A comparison of pituitary-adrenal responses to corticotropin-releasing hormone,hypoglycaemia and metyrapone in children with brain tumours and growth hormone deficiency

To assess hypothalamic-pituitary function, a corticotropin-releasing hormone (CRH) stimulation test was performed in nine children following treatment for brain tumours and in 27 growth hormone deficient (GHD) children whose pituitary adrenocorticotropin (ACTH) secretion was normal. In both groups, CRH tests were compared with ACTH and cortisol responses to insulin-induced hypoglycaemia and with ACTH response to metyrapone stimulation. In the patients with brain tumours (five craniopharyngiomas, two suprasellar germinomas, one cerebellar medulloblastoma and one cerebellar ependymoma), ACTH responses to CRH varied greatly with absent or blunted, normal, and exaggerated reactions. Cortisol and ACTH responses were not always correlated. In GHD children but not in children with brain tumours the responses to CRH, insulin tolerance test and metapyrone test were correlated. The marked variability of the CRH test was possibly caused by compounding factors such as preceding corticosteroid therapy, concomitant desmopressin therapy and spontaneous regeneration of damaged brain structures.     

Fetal endocrine signals and preterm labor

Increased uterine contractility at term and preterm results from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. Cortisol, derived from the fetal adrenal in cases of intrauterine compromise or from the maternal adrenal in response to stress, or generated locally from cortisone in choriodecidual trophoblasts, provides a crucial link to uterine stimulation. Cortisol contributes to the increased production of prostaglandins (PGs) by fetal membranes and the decidua through the upregulation of PG synthase and the downregulation of PG dehydrogenase enzymes. Cortisol also stimulates placental corticotropin-releasing hormone (CRH) output, although CRH may both relax and stimulate uterine activity depending on the distribution and affinity of its receptor subtypes. Other agents such as cytokines may intercede in this sequence to stimulate PGs and/or CRH, giving rise to a cascade phenomenon that results in preterm birth.     

Relationships between adrenocorticotropic hormone and cortisol are altered during clustered nursing care in preterm infants born at extremely low gestational age

BACKGROUND: Little is known about the effects of clustered nursing care on hypothalamic pituitary axis (HPA) responses in preterm infants in the neonatal intensive care unit. AIMS: To examine facial responses, adrenocorticotropic hormone (ACTH) and cortisol levels, and the relationship between ACTH and cortisol in preterm infants in two gestational age groups (extremely low gestational age [ELGA: < or =28 weeks]; very low gestational age [VLGA: 29-31 weeks]) under basal conditions and in response to routine nursing procedures. STUDY DESIGN: Within subjects' cross-over design in random order. SUBJECTS: Ninety preterm infants with no postnatal steroid exposure were studied at 32+/-1 weeks postconceptional age. OUTCOME MEASURES: Facial actions, ACTH and cortisol levels were measured after a 30 minute rest period and in response to routine clustered nursing care (CC). Changes in facial actions were analyzed using repeated measures ANOVA. MANOVA or Mann-Whitney U tests were used to determine differences in ACTH and cortisol between gestational age groups. Spearman rank correlations were used to examine relationships between perinatal variables and facial, ACTH and cortisol levels. RESULTS: All infants had significantly increased facial responses to CC (p=0.001). Infants having experienced higher numbers of skin breaking procedures 24 h before basal assessment had higher basal cortisol levels (r=0.30, p=0.01). In response to CC, ELGA infants showed no correlation between ACTH and cortisol levels; VLGA infants showed a strong, positive correlation (r=0.62, p=0.02). CONCLUSION: The pattern of relationship between ACTH and cortisol differs depending on gestational age at birth in response to clustered nursing care. Prior pain alters responsiveness and HPA dysregulation is apparent in ELGA infants.     

Effect of cerebral hypothermia on cortisol and adrenocorticotropic hormone responses after umbilical cord occlusion in preterm fetal sheep

The hypothalamic-pituitary-adrenal (HPA) axis is essential for adaptation to stress. In the present study, we examined the hypothesis that head cooling with mild systemic hypothermia would adversely affect fetal adrenocorticotropic hormone (ACTH) and cortisol responses to an asphyxial insult. Chronically instrumented preterm fetal sheep (104 d of gestation, term is 147 d) were allocated to sham occlusion (n = 7), 25 min of complete umbilical cord occlusion (n = 7), or occlusion and head cooling with mild systemic hypothermia (n = 7, mean +/- SEM esophageal temperature 37.6 +/- 0.3 degrees C vs 39.0 +/- 0.2 degrees C; p < 0.05) from 90 min to 70 h after occlusion, followed by spontaneous rewarming. During umbilical cord occlusion, there was a rapid rise in ACTH and cortisol levels, with further increases after release of cord occlusion. ACTH levels returned to sham control values after 10 h in both occlusion groups. In contrast, plasma cortisol levels remained elevated after 48 h in both occlusion groups and were still significantly elevated in the hypothermia-occlusion group 2 h after rewarming, at 72 h, compared with the normothermia-occlusion and sham groups. In conclusion, hypothermia does not affect the overall HPA responses to severe asphyxia in the preterm fetus but does prolong the cortisol response.     

Correlation between plasma and salivary cortisol levels in preterm infants

We sought to determine correlations between plasma and salivary cortisol levels in preterm infants in the basal state and after adrenocorticotropic hormone (ACTH) stimulation during the first week of life. Infants (n = 48) were given ACTH or saline solution; each injection was separated by 24 hours. Salivary and plasma cortisol levels correlated at baseline (r = 0.67, P <.0001) and 1 hour after ACTH stimulation (r = 0.40, P =.0047). ACTH increased cortisol levels in plasma from 12.3 +/- 6.4 to 30.3 +/- 13.2 microg/dL (P <.0001) and in saliva from 1.0 +/- 0.8 to 2.6 +/- 1.0 microg/dL (P <.0001). The adrenal response to ACTH can be detected in the saliva of premature newborns during the first week of life.     

危重症时早产儿促肾上腺皮质激素、皮质醇及醛固酮的变化

目的 以血清皮质醇、醛固酮、促肾上腺皮质激素(ACTH)水平作为监测指标,观察危重症对早产儿下丘脑-垂体-肾上腺(HPA)轴相关激素的影响.方法 以出生72 h内的早产儿90例(胎龄<37周)为研究对象,分为胎龄≥34周组及胎龄<34周组,在入院时及日龄7 d、14d行新生儿危重症评分,取最低值进行分组,分为危重组,非危重组;全部患儿分别在入院时及日龄7 d、14d时采血检测血清皮质醇、ACTH、醛固酮水平.结果 (1)危重组血清皮质醇浓度均高于非危重组.日龄≤72 h、胎龄≥34周早产儿危重组与非危重组比较,差异有显著性(t＝-2.263,P=0.029);日龄14 d、胎龄<34周早产儿危重组与非危重组比较,差异有显著性(t=-2.913,P=0.006).(2)在危重组中,日龄≤72 h时,胎龄≥34周组血清皮质醇浓度显著高于胎龄<34周组(t=-2.641,P=0.010);日龄14 d时,胎龄<34周组血清皮质醇浓度显著高于胎龄≥34周组(t=-2.189,P=0.036).(3)胎龄≥34周危重组早产儿血清皮质醇浓度随日龄增加显著下降(F=4.679,P=0.012).(4)ACTH、醛固酮水平危重组与非危重组比较,差异无显著性(P>0.05).结论 早产儿应激发生时机体已具有调节皮质醇分泌的能力,胎龄越大,这种能力越成熟.危重症时早产儿血清皮质醇浓度增高,血清醛固酮、ACTH浓度与疾病的严重程度无显著相关性.     

Response to ACTH in the newborn.

Adrenocortical function was studied in 52 newborn infants who had been divided into three groups: preterm well, preterm ill, and term ill. Basal plasma 17-hydroxyprogesterone concentrations were significantly increased in both groups of preterm infants. There was no significant difference in basal plasma cortisol concentrations, although they were highest in preterm ill infants. All infants responded to adrenocorticotrophic hormone (ACTH) stimulation (36 micrograms/kg intramuscularly) with a two to three fold increase in the concentration of both steroids. The peak plasma 17-hydroxyprogesterone response was significantly higher in preterm ill infants. A subgroup of five infants, who were highly stressed but had undetectable basal plasma cortisol concentrations, also showed an appropriate response to ACTH. The results provide useful reference data to assess adrenal function in the infant of a mother given glucocorticoids during pregnancy. There is also a change from the pattern of fetal adrenal steroidogenesis soon after birth, which may be affected by exogenous ACTH stimulation. Roughly 10% of stressed newborns failed to synthesise cortisol basally; temporary glucocorticoid replacement for such infants may be appropriate.     

The hypothalamic-pituitary-adrenal axis in preterm infants weighing ≤ 1250 g: association with perinatal data and chronic lung disease

The hypothalamic-pituitary-adrenal axis (HPA) was examined in 34 ventilated preterm infants weighing ≤ 1250 g during the first week of life to evaluate the association between adrenal suppression and subsequent chronic lung disease. The second aim of the study was to detect perinatal and clinical differences between the infants with and without persistent suppression of the HPA after completion of dexamethasone treatment for chronic lung disease. To evaluate the HPA, the corticotropin-releasing hormone stimulation test was performed, and the cortisol and adrenocorticotropic hormone (ACTH) levels were measured by radioimmunoassay. No association could be found between the synthesis of cortisol and ACTH at the end of the first week of life and the development of chronic lung disease. After treatment with dexamethasone, baseline cortisol levels < 138 nmol l^-1 were found in 12 infants (46.2%), 8 of whom (30.8%) had cortisol values below 83 nmol l^-1. The perinatal data of these patients did not differ from infants without HPA suppression. However, the infants with cortisol levels < 83 nmol l^-1 after dexamethasone showed a significantly shorter need for mechanical ventilation and supplemental oxygen ( p < 0:01) and a lower incidence of chronic lung disease ( p < 0:05).     

Long-term Treatment with Corticosteroids/ACTH in Asthmatic Children

Hypothalamic-pituitary-adrenal (HPA) function was studied in 23 children with severe bronchial asthma during and after long-term treatment with prednisolone and/or ACTH_1-24 (depot tetracosactrin) by means of ACTH stimulation test and insulin tolerance test. In the 14 children primarily treated with depot tetracosactrin, the Cortisol levels in insulin tests were within normal limits both during and after treatment. An enhanced response to ACTH stimulation was found during the treatment period. During treatment with prednisolone a marked impairment of the adrenocortical function was found, with low basal plasma Cortisol levels and subnormal response to ACTH stimulation, more marked the lower the age at the start of treatment and the higher the dose per kg body weight. After substitution with depot tetracosactrin the HPA-function was restituted, with plasma Cortisol levels within normal limits. Growth hormone levels after insulin induced hypoglycemia were ±7 ng/ml during and after treatment with depot tetracosactrin. As long-term treatment with depot tetracosactrin has little side-effects in terms of suppression of the HPA-axis it is a useful alternative to oral prednisolone in severe asthma in children.     

A randomized, masked study of triiodothyronine plus thyroxine administration in preterm infants less than 28 weeks of gestational age: hormonal and clinical effects

A randomized, placebo-controlled, masked study was conducted of the responses of thyroid parameters, cortisol, and the cardiovascular system to a single dose of triiodothyronine (T(3)) 24 h after birth, followed by a daily dose of thyroxine (T(4)) during 6 wk to infants <28 wk gestational age. Thirty-one infants were assigned to three groups: 1) group A: T(3) 24 h after birth plus daily T(4) during 6 wk; 2) group B: placebo T(3) and T(4) during 6 wk; and 3) group C: placebo T(3) and placebo T(4). T(4), free T(4), T(3), free T(3), reverse T(3), thyroid-stimulating hormone, and cortisol were measured in cord blood and on days 1, 3, 7, 14, 21, 42, and 56. Data on pulse rate, blood pressure, and cumulative dose of inotropic agents were collected. T(3) (0.5 microg/kg) resulted in a plasma increase until day 3. Thereafter, plasma T(3) levels were comparable between the groups. T(4), free T(4), and reverse T(3) were increased in groups A and B during the period of T(4) administration. Thyroid-stimulating hormone suppression was of shorter duration in group A. T(3) and T(4) administration did not have any effect on cortisol levels. We did not find any effects of T(3) or of T(4) administration on the cardiovascular system. A single injection of T(3) (0.5 microg/kg) given 22-26 h after birth only leads to a 2-d increase of T(3) levels and does not have effects on the cardiovascular system. This study does not support the use of T(3) according to our regimen in preterm infants.     

Hormonal factors in the morbidities associated with extreme prematurity and the potential benefits of hormonal supplement.

Cortisol and thyroid hormones are known to modulate the maturation of various fetal organ systems, enzymes, and biochemical pathways. The cortisol furnished by the structural and biochemical immature fetal adrenal gland renders the extremely premature infants relatively cortisol deficient in comparison with the term newborns. The premature infants also have elevated fetal androgens, the production of which persists until approximately 42 weeks of postconceptional age. The androgens produced by the fetal adrenal cortex and the müllerian inhibiting substance produced by the fetal testis have antiglucocorticoid and inhibitory effects on human fetal lung growth and maturation in vitro. Hypothalamic-pituitary-thyroid axis and thyroid function are also immature in extreme prematurity. In addition, there is reduced tissue thyroid hormone responsiveness. Superimposed on this is the reduced thyroid function seen in non-thyroidal illness in which elevated cytokine levels have been implicated. Repeated courses of antenatal steroids and high-dose postnatal dexamethasone appear to be deleterious to lung and brain development. This may be through inhibition of cell replication and catabolism as well as decreased thyroid-stimulating hormone secretion and reduced peripheral conversion of T(4) to T(3). Furthermore, dexamethasone has been found to enhance neurosteroid production in the immature brain, potentially altering brain development. Considered together, the relative cortisol deficiency/androgen excess and reduced thyroid function as well as prolonged high-dose postnatal dexamethasone therapy in these infants may be important factors in their high degree of morbidity. We propose to restrict antenatal steroids to a single course and hypothesize that the overall outcome of low-gestation infants would be improved with (1) hydrocortisone (i.v./p.o.) supplement at a fixed dose of 0.5 mg/kg birth weight every 12 h in infants <30 weeks of gestation from birth till 32 weeks of postconceptional age and (2) T(3) (i.v./p.o.) supplement at a fixed dose of 0.4 microg/kg birth weight every 12 h in those <27 weeks of gestation from birth till 32 weeks of postconceptional age.     

Long-term treatment with corticosteroids/ACTH in asthmatic children. II. Hypothalamic-pituitary-adrenal function

Hypothalamic-pituitary-adrenal (HPA) function was studied in 23 children with severe bronchial asthma during and after long-term treatment with prednisolone and/or ACTH1-24 depot tetracosactrin) by means of ACTH stimulation test and insulin tolerance test. In the 14 children primarily treated with depot tetracosactrin, the cortisol levels in insulin tests were within normal limits both during and after treatment. An enhanced response to ACTH stimulation was found during the treatment period. During treatment with prednisolone a marked impairment of the adrenocortical function was found, with low basal plasma cortisol levels and subnormal response to ACTH stimulation, more marked the lower the age at the start of treatment and the higher the dose per kg body weight. After substitution with depot tetracosactrin the HPA-function was restituted, with plasma cortisol levels within normal limits. Growth hormone levels after insulin induced hypoglycemia were greater than or equal to 7 ng/ml during and after treatment with depot tetracosactrin. As long-term treatment with depot tetracosactrin has little side-effects in terms of suppression of the HPA-axis it is a useful alternative to oral prednisolone in severe asthma in children.     

Adrenal function in sick very preterm infants

Some very preterm neonates admitted to the neonatal intensive care unit show circulatory and respiratory problems that improve after administration of steroids. It is unclear whether these symptoms could be caused by adrenal insufficiency. The objective of our study was to investigate the cortisol levels and the cortisol release from the adrenals after ACTH in very preterm infants with and without severe illness and to find whether a relation exists between adrenal function and outcome. An ACTH test (0.5 microg) was performed on d 4 in 21 very preterm infants (gestational age, 25.6-29.6 wk; birth weight, 485-1265 g). Baseline cortisol and 17-hydroxyprogesterone (17OHP) levels and the cortisol levels 30, 60, and 120 min after ACTH administration were measured. The Score for Neonatal Acute Physiology was used to measure illness severity. All infants showed an increase in cortisol levels after ACTH, but the cortisol levels were significantly lower in the ventilated more severely ill infants. After adjusting for birth weight and gestational age, the mean baseline cortisol levels and cortisol/17OHP ratios were significantly lower and the 17OHP levels significantly higher in the ventilated infants compared with the nonventilated infants. Patients with an adverse outcome had significantly lower baseline cortisol/17OHP ratios and 60-min cortisol levels during ACTH testing (p = 0.002 and p = 0.03, respectively). These data suggest an insufficient adrenal response to stress in sick ventilated very preterm infants with gestational ages younger than 30 wk compared with nonventilated less sick preterm infants. Further studies are required to investigate whether supplementation with physiologic doses of hydrocortisone may benefit the outcome.     

Steroid and growth hormone levels in premature infants after prenatal betamethasone therapy to prevent respiratory distress syndrome

Prenatal maternal therapy with glucocorticoid reduces the incidence of respiratory distress syndrome (RDS) in premature infants. To investigate the effects of this treatment on the fetal endocrine system, we determined serum concentrations of betamethasone, cortisol, dehydroepiandrosterone sulfate, growth hormone, and prolactin in cord blood of 215 treated infants and 117 untreated infants of 26--36 wk of gestation. Cortisol levels are suppressed within 6 hr of betamethasone treatment, decrease to 45% of the concentration in untreated infants (8.4 micrograms/dl), and return to normal by 7 days. Dehydroepiandrosterone sulfate is reduced maximally by 65% and returns to normal concentrations (123.5 micrograms/dl in 7 1/2 days. The suppression of both steroids was similar after treatment with 12 mg betamethasone (acetate and phosphate) daily 2 times or with 6 mg betamethasone (alcohol) twice daily 4 times. Peak betamethasone levels were higher after the 12 mg dose, but the two-treatment regimens produced a similar total exposure of the fetus to elevated serum glucocorticoid activity for 2 1/2 days and decreased plasma activity for the subsequent 4 1/2 days. Treated infants with low cortisol concentrations at birth increased their cortisol levels severalfold after birth in response to either intrapartum asphyxia or RDS. Betamethasone therapy did not affect cord serum prolactin levels, but the concentration of growth hormone was reduced at all ages. The suppression was greatest (53% decrease) among infants of 28 less than 32 wk, and, among older infants, there was a subsequent increase above control levels between 2 and 4 days after treatment. This study indicates that prenatal betamethasone treatment causes a transient suppression of fetal growth hormone and presumably those pituitary hormones which regulate steroid production by both the definitive and fetal zones of the fetal adrenal. However, the suppression of fetal cortisol does not interfere with the pituitary-adrenocortical response to stress after birth.     

Assessing adrenal function in primary care settings with a single sample subcutaneous glucagon test

OBJECTIVE: To test the efficacy of the low-dose glucagon test in assessing adrenal gland function. STUDY DESIGN: Subcutaneous glucagon was used to assess the hypothalamo-pituitary-adrenal gland (HPA) axis in 215 healthy children. Concordance of this test with the low-dose intravenous ACTH test was established for 42 children. Glucagon testing was conducted for 150 minutes after subcutaneous glucagon administration and for 30 minutes after 1 microg intravenous ACTH. RESULTS: Mean peak serum cortisol concentrations were 22.4 +/- 0.6 microg/dL (SEM) after subcutaneous glucagon and 20.0 +/- 0.6 microg/dL after intravenous ACTH. Specificity of 95% was found at peak cortisol concentrations of 9.5 and 12.5 microg/dL for the glucagon and ACTH tests, respectively. Concordance between the glucagon and ACTH tests was 90.5%. CONCLUSIONS: The glucagon test was found to be as good a test of the HPA axis as the ACTH test and had a 90.5% concordance with it. The ease of performing the glucagon test, namely, obtaining a single sample of blood 150 minutes after the subcutaneous administration of glucagon, makes it a useful method of assessing the HPA axis in primary care settings.     

Timing of peak serum cortisol values in preterm infants in low-dose and the standard ACTH tests

The low-dose ACTH test seems to reveal mild cases of adrenal insufficiency and is beginning to be preferred over the standard ACTH test in the evaluation of adrenal suppression both in infants and in adults. The concentration-time profile of plasma cortisol in infants after a low ACTH dose is obscure. In this crossover study, we compared timing of the peak values in the low-dose and the standard ACTH stimulation tests in preterm and full-term infants. We performed the standard ACTH tests (250 microg/1.73 m2) and the low-dose ACTH tests (1 microg/1.73 m2) on 10 infants (26-40 wk gestational age) and measured serum cortisol concentration at 0, 30, 40, 60, and 120 min by RIA. Nine of the infants had received postnatal glucocorticoid treatment, and most of them had also been treated with dexamethasone antenatally. In the low-dose test, the peak values occurred at 30 or 40 min in 9/10 patients. In the standard-dose test, the peak values occurred at 60 or 120 min in 8/10 patients. These results are comparable with those from adults. According to this study, blood samples for the low-dose ACTH test in infants should be taken before dosing and between 30 and 40 min after dosing.     

Comparison of adrenal function tests in children--the glucagon stimulation test allows the simultaneous assessment of adrenal function and growth hormone response in children

The accurate assessment of adrenal function is necessary in many children with suspicion of pituitary insufficiency. The objective of this study was to evaluate the adrenal response during the glucagon stimulation test (GST) and its diagnostic utility in children. A total of 290 children, aged 10.1 +/- 5.0 years, were evaluated for adrenal function using the corticotrophin releasing hormone (CRH) test, the GST, and/or the insulin tolerance test (ITT). Glucagon stimulation provoked a substantial rise in cortisol and adrenocorticotropin (ACTH) that was independent of gender, age, or underlying growth hormone deficiency. There were no differences in peak cortisol levels in the GST compared to the CRH test in pair-wise intra-individual analyses in children with both tests performed within one year (615.4 +/- 30.5 vs 602.8 +/- 22.4 nmol/l, n=52). Similarly, there were no differences in the cortisol response between the ITT and CRH test. Peak cortisol levels in the CRH test correlated with the GST and the ITT. The magnitude of ACTH response, in contrast, was highest in the ITT with a 9.8-fold increase over baseline, while the increase in the GST (3.1-fold) and CRH test (1.6-fold) were more subtle. Since there is controversy concerning reliable cut-off values for adrenal function tests in children, we analyzed cut off levels in 186 children, including 26 children with adrenal insufficiency, using the CRH test. A peak cortisol level of 450 nmol/l provided the best balance of sensitivity (88.5%) and specificity (86.8%), while higher cut-off levels did not increase sensitivity but lost in specificity. In summary, the GST constitutes an1 equally sensitive test for the assessment of adrenal function in children that is not confounded by anthropometric parameters and is generally not accompanied by major side effects. It allows the simultaneous assessment of corticotroph and somatotroph function and may thus constitute a valuable alternative to the ITT.     

Chronic maternal fluoxetine infusion in pregnant sheep: effects on the maternal and fetal hypothalamic-pituitary-adrenal axes

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n = 7, 98.5 microg/kg/d) or sterile water (control, n = 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life.     

Corticotropin-releasing hormone as adrenal androgen secretagogue.

The regulation of adrenarche is one of the enigmas of pediatric endocrinology. Adrenarche is thought to be governed by a dual control mechanism in which an adrenal androgen secretagogue acts upon a zona reticularis primed by ACTH. We hypothesized that corticotropin-releasing hormone (CRH) may serve as adrenal androgen secretagogue. We tested the concept by infusing either saline or human (h) CRH (1 microg/kg/h in saline) over 3 h, after overnight dexamethasone pretreatment, into eight young men within a randomized, cross-over study design. Serum ACTH and dehydroepiandrosterone-sulfate were measured once hourly; DHEA, androstenedione and 17-hydroxy-progesterone were determined at baseline and after 3 h of saline/hCRH infusion. ACTH levels remained unaltered during saline infusion and average ACTH responses amounted to 13 pg/mL (3.3 pmol/L) during hCRH infusion. Neither saline nor hCRH infusion altered 17-hydroxy-progesterone levels. Serum dehydroepiandrosterone-sulfate rose swiftly within 3 h of hCRH infusion and remained unchanged after saline (mean increase 37 versus 1%; p < 0.01). On average, serum DHEA doubled and androstenedione tripled during hCRH infusion, although no changes were observed during saline infusion (p < 0.01). In conclusion, CRH appears to have the capacity to act as adrenal androgen secretagogue. We suggest that the enigma of adrenarche may have an elegant solution, with CRH and ACTH coupled in sequence at the hypothalamic-pituitary level, and in parallel within the zona reticularis, just as they presumably are within the fetal adrenal, which is exposed to CRH of placental origin.     

A 3-year-old girl with Graves' disease with hypoglycemia following transient adrenal hyporesponsiveness

A 3-year-old girl with Graves' disease developed a generalized convulsion as a result of hypoglycemia (25 mg/dL). At the time of the hypoglycemic seizure, her plasma adrenocorticotropin (ACTH) level (1460 pg/mL) was extremely high, but her serum cortisol level (28.4 microg/dL) was relatively low given the severe stress. The cortisol-releasing hormone (CRH) provocation test done after thyroid function had improved revealed normal ACTH and cortisol responses. Since there was no other cause of hypoglycemia, such as hyperinsulinemia, long-term starvation, suddenly advanced emaciation, or prolonged fasting, it was suspected that the transient adrenal hyporesponsiveness was the main cause of hypoglycemia.