I thought that I would put this at the top. I felt it was needed since we have had so many queries about the whole thing. I hope that this helps other's to understand the study a little better.
Conventional Dosing Defined:
**Giving the largest dose or any dose of steroid in the PM. Say around for example 9-10pm. Perhaps a smallest dose in the afternoon.
The purpose of giving that dose PM dose?
**To make sure that the child's HPA axis (Hypothalamic-Pituitary-Adrenal axis) is switched off.
As we know if this is not achieved children with CAH make high levels of androgens instead of cortisol. This is too be avoided at all cost, especially when levels of 17 OHP reach above 50nmol/L (300 ng/dl) as this causes the problem of growth acceleration and also other androgens are then released such as Androstenedione and Testosterones in large amounts. These are what cause all the negative side-effects such as accelerated growth and pubertal hormones or masculinization in girls. None of which are desirable in small children.
However, the object is only to dose the med's in the correct doses that they need to be across the hole of a 24 hour period and always has been. These children only need cortisol replacement at the level that their own bodies would make it and a tad more to stop side-effects remember? Each dose across a 24hour period will differ as due to recent studies on Circadian variation in these children we see that this is a normal occurance for these children, so they have the same needs where cortisol is concerned throughout the 24 hour period as any healthy person with fully functional adrenals. Below is the chart for 17 OHP which was measured in all the children within the study. All children were having different degrees of severity where CAH is concerned. In other words varying anything from slight to severe impairment where the ability to make cortisol is concerned. they were different ages and they were all on different doses.
17 OHP
Study the times along the bottom of the chart. All children were on the Conventional Dosing regime. This is designed to put steroid into the blood serum and stop the HPA axis from switching on during the night. It was intended to actually provide coverage until the morning dose of Hydrocortisone. However if you study the chart at 8am (which is noted at both left and right of the chart) you will see a large peak where 17 OHP surged within the blood serum for these children. Looking to the right of the chart, find 4am along the bottom. You will see that this is where levels of 17 OHP start to climb in each child within the study. This effectively means that the doses of Hydrocortisone, no matter what amount or what severity of CAH in each child, all shared a common bond in that they were not suppressing 17 OHP sufficiently. In other words, whatever the dose or severity of CAH, Hydrocrotisone does not do the job that it has been given to do in the evening in effect. Study the normal circadian rythyms of cortisol below:
Normal Cortisol Rythyms
We see that there is a large peak at 8am. This correlates with the large peak of 17 OHP on the first chart. It confirms that children with CAH have "normal" circadian rythms where cortisol is concerned because like I stated before they make 17 OHP in large amounts when the pituitary senses that there is not enough cortisol in the blood. Rather like a thermostat sense when the temperature of the room has lowered. It then is sensed by the mechanisms of the central heating and the radiotors come back on and start to bring the temperature of the room back up to the required temperature you set the thermostat to. Imagine that the pituitary does the same. it senses at 4am that the cortisol levels are not high enough for that time in the morning as this is where the 10pm dose of cortisol has reached very los to non-existent levels. or should I say certainly not what they would be normally. That 10pm dose has done nothing therefore it was meant to do. In fact if you study the above chart you will see that from 10pm to 4am the cortisol levels are considerably low marked as a minimum of 1. on the chart infact. Still there and ticking over but in the background. Certainly not as high as they were at 8am. Yet they advocate giving these children a very large dose of Hydrocortisone and in some instances larger than the morning dose! This is where in Conventional dosing the unnecessary side-effects of steroid would be taking place for these children.
GROWTH HORMONE
Growth hormone (GH) usually kicks in two hours after deep sleep occurs. It occurs in short bursts on a negative feedback principle just like the hormones made by the adrenals. However, large doses of cortisol hamper GH. So in effect the large dose taken by these children between 10pm where it is not needed actually is in the wrong place at the wrong time. It not only causes all the side effects asscoiated with corticosteroids. It also hampers the very thing that would help the children to grow between 10pm and 4am also. After 4am when the 17 OHP starts to be secreted in large amounts, this is where our children will be having overly large amounts of 17 OHP and thus other androgenic steroids. These I believe are where our children with CAH would most likely to be growing. I guess really they need to do a study in GH in these children and measure where it is most made to confirm this. (Well this is what I would do if I where a Doctor treating children with CAH).
In the periods where these children are over suppressed, this causes an unpleasant side-effect of bone loss and calcium excretion. So from 10pm to 4am they are having a deficiency in GH and calcium and bone loss is occuring at it's largest amount with conventional dosing.
Here is the chart that they compiled from the same children within that study where cortisol is concerned to confirm the episodes of over suppression in these children.
Cortisol
You will see that from hour 20 on this scale (8pm) the evening dose of steroid is given and if you compare this peak with the peak on the chart given above for normal cortisol levels you will see that it is doing exactly the opposite of what "Normal Circadian Rythms" of cortisol WOULD be doing in these CAH kids. This confirms the over suppression that is occuring in ALL children given a bed time dose of Hydrocortisone. As I do not have to post the side effects of these drugs here (as I beleive you all know what they are and why they occur) this is a basic Layman's explanation of the abstract titled:
"Serum Cortisol & Hydroxyprogesterone Interrelation in Classic 21-Hydroxylase Deficiency : Is Current replacement Therapy Satisfactory?
Can you see studying the chart at around 4am that the cortisol levels from the PM dose of steroid given is falling to low? This correlates with the chart for 17 OHP where the 17 OHP levels start to rise. Here is the chart that we noted in the study done before this by the same doctors on the same children at the same time titled:
"Bioavailability of oral Hydrocortisone."
You will note that one line denoted IV administered Hydrocortisone and the other denoted oral administration. This shows that in these children in the study, that no matter which was used, they were both falling to low and non-existent in the blood serum and excreted in the same time. All the children remember were on the DIFFERENT doses of Hydrocortisone. They all had differing severities of CAH. Therefore what this study proves is that no matter WHAT dose of Hydrocortisone is given---high or low---it is ALL secreted out at the same time. In other words it does not last any longer in some children than it does in others. Also it proves that even if you gave 20mg of Hydrocortisone, it would ALL be out of the blood serum exactly 6-7 hours after secretion. You will note that on Conventional dosing, up to now they have advised us to give the PM dose at or after 10pm. So in other words that pm dose bearly does it's job and they STILL have abnormal levels of 17 OHP during the night between 4am and 8am dose or morning dose.
I note that on the 17 OHP chart it only reads as slightly higher than 200 ng/dl at it's peak. However, although that is not exceeding 50nmol when converted, it concerns me that it is still nevertheless an abnormal amount of 17 OHP in the blood serum for that particular time in the night. GH would probably kick in at this point in time and most certainly there would be a growth spurt. However, since the 17 OHP levels are not as they "Normally" would be, it is my theory that between 4am and 8am when the morning dose of med is given, that abnormally accelrated growth spurts would be taking place and at the wrong time really too. We know that on long term that such acclerated growth spurt are negative in a CAH child as the growth is not "true" growth at the steady rate that it should be at. Also going back to my concerns about emotions and behaviour, I feel it would affect children to be high cortisol levels where they should not be, i.e. in sleep, and then low levels where they are not meant to be. On the Addisons message board we discussed adults feeling fatugued first thing in the morning and wobbly on their feet. This may be because their adrenals did not start making cortisol at 3am as it should do. This I believe is just a rev up before the big peak at 8am.
Hope that this explains both abstract a little better for parents. I felt it needed to go at the top.
Adina: This is what I meant when I stated that your child is both under and over suppressed in a 24 hour period. All kids on conventional dosing are really according to this study. All the side effects apply for BOTH extremes. high androgen and low cortisol and high cortisol. They are ALL getting a wash of both over a 24 hour period and especially so if you dose as they advocate currently.