Gonadotrophin-secretion in adrenocortical insufficiency: impact of glucocorticoid substitution

In patients with deficient endogenous glucocorticoid production due to primary adrenal insufficiency (n = 4) or bilateral adrenalectomy (n = 2) a rise in LRH-stimulated concentrations of LH was seen following withdrawal of substitution therapy for 84 h. Consecutive re-administration of glucocorticoids (dexamethasone 2.0 mg/day for 3 days) resulted in increased basal concentrations of LH and FSH and a diminished secretory response of LH upon iv LRH (100 micrograms). Five patients substituted with glucocorticoids because of adrenocortical insufficiency presented upon the administration of exogenous ACTH1-24 with unchanged basal and LRH-stimulated concentrations of LH and FSH as compared to a placebo experiment. These data suggest that the withdrawal and subsequent re-administration of gluco-corticoid substitution alters basal and stimulated concentrations of gonadotrophins in patients with adrenocortical insufficiency, thus providing evidence for the importance of adequate glucocorticoid supply in the regulation of gonadotrophin secretion.     

A radioimmunoassay for 3',5'-diiodothyronine.

The present report describes a RIA for 3',5'-diiodothyronine (T2) that can be performed on unextracted serum and which has a lower limit of detectability of 2 ng/dl. Cross-reactivity with other iodothyronines was negligible, except for rT3 which began to demonstrate cross-reactivity when rT3 levels were elevated to 180 ng/dl. Employing this RIA for T2, we have determined that 83 healthy individuals had a mean (+/-SE) serum T2 concentration of 5.0 +/- 0.3 ng/dl, thyrotoxic subjects (n = 12) had a mean T2 level that was elevated to 10.8 +/- 0.8 ng/dl, and each of 6 hypothyroid subjects had undetectable (less than 2 ng/dl) concentrations. Athyreotic patients (n = 8), receiving 0.4 mg T4 daily, had serum T2 concentrations of 15.0 +/- 3.0 ng/dl. Fasting in obese subjects was associated with an increase in serum T2 to 6.9 +/- 0.6 ng/dl from a basal level of 4.4 +/- 0.4 ng/dl in the fed state (P less than 0.01). Despite the fact that rT3 levels may be elevated in amniotic fluid and that rT3 is expected to represent the major source from which extrathyroidal T2 arises, T2 levels were low in amniotic fluid, being undetectable (less than 2 ng/dl) in 9 of 19 samples; the mean (+/-SE) T2 concentration in the 10 detectable samples was 5.4 +/- 1 ng/dl. These data indicate T2 is a normal component of serum and that the majority of serum T2 is probably derived from peripheral conversion. Furthermore, these observations suggest that situations associated with elevated rT3 levels (e.g. thyrotoxicosis and fasting) may also have increased T2 values.     

Serum 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine concentrations during acute heat load.

To determine the changes in thyroid hormone metabolism during short periods of exposure to heat, 30 euthyroid healthy male volunteers (aged 23--40 yr) were placed in a climatic chamber for 2 h (35 C, 50% relative humidity). The subjects were at complete rest during the first hour and performed light work (40 watts) during the second hour. Blood samples for T4, T3 and rT3 were drawn at 0, 60, and 120 min. Rectal temperature and heart rate were monitored continuously. No significant changes in T4, T3, rT3, rectal temperature, or heart rate were observed after the first hour (basal levels, 8.5 +/- 0.3 microgram/dl, 160 +/- 5 ng/dl, 14.5 +/- 2.5 ng/dl, 37.2 +/- 0.1 C, and 78 +/- 8 beats/min, respectively; mean +/- SEM). During the second hour, a significant rise in body temperature was recorded (38.5 +/- 0.1 C), accompanied by a significant decrease in mean serum T3 concentration and a rise in mean serum rT3 concentration, T4 concentration remained unchanged. Our findings suggest that, parallel to the elevation in body temperature, there is a shift in the conversion of T4 to the noncalorigenic rT3 metabolite rather than to T3.     

COMPARATIVE EFFECTS OF SODIUM IPODATE AND IODIDE ON SERUM THYROID HORMONE CONCENTRATIONS IN PATIENTS WITH GRAVES'' DISEASE

Patients with thyrotoxic Graves' disease were treated daily for 10 d with 1 g sodium ipodate, an iodine rich X-ray contrast agent which impairs outer ring (5'-) deiodination of T4 to T3, or with 12 drops of a saturated solution of potassium iodide (SSKI). T4, T3 and reverse T3 (rT3) concentrations were measured before, during, and 5 and 10 d after the administration of each drug. SSKI therapy induced a decrease in the serum T4 concentration from 14.7 +/- 1.3 microgram/dl (mean +/- SE) to a nadir of 7.9 +/- 0.9 on days 9 and 10 of therapy, all values reaching the normal range by day 9; a decrease in the serum T3 concentration from 402 +/- 43 ng/dl to a nadir of 143 +/- 20 on day 10, remaining elevated in all patients until day 5 and decreasing into the normal range in all except one patient on days 9 and 10; and no change in the serum rT3 concentration. Serum T4 and T3 concentrations returned to baseline values 10 d after withdrawal of SSKI. In contrast sodium ipodate therapy induced only a modest decrease in the serum T4 concentration from 15.1 +/- 0.7 micrograms/dl to a nadir on day 9 of 11.3 +/- 1.0 and serum T4 remained above the normal range in most patients until day 8; a striking and rapid decrease (within 12 h) in ther serum T3 concentration from 340 +/- 36 ng/dl to mean values ranging from 79 to 85 during the last 5 d of therapy, with most values below the normal range during the last 3 d; and a marked increase in the serum rT3 concentration from 111 +/- 15 ng/dl to a peak value of 376 +/- 59 on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)     

Seasonal variation and the influence of body temperature on plasma concentrations and binding of thyroxine and triiodothyronine in the woodchuck.

Woodchuck plasma was collected during four seasons of the year and assayed for total and dialyzable (free) T4 and T3 and for rT3. Plasma concentrations of total and free T4 and T3 were higher in the spring (T4, 5.4 +/- 0.6 microgram/dl; free T4, 3.0 +/- 0.4 ng/dl; T3, 202 +/- 22 ng/dl; free T3, 0.51 +/- 0.04 ng/dl) and lower in the prehibernatory fattening period in summer (T4, 2.3 +/- 1.0 microgram/dl; free T4, 1.2 +/- 0.5 ng/dl; T3, 45 +/- 27 ng/dl; free T3, 0.16 +/- 0.10 ng/dl) and fall (T4, 3.2 +/- 1.0 microgram/dl; free T4, 1.3 +/- 0.2 ng/dl; T3, 130 +/- 12 ng/dl; free T3, 0.25 +/- 0.02 ng/dl). In spite of the extremely high concentrations of T3 in the winter (437 +/- 32 ng/dl), free T3 concentrations (0.034 +/- 0.003 ng/dl), when measured at the appropriate temperature for hibernation, were significantly lower than those found at other seasons of the year. Plasma binding of T3 was lower during the summer and increased again to approximately double the spring value during the winter. rT3 was at or below the sensitivity of the method (6 ng/dl) at all seasons. It is suggested that the wide seasonal variations in thyroid hormone concentrations and altered plasma protein binding may represent important adaptations influencing the metabolic rate and the process of hibernation in the woodchuck.     

Total and free serum thyroid hormone concentrations in fetal and adult pregnant and nonpregnant guinea pigs

Information on total and free serum thyroid hormone concentrations in the adult and fetal guinea pig (Cavia porcellus) is limited. These variables were studied in adult male and female guinea pigs and in pregnant guinea pigs and their fetuses at various times during gestation. Total serum T4 levels in adult males, nonpregnant females, and pregnant females did not differ significantly [range, 2.5 +/- 0.3 to 3.2 +/- 0.8 micrograms/dl (mean +/- SD)]. Similarly, there were no significant differences in the percent free T4 (0.046-0.068%), free T4 (1.26-2.03 ng/dl), total T3 (39-44 ng/dl), the percent free T3 (0.521-0.638%), and free T3 (0.221-0.260 ng/dl) among adult males, nonpregnant females, and pregnant females. rT3 was undetectable in adult male, nonpregnant female, and pregnant female guinea pig serum. T4 values were similar and those for T3 were lower in fetal compared to maternal serum at 45 days of gestation, whereas serum rT3 was detectable in fetal serum. Between 45 and 62 days of gestation, fetal serum T4 increased from 2.5 to 0.3 to 4.3 +/- 1.3 micrograms/dl (mean +/- SD, P less than 0.01), fetal serum T3 remained unchanged, and fetal serum rT3 increased from 5.2 +/- 3.3 to 25.0 +/- 11.4 ng/dl (P less than 0.01). Near term, fetal serum total and free T4 and total rT3 concentrations were significantly higher and total and free T3 concentrations were significantly lower than the corresponding values in maternal serum. Total serum T4 is higher in the guinea pig than in the rabbit, is similar to values in the rat, and is lower than values in man. The free T4 concentration in guinea pig serum is similar to those in humans and rats. The ontogenesis of thyroid hormones differs strikingly in the guinea pig fetus compared to that in the rat fetus and shares many similarities with sheep and human fetal thyroid development.     

Effects of dexamethasone on fetal and maternal thyroxine, triiodothyronine, reverse triiodothyronine, and thyrotropin levels.

The concentrations of T4, T3, rT3, and TSH were measured at term pregnancy in maternal and umbilical plasma and in amniotic fluid of 11 normal patients who received 8-16 mg dexamethasone 3-48 h before elective cesarean section and of 10 control patients who received no dexamethasone. The mean (+/- SE) concentrations of T4 (micrograms per dl) in maternal and umbilical plasma of dexamethasone-treated patients (12.5 +/- 0.9 and 13.0 +/- 0.9) were not significantly different (P less than 0.05) from those of the control patients (13.9 +/- 1.5 and 10.4 +/- 0.6, respectively). The mean (+/- SE) maternal plasma concentrations of T3 and rT3 (nanograms per dl) of dexamethasone-treated patients (204 +/- 6 and 82 +/- 11) were not significantly different (P less than 0.05) from those of the control patients (201 +/- 26 and 72 +/- 6, respectively). However, the mean (+/- SE) concentrations of T3 and rT3 (nanograms per dl) in umbilical plasma of dexamethasone-treated patients (106 +/- 13 and 360 +/- 35) were 3- and 2-fold and significantly higher (P less than 0.05) than those of the control group (39 +/- 6 and 195 +/- 19, respectively). No significant differences (P less than 0.05) were observed between the mean concentrations of TSH (microunits per ml) in maternal and umbilical plasma of dexamethasone-treated patients (2.5 +/- 0.5 and 3.0 +/- 1.0) and those of the control group (2.8 +/- 0.5 and 6.9 +/- 2.7, respectively). Under the conditions studied, no differences in the mean concentrations of amniotic fluid T4, T3, rT3, or TSH were observed between the two groups of patients (P less than 0.05). The increase of T3 and rT3 levels in umbilical plasma after dexamethasone administration indicates alteration in fetal thyroid economy.     

Effect of single doses of dexamethasone and adrenocorticotrop hormone on serum bone markers in healthy subjects and in patients with adrenal incidentalomas and Cushing's syndrome

The aim of the present study was to explore whether short-term changes in glucocorticoid activity which occur during dynamic testing of the pituitary adrenal axis with dexamethasone, ACTH, or metyrapone could have an effect on serum osteocalcin (OC) and beta-crosslaps (beta-CTx) concentrations in healthy subjects, in patients with adrenal incidentalomas and in those with Cushing's syndrome. The study included 40 healthy subjects (35 women and 5 men, age range 18-69 yr), 49 patients with adrenal incidentalomas (34 women and 15 men, age range 19-77 yr) and 8 patients with Cushing's syndrome (5 cortisol-producing adenomas and 3 pituitary-dependent Cushing's syndrome, 3 women and 5 men, age range 19-70 yr). Serum OC and beta-CTx concentrations were determined with electrochemoluminescent immunoassays at midnight, after an overnight fast between 08:00 and 09:00 h, after an overnight dexamethasone test (1 mg, orally) and after a single dose of metyrapone (30 mg/kg, orally). In healthy subjects and in patients with adrenal incidentalomas, serum bone marker concentrations were also measured after a single dose of ACTH injection (Cortrosyn depot, 1 mg im). Patients with Cushing's syndrome, but not those with adrenal incidentalomas, showed significantly lower serum OC at midnight (18.5+/-12 ng/ml, mean+/-SD) and between 08:00 and 09:00 h (17.7+/-9.6 ng/ml) compared to corresponding values obtained in healthy subjects (24.5+/-7.0 and 28.3+/-12.2 ng/ml, respectively). Serum OC concentrations were significantly decreased after a single dose of 1-mg dexamethasone in healthy subjects (from 28.3+/-12.2 to 21.8+/-9.5 ng/ml) and in patients with adrenal incidentalomas (from 29.8+/-15.9 to 24.1+/-14.1 ng/ml), whereas serum OC concentrations remained unchanged in patients with Cushing's syndrome. In addition, serum OC concentrations were even more markedly decreased after a single dose of ACTH injection in both healthy subjects (12.5+/-4.6 ng/ml) and in patients with adrenal incidentalomas (12.2+/-6.5 ng/ml). By contrast, metyrapone administration failed to induce significant changes in OC levels. There were no significant differences in beta-CTx concentrations between the three groups or after drug treatments. Thus, serum OC levels should be interpreted with caution when obtained during testing of the pituitary-adrenal axis with dexamethasone or ACTH.     

Relation of serum reverse T3 to amiodarone antiarrhythmic efficacy and toxicity

The relation of serum reverse T3 (rT3) to amiodarone efficacy and toxicity was studied in 31 patients with frequent and complex ventricular arrhythmias. Baseline studies included 48-hour Holter recordings and rT3 levels (normal 33 ng/dl or less). Amiodarone therapy was initiated with a 5 mg/kg infusion followed by 600 to 800 mg/day for 7 to 10 days, then 200 to 400 mg/day. Holters and rT3 levels were repeated every 1 to 3 months and amiodarone was titrated to achieve at least a 70% reduction in total ventricular premature complexes, at least a 90% reduction in couplets and abolition of ventricular tachycardia. The baseline rT3 level was 18 +/- 7 ng/dl (range 10 to 30) and patients were followed 12 +/- 9 months. Arrhythmia control was achieved in 25 patients (81%), including 21 patients with elevated rT3 levels (36 to 105 ng/dl) and 4 patients with normal rT3 (15 to 33 ng/dl). Six patients were uncontrolled with rT3 (27 to 90 ng/dl) and 14 patients had minor side effects with rT3 (27 to 123 ng/dl). Three of 4 patients in whom rT3 levels exceeded 130 ng/dl died suddenly (137 to 174 ng/dl before the event). Thus, amiodarone efficacy and minor toxicity occurs at rT3 levels less than 105 ng/dl and sudden death may be associated with levels greater than 130 ng/dl.     

Alterations in thyroxine metabolism in Crohn's disease

To evaluate the possible alterations in thyroxine metabolism in patients with Crohn's disease (C.D.), the serum concentrations of thyroxine (T4), triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), and thyroxine binding globulin (TBG) were determined in 23 patients with C.D. and in 25 healthy controls. While concentrations of T4 and rT3 in patients with C.D. were similar to those seen in healthy controls, serum T3 was lower in patients with C.D. (0.93 +/- 0.4 ng/ml) than in controls (1.20 +/- 0.3 ng/ml, p less than 0.005). TBG concentrations were elevated in two patients with C.D., and below normal in two others. However, the group mean of TBG concentrations in patients with C.D. (23.7 +/- 6.9 micrograms/ml) was similar to that of healthy controls (21.9 +/- 3.6 micrograms/ml, p greater than 0.05). Changes in peripheral deiodination of thyroxine, enhanced in some cases by treatment with glucocorticoids and/or increased turnover of T3 may be the cause of the decreased concentration of T3 in some patients with Crohn's disease.     

Cortisol resistance in acquired immunodeficiency syndrome.

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 +/- 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 +/- 2.6 fmol/million cells; P less than 0.01) and sex- and age-matched controls (3.15 +/- 2.3 fmol/million cells; P less than 0.01). The affinity of glucocorticoid receptors (Kd) was strikingly decreased (9.36 +/- 3.44 nM in group 1; 3.2 +/- 1.5 nM in group 2; 2.0 +/- 0.8 nM in controls; P less than 0.01). [3H]Thymidine incorporation was decreased dose-dependently by dexamethasone in controls and patients; the effect was significantly blunted (P less than 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implies a complex change in immune-endocrine function, which may be important in the course of immunodeficiency syndrome.     

Increased fetal glucocorticoid exposure delays puberty onset in postnatal life

The fetal environment is now recognized as a key determinant of the adult phenotype, being linked to development of diseases, including hypertension, as well as the timing of puberty. Such links may be related, in part, to the level of fetal exposure to maternal glucocorticoids in utero, which is normally regulated by placental expression of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). The present study examined whether manipulation of fetal glucocorticoid exposure, either directly or indirectly via 11beta-HSD inhibition, influences the subsequent timing of puberty. Administration of dexamethasone acetate at low (LDEX, 0.25 microg/ml drinking water) or high doses (HDEX, 1 microg/ml) or carbenoxolone (CBX, 2 x 10 mg/day, sc; an inhibitor of 11beta-HSD) to pregnant rats from day 13 to term (day 23) reduced offspring birthweight (LDEX: 9%; HDEX: 27%; CBX: 8%) and resulted in a subsequent delay in the onset of puberty in females (control: 41.4 +/- 0.5; LDEX: 44.8 +/- 0.7; HDEX: 48.5 +/- 0.4; CBX: 43.6 +/- 0.5 days). Importantly, the effects of CBX were not observed in the absence of maternal adrenals, indicating that they were mediated by increased fetal exposure to endogenous maternal glucocorticoids. In contrast, maternal treatment with metyrapone (MET; an inhibitor of glucocorticoid synthesis; 500 microg/ml drinking water from day 13) increased birthweight by 5% and advanced puberty onset in male offspring (control: 48.8 +/- 1.0; MET: 45.7 +/- 0.8 days). Changes in the timing of puberty onset were not attributable to changes in either bodyweight at puberty or peripubertal plasma leptin concentrations. Peripubertal plasma LH was also unaffected in animals with delayed puberty but was elevated in male offspring of MET-treated mothers. Collectively, these results demonstrate that fetal glucocorticoid exposure is an important determinant of the timing of puberty onset in postnatal life, and that this effect is operable within the normal physiological range of glucocorticoid concentrations.     

Suppressed Levels of Serum Cortisol Following High-Dose Oral Dexamethasone Administration Differ between Healthy Postmenopausal Females and Patients with Established Primary Vertebral Osteoporosis

Hypercortisolism and glucocorticoid treatment, even in a low dose or administered topically, may influence bone metabolism. It was the aim of this study to investigate whether there might be differences in the regulation of endogenous cortisol secretion between patients with established primary vertebral osteoporosis and healthy controls. Suppressed morning serum cortisol concentrations in a 3 mg dexamethasone overnight suppression test were compared in well-defined healthy postmenopausal women (n = 149) and osteoporotic patients classified as having established primary vertebral osteoporosis with no clinical features of hypercortisolism (n = 78). Suppressed cortisol in the healthy controls was 1.08 +/- 0.44 microg/dl and in the primary osteoporotics 1.58 +/- 1.42 microg/dl (p < 0.0001). Of the investigated primary osteoporotics 15.4% (n = 12) had suppressed cortisol levels above the 97.5th percentile (1.96 microg/dl) of the healthy controls. Subgroup analysis regarding the influence of gonadal steroid hormone replacement in both groups and gender in the osteoporotic group did not change the results. Four of the 12 patients with incomplete suppressive cortisol underwent adrenal endosonography, unilateral adrenal nodular hyperplasia being detected in three cases. In two patients the diagnosis was confirmed by histology and normalisation of a dexamethasone suppression test following endoscopic adrenalectomy. These data yield evidence for a difference in the regulation of cortisol secretion following high-dose dexamethasone administration between healthy subjects and a subgroup of patients with primary osteoporosis. This might be due to a relevant amount of autonomous cortisol secretion in some of these patients; however, even cortisol resistance has to be taken into account.     

EFFECT OF THE COMBINATION OF DEXAMETHASONE AND SODIUM IPODATE ON SERUM THYROID HORMONES IN GRAVES'' DISEASE

To investigate the effect of the combination of dexamethasone (Dex) and sodium ipodate (SI) on hyperthyroidism, we studied 24 patients with typical Graves' disease, divided into four groups of six persons each. Three groups (Study I) were studied acutely (24 h) to determine the effects of Dex (5 mg every 12 h intramuscularly), SI (one oral dose of 3 g) and both drugs at the same doses, upon T4, T3, and rT3 at 0900 h before therapy was started and 24 h later. The group on Dex and that on SI had a similar T3 decrement of 25.9 +/- 4.0% and 35.8 +/- 5.0%, respectively, (P less than 0.05), whereas the effect of both drugs combined was greater (64.2 +/- 3.6%; P less than 0.01, Dex, and P less than 0.01, SI, respectively). The increment of rT3 was markedly greater in those patients on SI than in those on Dex (561.3 +/- 149.2% and 58.9 +/- 11%, respectively, P less than 0.025). A fourth group (Study II) was studied for seven days while receiving both Dex (1 mg orally three times per day) and SI (500 mg orally three times per day). Both T4 (from 18.8 +/- 1.1 to 13.1 +/- 1.1 micrograms/dl, P less than 0.02) and T3 (from 593 +/- 41 to 136.3 +/- 12.7 ng/dl, P less than 0.001) decreased at day 8. The initial brisk increment of rT3 at 24 h (808 +/- 149%, P less than 0.005) then diminished concomitantly with the fall of its precursor, T4.(ABSTRACT TRUNCATED AT 250 WORDS)     

Divergent effects of short term glucocorticoid excess on the gonadotropic and somatotropic axes in normal men.

We investigated the effects of short term glucocorticoid excess on the gonadotropic and somatotropic axes in healthy men. Subjects (n = 5) underwent blood sampling at 10-min intervals for 6 h before and on days 2, 5, and 8 of glucocorticoid treatment, and for 24 h (n = 6) to examine pulsatile LH and GH release before and during dexamethasone administration (1.5 mg orally twice daily for 1 week). In the time-course study, we found significant decreases on day 8 in serum concentrations of estradiol (from 144 +/- 18 to 99 +/- 18 pmol/L), free testosterone (from 105 +/- 10 to 87 +/- 10 pmol/L), and dehydroepiandrosterone sulfate (from 6.0 +/- 1.6 to 1.7 +/- 0.3 mumol/L; P less than 0.05). Mean serum LH concentrations did not change (baseline, 5.3 +/- 1.2 IU/L; glucocorticoid, 4.2 +/- 0.61 IU/L). The mean plasma somatomedin-C concentration rose from 0.74 +/- 0.08 to 2.0 +/- 0.35 U/mL (P less than 0.05), and the mean serum GH concentration increased from 1.2 +/- 0.90 micrograms/L (basal) to 4.2 +/- 1.5 micrograms/L (day 8 of dexamethasone; P less than 0.01). Deconvolution analysis of 24-h serum GH and LH concentration profiles revealed that the half-life of endogenous GH and the duration and amplitude (maximal rate of secretion) of computer-resolved GH secretory bursts were not influenced significantly by dexamethasone. The mass of GH secreted per burst rose 1.6-fold. Glucocorticoid treatment also increased detectable GH secretory burst frequency from 12 +/- 1.6 to 18 +/- 1.6 episodes/24 h, decreased the GH interburst interval from 127 +/- 23 to 79 +/- 5 min, and increased the daily GH secretion rate from 41 +/- 11 to 101 +/- 11 micrograms/L.day. These effects on the somatotropic axis were specific, since the half-life of LH; LH secretory burst frequency, amplitude, mass, and duration; and the total daily LH production rate (and LH secretion in response to exogenous GnRH) were not altered by dexamethasone administration. We conclude that short term moderate glucocorticoid excess augments pulsatile GH secretion without influencing the episodic release of LH in normal men.     

Differential effects of maternal dexamethasone treatment on circulating thyroid hormone concentrations and tissue deiodinase activity in the pregnant ewe and fetus

Clinically, treatment of pregnant women at risk of preterm delivery with synthetic glucocorticoids accelerates fetal maturation. This study investigated the effect of maternal dexamethasone treatment, in clinically relevant doses, on plasma thyroid hormone concentrations and tissue deiodinase activities (D1, D2, and D3) in ewes and their fetuses. From 125 d of gestation (term 145 +/- 2 d), pregnant ewes were injected twice im with either saline (2 ml of 0.9% NaCl, n = 11) or dexamethasone (2 x 12 mg in 2 ml of saline, n = 10) at 24-h intervals. Maternal dexamethasone treatment increased plasma T(3) and reverse T(3) (rT(3)), but not T(4), concentrations in the fetuses. In the dexamethasone-exposed fetuses, hepatic D1 activity was higher, and renal and placental D3 activities were lower, than in the saline-exposed fetuses. In the ewes, plasma concentrations of T(3) and T(4) were reduced, and rT(3) increased, by dexamethasone treatment without any change in tissue deiodinase activity. Therefore, maternal dexamethasone treatment has different effects on the thyroid hormone axis of the pregnant ewe and fetus. In the fetus, the dexamethasone-induced rise in circulating T(3) may be due to both increased hepatic production of T(3) from T(4), and reduced clearance of T(3) by the kidney and placenta. Changes in T(3) bioavailability may mediate some of the maturational effects of antenatal glucocorticoid treatment in the preterm fetus.     

Effect of dexamethasone on thyroid hormone response to TSH.

The effect of short-term dexamethasone administration (8 mg daily for 3 days) on thyroid hormone response to exogenous TSH (bovine TSH, 5 IU i.m.) was studied in 16 euthyroid volunteers. Serum T3 and T4 concentrations were measured by radio-immunoassay prior to and 2, 6, 12, 24, and 49 hr after bTSH injection, both under basal conditions and during dexamethasone treatment. In all subjects bTSH administration raised both T3 and T4 concentrations significantly. Dexamethasone treatment induced a slight depression of endogenous TSH (m +/- SEM = 2.0 +/- 0.4 versus 1.6 +/- 0.3 muU/ml) and T4 (6.8 +/- 0.4 versus 6.1 +/- 0.2 mug/100 ml) basal values and a significant decrease in T3 value (1.16 +/- 0.09 versus 0.64 +/- 0.06 ng/ml, p = 0.005). The mean increment of both T3 and T4 after bTSH injection was percentually unchanged during dexamethasone treatment but, due to lowered basal value, T3 levels at each time interval after TSH + dexamethasone were significantly lower than the corresponding values observed after TSH alone. The present data show that high dexamethasone doses decrease T3 serum levels significantly without inhibiting T3 response to TSH stimulation. Only a slight lowering was observed in T4 levels.     

Noninvasive monitoring of adrenocortical activity in roe deer (Capreolus capreolus) by measurement of fecal cortisol metabolites

A method for measuring glucocorticoids noninvasively in feces of roe deer was established and validated. The enzyme immunoassay (EIA) measures 11,17-dioxoandrostanes (11,17-DOA), a group of cortisol metabolites. Such measurement avoids blood sampling and reflects a dampened pattern of diurnal glucocorticoid secretion, providing an integrated measure of adrenocortical activity. After high-performance liquid chromatography, the presence of at least three different immunoreactive 11,17-DOA in the feces of roe deer was demonstrated. The physiological relevance of these fecal cortisol metabolites to adrenocortical activity was evaluated with an adrenocorticotropic hormone challenge test: cortisol metabolite concentrations exceeded pretreatment levels (31-78 ng/g) up to 13-fold (183-944 ng/g) within 8-23 h. Starting from basal levels between 13 and 71 ng/g, a suppression of adrenocortical activity after dexamethasone administration, indicated by metabolite levels close to the detection limit, was obtained 36-81 h after treatment, whereas unmetabolized dexamethasone was detectable in feces 12 h after its injection. Fecal glucocorticoid metabolite assessment via EIA is therefore of use in the monitoring of adrenocortical activity in roe deer. In a second experiment, capture, veterinary treatment, and transportation of animals were used as experimental stresses. This resulted in a 7.5-fold increase of fecal metabolites (1200 +/- 880 ng/g, mean +/- SD) compared to baseline concentrations. The administration of a long-acting tranquilizer (LAT), designed to minimize the physiological stress response, 2 days prior to a similar stress event led to a reduced stress response, resulting in only a 4-fold increase of fecal metabolites (650 +/- 280 ng/g; mean +/- SD). Therefore, LATs should be further investigated for their effectiveness in reducing stress responses in zoo and wild animals, e.g., when translocations are necessary.     

Dexamethasone-inhibitable stimulation of plasma prorenin by ketamine in cats

Plasma prorenin in humans is derived from both renal and extrarenal sources, but in the cat most plasma prorenin is normally of renal origin. Sodium depletion and beta-adrenergic blockade can increase plasma prorenin in cats, but the effects of sedatives and glucocorticoids are unknown. We examined the effect of ketamine, a centrally acting nonbarbiturate anesthetic, and of the glucocorticoid dexamethasone on plasma prorenin and renin. Intramuscular injection of ketamine (20 mg/kg, three times a day) for 4 days increased plasma prorenin slowly and consistently, from 7.4 +/- 1.4 (+/- SEM) to 11.4 +/- 2.2, 17.1 +/- 2.5, 20.2 +/- 3.0, and 29.2 +/- 3.4 ng/ml.h (P less than 0.001) on days 1, 2, 3, and 4, respectively, without any effect on plasma active renin. Plasma renin substrate and cortisol were also unchanged. Bilateral nephrectomy reduced both baseline and stimulated plasma prorenin to undetectable levels. Treatment with alpha 1-blocker, beta 1-blocker, angiotensin-converting enzyme inhibitor, or Ca2+ antagonist did not affect the rise in prorenin induced by ketamine, but dexamethasone completely blocked the response. In contrast, dexamethasone alone had little effect on plasma prorenin. These results demonstrate that repetitive ketamine administration selectively increases plasma prorenin, suggesting that renal prorenin secretion may be regulated independently of active renin. Blockade of stimulated, but not baseline, plasma prorenin by dexamethasone is consistent with a negative effect of glucocorticoids on the regulatory elements of the renin gene.