Alteration of stimulated TSH and prolactin response in children treated with growth hormone.

The plasma TSH and prolactin responses to thyrotropin releasing hormone (TRH) were measured in 5 children with isolated growth hormone deficiency prior to, during and after the administration of human growth hormone (hGH). TSH and prolactin secretory patterns were not uniformly concordant. TSH responses to TRH infusion were suppressed in 4 subjects after 5 days or 1 month of hGH administration despite normal serum thyroxin concentrations. Prolactin responses were suppressed in all 5 subjects after 5 days of hGH administration. After 8 months of hGH therapy both TSH and prolactin responses returned toward pre-hGH values. Our finding that suppression of the TRH-induced TSH and prolactin secretory responses are reversible during hGH administration supports the concept of altered neuroregulation in this form of hypothalamic disorder.     

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.     

Exaggerated ANF response to exercise in middle-aged vs. young runners

Hormonal, electrolyte, and renal responses were measured before, during, and after a marathon (42.2 km) in 14 runners: 8 young (Y) (mean age 27.8 yr) and 6 middle aged (MA) (mean aged 46.7 yr). No differences between groups in prerun values for heart rate (HR), plasma osmolality (OSM), antidiuretic hormone (ADH), aldosterone (ALDO), atrial natriuretic factor (ANF), or plasma renin activity (PRA) were found. Renal and urinary measurements were also similar between groups before the marathon. After 10 km of running, both groups had significant increases in HR, ALDO, ANF, and PRA, while OSM, Na+, and ADH remained unchanged from prerun values. The increase in plasma ANF concentrations at this point was significantly greater in the MA subjects compared with the Y (mean increase 104.1 vs. 42.8 pg/ml, respectively; P less than 0.01). Immediate postmarathon values for OSM, ADH, and Na+ were significantly higher than initial values in both groups, while HR, PRA, and ALDO continued to increase above the elevated levels found at 10 km. ANF values immediately postmarathon remained higher than prerun concentrations but were significantly reduced from those obtained at 10 km. In contrast, HR continued to rise until the completion of the run. These data are consistent with recent reports of an exaggerated ANF response in older subjects in response to central blood volume expansion.     

Responses of atrial natriuretic peptide and other fluid regulating hormones to long distance swimming in the sea

The plasma hormonal response following a swimming competition in the sea (18 km) was evaluated in 12 top level male endurance swimmers. At the end of the effort, while plasma renin activity (PRA) and aldosterone concentration (ALDO) were unchanged, a significant increase in plasma atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) concentrations were recorded. These changes were associated with a decrease in haematocrit and an increase in Na⁺ and Cl^– plasma concentrations. The individual variations of ANP (difference between the final and initial concentrations) were inversely correlated with the corresponding individual variations of PRA and ADH. The results suggest that, during prolonged swimming, ANP may exert an inhibitory effect on the PRA-ALDO axis and have a modulatory role with regard to ADH secretion.     

Time course of plasma corticosterone, 18-hydroxycorticosterone and aldosterone concentrations following CRF administration in the rat. A phase of corticosterone inhibition

Synthetic ovine CRF (8 micrograms/rat) injected intravenously in nembutal anaesthetized rats increased not only plasma ACTH and corticosterone but also aldosterone and 18-hydroxycorticosterone concentrations. The maximum elevation occurred 30 min after oCRF administration. 2 h and 4 h after injection the hormone concentrations declined and after 6 h the corticosterone and 18-hydroxycorticosterone values were lower than the corresponding controls. At this time aldosterone remained slightly elevated and ACTH unchanged. 24 h after oCRF injection no difference between the control and oCRF treated animals were evident.     

Plasma atrial natriuretic peptide, plasma renin activity and aldosterone during treatment of hyperthyroidism due to Graves' disease

Plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and aldosterone were consecutively measured during methimazole treatment in patients with hyperthyroidism due to Graves' disease. ANP values of untreated hyperthyroid patients varied greatly from patient to patient, but decreased progressively with a decrease of serum thyroid hormone concentration during methimazole treatment. PRA was elevated in hyperthyroid patients but less aldosterone was secreted as evidenced by lower aldosterone/PRA ratio in these patients than in normal subjects and in hypertensive patients treated with thiazide. In addition, aldosterone/PRA ratio increased progressively with a decrease of ANP during methimazole treatment. The data indicated that ANP secretion was increased and ANP thus secreted depressed aldosterone secretion in hyperthyroid patients. Propranolol depressed pulse rate but failed to affect ANP secretion. It is suggested that thyroid hormone specifically acts on myocytes to stimulate ANP secretion but physiologic significance of such increased ANP secretion remains to be solved.     

A comparison of subcutaneous and intramuscular administration of human growth hormone (hGH) and increased growth rate by daily injection of hGH in GH deficient children

Plasma human growth hormone (hGH) profiles and biological activities of recombinant hGH were compared after im and sc injection in 8 normal volunteers. The time to reach maximal plasma GH and plasma hGH concentrations and the areas under the curve of hGH profiles did not differ significantly after im and sc injections. The biological effect of hGH in increasing nonesterified fatty acid and insulin-like growth factor-I (IGF-I) was the same after both im and sc injections. During 6 months of daily sc administration of recombinant hGH in 20 naive patients, their height increased between 5 and 16.5 cm with a mean of 11.0 +/- 3.0 cm/year. In 27 patients who switched from hGH injections of 2-4 times/week to daily injections, the height increased between 5.3 and 16.5 cm with a mean of 8.3 +/- 2.2 cm/year. These values were greater than those observed in a previous study in which the same amount of hGH was injected in 2-4 doses per week. Plasma IGF-I increased more with daily sc administration than with 2-4 doses per week. The rate of appearance of an antibody to hGH was low (0.5%) and there were no notable changes in blood cell count, urinalysis and/or routine chemistries during the 6 months of daily recombinant hGH treatment. These results show that sc daily administration of hGH is safe, has a greater growth promoting effect, and can be recommended for the treatment of patients with GH deficiency.     

Behavior of the plasma level of digoxin in the rat in induced experimental hyperreninemia]

PRA, plasma and urine aldosterone levels and plasma digoxin were measured in rats in which digoxin had been administered under conditions of high PRA and high aldosterone levels experimentally induced by administering distilled water load and in rats in which digoxin had been administered without distilled water load. Results show that under conditions of high PRA and high aldosterone levels, plasma digoxin concentrations as measured 6 h after treatment were higher (45,3%) than in rats having received digoxin without water load. In assays carried out on rats sacrificed 12 h after digoxin treatment (with or without water load) all values approach basic levels again, thus suggesting that in rats too aldosterone might compete with digoxin at the level of tubular excretion.     

Growth hormone activates renin-aldosterone system in children with idiopathic short stature and in a pseudohypoaldosteronism patient with a mutation in epithelial sodium channel alpha subunit

Growth hormone (GH) treatment causes salt and water retention, and this effect has been suggested to be mediated by activation of epithelial sodium channel (ENaC). Multi-system pseudohypoaldosteronism (PHA) is a salt wasting disease resulting from mutations in ENaC subunit genes. We examined effects of GH therapy for 12-21 months on the renin-angiotensin-aldosterone system (RAAS) in 12 children with idiopathic short stature (ISS) and a PHA patient with defective ENaC function and concomitant GH deficiency. On GH therapy (0.7 U/kg/week), plasma renin activity (PRA), serum aldosterone and insulin-like growth factor-I (IGF-I) levels were periodically determined every 1-3 months in all children. The PHA patient was studied for 6 yr during which time serum, urine, and sweat electrolytes and secretion rate were also examined before, on and off GH therapy. In the PHA patient, mean plasma aldosterone concentration, 7.7 nmol/l (278 ng/dl) before therapy (n=9) rose to 73 nmol/l (2650 ng/dl) 10 months after GH. PRA and IGF-I increased similarly, reaching a plateau between 8 and 12 months. Off GH, there was a decrease to pretreatment levels in 30 months. Aldosterone and PRA strongly correlated with IGF-I (r=0.66 and 0.67). GH therapy also improved the growth rate, and increased both sweat secretion rate and Na(+)/K(+) ratio. In children with ISS, aldosterone and IGF-I peaked 6-12 months after GH. Off GH their levels normalized in 3 months. These findings indicate that long-term GH activates the RAAS in both children with ISS and a PHA patient, and that this effect does not depend on a fully functional ENaC.     

Effects of 3-day bed rest on physiological responses to graded exercise in athletes and sedentary men.

To test the hypotheses that short-term bed-rest (BR) deconditioning influences metabolic, cardiorespiratory, and neurohormonal responses to exercise and that these effects depend on the subjects' training status, 12 sedentary men and 10 endurance- and 10 strength-trained athletes were submitted to 3-day BR. Before and after BR they performed incremental exercise test until volitional exhaustion. Respiratory gas exchange and heart rate (HR) were recorded continuously, and stroke volume (SV) was measured at submaximal loads. Blood was taken for lactate concentration ([LA]), epinephrine concentration ([Epi]), norepinephrine concentration ([NE]), plasma renin activity (PRA), human growth hormone concentration ([hGH]), testosterone, and cortisol determination. Reduction of peak oxygen uptake (VO(2 peak)) after BR was greater in the endurance athletes than in the remaining groups (17 vs. 10%). Decrements in VO(2 peak) correlated positively with the initial values (r = 0.73, P < 0.001). Resting and exercise respiratory exchange ratios were increased in athletes. Cardiac output was unchanged by BR in all groups, but exercise HR was increased and SV diminished in the sedentary subjects. The submaximal [LA] and [LA] thresholds were decreased in the endurance athletes from 71 to 60% VO(2 peak) (P < 0.001); they also had an earlier increase in [NE], an attenuated increase in [hGH], and accentuated PRA and cortisol elevations during exercise. These effects were insignificant in the remaining subjects. In conclusion, reduction of exercise performance and modifications in neurohormonal response to exercise after BR depend on the previous level and mode of physical training, being the most pronounced in the endurance athletes.     

Effect of licorice on PTH levels in healthy women

Licorice has been considered a medicinal plant for thousands of years. Its most common side effect is hypokalemic hypertension, which is secondary to a block of 11beta-hydroxysteroid dehydrogenase type 2 at the level of the kidney, leading to an enhanced mineralocorticoid effect of cortisol. This effect is due to glycyrrhetinic acid, which is the main constituent of the root, but other components are also present, including isoflavans, which have estrogen-like activity, and are thus involved in the modulation of bone metabolism. We investigated nine healthy women 22-26 years old, in the luteal phase of the cycle. They were given 3.5 g of a commercial preparation of licorice (containing 7.6%, w/w of glycyrrhizic acid) daily for 2 months. Plasma renin activity (PRA), aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D (1,25OHD), 25-hydroxycholecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase (ALP), calcium, phosphate and creatinine, urinary calcium and phosphate and mineralometry were measured. PTH, 25OHD and urinary calcium increased significantly from baseline values after 2 months of therapy, while 1,25OHD and ALP did not change during treatment. All these parameters returned to pretreatment levels 1 month after discontinuation of licorice. PRA and aldosterone were depressed during therapy, while blood pressure and plasma cortisol remained unchanged. CONCLUSIONS: licorice can increase serum PTH and urinary calcium levels from baseline value in healthy women after only 2 months of treatment. The effect of licorice on calcium metabolism is probably influenced by several components of the root, which show aldosterone-like, estrogen-like and antiandrogen activity.     

Growth response to growth-hormone administration during the decelerating phase of the pubertal growth spurt in short normal children

In order to investigate the value of growth hormone (GH) treatment during late puberty, we studied the effect of human GH (hGH) administration (0.85 +/- 0.30 IU/kg/week; range: 0.44-1.28) on height velocity (HV) after the peak of the pubertal growth spurt in a group of 10 (4 girls and 6 boys) short normal children (GH peak after pharmacological stimulation: 15.5 +/- 2.3 ng/ml) with growth retardation (height: 2.6 +/- 0.3 SD) and puberty Tanner stage 4. A group of 10 untreated children, observed prior to the study, served as controls. The children were regularly measured during their pubertal growth spurt, and HV (cm/year) was calculated every 6 months. The pretreatment evaluation consisted of 2 consecutive 6-month periods characterized by a decrease in HV of at least 25%. In the group of selected children, hGH administration was then initiated and growth variables were evaluated after 6 and 12 months of therapy. Skeletal maturation was evaluated at the beginning as well as after 6 months and 12 months of hGH therapy. In the controls, HV (mean +/- SD) had decreased from 8.8 +/- 1.8 to 4.9 +/- 1.4 cm/year during the pretreatment period (in girls from 7.9 +/- 1.4 to 4.1 +/- 0.6 cm/year and in boys from 9.6 +/- 1.6 to 5.8 +/- 1.2 cm/year). During the following semester, HV was 3.3 +/- 0.8 cm/year (girls: 3.4 +/- 1.0 and boys: 3.2 +/- 0.2 cm/year).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the acute metabolic effects of 22,000-dalton and 20,000-dalton growth hormone in human subjects

The acute metabolic effects of 20,000-dalton human growth hormone (hGH20K) in man have not previously been tested. We compared changes in concentrations of free fatty acids (FFA), glucose, and insulin in nine growth hormone deficient children following injection of 22,000-dalton intact human growth hormone (hGH22K) and the smaller variant, hGH20K. There was a significant decline (37%) in the mean FFA concentration from baseline to 1/2 hour post-injection and from baseline to 1 hour post-injection (36%) in the children given hGH22K, but no such decline was seen after injection of hGH20K. No significant differences in mean insulin or glucose concentrations were noted between the two treatment groups, and glucose and insulin concentrations did not acutely change after injection of either hormone. The results of this study indicate that hGH20K has a diminished activity for suppression of FFA as compared to hGH22K. This suggests that GH residues 32-46, missing in hGH20K, constitute all or part of the region of hGH22K producing this response, or that the different primary structures of the two hormones result in tertiary structural differences and altered biological activity.     

Renin, aldosterone, and converting enzyme during exercise and acute hypoxia in humans

The possibility that hypoxia might inhibit the secretion of angiotension-converting enzyme (ACE) would explain the low concentrations of aldosterone reported in humans at high altitude. To observe the effect of such a reduction in ACE concentration on the plasma aldosterone concentration (PAC) four subjects performed mild exercise throughout a 2-h study so as to elevate their plasma renin activity (PRA). After the first 60 min breathing air they were switched to breathing 12.8% O2 (4,000 an altitude equivalent). Venous samples were taken at intervals for hormone analysis. Results showed the expected rise of PRA and PAC both tending toward a plateau after about 45 min. There was no significant change in ACE activity (F = 0.065). Hypoxia produced a further 50% rise in PRA but a fall in PAC and a 30% reduction in ACE activity. Angiotensin I concentrations closely followed PRA throughout (r = 0.984). These results indicate that during exercise acute hypoxia changes the usual close relationship between PAC and PRA by reducing ACE activity.     

Plasma vasopressin, neurophysin, renin and aldosterone during a 4-day head-down bed rest with and without exercise

The purpose of this study was to investigate the main renal and hormonal responses to head-down bed rest, which is currently considered a reliable experimental model for the simulation of weightlessness. Urinary output and electrolytes, plasma renin activity (PRA), aldosterone (PA), antidiuretic hormone (ADH) and immunoreactive neurophysin-I (Np) were measured in eight adult volunteers submitted to a 4-day head-down bed rest (-6 degrees) after a 24-h control period in the horizontal position (day 0). Four of the eight subjects were submitted to two 1-h periods of controlled muscular exercise (50% VO2max) from day 1 to day 4. Throughout the head-down bed rest period, urinary output remained stable, although lower than in the control period (day 0), but the urinary Na/K ratio decreased. Plasma electrolytes and osmolality, and creatinine clearance remained unchanged. There was no significant difference between exercising and non-exercising subjects. At the hormonal level, PRA and PA increased during the head-down bed rest. This increase was more pronounced in the group with exercise. At the end of the tilt period, PRA and PA were about 3 times higher than on day 1. No significant changes could be observed for ADH and Np. It is concluded that a 4-day head-down bed rest results in no apparent changes in neurohypophyseal secretory activity, and in a progressive secondary hyperaldosteronism.     

Plasma renin activity and aldosterone concentration in children.

Using semi-micro methods, plasma renin activity (PRA) and plasma aldosterone concentration (PA) were measured concurrently in 79 healthy children aged 1 month to 15 years to establish a reference range. PRA and PA varied inversely with age. Eleven children with renal hypertension had higher PRA and PA than age-matched controls. In contrast, PRA was much greater in 38 saline-depleted children. PA was not uniformly increased in this group and was within the normal range in children with adrenal diseases compared with the high values seen in other salt-wasting states. The findings emphasise the need to relate data from patients to age-matched control values before attempting interpretation and suggest that sodium depletion is a more potent stimulator of renin-aldosterone release than renovascular disease or renal scarring in children. Plasma renin-aldosterone profiles were also valuable in discriminating between renal and adrenal causes of salt loss in childhood.     

Effects of angiotensin I-converting enzyme inhibitor, SQ 14225, in nomal men.

Effects of an orally active angiotensin I-converting enzyme inhibitor, SQ 14225, on the actions of angiotensin I (AI) infused intravenously for 120 to 390 min were studied in 5 normal men. When 20 ng/kg/min of AI infusion was started immediately after a single oral administration of 100 mg of SQ 14225, a significant rise in blood pressure (BP) was observed for the first 15 min, but BP began to fall from 17 min and returned to the pretreatment level at 45 min. This BP level continued at least to 120 min and in one subject to 180 min. In this subject BP began to rise again from 185 min and reached the level of 15 min at 390 min. Plasma AI level increased gradually from 45 min. At 15 min plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased, but then PRA began to increase and PA began to decrease. At 120 min the values of PRA and PA were similar to the pretreatment values. In one subject plasma AI and PRA began to decrease and PA began to increase after 120 or 180 min. On the other hand, in the 5 men sole AI infusion caused a continued BP rise, PRA decrease and PA increase, and sole SQ 14225 administration caused increases in plasma AI and PRA and a decrease in PA but no BP change. From these results it was concluded that complete blockade and partial inhibition of AI conversion by 100 mg of oral SQ 14225 lasted for about 2.5 and 6.5 hr, respectively and that BP rise, PRA suppression and aldosterone stimulation after AI infusion were entirely due to the actions of angiotensin II converted from AI.     

Effect of hypoxemia on the renin-angiotensin-aldosterone system in humans

Hypoxemia was induced in five subjects older than 40 (group 1) and five younger than 35 yr (group 2) on normal and low-salt diets by having the subjects breathe hypoxic gas. The fractional inspired O2 of the hypoxic gas was regulated so that group 1 hemoglobin saturations fell to 90% for 1 h. Group 2 subjects had desaturation to 90% for 1 h followed by desaturation to 80% for a 2nd h. Plasma renin activity (PRA), angiotensin-converting enzyme activity (ACE), and plasma cortisol levels did not change during hypoxemia. Plasma aldosterone levels fell in both groups during the 1st h of hypoxemia. Decreases were greatest during salt restriction and were significant (P less than 0.01) for the combined groups. Plasma aldosterone levels plateaued during the 2nd h of more severe hypoxemia in group 2. Hepatic blood flow, measured by indocyanine green clearance, and the adrenal response to exogenous adrenocorticotropic hormone, measured by changes in plasma cortisol and aldosterone, were not changed by hypoxemia in group 2 subjects. These results indicate that plasma aldosterone falls during hypoxemia despite unchanged PRA, ACE, hepatic blood flow, and adrenal function.     

Plasma aldosterone, renin activity, and cortisol responses to heat exposure in sodium depleted and repeleted subjects.

The effect of 90-min heat exposure (46 degrees C, 35 mbar) on plasma aldosterone (PA) patterns was studied and the respective roles of plasma renin activity (PRA), adrenocorticotropin (ACTH), Na+ and K+ concentrations in the control of PA response were in investigated in eight subjects on a low sodium diet and in five subjects on a high sodium diet. In all subjects, transitory PA increases of varying importance were observed, which were not related to sweat losses (less than 1% bodyweight) or to rectal temperature rise. In sodium-repleted subjects, basal PA and PRA levels as well as heat-induced rises were low (mean PA peak level = 12.62 +/- 1.15 ng/100 ml). They were enhanced by sodium depletion and PA reached a mean peak level of 34.07 +/- 2.73 ng/100 ml. But, in both conditions, the heat-induced PA peaks were 3-times higher than the initial levels. PA correlated with PRA in all but one of the sodium-repleted subjects and in 6 of the 8 sodium-depleted subjects. ACTH release, as measured by plasma cortisol (PC) levels, occurred in those subjects who noted an increased feeling of annoyance and discomfort. Thus, PA correlated positively with PC in 4 sodium-depleted subjects. A high sodium intake improved heat-tolerance. Plasma K+ and Na+ concentrations were not significantly modified by exposure to heat. PA increases can occur without concomitant changes in PRA, PC, K+ or Na+, which suggests that an additional factor may play a role in aldosterone regulation during acute heat exposure.     

Effects of human growth hormone administration on growth rate and growth-stimulating activity of serum, measured by lymphocyte bioassay in hypopituitary children

The acute effect of human growth hormone (hGH) upon the serum bioassayable growth-stimulating activity was compared to the long-term effects of hGH on growth rate in two groups of hypopituitary patients aged 2-18 years. 12 patients had complete GH deficiency with GH peak below 3.5 ng/ml at two stimulation tests. 15 others, having both GH peaks below 8 ng/ml and at least one above 3.5 ng/ml, were considered as having partial GH deficiency. The growth-stimulating activity of serum was measured by its effect at concentrations 0.03 to 1.25% upon thymidine incorporation into lectin-activated normal human lymphocytes, named thymidine activity (TA). In patients with complete GH deficiency, the pre-treatment TA was positively correlated with the peak response of GH to stimulation tests. The increase of TA after 3-4 days of hGH treatment was positively correlated with the pretreatment TA level, and negatively correlated with the peak GH level. The effect of a 6-12 months therapeutic course of hGH upon the growth rate was positively correlated with the acute increase of TA. No such correlations were found in patients with partial GH deficiency. Many works have discussed the relationship of acute somatomedin responses and long-term clinical results of treatment with hGH in GH-deficient children. The present data, using a highly sensitive bioassay of serum stimulating activity, suggest that the degree of GH deficiency is an important factor to be considered. The response of GH-dependent serum growth factors to acute treatment with hGH could have more predictive value in cases with total lack of growth hormone than in cases of partial deficiency.