A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia.
Classic congenital adrenal hyperplasia (CAH) management remains challenging, given that supraphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven adrenal androgen overproduction.



This study sought to approximate physiologic cortisol secretion via continuous subcutaneous hydrocortisone infusion (CSHI) and evaluate the safety and efficacy of CSHI in patients with difficult-to-treat CAH.



Eight adult patients with classic CAH participated in a single-center open-label phase I-II study comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevated adrenal steroids and one or more comorbidities at study entry. Assessment while receiving conventional therapy at baseline and 6 months following CSHI included: 24-hour hormonal sampling, metabolic and radiologic evaluation, health-related quality-of-life (HRQoL), and fatigue questionnaires.



The ability of CSHI to approximate physiologic cortisol secretion and the percent of patients with 0700-hour 17-hydroxyprogesterone (17-OHP) ≤1200 ng/dL was measured.



CSHI approximated physiologic cortisol secretion. Compared with baseline, 6 months of CSHI resulted in decreased 0700-hour and 24-hour area under the curve 17-OHP, androstenedione, ACTH, and progesterone, increased osteocalcin, c-telopeptide and lean mass, and improved HRQoL (and SF-36 Vitality Score), and fatigue. One of three amenorrheic women resumed menses. One man had reduction of testicular adrenal rest tissue.



CSHI is a safe and well-tolerated modality of cortisol replacement that effectively approximates physiologic cortisol secretion in patients with classic CAH poorly controlled on conventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest that CSHI should be considered a treatment option for classic CAH. The long-term effect on established comorbidities requires further study.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Aikaterini A
AA
Nella
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Ashwini
A
Mallappa
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Ashley F
AF
Perritt
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Verena
V
Gounden
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Parag
P
Kumar
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Ninet
N
Sinaii
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Lori-Ann
LA
Daley
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Alexander
A
Ling
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Chia-Ying
CY
Liu
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Steven J
SJ
Soldin
Eunice Kennedy Shriver National Institute of Child Health and Human Development (A.A.N. D.P.M.), National Institutes of Health, Bethesda, Maryland 20892; and National Institutes of Health Clinical Center (A.A.N., A.M., A.F.P., V.G., P.K., N.S., L.-A.D., A.L., C.-Y.L., S.J.S., D.P.M.), Bethesda, Maryland 20892.
Deborah P
DP
Merke
D000312:Adrenal Hyperplasia, Congenital / Q000097:blood* / Q000188:drug therapy*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055104:Infusions, Subcutaneous; D008297:Male; D017063:Outcome Assessment, Health Care; D055815:Young Adult
D015415:Biomarkers; D005938:Glucocorticoids; D006854:Hydrocortisone
J Clin Endocrinol Metab. 2001 Jun;86(6):2701-8
11397874
J Clin Endocrinol Metab. 2012 Feb;97(2):568-76
22090270
ISRN Endocrinol. 2011;2011:219494
22363868
J Clin Epidemiol. 1998 Nov;51(11):903-12
9817107
Diabetes Care. 1999 Sep;22(9):1462-70
10480510
J Clin Endocrinol Metab. 2015 Mar;100(3):1137-45
25494662
J Steroid Biochem Mol Biol. 2016 Sep;162:110-6
26721696
Clin Endocrinol (Oxf). 2004 Sep;61(3):367-75
15355454
J Clin Endocrinol Metab. 2012 Dec;97(12):4429-38
22990093
J Rheumatol. 1995 Apr;22(4):639-43
7791155
J Clin Endocrinol Metab. 2014 Nov;99(11):4149-57
25127090
Eur J Endocrinol. 2015 Dec;173(6):727-37
26340969
Cochrane Database Syst Rev. 2016 Aug 28;(8):CD008815
27567593
J Diabetes Sci Technol. 2012 Jul 01;6(4):954-64
22920824
J Pediatr Endocrinol Metab. 2011;24(7-8):561-3
21932600
Diabetes Care. 2003 Dec;26(12):3320-5
14633821
J Clin Endocrinol Metab. 2009 Sep;94(9):3477-80
19567522
Lancet. 2005 Jun 18-24;365(9477):2125-36
15964450
J Clin Endocrinol Metab. 2009 May;94(5):1548-54
19223520
J Clin Endocrinol Metab. 2010 Nov;95(11):5110-21
20719839
J Clin Endocrinol Metab. 2014 May;99(5):1665-74
24517155
Am J Gastroenterol. 1999 Apr;94(4):1018-22
10201476
Br Med J (Clin Res Ed). 1986 Jan 4;292(6512):13-5
3080046
Clin Endocrinol (Oxf). 2006 Jul;65(1):45-50
16817818
Clin Chim Acta. 2006 Oct;372(1-2):76-82
16707118
J Clin Endocrinol Metab. 2008 Mar;93(3):653-60
18326005
J Am Diet Assoc. 1997 Jun;97(6):632-8
9183325
J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60
20823466
Int J Pediatr Endocrinol. 2009;2009:624823
19956703