Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia

Abstract

Background: In a phase 2 short-term (6 months) study of patients with congenital adrenal hyperplasia (CAH), continuous subcutaneous hydrocortisone infusion (CSHI) was found to be a safe, effective and well-tolerated method of replacing cortisol with improved disease and patient-related outcomes.

Objective: To evaluate the safety and efficacy of long-term CSHI.

Design: Single-centre, open-label, phase 2 extension study.

Patients: Five adults with classic CAH.

Measurements: Biomarkers of disease control, metabolic indices and health-related quality-of-life (HRQoL) estimates.

Results: Six of eight patients chose to continue on long-term CSHI therapy. Compared to baseline, eighteen months of CSHI resulted in decreased (P = 0.043) 0700-hour ACTH, 17-hydroxyprogesterone, androstenedione and progesterone; increased whole-body lean mass (P = 0.024); and improved HRQoL, especially symptoms of adrenal insufficiency (P = 0.003). Findings at six and eighteen months did not differ, and improvements achieved in androgen control, lean body mass and HRQoL after 6 months of CSHI were maintained at eighteen months. The hydrocortisone dose appeared to decrease with time [6 vs 18 months: 38.3 ± 8.8 vs 33.6 ± 12.2 mg/day (P = 0.062)], especially in women receiving oral contraceptives. Reduction of testicular adrenal rest and adrenal size observed at 6 months remained stable. In one patient, an adrenal adenoma continually decreased over time. Subjective improvement in hirsutism was reported.

Conclusions: Long-term use of CSHI is a safe and well-tolerated treatment option in a select set of adults with classic CAH. Improvements observed short term in disease control and subjective health status continued long term.

Trial registration: ClinicalTrials.gov NCT01859312.

Keywords: circadian; congenital adrenal hyperplasia; continuous subcutaneous hydrocortisone infusion.

Conflict of interest statement

Conflict of Interest/Disclosures: Deborah P. Merke, received unrelated research funds from Diurnal Limited and Millendo Therapeutics, through NIH Cooperative Research and Development Agreements. All other authors have no conflicts of interest to declare.

Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1:

Serum total cortisol levels over 24-hours on continuous subcutaneous hydrocortisone infusion (CSHI) therapy at 6 months and 18 months by sex. Females were receiving OCP therapy at 18 months. An increase of approximately 45% in serum total cortisol levels was observed following initiation of OCP therapy. Measurement of free cortisol was not performed.

Figure 2:

Comparison of 24-hour serial hormone levels on conventional glucocorticoid therapy (baseline) vs. continuous subcutaneous hydrocortisone infusion (CSHI) therapy for 6 and 18 months.

Figure 3:

Glucocorticoid dose (Panel A) and metabolic characteristics (Panel B-F) on conventional glucocorticoid therapy at baseline, and following continuous subcutaneous hydrocortisone infusion therapy for 6 and 18 months. Abbreviations: GC, glucocorticoid; HOMA-IR, Homeostasis model assessment–insulin resistance Glucocorticoid equivalent dose (mg/day): hydrocortisone X 1, prednisone and prednisolone X 5, and dexamethasone X 80 (2)

Figure 4:

Health-Related Quality-of-Life Scores (HRQoL) on Conventional Glucocorticoid Therapy at Baseline and following 6 and 18 months of continuous subcutaneous hydrocortisone infusion therapy. Abbreviations: SF-36, 36-item short-form health survey; PF, Physical Functioning; GH, General Health; VT, Vitality; MH, Mental Health, AddiQoL, Adrenal insufficiency-specific quality-of -life questionnaire.