CHRONOPHARMACOLOGY OF HYDROCORTISONE AND 9A-ALPHA FLUORHYDROCORTISONE IN TREATMENT FOR CONGENITAL ADRENAL HYPERPLASIA*

MOELLER : GERMANY

ABSTRACT

The conventional treatment of CAH with hydrocortisone (16-19 mg/m2 per day) and 9a-F cortisol (just enough to normalize renin concentrations, started at 17:00 h) was effective in suppressing the early morning rise of 17 OH-progesterone and in turn androgens in abbot 20% of our patients. The present work explored the effect of a modified dosage regimen of the drug in five patients. The schedule was:

03:00 h F 33% = 9a-F-F 33%; 07:00 h F 30%; 12:00 h F 22% = 9a-F-F 33%; 17:30 h F 15% = 9a-F-F 33%.

Monitored levels of circulating 17-OH progesterone, testosterone, and individual urinary 17-ketosteroids showed significant improvement, which was not achieved by giving higher or later doses. Menarche was induced in two girls (bone age 15 years). The modified dosage schedule offers on one hand the possibility of better management of CAH, and on the other hand the other, cuts down the risk of enhanced Cushing-like effects, which in animal models have been related frequently to dosage schedules not corresponding to the circadian rhythm. The difficulty of administering the drugs at 03:00 H should be over come by development of a late releasing preparation.

KEY WORDS:

Chronopharmacology - Congenital Adrenal Hyperplasia - Hydrocortisone - 9a Fludrocortisone - Treatment.

INTRODUCTION

Congenital Adrenal Hyperplasia (CAH) which is due to deficiency of the steroid 21 Hydroxylase, is commonly treated by the administration of 16-19 mg hydrocortisone per m2 body surface area divided into three doses. Persistently elevated levels of circulating renin indicate the continuation of salt wasting which, however, may be compensated as indicated by normal concentrations of electrolytes in serum and urine samples. In conditions of salt wasting, compensated or not, additional therapy with 9 a-F-hydrocortisone is recommended using a dosage large enough to normalize renin concentration (for review see [5]).

This schedule, however, has failed to normalize the elevated 17-OH progresterone and androgen levels in about 5 of our patients. The present study documents the improvement in five such patients through further adaptations the circadian distribution of the doses spaced according to the biorhythm of hormone levels in healthy persons.

PATIENTS

Fifteen patients, aged 6-20 years, were not responding well to the conventional therapy, although good compliance was documented. As adrenal over production of 17-OH progesterone and androgens was not suppressed, bone age and development of pubic hair continued to accelerate. Following this both menarche and the development of breasts in girls and testes in boys were delayed with respect to bone age.

METHODS

The treatment of the patients is shown in Table 1. Plasma steroids and renin were measured by radio immuno assay using commercial reagents. The normal range of activity is 0.6-4.0 ng AT/ml per h in active patients at 08:00 h. The individual 17-Ketosteroid levels in the urine were estimated by (blank?) chromotography as described by Gupta [2].

The circadian profiles of cortisol and 17-OH-progesterone were measured in all patients receiving conventional therapy as well as in five patients whose dosage schedule the unchanged total dose of hydrocortisone.

RESULTS

Figure 1 shows the circadian rhythm (medians) of and 17-OH-progesterone levels in the serum of all 15 patients on conventional therapy. The step shaped line, which shows considerable diurnal variation, gives the threshold levels of cortisol concentration when ACTH released by healthy persons (drawn after Kreiger [3] and Gallagher et al. [2]). Between 03:00 and 06:00 h the cortisol concentrations were below the threshold for ACTH and followed by a pathologically high 17-OH progesterone peak (median 11 ug/dl, miax-(?) 25 ug/dl) falling to lower levels as late as 15:00 h. At 15:00 h the cortisol concentrations again touched the threshold consequently, 17-OH-progesterone levels showed a (?) instead of a continuous decrease. During the night cortisol concentrations were slightly above the threshold, and no over production of 17-OH-progresterone occurred until 03:00. Figure 2a shows the circadian rhythms of cortisol and 17-OH progesterone levels in a 15 year-old girl over 4 consecutive days. On days 1 and 2 she received the conventional therapy and days 3 and 4 the modified one. On conventional therapy the 06:00 h concentrations were 20-25 ug/dl, declining to lower levels not earlier than 21:00 h. These pathologically high values promptly decreased during the modified therapy on days 3 and 4. When the cortisol level fell below the threshold (Fig.1) a peak or a shoulder in the 17-OH-progesterone concentration was visible between 03:00 h and 15:00 h but had disappeared by midnight.

All patients tested according to this therapy schedule showed improvements in the concentrations of 17-OH-progesterone with, however, variable response and intensity. Figure 2b shows the data on the patient with poorest improvement. Here the modified therapy decreased the integrated 17-OH-progesterone concentrations by only 21%.

Five patients who were responding poorly to conventional therapy have now been on the modified therapy for more than a year. In all of these patients elevated morning values of circulating 17-OH-progesterone, testosterone and individual urinary 17-ketosteroids were decreased (Table 2). In two girls menstruation, which was delayed in relation to bone age, occurred 3 months after changing the dosage schedule, and now continues regularly.

DISCUSSIONS

In about 20% of our CAH patients, conventional therapy failed to sufficiently to suppress the adrenal over-production of androgens. Increasing the cortisol dosage, however, induced Cushingoid symptoms, indicating that the inefficacy of the therapy lay more in the circadian distribution rather than in the total daily dose of the drugs. Figure 1 supports this hypothesis: the first dose of cortisol should be given at about 03:00 h in the morning to prevent the well documented dawn adrenal over-activity. the hypothesis is proven by 4 days of circadian investigations in five in-patients (Fig. 2a and b), and are at least 1 year in five out patients (Table 1 and 2).

(1) The consequences of this knowledge follow below:
(1)The cortisol levels should be brought to within a narrow range above the threshold line shown in Fig 1 according to the endogenous circadian rhythm of ACTH in relation to cortisol secretion. Levels below the threshold would result in over production of 17-OH-progeserone and androgens.

In contrast to our results, Winterer et al did not observe significant differences in the mean of 24-h urine level of plasma 17-OH-progesterone or in 24-h urine concentrations of pregnantriol or 17-ketosteorids in their six patients who were kept on sequentially different dosage schedules. The total daily dose, however, was not more than 12.5 mg hydrocortisone per m2, which was lower than ours [8].

(2) The benefit of nocturnal doses of glucocorticosteroids is somewhat controversial. Nieshlag et al. [4] recommended three daily doses, the last one being given as late as possible and comprising about 38% (25%-62.5%) of the total dose (average 30mg/m2), whereby 17-OH-progesterone levels were normalized. In their studies, however, such high doses without exception induced Cushing-like symptoms. Smith et al [6} found no advantage in replacing the afternoon dose of a twice-a-day hydrocortisone schedule by an equivalent nocturnal dose of dexamethasone. On the other hand doses schedules not corresponding to the circadian rhythm do enhance the risk of Cushing-like side effects in animal models [7], indicating that late high evening doses should be avoided.

[3] Our results indicate that neither late nor high evening doses are necessary. for maintaining sufficiently high concentrations until 03:00 in the morning. Early morning adrenal hyper-activity can be suppressed by a 03:00 h dose of hydrocortisone, which is in agreement with the circadian rhythm of cortisol. Of course it is not in agreement for the patients need for deep and continuous sleep. therefore only exceptional patients will accept the modified schedule. These difficulties should be over come by development of a preparation containing hydrocortisone which can be taken at 21:00 h, releasing the drug suddenly and completely 6 hours later.

CONCLUSION

Adaptation of the dosage regimen to the endogenous rythym of circulating cortisol including a 03:00 dose may improve the treatment of problematic CAH patients.

This work was presented in part on the 80th Annual meeting of the Deutshe Gessellschaft for kinderheilkunde, September 16-19, 1984, in Tubingen.