Cortisol Equivalents Research Articles

Abstract 1015: Potential of kava in reducing lung cancer risk and associated disparities: Mechanism-based biomarker discovery and analysis

Abstract Background: Lung cancer is the leading cause of cancer-related deaths. Tobacco smoke is well-recognized as the dominant risk factor. Stress, lung inflammation, air pollution and other factors also contribute to the risk of developing lung cancer Racial/ethnic disparities in lung cancer risks exit as well. The quantitative contributions of different these risk factors to lung cancer and associated disparities, however, have not been systematically characterized. One major barrier is the lack of tools to non-invasively and objectively quantify these risk factors, which precludes the identification of high-risk individuals and the development of effective prevention. Data from our group, particularly results from a pilot clinical trial, suggest that kava, traditionally consumed in the South Pacific Islands as a beverage to reduce stress and promote relaxation, may holistically reduce lung cancer risk by impacting multiple factors that contribute to lung cancer risk. Aim: This study aims to discover mechanism-based non-invasive biomarkers reflective of different lung cancer risk factors and explore their potential roles in lung cancer risk disparities. Such biomarkers are also employed to characterize the holistic effects of kava in reducing lung cancer risk and its potential in mitigating associated disparities. Results and Analysis: One-week of kava significantly reduced the level of nicotine exposure among smokers, quantified by the Total Nicotine Equivalents (TNE) in the 24-h urine sample. Excitingly the reduction in TNE appeared to be higher among African American smokers in comparison to participants of other race/ethnicity. Biomarkers for stress (plasma cortisol and urinary total cortisol equivalents (TCE)) were significantly reduced upon one-week kava use, which may mechanistically contribute to the reductions in tobacco use. The reduction in plasma cortisol and TCE were higher among African American smokers as well. One-week kava exposure also increased urinary excretion of total NNAL and reduced urinary 3-methyladenine (3-mA) in participants, suggestive of its ability to reduce the carcinogenicity of nicotine-derived nitrosamine ketone (NNK). Kava effects on NNAL and 3mA were again more pronounced among African American smokers. Conclusion and future directions: These results demonstrate the potential of mechanism-based biomarkers in investigating lung cancer risks and associated disparities. Such biomarkers may also facilitate the translational development of effective and targeted interventions, such as kava, which may not only reduce lung cancer risk but also mitigate the associated disparities. Additional mechanism-based biomarkers on other tobacco carcinogens and inflammation are currently under development. Two clinical trials are ongoing that the current clinical samples will help validate these discoveries. Citation Format: Chengguo Xing, Breanne Freeman, Jessica Mamallapalli, Allison Lynch, Naomi Fujioka, Ramzi G. Salloum, John Malaty, Frank Orlando, Zhiguang Huo. Potential of kava in reducing lung cancer risk and associated disparities: Mechanism-based biomarker discovery and analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1015.

The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers.

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

Endocrine disrupting compounds affecting corticosteroid signaling pathways in Czech and Swiss waters: potential impact on fish.

This study investigated the occurrence of corticosteroid signaling disruptors in wastewaters and rivers in the Czech Republic and in Switzerland. 36 target compounds were detected using HPLC-MS/MS, with up to 6.4 μg/L for azole antifungals that indirectly affect corticosteroid signaling. Glucocorticoid receptor (GR)-mediated activity was determined using the GR-CALUX bioassay with dexamethasone equivalent concentrations ranging from <LOD-2.6, 19-37, and 78-542 ng/L for river water, treated, and untreated wastewater, respectively. For most samples, the chemically predicted GR-mediated response was higher than that determined by the bioassay. Correspondingly, antiglucocorticoid activity was observed in some fractions. The fish plasma model (FPM), which predicts plasma concentrations, was applied to evaluate the potential of detected pharmaceuticals to cause receptor-mediated effects in fish. With one exception, medroxyprogesterone, the FPM applied to individual compounds predicted fish plasma concentrations to be below the level of human therapeutic plasma concentrations. To account for the activity of the sum of GR-active compounds, we introduce the "cortisol equivalents fish plasma concentration" approach, through which an increase in fish glucocorticoid plasma levels comparable to 0.9-83 ng/mL cortisol after exposure to the analyzed river waters was estimated. The results suggest that these chemicals may impact wild fish.

Serum glucocorticoids and adiponectin associate with insulin resistance in children born small for gestational age

Altered glucocorticoid activity is one possible mechanism linking fetal growth restriction with later insulin resistance (IR) and type 2 diabetes. We aimed to investigate whether serum glucocorticoid parameters are related to IR in children born small for gestational age (SGA). A total of 110 children (55 age- and gender-matched pairs born SGA or appropriate for gestational age (AGA) in a case-control setting) were studied at the mean age of 12.2 (s.d. 0.2) years. Serum cortisol, corticosteroid-binding globulin (CBG), free cortisol index (FCI=cortisol/CBG), and glucocorticoid bioactivity (GBA, transactivation assay) were analyzed and related to serum adiponectin and insulin-like growth factor-binding protein 1 (IGFBP1) concentrations and homeostasis model assessment for IR (HOMA-IR) and QUICKI indices. In the pooled study population, GBA correlated well with cortisol and FCI (r=0.681 and 0.586 respectively; P<0.001 for both). Serum cortisol, CBG, FCI, GBA, HOMA-IR, or QUICKI did not differ between the SGA and AGA subjects, but the SGA children had lower body mass index (P=0.005) and waist circumference (WC) (P=0.001). The mean GBA in the highest GBA quartile was higher among the SGA subjects than among the AGA subjects (138.6 vs 96.4 nmol/l cortisol equivalents, P<0.001). In the SGA children, GBA correlated positively with HOMA-IR (r=0.522, P<0.001) and inversely with adiponectin (r=-0.278, P=0.042) (WC/height ratio adjustments), and in logistic regression analysis, higher GBA (odds ratio (OR) 1.3; P=0.013), lower adiponectin (OR 1.4; P=0.038), and lower IGFBP1 (OR 1.9; P=0.010) associated independently with higher HOMA-IR. These findings suggest that increased glucocorticoid activity and low serum adiponectin concentrations associate with IR in SGA children.

Circulating Glucocorticoid Bioactivity During Peroral Glucocorticoid Treatment in Children and Adolescents With Inflammatory Bowel Disease

Our objective was to investigate the changes in circulating glucocorticoid bioactivity (GBA) at the onset of systemic glucocorticoid therapy in pediatric patients with inflammatory bowel disease. Prednisolone (1 mg/kg/d) or budesonide (9 mg/d) was introduced as a single daily dose, and the patients (n=22) were subsequently followed up at 2 to 4 week intervals. The limit for a raised value of serum GBA was defined in pediatric patients (mean+2 SD; 118 nM cortisol equivalents; n=142). Two weeks of prednisolone brought about an increase in serum GBA from 84+/-14 to 336+/-38 nM cortisol equivalents (mean+/-SE; P<0.001). Young patients (<10 y) had similar GBA values to older patients, even though their prednisolone dose was higher (1.3 vs. 0.79 mg/kg; P<0.05). Patients treated with budesonide displayed a minor increase in GBA (151+/-20 vs. 267+/-21 nM cortisol equivalents after 4 wk of treatment; P<0.05; n=3), and when switched to prednisolone (n=2), their GBA level increased 3-fold. GBA levels did not predict the development of glucocorticoid-related side effects. Prednisolone doses used in the treatment of pediatric inflammatory bowel disease patients elicit a 4-fold increase in serum GBA that is significantly higher than the increase induced by budesonide. The GBA measurement is an additional tool for assessing steroid therapy at an individual level during systemic glucocorticoid treatment.

Detection of Multiple Hormonal Activities in Wastewater Effluents and Surface Water, Using a Panel of Steroid Receptor CALUX Bioassays

It is generally known that there are compounds present in the aquatic environment that can disturb endocrine processes, for example via interaction with the endogenous hormone receptors. Most research so far has focused on compounds that bind to the estrogen and/or androgen receptor, but ligands for other hormone receptors might also be present. In this study, a newly completed panel of human cell derived CALUX reporter gene bioassays was utilized to test water extracts for estrogen (ER), as well as androgen (AR), progesterone (PR), and glucocorticoid (GR) receptor mediated transactivation activity. Effluents from industry, hospital, and municipal sewage treatment plants, as well as tap water and different sources of surface water were tested. The CALUX reporter gene panel showed high sensitivity and specificity to known agonists, enabling discrimination between different receptor based endocrine responses present in the aquatic environment. Our results clearly showed the presence of agonistic activity on the ER, as well as on the AR, PR, and GR in the raw and wastewater and surface water extracts. However, no hormone receptor-mediated transactivation was detected in the drinking water or in the blank water. The levels of estrogenic activity were 0.2-0.5 ng E2-equiv/L for surface water and 0.4-1.0 ng E2-equiv/L for municipal effluents, which was consistent with previous studies. Surprisingly, the other hormonal activities were found to be present in similar or much higher levels. Most notably, glucocorticoid-like activity was detected in all samples, at surprisingly high levels ranging from 0.39-1.3 ng Dex-equiv/L in surface water and 11-243 ng Dex-equiv/L in effluents. When regarding the fact that dexamethasone in the GR CALUX bioassay is a factor 12 more potent than the natural hormone cortisol, results expressed as cortisol equivalents would range up to 2900 ng cortisol equiv/L. Further studies are needed to establish the identity of the active compounds and to understand the significance of the level of activities with regard to human and ecotoxicological risks.

The risk of posterior subcapsular cataracts in granulocyte donors

Therapeutic use of adrenal corticosteroids is a risk factor for the development of posterior subcapsular cataract (PSC). Because corticosteroids are given to donors of apheresis granulocytes (PMNs) to improve yield, this study was performed to determine the prevalence of PSCs in PMN donors relative to a matched control group of apheresis platelet (PLT) donors. This study was a cross-sectional study stratified by age, sex, and lifetime apheresis experience at three sites. Individuals who had made at least five PMN donations preceded by corticosteroids were eligible. The presence of PSC was ascertained by grading digital retroillumination images of both lenses. A random subset of participants underwent clinical eye examinations by ophthalmologists masked as to study group. A logistic regression model was used to compute odds ratios (ORs). Granulocyte donors had given a mean of 13 donations (range, 5-39 donations) over a mean period of 8.5 years (range, 0.3-25.2 years). The mean corticosteroid exposure, in cortisol equivalents, was 2840 mg (range, 1067-9040 mg). Six of 89 PMN donors had photographic evidence of PSCs versus 4 of 89 controls. This difference was not significant (OR, 1.54; 95% confidence interval [CI], 0.46-5.08). Five of 33 PMN donors and 3 of 30 PLT donors had evidence of PSC by clinical examination. This difference was also not significant (OR, 1.61; 95% CI, 0.35-7.39). This study does not support the hypothesis that corticosteroid stimulation of PMN donors is associated with an increased risk of developing a PSC.

Relationship between systemic corticosteroid exposureand growth velocity: development and validation of a pharmacokinetic/pharmacodynamic model

Background: Use of high-dose oral corticosteroids (CSs) can reduce growth velocity (GV) in children, whereas use of low-dose topical CSs has either no effect or transient effects on short-term growth and no effect on final adult height Despite the large body of literature on this topic, some fundamental questions remain concerning the relationship between CS exposure and growth effects. Objectives: The aims of this study were to determine the relationship between CS exposure and GV in children receiving CS therapy for asthma or rhinitis, and to examine whether there is likely to be a link between GV and cortisol suppression. Methods: Data from 32 published studies of the effect on growth of inhaled, intranasal, and oral CSs, includingdelivery by dry powder inhaler, metered-dose inhaler, and aqueous nasal spray, were consolidated by expressing CS exposure in cortisol equivalents using a physiologically based pharmacokinetic/pharmacodynamic approach. The relationship between change in GV and CS exposure in cortisol equivalents was described using a nonlinear sigmoid maximum-effect (E max) model with the following parameters: E max = −5.9 cm/y; steady-state unbound AUC for 50% reduction in GV, in cortisol equivalents = 20,000 ng-h/L; Hill constant= 1.2; and change in GV at zero systemic exposure = 0.06 cm/y. Validation was achieved by comparing the model's predictions with data from 5 studies that were not included in the model development The model was also used to predict the potential of various CS regimens to reduce GV Results: Exploratory data analysis established that change in GV was highly correlated with exposure in cortisol equivalents ( P < 0.001). CSs with high systemic bioavailability by the intranasal route were predicted to have short-term growth effects exceeding the clinical equivalence limit for change in GV (±0.8 cm/y), whereas those with lower bioavailability were predicted to produce systemic exposures below the threshold for significant effects on GV The findings were similar for inhaled CSs and for regimens combining delivery by the intranasal and inhaled routes. In descending order, the model predicted the following ranking of the potential of the various intranasal, inhaled, and oral regimens to reduce GV, expressed as fractions or multiples of the pediatric dose (in μg/d): oral prednisolone 5000 μg/d, 0.14; inhaled beclomethasone dipropionate metered-dose inhaler 400 μg/d, 0.54; inhaled budesonide dry powder inhaler 400 μg/d, 0.66; intranasal triamcinolone acetonide aqueous nasal spray 220 μg/d, 0.74; inhaled triamcinolone acetonide metered-dose inhaler 400 μg/d, 0.75; intranasal beclomethasone dipropionate aqueous nasal spray 336 pg/d, 0.89; inhaled mometasone furoate dry powder inhaler 200 μg/d, 2.4; intranasal budesonide aqueous nasal spray 128 μg/d, 2.5; inhaled fluticasone propionate dry powder inhaler 200 μg/d, 2.6; intranasal mometasone furoate aqueous nasal spray 100 μg/d, 120; and intranasal fluticasone propionate aqueous nasal spray 100 pg/d, 150. Values >1 are predictive of no significant effect on GV The model predicted that a 10% to 15% reduction in plasma cortisol concentration should be detectable at the lower equivalence limit for growth reduction (−0.8 cm/y). The validation procedure showed that the model was capable of predicting the results of the 5 comparative growth studies not included in model development with a correlation coefficient of 0.98. Conclusions: Growth effects appear to be nonlinearly related to CS exposure; therefore, no-effect exposure should be possible for CSs with low systemic exposure. Growth inhibition appears unlikely to occur in the absence of detectable reductions in cortisol concentrations.

Circulating glucocorticoid bioactivity in the preterm newborn after antenatal betamethasone treatment.

Antenatal glucocorticoid treatment of mothers at risk of premature delivery is highly cost-effective in reducing neonatal mortality and morbidity. However, there is only limited information on the actual glucocorticoid bioactivity (GBA) reaching the fetus. By employing a recently developed recombinant cell bioassay, we studied circulating GBA in preterm newborns exposed to the standard antenatal betamethasone regimen (12 mg betamethasone twice, 24-h interval, for the mother; repeated in 7-10 d if required). Plasma GBA and cortisol concentrations were measured in cord blood of 71 infants (mean gestational age, 28.9 wk; range, 24.6-32 wk; mean birth weight, 1208 g; range, 480-2010 g). The median time between the last administered betamethasone dose and birth was 2.0 d. Cord GBA ranged from less than 15.6 to 170 nmol/liter cortisol equivalents. The level was highly dependent on the time between the last betamethasone dose and birth, i.e. infants born shortly (<12 h) after the last steroid dose displayed on average 4-fold higher GBA than that in the reference group (infants with >7 d since the last betamethasone dose before birth or without treatment; 74 vs. 21 nmol/liter cortisol equivalents; P < 0.0001). By contrast, if more than 72 h had elapsed between the last steroid dose and birth, circulating GBA was strongly dependent on cord cortisol (r = 0.85; P < 0.0001; n = 30). In multiple regression analysis adjusted for cord cortisol concentration and the time since the last steroid dose, increased umbilical artery resistance, a sign of severe fetal distress, was associated with lower cord GBA (P = 0.01). In conclusion, antenatal exposure of preterm fetuses to betamethasone causes a sizeable, but brief, peak of supraphysiological GBA, and approximately 3 d after the last betamethasone dose, circulating GBA derives from cord cortisol concentration.

Identifying corticosteroid dose regimens that do not inhibit growth

Rationale Low dose topical corticosteroids (CS) have either no effect on growth velocity (GV) or transient effects without impact on final adult height. Although many growth studies have been conducted; the relationship between CS exposure and GV, the no-effect exposure level and the relative sensitivity of GV versus cortisol suppression as markers of CS exposure, are poorly defined. Methods The data from 32 published stadiometry and knemometry studies were collated and CS exposure estimated in cortisol equivalents (CE, pg.h/mL). This was compared to the annualized ▵GV data (cm/y). Results ▵GV and CE were highly correlated and described by a non-linear sigmoid Emax model. The model predicted rank order potential to reduce GV, expressed as multiples of the pediatric dose (μg/d) were: oral prednisolone (5000μg/d) 0.14 > inhaled beclomethasone (400μg/d) 0.55 > inhaled budesonide (400μg/d) 0.68 > intranasal triamcinolone (220μg/d) 0.77 > inhaled triamcinolone (400μg/d) 0.78 > intranasal beclomethasone (336μg/d) 0.89 > inhaled mometasone (200μg/d) 2.0 > intranasal budesonide (128μg/d) 2.6 > inhaled fluticasone (200μg/d) 2.8 > intranasal mometasone (100μg/d) 120 > intranasal fluticasone (100μg/d) 150. Values >1 predict no significant impact on GV. The model also predicted that a detectable reduction in plasma cortisol should be apparent when ▵GV falls below −0.8cm/y, an equivalence endpoint used in growth studies. Conclusions Since ▵GV was non-linearly related to CS exposure, no-effect dose regimens are possible for CS with low systemic exposure. It also appears unlikely that growth inhibition should occur in the absence of detectable reductions in cortisol.

Termination of pregnancy with mifepristone and prostaglandin suppresses transiently circulating glucocorticoid bioactivity.

Mifepristone is a potent antiglucocorticoid, the administration of which results in a dose-dependent activation of the hypothalamic-pituitary-adrenal axis. However, the net effect of this compound on circulating glucocorticoid activity is not known. We have used a recombinant cell bioassay to study glucocorticoid bioactivity (GBA), measured directly from serum, in 18 women undergoing medical termination of an early pregnancy with 200 mg mifepristone, followed by 0.8 mg misoprostol, a prostaglandin. Increased serum mifepristone was accompanied by an increase in serum cortisol that was insufficient to maintain circulating GBA within the normal (pre-mifepristone) range (34.7-93.8 nM cortisol equivalents); after approximately 43, 46, and 68 h of mifepristone ingestion, the mean serum GBA levels were much lower than the mean pre-mifepristone level (P < 0.0001). At the corresponding times, 16, 13, and 12 women displayed subnormal serum GBA levels (ranges, <15.6-23, <15.6-25.6, and <15.6-32.5 nM cortisol equivalents, respectively). Altogether 11 subjects displayed subnormal serum GBA (range, <15.6-32.5 nM cortisol equivalents) continuously in the presence of high concentrations of mifepristone. Two weeks after mifepristone administration, circulating GBA had returned to normal levels in all subjects. We conclude that 200 mg mifepristone elicits a significant suppression of serum GBA, to one third of the pretreatment value, despite the compensatory increase in the serum cortisol concentration.

Clinical use of antenatal corticosteroids: benefits and risks.

After completing this article, readers should be able to: 1. Describe the rationale for the use of antenatal corticosteroids for human fetal maturation. 2. Delineate recommendations of the 1994 National Institutes of Health Consensus Conference on Antenatal Corticosteroids. 3. Review areas of controversy in the clinical use of antenatal corticosteroids. 4. Describe the potential risks of multiple courses of antenatal corticosteroids. 5. Delineate current recommendations for clinical use of antenatal corticosteroids to promote fetal maturation. Glucocorticoid administration initially was appreciated as a method for accelerating development of the intestine more than 40 years ago. Since that time, developmental effects of these agents have been defined in at least 16 tissues of mammals. More than 30 years ago, while studying the mechanism of initiation of labor in sheep, Liggins made the observation that infusion of corticosteroids into fetal lambs was associated with improved survival and decreased lung disease in animals delivered preterm. Subsequently, numerous studies in cell culture, animal models, and human fetal tissue have delineated the multiple effects of glucocorticoids on the developing lung. These include increases in both the total tissue and alveolar surfactant pools; a decrease in vascular permeability, with less protein leak into the alveolar spaces; enhanced clearance of lung water; maturation of parenchymal structure; increase in lung compliance and maximal lung volume; enhanced response to surfactant treatment; and improvement in respiratory function, outcome, and survival. (See accompanying article on scientific rationale for use of antenatal glucocorticoids.) In 1972, the first randomized clinical trial of administration of antenatal corticosteroids (ANCS) in humans demonstrated decreased mortality and a decreased incidence of respiratory distress syndrome (RDS) in preterm infants born at less than 34 weeks’ gestation, who were treated with betamethasone for at least 24 hours before delivery. Over the ensuing 20 years, multiple clinical investigations continued to document the effectiveness of ANCS on …

Fecal Glucocorticoids Document Stress in Female Barbary Macaques (Macaca sylvanus)

Patterns of received aggression and the endocrine response were related to an increase in fecal glucocorticoid metabolites in an intact semifree-ranging group of Barbary macaque females in order to quantify the social stress incurred over a 20-week observation period. The novel result showed that immunoreactive cortisol and 11-oxoetiocholanolone found in the feces can indeed determine the endocrine response of the adrenal gland after a social stressor. After HPLC separation of pooled fecal samples, EIA analyses using three different assays (corticosterone, cortisol, and 11-oxoetiocholanolone) to quantify immunoreactive steroids showed that the corticosterone EIA had no distinctive immunoreactive peaks. Cortisol and 11-oxoetiocholanolone immunoassays showed respectively four and two immunoreactive substances. Time series analyses revealed a behaviorally initiated increase in concentrations of cortisol and 11-oxoetiocholanolone equivalents. Furthermore, both hormone curves exhibit comparable time functions. Either antibody is very suitable for determining glucocorticoid secretion after periods of stress.

BETAMETHASONE INDUCTION OF LECITHIN SYNTHESIS AND PHOSPHATIDIC ACID PHOSPHATASE IN FETAL LUNG

We studied the effect of maternal glucocorticoid treatment on lecithin synthesis by lung slices and on the activity of three key enzymes (phosphatidic acid phosphatase (PAPase), choline phosphotransferase and phosphatidylglycerolphosphate synthetase) involved in surfactant synthesis. Pregnant rabbits (n=23) were injected with betamethasone (acetate plus phosphate) at 0.25 mg/ kg IM (1 or 2 doses) or with saline (controls), and fetal tissues were obtained at 26 days gestation 12-48 hr after treatment. Glucocorticoid activity in maternal and fetal plasma reached peak levels of 129 and 33 μg/dl cortisol equivalents, respectively, at 1-2 hr and returned to preinjection levels (4.2 and 1.4) between 24 and 48 hr. Treatment significantly increased the rate of choline incorporation into lecithin (pmol/mg tissue/hr) and the activity of PAPase (nmol P/mg protein/min) in lung, but not liver, homogenate. Mean ±SE values are:There was no significant change in the other lung enzymes. We conclude that betamethasone, at a dose equivalent to that used in human prenatal therapy, stimulates both lecithin synthesis and the specific activity of PAPase in fetal rabbit lung.

Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.

Serum glucocorticoid levels were determined in 20 mothers and 43 premature infants who received prenatal betamethasone therapy for prevention of respiratory distress syndrome (RDS). Maternal betamethasone peaked at 75 microg cortisol equivalents per 100 ml 1 h after injection of 12 mg steroid and declined to half by 6 h. Betamethasone in cord blood was 14.3 microg cortisol equivalents per 100 ml at 1 h, decreased to a level of 4.7 at 20 h, and was not detected 2 days after a second dose at 24 h. After the second dose, the mean level of cortisol in cord blood was 5.9 microg per 100 ml compared with 13.05 microg per 100 ml (p less than 0.001) in untreated premature infants. The unbound glucocorticoid activity in treated infants delivered 1-10 h after the second dose (mean, 8.4 microg per 100 ml) is similar to the unbound cortisol level after birth in untreated premature infants who develop RDS. These findings indicate that (a) serum glucocorticoid levels in the physiologic stress range can induce lung maturation in the human and (b) antenatal treatment with this dose of betamethasone does not expose the human fetus to potentially harmful pharmacologic levels of steroid.

A Model for the Circadian-Episodic Secretion of Cortisol

Cortisol measurements were made on plasma obtained every 30 min. for 25 hrs. In a model using a catenary system consisting of adrenals and a body compartment, a cosine function was assumed to reflect the circadian variation in adrenal synthesis of cortisol, a switch function to describe its episodic release and first order kinetics to describe plasma clearance. Data was subjected to computer non-linear regression analysis to obtain least square estimates of model parameters. A correlation coefficient of 0.94 was obtained. Results (mean ± 1 S.D.) on 7/8 normal children (5-17 yrs.) are as follows. Adrenal secretory rate (SR) was 312 ± 84 ug/hr/m2 (or 7.5 ± 2.0 mg/d/m2) with an amplitude of 255 ± 57 ug/hr/m2 giving a mean maximum and minimum SR of 567 and 57 ug/hr/m2, respectively. Adrenal was maximally on 22% of the day and slowly secreting 54%. The results indicate that troughs of plasma cortisol concentration are caused by diminished secretion rather than lack of secretion. Maximal secretion occurred at 7.9 ± 1.9 hrs.A.M. Plasma clearance of cortisol was 104 ± 24 l/d/m2 corresponding to a half-life of 58 ± 11 min. Apparent adrenal content of cortisol equivalents was 337 ± 199 ug/m2(4.5% SR). This method has great potential for assessing adrenocortical metabolism during stress or during glucocorticoid therapy.