Dr Martijn Finken, Prof. Dr. Andries Kalsbeek, Prof. Dr. Stefan Wudy, “Exploring hypothalamus-pituitary-adrenal axis rhythm development across early infancy“, 60000 Euros

In adults and older children the secretion of the stress hormone cortisol is high in the early-morning and declines over the course of the day to a nadir at midnight. In the first year of life, not much is known about the daily rhythm of cortisol secretion. Therefore, infants with an inborn defect of cortisol secretion called congenital adrenal hyperplasia (CAH) are usually supplemented based on clinical experience with 3-4 equal doses of hydrocortisone per day. Between 6 and 12 months of age, a switch towards another scheme is made, with the morning dose being twice as high as the afternoon and evening doses in an attempt to mimic the daily pattern of cortisol secretion as seen later. This strategy is likely to be accompanied by overtreatment with hydrocortisone, which carries risks of cardiovascular diseases and diabetes mellitus in adulthood.
With a team of basic and clinical researchers from The Netherlands and Germany, we aim to study the rhythm of cortisol secretion across infancy, including its predictors and its consequences for brain development, in saliva samples from 60 healthy children up until the age of 1 year. These data will be enriched with subject-level data from published studies, resulting in a large dataset with the aim to develop an algorithm for optimal hydrocortisone dosing in infants with CAH.

Dr Niels Krone, Professor Peter Hindmarsh, Professor Mehul Dattani, Professor Brian Keevil,Establishing novel improved biomarker profiles in congenital adrenal hyperplasia“, 110000 Euros

Individuals with congenital adrenal hyperplasia are at risk to develop significant health problems during their life. Monitoring of CAH control represents a key factor in establishing optimal treatment; however, it is well recognised that this remains suboptimal. We have, therefore, developed a programme of work that will define the circadian pathophysiology of CAH and establish optimised biomarker profiles for CAH monitoring. Firstly, our project will establish a strategy to monitor glucocorticoid exposure and adrenal-specific androgen excess by using novel blood tests and non-invasive strategies. Secondly, we have devised a strategy that will define mineralocorticoid metabolism and improve monitoring of mineralocorticoid replacement therapy. Thirdly, we perform an in-depth analysis of the effects of glucocorticoid treatment on circadian metabolism, which will lead to novel pathophysiological insights and superior expanded biomarker panels to assess metabolic effects. Overall, we believe that the results of our project support an improved personalised approach to CAH management.

Dr. Emanuelle Pignatti,Targeting androgen release in adrenocortical cells to prevent hyperandrogenism in CAH“, 80000 Euros

Congenital Adrenal Hyperplasia (CAH) is a common life-threatening disorder of the adrenal glands characterized by unbalanced production of many steroid hormones. Among these steroid unbalances CAH also features an overproduction of androgens, which causes problems of fetal development and impaired reproduction in the adult. To obviate these conditions, several studies have been so far focused on reducing the production of androgens in adrenal cells, while we propose that also blocking the secretion of androgens from cells is a viable approach. In fact, based on recent initial discoveries, we anticipate that ABCG proteins can transport androgens out of the cells. We want to validate these discoveries and show that inhibition of the ABCG proteins can effectively reduce the amounts of androgens in circulation. This will indicate that the inhibition of the ABCG protein in CAH patients is a therapeutic approach to adrenal steroid excess that is worth testing further.