Assessment of hypothalamic-pituitary-adrenal axis impairment and effects of hydrocortisone treatment in adults with Prader-Willi syndrome

Abstract

Objective: The prevalence of hypothalamic-pituitary-adrenal impairment (HPAI) in adults with Prader Willi Syndrome (PWS) remains unclear despite its clinical relevance. The aim of our study was to assess the prevalence of HPA axis impairment in adults with PWS based on the results of the high dose short synacthen test (HDSST), as well as to analyze the effects of hydrocortisone (HCT) therapy in this population.

Design: Retrospective analysis.

Patients: Thirty adult patients (14 men, 16 women, aged 18-28 years) with genetically confirmed PWS. Twenty-two patients (73.3%) had been adequately treated with human recombinant growth hormone (rhGH). Due to hypogonadotropic hypogonadism, all patients received hormone replacement therapy.

Measurements: Physical examination included measuring height, weight and body fat percentage (using the electrical bioimpedance method). Based on HDSST results, patients were divided into two groups: with HPA axis impairment (cortisol < 500 nmol/L at 30^th minute), and AS (adrenal sufficiency; cortisol ≥ 500 nmol/L at the 30^th minute). Clinical symptoms of adrenal insufficiency (AI), body weight and body fat percentage were evaluated at baseline, after 6 and 12 months of follow-up.

Results: Fourteen of the 30 patients (46.7%) showed a 30-min cortisol peak <500 nmol/L, and were assigned to the HPAI group. Peak cortisol levels at 30' and 60' were significantly lower in the HPAI group compared to the Control one, respectively (P<0.001) Correlation analysis revealed that basal cortisol was positively correlated with cortisol levels at both 30' and 60' of the HDSST (r = 0.872, P < 0.001 and r = 0.829, P < 0.001, respectively). Fatigue, myalgia and muscle weakness occurred more often in the HPAI group than in the Control group (90.9% vs. 20%, P= 0.01, 90.9% vs. 0%, P=0.001, respectively). All symptomatic patients with HPAI received HCT treatment (10 mg/day) in two divided doses. Fatigue, myalgiaand muscle weakness improved significantly after 12 months of HCT therapy (P<0.001). No adverse effects of HCT treatment were observed, such as weight gain, body fat percentage increase or metabolic abnormalities.

Conclusions: The results of our study suggest that the HPA axis should be routinely evaluated in adult patients with PWS. Short term, low-dose HCT treatment in symptomatic patients with HPAI is safe and can reduce symptoms of fatigue, myalgia and muscle weakness. However, the benefits and adverse effects of HCT treatment in this population require confirmation in prospective, placebo-controlled randomized clinical studies.

Keywords: Prader-Willi syndrome; adrenal insufficiency; high dose short synacthen test; hydrocortisone treatment; hypothalamic-pituitary-adrenal axis impairment; rare disease.

Figure 1

Morning cortisol, ACTH and DHEA-S values in patients with Prader-Willi Syndrome. (A) Morning cortisol. Reference values for morning cortisol are: 133–537 nmol/L (4.82-19.5 μg/dL). SI conversion factor: to convert cortisol from nmol/L to μg/dL divide by 27.59. (B) ACTH. Reference values for morning ACTH are: 1.6–13.9 pmol//L (7.22–63.3 pg/ml). SI conversion factor: to convert ACTH from pmol/L to pg/mL divide by 0.22. (C) DHEA-S. Reference values for DHEA-S in our study group are: 5.72–13.35 μmol/L (211-492 μg/dL). SI conversion factor: to convert DHEA-S from μmol/L to mg/dL multiply by 36.85. ACTH, adrenocorticotropine hormone; HPAI, hypothalamic-pituitary-adrenal axis impairment; DHEA-S, dehydroepiandrosterone sulfate..

Figure 2

High-dose short synacthen test results in the study groups. (A) Hypothalamic-pituitary-adrenal axis impairment (HPAI) group (B) Control group. (C) Median values in the study groups. Morning (baseline) cortisol and peak cortisol levels of the HDSST at 30’ and 60’ are shown. Reference values for morning cortisol are: 133–537 nmol/L (4.82-19.5 μg/dL). SI conversion factor: to convert cortisol from nmol/L to μg/dL divide by 27.59. HPAI, hypothalamic-pituitary-adrenal axis impairment.