Sorry about the post below.  It is very difficult to explain things without diagrams in a way to make it simple and understandable.  I am also not the worlds best at getting what I need to across within writing and hence the mess ups.  I am going to try though to do that here though because half the time people get confused with my posts.  :)

First of all I need to go over how dosing our kids is much much different to the way healthy kids adrenal glands make cortisol because of a misconception that seems to ruminate from HPA becoming active when the doses wears off.  As I said normal kids make cortisol steadily all the time due to the negative feedback loop that exists between that and the Hypothalmus.  this happens then within seconds literally half the time.  So in normal kids they are making cortisol at a steady rate and the adrenals keep adding enough cortisol to keep it at that constant rate in the blood with the aid of the hypothalmus instructing it perhaps every few seconds to release a little more to keep things as they should be.     We all know this occurs because of what can happen within an injury when it suddenly ups the tempo and masive amounts are needed.  or we get stressed and need more perhaps.  Or maybe we excert ourselves and excercise.  We create a deficit for a brief period when this happens and then the hypothalmus repsonds to that at length.  r  So normal kids  make steady amounts all the time and the HPA is therefore always on standby.

Because their cortisol is at a steady rate they only release small amounts at anyone time to keep things ticking over at the right amount and rate for the time of day.  Looking at the Mayo chart for normal cortisol production rate during the day they make it higher first thing at 7-8am and lowest at midnight at around approx three quarters less than they did at 7-8am.  However, they are STILL making it every few seconds and constantly but at lowered amounts that’s all.  At ANYTIME their sleep is disturbed that pattern would surge and they would make more to meet the activity.  However, on average healthy people sleep right through and are in a completely rested state hence their steady low levels up to 3-4am.   From 3am they start to produce ACTH and thus cortisol again and it climbs until it peaks at 8am and then again it declines throughout the day.  They also make GH in this fashion.  You could say that wherever the cortisol lowers, they make more GH in a pulsatile fashion, but their production of it is similar to the production of cortisol and is made to suit the condtions so unlike a CAH’er that cannot make it until their cortisol levels from the last dose lowered, they merely make more when they exert themselves and lower the cortisol levels.  I don’t know if anyone knows it here but GH is made during excercise and excertion also during the day and I think that is because we use up excess cortisol and the levels dip.  So they get more frequent pulses of it throughout the day on and off due to what the cortisol levels are doing.  This ties in because fit people are healthier and are probably getting good generous dollops of GH and more so than someone who does not excercise. 

In sharp contrast because our kids don’t make cortisol at all and we have to replace it there are several ways of doing this.  Twice, three times or four times per day dosing.  This means that on any one of those given doses, their cortisol is higher approx an hour after they first take it and then lower at the other end.  The trick is to maintain their "lower" states so that they don;’t make an excess within that period from one dose to the other of any of the hormones that a normal person would make within that time period.  That althought they make less at one end of the dose period and more at the other end in total what they made was not anymore than a normal healthy person--or that it did not lead to production of androgens because too much 17 OHP was made.  They can check this and do by taking bloods off before the next dose is due to make sure that the 17 OHP is within the normal ranges for a CAH’er. 

So when they do this they can adjust that dose to suit given what they knowabout the levels of 17 OHP and do this with each dose within a 24 hour period.  At 10pm traditionally in conventional dosing this last dose of the day is highest.  this is in stark contrast to what a normal child’s production of cortisol would be as reflected in the Mayo chart.  

Also, when they dose at 7-8am to last an 8 hour period, obviously after 8 hours the dose would be at it’s lowest it will be before the next one is given.  Although the 17 OHP taken off at this time is higher than a normal persons 17 OHP, this as I explained above reflects the fact that they made their 17 OHP much later and not as constantly as a person being dosed cortisol every second because their adrenals are producing it.  The ratios in a normal person of 17 OHP and cortisol are as they would be for that particular instance.  the ratios for our kids at one end just after their dose is given would be very low 17 OHP to very high cortisol ratio unlike a normal person at that instance.  Then 8 hours after that dose the ration would be very low cortisol to very high 17 OHP.  This is the best that can be don given the circumstances, but when you think about it, what they did not get in the first few hours, they more than make up for and catch up in the latter part of the time period before the next dose.  As long as they don’t make so much that androgens are made and they are at a level between 500-1000ng/dl when bloods are drawn off just before the next dose then they would be ok. 

The same could be said for the dose perhaps given at say 12.00 noon to last until 5.30pm or the dose given at 3pm to last until 10pm. 
The problem of course is that children sleep from anywhere between around 8pm onwards and of course when they often don’t wakeup until 8am the following day--well mine don’t --- and this equals an 11-12 hour gap. As we know hydrocortisone just cannot last that long---not even when the body is rested so it seems going by that abstracton Bioavailability.  This is no surprise because as the 10pm dose wears off the body wants to start making cortisol and this is where the deficit occurs---before a child get’s that first top of the day dose at say 7-8am.    This is from 3-4am in the morning.  The study done by Hindmarsh, Brooke et al and also Moeller reflected this within their blood tests done on the children in that study group. 

So now we know now that even on the conventional dosing where doses are given at 10pm, they did not even cover the child fir the time period (12 hours) that they expect them to.   Also we knew that at THAT time, it was a bigger deal because that was were ACTH is generallt released and the adrenals ramp up in an effort to produce it or where the hypothalmus would expect MORE cortisol.  So effectively, this meant that at a time where they should be making that cortisol, a CAH’er instead would obviously make large amounts of 17 OHP and possibly androgen there.  Not only this but since doing studies on cortisol levels for a normal healthy person, it reflected that cortisol levels were lowering throughout the day until they reached very low levels around midnight, and therefore we knew that in giving a HIGH dose of cortisol at 10pm we were contradicting what SHOULD happen.
 
Coincidentally, WHEN CORTISOL LEVELS ARE LOW (and especially at night) more GH is made.  More so than during the day due to the rise in cortisol levels but nevertheless made for normally healthy folks.   So the dose from 7am and 12.00 noon being the highest in the blood serum reflected the high levels of cortisol in normal folks and consequently less GH production.  The low dose at 5.30pm reflected the lower cortisol levels and the heightened possibility for GH to be produced.  Like attracts like. 

In normal healthy folks however, the GH levels would perhaps not be as high as they were for a normal person at the "same" time they are due for a dose of hydrocortisone, the fact is that they needed to make higher levels than a normal person to make up for the suppression of them just after taking their hydrocortisone earlier.  So these things balance out where it comes to total GH production or ACTH production or 17 OHP production throughout the said dose period.  Get the dose and the time of the dose right and the rest follows suit and should effect a more normal of everything else influneced by such.  The highs and the lows (if the dose is adjusted correctly) should equate to the SAME exposure to such hormones as 17 OHP levels and other hormones within that given period of coverage for a normal person.  Albeit more concentrated at one end and lacking at the other, this is as balanced as we will ever get it dosing so crudely and dosing so far apart. 

So although CAH’er’s 17 OHP look higher just before their doses are due than an average person--this is the reason why. Same for their cortisol levels if taken an hour after their med’s.  They appear higher than a normal persons because they have been given that cortisol all in one go as opposed to at intemittent amounts like a normal person recieves their quota where cortisol is concerned. 

So from the above we can deduce that a CAH ’er has higher levels of all other hormones including GH at a time where cortisol is lower in the blood, but that this reflects the fact that they did not get those hormones on an intermittent baisis because they had a large dose of cortisol at one end of it and a lower amount when the levels declined.
Although they got their dose of 17 OHP or GH all concentrated at one end of that 4-6 hour (or 8 hour ) period, nevertheless they did (if each dose is adjusted to the right amount) get the "same amount" of said hormone the same perod of time as the normal healthy person did overall "throughout" that time period. 

Hopefully you can see now that it is ok for there to be activity and for ACTH to be made from 12.00 midnight.  It needs to be for 17 OHP to be made because that is the only time a child is liely to make up the difference due to the high dose at the outset.  Although they are receiving their replacement on a crude 4-6 or 8 hourly schedule, all other hormones follow suit where their production is concerned eventually, but they have to be made in much cruder amounts to amount to the same exposure as a normal healthy person.

Going back to the 5.30pm dose therefore and your hypothesis that at midnight there is possibly some activity.  So that dose at 5.30pm is low?  However, given the above it aptly reflects the level of Gh that should be made in that time period really.   Because a normal child would probably make GH in larger amounts intermittently from 5.30pm to 3am so should our kids make theirs more in that time slot.  Why not really because their not expected to make huge amounts of cotisol, so there should be much less possibility for androgens to be made.  Also they get the GH bang where they are rested as it is in normal children.  They start off at a disadvantage with their 5.30pm dose (albeit small--it is probably more cortisol than a normal kids has in the blood serum at that time really) causing a delayed start where making GH is concerned---but effectively when that dose wears off all they are doing is catching up---but at the right time to catch up.  You could argue that all that 17 OHP made after 3am is just catching up, but I just do not like the idea of giving my child so much cortisol replacement when they are asleep knowing the side-effects on bones and growth in this scenario.  I’d rather give it when it should be given.  When their body is and should be psyching itself up to the big build up at 7am and waking hours.  So as you can see it is actually quite normal for things to start being active from 12.00 midnight or whenever they become active---just make sure that before the next dose those 17 OHP levels are in range and there is not production of androgens.  A child will then be fine.   

The only reason they cannot make GH sooner than 3-4 am in conventional dosing is because obviously the HIGH HIGH dose they were given at 10pm completely obliterates any ability to start making such until much much further on at around 3-4am possibly when it wears off, and there is a super huge amount made there which is far more likely to result in making androgen if it climbs to high.  thats due to the fact that the adrenals want to make more cortisol at that time than they do at say midnight.   

I could not explain the HPA axis normally versus what we are trying to do for kids in circadian dosing or the conventional dosing in anymore a basic way.   I can see that some people are concerned about any androgen production, but the fact is that "each" dose in the day needs to be checked and rechecked by means of blood filter paper testing or 24 hour profiling if your going to get really pickly about that and wanting to run with good 17 OHP ranges to avoid it.  No matter what regime you choose to dose your child with this is the case though, not just circadian dosing I would have thought.   That is also yet another "crude" situation that needs to improve where these kids are concerned.  The type of monitoring that we have needs to change and become a little bit more reflective of each dose to make sure the dose is accurate.  As we have blood spot testing and the technology there is no reason why any childs doses cannot be checked at home over a 24 hour period to make sure that they are covered where that is concerned. 

That explanation above should also help you to undertand why our kids 17 OHP levels are very different to normal children when measured.  Why they can look lower than normal childrens ( eg when bloods are taken an hour after they have taken med’s) or very much higher if bloods are taken just before their morning meds are due.  Unlike normal children they just did 12 hours without any doses of cortisol, so their 17 OHP results reflect the higher ranges.

Hope that is a better explanation anyway.  LOL!

Regards,

Anne-Marie