Total Cortisol Concentrations Research Articles

Live “Free” or Die: Total or Free Serum Cortisol Measure in the Critically Ill

Synopsis: The interpretation of baseline and cosyntropin-stimulated serum total cortisol should be done with respect to the patient's protein status, since hypoproteinemia results in lower-than-expected concentrations of serum total cortisol in critically ill patients, despite an adequate adrenal response as evidenced by measurement of serum free cortisol levels. Source: Hamrahian A et al. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350:1629-1638.

Measurements of serum free cortisol in critically ill patients.

Because more than 90 percent of circulating cortisol in human serum is protein-bound, changes in the binding proteins can alter measured serum total cortisol concentrations without influencing free concentrations of this hormone. We investigated the effect of decreased amounts of cortisol-binding proteins on serum total and free cortisol concentrations during critical illness, when glucocorticoid secretion is maximally stimulated. Base-line serum total cortisol, cosyntropin-stimulated serum total cortisol, aldosterone, and free cortisol concentrations were measured in 66 critically ill patients and 33 healthy volunteers in groups that were similar with regard to sex and age. Of the 66 patients, 36 had hypoproteinemia (albumin concentration, 2.5 g per deciliter or less), and 30 had near-normal serum albumin concentrations (above 2.5 g per deciliter). Base-line and cosyntropin-stimulated serum total cortisol concentrations were lower in the patients with hypoproteinemia than in those with near-normal serum albumin concentrations (P<0.001). However, the mean (+/-SD) base-line serum free cortisol concentrations were similar in the two groups of patients (5.1+/-4.1 and 5.2+/-3.5 microg per deciliter [140.7+/-113.1 and 143.5+/-96.6 nmol per liter]) and were several times higher than the values in controls (0.6+/-0.3 microg per deciliter [16.6+/-8.3 nmol per liter], P<0.001 for both comparisons). Cosyntropin-stimulated serum total cortisol concentrations were subnormal (18.5 microg per deciliter [510.4 nmol per liter] or less) in 14 of the patients, all of whom had hypoproteinemia. In all 66 patients, including these 14 who had hypoproteinemia, the base-line and cosyntropin-stimulated serum free cortisol concentrations were high-normal or elevated. During critical illness, glucocorticoid secretion markedly increases, but the increase is not discernible when only the serum total cortisol concentration is measured. In this study, nearly 40 percent of critically ill patients with hypoproteinemia had subnormal serum total cortisol concentrations, even though their adrenal function was normal. Measuring serum free cortisol concentrations in critically ill patients with hypoproteinemia may help prevent the unnecessary use of glucocorticoid therapy.

Hormonal profile of men with premature balding.

Premature androgenic alopecia has been suggested as a feature of the male equivalent of the syndrome of polycystic ovary. However, the hormonal pattern of men with premature balding has been investigated in only a few studies with inconsistent results. We examined 37 men with premature balding (defined as frontoparietal and vertex hair loss before the age of 30 years with alopecia defined as grade 3 vertex or more on the alopecia classification scale of Hamilton with Norwood modification). The plasma concentrations of total testosterone, dihydrotestosterone, epitestosterone, androstenedione, cortisol, 17-OH-progesterone (17OHP), estradiol, LH, FSH, prolactin, SHBG and TSH and free thyroxine were measured. The frequency of subnormal values in SHBG, FSH, testosterone and epitestosterone (but not in free androgen index) was significant in the balding men. A borderline significant trend was recorded with respect to increased levels in 17OH-P and prolactin. The hormonal pattern of a substantial number of men with premature balding resembles in some respects the hormonal pattern of women with polycystic ovary syndrome.

A comparative study on the effects of a contraceptive vaginal ring NuvaRing® and an oral contraceptive on carbohydrate metabolism and adrenal and thyroid function

Objectives To compare carbohydrate metabolism, adrenal and thyroid function during use of a combined contraceptive vaginal ring (NuvaRing®, NV Organon, Oss, The Netherlands) with those of a combined oral contraceptive. Methods Healthy women aged 18-40 years used either the vaginal ring, delivering 15 μg ethinylestradiol and 120 μg of etonogestrel per day, or a combined oral contraceptive containing 30 μg ethinylestradiol and 150 μg levonorgestrel, for six cycles. Each cycle comprised 3 weeks of use of the ring or the pill followed by 1 ring- or pill-free week. The following parameters were measured at baseline and at the end of cycles 3 and 6: carbohydrate metabolism (glucose, insulin, glycosylated hemoglobin); adrenal function (total cortisol, cortisol binding globulin, dehydroepiandrosterone sulfate); thyroid function (thyroid stimulating hormone, free thyroxine). Results Small and similar increases in insulin were seen in both groups. Concentrations of cortisol binding globulin and total cortisol rose significantly less during ring use than during combined oral contraceptive use (cycle 3, p = 0.0002; cycle 6, p < 0.0001). Levels of dehydroepiandrosterone sulfate did not change in either group. Thyroid stimulating hormone levels increased significantly more in the ring group at cycle 3 (p = 0.0016) but free thyroxine levels were unchanged in both groups. Conclusions Both the vaginal ring and the oral contraceptive have no clinically relevant effects on carbohydrate metabolism, adrenal or thyroid function.

The effect of positive or negative handling on the behavioural and physiological responses of nonlactating heifers

This experiment investigated the effects of positive and negative tactile handling on the stress physiology and behaviour of dairy heifers. Forty-eight 5–14-month-old nonlactating Holstein–Friesian heifers were allocated to one of two handling treatments, either positive or negative tactile handling, over four time replicates. Handling was imposed twice daily, 2–5 min per session and involved moving animals individually along a 64 m outdoor route. The negatively handled heifers took longer to approach within 1 and 2 m of a stimulus person in a standard test, than their positively handled counterparts ( P<0.001) and had a greater flight distance to an approaching stimulus ( P<0.001). The time taken by the heifers to approach within 1 and 2 m of a familiar person was similar to that taken to approach within 1 and 2 m of an unfamiliar person in the standard test ( P<0.05). There was a tendency for heifers to have a greater flight distance from the approaching unfamiliar person than from the approaching familiar person ( P=0.06). The negatively handled heifers had greater ( P<0.05) increases in total cortisol concentrations 5, 10 and 15 min after exposure to a human and had higher ( P<0.05) free cortisol concentrations in the afternoon than the positively handled heifers. It is concluded that the nature of the human contact affects the subsequent behavioural response of heifers to humans. This behavioural response may extend to other humans through the process of stimulus generalisation, although there was some evidence of moderate discrimination. Negative handling results in an acute stress response in the presence of humans and also leads to a chronic stress response. Further research into the effect of these stress responses on milk production and welfare in fearful cows in a commercial situation is suggested.

Muscle hypertrophy, hormonal adaptations and strength development during strength training in strength-trained and untrained men.

Hormonal and neuromuscular adaptations to strength training were studied in eight male strength athletes (SA) and eight non-strength athletes (NA). The experimental design comprised a 21-week strength-training period. Basal hormonal concentrations of serum total testosterone (T), free testosterone (FT) and cortisol (C) and maximal isometric strength, right leg 1 repetition maximum (RM) of the leg extensors were measured at weeks 0, 7, 14 and 21. Muscle cross-sectional area (CSA) of the quadriceps femoris was measured by magnetic resonance imaging (MRI) at weeks 0 and 21. In addition, the acute heavy resistance exercises (AHRE) (bilateral leg extension, five sets of ten RM, with a 2-min rest between sets) including blood samples for the determination of serum T, FT, C, and GH concentrations were assessed before and after the 21-week training. Significant increases of 20.9% in maximal force and of 5.6% in muscle CSA in NA during the 21-week strength training period were greater than those of 3.9% and -1.8% in SA, respectively. There were no significant changes in serum basal hormone concentrations during the 21-week experiment. AHRE led to significant acute decreases in isometric force and acute increases in serum hormones both at weeks 0 and 21. Basal T concentrations (mean of 0, 7, 14 and 21 weeks) and changes in isometric force after the 21-week period correlated with each other (r=0.84, P<0.01) in SA. The individual changes in the acute T responses between weeks 0 and 21 and the changes in muscle CSA during the 21-week training correlated with each other (r=0.76, P<0.05) in NA. The correlations between T and the changes in isometric strength and in muscle CSA suggest that both serum basal testosterone concentrations and training-induced changes in acute testosterone responses may be important factors for strength development and muscle hypertrophy.

Work-related stress in an emergency medical dispatch center

Study objective: Stress is an emergent occupational problem in modern societies. Among workers, medical practitioners are particularly exposed. However, data objectifying stress levels during work time are scarce. The aim of this study was to establish diurnal salivary cortisol levels in a highly stressful work environment, the medical dispatch center of an emergency care unit. Methods: Eight emergency medical dispatchers agreed to be sampled every 2 hours from 9 AM to 7 PM during a usual day of work. Eight matched control subjects sampled during their leisure time were used as a control group. Results: Whatever the time of the day, emergency medical dispatchers showed significantly increased cortisol levels during their work time compared with levels found in the control group. There was a significant difference in the amount of daytime cortisol secretion between control subjects and emergency medical dispatchers (0.345 nmol/L; 95% confidence interval [CI] 0.04 to 0.93 nmol/L), with a mean daytime augmentation of 22.8% in emergency medical dispatchers compared with that in control subjects. In addition, among emergency medical dispatchers, the subjective perception of emotional stress was positively correlated with total cortisol concentrations per day (r =0.78; 95% CI 0.39 to 1). Conclusion: Our data show that work tasks of emergency medical dispatchers led to a hypersecretion of cortisol. Because the damaging effects of persistent cortisol increases on health and cognitive functions are well recognized in human beings, it seems necessary to rapidly identify stressful work situations and targets for organizational improvements to minimize stress in these situations. [Ann Emerg Med. 2003;41:500-506.]

Free Serum Cortisol during the Postoperative Acute Phase Response Determined by Equilibrium Dialysis Liquid Chromatography-Tandem Mass Spectrometry

In severely ill patients low concentrations of the corticosteroid binding globulin are typically found; the aim of this study was to quantify directly free bioactive cortisol concentrations in the sera of postoperative cardiosurgical patients. Serum samples of 12 consecutive patients undergoing aortocoronary bypass surgery taken preoperatively and on the postoperative days 1 to 4 were analyzed. Total serum cortisol was quantified using liquid chromatography-tandem mass spectrometry with an on-line sample extraction system and tri-deuterated cortisol as the internal standard, and free serum cortisol was measured after over-night equilibrium dialysis. Whereas on the first postoperative day, the median total serum cortisol concentration was approximately two-fold increased compared to preoperative samples (preoperatively, 245 nmol/l (interquartile range (IQR) 203-293 nmol/l); first postoperative day, 512 nmol/l (IQR 410-611 nmol/l)), median dialyzable free cortisol concentration was almost seven-fold increased (preoperatively, 14.2 nmol/l (IOR 10.9-20.7 nmol/l); first postoperative day, 98.3 nmol/l (IQR 81.3-134 nmol/l)). On the fourth postoperative day, median free cortisol was still significantly increased compared to baseline sampling (p < 0.05), whereas median total cortisol was not. A median of 5.7% (IQR 5.4-7.0%) of total cortisol was found as free cortisol on the preoperative day, 21.2% (IQR 18.9-23.5%) on the first postoperative day and 10.5% (IQR 9.8-14.0%) on the fourth postoperative day. It is concluded that during the postoperative period the free-to-bound ratio of cortisol is highly variable and that during the acute phase response direct quantification of free bioactive cortisol concentrations seems to be biologically more appropriate than the measurement of total cortisol concentrations.

Influence Of Brackish Water On Survival And Growth Of The Juvenile White Grouper, Epinephelus aeneus

The natural habitat of the white grouper, Epinephelus aeneus, is the Mediterranean Sea, which has a salinity of approximately 35 ppt. As fish species vary in their tolerance of environmental conditions, potential production in specific conditions must be determined empirically. The growth, survival and cortisol level of 1.7 g grouper juveniles grown in diluted sea water (4 ppt) or brackish water (4 ppt) from the Tsofar well in the Arava (southeastern Negev, Israel) was com- pared to the growth of similar fish in sea water (43 ppt). Survival in all treatments was 100%. During the first ten days, the fish grown in brackish water grew significantly less (p&lt;0.01) than the fish grown in full-strength or diluted sea water. There were no significant differences between the treatments during the second growth period or in the final weight (approximately 9 g). Total cortisol concentrations ranged 2.7-4.5 ng/l and did not significantly differ between treatments. Results indicate that the white grouper can flourish in water with salinity as low as 4 ppt and that there are no detrimental chemical factors in the brackish water from the Tsofar well.

Size at birth, gestational age and cortisol secretion in adult life: foetal programming of both hyper- and hypocortisolism?

Recent studies have suggested that lifelong programming of the hypothalamic-pituitary-adrenal (HPA) axis in utero is an important mechanism in explaining the link between small size at birth and adult cardiovascular disease. However, direct evidence from human birth cohorts has so far been contradictory. We set out to study reasons for this discrepancy by examining the relationship between adult HPA axis function and birthweight and body proportions at birth in a group of elderly subjects with detailed birth records. Birth cohort study. Four hundred and twenty-one men and women (mean age 69.5 years, range 65.1-75.8 years) born at term in Helsinki, Finland, during 1924-33, with body size and gestational age at birth recorded. Fasting serum cortisol and cortisol-binding globulin concentrations. The concentration of free cortisol was estimated by their ratio. There was no significant correlation between fasting cortisol concentrations and birthweight in either men or women. However, there was a weak inverse association between fasting cortisol and length at birth in women but not in men. There was also a significant positive association between cortisol and ponderal index in both genders. We found that the association between foetal growth on fasting total and free cortisol concentrations differed in subjects born at different gestational ages. In subjects born before 39 weeks of gestation, both total and free cortisol showed inverse correlations with birthweight (P = 0.02 and P = 0.09, respectively) and length at birth (P = 0.001 and P = 0.02), whereas in subjects born after 40 weeks of gestation there were positive correlations with birthweight (P = 0.06 and P = 0.002) and ponderal index at birth (P = 0.003 and P = 0.003). The interactions between birthweight and gestational age were statistically significant (P = 0.01 for total and P = 0.003 for free cortisol). These data suggest that the relationship between size at birth and cortisol concentrations in adult life is different in subjects born at different gestational ages: both hyper- and hypocortisolism may arise as a consequence of foetal programming of the hypothalamic-pituitary-adrenal axis during intrauterine life.

Dialyzable free cortisol after stimulation with Synacthen®

Objectives To compare the changes in free vs. total serum cortisol concentrations after acute stimulation of the adrenal cortex. Design and methods Paired serum samples of ten individuals taken immediately before and 1 h after stimulation with 250 μg ACTH (1–24) (Synacthen®) given i.v. were analyzed. Total cortisol was quantified using liquid chromatography tandem-mass spectrometry with an online sample extraction system and tri-deuterated cortisol as the internal standard. Free cortisol was measured with the same method after equilibrium dialysis. Concentrations of the corticosteroid-binding globulin (CBG) were determined by radioimmuno assay. Results Total cortisol increased by a mean of 106% (mean basal cortisol 312 nmol/L (SD 140 nmol/L), stimulated 686 nmol/L (SD 163 nmol/L); p < 0.001, paired t-test for differences); no significant change of CBG concentrations was found (874 nmol/L (SD 179 nmol/L) before stimulation, 869 nmol/L (SD 225 nmol/L) after stimulation). The mean increase of free cortisol was 263% (mean basal free cortisol 20.3 nmol/L (SD 13.2 nmol/L), stimulated 73.8 nmol/L (SD 26.7 nmol/L); p < 0.001) and thus substantially more pronounced compared to the increase of total cortisol ( p < 0.01). The ratio of free to total serum cortisol was significantly increased after stimulation (6.1% (SD 1.7%) before stimulation, 10.6% (SD 1.9%) after stimulation; p < 0.001). Conclusions After acute neuroendocrine stimulation of the adrenal cortex the relative increase of free bioactive cortisol concentrations is substantially more pronounced than the increase of total cortisol concentrations.

Status and metabolism of iron in elite sportsmen during a period of professional competition.

The aim of this study was to determine the effect of both acute exercise and maintained training during a period of competition (3 mo, at the start of the season) on iron metabolism in sportsmen on a professional volleyball team. Twelve sportsmen volunteered for this study. The exercise test was performed on a mechanically braked Monark cycle ergometer and consisted of a triangular progressive test. Three blood samples were obtained in each test: at rest, just after exercise, and after recovery. The following hematological parameters were determined: red blood count (RBC), hemoglobin (Hb) and hematocrit (Hto), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), total proteins (TP), serum iron (Fe) and total iron-binding capacity (TIBC), ferritin (FER), transferrin (TRF), haptoglobin (HPT), and serum cortisol (COR) concentrations. We have found changes in hematological and biochemical variables related to Fe metabolism during the study. The changes observed could be the result of hemoconcentration processes after exercise and, at least in part, to physical stress and muscular damage. We conclude that athletes, after a period of adaptation, with a good plan of work/recovery series, undergo a biological redistribution on hematological and biochemical parameters concerning Fe metabolism during the training and competition period. Also, daily Fe supplementation could restore and mask the true repercussions of maintained training observed in other sports.

Free and total cortisol levels in semelparous and iteroparous chinook salmon

Total cortisol, free cortisol and percent free cortisol were all significantly higher in semelparous male chinook salmon Oncorhynchus tshawytscha than in iteroparous and immature fish. The findings suggest that the regulation of both total and free cortisol concentrations may play key roles in mediating the post‐spawning death of semelparous Pacific salmon.

The hypothalamic-pituitary-adrenal response to critical illness.

The maintenance of life depends on the capacity of the organism to sustain its equilibrium via allostasis'-the ability to achieve stability through change. Life-threatening disease induces acute adaptive responses specific to the stimulus and generalized responses when the disturbances are prolonged. These changes are associated with increased activity of the hypothalamic-pituitary-adrenal axis and may have survival value in preparing the body for fight or flight'. There is a shift towards an increase in glucocorticoid production and away from mineralocorticoid and androgen production, as well as an increase in the biological effects of glucocorticoids through an increased cortisol free fraction and an increased glucocorticoid receptor sensitivity. During the prolonged phase, there is a dissociation between high plasma cortisol and low adrenocorticotropin hormone levels, suggesting non-adrenocorticotropin hormone-mediated mechanisms for the regulation of the adrenal cortex. This hypercortisolism is in contrast to the very low dehydroepiandrosterone sulphate level, indicating an imbalance between the immunostimulatory and immunosuppressive adrenocortical hormones. The question is whether the total serum cortisol concentration represents sufficient glucocorticoid biological activity during the prolonged phase of critical illness.

A nonlabeled method to evaluate cortisol production rate by modeling plasma CBG-free cortisol disposition.

This study aimed to develop a nonlabeled method for the measurement of cortisol production rate to evaluate adrenal function. The cortisol production rate determination requires that of cortisol clearance, which is not a parameter but a variable resulting from the saturable binding of cortisol to corticosteroid-binding globulin (CBG). Our method is based on evaluation of the plasma clearance of the CBG-free cortisol fraction. This parameter was evaluated from a pharmacokinetic model of total plasma cortisol disposition that takes into account specific binding of the corticoid to CBG in the plasma. We have shown that the CBG-free cortisol kinetics and CBG-binding parameters thus evaluated are not statistically different from those obtained by the radioisotopic method and equilibrium dialysis, suggesting that the plasma CBG-free cortisol clearance is independent of the total plasma cortisol concentrations and represents the actual parameter of cortisol elimination. We validated this modeling approach by using it to calculate the in vivo entry rate of cortisol mimicked by the perfusion of cortisol at a known rate.

Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: Alterations in Cortisol Pharmacokinetics at Puberty

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis. We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m2 body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1–10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6–16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2–20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9α-fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA. The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; sd, 133.4) compared with the prepubertal (mean, 248.7 mL/min; sd, 100.6) and postpubertal (mean, 292.4 mL/min; sd, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; sd, 12.2) than the prepubertal (mean, 27.1 L; sd, 8.4) patients but not in the postpubertal (mean, 40.8 L; sd, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; sd, 19.4), pubertal (mean, 84.4 min; sd, 24.9), and postpubertal (mean, 96.7 min; sd, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04). These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty.

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis. We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m(2) body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1--10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6--16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2--20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9 alpha-fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA. The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; SD, 133.4) compared with the prepubertal (mean, 248.7 mL/min; SD, 100.6) and postpubertal (mean, 292.4 mL/min; SD, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; SD, 12.2) than the prepubertal (mean, 27.1 L; SD, 8.4) patients but not in the postpubertal (mean, 40.8 L; SD, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; SD, 19.4), pubertal (mean, 84.4 min; SD, 24.9), and postpubertal (mean, 96.7 min; SD, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04). These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.

Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.

A Preliminary Study of Circadian Serum Cortisol Concentrations in Response to a 72-hour Fast in Rheumatoid Arthritis Patients not Previously Treated with Corticosteroids

The aim of the study was to investigate the effects a 72-h fast upon serum total and free cortisol concentrations in RA patients not previously treated with glucocorticoids. Total serum cortisol and transcortin concentrations were measured in four RA patients with active disease at 4-h intervals during two 24-h periods (1200 h-1200 h), the first while eating a normal diet (fed state) and the second during the last 24 h of a 72-h water fast. Free cortisol concentrations were calculated from the total cortisol and transcortin values. The 3-day fast increased overall 24-h free and total cortisol concentrations by 50% and 35%, respectively. This was due largely to a marked increase in nocturnal serum cortisol concentrations during fasting, particularly at 0400 h, when mean total and free cortisol levels were increased by 170% and 260% compared to the fed state. Between 2000 and 0800 h overall total- and free cortisol concentrations were increased by 72% and 99%, respectively. These results suggest that an increase in nocturnal concentrations of cortisol occurs in response to fasting in RA patients not previously treated with glucocorticoids. These increases may mediate the beneficial clinical response previously found in studies of longer fasting periods in RA patients.

Asthma and sex hormones.

A chronic in ammatory state of the airways is considered the hallmark of asthma (1). However, the incidence, severity, and prognosis of asthma can be affected by a number of factors, including the patient's sex and age. The sex of the fetus seems to in uence the development of the respiratory apparatus. In fact, between weeks 28 and 40 of gestation, the lungs are in a more advanced state in females than in males (2), a fact which could explain, at least in part, the higher incidence of respiratory distress in male infants (3). Clinical observations and epidemiologic studies agree that childhood asthma is more frequent in boys than in girls (4). Moreover, in some children, usually boys, asthmatic symptoms that started in infancy disappear around puberty (5), while many girls have the disease only during adolescence (6). Age has been implicated in the severity of asthma. Asthma beginning during adulthood is generally more severe than childhood-onset asthma (7). Asthma that starts around the menopause or in old age is generally quite severe (5). According to two recent epidemiologic investigations, the patient's sex and age affect the hospitalization rate for asthma (8, 9), which is a marker of severity. In the ®rst study (a retrospective study of 33 269 patients), the admission rate of boys in the 0±10-year age group was almost twice that of girls. In the next decade, sex differences in the hospitalization rate were irrelevant, although there was a small, but signi®cant prevalence of females. At all ages above 20 years, hospital admission rates were higher in women than men, with a female/ male ratio ranging from 3:1 in subjects aged 20±50 years to 2.5:1 in those over 50 years of age (8). Similar data were reported by Elliasson (9). Both studies found a relationship between the age and sex of the patient and the severity of the asthma attack as indicated by duration of hospitalization. In fact, the duration of hospitalization increased with age in both sexes; moreover, hospital stays were longer in women over 30 years of age than in men of the same age (8, 9). Abbreviations. FSH: follicle-stimulating hormone; LH: luteinizing hormone; NK cell: natural killer cell; IL-1, -4, -5, -6: interleukin-1, -4, -5, -6; TGF-b: tumor growth factor-beta; PEFR: peak expiratory ow rate. Allergy 2001: 56: 13±20 Printed in UK. All rights reserved Copyright # Munksgaard 2001