Hi Sue,

I think you pose some really good questions and make some interesting observations, but I would agree with Anne-Marie that the times you noted for ACTH secretion are not the same ones I’ve seen.  ACTH does follow a day-night rhythm, but it doesn’t peak at Midnight...it peaks at around 8 am.  It generally starts to rise at around 3 am; reaches a sharp peak ~8 am, then gradually decreases to its lowest levels in the nighttime hours. 

Generally, in a "normal" individual, cortisol levels rise in response to ACTH, so the pattern of "normal" cortisol secretion can be expected to follow a similar curve.  When cortisol rises, ACTH then diminishes.

In a CAH person, cortisol levels do not rise, in response to ACTH secretion.  When there is no increase in cortisol, ACTH continues to be be secreted, and androgens are overproduced instead.  

As you said in #1 above, the basic goal of glucocorticoid treatment is to 1. provide replacement cortisol and 2. prevent androgen oversecretion. If one could artificially deliver cortisol in a fashion approximating both the times and amounts that are normally secreted, then---in theory---one should be able to achieve the above with the least amount of side effects.  (Right????).  When talking about when best to give medication, I think this is where the idea of "mimicking circadian rhythm" comes in. 

Re. what you said in #3 and 4 above:  I agree with your basic thinking about the amount of time that a dose of HC stays in circulation.  But if you adjust the times, as per above, you would end up with that 10 pm dose given at ~6 am instead.  I think this is where the "give the largest dose in the am" school of thought comes from.  

I thought what you asked in #5 was a really good question, but from what I’ve read, I believe that the answer to the last part is "no." Regardless of when you dose, I believe the same ACTH rhythms persist. However, I have also read that those rhythms can be abolished in the face of overtreatment. 

I also think that what you asked about a 25- vs. 24- hour cycle is interesting.  The way I understand it, our internal alarms reset themselves daily, based on a 24-hr. light-dark cycle.  So even if we may be naturally "off" a little, I believe our systems would constantly readjust, so this should not be an issue, where dosing is concerned.

Anyway.....my "two cents."  Interesting stuff, isn’t it?