The Value of Low Dose (1 μg) ACTH Stimulation Test in the Investigation of Non-Classic Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency

Summary

Non-classic congenital adrenal hyperplasia (NCAH) is a rare cause of hirsutism and it results from a defect in the biosynthetic pathway of cortisol and/or aldosterone. 250 μg ACTH test (SDT) is used in the diagnosis of this disease. Our aim was to investigate the responses of 11-deoxycortisol to 1μg ACTH (LDT) test in women with NCAH due to 11-beta hydroxylase (11-β OH) deficiency and to compare them with the values obtained after SDT in the patients and in the control subjects. Eleven patients with NCAH due to 11-β OH deficiency and 15 control subjects were involved in the study. The main complaint of the patients with NCAH was hirsutism and the diagnosis was made if the adrenal 11-deoxycortisol response to SDT exceed threefold the 95th percentile of controls. ACTH stimulation tests were carried out consecutively by using 250 μg and 1 μg intravenous ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0,30 and 60 min. Peak cortisol, 17-hydroxyprogesterone (17-OHP) and DHEAS responses were similar in LDT and SDT while 11-deoxycortisol responses to LDT (15.7 ± 1.8 nmol/L) were significantly (p < 0.005) lower than the results obtained after SDT (76.3 ± 21.4 nmol/L) in women with 11-β OH deficiency. Peak cortisol and 17-OHP responses to LDT in patients and control subjects were similar. Peak 11-deoxycortisol responses to LDT were significantly (p < 0.05) higher in NCAH patients (15.7 ± 1.8 nmol/L) than in the control subjects (6.5 ± 0.8 nmol/L). However, in LDT, all patients had peak 11-deoxycortisol level lower than threefold the 95th percentile (25.8 nmol/L) of controls. This study represents the first demonstration that LDT gives similar cortisol but not 11-deoxycortisol responses to SDT in patients with 11-β OH deficiency. This study also showed that LDT can not replace SDT in every clinical situation.

ACTH test and 11β-hydroxylase deficiency

References

• 1 Abdu T AM, Clayton R N. The low-dose synacthen test for the assessment of secondary adrenal insufficiency.  Curr Opin Endocrinol and Diabetes. 2000;  7 116-121
• 2 Akıncı A, Yordam N, Ersoy F, Uluşahin N, Ogˇuz H. The incidence of non-classical 21-hydroxylase deficiency in hirsute adolescent girls.  Gynecol Endocrinol. 1992;  6 99-106
• 3 Azziz R, Bradley E L, Pottre H D, Boots L R. Adrenal androgen excess in women: Lack of a role for 17-hydroxylase and 17,20-Lyase dysregulation.  J Clin Endocrinol Metab. 1995;  80 400-405
• 4 Azziz R, Dewailly D, Owerbach D. Nonclassic adrenal hyperplasia: current concepts.  J Clin Endocrinol Metab. 1994;  78 810-815
• 5 Azziz R, Rafi A, Smith B R, Bradley E R, Zacur H A. On the origin of the elevated 17-hydroxyprogesterone levels after adrenal stimulation in hyperandrogenism.  J Clin Endocrinol Metab. 1990;  70 431- 436
• 6 Castro-Magana M, Angulo M, Canas J A, Mazur B, Sarrantonio M, Vitollo P, Palekar A, Fuentes B, Lee A. Characterization of zona glomerulosa function in patients with classic and non-classic forms of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.  J Pediatr Endocrinol Metab. 1995;  8 19-25
• 7 Conn J J, Jacobs H S. The clinical management of hirsutism.  Eur J Endocrinol. 1997;  136 339-348
• 8 Crowley S, Hindmarsh P C, Holownia P, Honour J W, Brook C GD. The use of low doses of ACTH in the investigation of adrenal function in man.  J Endocrinol. 1991;  130 475-479
• 9 Daidoh H, Morita H, Mune T, Murayama M, Hanafusa J, Nih S H, Yasuda K. Responses of plasma adrenocortical steroids to low dose ACTH in normal subjects.  Clin Endocrinol. 1995;  43 311-315
• 10 Dickstein G, Shechner C, Nicholson W E, Rosner I, Shen-Orr Z, Adawi F, Lahav M. Adrenocorticotropin stimulation test: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test.  J Clin Endocrinol Metab. 1991;  72 773-778
• 11 Dökmetaş H S, Çolak R, Keleştimur F, Selçuklu A, Ünlühızarcı K, Bayram F. A comparison between the 1 μg adrenocorticotropin (ACTH) test, short ACTH (250 μg) test and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery.  J Clin Endocrinol Metab. 2000;  85 3713-3719
• 12 Hasinski S. Assessment of adrenal glucocorticoid function.  Postgrad Med. 1998;  104 61-71
• 13 Hatch R, Rosenfield R L, Kim M H, Tredway D. Hirsutism: implications, etiology and management.  Am J Obstet Gynecol. 1981;  140 815-830
• 14 Keleştimur F. Hirsutism of adrenal origin in adolescents: consequences in adults.  J Ped Endocrinol Metab. 2001;  14 1309-1315
• 15 Keleştimur F, Göktaş Z, Gülmez İ, Ünlühızarcı K, Bayram F, Özesmi M, Güven M, Tutuş A. Low dose (1 μg) adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitary-adrenal axis in patients with active pulmonary tuberculosis.  J Endocrinol Invest. 2000;  23 235-239
• 16 Keleştimur F, Şahin Y, Ayata D, Tutuş A. The prevalence of non-classic adrenal hyperplasia due to 11β-hydroxylase deficiency among hirsute women in a Turkish population.  Clin Endocrinol. 1996;  45 381-384
• 17 Kırnap M, Çolak R, Eser C, Özsoy O, Tutuş A, Keleştimur F. A comparison between low dose (1 μg), standard-dose (250 μg) ACTH stimulation tests and insulin tolerance test (ITT) in the evaluation of hypothalamo-pituitary-adrenal (HPA) axis in primary fibromyalgia syndrome.  Clin Endocrinol. 2001;  55 455-459
• 18 Laureti S, Arvat E, Candeloro P, Di Vito L, Ghigo E, Santesanio F, Falorni A. Low dose (1 μg) ACTH test in the evaluation of adrenal dysfunction in pre-clinical Addison's disease.  Clin Endocrinol. 2000;  53 107-115
• 19 Mayenknecht J, Diederich S, Bahr V, Plöckinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease.  J Clin Endocrinol Metab. 1998;  83 1558-1562
• 20 Phillipov G. Effect of hypercortisolism and ACTH on the metabolism of cortisol.  Exp Clin Endocrinol Diabetes. 1998;  106 57-60
• 21 Rosler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase deficiency) among Jews from Morocco.  Am J Med Genet. 1992;  42 827-834
• 22 Şahin Y, Keleştimur F. The frequency of late-onset 21-hydroxylase and 11β-hydroxylase deficiency in women with polycystic ovary syndrome.  Eur J Endocrinol. 1997;  137 670-674
• 23 Ünlühızarcı K, Bayram F, Güven M, Kula M, Çolak R, Keleştimur F. Cortisol responses to low (1 μg) and standard (250 μg) dose ACTH stimulation test in patients with primary hypothyroidism.  Clin Endocrinol. 2001;  54 700-702
• 24 White P C. Steroid 11β-hydroxylase deficiency and related disorders.  Endocrinol Metab Clin North Am. 2001;  30 61-79
• 25 White P C, Speiser P W. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Endocrine Reviews. 2000;  21 245-291