Growth hormone: metabolic clearance rates, integrated concentrations, and production rates in normal adults and the effect of prednisone.

A constant withdrawal pump was used to determine the integrated concentration of growth hormone (ICGH) which was used in conjunction with the metabolic clearance rate (MCR) of growth hormone (GH) to calculate the GH production rates (GHPR) in normal adults, acromegalics, and normal controls receiving prednisone. The mean ICGH for 22 premenopausal females on no medication was 3.0+/-1.6 ng/ml (sd) which is significantly lower (P < 0.005) than the mean of 6.6+/-2.9 for 10 women receiving oral contraceptives and significantly higher than the means of 1.5+/-0.75 for 5 postmenopausal females (P < 0.05) and 1.8+/-1.0 for 16 adult males (P < 0.01) which are comparable. The mean GHPR's in mg/24 hr per m(2) for the four groups are: normal females = 0.52+/-0.24 (sd), females receiving contraceptive pills = 1.65+/-0.58 (P < 0.005), postmenopausal females = 0.26+/-0.12 (P < 0.025), and adult males 0.35+/-0.23 (P < 0.025).Three untreated acromegalic patients had ICGH's of 59, 82, and 93 ng/ml and GHPR's ranging from 14.5 to 17.9 mg/24 hr. Prednisone in a dose of 20 mg t.i.d. for 8 days significantly decreased both the ICGH and GHPR. Alternate day prednisone (60 mg in a single q.o.d. dose) resulted in less consistent inhibition of GH release which may play a role in the more normal growth seen in children receiving q.o.d. prednisone.

The regulation of aldosterone secretion in anephric man.

The regulation of aldosterone secretion in anephric man was investigated in studies on nephrectomized patients who were being intermittently hemodialyzed while awaiting renal transplantation. The effects of supine and upright posture on the concentration of plasma aldosterone on the 1st day postdialysis and on a 3rd or 4th day postdialysis were compared to the effects of postural variation in normal subjects who were on a low sodium intake and on a high sodium intake. In contrast with the normal subjects who exhibited higher concentrations of plasma aldosterone after 2 hr of upright posture than in the supine position and low concentrations of plasma aldosterone on a high sodium intake, the anephric patients showed less consistent variations in plasma aldosterone due to changes in posture and exhibited higher concentrations of plasma aldosterone on the 3rd or 4th day postdialysis, despite an increase in body weight, than on the 1st day postdialysis. The increase in the concentration of plasma aldosterone in the anephric patients between the 1st day postdialysis and the 3rd or 4th day postdialysis indicates that aldosterone secretion is not responding primarily, in this situation, to volume-related stimuli. There was a high degree of correlation between the concentration of plasma aldosterone and the corresponding levels of serum potassium concentration, which also rose significantly between the 1st day postdialysis and the 3rd or 4th day postdialysis. Furthermore, when potassium accumulation between dialyses was prevented in three of these patients, the concentration of plasma aldosterone fell to minimally detectable levels. The results of these studies suggest that the primary regulator of aldosterone secretion in the absence of the kidneys is potassium.

Transplacental passage and fetal secretion of aldosterone.

The transplacental passage and the production of aldosterone were studied in late pregnancy during a constant infusion of 1,2-aldosterone-(3)H to mothers at the time of elective cesarean section. It was found that, while maternal aldosterone crossed the placenta, there was a significant secretion of aldosterone by the fetus. The aldosterone concentration in fetal plasma was 2-12 times higher than that of the corresponding mothers. Pregnancy had no effect on the metabolic clearance rate of aldosterone, but it increased the rate of production of this steroid. However, the increments that we observed were smaller than those reported in previous reports. The discrepancy was probably due to differences in body posture, our subjects being supine for at least 10 hr at the time of study.

Plasma aldosterone concentration at delivery and during the newborn period.

Aldosterone concentrations in plasma of women on normal sodium intake undergoing cesarean section were 3.7+/-1.4 ng/100 ml (mean+/-1 SD). These values were significantly lower (P < 0.001) than those observed in mothers on normal sodium diet, delivered by the vaginal route (14.9+/-7.0 ng/100 ml). A significant elevation (P < 0.001) of the concentrations was found if the mothers had been on sodium restriction and/or diuretics (44.9+/-24.2 ng/100 ml). In supine position, adult nonpregnant subjects have aldosterone concentrations in plasma of 1.7+/-1.4 ng/100 ml on normal sodium intake and of 16.7+/-8.1 ng/100 ml on low sodium diet.Simultaneous determinations of aldosterone levels in cord blood showed that cord values were significantly higher than those of the corresponding mother (P < 0.01 by paired t test). However, values in cord blood of infants born to mothers on a normal sodium intake were significantly lower (P < 0.005) than those of infants whose mothers had required low sodium diet and/or diuretics during their pregnancy. Aldosterone concentrations in plasma of infants 1-72 hr of age and born to mothers on normal sodium intake were 25.9+/-11.7 ng/100 ml (mean +/-1 SD). These values were significantly lower (P < 0.005) than those of infants born to mothers on restricted sodium intake with or without diuretics (80.3+/-54.4 ng/100 ml). The concentrations at birth were not significantly different from those observed during the first 3 days of life (P > 0.6).

Blood glucose monitoring in symptomatic hypoglycemia.

The relationship between blood glucose levels and the onset of hypoglycemic symptoms was studied by continuous monitoring of blood glucose levels after an oral glucose load in nine adults with normal glucose tolerance, five with chemical diabetes without symptomatic hypoglycemia, and nine with chemical diabetes with symptomatic hypoglycemia. Symptoms were associated not only with a low level of blood glucose but with a rapid fall as well. These two parameters were used to calculate a "hypoglycemic index" (defined as the fall in blood glucose during a 90-minute period prior to reaching the minimum level, divided by the value of this minimum level). The hypoglycemic index was 2.3 +/- 0.6 (mean +/- S.D.) in the group of diabetic patients with symptomatic reactive hypoglycemia and 0.7 +/- 0.3 for the other groups. This index may aid in the diagnosis of patients with symptoms of hypoglycemia and equivocally low values of blood glucose.

Increased integrated concentration of norepinephrine, epinephrine, aldosterone, and growth hormone in patients with uncontrolled juvenile diabetes mellitus.

The 24-h integrated plasma concentration of glucose (IC-glucose), norepinephrine (IC-NE), epinephrine (IC-E), cortisol (IC-F), growth hormone (IC-GH), aldosterone (IC-ALDO), and plasma renin activity (IC-PRA) were measured in 11 nonobese juvenile-onset nonketotic diabetic patients exhibiting hyperglycemia and glycosuria and 34 matched control subjects using a portable pump, drawing blood at a constant rate through a nonthrombogenic i.v. catheter. The diabetic patients had a noticeable rise of their IC-NE, IC-E, IC-GH, and IC-ALDO. There was no significant difference between the IC-F and IC-PRA of the patients and the control subjects.

Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects.

Direct methods for measuring the secretion rate of insulin are too cumbersome for clinical application. Since C-peptide is secreted in an equimolar ratio with insulin and is excreted into the urine, measuring the urinary excretion rate of C-peptide (U-C) could serve as an indicator of its secretion rate (SR-C) if its urinary clearance (UCI-C) is constant and unaffected by plasma C-peptide concentration, body mass, or diabetes. We measured clearance ratios of C-peptide/creatinine (CR) in the fasting state and integrated 0-1, 1-3, and 3-5 h after 100 g of glucose p.o. as well as over a full 24-h in eight obese, eight lean, and six maturity-onset diabetic subjects. CR did not differ significantly when values in the fasting state were compared with those in the postprandial periods and was therefore unaffected by plasma C-peptide concentration. Furthermore, CR was similar in the lean, obese, and diabetic subjects. SR-C, determined as the product of the metabolic clearance rate of C-peptide and its fasting or integrated plasma concentrations, correlated significantly with U-C in all the subjects (r = 0.87, P less than 0.0001). The correlation of U-C with SR-C in the diabetic subjects alone was also significant (r = 0.88, P less than 0.0001). In conclusion, our data support the use of U-C as an indirect measure of SR-C and therefore of SR-I.

Correlation of urinary excretion of C-peptide with the integrated concentration and secretion rate of insulin.

The secretion rate of insulin (SR-I) of 50 normal subjects was calculated from the 24-h integrated concentration of insulin (IC-I), the peripheral metabolic clearance of insulin (pMCR-I), and the mean fractional hepatic insulin extraction (fhMCR-I) that was derived from our data. fhMCR-I was determined as the difference in the molar secretory rate of C-peptide (SR-C) and the molar peripheral clearance of insulin (pMCR-I x IC-I) divided by SR-C. The IC-I in our 50 subjects was 1.19 +/- 0.38 ng/ml and the IC-C was 2.93 +/- 0.58 ng/ml. Based on these data, the fhMCR-I was 0.40 and the Sr-I was estimated to be 54.8 +/- 18.0 U/24 h. The 24-h urinary C-peptide excretion (U-C), 44.9 +/- 20.4 micrograms/24 h, had a statistically significant correlation with SR-I (r = 0.838, P less than 0.0001), while the IC-I correlated significantly with the 24-h urinary C-peptide/g of creatinine (r = 0.838, P less than 0.0001). The U-C may thus serve as a practical method for estimating the SR-I.

Evidence for elevated glucose threshold in patients with impaired glucose tolerance and symptoms of hypoglycemia during OGTT.

We evaluated the relationship between hypoglycemic symptoms, glucose nadir levels, and hormone changes in patients with impaired glucose tolerance (IGT) after an oral glucose tolerance test (OGTT). The peak counterregulatory hormone response was determined at the glucose nadir identified by continuous glucose monitoring. Eight patients with IGT who had symptoms and signs typical of hypoglycemia at the glucose nadir were compared with completely asymptomatic subjects (5 IGT patients and 13 patients who had normal glucose tolerance [NGT]). The mean glucose nadir of symptomatic IGT patients was 3.50 +/- 0.46 mM, which was not statistically different from the mean of asymptomatic NGT patients (4.10 +/- 0.56 mM) but was significantly lower than that for asymptomatic IGT patients (5.10 +/- 0.81 mM, P less than 0.001). Seven of 8 symptomatic IGT patients had glucose levels that never fell below the range of glucose nadirs for asymptomatic NGT patients. However, the symptomatic IGT group had significantly higher levels of growth hormone, cortisol, epinephrine, and norepinephrine than the asymptomatic groups in response to the nadir. We conclude that patients with IGT are capable of experiencing signs and symptoms of hypoglycemia at physiological glucose levels during OGTT with reflex stimulation of counterregulatory hormone release. This may indicate that symptomatic IGT patients have a higher glucose threshold for eliciting characteristic hypoglycemic symptom episodes than individuals with NGT.

The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation.

Eleven insulin-dependent (type I) diabetic subjects were studied during a 24-h period to assess intraday blood glucose (BG) variation and related free insulin (FI) levels. Ten patients exhibited the dawn phenomenon, a rise in early morning fasting blood glucose (123 +/- 81.1 m/dl; mean +/- SD). This increase was positively and significantly correlated with the morning postprandial BG peak (r = 0.723; P = 0.012). FI/BG ratios were highest during the night (0.717 and 0.666 at 2200 and 0400 h, respectively) and lowest during the early morning (0.294 at 0800 h) (P less than 0.01). Three of the four observed hypoglycemic episodes occurred during the period when free insulin levels were high relative to BG. We conclude that the dawn phenomenon contributed directly and significantly to the BG maximum and indirectly, in some cases, to nocturnal hypoglycemia. It thus played an important role in the intraday blood glucose variation of such patients.

Effect of testosterone on insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the hypophysectomized rat.

Circulating levels of insulin-like growth factor-I (IGF-I) increase during puberty, concurrent with an increase in the levels of GH and the gonadal steroids. The relationship between the changes observed in IGF-I and testosterone (T) levels are not understood. This study was designed to determine whether T has a direct effect on IGF-I serum levels, liver IGF-I gene expression, and epiphyseal growth plate IGF-I and IGF-I receptor gene expression. Hypophysectomized castrated rats were divided into four groups of six animals. The T group was treated with sc T for 5 days. The GH group was treated with a single dose of GH. The GH plus T group was treated with T for 5 days and with GH on the last day of treatment. The control group was injected for 5 days with vehicle alone. Serum IGF-I levels in the T group were not significantly different from those in the control group, and the levels in the GH plus T group were not significantly different from those in the GH group. There was an 11-fold increase in liver IGF-I mRNA abundance in the GH group compared to the control group (P less than 0.01). Liver IGF-I mRNA levels in the T group were not significantly different from those in the control group. When liver IGF-I mRNA levels in the GH plus T group were compared to those in the GH-treated group, no significant differences were found. In the epiphyseal growth plate region, there was a 12-fold increase in IGF-I mRNA levels in the GH group compared to those in the control group, but there was no statistical difference between the control and T groups. IGF-I mRNA levels in the GH plus T group were not significantly different from those in the GH-treated group. IGF-I receptor mRNA abundance was not significantly different in the T group compared to that in the control group. GH decreased IGF-I receptor mRNA by 2.3-fold, but T treatment before GH injection did not change this effect. We conclude that in castrated hypophysectomized rats, T does not stimulate IGF-I gene expression in the liver, nor does it increase IGF-I serum levels. T alone also does not have a stimulatory effect on IGF-I or IGF-I receptor gene expression in the epiphyseal growth plate region.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal integrated concentration of aldosterone and plasma renin activity: effect of age.

The integrated concentration of aldosterone (IC-ALDO) and PRA (IC-PRA) was studied in 78 normal subjects ranging in age from 9--50 yr. Whereas the IC-ALDO to IC-PRA were found to decrease with age, the ratio of IC-ALDO to IC-PRA was not affected by age. A significant lowering of the normal range and variance was achieved by measuring the 24-h integrated concentration instead of the concentration in discrete samples.

The definition of a spontaneous growth hormone (GH) peak: studies in normally growing and GH-deficient children.

GH spontaneous peaks and their diagnostic utility have not been previously evaluated by means of a 24-h continuous withdrawal (CW) procedure in children with growth disorders. Using a CW pump, we studied the 24-h spontaneous secretion of GH in 129 prepubertal subjects grouped as follows. The control group (C) consisted of 20 children of normal height and growth rate. Group GHD consisted of 53 patients with classical GH deficiency (48 idiopathic and 5 organic). The NSD group consisted of 36 patients with a growth velocity below 4.5 cm/yr, normal GH response to provocative stimuli (PS), but a mean 24-h GH in the deficient range. Group NSS consisted of 20 short children with normal growth velocity, normal PS, and normal mean 24-h GH concentration. The mean GH levels for the 24-h period were 4.1 +/- 1.7, 1.4 +/- 0.5, 2.1 +/- 0.7, and 4.2 +/- 1.9, respectively, for the C, GHD, NSD, and NSS groups. For each subject, GH levels were determined in 48 0.5-h samples collected during the CW study, and the GH profile was analyzed by the Pulsar computer program. The mean number of peaks was 9.0 +/- 2.5 for C, 9.5 +/- 3.7 for GHD, 10.5 +/- 1.8 for NSD, and 9.5 +/- 3.2 for NSS. There was no statistical difference between groups. The mean amplitude of peaks was 9.8 +/- 8.9 for C, 1.6 +/- 1.0 for GHD, 2.9 +/- 1.3 for NSD, and 9.9 +/- 9.1 for NSS. Mean peak amplitudes in both GHD and NSD were significantly lower than in the C and NSS groups. The presence of peaks of more than 8 micrograms/L during the daytime (0800-2000 h) was a characteristic of children with normal integrated GH concentration (IC-GH) and was seen in 90% of normally growing children but in only 7% of poorly growing children with subnormal IC-GH. There was no significant difference in the number of pulses during the night between C and NSD groups. We conclude that differences in IC-GH between normally growing and poorly growing children are due to a lower amplitude of peaks during the daytime hours.

Integrated concentration of epinephrine and norepinephrine in normal subjects and in patients with mild essential hypertension.

Since the level of plasma catecholamines fluctuates rapidly during the day, measurement in a single blood sample could be misleading. A portable nonthrombogenic blood withdrawal system, permitting normal activity and sleep, was used for obtaining the 24-h integrated concentration (IC) of epinephrine (E) and norepinephrine (NE) in 46 normal control subjects, 30 patients with mild essential hypertension, and 1 patient with pheochromocytoma. The mean IC of E (ICE) and the mean IC of NE (ICNE) of the control subjects were 31 +/- 15 and 194 +/- 106 pg/ml, respectively (mean +/- 1 SD). The mean ICE and ICNE of the essential hypertensive patients were 30 +/- 21 and 224 +/- 90 pg/ml, respectively. No significant difference could be found between the levels found in essential hypertensive and normal control subjects. The levels of ICE and ICNE in the patient with pheochromocytoma were 1350 and 882 pg/ml, respectively, which are 88 and 6.5 SD above the mean of the normal control subjects.

Effect of food intake on the metabolic clearance rate of aldosterone.

The effect of eating on the metabolic clearance rate (MCR) of aldosterone was investigated in 10 adult individuals. 3H-aldosterone was infused continuously over a period of 5 h while the subjects remained supine. Three h after the start of the infusion, each subject ate a bowl of soup. The MCR of aldosterone, before and after the intake of food, was calculated by dividing the rate of infusion of 3H-aldosterone by the mean concentration of under the same conditions but without eating. The MCR of aldosterone (mean +/- 1 SD) was 1284 +/- 513 L/24 h before food intake and 2182 +/- 180 L/24 h after food intake in the 10 individuals who ate. The MCR in the 11 subjects who did not eat was 1363 +/- 446 and 1357 +/- 434 during the same periods (p greater than 0.05). The 29% increase in the MCR induced by eating was highly significant (p less than 0.001); it was similar in magnitude and duration to a previously reported effect of food intake on the hepatic blood flow (13).

Integrated concentration of plasma aldosterone in normal subjects: correlation with cortisol.

The integrated concentration (I. C.) of plasma aldosterone and cortisol was determined every 30 min during a 24-h period, using a blood collection system composed of a nonthrombogenic catheter and a small, portable withdrawal pump. The experiments were carried out in 8 normal adult men during daily routine life, and repeated in 2 of the subjects while recumbent in bed most of the day. The following conclusions were made: a) The 30-min I. C. of aldosterone fluctuated widely throughout the day. b) Although peaks of increased concentration occurred after a change in posture from supine to erect, there were many peaks of concentration that occurred during the supine posture. The 24-h I.C. of aldosterone in 2 subjects that were studied a second time while staying in bed most of the day was lower than the I. C. observed during normal activity. Furthermore, there was a significant correlation between 24-h I. C. and percentage of time spent in supine position. c) A weak, but significant correlation was found between the 30-min I. C. of aldosterone and cortisol in 4 out of the 7 subjects tested. The overall correlation for all experiments was also significant (R = 0.3. p smaller than 0.001). D) The 4-h I. C. of aldosterone and cortisol showed that the lowest mean values were between 4 PM and 4 AM and the highest values between 4 AM and 4 PM for both steroids.

Evaluation of the 6-hour integrated concentration of cortisol as a diagnostic procedure for Cushing's syndrome.

The diagnostic value of the 24-h integrated concentration (IC) test of cortisol (IC-24-F) was found to be superior to the value of both urinary 17OHCS and urinary free-cortisol tests. The IC-24-F test is too cumbersome for widespread clinical use. The purpose of the present study was to evaluate the diagnostic value of an abbreviated and practical 6-h IC of cortisol (IC-6-F) test. The IC of cortisol (IC-F) was measured in 68 normal subjects and 13 patients with surgically proven Cushing's syndrome. A portable nonthrombogenic constant blood withdrawal system was used over a 24-h period. The IC-F was measured in plasma withdrawn during each 1/2-h period (IC-1/2-F). The mean of 12 consecutive measurements of IC-1/2-F yielded the IC-6-F. The mean of all the IC-1/2-F collected over a 24-h period constituted the IC-24-F. The IC-1/2-F of the patients and their IC-6-F from 0800-1400 h, 1400-2000 h, and 2000-0200 h overlapped the corresponding levels in the control subjects. There was no overlap between the IC-24-F and the IC-6-F (from 2000-0200 h) of the patients and the control subjects. It was concluded that the diagnostic value of a 6-h IC-F test conducted during the afternoon and early part of the might is equal to the diagnostic value of the 24-h IC-F test.

Assessment of growth hormone secretion in normal stature children using 24-hour integrated concentration of GH and pharmacological stimulation.

The integrated concentration of serum GH (IC-GH) is used for the assessment of spontaneous GH secretion. In order to use the IC-GH as a diagnostic tool a normative reference range needs to be established. We determined the IC-GH by continuous blood withdrawal in 119 children of normal height, weight and growth rate. Although the mean IC-GH increased with pubertal status, 4.4 +/- 1.2 micrograms/L at Tanner I (n = 36), 5.5 +/- 2.1 micrograms/L at Tanner II-III (n = 43), and 5.8 +/- 1.6 at Tanner IV-V (n = 40) (P less than 0.03), there was a considerable overlap of individual IC-GH levels between the pubertal groups. Gender affected the mean IC-GH level slightly, but not the range. Although the mean IC-GH of girls tended to be higher than that of boys this difference was not statistically significant. Ninety five percent of the IC-GH values were above the 3.2 micrograms/L level. The response to pharmacological stimulation (clonidine, insulin, or arginine) was also evaluated in 68 of the subjects. The peak GH response to pharmacological stimulation (micrograms/L) with clonidine 21.0 +/- 10.7 (n = 66) was significantly higher than to either arginine 13.1 +/- 6.1 (n = 23) or insulin 14.2 +/- 6.3 (n = 19) (P less than 0.01). The peak response to clonidine increased significantly with pubertal status (P less than 0.001) and there was an interactive effect of gender and pubertal stage where the GH response of prepubertal boys exceeded that of prepubertal girls but the response of pubertal girls exceeded that of pubertal boys (P less than 0.02). The peak stimulated GH levels was correlated with IC-GH in this subgroup r = 0.52, P less than 0.0001). This study provides a large normative data base for IC-GH and the GH provocative tests in normally growing children of varying pubertal status.

Preferential binding of testosterone over epitestosterone by human plasma.

The main purpose of this study was to investigate if the specificity of the binding of testosterone to plasma proteins could be defined as a preferential binding of this steroid over epitestosterone. The amount of testosterone that is specifically bound was calculated using the formula: (see article) concentration, where "Ri" is the ratio (14C) testosterone: (3H) epitestosterone in plasma prior to centrifugation, "Ru" is the isotope ratio in the protein-free supernatant obtained after ultracentrifugation (149,000 x g, at 0 C, for 18 h) and "T concentration" is the testosterone concentration in plasma resulting from addition of (14C) testosterone, the endogenous steroids having been removed by preliminary charcoal extraction. The theoretical separation of the binding sites for testosterone into two populations, one non-specific with no preference for testosterone over epitestosterone, and another with absolute specificity for testosterone over its physiologically inactive stereoisomer, proved to be useful. Ovalbumin was found to be an example for non-specific, non-preferential binding. Determination of the ratio (14C) testosterone: (3H) epitestosterone in the successive fractions of various ultracentrifuged preparations showed a small but significant preference for (14C) testosterone by human and bovine serum albumin, while alpha1-acid glycoprotein had a preference for (3H) epitestosterone. Saturation curves showed at least two components: the first one, presumably corresponding to TeBG, had a higher affinity and lower capacity. This binding capacity can be accurately determined by extrapolation to the ordinate or the second component, a straight line corresponding to a binding of somewhat lower affinity and much larger capacity.

Detection of primary aldosteronism by the 6-hour integrated aldosterone/renin ratio.

An outpatient diagnostic procedure measuring the 6-hour integrated plasma concentration of aldosterone and plasma renin activity was used to detect primary aldosteronism in 12 patients with low renin hypertension, including six with mild hypertension and normal urinary excretion and spot plasma levels of aldosterone. The ratio of integrated plasma concentration of aldosterone to plasma renin activity in the 12 patients (mean, 339; range, 116-700; p less than 0.0001) did not overlap with that measured in 105 normotensive controls (mean, 27.8; range, 5-97) or in 87 subjects with essential hypertension (mean, 29.2; range, 4-67). Eight patients had surgically proven adenomas (3 of which measured less than 5 mm) with normalization of blood pressure following adrenalectomy. The four remaining patients had bilateral hyperplasia. The 6-hour integrated plasma concentration of aldosterone to plasma renin activity ratio was found to be a useful new outpatient diagnostic tool for evaluation of primary hyperaldosteronism.