Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushing’s disease: 12-month, Phase III pasireotide study

Abstract

Measuring salivary cortisol is a simple, convenient and accurate technique with potential value in monitoring patients with hypercortisolism. This analysis reports changes in late-night salivary cortisol (LNSC) during a 12-month, multicentre, Phase III study of patients with Cushing’s disease who were randomized to pasireotide 600 or 900 μg sc bid. LNSC assessment was an exploratory objective based on a single, optional measurement at midnight ± 1 h on the same day as one of the 24-h urinary free cortisol (UFC) measurements. Of 162 enrolled patients, baseline LNSC was measured in 93. Sixty-seven patients had levels above the upper limit of normal (ULN); median baseline levels were 19.7 and 20.7 nmol/L in the groups subsequently randomized to 600 μg (n = 40) and 900 μg (n = 27), respectively. Median LNSC levels decreased from baseline to month 12; median changes in patients who had baseline LNSC > ULN in the 600 and 900 μg groups were −13.4 nmol/L (–52.6 %; n = 19) and −11.8 nmol/L (–56.1 %; n = 14), respectively. LNSC normalized at months 6 and 12 in 25/67 (37.3 %) and 13/67 (19.4 %) patients, respectively; 10/25 and 8/13 patients also had normalized UFC, and 7/25 and 4/13 had partial UFC control (UFC > ULN and ≥50 % decrease from baseline). There was a moderate correlation (r = 0.55) on the log scale between individual patient LNSC and UFC values when all time points were pooled. Pasireotide decreased LNSC levels during 12 months of treatment. Salivary cortisol may be a simple, convenient biomarker for assessing treatment response in patients with Cushing’s disease.

Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

“…However, there are important limitations to the use of UFC, which include the need for a patient to collect a complete 24-h urine sample (18,19), as well as high intra-patient variability in daily 24-h UFC measurements (7). Consistent with findings from a previous exploratory analysis of single LNSC samples from a large Phase III study of s.c. pasireotide in Cushing's disease (14), we found a moderate correlation between individual and mean UFC and LNSC values, the samples for which were collected in the same 24-h period. In the current analysis, 32% and 28% of patients had an elevated mLNSC level at months 7 and 12, respectively, in the presence of normalized mUFC.…”

“…In our study, elevated mLNSC in patients with normal mUFC may have resulted from suboptimal recovery of normal circadian cortisol rhythm -characterized by an earlymorning cortisol peak and a gradual decrease during the day to low midnight levels (3) -despite an overall reduction in daily cortisol secretion. Indeed, dysregulation of cortisol circadian rhythm has been shown to persist in some patients during medical therapy even after normalization of mUFC (6,14,16). However, additional salivary cortisol assessments within a single day, including early in the morning and late at night, may be required to confirm the effects of medical therapy on circadian rhythm of cortisol secretion (6), which was not planned in the present study.…”

“…Collection of late-night salivary samples is both simple and convenient for patients to carry out in their own homes, with samples being stable at room temperature for up to 2 weeks and easy to store (12,13). Few studies have examined the role of LNSC in monitoring response to pharmacotherapy in patients with Cushing's disease (6,14).…”

Current management of Cushing's disease

“…Pasireotide therapy led to 24‐hr UFC normalization in approximately 21% of 162 patients with CD . Pasireotide may also control nadir cortisol levels, as measured by late‐night salivary cortisol . In another study of 150 patients with CD, pasireotide LAR administration normalized 24‐h UFC in about 40% of treated patients .…”

Is receptor profiling useful for predicting pituitary therapy?

“…Preclinical and clinical studies demonstrated the efficacy of long-acting SSA in the treatment of PT, particularly GH (18) and TSH-secreting tumours (19). Moreover, international multi-centre studies demonstrated the efficacy of pasireotide in the medical management of Cushing's disease (20,21) and GH-secreting PTs (22). Cabergoline, on its side, is an ergot-derived DA with high affinity for DR2 and lower affinity for DR1, α1-and α2adrenergic, and 5-HT1-and 5-HT2-serotonin receptors (23,24).…”