Search Results

You are looking at 1 - 4 of 4 items for

  • Author: Miguel Debono x
  • All content x
Clear All Modify Search
Free access

Miguel Debono, Richard J Ross, and John Newell-Price

Patients with adrenal insufficiency need lifelong glucocorticoid replacement, but many suffer from poor quality of life, and overall there is increased mortality. Moreover, it appears that use of glucocorticoids at the higher end of the replacement dose range is associated with increased risk for cardiovascular and metabolic bone disease. These data highlight some of the inadequacies of current regimes.

The cortisol production rate is estimated to be equivalent to 5.7–7.4 mg/m2 per day, and a major difficulty for replacement regimes is the inability to match the distinct circadian rhythm of circulating cortisol levels, which are low at the time of sleep onset, rise between 0200 and 0400 h, peaking just after waking and then fall during the day. Another issue is that current dose equivalents of glucocorticoids used for replacement are based on anti-inflammatory potency, and few data exist as to doses needed for equivalent cardiovascular and bone effects. Weight-adjusted, thrice-daily dosing using hydrocortisone (HC) reduces glucocorticoid overexposure and represents the most refined regime for current oral therapy, but does not replicate the normal cortisol rhythm. Recently, proof-of-concept studies have shown that more physiological circadian glucocorticoid therapy using HC infusions and newly developed oral formulations of HC have the potential for better biochemical control in patients with adrenal insufficiency. Whether such physiological replacement will have an impact on the complications seen in patients with adrenal insufficiency will need to be analysed in future clinical trials.

Free access

Miguel Debono, Ashwini Mallappa, Verena Gounden, Aikaterini A Nella, Robert F Harrison, Christopher A Crutchfield, Peter S Backlund, Steven J Soldin, Richard J Ross, and Deborah P Merke

Objectives

The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids.

Design

This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH.

Methods

Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (T minAC) and maximal (T maxAC) adrenocortical hormone levels after dose administration was calculated.

Results

A significant rhythm was confirmed for ACTH (r 2, 0.95; P<0.001), 17OHP (r 2, 0.70; P=0.003), androstenedione (r 2, 0.47; P=0.043), androsterone (r 2, 0.80; P<0.001), testosterone (r 2, 0.47; P=0.042) and progesterone (r 2, 0.64; P=0.006). The mean (s.d.) T minAC and T maxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0–24 h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP.

Conclusion

In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.

Free access

Miguel Debono, Lorcan Sheppard, Sarah Irving, Philip Jackson, Jo Butterworth, Zoe L S Brookes, John Newell-Price, Jonathan J Ross, and Richard J Ross

Objective

Patients with cortisol deficiency poorly tolerate any systemic inflammatory response syndrome (SIRS), and may die if not treated with sufficient exogenous glucocorticoids. Controversy surrounds what constitutes a ‘normal’ adrenal response in critical illness. This study uses conventional tests for adrenal insufficiency to investigate cortisol status in patients undergoing elective coronary artery bypass surgery, a condition frequently associated with SIRS.

Design

A prospective, observational study.

Methods

Thirty patients with impaired left ventricular function (ejection fraction >23% <50%) underwent basal ACTH measurement, and a short cosyntropin test (250 μg, i.v.) 1 week preoperatively, and at +4 h following induction of general anaesthesia. Preoperatively, a 30 min cortisol level post cosyntropin >550 nmol/l was taken as a normal response.

Results

Prior to surgery, all patients had a normal response to cosyntropin. Postoperatively, eight patients (26.7%) did not achieve stimulated cortisol levels >550 nmol/l and the mean peak cortisol postoperatively was lower (1048 vs 730 nmol/l; P<0.001). There was a significant rise in ACTH after surgery (21 vs 184 ng/l; P=0.007) and reduction in Δ-cortisol post cosyntropin (579 vs 229 nmol/l; P<0.001). There was no change in basal cortisol pre- and post-operatively (447 vs 501; P=0.4). All patients underwent routine, uneventful postoperative recovery.

Conclusion

Up to one quarter of patients with a normal cortisol status preoperatively demonstrated a raised ACTH and deficient cortisol response postoperatively. Despite these responses, all patients had uneventful outcomes. These data reinforce the need for caution when interpreting results of endocrine testing following major surgery or in the intensive care environment, and that prognostic value of these results may be of limited use.

Free access

Ann McCormack, Olaf M Dekkers, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Gerald Raverot, Pia Burman, and ESE survey collaborators

Objective

To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment.

Design

Electronic survey to ESE members Dec 2015–Nov 2016.

Results

Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4–79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%.

Conclusion

This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.