Date of Award

2014

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Dr Amar Agha

Funder/Sponsor

Pfizer Endocrin Care, Novo Nordisk.

Keywords

Inappropriate cortisol replacement, morbidity and mortality, hypopituitarism, adrenocorticotropin (ACTH) deficiency.

Abstract

Inappropriate cortisol replacement has been proposed as a contributing factor in the increased morbidity and mortality associated with hypopituitarism. The aim of this study is to examine the effect of three commonly prescribed hydrocortisone replacement regimens on predefined metabolic end points and quality of life (QoL) in male subjects with severe adrenocorticotropin (ACTH) deficiency with a view to identifying the most physiologic regimen.

10 hypopituitary men participated in a prospective, randomised, crossover, open protocol of 6 weeks on each of the following regimens: Dose A (20mg AM, 10mg PM), Dose B (10mg AM, 10mg PM), Dose C (10mg AM, 5mg PM). Results were compared between dose regimens and to healthy control subjects.

The lowest dose regimen, dose C (10mg/5mg), was associated with a 24 hour serum cortisol profile that most closely approximated that of the control subjects, without any difference in QoL between doses.

There were significant increases in serum markers of bone formation in the lower dose regimen dose C, with an 86% increase in procollagen type I N-propeptide (PINP), and a 56% increase in intact osteocalcin (OC[1-49]) compared to dose A, without concurrent increases in bone resorption markers. These findings reflect a more positive bone remodelling balance in the lowest dose regimen, resulting in net bone gain.

Tissue exposure to cortisol was assessed by examining 24hour urinary cortisol metabolites. Dose A (20mg/10mg) was associated with significantly higher total cortisol metabolites compared to the two other dose regimens and compared to healthy controls. We also demonstrated increased tissue cortisol exposure across all dose regimens compared to healthy controls; however it was highest with dose A.

There was no difference between dose regimens or compared to controls in glucose or insulin metabolism or in 24 hour blood pressure. Dose C (10mg/5mg) was associated with a reduction in the ambulatory arterial stiffness index (AASI) and a more physiological nocturnal blood pressure dip which may indicate a more favourable vascular status.

This study demonstrates a lower dose hydrocortisone replacement regimen in severe ACTH deficiency is associated with a more favourable metabolic profile without adversely affecting QoL. These findings suggest that physicians may safely aim for a reduction in prescribed hydrocortisone replacement doses.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

7,956 KB

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2014.

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