Peter Hindmarsh is professor of paediatric endocrinology at University College London and consultant in paediatric endocrinology and diabetes at University College London Hospitals and Great Ormond Street Hospital for Children.
He is currently divisional clinical director for paediatrics at University College London Hospitals.
He is applying the process of 24 hour cortisol profile assessment to better understand glucocorticoid replacement therapy in adrenal disorders.
His research interests are in using pump therapy to deliver hydrocortisone treatment in congenital adrenal hyperplasia and to better model absorption and clearance of cortisol. He developed the cortisol pump method which includes a series of tests and with the data, established a formula to derive individualised rates to deliver hydrocortisone mimicking the circadian rhythm. The pump method is being successfully used worldwide and has not only reduced side effects from over and under replacement which occurs with oral treatment, but also improved the quality of life in many patients who use it.
Work in the field of congenital adrenal hyperplasia focusses on improving cortisol replacement. The aim of replacement therapy is to mimic as closely as is possible the normal circadian rhythm of cortisol.
To do this, knowledge of how the individual handles hydrocortisone (the synthetic form of cortisol) is necessary. Over the last 10 years he has studied the absorption and clearance of hydrocortisone in individuals with congenital adrenal hyperplasia and in other patients with a variety of disorders causing adrenal insufficiency. These studies use 24 hour blood cortisol profiles to help understand what happens in the circulation when a tablet of hydrocortisone is taken.
This information is then processed with knowledge of the individual’s clearance of hydrocortisone from the circulation obtained by intravenous studies of the fate of a bolus of hydrocortisone. From studies such as these it is possible to define fast, normal and slow absorbers and fast, normal and slow clearers. This data then inform how best to dose with hydrocortisone and how often the tablets should be taken. These studies have shown that individual clearance rates of hydrocortisone are extremely variable, indicating that not only dose but dose timing is very important to avoid over stacking of cortisol. Figure 3 shows the range of half-life values for cortisol in different people.
24 hour blood cortisol profiles form the mainstay of the clinical practice at University College Hospital and are used to determine how well replacement therapy is going. With over 300 profiles undertaken over the last 10 years there is a wealth of experience in interpreting the information obtained. This results in hydrocortisone replacement therapy which is tailored to the metabolism of the person, so that excessively high peaks are avoided and at the same time good coverage is given over the 24 hour period. The change in dosing schedule has led to better growth of patients, less weight gain and a marked reduction in side effects such as hypertension.
Working with 24 hour profiles and understanding the cortisol rhythm, has allowed Professor Hindmarsh to use insulin pumps to deliver hydrocortisone instead of insulin in patients who metabolise hydrocortisone too fast and are unable to receive optimal therapy using tablets. By working out from clearance studies, it is possible using a series of inter-related formulae to calculate the exact amount of hydrocortisone which needs to be delivered on an hourly basis, by the pump, to mimic the normal cortisol circadian rhythm. What has been learned is that it is possible to mimic exactly the normal cortisol circadian rhythm without over or under exposure to hydrocortisone. If the cortisol is right then the other parameters often measured in congenital adrenal hyperplasia such as 17-hydroxyprogesterone and androstenedione follow suit. This means that if we get the cortisol right then everything else will fall into place. Pump therapy has not only got replacement right for these individuals but has also improved their quality of life such that they can do things that people without adrenal problems can do.
Current research is looking to extend these studies and develop better ways of giving hydrocortisone using complex mathematical modelling to refine dosing schedules. In addition, we are using the knowledge of how hydrocortisone works to develop better ways of giving hydrocortisone in emergency situations. Finally, because the 24 hour profile approach is so valuable in getting replacement therapy right we are actively exploring ways of miniaturising the cortisol measurement system for home use.
Professor Hindmarsh has also conducted studies on the production of cortisol and other hormones in both adults and children who do not have any adrenal problems. Cortisol profiles from several patients who use the Peter Hindmarsh pump method are almost indistinguishable when superimposed on normal control profiles obtained from the studies.
- Adrenal disorders
- Diabetes and intensive insulin therapies
- Charmandari E, Johnston A, Brook CGD, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocr 2001; 169: 65-70.
- Charmandari E, Hindmarsh PC, Johnston A, Brook CGD. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Alterations in cortisol pharmacokinetics at puberty. J Clin Endocrinol Metab 2001; 86: 2701-8.
- Charmandari E, Lichtarowicz-Krynska EJ, Hindmarsh PC, Johnston A, Aynsley-Green A, Brook CGD. Congenital adrenal hyperplasia: management during critical illness. Arch Dis Child 2001; 85: 26-8.
- Charmandari E, Pincus SM, Matthews DR, Dennison E, Fall CHD, Hindmarsh PC. Joint growth hormone and cortisol spontaneous secretion is more asynchronous in older females than in their male counterparts. J Clin Endocrinol Metab 2001; 86: 3393-9.
- Charmandari E, Matthews DR, Johnston A, Brook CGD, Hindmarsh PC. Serum cortisol and 17 hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: Is current replacement therapy satisfactory? J Clin Endocrinol Metab 2001; 86: 4679-85.
- Charmandari E, Pincus SM, Matthews DR, Johnston A, Brook CGD, Hindmarsh PC. Oral hydrocortisone administration in children leads to more synchronous joint GH and cortisol secretion. J Clin Endocrinol Metab 2002; 87: 2238-44.
- Roche EF, Charmandari E, Dattani MT, Hindmarsh PC. Blood Pressure in Children and Adolescents with Congenital Adrenal Hyperplasia (21-hydroxylase deficiency): a preliminary report. Clin Endocrinol 2003; 58: 589-96.
- Charmandari E, Pincus SM, Matthews DR, Johnston A, Brook CGD, Hindmarsh PC. Sexual Dimorphism in the Synchrony of Joint Growth Hormone and Cortisol Dynamics in Children with Classic 21hydroxylase Deficiency. J Pediatr Endoc Metab 2003; 16: 111930.
- Bryan SM, Honour JW, Hindmarsh PC.Management of altered hydrocortisone pharmacokinetics in a boy with congenital adrenal hyperplasia using a continuous subcutaneous hydrocortisone infusion. J Clin Endocrinol Metab. 2009; 94: 3477-3480.
- Hindmarsh PC.Management of the child with congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009; 23: 193-208.Khalid JM, Oerton JM, Dezateux C, Hindmarsh PC, Kelnar CJ, Knowles RL.Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Arch Dis Child. 2012; 97: 101-6.
- Krone N, Reisch N, Idkowiak J, Dhir V, Ivison HE, Hughes BA, Rose IT, O'Neil DM, Vijzelaar R, Smith MJ, Macdonald F, Cole TR, Adolphs N, Barton JS, Blair EM, Braddock SR, Collins F, Cragun DL, Dattani MT, Day R, Dougan S, Feist M, Gottschalk ME, Gregory JW, Haim M, Harrison R, Haskins Olney A, Hauffa BP, Hindmarsh PC, Hopkin RJ, Jira PE, Kempers M, Kerstens MN, Khalifa MM, Köhler B, Maiter D, Nielsen S, O'Riordan SM, Roth CL, Shane KP, Silink M, Stikkelbroeck NM, Sweeney E, Szarras-Czapnik M, Waterson JR, Williamson L, Hartmann MF, Taylor NF, Wudy SA, Malunowicz EM, Shackleton CH, Arlt W.Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency. J Clin Endocrinol Metab. 2012; 97: E257-67.
- Peters CJ, Hill N, Dattani MT, Charmandari E, Matthews DR, Hindmarsh PC.Deconvolution Analysis Of 24h Serum Cortisol Profiles Informs The Amount And Distribution Of Hydrocortsione Replacement Therapy. Clin Endocrinol (Oxf) 2013; 78: 347-51.
- Knowles RL, Khalid JM, Oerton JM, Hindmarsh PC, Kelnar CJ, Dezateux C.Late clinical presentation of congenital adrenal hyperplasia in older children: findings from national paediatric surveillance. Arch Dis Child 2014; 99: 30-4.
- Subbarayan A, Dattani MT, Peters CJ, Hindmarsh PC.Cardiovascular risk factors in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 2014; 80: 471-7
- Hindmarsh PC. The child with difficult to control Congenital Adrenal Hyperplasia: is there a place for continuous subcutaneous hydrocortisone therapy. Clin Endocrinol (Oxf). 2014; 81: 15-8.
- Hindmarsh PC, Charmandari E.Variation in Absorption and Half-life of Hydrocortisone Influence Plasma Cortisol Concentrations. Clin Endocrinol (Oxf). 2015; 82: 557-61.
- Krone N, Webb EA, Hindmarsh PC.Keeping the pressure on mineralocorticoid replacement in congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2015; 82: 478-80.
- Maccabee-Ryaboy N, Thomas W, Kyllo J, Lteif A, Petryk A, Gonzalez-Bolanos MT, Hindmarsh PC, Sarafoglou K.Hypertension in children with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2016; 85: 528-34.