Improved salivary cortisol rhythm with dual-release hydrocortisone

Abstract

Introduction and AimThe purpose of replacement therapy in adrenal insufficiency (AI) is mimicking endogenous cortisol levels as closely as possible: dual release hydrocortisone (DR-HC) has been introduced to replicate the circadian cortisol rhythm. Multiple daily saliva collections could be used to assess the cortisol rhythm during real life: our aim was to study the salivary cortisol profile in AI.Materials and MethodsWe prospectively evaluated, in an observational study, 18 adult outpatients with AI (11 primary and 7 secondary AI), switched from conventional treatment (conv-HC, 25 mg/day) to the same dose of DR-HC. We collected six samples of saliva in a day, measuring cortisol (F) and cortisone (E) with LC-MS/MS. Forty-three matched healthy subjects served as controls.ResultsF levels were similar in the morning (and higher than controls) in patients treated with conv-HC or DR-HC; otherwise F levels and exposure were lower in the afternoon and evening in patients with DR-HC, achieving a cortisol profile closer to healthy controls. Daily cortisol exposure, measured with area under the curve, was lower with DR-HC. Morning F and E presented sensitivity and specificity >90% to diagnose AI (respectively threshold of 3 and 9.45 nmol/L). Total cholesterol and HbA1c levels reduced with DR-HC.ConclusionsSalivary cortisol daily curve could be used as a new tool to assess the cortisol profiles in patients treated with conv-HC and DR-HC. A lower daily cortisol exposure was achieved with DR-HC (despite the same HC dose), especially in the afternoon-evening.

Systematic review and meta‐analysis of the metabolic effects of modified‐release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency

“…Patients with primary AI but not secondary AI had significant improvement in HbA1c following switch to MR-HC in the study reported by Mongioi et al 26 There were no reports of any significant changes in HbA1c in the other studies. 23,25 The only paper to report on body weight was by Giordano et al, 27 which showed no significant changes.…”

“…24 A further non-RCT was a retrospective cohort study from Italy with patients switched to MR-HC (n = 53) and those remaining on standard hydrocortisone (n = 47), with metabolic outcomes compared at baseline up to 48-months. 29 The single-arm studies all took place in Italy, with three prospective studies 23,26,27 and two retrospective studies. 25,28 The single-arm prospective studies each included 19 participants.…”

Evaluation of the bioavailability of hydrocortisone when prepared as solid dispersion

“…These factors may include gastric and intestinal pH that significantly influences the absorption of orally administered drugs (Mitra and Kesisoglou, 2013, Taniguchi et al, 2014). In the past, modified release formulations of hydrocortisone have been proposed and studied targeting hydrocortisone hormone replacement therapy (Ceccato et al, 2018, Whitaker et al, 2014). The PEG 4000 appears to be controlling the release of hydrocortisone in-vivo in a way that restricts the quick absorption of all the hydrocortisone after oral administration.…”

Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment

“…Elevated levels of cortisol-binding globulin in women receiving estrogen treatment may increase total serum cortisol levels; therefore, in some cases, a woman with suspected CAI may present a misleading normal serum cortisol concentration [43]. Contrariwise, morning salivary cortisol level is free: it has been studied in women using oral contraceptive pill or during pregnancy [45], and in suspected adrenal insufficiency with immunometric assay [46] or with LC-MS/MS [47]. However, the diagnostic accuracy of salivary cortisol in suspected adrenal insufficiency is questionable [48], and its routine use is not yet suggested [1,10].…”

“…In 2012, we described that multiple saliva collections could be used to measure salivary cortisol and to compute area under the curve (to assess daily GC exposure), in a small group of patients with CAI treated with CA. Multiple saliva sampling, a convenient easy-to-manage and stressfree tool for outpatients, could pave the way to a future application of salivary cortisol assays for assessing the adequacy of replacement therapy because samples could be performed before and after GC dose [47,82]. Recently, we reported, in a proof-of-concept prospective study, that the reduction of GC treatment (assessed with daily salivary cortisol) resulted in a better replication of circadian cortisol rhythm and in an improvement of diastolic blood pressure [83].…”