Late consequences of classic congenital adrenal hyperplasia and its long-term poor control in men (case report and literature review)

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of the adrenal cortex characterized by impairment of cortisol biosynthesis (with possible impairment of aldosterone biosynthesis) and excessive pituitary ACTH release, which promotes oversecretion of intact pathways products: 17-hydroxyprogesterone (17OHP), progesterone, and adrenal androgens – androstendione and testosterone. 21-hydroxylase deficiency, being the most common cause of congenital adrenal hyperplasia is a chronic disorder, that requires life-long glucocorticoid treatment, that aims both to replace cortisol and prevent ACTH-driven androgen excess. Nevertheless, reaching the optimal glucocorticoid dose is challenging because currently available glucocorticoid formulations cannot replicate the physiological circadian rhythm of cortisol secretion. The difficulties in striking the balance between uneffective normalizing of ACTH-level and excess glucocorticoid exposure leads to different abnormalities, that starts to develop at first months of life and progress, frequently gaining especial clinical meaning in adult age. In the present clinical case we introduce 35 years old male patient with salt-wasting form of 21-hydroxylase deficiency, which had either complications considered to progress due to insufficient glucocorticoid therapy, and some metabolic abnormalities, associated with supraphysiological doses of glucocorticoids.

1. Мельниченко Г.А., Трошина Е.А., Молашенко Н.В., и др. Клинические рекомендации Российской Ассоциации эндокринологов по диагностике и лечебно-профилактическим мероприятиям при врожденной дисфункции коры надпочечников у пациентов во взрослом возрасте. // Consilium Medicum. – 2016. – Т.18. – № 4. – С. 8–19. [Mel’nichenko GA, Troshina EA, Molashenko NV, et al. Russian Association of Endocrinologists clinical practice guidelinesfor diagnosis, treatment and preventive measures in congenital adrenal hyperplasia due to 21-hydroxylase deficiency patients in adulthood. Consilium Medicum. 2016;18(4):8-19. (In Russ).]

2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. DOI:10.1210/jc.2018-01865

3. Arlt W, Willis DS, Wild SH, et al. Health Status of Adults with Congenital Adrenal Hyperplasia: A Cohort Study of 203 Patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. DOI:10.1210/jc.2010-0917

4. Witchel SF. Congenital Adrenal Hyperplasia. J Pediatr Adolesc Gynecol. 2017;30(5):520-534. DOI:10.1016/j.jpag.2017.04.001

5. Tusie-Luna MT, Traktman P, White PC. Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem. 1990;265(34):20916-20922.

6. Tardy V, Menassa R, Sulmont V, et al. Phenotype-Genotype Correlations of 13 Rare CYP21A2 Mutations Detected in 46 Patients Affected with 21-Hydroxylase Deficiency and in One Carrier. J Clin Endocrinol Metab. 2010;95(3):1288-1300. DOI:10.1210/jc.2009-1202

7. Thil’en A, Nordenström A, Hagenfeldt L, von Döbeln U, Guthenberg C, Larsson A. Benefits of neonatal screening for congenital adrenal hyperplasia (21-hydroxylase deficiency) in Sweden. Pediatrics. 1998;101(4):E11. doi: 10.1542/peds.101.4.e11

8. Pang S, Wallace MA, Hofman L, et al. Worldwide Experience in Newborn Screening for Classical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. J Urol. 1988;140(6):1606. DOI:10.1016/S0022-5347(17)42164-1

9. Speiser PW, Dupont BO, Rubinstein P, Piazza A, Kastelan A, New MI. High Frequency of Nonclassical Steroid 21-Hydroxylase Deficiency. Obstet Gynecol Surv. 1986;41(4). DOI:10.1097/00006254-198604000-00017

10. Verma S, Vanryzin C, Sinaii N, et al. A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2010;72(4):441-447. DOI:10.1111/j.1365-2265.2009.03636.x

11. Debono M, Ross RJ, Newell-Price J. Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy. Eur J Endocrinol. 2009;160(5):719-729. DOI:10.1530/EJE-08-0874

12. Сазонова А.И., Трошина Е.А., Молашенко Н.В. Метаболические нарушения у взрослых пациентов с врожденной дисфункцией коры надпочечников // Проблемы эндокринологии. — 2012. — Т. 58, № 5. — С. 3-9. [Sazonova A.I., Troshina E.A., Molashenko N.V. Metabolic disorders in the adult patients presenting with congenital adrenal hyperplasia. Problems of endocrinology. 2012;58(5):3-9. (In Russ).]

13. Reisch N, Scherr M, Flade L, et al. 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. DOI:10.1210/jc.2009-1929

14. Chen W, Xu Z, Sullivan A, et al. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem. 2012;58(2):421-430. DOI:10.1373/clinchem.2011.174037

15. Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A. 1986;83(9):2841-2845. DOI:10.1073/pnas.83.9.2841

16. White PC, Speiser PW. Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency 1. Endocr Rev. 2000;21(3):245-291. DOI:10.1210/edrv.21.3.0398

17. New MI, Abraham M, Gonzalez B, et al. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 2013;110(7):2611-2616. DOI:10.1073/pnas.1300057110

18. Griffiths KD, Anderson JM, Rudd BT, Virdi NK, Holder G, Rayner PH. Plasma renin activity in the management of congenital adrenal hyperplasia. Arch Dis Child. 1984;59(4):360 LP-365. DOI:10.1136/adc.59.4.360

19. Bonfig W, Dalla Pozza SB, Schmidt H, Pagel P, Knorr D, Schwarz HP. Hydrocortisone Dosing during Puberty in Patients with Classical Congenital Adrenal Hyperplasia: An Evidence-Based Recommendation. J Clin Endocrinol Metab. 2009;94(10):3882-3888. DOI:10.1210/jc.2009-0942

20. Han TS, Conway GS, Willis DS, et al. Relationship Between Final Height and Health Outcomes in Adults With Congenital Adrenal Hyperplasia: United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). J Clin Endocrinol Metab. 2014;99(8):E1547-E1555. DOI:10.1210/jc.2014-1486

21. El-Maouche D, Collier S, Prasad M, Reynolds JC, Merke DP. Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 2015;82(3):330-337. DOI:10.1111/cen.12507

22. Falhammar H, Filipsson Nyström H, Wedell A, Thorén M. Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol. 2011;164(2):285-293. DOI:10.1530/EJE-10-0877

23. Debono M, Ghobadi C, Rostami-Hodjegan A, et al. Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles. J Clin Endocrinol Metab. 2009;94(5):1548-1554. DOI:10.1210/jc.2008-2380

24. Trapp CM, Speiser PW, Oberfield SE. Congenital adrenal hyperplasia: an update in children. Curr Opin Endocrinol Diabetes Obes. 2011;18(3):166-170. DOI:10.1097/MED.0b013e328346938c

25. Merke DP. Approach to the Adult with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2008;93(3):653-660. DOI:10.1210/jc.2007-2417

26. Bonfig W, Bechtold S, Schmidt H, Knorr D, Schwarz HP. Reduced Final Height Outcome in Congenital Adrenal Hyperplasia under Prednisone Treatment: Deceleration of Growth Velocity during Puberty. J Clin Endocrinol Metab. 2007;92(5):1635-1639. DOI:10.1210/jc.2006-2109

27. Falhammar H, Filipsson H, Holmdahl G, et al. Metabolic Profile and Body Composition in Adult Women with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2007;92(1):110-116. DOI:10.1210/jc.2006-1350

28. Han TS, Stimson RH, Rees DA, et al. Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2013;78(2):197-203. DOI:10.1111/cen.12045

29. Plat L, Leproult R, L’Hermite-Baleriaux M, et al. Metabolic Effects of Short-Term Elevations of Plasma Cortisol Are More Pronounced in the Evening Than in the Morning. J Clin Endocrinol Metab. 1999;84(9):3082-3092. DOI:10.1210/jcem.84.9.5978

30. Elbelt U, Hahner S, Allolio B. Altered insulin requirement in patients with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy. Eur J Endocrinol. 2009;160(6):919-924. DOI:10.1530/EJE-08-1003

31. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435-1439. DOI:10.1016/S0140-6736(99)01376-8

32. Hagenfeldt K, Janson PO, Holmdahl G, et al. Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod. 2008;23(7):1607-1613. DOI:10.1093/humrep/den118

33. Kim MS, Ryabets-Lienhard A, Bali B, et al. Decreased adrenomedullary function in infants with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2014;99(8):E1597-601. DOI:10.1210/jc.2014-1274

34. Merke DP, Chrousos GP, Eisenhofer G, et al. Adrenomedullary Dysplasia and Hypofunction in Patients with Classic 21-Hydroxylase Deficiency. N Engl J Med. 2000;343(19):1362-1368. DOI:10.1056/NEJM200011093431903

35. Falhammar H, Filipsson H, Holmdahl G, et al. Increased liver enzymes in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr J. 2009;56(4):601-608. DOI:10.1507/endocrj.K08E-312

36. Ruttmann E, Brant LJ, Concin H, Diem G, Rapp K, Ulmer H. γ-Glutamyltransferase as a Risk Factor for Cardiovascular Disease Mortality. Circulation. 2005;112(14):2130-2137. DOI:10.1161/CIRCULATIONAHA.105.552547

37. Mnif MF, Kamoun M, Mnif F, et al. Long-Term Outcome of Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency. Am J Med Sci. 2012;344(5):363-373. DOI:10.1097/MAJ.0b013e31824369e4

38. Muthusamy K, Elamin MB, Smushkin G, et al. Adult Height in Patients with Congenital Adrenal Hyperplasia: A Systematic Review and Metaanalysis. J Clin Endocrinol Metab. 2010;95(9):4161-4172. DOI:10.1210/jc.2009-2616

39. 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. doi: 10.1210/jcem.86.7.7668

40. Finkielstain GP, Kim MS, Sinaii N, et al. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2012;97(12):4429-4438. DOI:10.1210/jc.2012-2102

41. Claahsen-van der Grinten HL, Noordam K, Borm GF, Otten BJ. Absence of Increased Height Velocity in the First Year of Life in Untreated Children with Simple Virilizing Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2006;91(4):1205-1209. DOI:10.1210/jc.2005-1701

42. Barker DJ, Fall CH. Fetal and infant origins of cardiovascular disease. Arch Dis Child. 1993;68(6):797-799. DOI:10.1136/adc.68.6.797

43. Falhammar H, Filipsson H, Holmdahl G, et al. Fractures and Bone Mineral Density in Adult Women with 21-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2007;92(12):4643-4649. DOI:10.1210/jc.2007-0744

44. Jääskeläinen J, Voutilainen R. Bone mineral density in relation to glucocorticoid substitution therapy in adult patients with 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 1996;45(6):707-713. DOI:10.1046/j.1365-2265.1996.8620871.x

45. Hagenfeldt K, Martin Ritzén E, Ringertz H, Helleday J, Carlström K. Bone mass and body composition of adult women with congenital virilizing 21-hydroxylase deficiency after glucocorticoid treatment since infancy. Eur J Endocrinol. 2000;143(5):667-671. DOI:10.1530/eje.0.1430667

46. King JA, Wisniewski AB, Bankowski BJ, Carson KA, Zacur HA, Migeon CJ. Long-Term Corticosteroid Replacement and Bone Mineral Density in Adult Women with Classical Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2006;91(3):865-869. DOI:10.1210/jc.2005-0745

47. Дзеранова Л.К., Тюльпаков А.Н., Пигарова Е.А., Рубцов П.М., и др. «Новая мутация в гене CYP17: описание клинического случая». Проблемы эндокринологии. 2006. - Т. 52. - № 6. - С. 41-45. [Dzeranova L.K., Tyul’pakov A.N., Pigarova E.A., Rubtsov P.M., et al. «Novaya mutatsiya v gene CYP17: opisanie klinicheskogo sluchaya». Problems of endocrinology. 2006;52(6):41-45. (in Russ).]

48. Dardis A, Saraco N, Rivarola MA, Belgorosky A. Decrease in the Expression of the 3β-Hydroxysteroid Dehydrogenase Gene in Human Adrenal Tissue during Prepuberty and Early Puberty: Implications for the Mechanism of Adrenarche. Pediatr Res. 1999;45(3):384-388. DOI:10.1203/00006450-199903000-00016

49. Topor LS, Asai M, Dunn J, Majzoub JA. Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2. J Clin Endocrinol Metab. 2011;96(1):E31-9. DOI:10.1210/jc.2010-0692

50. Verma S, Green-Golan L, VanRyzin C, et al. Adrenomedullary Function in Patients with Nonclassic Congenital Adrenal Hyperplasia. Horm Metab Res. 2010;42(08):607-612. DOI:10.1055/s-0030-1253385

51. Sellers EP, MacGillivray MH. Blunted adrenarche in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Res. 1995;21(3):537-544. DOI:10.1080/07435809509030471

52. Völkl TMK, Öhl L, Rauh M, Schöfl C, Dörr HG. Adrenarche and Puberty in Children with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. Horm Res Paediatr. 2011;76(6):400-410. DOI:10.1159/000333696

53. Helleday J, Siwers B, Ritzén EM, Carlström K. Subnormal androgen and elevated progesterone levels in women treated for congenital virilizing 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1993;76(4):933-936. DOI:10.1210/jcem.76.4.8473408

54. Brunelli VL, Chiumello G, David M, Forest MG. Adrenarche does not occur in treated patients with congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 1995;42(5):461-466. DOI:10.1111/j.1365-2265.1995.tb02663.x

55. Chakhtoura Z, Bachelot A, Samara-Boustani D, et al. Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency. Eur J Endocrinol. 2008;158(6):879-887. DOI:10.1530/EJE-07-0887

56. Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Metab. 2006;291(5):E965-E973. DOI:10.1152/ajpendo.00070.2006

57. Helseth A, Siegal GP, Haug E, Bautch VL. Transgenic mice that develop pituitary tumors. A model for Cushing’s disease. Am J Pathol. 1992;140(5):1071-1080.

58. DAHL E V, BAHN RC. Aberrant adrenal contical tissue near the testis in human infants. Am J Pathol. 1962;40:587-598.

59. 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. DOI:10.1159/000316531

60. Avila NA, Shawker TS, Jones J V, Cutler GB, Merke DP. Testicular adrenal rest tissue in congenital adrenal hyperplasia: serial sonographic and clinical findings. Am J Roentgenol. 1999;172(5):1235-1238. DOI:10.2214/ajr.172.5.10227495

61. Willi U, Atares M, Prader A, Zachmann M. Testicular adrenal-like tissue (TALT) in congenital adrenal hyperplasia: detection by ultrasonography. Pediatr Radiol. 1991;21(4):284-287. DOI:10.1007/bf02018626

62. Stikkelbroeck NMML, Suliman HM, Otten BJ, Hermus ARMM, Blickman JG, Jager GJ. Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features. Eur Radiol. 2003;13(7):1597-1603. DOI:10.1007/s00330-002-1786-3

63. CLARK R V., ALBERTSON BD, MUNABI A, et al. 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. DOI:10.1210/jcem-70-5-1408

64. Rohayem J, Tüttelmann F, Mallidis C, Nieschlag E, Kliesch S, Zitzmann M. Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia. Eur J Endocrinol. 2014;170(4):K11-K17. DOI:10.1530/EJE-13-0449

65. Rutgers JL, Young RH, Scully RE. The Testicular “Tumor” of the Adrenogenital Syndrome. Am J Surg Pathol. 1988;12(7):503-513. DOI:10.1097/00000478-198807000-00001

66. Cutfield RG, Bateman JM, Odell WD. Infertility caused by bilateral testicular masses secondary to congenital adrenal hyperplasia (21-hydroxylase deficiency). Fertil Steril. 1983;40(6):809-814. DOI:10.1016/S0015-0282(16)47485-6

67. Cunnah D, Perry L, Dacie JA, Grant DB, Lowe DG, Savage MO, et al. Bilateral Testicular Tumours In Congenital Adrenal Hyperplasia: A Continuing Diagnostic And Therapeutic Dilemma. Clin Endocrinol (Oxf). 1989;30(2):141-147. DOI:10.1111/j.1365-2265.1989.tb03735.x

68. 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(9):861-869. DOI:10.1210/jcem-23-9-861

69. Claahsen-van der Grinten HL, Otten BJ, Sweep FCGJ, et al. 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. DOI:10.1210/jc.2007-0337

70. Stikkelbroeck NMML, Otten BJ, Pasic A, et al. 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. DOI:10.1210/jcem.86.12.8090

71. Reisch N, Flade L, Scherr M, et al. High Prevalence of Reduced Fecundity in Men with Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2009;94(5):1665-1670. DOI:10.1210/jc.2008-1414

72. Claahsen-van der Grinten HL, Hermus ARMM, Otten BJ. Testicular adrenal rest tumours in congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2009;2009:624823. DOI:10.1155/2009/624823

73. 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. DOI:10.1016/s0022-5347(01)65023-7

74. Blumberg-Tick J, Boudou P, Nahoul K, Schaison G. Testicular Tumors in Congenital Adrenal Hyperplasia: Steroid Measurements from Adrenal and Spermatic Veins. J Clin Endocrinol Metab. 1991;73(5):1129-1133. DOI:10.1210/jcem-73-5-1129

75. Urban MD, Lee PA, Migeon CJ. Adult Height and Fertility in Men with Congenital Virilizing Adrenal Hyperplasia. N Engl J Med. 1978;299(25):1392-1396. DOI:10.1056/NEJM197812212992505

76. Augarten A, Weissenberg R, Pariente C, Sack J. Reversible male infertility in late onset congenital adrenal hyperplasia. J Endocrinol Invest. 1991;14(3):237-240. DOI:10.1007/BF03346799

77. Bonaccorsi AC, Adler I, Figueiredo JG. Male infertility due to congenital adrenal hyperplasia: testicular biopsy findings, hormonal evaluation, and therapeutic results in three patients. Fertil Steril. 1987;47(4):664-670. DOI:10.1016/s0015-0282(16)59119-5

78. Winters SJ, Troen P. Evidence for a Role of Endogenous Estrogen in the Hypothalamic Control of Gonadotropin Secretion in Men*. J Clin Endocrinol Metab. 1985;61(5):842-845. DOI:10.1210/jcem-61-5-842

79. Pitteloud N, Dwyer AA, DeCruz S, et al. Inhibition of Luteinizing Hormone Secretion by Testosterone in Men Requires Aromatization for Its Pituitary But Not Its Hypothalamic Effects: Evidence from the Tandem Study of Normal and Gonadotropin-Releasing Hormone-Deficient Men. J Clin Endocrinol Metab. 2008;93(3):784-791. DOI:10.1210/jc.2007-2156

80. Balestrieri A, Zirilli L, Madeo B, et al. 21-Hydroxylase Deficiency and Klinefelter Syndrome in an Adult Man: Striking a Balance Between Androgen Excess and Insufficiency. J Androl. 2008;29(6):605-609. DOI:10.2164/jandrol.107.004648

81. Claahsen-van der Grinten HL, Otten BJ, Takahashi S, et al. Testicular Adrenal Rest Tumors in Adult Males with Congenital Adrenal Hyperplasia: Evaluation of Pituitary-Gonadal Function before and after Successful Testis-Sparing Surgery in Eight Patients. J Clin Endocrinol Metab. 2007;92(2):612-615. DOI:10.1210/jc.2006-1311

82. Marchini GS, Cocuzza M, Pagani R, Torricelli FC, Hallak J, Srougi M. Testicular adrenal rest tumor in infertile man with congenital adrenal hyperplasia: case report and literature review. Sao Paulo Med J. 2011;129(5):346-351. DOI:10.1590/s1516-31802011000500010

83. Aycan Z, Bas VN, Cetinkaya S, Yilmaz Agladioglu S, Tiryaki T. Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2013;78(5):667-672. DOI:10.1111/cen.12033

84. Padrón RS, Wischusen J, Hudson B, Burger HG, De Kretser DM. Prolonged Biphasic Response of Plasma Testosterone to Single Intramuscular Injections of Human Chorionic Gonadotropin*. J Clin Endocrinol Metab. 1980;50(6):1100-1104. DOI:10.1210/jcem-50-6-1100

85. Карева М.А., Чугунов И.С. Федеральные клинические рекомендации - протоколы по ведению пациентов с врожденной дисфункцией коры надпочечников в детском возрасте. // Проблемы эндокринологии. - 2014. - Т. 60. - №2 - С. 42-50. [Kareva MA, Chugunov IS. Federal clinical practice guidelines on the management of the patients presenting with congenital adrenal hyperplasia. Problems of endocrinology. 2014;60(2):42. (In Russ.)]. DOI:10.14341/probl201460242-50.

86. Nakayama Y, Matayoshi N, Akiyama M, et al. Giant Adrenal Myelolipoma in a Patient without Endocrine Disorder: A Case Report and a Review of the Literature. Case Rep Surg. 2018;2018:4854368. DOI:10.1155/2018/4854368

87. Nermoen I, Rørvik J, Holmedal SH, et al. 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. DOI:10.1111/j.1365-2265.2011.04151.x

88. Meyer A, Behrend M. Presentation and therapy of myelolipoma. Int J Urol. 2005;12(3):239-243. DOI:10.1111/j.1442-2042.2005.01034.x

89. Lam KY, Lo CY. Adrenal lipomatous tumours: a 30 year clinicopathological experience at a single institution. J Clin Pathol. 2001;54(9):707-712. DOI:10.1136/jcp.54.9.707

90. Iorio B, Gravante G, Pietrasanta D, et al. [Description of a case of giant adrenal myelolipoma and survey of the literature]. Minerva Chir. 2003;58(4):595-600.

91. Daneshmand S, Quek ML. Adrenal myelolipoma: diagnosis and management. Urol J. 2006;3(2):71-74.

92. Kenney PJ, Wagner BJ, Rao P, Heffess CS. Myelolipoma: CT and pathologic features. Radiology. 1998;208(1):87-95. DOI:10.1148/radiology.208.1.9646797

93. Tyritzis SI, Adamakis I, Migdalis V, Vlachodimitropoulos D, Constantinides CA. Giant adrenal myelolipoma, a rare urological issue with increasing incidence: a case report. Cases J. 2009;2:8863. DOI:10.4076/1757-1626-2-8863