Julia,
If you're giving 3 HC doses/day, I think they should probably be in the neighborhood of ~6-7AM; ~11 AM; and ~4 PM, with the largest dose being the first one of the morning. Laura K. has been studying this like mad, and plotting all sorts of graphs, so hers would be a great brain to pick on this issue. Last I remember, this is approx. the same schedule Laura came up with for at least one of her daughters, with the addition of another 4th dose at ~3 AM. At any rate, if she has moved things around a bit, and fine-tuned her dosing regimen even more, I'm sure she'll be able to give you a great explanation why. I'll pass the buck and let her explain the nitty-gritty details! (Sorry, Laura!)
Just so you have a context in which to evaluate this, this all has to do with the discussion on circadian rhythm, and that article by the British researchers Charmandari, et. al, that was talked about on this mb, back a month, or so, ago. ( I'll paste the abstract in below, again.) In a nutshell, the reason why this article was so interesting was that it studied, apparently for the first time, the relationship between cortisol and 17-ohp levels in two groups of CAH patients---one that was considered to be well-controlled; and another that was considered to be poorly-controlled. Basically, the researchers were trying to see what the different patterns of hormone secretion were in these two different groups. What they found was that irregardless of level of control, 17-ohp was almost always low in the late night-early am hours. This is significant because it indicates that late-evening doses of hc do little to no good. Essentially, nothing much happens in the body for the medication to work on from ~11PM to ~3AM. By the time, cortisol starts to rise at ~3 or 4 AM, whatever dose was given as the last one at night, is pretty eliminated from the system, anyway.
I know that the theory of a late evening dose, and especially a large late evening dose---as you said---has to do with hoping that it sticks around long enough to address the AM rise. But seeing that a dose of HC stays in circulation for ~6 hours (actually, that really depends on the size of the dose, too), if the last dose of the day is taken, say, at ~10 pm, you can see that it is potent during a time when there really isn't much for it to do, but pretty much out of circulation by ~4 AM, when it is really needed. So, in essence, that last dose is nothing more than one big side effect.
I am sure there are no official studies on this, but it has been extremely interesting to me the numbers of parents who report children with very poor growth, but no other classic signs of oversuppression (like weight gain, moon face, etc.), whose children either take a dose very late at night or take the largest hc dose at night, rather than in the morning. Interestingly enough, like your daughter, none of these kids seem to be on very big doses of steroids, what one would assume would be causing the problem. Though I am not sure of the exact mechanism by which this happens, I do know that the reason why glucocorticoids are detrimental to growth, is because they somehow interfere with Growth Hormone secretion, which generally is greatest at night. Doesn't it make sense that poor growth might occur in these kids because of the double-whammy effects of this late evening dose? It does to me, anyway, though---admittedly---I may be looking at things too simplistically.
One last comment: I know that the discussion on this article got sidetracked last time into a discussion on 2 vs. 3 doses of hc/day, and which one was better. Let me just say that this article doesn't try to address the issue of how often one should dose hc. It only addresses the issue of when to dose. Two separate, though related, issues. And the bottom line conclusion it makes is that dosing should take place between 4 AM and 4 PM.
| J Clin Endocrinol Metab 2001 Oct;86(10):4679-85 | Related Articles, Books, LinkOut |
Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?
Charmandari E, Matthews DR, Johnston A, Brook CG, Hindmarsh PC.
London Center for Pediatric Endocrinology, University College London (E.C., C.G.D.B., P.C.H.), London W1T 3AA, United Kingdom.
One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 &mgr;g/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 &mgr;g/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.
PMID: 11600525 [PubMed - in process]