Basal Serum Growth Hormone Levels Research Articles

Acromegaly with Normal IGF-1 Levels Probably due to Poorly Controlled Diabetes Mellitus

Acromegaly is characterized by the somatic disfigurement and excessive production of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Here we report a patient with aromegaly and diabetes mellitus, who showed normal IGF-1 levels in spite of elevated GH levels. The patient was a 52-year-old woman with acromegalic manifestations. Serum GH level was elevated (32.4 ng/mL) with hyperglycemia (fasting plasma glucose, 277 mg/dL) and an extremely high level of glycosylated hemoglobin (HbA1c 17.7%), whereas serum IGF-1 level was within normal range (110 ng/mL, normal range 37-266). Brain magnetic resonance imaging detected a pituitary tumor, with involvement of the right cavernous sinus. Oral glucose tolerance test (OGTT) showed no suppression of serum GH. Thyrotropin-releasing hormone test showed paradoxical increases in serum GH. We therefore diagnosed acromegaly accompanied with diabetes mellitus. A large amount of insulin (34 units/day) was required to control the blood glucose level. The patient was treated with octreotide, a somatostatin analogue, followed by transsphenoidal surgery. After the surgery, serum GH levels were suppressed by OGTT, although basal serum GH levels remained to be high. Basal serum GH levels, however, were normalized 5 months later. Blood glucose became well controlled by the diet alone. In contrast, serum IGF-1 increased to the range of 219-233 ng/mL. Pre-operative serum IGF-1 levels were low probably due to poorly controlled diabetes mellitus. In conclusion, the presence of normal serum IGF-1 levels cannot exclude the diagnosis of acromegaly especially when the patient is accompanied by diabetes mellitus.

Body mass index and blood glucose: correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH)

Obesity is a frequent co-morbid condition associated with diffuse idiopathic skeletal hyperostosis (DISH). Serum growth hormone (GH), insulin-like growth factor (IGF-1) and insulin are significantly elevated in patients with DISH. In this study, we examined the relationship between body mass index (BMI) and basal serum GH, IGF-1, and insulin concentration in a group of 36 DISH patients. Basal serum insulin levels were significantly elevated (P<0.001) in DISH patients with a BMI>28 kg m(-2), classified as obese, compared with DISH patients with BMI ranging from 23 to 28 kg m(-2). In addition, BMI strongly positively correlated with serum insulin concentration in DISH patients (adjusted r2 = 0.348, P<0.001). However, BMI did not correlate with either basal serum GH (adjusted r2 = -0.013) or IGF-1 levels (adjusted r2 = -0.010) in DISH. We conclude that BMI does not seem to contribute to elevated serum GH and IGF-1 levels in symptomatic DISH.

Serum growth hormone and insulin but not insulin-like growth factor-1 levels are elevated in patients with fibromyalgia syndrome

Standard radioimmunoassay (RIA) was employed to quantify basal serum growth hormone (GH), insulin-like growth factor-I (IGF-1), and insulin levels in 32 normoglycemic patients with clinically active fibromyalgia and in 29 normoglycemic control subjects. The GH concentration was significantly higher (P < 0.001) in female fibromyalgia patients than age-matched, normal female subjects. In contrast, basal serum IGF-1 concentrations did not differ between these groups. A scatter plot generated from two-stage, least-squares analysis showed that serum GH lacked correlation with the serum IGF-1 concentrations of normal female subjects (P = 0.73) and female fibromyalgia patients (P = 0.19). In addition to the results from serum GH and IGF-1 RIA, we also found significantly higher fasting serum insulin levels (P = 0.03) in male fibromyalgia patients and a trend toward elevated fasting serum insulin levels in the female fibromyalgia population ( P = 0.07), with the mean fasting level in the male fibromyalgia group (35.7 microU/ml(-1)) exceeding the upper limit of normal serum insulin levels (i.e., 27 microU/ml(-1)). Based on these results, basal serum GH and fasting serum insulin levels appear to be valuable surrogate markers in clinically active, normoglycemic fibromyalgia patients.

The inhibitory effects of (gamma)-aminobutyric acid (GABA) on growth hormone secretion in the goldfish are modulated by sex steroids.

Double-labelling studies at the electron microscopic level demonstrated that gamma-aminobutyric acid (GABA)-immunoreactive nerve endings are associated with growth-hormone-secreting cells in the proximal pars distalis of the goldfish pituitary gland, suggesting that GABA may be important for the control of growth hormone release in this species. An in vitro assay for GABA-transaminase activity demonstrated that the pituitary is a site for the metabolism of GABA to succinic acid. In vitro, GABA or the GABA antagonists bicuculline and saclofen did not affect the rate of growth hormone release from dispersed pituitary cells in static incubation. In contrast, intracerebroventricular injection of GABA reduced serum growth hormone levels within 30 min. During the seasonal gonadal cycle, intraperitoneal injection of GABA was without effect in sexually regressed goldfish, but caused a significant decrease in serum growth hormone levels in sexually recrudescent animals. Intraperitoneal implantation of solid silastic pellets containing oestradiol increased serum GH levels fivefold in sexually regressed and recrudescent goldfish; in both groups, GABA suppressed the oestradiol-stimulated increase in circulating growth hormone levels. The effect of oestradiol on basal serum growth hormone levels was specific since progesterone and testosterone were without effect. However, in recrudescent animals treated with progesterone and testosterone, the inhibitory effects of GABA on serum growth hormone levels were absent, indicating a differential role for these steroids in growth hormone release. Taken together, these results demonstrate that GABA has an inhibitory effect on growth hormone release in goldfish.

Alcoholism abolishes the effects of melatonin on growth hormone secretion in humans.

Chronic alcohol consumption profoundly affects hypothalamic-pituitary function. The present study was performed in order to establish whether alcoholism modifies the effects of melatonin (MEL) on the neuroendocrine control of growth hormone (GH) secretion. For this purpose, the effects of oral administration of 12 mg MEL or placebo on basal and hypoglycemia-stimulated GH secretion were tested in nine (40-52-year-old) alcoholic men after 10-31 days of abstinence and in nine age- and weight-matched normal controls. Hypoglycemia was induced with an intravenous bolus injection of 0.15 IU/kg body weight of insulin. MEL but not placebo administration induced a small, but significant increase in basal GH secretion in the normal controls. In contrast, neither MEL nor placebo treatment significantly changed the basal serum GH levels in alcoholic men. Both groups showed a similar hypoglycemic pattern after insulin administration. The GH response to insulin-induced hypoglycemia was significantly lower in alcoholic than in normal subjects. MEL administration significantly reduced hypoglycemia-induced GH rise in the normal controls, but not in alcoholic patients. These data show that alcoholism not only reduces the GH response to insulin-induced hypoglycemia, but also abolishes MEL actions on basal and hypoglycemia-stimulated GH secretion.

Arginine but not pyridostigmine, a cholinesterase inhibitor, enhances the GHRH-induced GH rise in patients with anorexia nervosa

Pirenzepine, a muscarinic antagonist probably acting via stimulation of hypothalamic somatostatin release, abolishes the growth hormone releasing hormone (GHRH)-stimulated growth hormone (GH) rise in normal subjects but only blunts it in patients with anorexia nervosa (AN). This finding suggested the existence in AN of an alteration of cholinergic system and/or somatostatinergic tone. To further investigate these mechanisms, in 11 AN women patients (age 18.8 ± 0.9 years; BMI 13.4 ± 0.4 we studied the GH response alone (1 μg/Kg IV as a bolus at 0 min) and combined with pyridostigmine (PD, 120 mg orally, 60 min before GHRH administration), a cholinesterase inhibitor, or arginine (ARG 30 g infused over 30 min starting at 0 min), two compounds probably acting via inhibition of hypothalamic somatostatin (SS) release. The GH response to GHRH preceded by a previous (120 min before) neurohormone administration also was studied. All these tests also were performed in 20 normal age-matched women (age22.0 ± 1.8 yrs; BMI 20.1 ± 2.4). Basal serum GH levels were higher in AN patients than in normal volunteers (NV) (10.3 ± 3.4 versus 2.8 ± 0.3 μg/ L; p 0.001), whereas plasma IGF-1 levels were lower in AN patients than in NV (43.3 ± 10.6 versus 172.4 ± 13.9 μg/ L; p 0.00001). In AN patients, GHRH administration induced a GH rise higher, though not significantly, than that in NV [Δ area under the curve (AUC) 11173.6 ± 167.6 versus 834.6 ± 188.1 μg/ L/ h). The GH response to the second of two consecutive GHRH boluses was lower (p 0.01) than that of the first one either in AN patients or in NV (67.6 ± 27.4 and 53.1 ± 25.7 μg/ L/ h, respectively). PD administration failed to modify the GHRH-induced GH rise in AN patients (1370.4 ± 228.4 versus 1268.8 ± 205.8 μg/ L/ h), but enhanced it in NV 2285.4 ±234.6 versus 1070.1 ± 159.4 μ/ L/ h; p 0.01). The GH response to PD + GHRH in AN patients was lower (p 0.01) than that in NV, ARG administration enhanced the GHRH-induced GH rise either in AN patients (3843.0 ± 659.7 μg/ L/ h; p 0.02 versus GHRH alone) or in NV (3346.6 ± 424.1 μ/ L/ h; p 0.01 versus GHRH alone), the two responses being similar. Our results demonstrate that, although ARG fails to modify the GHRH-induced GH response in NV, in AN the GH response to GHRH is inhibited by a previous neurohormone administration. These findings indicate the existence in AN of somatotroph refractiries to cholinergic influence but not to metabolic fuels such as arginine, whereas the negative GH-autofeed-back mechanism is preserved. Somewhat specific alterations of the somatostatin-mediated cholinergic influence or, alternatively, different actions for PD and ARG may be hypothesized.

Change in the Growth Hormone(GH) Response to GH-Releasing Factor(GRF) Caused by Exogenous GH in Short Children.

To determine whether exogenous GH induces feedback of GH release in children, growth hormone-releasing factor (GRP) tests were performed before and after 10-day GH administration. Sixteen non-obese short boys, aged 5-14 yr, with normal GH response to pharmacological tests were studied. Mean basal and peak serum GH levels in GRF tests before and after exogenous GH were not significantly different. The subjects were divided into two groups, A and B, according to the percent change in integrated areas under the GH curves in GRF tests (GH AUC) before and after 10-day GH administration. Group A consisted of 6 boys with decreased GH AUC and group B consisted of 10 boys with increased GH AUC. Mean peak GH in GRF tests and mean GH AUC were significantly higher before exogenous GH in group A than in group B. The boys in group A were all prepubertal, while 4 boys in group B had begun their early pubertal change. The mean age in group A (7.8 +/- 1.8 yr) was significantly lower than that of group B (11.9 +/- 2.4 yr). GH AUC before exogenous GH showed a significant correlation with the percent change in AUC (= -0.742, p less than 0.01). These data demonstrated that the exogenous GH suppressed the GH response to GRF in prepubertal children with good response to GRF before exogenous GH, while it exaggerated the GH response to GRF in older children with relatively poor response before GH.

Growth hormone (GH) response to GH-releasing hormone in depression.

To explore the GHRH-GH-somatomedin axis integrity in major depressive disorder, 11 drug-free patients and normal subjects matched for age, sex, ovarian status, and body weight received 1 microgram/kg synthetic human GHRH-44 amide as an iv bolus dose. Compared to the normal subjects, the depressed patients had reduced mean basal serum GH levels [2.2 +/- 0.5 (+/- SE) vs. 1.1 +/- 0.2 ng/mL (micrograms/L); P less than 0.05] and a significant attenuation of the net GH response to GHRH [1346 +/- 499 vs. 217 +/- 46 ng.min/mL (micrograms.min/L); P less than 0.01]. The blunted GH responses occurred in the face of significantly increased plasma somatomedin C (Sm-C) levels [1.1 +/- 0.2 vs. 0.6 +/- 0.1 U/mL; P less than 0.05]. The magnitude of GH responses to GHRH did not differ between men and women and was not significantly correlated with age, body weight, baseline serum GH levels, or plasma Sm-C levels in either individual groups or both groups combined. The increased plasma Sm-C levels in the depressed patients could have resulted from diurnal hypersecretion of GH, and the diminished GH responses to GHRH may reflect normal Sm-C-mediated feedback at the level of the pituitary. The presumed GH hypersecretion may be due to decreased hypothalamic somatostatin release and/or hyperactivity of GHRH-containing neurons. Thus, the pathological process resulting in abnormal GH secretory patterns associated with depression may occur primarily at a suprapituitary site.

Responses of growth hormone (GH) and somatomedin-C to GH-releasing hormone in healthy aging men.

Although controversy exists regarding the effects of aging on GH secretory responses to indirect stimulation, in the only prior study of GH-releasing hormone (GHRH)-mediated GH secretion decreased GH responsivity occurred in healthy men after age 40 yr. We measured serum GH before and up to 180 min after and somatomedin-C (SM-C) levels before and 24 h after single morning bolus iv injections of GHRH-(1-44)-NH2 (1 microgram/kg) in 50 healthy fasted men, aged 21-86 yr, from the Baltimore Longitudinal Study of Aging. Only subjects with a body mass index (BMI; kilograms per m2) between 20.0 and 29.0 were studied. Basal serum GH levels were undetectable (less than 0.7 ng/ml) in all but 2 men. Neither the frequency of GH responses (P greater than 0.8), the magnitude of response (P greater than 0.2), nor the timing (P greater than 0.05) of the peak GH responses to GHRH were significantly altered with age. Although BMI values did not vary significantly with age in our study group, there was a significant negative correlation (r = -0.37; P less than 0.01) of peak GH with BMI. Regression analysis revealed a slight but significant increase in the level of fasting blood sugar with age, but no significant correlation between fasting blood sugar and peak GH levels. Serum levels of SM-C were significantly lower in older men both before (P less than 0.001) and 24 h after (P less than 0.02) GHRH injection. Repeated measures analysis of variance revealed significant (P less than 0.001) responses of SM-C to endogenous GH elevations produced by GHRH at all ages, but no age-dependent alterations in the magnitudes of these responses (P greater than 0.7). Our findings suggest that increasing age in adult men has little effect on the secretory responsiveness of pituitary somatotropes to GHRH. However, the finding of lower serum levels of SM-C with intact SM-C responsivity to endogenous GH is compatible with prior observations of an age-related decrease in the total daily spontaneous secretion of GH.

Growth hormone responses to growth-hormone-releasing hormone and thyrotropin-releasing hormone in diabetic patients with and without retinopathy.

Growth hormone (GH) responses to growth-hormone-releasing hormone (GRH) and thyrotropin-releasing hormone (TRH) were studied in 17 diabetic patients. Ten patients (group 1) had retinopathy corresponding to stage III-V (Scott's classification), and the remaining seven patients (group 2) had no retinopathy despite longer duration of diabetes in comparison with the patients in group 1. There were no differences in age, percent of ideal body weight, and serum HbA1 levels between the two groups. Basal serum GH levels were 1.9 +/- 0.4 ng/ml (mean +/- SEM) in group 1, and not different from the values in group 2 (1.6 +/- 0.7 ng/ml). However, GH responses to synthetic human GRH-44 (1 micrograms/kg body wt, i.v. bolus) were significantly greater in group 1, as judged by the maximal response or integrated GH secretion after the administration of GRH. There were no differences in serum insulin-like growth factor I (IGF-I) levels between group 1 (262 +/- 35 ng/ml) and group 2 (232 +/- 30 ng/ml), and no significant correlation was found between serum IGF-I levels and GH responses to GRH in either of the two groups. Paradoxical GH responses to TRH (500 micrograms, i.v. bolus) were found in only one patient in each group. We have thus demonstrated that GH responses to GRH are more pronounced in diabetic patients with retinopathy than in patients without this complication, although it remains to be determined whether or not greater GH responses to GRH are causally related to the development of diabetic retinopathy.

Pituitary response to growth hormone-releasing factor in diabetes. Failure of glucose-mediated suppression.

To evaluate the mechanism underlying raised growth hormone levels in diabetes, we compared the response to growth hormone-releasing factor (GRF) in type I diabetic and healthy control subjects. In 12 poorly controlled diabetic subjects (fasting plasma glucose 276 +/- 27 mg/dl) basal serum growth hormone levels were elevated by 200-300% (P less than 0.02), yet the incremental increase in growth hormone after GRF injection was no greater than in control subjects. Furthermore, five additional diabetic subjects with normal growth hormone levels after long-term insulin pump treatment also showed an identical response to GRF. Thus, raised basal growth hormone levels in diabetes and the fall that follows intensive insulin treatment may reflect changes in hypothalamic regulation of, rather than in pituitary responsiveness to, GRF. However, when five normal subjects were restudied during glucose infusion, even quite modest hyperglycemia (plasma glucose approximately 150 mg/dl) caused marked suppression of the response to GRF (P less than 0.005). Thus, the "normal" response to GRF in poorly controlled diabetes is actually inappropriate. Failure of the pituitary to suppress in response to hyperglycemia in diabetes implies a second abnormality that may further aggravate disordered growth hormone secretion.

Role of the pituitary gland in experimental hormonal induction and prevention of benign prostatic hyperplasia in the dog.

The antiandrogen, cyproterone acetate (CPA), prevents development of prostatic hyperplasia, induced in castrated dogs by a 6 month-treatment with 5 alpha-androstane-3 alpha, 17 beta-diol (A)alone or in combination with 17 beta-oestradiol (E2). The immunoperoxidase technique was used to study functional cell types in the pars distalis of the pituitary gland and to detect growth hormone (GH) and prolactin (PRL) target sites in the prostate gland. Homologous radioimmunoassays for estimation of serum canine GH and PRL concentrations were also performed. Treatment with the combinations A + E2 and A + E2 + CPA resulted in morphological indications of stimulated GH and PRL cells and depressed gonadotrophs. This correlates well with an increase in PRL-dependent staining in glandular epithelium and fibromuscular tissue of the prostate gland. However, basal serum PRL and GH levels were not significantly affected. Treatment with A and A + E2 stimulated, while additional treatment with CPA clearly suppressed adrenocorticotrophin/melanotrophin (ACTH/MSH) cells. These findings indicate that an endocrine imbalance in hypothalamic-pituitary-adrenal function may be involved in induction and prevention of prostatic hyperplasia in the dog.

The results of transsphenoidal operation in acromegalic patients (author's transl)

Twenty-three patients with active acromegaly were subjected to transsphenoidal microsurgery, during the past two years. These patients were preoperatively classified into 14 TRH responders, 5 LH-RH responders and 2 nonresponders. L-DOPA and bromocryptine effectively reduced serum growth hormone (GH) levels in most of TRH responders, but in none of LH-RH responders and non-responders. Pre and post-operative basal serum GH levels ranged between 9.0 and 484.0 ng/ml, 3.6 and 80.6 ng/ml, respectively. In 19 patients who could be followed up longer than 3 months, post-operative serum GH concentrations were below 10 ng/ml in 14 patients, but in many cases abnormal GH responses to TRH and LH-RH were still present. However, in 6 cases abnormal GH responsiveness to TRH or LH-RH was reverted to normal, preserving normal GH increase after insulin hypoglycemia. Overall results suggest that surgical success is very high when the tumor is localized in the sella. Autonomy of GH secretion by the surgical specimen from 4 patients was found to be continuing a month later by the culture method and rich secreting granules were confirmed in the cytoplasm. These results suggest that the primary lesion in acromegaly would be in the pituitary gland, being partly influenced by hypothalamic factors. Revertion of abnormal GH responsiveness to non-specific releasing hormone is a good indicator of the completeness of the operation and these provocative tests are very useful for postoperative follow-up study in acromegaly. L-DOPA or bromocryptine treatment should be applied to cases with insufficient operative results.

Hypothalamic endocrine dysfunction in anorexia nervosa.

ABSTRACT The hypothalamic-pituitary function of 21 women with anorexia nervosa, aged 15–34 years, was studied. The tests included, in addition to the usual tests of thyroid function, a TRH stimulation test with 200 μg of synthetic TRH given iv; the response of serum immunoreactive growth hormone to insulin; and the diurnal variation and response of plasma cortisol to insulin hypoglycaemia. The mean serum TSH level of the patients was higher than that of healthy controls. The mean maximal increment of TSH after TRH was similar in the patients and the controls. However, 18 of the patients but none of the controls showed a delayed TSH-response to TRH, i. e. the TSH-level at 60 min was higher than that recorded 20 min after TRH. Four of the patients had a low free thyroxine index, computed from the PBI and T3 Sephadex uptake values, and 3 of these were clinically hypothyroid. The means for PBI, T4 and the free thyroxine index were all significantly below the means for the controls. The basal serum growth hormone levels were increased in 9 out of 17 patients. In 4 of these an inadequate response to insulin or to glucagon was found. In 5 out of the 8 patients with normal basal growth hormone levels a normal response was found, whereas the remaining 3 showed a subnormal response. The serum growth hormone level was correlated with the degree of weight loss but not with the serum albumin concentration. Plasma cortisol at 08.00 was increased in 9 patients and the diurnal variation was inadequate in 6. Four patients showed a subnormal response to insulin-induced hypoglycaemia, and 2 out of 5 patients tested failed to show adequate suppression of plasma cortisol after 1 mg of dexamethasone. Dysfunction of the hypothalamic-pituitary axis is common in anorexia nervosa. A delayed TSH-response to TRH, compatible with hypothalamic dysfunction, seems to be an almost consistent feature of the disorder, and in some of the patients even clinical hypothalamic hypothyroidism may be evident.

Conventional Radiation Therapy in Acromegaly

External pituitary radiotherapy is sufficiently free of serious side effects to argue for it being a first choice of treatment in acromegaly provided it is therapeutically effective. Of 28 acromegalic patients who had received external radio-therapy to the pituitary gland, 22 or 78% had normal or very near normal basal serum growth hormone levels. This experience compares with a recent report of favorable results with conventional radiation therapy but contrasts with experience from some centers. Disparate results between centers argue for analysis of factors which may contribute to varying therapy results. Some of these factors, as well as the comparative morbidity associated with external radiotherapy and other forms of treatment in acromegaly, are reviewed and considered. External radiation therapy of the pituitary in acromegaly continues to represent appropriate therapy in this disease.