Final PhD Thesis- Rosemary Dineen.pdf (4.69 MB)
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Optimising Steroid Replacement in Patients with Adrenal Insufficiency

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posted on 15.02.2022, 12:19 by Rosemary Dineen

Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. Furthermore, within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI due to supraphysiological GC replacement therapy, and the non-physiological pattern of current HC replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may address unmet clinical needs.

We performed an investigator-initiated, prospective, cross-over study in 51 patients with AI [primary (PAI) and secondary (SAI)]. Patients were assessed at baseline and thereafter switched from their usual hydrocortisone (HC) regimen to a once-daily dose equivalent of DR-HC for 12 weeks. Cardiometabolic risk factors, and QoL coupled with an in-vivo assessment of tissue corticosteroid metabolism using urinary steroid metabolomics, cortisol generation curves, and adipose tissue biopsies, were assessed in the patient population before and after DR-HC and compared to age-and BMI-matched controls.

After 3 months of DR-HC, the mean SBP in our study population decreased by 4.5mmHg, p=0.04 and DBP decreased by 4.2mmHg, p=0.01.There was also a significant reduction in mean weight (-1.17kg, p=0.03) and BMI (-0.3kg/m2, p=0.03). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC therapy (-5.8mmHg vs -4 mmHg, p=0.01). Additionally, patients reported significant improvements in QoL. In vivo analysis demonstrated that patients with AI receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6-124.2) vs 51.85 (35.5-72.3), p=0.02], with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue

Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in corticosteroid metabolism in patients with primary and secondary adrenal insufficiency, driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability. Patients receiving conventional immediate-release hydrocortisone experience diurnal fluctuations in tissue cortisol exposure, which can be improved following treatment with DR-HC.


History

First Supervisor

Prof. Mark Sherlock

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2020

Published Citation

Dineen R,. Optimising Steroid Replacement in Patients with Adrenal Insufficiency [PHD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/11/2020

Programme

  • Doctor of Philosophy (PhD)

Research Area

  • Endocrinology

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