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Human growth hormone release
Abstract
Twenty normal adult volunteers were systematically tested with five known provocative agents of human growth hormone (HGH) release in order to ascertain which procedure was the most effective stimulus for pituitary testing purposes. Ninety-five per cent responded normally (5 ng/ml increment) to levodopa (l-dopa) and 90 per cent to insulin-hypoglycemia. Arginine, vasopressin and glucagon were less potent stimuli; however, arginine (80 per cent response rate) was superior to vasopressin and glucagon (60 and 55 per cent, respectively).
... The inherently greater specificity of antigen-antibody interaction yields a higher degree of purification than that achieved by Concanavalin A. However, the use of immobilized antibodies for glycoprotein hormone purification has been infrequent and only partially successful. Gospodarowicz demonstrated that during elution of im- Protein (mg) TSH (RIA; juIU) [28] TSH (bioassay; 0 /uIU) [20] TSH (RIA)/protein (/iIU/mg) FSH (mlU) [32] LH (mlU) [32] a-Subunit (ng) [29] PRL (ng) [33] GH (ng) [34] Applied to columns (in 30 ml serum) Reference numbers are shown in brackets. " Adenylate cyclase stimulation. ...
Immunoaffinity methods for separation of TSH and other glycoprotein hormones as well as their common α-subunit are described. Partially purified antibodies to TSH and the α-subunit of CG were coupled to agarose and packed in columns (15 x 0.9 cm). The anti-TSH column had a capacity of 31 μg TSH/ml agarose, and the anti-α had a column capacity of 3.6 μg TSH/ml agarose. Material that had been applied and adsorbed to the columns was eluted with 0.1-4.0 M guanidine HCl, pH 3.2, at 4 C. This procedure yielded high recovery of TSH immunoactivity and adenylate cyclase-stimulating activity. Less than 5% dissociation of the hormone into its subunits occurred during such immunoaffinity purification. For separation of the glycoprotein hormones and the free α-subunit, advantage was taken of their different affinities for the antibodies. When adsorbed radiolabeled material was exposed to a linear guanidine gradient, substances with lower affinities for the antibodies eluted earlier than substances with higher affinities. Thus, from the anti-TSH column, peak elution of CG, FSH, and LH occurred at 0.5 M guanidine, well separated from the TSH peak at 1.2 M. Similarly, CG and TSH eluted from the anti α column at 0.4 M guanidine, clearly earlier than the α-peak at 0.9 M. The affinity chromatography columns were also used for copurification of TSH with other glycoprotein hormones and the α-subunit from hypothyroid serum. The fractions of serum that bound to the columns were eluted with a constant concentration of guanidine (the anti-TSH column with 3 M and the anti-α column with 2 M) in a volume approximately 1.5 times the column bed. Such a one-step elution allowed a 62-91% recovery of serum TSH with a 100- to 200-fold purification (TSH activity/total protein). Simultaneously, 41-58% of FSH, 39-51% of LH, and 64-89% of free α-subunit were recovered. These immunoaffinity methods provide a convenient tool to improve the sensitivity and specificity of TSH and other glycoprotein hormone assays by prepurification and concentration of serum samples. The methods are also of potential value for large scale isolation and purification of glycoprotein hormones.
The role of hypophysectomy in the treatment of cancer pain has been debated for several years. Although transcranial hypophysectomy for the treatment of malignant tumors was first described in 1952 [24, 29], it was originally conceived as a means of achieving objective regression of metastatic prostate and breast carcinoma. This procedure was a logical extension of the hormonal manipulation by gonadectomy and/or adrenalectomy pioneered by Charles Huggins [10]. It was soon found that hypophysectomy, like its antecedent operations, produced pain relief in cases of metastatic breast and prostate carcinoma more consistently than it caused objective tumor regression [26, 30]. With the advent of stereotactic and open transsphenoidal hypophysectomy, pituitary ablation could be accomplished with greater safety. Similarly, the introduction of chemical hypophysectomy by Moricca in 1963 [22] offered another nonoperative route for pituitary destruction. These types of surgery and their variations then became a practical option for providing pain relief, not only for patients who were too debilitated by advanced cancer to undergo craniotomy, but also for patients who were candidates for craniotomy.
Growth hormone (GH) hypersecretion in the human may be due to a GH-secreting tumor, to a GH-releasing-hormone (GHRH) secreting tumor, to disorders of GH feedback regulatory mechanisms, or to functional disturbance of GH regulation in association with systemic disorders, malnutrition, or psychiatric disease (Table 1). It is only in the first two circumstances that the clinical syndrome of acromegaly develops. In this chapter the pathophysiology of these disorders will be reviewed, the primary emphasis being given to the pathogenesis of GH-producing pituitary tumors.
This chapter reviews some experimental evidence linking classical and putative neurotransmitters with the secretion of anterior pituitary hormones. The hypothalamus and median eminence (ME) are densely innervated by neurons containing the three classical neurotransmitters—dopamine (DA), norepinephrine (NE), and serotonin (5-HT)—their receptors, and other putative neurotransmitter substances. Although there is some confusion about the exact role played by some of the conventional neurotransmitters in pituitary function, it is widely recognized that these neurons, and probably many other more distant ones, regulate the secretion and/or synthesis of hypothalamic hormones that release or inhibit the secretion of all anterior pituitary hormones. Substances traditionally considered to be neurotransmitters—such as DA—can influence the secretion of a pituitary hormone directly at the pituitary level, thus functioning as a hypothalamic neurohormone. Other substances with wide central nervous system distribution—such as the pentapeptides methionine and leucine, enkephalin, or vasoactive intestinal peptide—have been found in high concentrations in the hypothalamus, suggesting that these substances may be involved, as neurotransmitters or modulators, in the hypothalamic control of pituitary function.
Following the description of the technique of radioimmunoassay1 (RIA) and its application to the measurement of pituitary hormones, disorders of pituitary function could be diagnosed much more readily than before. The subsequent development of a specific RIA for human prolactin2 (PRL) has revolutionized our means of diagnosing pituitary tumors, for it has become clear that 50–80% of tumors that previously were categorized as inactive chromophobe adenomas actively secrete PRL.3
Growth is intrinsically linked with both an increment in cell mass and an acceleration of cellular proliferation. Growing mammalian cells have in common a characteristic set of biochemical phenomena, including an increase in protein synthesis, increased incorporation of nucleic acid precursors into RNA and DNA, and poly-some aggregation (Hershko et al.,1971). These growth-mediating processes are limited by the availability of various nutrients, metabolites, and ions in the extracellular environment, but are also susceptible to regulation by a variety of agents, including hormones. Control points for this hormonal influence upon growth include: membrane-associated processes involved with the transport of amino acids, energy substrates, and ions; transcriptional processes involved in the expression of genetic information through the synthesis of new RNA; and translational processes as reflected in the numbers and efficiency of ribosomal protein-synthesizing units.
In the field of endocrinology, there is an increasing number of examples of hormones that were originally identified and named on the basis of some particular effects and then subsequently found to exert other effects as well, some of which turn out to be of greater physiological importance than the original ones. Vasopressin (VP) is one of the earlier examples of this phenomenon in that it was identified and named because of its vasopressor properties; only later was it recognized that it is of even more importance as an antidiuretic hormone. Still later, this same peptide began attracting attention for its effects on the functions of a variety of endocrine organs, and it is this aspect of the physiology of VP that is addressed in this chapter. Because the earlier literature in this field was reviewed in 1968 by Doepfner, we concentrate on the advances since that time. As is often the case, many of these advances in our knowledge of the physiology involved have been possible only because of recent technological advances. For example, assays for the hormones affected by VP (as well as for VP itself) have improved dramatically, and the structures of some of these hormones (e.g., the hypophys-iotropic hormones) have only recently been elucidated. Also, the availability of synthetic agonists and antagonists for VP is proving to be as valuable to the study of the receptors involved in endocrine effects as it has been for the more classical pressor and antidiuretic effects of VP. Finally, the widespread use of the Brattle-boro rat, with its congenital lack of VP, has made a particularly strong contribution to the study of the endocrine effects of VP. The endocrinopathies of the Brat-tleboro rat are considered to some extent in this chapter, but the reader is also referred to a recent monograph (Sokol and Valtin, 1982) for further details.
A new molecular design of hyaluronic acid (HA) hydrogel networks by Michael addition between aminoethyl methacrylated HA (HA–AEMA) and thiolated HA (HA–SH) enabled the controlled release of human growth hormone (hGH) for up to 4 weeks.
In a total of 95 children with idiopathic scoliosis and 60 controls between the ages of 7 and 17 years, a prospective study of hormones related to growth and maturation was carried out. the pituitary release mechanism for growth hormone was evaluated using the propanolol/L-dopa stimulation test. in addition the blood levels of testosterone, sex hormone binding globulin, oestradiol, thyroxin, prolactin, Cortisol, follicle stimulating hormone and luteinizing hormone were determined. the girls were divided into age groups and all results were evaluated according to chronological and skeletal age. the number of boys was too small (25) to allow subdivision into age groups. the girls with idiopathic scoliosis had a significantly higher response to the growth hormone stimulation test than had the controls between the ages of 7 and 12 years whereas no significant difference could be found for the older girls. in girls with a skeletal age between 9 and 12 years a significantly higher mean serum level of testosterone was found (P < 0.05). No significant differences could be demonstrated for the remaining hormones. Growth hormone and testosterone are the most important growth factors in prepubertal and pubertal children. Thus, the present findings suggest a hormonal basis for the increased stature in children with idiopathic scoliosis which has previously been reported. © 1980 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Transsphenoidal microsurgical hypophysectomy was performed in 53 men with disseminated carcinoma (Stage IV) of the prostate gland. The mean age was 64.8 years. Forty-three of the 53 men had severe pain due to their disease. Significant pain relief was obtained following hypophysectomy, usually within 24 hours, in 39 (91%) of these 43 patients. Objective remission occurred in 16 (36%) of 45 patients in whom the follow-up review was adequate to make this decision. Although dramatic, pain relief was not permanent in every patient. Four patients died in the early postoperative period, and in one, death was directly related to the operative procedure. Significant complications included partial diabetes insipidus in 40 cases (75.5%), and cerebrospinal fluid leaks in six (11.3%).
The authors conclude that hypophysectomy is an appropriate operation in patients with disseminated carcinoma of the prostate gland, particularly when pain is a significant feature of the illness. Further, the transsphenoidal microsurgical approach appears to be the operative procedure of choice for performing hypophysectomy.
The availability of radioimmunoassay techniques and newer physiologic knowledge have generated a variety of test procedures designed to challenge hypothalamic-pituitary function. Most of these dynamic tests provoke the discharge of pituitary hormones and are helpful primarily in cases with low or normal basal levels, i.e., in evaluation of pituitary-hypothalamic failure. Not all of the reported stimulation tests (or their many modifications) have proved equally reliable, but selected use of an assortment of newer diagnostic techniques permits reasonable confirmation and localization of pituitary hormonal disorders.
In an attempt to identify possible adverse effects of CNS prophylaxis (cranial radiation and intrathecal chemotherapy), we examined hypothalamic-pituitary function in 23 patients with acute lymphocytic leukemia (ALL). Of 18 patients who had received both cranial radiation and intrathecal chemotherapy, nine had abnormally low growth hormone responses to insulin-induced hypoglycemia (less than 7.0 ng/ml). Seven of the nine patients with abnormally low growth hormone responses also manifested ventricular dilatation on computed tomography (CT) brain scans, whereas only one of the nine patients with normal growth hormone responses demonstrated this CT scan finding (P = 0.015). The remaining patients, who had not received cranial radiation, had normal growth hormone responses and normal CT scans. There is significant correlation between ventricular dilatation on CT and abnormally low peak growth hormone responses following CNS prophylaxis in ALL.
The authors review the present knowledge of the hypothalamic-pituitary endocrine axis. The physiology and pathophysiology are discussed along with outlines of standard approaches to diagnosis of disorders. An appendix of useful provocative tests is included.
Forty-eight normal volunteers, thirteen subjects with short stature without apparent cause and thirty-one patients with delayed growth clinically highly suggestive of growth hormone deficiency (GHD), with chronological ages of 11.4 ±0.4 years (mean±SEM), 14.0 ±0.7 years and 12.8 ± 0.8 years; height age of 11.0 ± 0.4 years, 8.9 ± 0.7 years and 6.3 ± 0.4 years and bone age of 10.7 ± 0.7 years, 9.9 ± 0.8 years and 7.5 ± 0.7 years respectively, were tested with provocative tests of human growth hormone (hGH) release—insulin-induced hypoglycaemia, arginine infusion, l-DOPA, exercise and sequential exercise and l-DOPA-in order to identify growth hormone deficiency. In the ‘normal’ subjects (control plus short stature) the sequential exercise and l-DOPA test induced the greatest peak and integrated secretion rates of plasma hGH (16.5 ± 1.2 ng/ml and 679 ± 70 ng/ml/120 min respectively) when compared to other tests. This combined stimulus was the only one to which all ‘normal’ subjects responded: a similar degree of responsiveness has not been earlier described for other hGH-stimuli. The responses observed with all stimuli were significantly lower (P < 0.001) in GHD group compared to the ‘normal subjects’.
Emphasis was given to the sequential exercise and l-DOPA test as an innocuous, sensitive and simplified procedure in the evaluation of children with growth retardation.
Based upon the experience gained in the evaluation of 60 patients with abnormal polytomography and/or elevated prolactin levels, the following observations can be made: Patients with amenorrhea, amenorrhea and galactorrhea, galactorrhea alone, or anovulatory cycles and infertility may or may not have pituitary tumors. Clinical symptoms do not always correlate with the prolactin level, and patients with normal prolactins may have pituitary tumors. The incidence of empty sella is significant (15.8% in this series). Visual field examination is not a useful screening procedure, but evaluation of thyroid function is important to detect the occasional patient with hypothyroidism (3.5% in this series). The insulin tolerance test is not helpful in detecting the presence of pituitary tumors or in guiding management decisions, and the CT scan contributes little and should be omitted from the evaluation process. A straightforward, economical, and efficient approach to this clinical problem is presented.
Apomorphine, a dopaminergic receptor stimulant, was tested and compared in subemetic doses (0.76 mg subcutaneously) to levodopa (500 mg orally) as a stimulant of growth hormone release in 10 normal volunteer subjects (five male, five female). The administration of levodopa failed to cause a normal increment in serum growth hormone levels (greater than 5 ng/ml from base line) in four patients, produced a borderline normal response in two patients with a normal response in four patients. Apomorphine stimulation produced a borderline normal response in one patient and a normal response in the remaining nine patients. The peak response to apomorphine administration was 26.94 +/- 6.60 ng/ml and to levodopa 9.76 +/- 2.67 ng/ml (p less than 0.025). There was no statistical difference between men and women in whom apomorphine testing was utilized. Side effects (nausea, vomiting) were seen in three patients tested with levodopa and in four patients tested with apomorphine. Such symptoms began within 20 minutes of apomorphine administration, persisted from 30 to 40 minutes and disappeared abruptly. All patients treated with apomorphine noted transient drowsiness.
Determination of the functional reserve of the anterior pituitary gland requires the serial measurement of hormones released from the pituitary by specific stimuli. Individually, insulin-induced hypoglycaemia, thyrotrophin releasing hormone (TRH) and gonadotrophin releasing hormone (GnRH) have proved to be reliable stimuli for the release of the various pituary hormones. The maximum incremental hormone response of growth hormone, cortisol, luteinising hormone, follicle stimulating hormone, thyrotrophin, triiodothyronine and prolactin has been assessed after the simultaneous administration of insulin, TRH and GnRH in six normal subjects. These responses have been compared to previously determined responses in a normal population when insulin, TRH or GnRH have been given separately. There were no significant differences in the peak response or the maximum incremental response of any hormone. The test has been used to assess the pituitary reserve of 54 patients with disorders of the hypothalamic-pituitary axis, and five patients have been assessed both before and after hypophysectomy. The test is found to be convenient, sensitive and reliable in the assessment of pituitary reserve.
The authors studied changes in indices of thyroid function prospectively in a group of 11 patients given amitriptyline to treat depression. The drug caused no significant alteration in these indices, but scores on the Hamilton Depression Rating Scale improved significantly. In another group of subjects with depression, the stimulation of growth hormone secretion by L-dopa was unaffected by amitriptyline therapy.
The association between hypogonadotropic hypogonadism and multiple CNS lesions in a variety of disorders suggests a possible causative link between these clinical findings. Neural afferent input into the hypothalamus from higher CNS centers modulates GnRH secretion and derangements of these neural pathways could potentially result in diminished gonadotropin secretion and hypogonadism. This report describes a patient with multiple CNS defects secondary to Moebius syndrome and hypogonadotropic hypogonadism whose clinical features support the hypothesis that his CNS and endocrine defects may be causally associated. Comprehensive clinical evaluation in this patient revealed severe mental retardation; cranial nerve palsies; motor, reflex, and gait disturbances; and sexual infantilism secondary to hypogonadotropic hypogonadism. An MRI of the brain revealed atrophy or hypoplasia of the third cranial nerve and the olfactory gyri. Numerous syndromes including the Moebius syndrome are now described in which hypogonadotropic hypogonadism and CNS defects are associated. Detailed neuroanatomic and embryologic studies have demonstrated the important functional interrelationships between higher central nervous system centers and the hypothalamus. Taken together, these findings provide support for the causative association of multiple CNS defects and hypogonadotropic hypogonadism.
Growth hormone (GH) levels in nocturnal urine were measured in 96 short children and 73 children of normal height in order to investigate whether urinary GH levels reflect spontaneous GH secretion and whether they might be used to screen short children for GH treatment. GH levels in 24-hour urine samples were significantly correlated with urinary albumin and beta 2-microglobulin levels in normal children, demonstrating an influence of renal function on urinary GH measurements. Nocturnal urinary GH levels showed significant positive correlations with mean serum GH levels during 3 hours of sleep (r = 0.26, p less than 0.05) and plasma insulin-like growth factor I (IGF-I) levels, reflecting physiological GH secretion. Urinary GH levels were significantly lower in the eight children with complete GH deficiency (3.1 +/- 2.3 ng/g creatinine) than in the normal children (13.8 +/- 11.2 ng/g creatinine). Urinary GH levels in three other groups of short children, partial GH deficiency (11.1 +/- 16.9 ng/g creatinine), impaired GH secretion during sleep (10.4 +/- 12.6 ng/g creatinine) and non-endocrine short stature (18.8 +/- 19.5 ng/g creatinine), were not significantly different from those in the normal children. However, when the cut-off point for defining GH insufficiency was set at 5 ng/g creatinine, 87.5% (21 out of 24) of the short children with low urinary GH levels were suitable subjects for GH treatment (i.e. had complete GH deficiency, partial GH deficiency or impaired GH secretion during sleep).(ABSTRACT TRUNCATED AT 250 WORDS)
Human growth hormone (hGH), or somatotropin, is synthesized by the somatotrophic cells of the anterior pituitary gland. It is the most abundant hormone in the anterior pituitary and represents approximately 1–3% (5–15 mg) of the total weight of the gland (Wilhelmi,, 1961), hGH is a globular protein with a molecular weight of 22,000 daltons (22 kDa). It consists of a single polypeptide chain with 191 amino acid residues (Fig. 1). hGH has two disulfide bridges, no carbohydrate moieties, and a secondary structure that is predominantly α-helical (Li and Dixon, 1971; Niall, 1971; Li, 1982). Similarly, growth hormone (GH) purified from the pituitary glands of cattle, sheep, and pigs are also simple globular proteins (Wilhelmi, 1975). While approximately 90% of the hGH contained in the pituitary has a molecular weight of 22 kDa, six other variants have been identified (Fig. 2) (Chawla et al.,1983; Lecomte et al., 1987). These variant GH peptides have been isolated from either plasma, pituitary tissue, or pituitary complementary DNA (cDNA) libraries, and they differ from the 22-kDa form in molecular weight, electrophoretic mobility, or biological activity. The 45-kDa variant is an aggregate of the 22-kDa form and comprises about 1% of the GH immunoreactivity in the gland (Frohman et al.,1972). Since hGH has a tendency to form aggregates, it is possible that this dimer is formed during storage in the pituitary gland (Gorden et al., 1973).
Thirteen drug-free and not severely affected patients with idiopathic Parkinson's disease underwent an insulin-hypoglycaemia test, a TRH test and a levodopa test. The responses of growth hormone, prolactin, cortisol and thyrotropin were measured, and retested under stable therapy with levodopa and benserazide. Mean basal and stimulated hormonal concentrations were in the normal range before and during therapy. Minor abnormalities were observed in individual cases, but did not indicate a hypothalamic dopamine deficit.
In order to establish whether thyrotropin-releasing hormone (TRH) inhibits lysine-vasopressin (LVP)-induced growth hormone (GH) release, six normal men were tested with LVP alone or in combination with TRH. LVP strikingly increased serum GH levels; this response was not altered by TRH. These results indicate that in man TRH is not involved in the control of GH secretion in response to LVP.
The authors discribe a 37 year old male with a 6-month history of diffuse myalgia and arthralgia, due to a hypothalamic hypopituitarism.
The ketotic effects of both glucocorticoid and growth hormone were assessed in normal man. Experimental protocols, previously shown to induce marked ketosis in diabetic man, were utilized to explore the metabolic effects of these two stress hormones in subjects with normal insulin secretory capacity. Glucocorticoid was administered orally as 1 mg of dexamethasone at 24 and 8 h prior to study. Growth hormone was administered subcutaneously at a dosage of 1 mg, 12 h prior to study. During the 90-min study of the ketotic activity of these hormones, plasma nonesterified fatty acids were acutely increased by heparin administration to support hepatic ketogenesis. This technique permitted an assessment of the ketotic activity of glucocorticoid and growth hormone independent of their lipolytic activity. The results of this study demonstrate that glucocorticoid may cause minimal hyperketonemia in spite of hyperinsulinemia in normal man. However, this effect is accompanied by a glucocorticoid-induced instability in basal ketone body and nonesterified fatty acid concentration. In contrast, no effect of growth hormone on plasma ketone body concentration or insulin levels was observed. These results in normal man contrast to the marked ketosis previously induced by these two stress hormones in diabetic man.
TRADITIONALLY, the diagnosis of distal renal tubular acidosis has been established by measuring urine pH, blood pH, and plasma bicarbonate following the oral administration of ammonium chloride? This acidifying agent, however, is unpalatable and often produces emesis, which complicates the precise determination of the amount of ammonium chloride received. In the adult population, ammonium chloride has been administered in gelatin capsules in an attempt to minimize such side effects. Unfortunately, children often are unable to swallow the capsules. Moreover, maximum systemic acidosis may take as long as eight to nine hours to develop when the capsules are used. ~ The intravenous infusion of ammonium chloride is not well tolerated by children because of pain usually experienced at the site of infusion. Because of these problems and because ammonium chloride may induce severe uncompensated metabolic acidosis when administered to infants, 3 we have evaluated an alternate method for studying renal acidification of the urine. We chose to use arginine monohydrochloride, which is metabolized in the liver, generating free hydrogen ions? A commercial intravenous preparation is readily available for use in growth hormone stimulation testing.' This report summarizes our experiences with this agent. METHODS Twenty-two patients, whose ages ranged from 5 months to 15.5 years, were studied. Eight were investigated
Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK–PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 μg/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK–PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0→∞ and Cmax (normalised to the dose 1 μg/kg), t1/2α and t1/2β. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL·min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53).
An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 μg/kg (P < 10−4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.
Serial plasma glucose, NEFA, and HGH concentrations were measured in normal male subjects following saline injection (Group 1, 9 cases), nicotinic acid injection (Group 2, 5 cases), and nicotinic acid plus heparin injection (Group 3, 4 cases) for 180 minutes. There was no appreciable change of plasma glucose in all groups. In Group 1 there was no significant change of plasma, NEFA and HGH. In Group 2, plasma NEFA showed an initial decrease followed by the secondary rise at 180 minutes, and plasma HGH showed a marked rise at 120 minutes and/or at 180 minutes. In Group 3, plasma NEFA did not show significant reduction and plasma HGH showed no significant changes. From the results obtained, it was suggested that the lowering of plasma NEFA levels by nicotinic acid administration can stimulate the secretion of HGH, and an assumption was made that plasma NEFA could be at least one of the factors in regulating HGH secretion. It was also suggested that plasma HGH may, at least in part, participate in inducing the secondary rise of plasma NEFA following the injection of nicotinic acid.
Intramuscular vasopressin injections raised serum-growth-hormone (G.H.) levels in fifteen children and adults of both sexes, but not in four patients with hypopituitarism, whose serum-G.H. levels also failed to rise after insulin-induced hypoglycæmia.
The serum-growth-hormone (H.G.H.) response to 'Bovril ' has been evaluated in eleven normal adults, and in thirty-seven boys and twenty-six girls aged 3 months to 19 years who were inpatients. Only one of five men exhibited a marked response, but increased levels were produced in all the women. Of the sixty-three children, forty-nine showed a definite response to Bovril. Serum-insulin and blood-glucose levels were determined in four women and five of the children undergoing the Bovril tests, and no significant changes were found. Comparable responses to Bovril and insulin-induced hypoglycæmia were obtained in the seven children tested by both methods. The Bovril test is recommended as a convenient, safe method of testing children for ability to secrete growth-hormone.
Intravenous administration of a pseudomonas endotoxin (Piromen), 0.5 μg./Kg., to normal subjects produced a significant increase in plasma growth hormone concentration (mean maximum 25.5 ± 6.0 mμg./ml.) in addition to its well known stimulation of ACTH secretion. Other metabolic effects of Piromen administration included a rapid elevation of plasma free fatty acids presumed to be secondary to epinephrine release and a slight, but significant lowering of plasma glucose concentration. In 9 hypopituitary patients, the maximum plasma growth hormone concentration observed following Piromen administration was only 1.1 mμg./ml., whereas 6 of these patients exhibited a significant rise in plasma adrenal corticoids. Thus, absence of pituitary growth hormone release was found to be a more sensitive index of decreased pituitary function than impairment of ACTH release. Four hypopituitary patients with secondary adrenal insufficiency exhibited a dichotomy between the adrenal corticoid response to Piromen and methopyrapone testing. In these patients, adrenal cortical insufficiency could be attributed to a failure of ACTH release rather than to an absolute ACTH deficiency.
The secretion of pituitary growth hormone is precisely regulated by the central nervous system. This control is exerted by at least two hypothalamic hormones, growth hormone releasing factor which has not been identified and somatostatin (also called growth hormone release-inhibiting factor). Both substances are believed to be produced by neurosecretory neurons of the medial basal hypothalamus. This article reviews the physiologic (episodic) character of normal secretion of growth hormone, the role of biogenic amines in the control of growth hormone secretion, and the aberration of control which occurs in certain diseases such as acromegaly. In relation to the latter, consideration is given to the current controversy as to whether the disorder is due to a hypothalamic or a pituitary disturbance. The most reasonable hypothesis is that acromegaly arises as a neoplastic change in the pituitary, but that the adenoma retains to a degree its dependence upon normal growth hormone secretory controlling hormones. Altered pituitary receptors in the adenomatous tissue probably account for the aberrant inhibitory responses to dopamine agonists and the stimulation of growth hormone by thyrotropin releasing hormone.
DURING the past decade developments in the area of neuroendocrine research have transformed it into one of the most exciting and rapidly changing aspects of endocrinology. The chemotransmitter concept of neural control of the anterior pituitary gland has been established, several of the hypothalamic releasing factors or releasing hormones have been purified, characterized and even synthesized, and extensive investigation of neuropharmacologic control mechanisms has been performed. Several excellent reviews and symposia have recently appeared.1 2 3 4 5 6 7 This review will attempt to assess the current concepts of the neurochemical basis of hypothalamic releasing-factor control and to summarize at the clinical level the present . . .
Anterior pituitary hormone secretion following administration of crystalline glucagon was studied in three phases, i.e., after subcutaneous injection, after intravenous injection, and after intravenous injection during constant glucose infusion. Although changes in serum glucose and plasma insulin levels were predictable, significant increases did not occur in the mean levels of plasma cortisol, serum growth hormone, serum luteinizing hormone, or serum thyrotropin. Only nine of the 24 subjects had increased cortisol levels, and ten had growth hormone responses. The timing and the magnitude of these responses were inconsistent but correlated well with the glucose nadir. Only seven of the 13 subjects who developed stressful stimuli (nausea and/ or hypoglycemic manifestations) had hormonal changes. When four of the responsive subjects were restudied during constant glucose infusion, their hormonal levels were unaffected and stressful symptoms did not occur. These data suggest that glucagon does not directly influence polypeptide hormone release from the pituitary gland. Hormonal responses appear to be secondary to changes in serum glucose and/or nonspecific stress.
Ten patients, aged 5 to 20 years, with short stature were given l-DOPA orally to assess its effects on pituitary hormone secretion. The group included seven children with constitutional short stature, one with isolated HGH deficiency and two with idiopathic hypopituitarism. Doses of l-DOPA ranged between 200 and 500 mg. Six of the seven constitutionally short children responded with elevations in HGH concentration above 7 ng/ml, peak levels occurring between 30 and 120 min after drug administration. No HGH release was observed in the individual with isolated HGH deficiency or the subjects with idiopathic hypopituitarism. No effects were seen on the plasma concentrations of FSH, LH, TSH and cortisol in the five endocrinologically normal patients in whom they were measured.
The use of a single, oral, 500-mg dose of l-dopa has been compared to the arginineinsulin test as a stimulus for growth hormone (hGH) release in 15 patients. Whereas l-dopa induced a significant rise in hGH in 5 of 6 normals, it failed to do so in all 3 obese subjects, one patient with short stature and one with an enlarged sella, all of whom responded to arginineinsulin. The response to l-dopa in 2 hypothyroid patients was blunted. The hGH response to l-dopa appears to have limited usefulness in the clinical assessment of pituitary function.
Comparisons have been made of the secretion of growth hormone (HGH) following the induction of hypoglycemia with insulin and that induced by arginine infusion (0.5 g/kg /30 min) in order to determine the reliability of the latter procedure in the diagnosis of disturbances in growth hormone secretion in children and adult patients. In 49 normal individuals tested with arginine, the HGH level rose to a peak concentration of 21 mμg/ml; in 105 normal individuals tested with hypoglycemia, the mean peak concentration was 17 mμg/ml. The mean peak concentration in plasma HGH in both tests was slightly, but not significantly, higher in women than men. The growth hormone rise in response to arginine was not dependent on prior insulin secretion, for a normal rise was observed in 12 juvenile diabetic patients tested. In 17 normal individuals who were pair-tested, the coefficient correlation between the peak HGH level attained following arginine and following hypoglycemia was 0.20; in 23 children with growth retardation who were pair-tested the coefficient of correlation was 0.58. Of the 12 patients suspected of having pituitary dwarfism by clinical criteria, 8 failed to respond to arginine, 9 failed to respond to hypoglycemia. Of the 11 patients suspected of having constitutional delay by clinical criteria, 1 failed to respond to arginine, 5 failed to respond to hypoglycemia. The arginine infusion is an innocuous, reliable stimulus of growth hormone secretion in the study of patients in the diagnosis of hyposomatotropism, which avoids the undesirable side-effects of insulin- induced hypoglycemia.
The plasma concentration of growth hormone reaches a peak within one or two hours after the onset of sleep. During most of the day the levels may be almost unmeasurable. The conditions under which plasma is obtained for testing assume great significance in view of the unusual normal secretory pattern. Some applications and limitations of growth hormone assays are considered.
Plasma human growth hormone (HGH) was measured in 11 subjects given low doses of insulin. Significant elevations of plasma HGH, temporally related to the stimuli, were seen only with significant decreases in blood glucose. The threshold for release of HGH was a fall of blood glucose of between 20 and 30 mg/100 ml, which was not associated with subjective manifestations of stress.
Plasma 11-hydroxycorticosteroid values have been determined during continuous intravenous infusions of synthetic lysine-8-vasopressin and after its administration as single intravenous, intramuscular or subcutaneous injections, in an attempt to define the best procedure for investigating pituitary-adrenal function. The intramuscular injection of 10 pressor units (PU) proved most suitable. An adrenocortical response was obtained in all subjects studied when samples were taken 30 and 60 min after injection. The 3 criteria established for a normal response are: i) that the basal level should exceed 5 μg/100 ml, ii) the 30 and/or 60 min value should reach at least 16 μg/100 ml, and iii) the plasma 11-hydroxycorticosteroid increment should exceed 5 μg/100 ml. There was no advantage in prolonging the test beyond 1 hr. Side-effects were minimal with this procedure and there has been no clinical, electroencephalographic or electrocardiographic evidence of cerebral or myocardial ischemia. The plasma growt...
To improve the usefulness of testing pituitary function by the response of human growth hormone (HGH) to I.V. arginine loads, arginine infusions were given under a variety of conditions to healthy subjects aged 17 to 35. The minimum effective arginine load causing release of HGH was 1/6 gm per pound of body weight in men and 1/12 gm per pound of body weight in women. At each of three dosage schedules used, women responded with greater increases in plasma HGH than men. Treatment of men with diethylstilbestrol augmented their HGH response to arginine, whereas methyltestosterone pretreatment did not decrease the response in women. The HGH response to arginine was not abolished by acute hyperglycemia but was attenuated or delayed by a previous stimulus for HGH release. In the use of this test of pituitary function, it is necessary to use a proper dose of arginine, to avoid other stimuli of HGH release, and to pretreat men with estrogens.
Human growth hormone (HGH) has been measured in the plasma of fasting subjects at the moment of awaking and 1–3 hr later after normal activity. Basal levels of men and women were not different and were usually less than 1 mμg/ml. A marked rise in the later (“ambulatory”) specimens occurred in women, to a mean level of 6.5 mμg/ml. This rise was not seen in men, whose basal and ambulatory values were indistinguishable. Administration of estrogen to men resulted in a reproduction of the normal female pattern of HGH increase after activity. Variations of ambulatory but not basal HGH were noted in women followed throughout the menstrual cycle, with a distinct luteal phase rise beginning shortly after ovulation. It is postulated (a) that estrogens act to enhance pituitary sensitivity, or that of higher centers, to the HGH-releasing effects of physical activity and possibly other stimuli; and (b) that this effect may be at least partly responsible for the differences in plasma HGH noted between men and women, and in women during the menstrual cycle. It is also suggested that the increased HGH secretion following estrogen administration has a mammotropic action, and that the higher levels in normal women may play a physiologic role in the development and maintenance of the breast.
The effect of pyrogen on plasma GH, LH, TSH and cortisol levels has been measured in 17 normal subjects, 13 patients with pituitary disease, and 3 patients with primary hypothyroidism. In 16 of the 17 normal subjects the plasma GH was greater than 10 mμg/ml at some time during the test, and plasma cortisol level increased by at least 5 mμg/100 ml. The GH response was not suppressed by glucose infusion in 2 subjects. Pyrogen did not cause an increase in LH or TSH in any subject. The TSH levels in 3 patients with primary hypothyroidism decreased 1 hr after pyrogen at the same time that plasma GH levels were elevated. These data show that pyrogen is not a nonspecific stimulus to the hypothalamic-pituitary system causing release of all polypeptide hormones. Growth hormone levels of greater than 10 mμg/ml after pyrogen occurred in only 1 of 13 patients with pituitary disease. In 8 of the 13 patients, however, the plasma cortisol increment was greater than 5 μg/100 ml. Thus, measurement of plasma GH in...
For years investigators have sought an assay for insulin which would combine virtually absolute specificity with a high degree of sensitivity, sufficiently exquisite for measurement of the minute insulin concentrations usually present in the circulation. Methods in use recently depend on the ability of insulin to exert an effect on the metabolism of glucose in vivo or in excised muscle or adipose tissue. Thus, the insulin concentration in plasma has been estimated: a) from the degree of hypoglycemia produced in hypophysectomized, adrenalectomized, alloxan-diabetic rats (1); b) from the augmentation of glucose uptake by isolated rat hemidiaphragm (2); or c) from the increased oxidation of glucose-1-C14 by the rat epididymal fat pad (3). Since there have been reports indicating the presence, in plasma, of inhibitors of insulin action (4) and of noninsulin substances capable of inducing an insulin-like effect (5,6), these procedures, while yielding interesting information regarding the effects of various plasmas on glucose metabolism in tissues, are of doubtful specificity for the measurement of insulin per se (5).
The adrenocortical response to stress as shown by an increase of the plasma cortisol concentration during insulin-induced hypoglycaemia has been studied. The response was found to depend upon the degree and duration of the hypoglycaemia and upon the integrity of the entire hypothalamo-pituitary-adrenal axis. Thus, there was no response in subjects in whom the blood sugar did not fall below 40 mg./100 ml., nor in patients with severe hypothalamic or pituitary disorders.
The test was quick and simple to perform and did not require admission to hospital; it would seem to be of considerable value in the investigation of patients with suspected endocrine disease.
A sensitive and specific assay method has been used to demonstrate acute changes in plasma HCH in normal and diabetic subjects.
HGH secretion is suppressed by glucose administration and markedly stimulated by hypoglycemia, by a rapid fall in blood glucose without hypoglycemia, and by interference with intracellular glucose utilization. High levels of HGH were also observed during prolonged fasting, after exercise, and four to six hours following oral glucose administration.
Abnormalities in HGH secretion were found in association with acromegaly and obesity, and following section of the hypophyseal stalk.
The half time for disappearance of endogenous plasma HGH is twenty to thirty minutes.
Nine grossly obese individuals were starved for 4 to 14 days to study changes in plasma concentrations of nonesterified fatty acids (NEFA), glucose, growth hormone, and insulin. The effects of glucose administration and insulin-induced hypoglycemia on these plasma constituents were also studied. The obese patients responded to fasting with less of a rise in serum NEFA than nonobese subjects. Their plasma growth hormone concentrations were low throughout starvation. There was no significant change in plasma insulin concentration during fasting, but insulin secretion in response to oral glucose load was greater than normal. Glucose tolerance was impaired by starvation in obese subjects. In obese subjects, the increase in plasma growth hormone concentration following insulin-induced hypoglycemia was significantly smaller than in normal subjects. It is concluded that in obese individuals the rise in plasma free fatty acids and the impairment in carbohydrate tolerance which develop during starvation are not a consequence of low insulin or elevated growth hormone plasma concentrations. The impairment in glucose tolerance which develops after fasting may be a direct consequence of elevated plasma NEFA levels. Also, although not a significant factor in obese subjects, growth hormone may play a significant physiologic role in NEFA mobilization in normal individuals.
The Development of a specific and sensitive radioimmunoassay method for the determination of human growth hormone has made it possible to measure changes of plasma levels of endogenous growth hormone in response to a number of physiologic stimuli. Plasma levels of growth hormone have been shown to rise during or following spontaneous and experimentally induced hypoglycemia (1–3), prolonged fasting (1), vigorous muscular exercise (1, 2), surgical stress (4), inhibition of glucose utilization by 2-desoxy-glucose (1), and a rapid and significant fall in blood glucose levels (5). Administration of glucose to normal individuals promptly suppresses such elevated plasma levels of growth hormone (1, 5). It has been suggested that oral feeding of protein will also reduce levels of growth hormone (2).
Detection of growth hormone deficiency. The glucagon stimulation test
- Mitchell
The influence of levodopa (L-dopa) on release of anterior pituitary hormones in man (abstract)
- Boden
Catecholamines (Physiology in Medicine)
- Axelrod
Arginine-initiated release of human growth hormone
- Mérimée