Normal GH Levels Research Articles

Serum Growth Hormone Levels Measured by Radioimmunoassay and Radioreceptor Assay: A Useful Diagnostic Tool in Children with Growth Disorders?*

Serum GH levels were measured by RIA and RRA in 133 subjects (19 healthy controls and 114 patients with various growth disturbances, aged 2.3-24.8 yr). Serum samples obtained from 147 stimulation tests representing a total of 1065 samples were analyzed by both methods, and the results compared. The data are expressed in absolute values and in RRA/RIA ratios. The area under the curve after a stimulation test (area GH) was calculated by planimetry. RIA was performed by the classical double antibody method using a polyclonal anti-serum. For the RRA, human cultured lymphocytes (IM-9 cells) were used, and 125I-labeled human GH was purified by high performance liquid chromatography. The same human GH standard was used in both assay systems. In control subjects a significant (P less than 0.0001) positive correlation was found at all ages between GH levels measured by RIA and RRA (r = 0.69 after insulin and r = 0.77 after glucagon). The RRA/RIA ratio (mean +/- SEM) for the peak GH level was 0.88 +/- 0.05, and the area under the GH curve was 0.85 +/- 0.05. The peak mean RRA/RIA ratios were significantly lower (P less than 0.05 and P = 0.03, respectively). No relationship was found with the absolute value of either peak or area GH. In patients with growth delay and Turner's syndrome, lower GH levels were found than in control subjects in both assay systems. The RRA/RIA ratios were also lower. In the other patients with some growth disorder, normal GH levels and ratios were found. In patients with renal failure, high levels of RIA-GH and RRA-GH were found, with a normal RRA/RIA ratio. In patients with documented pituitary GH deficiency, GH-releasing factor administration resulted in an increase in GH levels that was identical in both assays. The RRA/RIA ratio remained constant throughout the test. No correlation was found between the ratio and the absolute value of either RIA-GH or RRA-GH regardless of the stimulation test used. It is concluded that the presence of an abnormal GH molecule is extremely rare in patients with short stature. Thus, the presence of a bioinactive hormone is not a common cause of growth failure. During provocative testing some changes in the ratio may occur that do not appear after GH-releasing factor, further illustrating the different mechanisms involved in GH secretion.

Measurement of plasma free and total growth hormone concentrations in patients with growth hormone antibodies developed in response to therapy.

Recombinant human growth hormone is more antigenic than pituitary preparations. Since GH antibodies interfere with radioimmunoassay of GH, we measured plasma free and total GH in patients with pituitary dwarfism with GH antibodies during treatment with a recombinant methionyl GH preparation. Plasma free GH was measured in the supernatant after polyethylene glycol precipitation. Total GH was measured after extracting plasma with acid-ethanol. In normal subjects, both free and total GH levels were similar to those measured in plasma by a direct conventional RIA. Peak free GH levels after administration of 4 IU methionyl GH to 3 normal subjects were 38.0, 30.7 and 13.2 micrograms/1, values similar to those measured in most of the patients with GH antibodies. All values were undetectable in one patient with a very high antibody titre. Total GH levels were similar to free GH levels in normal subjects. In patients with GH antibodies, total GH levels were high compared with their free levels, but similar to those assayed by conventional RIA. The patient with the highest antibody titre had total GH levels which were the lowest of those observed in the patients with GH antibodies in spite of having the highest GH levels measured by conventional RIA. The antibody in this particular case may have a high capacity and a high affinity. A relatively poor growth rate in this patient may be associated with the finding of undetectable free GH levels. Measurement of plasma free and total GH may be of value in examining GH dynamics and their relation to the clinical effectiveness of GH treatment in patients with GH antibodies.

Plasma growth hormone half-life after selective removal of adenoma in acromegalics determines the outcome of surgery.

We measured plasma GH levels during transsphenoidal surgery in eight patients with acromegaly. After removal of the adenoma GH levels fell monoexponentially in six subjects while they were still under general anaesthesia, but no decrease was noted for two other subjects. Normal postoperative GH and Somatomedin-C levels were found for those patients who exhibited a reduction in GH during surgery. During follow-up studies one patient with a normal GH level exhibited a paradoxical reaction to TRH, attributed to tumour remnants. The plasma half-life found for five patients was 18-33 min; for another cured subject it was longer, i.e. 58 min. The major fraction of the circulating GH, as determined by gel-chromatography, was mol. wt 22,000; this applied for six subjects, while the patient with the long plasma half-life appeared to have a mol. wt 33,000 variant. From this study we conclude that a clear drop in the plasma GH level after removal of the adenoma predicts a favourable outcome of surgery; however, if some tumour remnants are left behind, paradoxical reactions may occur despite normal basal GH levels.

Short stature, growth hormone, insulin-like growth factors, and serum proteins in the Mountain Ok people of Papua New Guinea.

Short stature in man may result from a deficiency of GH or insulin-like growth factors (IGFs). In African pygmies and other individuals with the pygmy trait, serum GH and IGF-II are similar to levels in taller subjects, but serum IGF-I levels are low. To determine whether another population with comparably short stature has similar or related defects, we studied the Mountain Ok population of Papua New Guinea. The mean height of adult men was 152 +/- 6.0 (+/- SD) cm (n = 141), and that of women was 146 +/- 5.7 cm (n = 150). Serum GH and IGF-II concentrations were in the normal (U.S.) range in the Mountain Ok subjects. In the men, serum IGF-I values were also normal, thereby distinguishing the endocrine profile associated with short stature in these subjects from that in African pygmies. Serum IGF-I was not measured in any Mountain Ok women. Since marginal dietary protein is characteristic of the traditional Papua New Guinea diet, we determined serum albumin and prealbumin concentrations in the Mountain Ok subjects. The serum proteins were in the normal (U.S.) range (30-50 g/L for albumin; 10-40 mg/dL for prealbumin), indicating that chronic or acute malnutrition was unlikely in these subjects. Taken together, these findings indicate that short stature in the Mountain Ok people of Papua New Guinea is associated with normal serum GH, IGF-I, IGF-II, and protein levels and indicate that other factors determine stature in some populations with short stature.

Isolated deficiency of immunocytochemically detected somatostatin in Snell dwarf, but not in “little,” mice

Immunocytochemical staining of the neuropeptide somatostatin was evaluated in the brains of two growth hormone-deficient mouse mutants, Snell dwarf (dw/dw), and “little” (lit/lit). In Snell dwarf mice, in which GH is undetectable, an isolated somatostatin deficiency was observed in hypothalamic median eminence and in anterior periventricular hypothalamic neurons which are afferent to median eminence, compared to somatostatin staining in normal mice of the same strain (DW/?). Somatostatin staining in all other CNS areas in dwarfs was identical to that in normal mice. In contrast, in little mice, which exhibit 5–10% of normal GH levels, somatostatin expression was comparable between mutants and normal mice (LIT/?) in all CNS areas, including median eminence-afferent neurons in anterior periventricular hypothalamus. The results suggest that expression of somatostatin in hypophysiotropic CNS is dependent upon minimal pituitary GH secretion.

Serum Factor Responsible for Thymidine Uptake by Lymphocytes Is Independent of Somatomedin-C

ABSTRACT Lymphocytes have specific receptors for somatomedin-C (Sm-C) and GH. To test whether these cells are sensitive to the growth-promoting properties of these growth factors, we studied serum (with low or normal Sm-C and GH levels) from children having various statural disorders by means of the lymphocyte proliferation assay. Peripheral lymphocytes from each subject were cultured in media containing either autologous serum (AS) or normal pooled human serum (HS). The mitogenic response (MR) was assessed by determining the amount of tritiated thymidine incorporated into cellular DNA. The MR was studied both in phytohemagglutinin-stimulated and in unstimulated lymphocytes. MR was expressed as thymidine uptake (CPM) in the presence of AS divided by CPM in the presence of HS. The MR in serum from (1) 27 control subjects was 1.01 ± 0.03 (SEM); (2) 14 children with short stature and normal serum GH-RIA and Sm-C levels was 0.98 ± 0.04; and (3) 12 children with GH deficiency showed two widely different responses. In four patients (subgroup 1), the MR was 0.05 ± 0.02 and in eight (subgroup 2) the MR was 1.11 ± 0.06. Eleven patients were studied after GH therapy (three from subgroup 1), and the MR was 1.12 ± 0.03. Neither Sm-C levels nor linear growth rate correlated well with the growth-promoting property of the serum when tested on lymphocytes. In seven additional patients with GHD, the MR when studied at varying concentrations of serum (0.1–5.0%), showed results identical to subgroup 2. Addition of purified Sm-C to cultures did not enhance the MR of serum from GHD patients prior to GH therapy. GH-dependent factors other than Sm-C may have a role in in vitro lymphocyte proliferation; in its current form, however, this bioassay is not sensitive enough to be useful in the diagnosis of children with GH deficiency.

Relationship between somatomedin-C and growth hormone levels in acromegaly: basal and dynamic evaluation.

The relationship between basal and stimulated plasma GH and somatomedin-C (SmC) levels in acromegalic patients was evaluated. The basal plasma SmC levels of 66 patients were significantly correlated (P less than 0.01) with mean daily plasma GH levels, but not with the percent GH increase after GH-releasing hormone or TRH or the GH decrease after acute bromocriptine administration. Bromocriptine (7.5-15 mg/day) administration for 9.2 +/- 0.9 (+/- SD) months in 20 patients significantly (P less than 0.05) decreased GH levels. SmC decreased significantly [from 9.8 +/- 1.9 to 5.1 +/- 0.7 U/ml (mean +/- SE)] only in the 10 patients who had the more marked GH inhibition. The administration of a somatostatin analog, SMS 201-995 (100 micrograms twice daily), to 12 patients for 16 weeks significantly decreased plasma GH and SmC levels beginning on the second day of therapy; normal SmC levels were achieved in 5 of 12 patients. Pituitary adenomectomy resulted in normal GH and SmC levels in 10 of 12 and 8 of 12 patients, respectively. Our data indicate an overall dependency of plasma SmC levels on plasma GH levels in acromegaly, although similar GH levels may have differing somatomedin-stimulating activities. A derangement in the feedback mechanisms controlling GH secretion is indicated by the failure of elevated SmC levels to influence the GH responsiveness to releasing hormones. In evaluating pharmacological or surgical treatments of acromegaly, a single plasma SmC value can reliably replace several plasma GH determinations.

Acromegaly: biochemical assessment of cure after long term follow-up of transsphenoidal selective adenomectomy.

This study reports the clinical and biological follow-up 5-11 yr after transsphenoidal selective adenomectomy in 25 patients with acromegaly. Eight patients had microadenomas, and 17 had macroadenomas. Initial normalization of plasma GH levels (basal values, less than 5 ng/ml; glucose-suppressed concentrations, less than 2.5 ng/ml) was achieved in all 8 patients with microadenomas and in 13 patients with macroadenomas. Of these, 3 patients with normal GH levels and dynamics had relapse of GH hypersecretion after intervals between 1-6 yr after microadenoma removal. Recurrence of pituitary adenoma was documented by surgery in 1 patient and by computed tomographic scanning in 2 others. Normal basal and glucose-suppressed plasma GH concentrations were maintained 7.4 +/- 0.5 (+/- SEM) yr after adenomectomy in 7 patients with microadenomas and in all 10 patients with macroadenomas. Thus, 88% of the patients with microadenomas and 59% of the patients with macroadenomas were cured, and the overall cure rate was 68%. We conclude that recurrence of acromegaly after successful surgery may occur late after adenoma removal and that it cannot be predicted by normal postoperative GH levels and dynamics. However, in view of the overall cure rate, transsphenoidal adenomectomy remains a most valuable treatment for acromegaly.

Long-term results of transsphenoidal pituitary microsurgery in 60 acromegalic patients.

Sixty patients with clinically and biochemically active acromegaly were treated by transsphenoidal surgery. All patients underwent a full assessment of pituitary function both preoperatively and postoperatively; these studies were repeated 6 months after surgery and every year, when possible. The mean follow-up period was 3.3 years (range 0.5-7 years). The GH level normalized in 62% of patients after surgery. A paradoxical reaction of GH to TRH was present in 35 patients before surgery and had normalized in 17 after surgery. Large tumours were associated with higher GH levels than smaller tumours. A prognostic factor in terms of normalization of both the GH level and an eventual paradoxical reaction to TRH or a glucose challenge was a low preoperative GH level. Three out of seven patients with either a positive postoperative TRH test but a normal GH level, or a slightly elevated GH level suffered a biochemical and clinical recurrence and two of them underwent reoperation. In contrast, when the TRH test had normalized (always in association with normal GH levels) no recurrence was found. The impact of surgery on the other pituitary functions was generally slight and the numbers of patients with preoperative and postoperative impairment were about equal. Postsurgical radiation therapy was administered to patients with an elevated GH level, a non-normalized TRH test irrespective of whether the GH level had normalized, or local invasion of the tumour. In 11 out of 17 patients with elevated GH levels after surgery, normalization was achieved by radiation therapy after a mean period of 2.7 years. The incidence of pituitary failure after irradiation appeared to be high; gonadal function in men and the GH reserve function were especially vulnerable. From this study we conclude that in many cases the adenoma can be removed effectively, without compromising the other pituitary functions. However, a substantial number of the patients require additional radiation therapy, leading to an inevitable loss of other pituitary functions.

Evaluation of treated acromegalic patients with normal growth hormone levels during oral glucose load.

Twenty-one treated acromegalics with plasma GH levels less than or equal to 5 ng/ml were evaluated during an oral glucose tolerance test (OGTT). Serum insulin-like growth factor (IGF) levels, measured by a competitive binding assay, were high in 10, normal in 8 and low in 3 patients. Urinary calcium excretion (Ca U), measured over 24 h, was elevated in 9 of the 10 patients whose IGF levels were high, whereas only 1 of the patients with normal or low IGF levels was hypercalciuric. A paradoxical rise in GH following TRH injection was observed in 5 of the 10 patients whose IGF levels were high, whereas all patients with normal or low IGF levels showed no GH response to TRH. GH levels greater than or equal to 10 ng/ml occurred during ornithine (ORN) administration in 6 of the 18 patients with normal or high IGF levels. The remaining 12 patients with no GH rise during ORN included 2 cases in which IGF levels were high and GH rose following TRH, and 2 cases in which IGF levels were normal and GH levels were greater than or equal to 10 ng/ml during insulin-induced hypoglycaemia (IIH), thus excluding a GH deficiency. These results show that acromegaly is not cured in certain treated patients with normal GH levels during OGTT. It seems that IGF and Ca U determinations are valuable indices of activity, in contrast to GH response to ORN. The GH response to TRH is also relatively useful.

Somatomedin C in treated acromegaly: poor correlation with growth hormone and clinical response.

To determine the usefulness of commercially available somatomedin C levels in the evaluation of the treatment of acromegaly, 15 patients were tested at 0.25-15.4 yr after onset of therapy. Clinical response, as determined by a numerical scoring system, was compared with RIA of GH and somatomedin C. Symptomatic response was poorly correlated with somatomedin C (r = 0.033) as well as with GH (r = 0.24). The correlation of GH and somatomedin C was also poor (r = 0.46, P greater than 0.05). Eighty-three percent of patients with clinical improvement had GH less than or equal to 10 ng/ml, 50% had GH less than or equal to 5 ng/ml, while 42% had somatomedin C less than or equal to 3.0 U/ml. All patients who were evaluated at 1 yr or less after therapy had elevated somatomedin C levels with normal or near normal GH values. In contrast only 2 of 11 patients evaluated at more than 1 yr after therapy had a mild persistence of somatomedin C elevation with normal GH levels. Determination of somatomedin c costs more than GH determinations and appears to offer no apparent advantage over GH in following patients treated for acromegaly.

Transsphenoidal microsurgery in the treatment of acromegaly and gigantism.

Twenty-five patients with acromegaly and 3 patients with gigantism underwent transsphenoidal microsurgery in an attempt to remove the tumor and preserve normal pituitary function whenever possible. An adenoma was identified and removed in 27 of 28 patients. Evaluation 3--6 months postoperatively revealed a GH level less than 5 ng/ml in 29 patients, 5--10 ng/ml in 4 patients and 11--29 ng/ml in 4 other patients. Dynamics of GH secretion were normal in 11 patients who had normal pituitary function and are considered cured. Two patients with low or undetectable GH levels are also considered cured at the expense of being hypopituitary. Three of 7 patients with normal basal GH levels but abnormal dynamics of GH secretion relapsed within 1 yr. Eleven of the 13 patients considered cured did not have extrasellar extension, while 14 of the 15 patients not cured had extrasellar extension. Five patients who were not cured with surgery received radiation therapy. Three patients were treated with an ergot derivative, Lergotrile mesylate, after surgery and radiation therapy failed to normalize GH levels. Transsphenoidal microsurgery is an optimal form of therapy for patients with acromegaly or gigantism, especially those with no extrasellar extension. Dynamics of GH secretion are very useful in evaluating the completeness of adenoma removal.

Growth Hormone Response to Thyrotropin-Releasing Hormone and Gonadotropin-Releasing Hormone Stimulation in Heroin Addicts

Previous endocrine investigations have demonstrated the presence of multiple impairments of pituitary-target gland function in heroin addicts suggesting a possible hypothalamic involvement. Since the response of the pituitary to nonspecific stimuli is considered an expression of hypothalamic dysfunction, indicating a disconnection between the central nervous system and the anterior pituitary, we thought it worthwhile to study the GH response to stimulation with thyrotropin-releasing hormone (TRH) or gonadotropin-releasing hormone (GnRH) in heroin addicts. 23 male heroin addicts, aged 18-40 years, with histories of addiction to heroin alone from 8 months to 4 years, and daily i.v. heroin intakes between 200 and 2,500 mg of the drug (containing 18% pure heroin) were studied. 8 patients received TRH 500 micrograms, GnRH 150 micrograms and 5 saline only, intravenously, and GH levels were assayed radioimmunologically in bloods taken 30 min before, at the moment of stimulation and 15, 30, 60, 90 and 120 min thereafter. The results show normal base GH levels. Stimulation with TRH and GnRH induced marked GH hypersecretion in 8 of the 18 patients examined. These results suggest that the hypothalamo-pituitary function may be impaired in heroin addiction.

Catecholaminergic Drugs in Chronic Schizophrenia

The effect of dopaminergic-related and stimulatory drugs have been studied in chronic hebephrenic schizophrenics untreated with neuroleptic drugs. 6 patients received therapy of 2 g L-dopa + 200 mg carbodopa per day orally for 30 days, then placebo for 30 days. Following that 3 of the same patients received therapy of 2 g L-dopa + 200 mg carbodopa + 300 mg imipramine orally for 30 days, then placebo for 30 days. Following that the same 3 patients received 1 mg apomorphine s.c. for 15 days, then placebo for 15 days, then 1 mg apomorphine s.c. + 2 g L-dopa + 200 mg carbodopa per os daily for 15 days, then placebo for 15 days. The patients were examined psychologically by the Wittenborn Rating Scale, the Weigl Object-Sorting Test, and tests for verbal learning and verbal association, before and after each therapeutic trial. Levels of FSH, LH, testosterone and GH were assayed radioimmunologically before, in the middle of and after each course of therapy. 2 patients showed improvement in the affective-behavioural symptomatology during therapy, while the other 4, who had a more severe degree of mental deterioration and destruction, were unchanged. FSH and LH levels, very low under basal conditions, did not change under therapy. Testosterone was very low before therapy and increased in only 1 subject. Normal basal GH levels increased during therapy in some of the patients, but not constantly. The results obtained are discussed in relation to the catecholamine hypotheses of schizophrenia.

REVERSIBLE PLASMA AND RED BLOOD CELLS VOLUMES INCREASES IN ACROMEGALY

Plasma volume (PV) and red blood cells volume (RBCV) were measured in 76 normotensive acromegalic patients (42 males and 34 females) and compared with those of 28 controls on the basis of body surface. In untreated males PV and RBCV were significantly higher than in normals (P less than 0.001) and total blood volume (TBV) was above the normal range in 85%. Untreated females also showed an elevated PV but had significantly lower RBCV than the male patients. The only vascular volume of the patients with correlated significantly with the body weight or surface was RBCV in females. One to five studies were done after treatment in 52 patients and analyzed as a function of plasma GH levels. Plasma volume reverted to the normal range (males) or was significantly lower than in untreated patients (females) in the groups of patients with normal GH levels while RBCV normalized at higher GH concentrations. At similar GH levels, treated patients without pituitary failure (n = 35) or given T4 and/or cortisol substitution for hypopituitarism showed similar vascular volumes. The plasma volume and TBV in both sexes and RBCV in males was significantly correlated with Log 10 GH levels. It is concluded from these data and other experimental evidence that endogenous GH hypersecretion is responsible for the reversible PV and RBCV increases frequently found in acromegalic patients.