Early Adrenal Insufficiency Research Articles

ODP310 Early Onset Adrenal Dysfunction in Infants with Adrenoleukodystrophy

Abstract Introduction X-linked adrenoleukodystrophy (ALD) is caused by mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein that transports very-long-chain fatty acids (VLCFAs) to peroxisomes for degradation. An early manifestation is primary adrenal insufficiency (AI). Our clinic's protocol to screen for AI involves obtaining a morning cortisol and ACTH every 6 months, followed by cosyntropin (ACTH) stimulation testing if screening ACTH >100pg/mL or cortisol <5μg/dL. The peak incidence of AI is 3-10 years old, however there have been reports of infants as young as 4.5 months. 1 We present 2 asymptomatic boys with ALD demonstrating AI already at 6-7 months. Cases Patient 1 is a 6 month old full-term male with ALD detected on New York state (NYS) newborn screen and a hemizygous pathogenic variant, c.1201C>T, p. R401W in the ABCD1 gene. At 6 weeks, ACTH and cortisol levels were acceptable (table 1). After screening ACTH was elevated(175pg/mL) at 5 months, ACTH stimulation testing was performed at 6 months. Baseline cortisol was 11ug/dL and stimulated cortisol was insufficient at 13ug/dL. There was no hyperpigmentation, but were neurological concerns such as inability to roll over, left arm preference, and waning moro response. A brain MRI was recommended. Patient 2 is a 7 month old full-term male with ALD detected on NYS newborn screen and a hemizygous pathogenic variant, c.1661G>A (p. R554H) in the ABCD1 gene. At 6 weeks, ACTH and cortisol levels were acceptable (table 2). At 7 months, ACTH was elevated (120.7pg/mL). ACTH stimulation testing was performed with baseline cortisol of 6.9ug/dL and insufficiently stimulated cortisol of 13.5ug/dL. Neurological evaluation was normal. Because of inadequate rises in cortisol to ACTH stimulation, stress dosing hydrocortisone was recommended for both patients. Discussion These infants with early onset adrenal dysfunction raise the question of whether the peak incidence of AI is earlier than previously thought. This would not be surprising as VLCFAs were found to accumulate in fetal adrenal glands. Our findings further support the need for widespread newborn screening for ALD, followed by routine adrenal screening consistent with published guidelines to avoid adrenal crisis. In a case series of 2 patients with ALD and early onset AI, the reported mutations were p. R660W and p. R401Q. 1 In patient 1, a mutation at position 401 of the ALD protein was also reported, which stresses the importance of registries to correlate genotypes and phenotypes. Early onset adrenal disease has not yet been correlated with early neurologic disease. However, the neurological changes noted in patient 1 raise this concern and highlight the importance of multidisciplinary clinics with endocrinology and neurology. Sources: 1. Eng, L., & Regelmann, M. O. (2019). Early Onset Primary Adrenal Insufficiency in Males with Adrenoleukodystrophy: Case Series and Literature Review. The Journal of pediatrics,211, 211–214. https://doi.org/10.1016/j. jpeds.2019. 04. 021 Presentation: No date and time listed

Comparison of intraoperative cortisol levels after preoperative hydrocortisone administration versus placebo in patients without adrenal insufficiency undergoing endoscopic transsphenoidal removal of nonfunctioning pituitary adenomas: a double-blind randomized trial.

In this double-blind randomized trial, the necessity of preoperative steroid administration in patients without adrenal insufficiency (AI) undergoing endoscopic transsphenoidal surgery (ETSS) for pituitary adenoma was evaluated. Forty patients with and without AI, defined as a peak cortisol level > 18 µg/dl on the insulin tolerance test or rapid adrenocorticotropic hormone (ACTH) test, undergoing ETSS for nonfunctioning pituitary adenomas were randomly allocated to treatment with either 100 mg of preoperative hydrocortisone (group HC, n = 20) or normal saline (group C, n = 20). The patients with pituitary apoplexy, the use of a drug within the last 3 months that could affect the hypothalamic-pituitary-adrenal axis, or a previous history of brain or adrenal surgery were excluded. Intraoperative cortisol and ACTH levels were measured after anesthesia induction, dura incision, and tumor removal, and at the end of surgery. Intraoperative hypotension, early postoperative AI, and postoperative 3-month pituitary function were investigated. Intraoperative serum cortisol levels were significantly higher in the HC group than in the C group after anesthesia induction (median 69.0 µg/dl [IQR 62.2-89.6 µg/dl] vs 12.7 µg/dl [IQR 8.4-18.2 µg/dl], median difference 57.5 µg/dl [95% CI 33.0-172.9 µg/dl]), after dura incision (median 53.2 µg/dl [IQR 44.9-63.8 µg/dl] vs 6.4 [IQR 4.8-9.2 µg/dl], median difference 46.6 µg/dl [95% CI 13.3-89.2 µg/dl]), after tumor removal (median 49.5 µg/dl [IQR 43.6-62.4 µg/dl] vs 9.2 µg/dl [IQR 5.75-16.7 µg/dl], median difference 39.4 µg/dl [95% CI 0.3-78.1 µg/dl]), and at the end of surgery (median 46.9 µg/dl [IQR 40.1-63.4 µg/dl] vs 16.9 µg/dl [IQR 12.1-23.2 µg/dl], median difference 32.2 µg/dl [95% CI -42.0 to 228.1 µg/dl]). Serum ACTH levels were significantly lower in group HC than in group C after anesthesia induction (median 3.9 pmol/L [IQR 1.7-5.2 pmol/L] vs 6.9 pmol/L [IQR 3.9-11.9 pmol/L], p = 0.007). No patient showed intraoperative hypotension due to AI. Early postoperative AI was observed in 3 and 5 patients in groups HC and C, respectively. The postoperative 3-month pituitary hormone outcomes including ACTH deficiency were not different between groups. Preoperative steroid administration may be unnecessary in patients without AI undergoing ETSS for nonfunctioning pituitary adenomas. However, a further large-scale study is needed to determine whether preoperative steroid administration has a significant impact on clinically meaningful events such as perioperative AI and postoperative 3-month ACTH deficiency in these patients.Korean Clinical Trial Registry no.: KCT0002426 (https://cris.nih.go.kr/cris/).

The Incidence of Long-Term Adrenal Insufficiency Following Unilateral Adrenalectomy is Low: Case Series and Review of Literature

Introduction: Acquired adrenal insufficiency is a known risk of unilateral adrenalectomy. However, the rates of early and prolonged adrenal insufficiency following unilateral adrenalectomy are not well defined in the literature. Patients and Methods: We reviewed a case series of 184 consecutive patients to determine the likelihood of steroid supplementation at 30 days and 1 year following adrenalectomy. 109 lesions were non-functional and 75 (41%) demonstrated functionality, including 33 pheochromocytomas, 20 cortisol-producing adenomas, 19 aldosteronomas, and 3 cases of cortisol-secreting hyperplasia. No patients with a nonfunctional lesion, pheochromocytoma, or aldosteronoma required steroid supplementation following surgery. Eleven of 23 patients (48%) with primary adrenal Cushing syndrome required cortisol supplementation at 30 days, and only 1 patient (4%) necessitated supplementation one year following surgery. Discussion: Approximately 50% of patients with cortisol-producing lesions in the adrenal gland will require supplementation 30-days following surgery. Only 4% will require persistent exogenous steroids at 1-year. Conversely, less than 1% of patients with different types of functional or non-functional tumors required supplementation after surgery. Conclusion: The incidence of adrenal insufficiency following unilateral adrenalectomy is low. A large majority of patients requiring steroid supplementation 30 days following surgery are able to wean off this requirement by 1 year. With this information, we can better counsel our patients and set clearer expectations for the potential need of cortisol supplementation following adrenalectomy

Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis

To assess the effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone on survival without bronchopulmonary dysplasia (BPD) in very preterm infants using an individual patient data meta-analysis. All existing randomized controlled trials testing the efficacy of the prophylaxis of early adrenal insufficiency using low-dose hydrocortisone on survival without BPD were considered for inclusion when data were available. The primary outcome was the binary variable survival without BPD at 36 weeks of postmenstrual age. Among 5 eligible studies, 4 randomized controlled trials had individual patient data available (96% of participants identified; n = 982). Early low-dose hydrocortisone treatment for 10-15 days was associated with a significant increase in survival without BPD (OR, 1.45; 95% CI, 1.11-1.90; P = .007; I2 = 0%), as well as with decreases in medical treatment for patent ductus arteriosus (OR, 0.72; 95% CI, 0.56-0.93; P = .01; I2 = 0%) and death before discharge (OR, 0.70; 95% CI, 0.51-0.97; P = .03; I2 = 0%). The therapy was associated with an increased risk of spontaneous gastrointestinal perforation (OR, 2.50; 95% CI, 1.33-4.69; P = .004; I2 = 31.9%) when hydrocortisone was given in association with indomethacin exposure. The incidence of late-onset sepsis was increased in infants exposed to hydrocortisone (OR, 1.34; 95% CI, 1.02-1.75; P = .04; I2 = 0%), but no adverse effects were reported for either death or 2-year neurodevelopmental outcomes as assessed in an aggregate meta-analysis. This individual patient data meta-analysis showed that early low-dose hydrocortisone therapy is beneficial for survival without BPD in very preterm infants.

90 90 90 Formulas and Symptoms of Adrenal Fatigue Syndrome (AFS) of Adult Men

Early decompressive adrenal fatigues have one of the leading causes of neurological disorders and stroke in pharmaceutical Institutions. Health has the ability of a biological system convert into personal satisfaction. The world health organization (WHO) literature for human health in a broader sense in its 1948 constitution as “a state of complete physical and well-being and not merely the absence of disease or infirmity. It has been subject to controversy, in particular as poor transportation facility in pharmacy institution lacking operational value, the ambiguity in developing low health strategies and because of the problem created by use of the word “social determinants of health†, which makes it practically impossible to achieve healthy environments. Understanding student health and disease with private based co-educational pharmaceutical institution has not transportation facility and low quality food in suburban areas of developing cities in India cannot ignore. Early decompressive adrenal insufficiency has accepted in medical science due to health imbalance. Adrenal fatigue especially from junior students to senior students living with private institution with poor quality of life and facility can translate into permanent disability in the world. We cannot compare adrenal fatigue with joint pain. Adrenal fatigue cannot ignore because it has weaken immunity has unfortunately not measured in the above series.

Adrenal Axis Insufficiency After Endoscopic Transsphenoidal Resection of Pituitary Adenomas.

Hormonal insufficiency of 1 or more pituitary axes can appear after pituitary surgery. Adrenal axis impairment after surgery can lead to serious consequences if not identified and treated. Assess early and late postoperative adrenal insufficiency (AI) and identify the risk factors predicting their occurrence after endoscopic transsphenoidal resection of pituitary adenomas. Retrospective review identified 176 pituitary adenomas resected using an endoscopic transsphenoidal approach. Patients taking steroids preoperatively, Cushing disease patients, and patients with incomplete records were excluded. Sixty-nine patients were excluded according to our exclusion criteria. The study group thus included 107 patients (total of 111 operations). The median age was 50 years (range, 18-89 years). The median duration of follow-up was 30 months (range, 6-74 months). Eighty-three patients (74.7%) had macroadenomas, and 89 (59.3%) had nonfunctional adenomas. Of the 111 procedures, 61 patients (55%) had early AI. Of the 61 patients, 48 patients (79%) were not taking steroids in long-term follow-up, and only 13 (21%) required long-term replacement. Sixteen of the patients undergoing 111 procedures (14.4%) had AI on long-term follow-up. Of those 16 patients, 13 were already taking steroids and 3 had new diagnoses of AI. Age, male gender, and cerebrospinal fluid (CSF) leaks were associated with persistent postoperative AI (P= 0.018, P=0.001,P=0.007, respectively). Hypothalamic pituitary adrenal axis insufficiency is common after endoscopic transsphenoidal surgery. Male gender, age greater than 50 years, visual impairment, and intraoperative CSF leak were correlated with late postoperative AI. More than two thirds of patients in whom early AI developed did not require steroids in the long term.

Brain ultrasonographic findings of late-onset circulatory dysfunction due to adrenal insufficiency in preterm infants.

Purpose:The aim of this study was to characterize the brain ultrasonographic findings of late-onset circulatory dysfunction (LCD) due to adrenal insufficiency (AI) in preterm infants.Methods:Among the 257 preterm infants born at <33 weeks of gestation between December 2009 and February 2014 at our institution, 35 preterm infants were diagnosed with AI. Brain ultrasonographic findings were retrospectively analyzed before and after LCD in 14 preterm infants, after exclusion of the other 21 infants with AI due to the following causes: death (n=2), early AI (n=5), sepsis (n=1), and patent ductus arteriosus (n=13). Results:Fourteen of 257 infants (5.4%) were diagnosed with LCD due to AI. The age at LCD was a median of 18.5 days (range, 9 to 32 days). The last ultrasonographic findings before LCD occurred showed grade 1 periventricular echogenicity (PVE) in all 14 patients and germinal matrix hemorrhage (GMH) with focal cystic change in one patient. Ultrasonographic findings after LCD demonstrated no significant change in grade 1 PVE and no new lesions in eight (57%), grade 1 PVE with newly appearing GMH in three (21%), and increased PVE in three (21%) infants. Five infants (36%) showed new development (n=4) or increased size (n=1) of GMH. Two of three infants (14%) with increased PVE developed cystic periventricular leukomalacia (PVL) and rapid progression to macrocystic encephalomalacia. Conclusion:LCD due to AI may be associated with the late development of GMH, increased PVE after LCD, and cystic PVL with rapid progression to macrocystic encephalomalacia.

Éducation thérapeutique dans l’insuffisance surrénale : un outil encore insuffisamment utilisé pour éviter ou traiter précocement l’insuffisance surrénale aiguë

Acute adrenal insufficiency is a rare, unknown, and life-threatening emergency. It seems therefore essential to help patients gain or maintain the skills they need to prevent or treat early acute adrenal insufficiency, which is the goal of therapeutic education. A program has been implemented within the service focused on patient empowerment.

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia. The proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic-pituitary-gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia. Long-term preservation of normal hypothalamic-pituitary-gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.

A novel DAX1 gene mutation in a Turkish infant with X-linked adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is a rare inherited disorder of the adrenal cortex commonly manifested as an early onset adrenal insufficiency syndrome. A novel DAX1 (NR0B1) gene mutation was detected in a Turkish newborn boy presenting with primary adrenal insufficiency. He was from a family with a history of unexplained death of three male siblings in the neonatal period. This report highlights the value of mutational analysis of the DAX1 gene for definitive diagnosis of AHC as well as for genetic counselling because this disorder shows an X-linked genetic pattern of transmission, providing the possibility of finding new cases even in presymptomatic individuals.

Prevalence and risk factors for delayed adrenal insufficiency after liver transplantation

Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid-free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end-stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained <20 mug/dL, was diagnosed in 23/87 patients (26.4%). Stepwise logistic regression analysis selected as significant predictors of FAGA the cumulative dosage of corticosteroids administered (P < 0.01), the increase in the body mass index after LT (P < 0.01), a low serum cholesterol concentration (P = 0.005), and a high adrenocorticotropin hormone (ACTH) serum level (P < 0.05) at the time CST was performed. In conclusion, FAGA is a common condition among LT recipients who are maintained on prolonged corticosteroid immunosuppressive treatment. Factors associated with FAGA include the cumulative steroid dose, weight changes after LT, and ACTH and cholesterol levels at the time of steroid withdrawal.

Growth and Neurodevelopmental Outcomes After Early Low-Dose Hydrocortisone Treatment in Extremely Low Birth Weight Infants

Low cortisol concentrations in premature infants have been correlated with increased severity of illness, hypotension, mortality, and development of bronchopulmonary dysplasia. A total of 360 mechanically ventilated infants with a birth weight of 500 to 999 g were enrolled in a randomized, multicenter trial of prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia. Mortality and bronchopulmonary dysplasia were decreased in the hydrocortisone-treated patients exposed to chorioamnionitis. We now report outcomes at 18 to 22 months' corrected age. Surviving infants were evaluated with standardized neurologic examination and Bayley Scales of Infant Development-II. Neurodevelopmental impairment was defined as a Mental Developmental Index or Psychomotor Developmental Index of <70, cerebral palsy, blindness or deafness. A total of 252 (87%) of 291 survivors were evaluated. Cerebral palsy was diagnosed in 13% of hydrocortisone-treated versus 14% of placebo-treated infants. Fewer hydrocortisone-treated infants had a Mental Development Index <70, and more of the hydrocortisone-treated infants showed evidence of awareness of object permanence. Incidence of neurodevelopmental impairment was not different (39% [hydrocortisone] vs 44% [placebo]). There were no differences in physical growth measures. Chorioamnionitis-exposed infants treated with hydrocortisone were shorter and weighed less than controls but had no evidence of neurodevelopmental impairment. Among infants not exposed to chorioamnionitis, hydrocortisone-treated patients were less likely to have a Mental Development Index of <70 or to be receiving glucocorticoids at follow-up. Early, low-dose hydrocortisone treatment was not associated with increased cerebral palsy. Treated infants had indicators of improved developmental outcome. Together with the short-term benefit previously reported, these data support additional studies of hydrocortisone treatment of adrenal insufficiency in extremely premature infants.

Placental 11β-HSD2 Activity, Early Postnatal Clinical Course, and Adrenal Function in Extremely Low Birth Weight Infants

The placental enzyme 11beta-hydroxysteroid dehydrogenase-2 (11beta-HSD2) transforms maternal cortisol to inactive cortisone. Fetal glucocorticoid excess due to reduced 11beta-HSD2 activity could make small preterm infants susceptible to early adrenal insufficiency when the maternal cortisol source is no longer sustained. We assessed whether placental 11beta-HSD2 activity is related to early adrenal insufficiency and postnatal clinical course in extremely low birth weight (<1000 g) infants. Mean gestational age of the 44 infants was 26.6 wk (range, 23.7-32.0), birth weight was 747 g (440-981), and relative birth weight was -1.9 SD (-4.9 to 1.0). We determined placental 11beta-HSD2 activity, baseline, and ACTH-stimulated cortisol and assessed illness severity by the Score of Neonatal Acute Physiology (SNAP). One standard deviation decrease in placental 11beta-HSD2 activity corresponded to a 1.85 (95% CI 0.55 to 3.14; p = 0.006) unit increase in SNAP score and 2.9 mm Hg decrease in minimum mean arterial pressure (95% CI 0.3 to 5.6 mm Hg; p = 0.03). Placental 11beta-HSD2 activity was not associated with cortisol concentrations, although the confidence interval of the ACTH-stimulated cortisol was close to zero: 1 SD increase corresponded to 17% (-18% to 49%) increase in ACTH-stimulated cortisol. Moreover, a 1 SD decrease in enzyme activity was associated with a hazard ratio for postnatal glucocorticoid treatment of 1.63 (95% CI 1.00 to 2.65); p = 0.05. In ELBW infants, lower placental 11beta-HSD2 activity is associated with more severe early postnatal illness and hypotension. Although an association with baseline or ACTH-stimulated cortisol was not seen, possible relationships with other components of the hypothalamic-pituitary-adrenal axis remain to be determined.

Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial

Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks' postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks' postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation > or =90%). Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

105 Cortisol Production Rates do not Increase During Critical Illness in Preterm Infants

Background: Controversy exists whether early adrenal insufficiency is present in preterm infants (PIs) or not. Urinary cortisol production rates (CPRs) provides an integrated index of adrenal function. The aim of this prospective study was to compare CPRs between well and ill PIs< 30 weeks gestational age. Methods: PIs were classified according to clinical criteria and the score for neonatal acute physiology (SNAP). All major neonatal glucocorticoid metabolites (GMs) (n= 14) were profiled by gas chromatography-mass spectrometry in 24-h urinary samples. Excretion rates of GMs were summed to calculate CPRs (μg/kg/d/mg creatinine). We developed an own non invasive urine collection procedure using specially manufactured cellulose nappies and extraction by hydraulic press. Results: CPRs were determined in 17 well (27.9 ± 1.8 wk; 1078 ± 321g) and 44 ill (27.3 ± 1.6; 984 ± 257) PIs. Medians of SNAP and CPRs of ill (well) PIs were given in the table, p< 0.051. During the observational period SNAP and CPRs behaved inversely in ill PIs. CPRs were not different in ill vs well PIs during critical illness. Conclusion: Concerning severity of illness, CPRs in ill PIs might reflect inadequate stress reaction. This could reveal persistence of intrauterine mechanisms of cortisol regulation. Supported by DFG grant (HE 3557/1–1) to M.H. and S.A.W.

Impaired urinary cortisol excretion and early cardiopulmonary dysfunction in immature baboons.

Early adrenal insufficiency is associated with cardiopulmonary dysfunction in immature infants. Isolated cortisol levels and ACTH stimulation testing may not adequately show ontogeny of postnatal cortisol secretion nor identify at risk infants. Our objectives were 1) to determine postnatal urinary cortisol excretion rate (UCER) from birth to 14 d in immature baboons and 2) to evaluate the relation between UCER and cardiac performance. UCER was assessed via 6-h blocked urine collections from birth to 336 h of age in twenty-one 125-d gestation (term = 185 d) baboons. Urinary cortisol was measured by RIA. Cardiopulmonary parameters were averaged over the same time periods as urine collection. Serial two-dimensional echocardiograms were performed. After 24-h age, a subgroup (n = 8) received up to four doses (0.5-1.0 mg/kg each) of hydrocortisone for refractory hypotension. UCER significantly increased from 0 to 6 h through 66 to 72 h age for non-cortisol-treated infants. Significantly reduced UCER patterns between birth and 24 h were found for animals subsequently requiring cortisol treatment. Cortisol-treated infants had lower mean blood pressure, worse metabolic acidosis, increased fluid needs, and impaired left ventricular function between 12 and 48 h of age. No group differences were found in gas exchange or ventilator support. We conclude that adrenal cortisol secretion significantly improves over the initial 72 h of life in the 125-d immature baboon. Failure to increase UCER after 12-24 h of life correlated with poor cardiovascular function that improved with hydrocortisone therapy. Adrenal hypofunction in the immature baboon is similar to the very preterm human and could serve as a model for future postnatal investigations.

Cortisol and adrenocorticotropic hormone response to surgical stress (splenectomy) in thalassemic patients

Many vital organs, including the endocrine glands, are affected by iron deposition in thalassemic (Thal.) patients. Involvement of the adrenal gland, although not uncommon, is usually not clinically evident, especially in non-stressful situations. Although the pituitary-adrenal axis (PAA) has been evaluated by several investigators, the impact of surgical stress has not yet been assessed. Do Thal. patients have an adequate adrenocorticotropic hormone (ACTH) cortisol response upon surgical insult? The PAA of 27 (8 female, 19 male) Thal. patients aged 4-15 years (mean 8.96) admitted during 1996-1997 for splenectomy was evaluated before and after surgical stress. Blood samples for measurement of ACTH and cortisol were taken 1 day before and about 2 h after the surgical insult. For comparison, 22 (9 female, 13 male) non-thalassemic (N. Thal.) patients aged 3.5-14 years (mean 7.95) admitted for elective laparotomy who had no evidence of chronic disease or malnutrition served as controls. Timing of blood sampling was similar to that of the study group. The cortisol response after surgical stress was significantly higher than baseline for both the Thal. (17.4 +/- 6.3 vs 30.81 +/- 11.49 microg/dl; P < 0.001) and N. Thal. groups (20.65 +/- 9.1 vs 36.87 +/- 11.08 microg/dl; P < 0.001). N. Thal. patients showed significant elevation of ACTH upon surgical stress (72.5 +/- 39.5 vs 129.09 +/- 67.9 pg/ml; P < 0.001), while the difference between pre- and post-stress was not statistically remarkable in Thal. patients (104.15 +/- 60.74 vs 186.8 +/- 246.24 pg/ml; P = 0.123). However, ACTH before operation in Thal. was significantly higher than that of N. Thal. patients (104.15 +/- 60.74 vs 72.5 +/- 39.5 pg/ml; P < 0.042), with no remarkable difference after surgical stress between both groups (186.8 +/- 246.24 vs 129.09 +/- 67.9; P = 0.261). The serum ferritin in 8 of 13 young Thal. patients (4-8 years old) was < 2,000 ng/ml and 2,000-3,000 in the remaining 5, while in the 14 older patients (9-15 years) it was < 2,000 in 5, 2,000-3,000 in 7, and more than 3,000 ng/ml in the oldest 2 (13 and 15 years). The PAA is usually intact and responsive in Thal. patients. However, the underlying cause of the significantly increased preoperative ACTH concentrations may be a decreased adrenal reserve, presumably related to age and iron load. For this reason, the possibility of primary partial or early adrenal insufficiency in spite of adequate but probably less than expected cortisol synthesis before and after surgical stress should be considered in every prepubertal or older Thal. patient.

Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus.

To investigate the relationship of cortisol concentrations during the first week of life to patent ductus arteriosus (PDA), markers of lung inflammation, and respiratory outcome in very low birth weight infants. Newborns <1,500 g birth weight were prospectively enrolled at 2 centers. Serum cortisol was measured 3 times during days 2 to 7 of life. Tracheal lavage was performed on intubated infants and analyzed for interleukin-1beta, -6, and -8, and for total protein, albumin, and alpha-1 protease inhibitor. Infants receiving prenatal glucocorticoids were excluded. We obtained 337 cortisol values from 125 infants. Infants treated for PDA had lower cortisol values after day 2. One hundred thirty-three tracheal fluid samples were obtained on matching days from 71 intubated infants. Cortisol correlated inversely with tracheal interleukins and proteins. Lower cortisol values during the second half of the week correlated with longer duration of supplemental oxygen therapy and with subsequent development of chronic lung disease at 28 days and at 36 weeks. Infants with lower cortisol values in the first week of life had an increased incidence of PDA, increased lung inflammation, and an increased incidence of chronic lung disease. These findings suggest that early adrenal insufficiency may underlie the previously observed association of increased lung inflammation and PDA with adverse respiratory outcome in this population.

Prophylaxis against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants

Prophylaxis against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants

Increased vasopressinergic activity as a possible compensatory mechanism for a normal hypothalamic-pituitary-adrenal axis response to stress in BALB/c nude mice.

A bidirectional relationship between the immune and neuroendocrine systems is now widely accepted. Since it is well known that the thymus plays an important role in the regulation of the immune function, we decided to explore whether a lack of the thymic function may influence hypothalamic-pituitary-adrenal (HPA) axis activity. Eight-week-old female mice of both strains, nude and control BALB/c, were used to study: (a) the in vivo response of the HPA axis to several stress stimuli acting at either the hypothalamic (insulin administration and ether vapor inhalation), pituitary (CRH and vasopressin injections) or adrenal (ACTH treatment) level and (b) the in vitro response of hypothalamic fragments to high KCl (48 mM) stimulation. The results indicate that: (1) basal plasma ACTH and vasopressin levels were significantly (p < 0.05) higher in nude than in control BALB/c mice, whereas basal plasma corticosterone concentrations were similar in both strains of mice; (2) although no significant strain-related difference in the stress-induced ACTH secretion in plasma was found, hypothalamic stimuli were able to induce a significantly (p < 0.05) higher secretion of glucocorticoid in plasma in nude than in control BALB/c mice; (3) the pattern of in vitro hypothalamic CRH release was similar in both strains of animals; however, basal AVP output and that stimulated by 48 mM KCl were significantly (p < 0.05) higher in nude than in control hypothalamic fragments, and (4) whereas hypothalamic CRH, pituitary ACTH and adrenal glucocorticoid contents were similar in both strains, hypothalamic AVP content was significantly (p < 0.05) higher in athymic than in control mice. In summary, our results indicate that nude mice have an increased vasopressinergic function which could contribute to a normal HPA axis activity; thus, adult athymic mice of BALB/c origin could compensate, due to their increased vasopressinergic function, for a robust glucocorticoid release to protect themselves immediately after aggression. It remains to be determined whether this enhanced vasopressinergic function is a result of an early adrenal insufficiency due to congenital deficiency of thymic factors known to stimulate HPA axis function.