Monitoring Medical Treatment in Adolescents and Young Adults with Congenital Adrenal Hyperplasia: Utility of Salivary 17α-Hydroxyprogesterone Day Profiles

Abstract

Introduction: Efficacy of medical treatment in patients with 21-hydroxylase deficiency is usually monitored by measurement of 17α-hydroxyprogesterone (17OHP). Saliva instead of serum sampling offers some advantages, such as painless handling and measurement of the bioactive free hormone. This study evaluated the diagnostic validity of salivary 17OHP for monitoring medical treatment, with samples collected at 7 time points throughout a day.

Subjects and Methods: Day profiles were performed in 23 adolescents and young adults with 21-hydroxylase deficiency and 43 healthy volunteers. During each profile, saliva and serum samples for 17OHP were simultaneously collected.

Results: With regard to the initial day profiles, samples were pathological in 63% (saliva) and 41% (serum). After the first day profile 14 patients underwent adjustment of medical treatment, either because of highly elevated 17OHP levels or with the aim of dose reduction. When comparing the best with the first day profile fewer samples were pathological (saliva: 32% vs. 71%; p<0.05; serum: 21% vs. 47%; n. s.), while the mean hydrocortisone equivalent dose was significantly reduced (20.09 mg vs. 27.27 mg; p<0.01). In 53% of profiles with controlled salivary 17OHP levels at 0700 h, the necessity for a treatment modification became only apparent when analyzing the whole day profile.

Conclusion: A single 0700 h value within the reference range does not allow for a reliable assessment of therapeutic efficacy. We therefore suggest 17OHP day profiles for monitoring medical treatment. In this context, saliva analysis appears to be more sensitive in identifying patients who are inadequately treated.

Key words

steroid 21-hydroxylase deficiency - glucocorticoids - substitution - transition - therapy

References

• 1 Atherden SM, Barnes ND, Grant DB. Circadian variation in plasma 17-hydroxyprogesterone in patients with congenital adrenal hyperplasia.  Arch Dis Child. 1972;  47 602-604
• 2 Bachelot A, Plu-Bureau G, Thibaud E. et al . Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Horm Res. 2007;  67 268-276
• 3 Castro M, Elias PC, Quidute AR. et al . Out-patient screening for Cushing's syndrome: the sensitivity of the combination of circadian rhythm and overnight dexamethasone suppression salivary cortisol tests.  J Clin Endocrinol Metab. 1999;  84 878-882
• 4 Charmandari E, Matthews DR, Johnston A. et al . Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?.  J Clin Endocrinol Metab. 2001;  86 4679-4685
• 5 Dressendorfer RA, Strasburger CJ, Bidlingmaier F. et al . Development of a highly sensitive nonisotopic immunoassay for the determination of salivary 17-hydroxyprogesterone: reference ranges throughout childhood and adolescence.  Pediatr Res. 1998;  44 650-655
• 6 Eugster EA, Dimeglio LA, Wright JC. et al . Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis.  J Pediatr. 2001;  138 26-32
• 7 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 4643-4649
• 8 Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Hum Reprod Update. 2004;  10 469-485
• 9 Frisch H, Parth K, Schober E. et al . Circadian patterns of plasma cortisol, 17-hydroxyprogesterone, and testosterone in congenital adrenal hyperplasia.  Arch Dis Child. 1981;  56 208-213
• 10 Groschl M, Rauh M, Schmid P. et al . Relationship between salivary progesterone, 17-hydroxyprogesterone, and cortisol levels throughout the normal menstrual cycle of healthy postmenarcheal girls.  Fertil Steril. 2001;  76 615-617
• 11 Groschl M, Rauh M, Dorr HG. Cortisol and 17-hydroxyprogesterone kinetics in saliva after oral administration of hydrocortisone in children and young adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  J Clin Endocrinol Metab. 2002;  87 1200-1204
• 12 Hammond GL, Langley MS. Identification and measurement of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in human saliva.  Acta Endocrinol (Copenh). 1986;  112 603-608
• 13 Hoeppfner W, Hubl W. Studies on the diurnal variations of 17-hydroxyprogesterone in saliva by enzyme immunoassay in patients with congenital adrenal hyperplasia.  Exp Clin Endocrinol. 1986;  87 189-194
• 14 Hofman LF. Human saliva as a diagnostic specimen.  J Nutr. 2001;  131 1621S-1625S
• 15 Hughes IA, Read GF. Control in congenital adrenal hyperplasia monitored by frequent saliva 17OH-progesterone measurements.  Horm Res. 1984;  19 77-85
• 16 Joint LWPES/ESPE CAH Working Group . Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology.  J Clin Endocrinol Metab. 2002;  87 4048-4053
• 17 King JA, Wisniewski AB, Bankowski BJ. et al . Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia.  J Clin Endocrinol Metab. 2006;  91 865-869
• 18 Lewis JG. Steroid Analysis in Saliva: An overview.  Clin Biochem Rev. 2006;  27 139-146
• 19 Merke DP, Bornstein SR. Congenital adrenal hyperplasia.  Lancet. 2005;  365 (9477) 2125-2136
• 20 Merke DP. Approach to the adult with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  J Clin Endocrinol Metab. 2008;  93 653-660
• 21 Mylonas PG, Makri M, Georgopoulos NA. et al . Adequacy of saliva 17-hydroxyprogesterone determination using various collection methods.  Steroids. 2006;  71 273-276
• 22 New MI. Diagnosis and management of congenital adrenal hyperplasia.  Annu Rev Med. 1998;  49 311-328
• 23 Ogilvie CM, Crouch NS, Rumsby G. et al . Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues.  Clin Endocrinol (Oxf). 2006;  64 2-11
• 24 Otten BJ, Wellen JJ, Rijken JC. et al . Salivary and plasma androstenedione and 17-hydroxyprogesterone levels in congenital adrenal hyperplasia.  J Clin Endocrinol Metab. 1983;  57 1150-1154
• 25 Papanicolaou DA, Mullen N, Kyrou I. et al . Nighttime salivary cortisol: a useful test for the diagnosis of Cushing
  's syndrome.  J Clin Endocrinol Metab. 2002;  87 4515-4521
• 26 Price DA, Astin MP, Chard CR. et al . Assay of hydroxyprogesterone in saliva.  Lancet. 1979;  2 368-369
• 27 Putignano P, Toja P, Dubini A. et al . Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing
  's syndrome.  J Clin Endocrinol Metab. 2003;  88 4153-4157
• 28 Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing
  's syndrome.  J Clin Endocrinol Metab. 1998;  83 2681-2686
• 29 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 1665-1670
• 30 Riad-Fahmy D, Read GF, Walker RF. et al . Steroids in saliva for assessing endocrine function.  Endocr Rev. 1982;  3 367-395
• 31 Riepe FG, Krone N, Viemann M. et al . Management of congenital adrenal hyperplasia: results of the ESPE questionnaire.  Horm Res. 2002;  58 196-205
• 32 Roche EF, Charmandari E, Dattani MT. et al . Blood pressure in children and adolescents with congenital adrenal hyperplasia (21-hydroxylase deficiency): a preliminary report.  Clin Endocrinol (Oxf). 2003;  58 589-596
• 33 Rosenfield RL. Serum cortisol and 17-hydroxyprogesterone concentrations in children with classic congenital adrenal hyperplasia.  J Clin Endocrinol Metab. 2002;  87 2993 ; author reply 2993
• 34 Shimon I, Kaiserman I, Sack J. Home monitoring of 17 alpha-hydroxyprogesterone levels by filter paper blood spots in patients with 21-hydroxylase deficiency.  Horm Res. 1995;  44 247-252
• 35 Solyom J. Diurnal variation in blood 17-hydroxyprogesterone concentrations in untreated congenital adrenal hyperplasia.  Arch Dis Child. 1984;  59 743-747
• 36 Solyom J, Hosszu E, Gacs G. Blood-spot 17-hydroxyprogesterone daily profiles in infants with congenital adrenal hyperplasia.  Exp Clin Endocrinol. 1990;  96 52-56
• 37 Stewart PM. The adrenal cortex. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR (eds). Williams Textbook of Endocrinology. 12th edn. Philadelphia: Saunders Elsevier; 2008: 459
• 38 Stikkelbroeck NM, 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 5721-5728
• 39 Trilck M, Flitsch J, Ludecke DK. et al . Salivary cortisol measurement – a reliable method for the diagnosis of Cushing
  's syndrome.  Exp Clin Endocrinol Diabetes. 2005;  113 225-230
• 40 White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Endocr Rev. 2000;  21 245-291
• 41 Young MC, Robinson JA, Read GF. et al . 170H-progesterone rhythms in congenital adrenal hyperplasia.  Arch Dis Child. 1988;  63 617-623
• 42 Zerah M, Pang SY, New MI. Morning salivary 17-hydroxyprogesterone is a useful screening test for nonclassical 21-hydroxylase deficiency.  J Clin Endocrinol Metab. 1987;  65 227-232
• 43 Zerah M, Ueshiba H, Wood E. et al . Prevalence of nonclassical steroid 21-hydroxylase deficiency based on a morning salivary 17-hydroxyprogesterone screening test: a small sample study.  J Clin Endocrinol Metab. 1990;  70 1662-1667

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