Jorg Winterer

CORTISOL PRODUCTION RATE IN CHILDHOOD AND ADOLESCENCE

We studied the daily cortisol production rate in 33 normal children and adolescents, using a stable isotope-dilution technique employing high-performance liquid chromatography-mass spectrometry. Two indwelling intravenous catheters were inserted and tracer 9,12,12-2H3-cortisol (deuterated cortisol) was infused continuously for 30 hours. After 6 hours of tracer infusion to allow for equilibration, blood was obtained every 20 minutes for 24 hours. The mean (+/- SD) cortisol production rate was 9.5 +/- 2.5 mg/day (6.8 +/- 1.9 mg/m2/day). Cortisol production rate did not vary with sex or pubertal stage. These results suggest that the cortisol production rate in children and adolescents is significantly lower than previously estimated.

Caloric balance, brain to body ratio, and the timing of menarche

Caloric availability regulates female reproductive function. Menses do not normally occur until the amount of stored fat is sufficient to meet the nutritional requirements of pregnancy. Unusual energy drains such as heavy exercise cause a reversible cessation of menses. The brain appears to monitor the balance between the availability of calories and their utilization, and reproduction is suppressed when the balance is unfavorable. We postulate that the juvenile human brain, with its unique metabolic requirements, constitutes an important energy drain in the premenarchal girl, and that caloric utilization by the brain may explain the delay of reproductive competence in man. It follows that the changing energy requirements of the brain relative to the body during normal premenarchal growth may play a key role in the timing of menarche. Pathological examples of altered brain to body ratios support this hypothesis: an increase of the brain to body ratio has been observed to delay menarche, a decrease of the brain to body ratio to advance menarche. We explore several clinical implications of this hypothesis and present suggestions for its experimental evaluation.

Effect of hydrocortisone dose schedule on adrenal steroid secretion in congenital adrenal hyperplasia

To explore the potential effect of dose schedule on the adrenal suppressive action of hydrocortisone in congenital adrenal hyperplasia, eight patients (six with 21-hydroxylase deficiency and two with 11-hydroxylase deficiency) were given five different dose schedules. Two of the schedules used single daily doses (morning or evening), two twice daily doses (two-thirds dose in the morning or evening), one and three equal doses at morning, noon, and night. Each dose schedule used the same total daily hydrocortisone dose (12.5 mg/m2/day), which is within the normal range of hydrocortisone production rate. Each schedule was given for 4 to 6 weeks. The different dose schedules caused the predicted alterations in the temporal pattern of adrenal steroid levels, with the greatest apparent suppression during the 2 to 4 hours after each dose. None of the schedules, however, caused significant differences in the mean 24-hour plasma concentration of 17-hydroxyprogesterone (21-hydroxylase deficiency) or 11-deoxycortisol (11-hydroxylase deficiency) or in the 24-hour urine pregnanetriol or 17-ketosteroid concentrations, either in the six patients undertreated at the dose of 12.5 mg/m2/day or in the two patients adequately treated. Nocturnal administration of all or a part of the daily dose did not improve adrenal suppression. These observations suggest that treatment of congenital adrenal hyperplasia with a once-a-day hydrocortisone dose schedule may be as effective as conventional multiple-dose schedules. Until this hypothesis has been tested by more extended clinical studies, however, we do not recommend a once-a-day schedule. Regardless of the dose schedule, the total daily hydrocortisone dose must be adjusted to achieve a normal rate of growth and bone age advancement.

The hypothalamic-pituitary-adrenal axis in infantile malnutrition.

We studied the circadian rhythm and the response of the hypothalamic‐pituitary‐adrenal (HPA) axis to ovine corticotrophin releasing hormone (oCRH) stimulation and dexamethasone suppression in 32 children with grade II‐III marasmus. Children were studied prior to and after nutritional rehabilitation. Mean baseline plasma cortisol concentrations were elevated at admission and decreased significantly after nutritional rehabilitation. Mean±SEM plasma cortisol response to oCRH increased from a basal of 480 ±41 to a peak of 582 ± 58 nmol/1 at the time of admission, and from a basal of 234±27 to a peak of 532±41 nmol/1 after caloric rehabilitation. Dexamethasone suppression in the malnourished group was associated with a decrease in the mean±SEM basal plasma cortisol concentration from 397±44 to 171 ±44 nmol/1. After caloric rehabilitation, basal cortisol levels decreased from 259±27 to 22±5 nmol/l following dexamethasone. Our results support the concept that malnutrition is associated with decreased responsiveness to oCRH and incomplete dexamethasone suppression, and that these abnormalities are restored after nutritional rehabilitation.

Thermal stability of a long-acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH)

The stability of solutions of a long-acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH [LHRHa] after heating to 60C for 5 days, after repeated freezing and thawing, and after refrigeration at 4C for 8 days has been examined. None of the treatments caused a detectable alteration in the HPLC profile, and none caused a significant change in biological activity in vivo. It is concluded that D-trp6-pro9-NEt-LHRH can withstand mild heating, repeated freezing and thawing, and short-term refrigeration without apparent change in HPLC profile or biological activity. It is also concluded that the results obtained with the HPLC method correlate well with the results from the in vivo bioassay.

Effect of Hydrocortisone Dose Schedule on Adrenal Steroid Secretion in Congenital Adrenal Hyperplasia

Glucocorticoid therapy has greatly improved the clinical management of children with congenital adrenal hyperplasia (CAH). However, maintaining an optimal therapeutic regimen throughout childhood is difficult because of the narrow therapeutic index of glucocorticoids-overtreatment causes Cushing’s syndrome and poor growth, while undertreatment results in accelerated skeletal maturation, premature epiphyseal fusion, and short adult stature. The mean adult height of 30 men with C A H who had received conventional glucocorticoid therapy was only at the fourth percentile of the normal population.’ The mean adult height of 26 women with CAH in whom treatment was begun during the first year of life approximated the 25th percentile for normal women.’ This suggests that currently recommended regimens for this disorder might be further improved. One approach to improve the effectiveness of glucocorticoid therapy has been to seek an optimal dose schedule for glucocorticoid administration. Acute (two day) studies in normal subjects indicated greater effectiveness of nocturnal compared to morning or afternoon dexamethasone doses in suppressing adrenal function.’ Nocturnal prednisone, however, was less effective in congenital adrenal hyperplasia than the same dose given twice daily.4 Most children with congenital adrenal hyperplasia have been treated with hydrocortisone or cortisone acetate, and to our knowledge there has been only one study that examined the comparative effectiveness of different hydrocortisone dose schedules. This study found no benefit from replacing the afternoon dose of a 2-dose hydrocortisone schedule with a nocturnal dose of dexamethasone that contained an equivalent amount of glucocorticoid activity.’ The current study was undertaken to compare the adrenal-suppressive effect of a constant dose of hydrocortisone while the time of administration was varied systematically among five treatment schedules. The data have been described in detail elsewhere!

193 CATECHOLAMINE EXCRETION IN PRECOCIOUS PUBERTY

Catecholamine excretion, when corrected for creatinine excretion, decreases throughout childhood, reaching adult levels at age 15. To explore the hypothesis that the pubertal process may play a role in this decrease we measured catecholamine and vanillylmandelic acid (VMA) excretion in 24 hour urine samples from 39 normal children (N) and from 42 children with precocious puberty (PP). The results (mean ± SEM), grouped according to age and pubertal stage, are shown in the Table:Children with precocious puberty had significantly decreased catecholamine and VMA excretion compared to age-matched normal subjects. Catecholamine and VMA excretion in PP decreased with increasing pubertal stage, mirroring the pattern seen in normal puberty.We conclude that puberty is associated with a decreased urinary catecholamine and VMA excretion and that children with precocious puberty have urinary catecholamine and VMA excretion that is decreased for age but appropriate for pubertal stage.