark RV, Albertson BD, Munabi A, Cassorla F, Aguilera G, Warren DW, Sherins RJ, Loriaux DL. Steroidogenic enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1990;70(5):1408–1413.
    1. Stikkelbroeck NM, Hermus AR, Suliman HM, Jager GJ, Otten BJ. Asymptomatic testicular adrenal rest tumours in adolescent and adult males with congenital adrenal hyperplasia: basal and follow-up investigation after 2.6 years. J Pediatr Endocrinol Metab. 2004;17(4):645–653.
    1. Claahsen-van der Grinten HL, Otten BJ, Sweep FC, Hermus AR. Repeated successful induction of fertility after replacing hydrocortisone with dexamethasone in a patient with congenital adrenal hyperplasia and testicular adrenal rest tumors. Fertil Steril. 2007;88(3):705e5–8.
    1. Hamwi GJ, Gwinup G, Mostow JH, Besch PK. Activation of testicular adrenal rest tissue by prolonged excessive ACTH production. J Clin Endocrinol Metab. 1963;23:861–869.
    1. Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86(7):3070–3078.
    1. Walker BR, Skoog SJ, Winslow BH, Canning DA, Tank ES. Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome. J Urol. 1997;157(4):1460–1463.
    1. Claahsen-van der Grinten HL, Otten BJ, Stikkelbroeck MM, Sweep FC, Hermus AR. Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009;23(2):209–220.
    1. Smeets EE, Span PN, van Herwaarden AE, Wevers RA, Hermus AR, Sweep FC, Claahsen-van der Grinten HL. Molecular characterization of testicular adrenal rest tumors in congenital adrenal hyperplasia: lesions with both adrenocortical and Leydig cell features. J Clin Endocrinol Metab. 2015;100(3):E524–E530.
    1. Knudsen JL, Savage A, Mobb GE. The testicular ‘tumour’ of adrenogenital syndrome--a persistent diagnostic pitfall. Histopathology. 1991;19(5):468–470.
    1. Reisch N, Rottenkolber M, Greifenstein A, Krone N, Schmidt H, Reincke M, Schwarz HP, Beuschlein F. Testicular adrenal rest tumors develop independently of long-term disease control: a longitudinal analysis of 50 adult men with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2013;98(11):E1820–E1826.
    1. Shanklin DR, Richardson AP Jr, Rothstein G. Testicular hilar nodules in adrenogenital syndrome. The nature of the nodules. Am J Dis Child. 1963;106:243–250.
    1. Bouman A, Hulsbergen-van de Kaa C, Claahsen-van der Grinten HL. Prevalence of testicular adrenal rest tissue in neonates. Horm Res Paediatr. 2011;75(2):90–93.
    1. Van der Kamp HJ, Otten BJ, Buitenweg N, De Muinck Keizer-Schrama SM, Oostdijk W, Jansen M, Delemarre-de Waal HA, Vulsma T, Wit JM. Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency patients. Arch Dis Child. 2002;87(2):139–144.
    1. Hargitai G, Sólyom J, Battelino T, Lebl J, Pribilincová Z, Hauspie R, Kovács J, Waldhauser F, Frisch H; MEWPE-CAH Study Group . Growth patterns and final height in congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency. Results of a multicenter study. Horm Res. 2001;55(4):161–171.
    1. Cordeiro GV, Silva IN, Goulart EM, Chagas AJ, Kater CE. Final height in congenital adrenal hyperplasia: the dilemma of hypercortisolism versus hyperandrogenism. Arq Bras Endocrinol Metabol. 2013;57(2):126–131.
    1. Muthusamy K, Elamin MB, Smushkin G, Murad MH, Lampropulos JF, Elamin KB, Abu Elnour NO, Gallegos-Orozco JF, Fatourechi MM, Agrwal N, Lane MA, Albuquerque FN, Erwin PJ, Montori VM. Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2010;95(9):4161–4172.
    1. Imamichi Y, Yuhki KI, Orisaka M, Kitano T, Mukai K, Ushikubi F, Taniguchi T, Umezawa A, Miyamoto K, Yazawa T. 11-ketotestosterone is a major androgen produced in human gonads. J Clin Endocrinol Metab. 2016;101(10):3582–3591.
    1. Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy MR, Layman LC, Honma S, Sasano H, Rainey WE. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab. 2013;98(3):1182–1188.
    1. Campana C, Rege J, Turcu A, Pezzi V, Gomez-Sanchez CE, Robins DM, et al. . Development of a novel cell based androgen screening model. J Steroid Biochem Mol Biol. 2016;156:17–22.
    1. Storbeck KH, Bloem LM, Africander D, Schloms L, Swart P, Swart AC. 11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? Mol Cell Endocrinol. 2013;377(1-2):135–146.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren