Baseline Growth Hormone Levels Research Articles

Response of Growth Hormones and Cortisol to One Session of Moderate-Intensity Endurance Exercise in Patients with Type 2 Diabetes: A Quasi-experimental Study.

Background: Therapeutic interventions for diabetes are one of the main components of treatment and having proper physical activity in these patients is important from different physical, psychological, and social aspects. The benefits of exercise in these people include improved cardiovascular health and increased self-confidence, contributing to maintaining proper weight, controlling blood pressure, lowering blood lipids, and lowering insulin levels. The objective of this study was to assess the baseline levels of growth hormones and cortisol and the response of these 2 hormones to 1 session of moderate-intensity exercise in type 2 diabetic patients and to compare them with healthy individuals. Methods: This was a quasi-experimental and applied study, with a pretest and posttest design and with 1 control group. Participants included 12 healthy people without diabetes and 12 patients with type 2 diabetes aged over 30 years who were referred to the Diabetes Clinic of Tohid hospital, Kurdistan, Iran. After describing the objectives and hypothesis of the study and the implementation method, informed consent was obtained from all participants. SPSS Version 22 software was used for data analysis and coding. The Shapiro-Wilk normality test was used to assess data distribution. A paired t test, an independent t test, the Wilcoxon test, and the Mann-Whitney U test were used to compare outcomes between the 2 groups before and after the intervention. Results: A total of 24 individuals were included: 5 men and 7 women were included in the diabetic group and 7 men and 5 women were included in the healthy group. The mean duration of diabetes in the diabetic group was 7.82 years. The results showed that there was no reason for rejecting a relationship between 1 session of moderate-intensity exercise and increased growth hormone secretion in healthy individuals (p=0.010), but the relationship between this factor and increased growth hormone secretion in the diabetic participants could be strongly rejected (p=0.900). Also, 1 session of the moderate-intensity exercise was not significantly correlated with cortisol secretion in healthy and diabetic participants (p>0.05). Conclusion: This study revealed that baseline growth hormone levels in healthy participants were higher than those of diabetic participants and 1 session of moderate-intensity exercise significantly increased the growth hormone secretion but did not significantly increase the cortisol secretion.

Differences in somatostatin receptor subtype expression in patients with acromegaly: new directions for targeted therapy?

PurposeTo analyze the expression of somatostatin receptor (SSTR)2a and 5 by immunohistochemistry (IHC) in surgically resected somatotrophic pituitary adenomas and to associate expression rates with tumor size and clinical, biochemical, and histological parameters and response to somatostatin analog (SA) therapy.MethodsForty-three microsurgically treated patients with histopathologically proven growth hormone (GH)–producing pituitary adenoma were included (WHO 2017). SSTR subtype expression was analyzed in adenoma tissues using monoclonal antibodies (Abcam, SSTR2a-UMB1, SSTR5-UMB4). Expression rates were classified as low (≤ 20% staining positivity), moderate (21–50%), and high (> 50%). Furthermore, biochemical parameters such as human growth hormone (hGH) and insulin-like growth factor-1 (IGF-1) levels were measured and clinical, biochemical, radiological, and histological data were evaluated.ResultsOf the 43 patients included in this study, 28 were female and 15 were male. The median age was 52 years (range 17–72 years). The median tumor size was 1.2 cm (range: 0.13–3.93 cm). All resected tumors showed positivity for somatotrophic hormone (STH). In all tissue samples, SSTR2a signal expression was detectable in immunohistochemistry, while only 39 samples were positive for SSTR5. Thirty-six samples had a high expression of SSTR2a, while three had a moderate and four a low SSTR2a signal. In comparison, SSTR5 signal was high in 26 out of 43 samples, while seven adenomas showed a moderate and six cases a low expression rate of SSTR5. The median IGF-1 was 714.2 µg/l and the median GH 19.6 mU/l (= 6.53 µg/l). The present study indicates that there is no significant relationship between the expression rates of receptor subtypes and the parameters we analyzed. However, our study revealed that smaller adenomas have a lower baseline GH level (p = 0.015),ConclusionIHC with monoclonal antibodies appears to be a suitable method to determine the expression rates of SSTR2a and 5 at protein levels, as it is not possible to draw conclusions regarding receptor subtypes solely on the basis of the parameters analyzed.

Is Metformin Use Associated With Decreased Thyroid Cancer Risk in Patients With Acromegaly?

Context: Acromegaly has long been blamed to portend an increased risk for benign and malignant thyroid neoplasia. Growth hormone (GH) and consequent insulin-like growth factor 1 (IGF-1) hypersecretion are implicated in cancer promotion. Metformin, a biguanide derived from the French lilac, is gaining considerable interest because of its plausible anti-tumor properties. Besides, metformin has been shown to inhibit somatotroph proliferation and decrease GH secretion in in vivo studies. Patients with acromegaly have high incidence of diabetes and were thereof treated with metformin. We hypothesized metformin use may be linked to decreased thyroid cancer incidence in patients with acromegaly. Study Design and Methods: The medical records of 508 patients with acromegaly followed at our tertiary referral center between 1969 and 2019 were retrospectively reviewed. The inclusion criteria were having a follow-up duration for at least 12 months and being regularly screened for nodular thyroid disease and thyroid cancer by ultrasonography as indicated in respective guidelines. Patients with acromegaly were evaluated based on ongoing or prior history of metformin use or thyroid cancer diagnosis. Metformin exposure was defined as use of metformin for at least 12 months on a regular basis between initial date of acromegaly and time prior to cancer diagnosis date. Considering the long patency period of cancer of interest, we excluded exposures in the year immediately prior to index cancer date. We evaluated the effect of metformin exposure on risk of thyroid cancer using Kaplan-Meier analysis. Results: Final analysis included 377 patients with acromegaly. Mean age at acromegaly diagnosis was 41.6 ± 11.7 and 60.5% of the patients were female. Three hundred twenty-two patients (85.4%) had undergone transsphenoidal surgery as primary therapy, 73 patients (19.4%) needed radiotherapy and 178 patients (46%) received post-operative medical therapy. Median follow-up duration was 73.5 months (IQR [31.0-137.7]). One hundred twenty patients (31.9%) had an ongoing or prior use of metformin, and total of 19 patients (5%) had thyroidcancer. Age at acromegaly diagnosis, gender distribution, baseline GH and IGF-1 levels, pituitary tumor size and invasiveness, biological aggressiveness, curative therapy options, treatment responses didn’t differ between metformin users and non-users, as well as between those having and not having thyroid cancer. Kaplan-Meier estimates for 1 year, 3 years and 5 years of metformin exposure showed decreased probability of thyroid cancer incidence (p<0.05 for all). Conclusion: Although our results imply decreased thyroid cancer risk upon metformin exposure, prospective study designs with larger cohorts are obliged in order to fully elucidate the effect of metformin use on thyroid cancer.

Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein.

To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity. Laron syndrome (LS) is a well-described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3 and GH binding protein (GHBP). Case presentation with in vitro functional studies. A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP. Growth hormone stimulation tests revealed baseline GH level of 20.9µg/L and maximum stimulated GH level of 52.7µg/L and GHBP level of 4868pmol/L. GHR gene sequencing revealed a novel heterozygous nonsense mutation (c.800G>A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH-induced STAT5 signalling that was overcome with increasing doses of recombinant human GH. Using an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH. To our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH-induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo.

Discordance Between Gh and Igf-1 Levels in Turkish Acromegalic Patients

Discordance between insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels is an important problem in the follow-up of patients diagnosed with acromegaly. Our aims were to evaluate the discordance between IGF-1 and GH levels and compare the performance of different cut-off levels for the nadir in GH (GHn) in acromegalic patients. The study included 63 acromegalic patients in a follow-up at a tertiary care university hospital facility. Levels of IGF-1, IGF binding protein-3 (IGFBP-3), and GH were investigated. The baseline GH and GHn levels were evaluated after an oral glucose tolerance test (cut-offs of 0.4 and 1 ng/mL, respectively). The discordance rates between GHn and IGF-1 levels, and IGF-1/IGFBP-3 ratios were determined. We first adopted a GHn cut-off value of 1 ng/mL and found that 27 patients (42.9%) exhibited biochemical remission (BR) (IGF-1 <95th percentile, GH <1), and 25 patients (39.7%) had no BR (NBR) (IGF-1 ≥95th percentile, GH >1). Discordance in the presence of normal IGF-1 and nonsuppressed GH (DC1) occurred in 2 of 63 (3.2%) patients; discordance in the presence of high IGF-1 and suppressed GH (DC2) occurred in 9 of 63 (14.3%) patients. If the GHn cut-off value adopted was 0.4 ng/mL, the distributions were 17 of 63 (27.0%) patients in BR, 29 of 63 (46.0%) patients in NBR, 12 of 63 (19.0%) in DC1, and 5 of 63 (7.9%) patients in DC2. If only the baseline GH values were considered, the distributions were very similar to those with a GHn cut-off value of 0.4 ng/mL. The IGF-1/IGFBP-3 ratio was lowest in the BR group. Adopting a GHn cut-off value of 0.4 ng/mL did not increase the test performance compared with baseline GH only. In contrast, in the follow-up of acromegalic patients, the IGF-1/IGFBP-3 ratio might be a useful measurement when discordance between IGF-1 and GH levels occurs. We propose that these values be considered in clinical practice. BR = biochemical remission DC1 = discordance group 1 DC2 = discordance group 2 DM = diabetes mellitus GH = growth hormone GHn = nadir in GH IGF-1 = insulin-like growth factor-1 IGFBP-3 = IGF binding protein-3 LAR = long-acting release NBR = not in biochemical remission OGTT = oral glucose tolerance test.

High prevalence of hypovitaminosis D in Sicilian children affected by growth hormone deficiency and its improvement after 12 months of replacement treatment.

Although the correlation between vitamin D and growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis is documented, as of date, few and conflicting studies have prospectively analyzed vitamin D before and after GH treatment. Our aim was to evaluate as to how the condition of GH deficiency (GHD) or GH treatment influences vitamin D in children. Eighty Sicilian GHD children (M/F 58/22; mean age 10.3 years), grouped according to the season of evaluation in group A (June-September; 41 children) and group B (November-February; 39 children), were evaluated at baseline and after 12 months of GH treatment. Twenty-eight children (35 %) were vitamin D insufficient and 32 (40 %) deficient at baseline, and lower vitamin D levels were found in group B than in A (17.3 ± 5.3 vs. 31.1 ± 11.1 ng/ml; p < 0.001). A positive correlation between vitamin D and baseline GH levels (p < 0.001) was found. After 12 months, increased vitamin D was found both in all children (34.4 ± 16.4 vs. 24.5 ± 11.1 ng/ml; p = 0.002) and in group A (38.5 ± 14 vs. 31.1 ± 11.1 ng/ml; p < 0.001) and B (30 ± 17.7 vs. 17.3 ± 5.3 ng/ml; p < 0.001). Overall, only 25 (31 %) children remained insufficient and 15 (19 %) deficient, with an increase in prevalence of children with normal levels (p = 0.001). Our data demonstrated a very high prevalence of hypovitaminosis D in Sicilian GHD children, with an improvement after 12 months of GH treatment. Vitamin D assessment should therefore be considered routinely in GHD children both at diagnosis and during the follow-up.

Niveles Séricos de Hormona de Crecimiento e IGF-I, y Ejercicio Físico Submáximo en Gran Altura y a Nivel del Mar

OBJETIVO: Estudiar los niveles de hormona de crecimiento (GH) y de factor de crecimiento tipo insulina I (IGF-I) en gran altura y a nivel del mar (NM), así como sus variaciones con el esfuerzo físico (EF). MÉTODOS: Se evaluó 50 soldados jóvenes de Cerro de Pasco (4340 nsmn) y 40 de Lima (150 msnm). Cada grupo fue sometido a EF diferente (caminata de 1,5; 3; 4,5 y 6 km. en altura y de 2; 4 y 6 km. a NM). Se determinó glucosa, GH, IGF-I, insulina y glucagón pre y post-EF. RESULTADOS: No hubo diferencias significativas entre los niveles basales de GH obtenidos a NM y en altura (0,79 ng/mL contra 0,98 ng/niL,p&amp;gt;0,05). En cambio, fueron mayores los niveles de IGF1 obtenidos a NM (299,38 ng/mL contra 63,71 ng/mL, p &amp;lt;0,01). Sólo a NM se obtuvo una correlación significativa entre los niveles basales de GH e IGF-I (r = 0,44). Los niveles de GH aumentaron significativamente con el EF submáximo (0,79 a 5,54 ng/mL [r = 0,51] y 0,98 a 8,47 ng/mL [r = 0,51] en altura y a NM, respectivamente). No se observó variación significativa en los otros parámetros. CONCLUSION: El EF submáximo, en gran altura y NM, sería el responsable de los altos niveles de GH observados en ayuno en el varón joven pero no favorecería mayores niveles de IGF-1 y glucosa.

Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly

To investigate whether pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and whether serum pegvisomant levels predict the therapeutic outcome. Seventeen patients (6 women), mean age 46·3 years (range: 23·2-76·2), were studied. For each patient, four hospital visits were identified including 'active disease' (no treatment) and last follow-up. At each visit, 12 blood samples were drawn during 3 h including an oral glucose tolerance test (OGTT). Eight patients received a somatostatin analogue in addition to pegvisomant on the last visit. Median (range) pegvisomant doses (mg/day) were 10 (10-10), 15 (10-15) and 15 (10-15) at visits 2, 3 and 4, respectively, and the mean duration of pegvisomant treatment was 17·5 ± 3·2 (SEM) months. Serum IGF-I changed significantly during the treatment period with the highest level at baseline and lowest levels at visits 3 and 4. GH levels increased in a dose-dependent manner during pegvisomant treatment and decreased at visit 4. Changes in IGF-I levels correlated negatively with changes in serum pegvisomant levels between visits. Serum pegvisomant at each visit correlated with baseline growth hormone levels, whereas no associations between serum pegvisomant and either dose, gender, age or body weight were found. (1) Serum GH levels increased initially, but remained stable during prolonged pegvisomant treatment in patients with acromegaly, (2) serum pegvisomant levels predicted the reduction in serum IGF-I during treatment and (3) the interindividual variation in serum pegvisomant levels seems not predicted by either age, gender or body composition.

Comparison of the Efficacy of Octreotide Long-acting Repeatable and Lanreotide Autogel in Acromegalic Patients

Background: Somatostatin analogues have been used as the first-line medical therapy for active acromegaly that is not completely cured, or which recurs after surgery. The aim of this study was to compare the effects of octreotide long-acting repeatable (LAR) and lanreotide Autogel. Such a comparison has not been reported in Korea. Methods: Twenty-seven patients who had previously undergone surgery for acromegaly from December 2003 to March 2005 were included. We retrospectively investigated eight patients who underwent operation only and 19 patients who additionally received medical treatment after surgery (octreotide LAR, n = 5; lanreotide Autogel, n = 5). Growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels were measured. Results: The mean pre-operative and post-operative levels of GH were lower in patients who underwent surgery only than in those who received adjuvant therapy, but IGF-I levels were not significantly different. In the 19 patients receiving medical treatment after unsuccessful surgery, the mean baseline GH levels were 24.2 g/L for octreotide LAR and 22.8 g/L for lanreotide Autogel (P = 0.711), and the mean GH levels 36 months post-treatment were 4.1 g/L and 2.5 g/L, respectively (P = 0.794). GH g/L represented 30% of octreotide LAR patients and 33.3% of lanreotide Autogel patients (P = 0.91). Patients with normal IGF-I levels represented 54.5% and 66.7%, respectively (P = 0.71). Conclusion: No significant difference in therapeutic effect of octreotide LAR and lanreotide Autogel was evident in 19 Korean acromegalic patients who were not completely cured by surgery and radiation therapy.

Growth hormone/insulin-like growth factor axis in patients with subclinical thyroid dysfunction

Objective Our aim was to evaluate serum concentrations of GH, IGF-I, and insulin-like growth factor-binding protein-3 (IGFBP-3) in patients with subclinical thyroid dysfunction before and after normalization of thyroid function. Design and methods The study included 51 patients (mean age 42.2 ± 1.8 years) with subclinical hypothyroidism and 30 patients (mean age 44.3 ± 2.4 years) with subclinical hyperthyroidism. A group of 37 euthyroid healthy subjects were studied as controls. Serum concentrations of TSH, FT4, FT3, GH, insulin, IGF-I, and IGFBP-3 were measured in all patients before starting therapy and after normalization of thyroid function. The dosage of levothyroxine (LT4) and antithyroid drugs was adjusted in attempt to keep the serum-free thyroxine (FT4) and thyrotropin (TSH) concentrations within the normal range. Main outcome Baseline growth hormone levels were similar with hypothyroid group and hyperthyroid group in relation to euthyroid control subjects. Fasting serum IGF-I levels were significantly lower in the subclinical hypothyroid group compared with the control group. On the other hand, IGF-I levels of subclinical hyperthyroid patients and control group were similar. After normalization of thyroid function tests, IGF-I concentrations were increased in subclinical hypothyroid subjects, but unchanged in subclinical hyperthyroid subjects. Patients with subclinical hyperthyroidism showed slightly lower mean serum IGFBP-3 concentrations than those found in control group, but the difference was not statistically significant. Serum GH and IGFBP-3 levels were unaltered by treatment. Conclusions In this study, it was shown that GH–IGF axis was not affected in patients with subclinical hyperthyroidism, while it was affected in patients with subclinical hypothyroidism. That is, investigation of the axis in subclinical hyperthyroidism would not bring any extra advantages, but LT4 replacement therapy could prevent abnormalities related to GH–IGF axis in patients with subclinical hypothyroidism.

Association of Low Prostate-Specific Antigen Concentration and Panhypopituitarism

ObjectiveTo report the association of undetectable or very low prostate-specific antigen (PSA) concentrations with hypopituitarism. MethodsWe present a case series of 4 patients with low or undetectable PSA concentrations and associated panhypopituitarism and summarize the clinical presentation and pertinent laboratory and radiologic findings. We review related literature and discuss possible mechanisms explaining the described association. ResultsFour men with PSA values below the second percentile of a healthy population had hypopituitarism. In 3 men, low PSA concentrations were noted before large pituitary tumors were diagnosed. No man had headaches, visual problems, or other symptoms that were severe enough to prompt a search for tumor. All 4 patients had undetectable total testosterone levels. Luteinizing hormone and follicle-stimulating hormone levels were low to low-normal in 3 of the 4 patients. Baseline growth hormone level was low in 1 patient and undetectable in the other 3. The insulinlike growth factor 1 concentration was less than 73 ng/mL in each patient. ConclusionsWe believe that the association of low PSA concentrations and hypopituitarism is not incidental and that the extremely low PSA values in this case series were a consequence of both gonadal and growth hormone deficiency. We suggest that low PSA is a marker of combined profound testosterone and growth hormone deficiency in men with panhypopituitarism. This marker is important because PSA is frequently measured during routine health care visits; a low concentration may be the first clue to the presence of hypopituitarism in an otherwise asymptomatic patient. (Endocr Pract. 2008;14:432-436)

An audit of treatment outcome in acromegalic patients attending our center at Bergamo, Italy

Acromegaly is a chronic disease impacting on morbidity and mortality. Increased mortality is reverted after the achievement of hormonal targets. The relative role of treatment options is still matter of debate. A retrospective chart review was performed on all the acromegalic patients attending our center along the last 20 years. Data about 159 patients (83 F) were retrieved and analyzed: 18% had been lost to follow-up, while follow-up was >5 years in 79%. Growth hormone (GH) at diagnosis was 24 microg/L (median, range 3-239). Pituitary MRI showed a macro-, micro-adenoma or no lesion in 73.6, 22.9, and 3.5%, respectively. Hyperprolactinemia (hyperPRL) was present in 20.8%. Ninety-six and 29 patients had been treated by neurosurgery (NS) and irradiated (RT), respectively. Drugs had been employed in 149 patients (in 58 as the only treatment). At the last evaluation, 22% of patients were cured (hypopituitarism and GH deficiency in 6.3%), 37.1% were controlled by ongoing pharmacological treatment, 22.6% had discordant GH and Insulin-like growth factor I (IGF-I) values, and 18.2% had still active disease (median follow-up in this last group was 9 months). By evaluating the outcome with a multimodal approach, safe GH and normal IGF-I had been achieved in 78 and 63.5% of the whole series, 80.5 and 59.7% in patients submitted to NS (and adjuvantly treated with drugs), 95.8 and 91.7% in those submitted to NS + RT (and drugs as well), 70.2 and 55.2% in those treated only with drugs (increased to 82.2 and 60.9% if considering only patients treated with modern long-acting drugs). Hypopituitarism had occurred in 25, 66.6, and 13.8% in the three groups, respectively. At multivariate analysis, previous RT and NS were significant positive predictors of cure, whereas previous NS, follow-up, and year of diagnosis were significant positive predictors of control. Diabetes was a negative predictor both of cure and control. Sex, age, baseline GH levels, hyperPRL, tumor size, extrasellar extension, and invasiveness were not independent predictors of either cure or control. This series seems to indicate that a multimodal approach can achieve control of disease in most patients.

Population pharmacodynamic analysis of octreotide in acromegalic patients.

Octreotide is an octapeptide analog of somatostatin used to normalize growth hormone levels in acromegaly. This article presents a population analysis of the relationship between octreotide and growth hormone concentrations in 94 patients with acromegaly, including 10 patients responding incompletely to subcutaneous treatment (poor responders). Growth hormone and octreotide concentrations were recorded hourly over 12-hour time periods during long-term subcutaneous treatment. Twelve-hour profiles were also collected on different days up to 2 months after intramuscular injection of the long-acting formulation. We modeled the inhibition of growth hormone secretion by octreotide with a direct maximum inhibition model. A joint analysis of both formulations was performed with NONMEM (GloboMax, LLC, Hanover, Md). During model building, we examined the relationships between parameters and demographic covariates or formulations with the use of likelihood ratio tests. The baseline growth hormone level was higher in poor responders and was best described by a bimodal distribution. The maximum inhibition was common to both formulations and had a mean of 90%, with low interindividual variability. Sensitivity to octreotide (50% inhibitory concentration) was found to be slightly lower on average with intramuscular administration than with subcutaneous administration. Given adequate doses of octreotide, in 72% of 94 patients, growth hormone would decrease to levels below 2.5 ng. mL(-1), considered to be a desirable target concentration in acromegaly. This study provides a way to identify poor responders during subcutaneous treatment, allowing an early clinical decision to be made to switch nonresponders to alternative therapies.

Effects of Long-Term Erythropoietin Therapy on the Hypothalamo–Pituitary–Testicular Axis in Male Capd Patients

Gonadal dysfunction has been recognized for a long time in uremic male patients. The present study assesses the hypothalamo-pituitary-testicular axis and growth hormone status in male continuous ambulatory peritoneal dialysis (CAPD) patients, before and after recombinant human erythropoietin (rHuEPO) therapy. Single-center prospective study. Ten anemic male patients with chronic renal insufficiency, and 11 healthy volunteers with normal renal function, matched for age, were included in the study. All patients were on CAPD therapy and none had received rHuEPO treatment previously. Blood samples were collected between 0800 and 0900 hr from all patients for the determination of basal follicle stimulating hormone (FSH), luteinizing hormone (LH), and growth hormone (GH) levels. A luteinizing hormone-releasing hormone (LH-RH) stimulation test was carried out using LH-RH 100 microg intravenous as a bolus injection. Blood for FSH, LH, and GH determinations was drawn every 30 minutes during the 3-hour test period. Human chorionic gonadotropin (hCG) test was performed after 48 hours. After estimations of basal serum total and free testosterone levels, 2000 IU hCG was administered intramuscularly and repeated 48 hours later. Total and free testosterone levels were measured in blood samples collected before and 48 hours after two injections of hCG. After improvement in anemia with exogenous rHuEPO, LH-RH and hCG tests were repeated. Baseline FSH concentrations before and after rHuEPO treatment were slightly higher in CAPD patients than in healthy volunteers (p = 0.85 and p = 0.70, respectively). Areas-under-the-curve (AUCs) for FSH secretion before and after rHuEPO treatment were also slightly higher in patients than in healthy volunteers (p = 1.00 and p = 0.75, respectively). The pretreatment basal LH levels in patients were significantly higher than in controls (p < 0.001). After the improvement in anemia with rHuEPO, serum LH levels declined significantly (p < 0.05). The AUCs for LH secretion before and after rHuEPO treatment were significantly higher in patients than in controls (p < 0.05). All patients had elevated basal levels of GH with paradoxical response to LH-RH. Baseline GH levels in patients were significantly higher than those in healthy subjects (p < 0.001) before rHuEPO treatment. After treatment with rHuEPO, basal GH levels declined but did not normalize, and baseline levels of free testosterone increased significantly (p < 0.05). Anemic uremic male patients on CAPD have normal levels of testosterone with normal response to hCG administration, elevated basal levels of GH, and elevated basal levels of LH, with exaggerated response to LH-RH administration. Improvement in anemia with rHuEPO reduced the basal levels of LH and GH, but exaggerated the LH response; paradoxical GH response to LH-RH administration persisted. These results indicate a defect at the level of the hypothalamus and pituitary gland in uremic male patients undergoing CAPD, and that the improvement in anemia with rHuEPO partially restores some of these endocrine abnormalities.

Gamma-hydroxybutyric acid and growth hormone secretion Studies in rats and dogs

Gamma-hydroxybutyric acid, a gamma-aminobutyric acid metabolite, and baclofen, a gamma-aminobutyric acid B agonist, are endowed with a small growth hormone-releasing activity in human beings. In this study, we have investigated the reciprocal interactions of gamma-hydroxybutyric acid and the gamma-aminobutyric acid B system by evaluating the growth hormone-releasing activity of the two compounds and their respective antagonists in in vivo and in vitro experiments performed in rats and dogs. In in vivo experiments, neither gamma-hydroxybutyric acid (25, 100, 150, and 300 mg/kg, SC) nor baclofen (0.25, 1, 2, 4, and 8 mg/kg, SC) significantly modified growth hormone secretion in 9-day-old rat pups. Similarly, no growth hormone and prolactin release was observed in adult anesthetized rats after administration of gamma-hydroxybutyric acid (100 mg/kg, IP) or baclofen (10 mg/kg IP). Equally ineffective on the somatotropic response was the administration of gamma-hydroxybutyric acid (200 mg/kg, IP) alone or associated with its specific receptor antagonist NCS-382 (150 mg/kg, IP) given to adult anesthetized rats. In addition, a toxicological dose of gamma-hydroxybutyric acid (1500 mg/kg, IP) did not alter baseline growth hormone levels in adult conscious rats. gamma-Hydroxybutyric acid (50 mg/kg, IP) given for 10 days to adult conscious rats did not alter the growth hormone response to the same gamma-hydroxybutyric acid dose given acutely. In conscious dogs, gamma-hydroxybutyric acid (20 and 50 mg/kg, IV) and baclofen (0.15, 0.30 mg/kg, IV) also were ineffective in stimulating growth hormone secretion. In this species, growth hormone response to hexarelin (31.25 μg/kg, IV), a potent growth hormone-releasing peptide, was not modified by coadministration of gamma-hydroxybutyric acid (50 mg/kg, IV). In in vitro experiments, increasing doses of gamma-hydroxybutyric acid (10 −7, 10 −5, and 10 −3 M) did not alter growth hormone concentrations in media of rat pituitary cell cultures. In contrast, growth hormone-releasing hormone (10 −7 M) induced a significant growth hormone release into the media. In conclusion (1) gamma-hydroxybutyric acid is not an effective growth hormone secretagogue; (2) the reciprocal functional interactions between gamma-hydroxybutyric acid and the gamma-aminobutyric acid B system could not be investigated, due to the ineffectiveness of gamma-hydroxybutyric acid and baclofen to stimulate growth hormone release; and (3) short-term administration of gamma-hydroxybutyric acid does not induce adverse effects amenable to activation of the somatotropic function.

Nitric oxide modulation of the growth hormone—releasing activity of hexarelin in young and old dogs

The growth hormone (GH)-releasing activity of Hexarelin, a potent GH-releasing peptide (GHRP) analog, was evaluated in eight young (aged 1 to 6 years) and five old (10 to 16 years) beagle dogs pretreated with erythrityl tetranitrate, a liposoluble nitric oxide (NO) donor, and/or indomethacin, an inhibitor of cyclooxygenase enzymes, and N-nitro-L- or N-nitro-D-arginine methylester (L-NAME and D-NAME), active and inactive NO synthase (NOS) inhibitors, respectively. Erythrityl tetranitrate (0.3 mg x kg(-1) oral [p.o.]) strikingly potentiated Hexarelin-stimulated GH secretion (31.25 microg x kg(-1) intravenous [i.v.]) in both young (area under the time-concentration curve at 0 to 90 minutes AUC(0-90)] 878.50 +/- 267.02 v 1,994.04 +/- 434.20 ng x mL(-1) x h, P < .01) and aged animals (314.82 +/- 117.11 v 1,314.12 +/- 484.75 ng x mL(-1) x h, P < .01). The NO donor alone did not modify baseline GH levels in either young dogs (188.68 +/- 85.24 ng x mL(-1) x h) or old dogs (120.49 +/- 22.03 ng x mL(-1) x h). L-NAME (5 mg x kg(-1) x 2 i.v.) suppressed GH release induced by the peptide in young dogs (1,367.68 +/- 251.87 v 411.12 +/- 68.49 ng x mL(-1) x h, P < .01), but potentiated it in old dogs (314.73 +/- 117.10 v 1,103.97 +/- 374.11 ng x mL(-1) x h, P < .01). D-NAME (5 mg x kg(-1) x 2 i.v.) did not affect the GH response to Hexarelin in either young (1,328.68 +/- 433.54 ng x mL(-1) x h) or aged (342.32 +/- 84.82 ng x mL(-1) x h) dogs. Indomethacin (1.5 mg x kg(-1) i.m.) abolished the NO-donor potentiation of the GH response induced by Hexarelin in both young dogs (1,627.25 +/- 260.90 v 1,163.37 +/- 334.84 ng x mL(-1) x h, P < .05) and old dogs (1,061.47 +/- 210.38 v 365.69 +/- 79.27 ng x mL(-1) x h, P < .01) without affecting the plasma GH peak evoked by the peptide alone (young dogs, 786.04 +/- 153.44 v 960.04 +/- 444.44 ng x mL(-1) x h, P = NS; old dogs, 474.55 +/- 47.30 v 490.82 +/- 144.86 ng x mL(-1) x h, P = NS). In conclusion, (1) NO donors are capable to further increase the strong GH-releasing activity of Hexarelin in both young and old dogs, although the site(s) and mechanism(s) of action of NO is still obscure; (2) the different GH response to the peptide after NOS inhibition in young and old dogs signifies in the latter an alteration of the somatotrope function; and (3) prostaglandins are the downstream effectors of the chain of events triggered by activation of the NO-ergic system.

GROWTH HORMONE SECRETION IN PRIMARY DEGENERATIVE DEMENTIA: CORRELATIONS WITH COGNITIVE IMPAIRMENT

Changes in brain peptides and neurotransmitters are thought to elicit alterations of growth hormone (GH) secretion in dementia. Baseline GH levels and hormone responses to GH-releasing hormone (GHRH)—administered alone or after pyridostigmine pretreatment—were evaluated in 17 patients, aged 52–83, with primary degenerative dementia quantified by the Clinical Dementia Rating (CDR) Scale and the Mini-Mental State Examination (MMSE) with a view to detecting correlations between neuroendocrine and clinical data. Basal GH levels were not statistically different in patients and in age-matched controls. However, when patients were split into the three CDR groups of disease severity, basal GH levels were significantly higher in those with more severe dementia than in all other patients and in controls. GH responses to GHRH, evaluated both in terms of peaks attained after simulation and of secretion areas under the curve (AUC), were significantly higher in patients than in controls after pyridostigmine pretreatment, but not after the infusion of GHRH alone. Patients with mild to moderate dementia had GH peaks after GHRH higher than more severe patients. Pyridostigmine did not potentiate GHRH effects in the more severe cases. The scores on Rey's 15-word test for memory function were directly correlated with GH peaks after GHRH. No correlations were found between GH data, age, body weight, disease duration and scores at other psychometric assessments such as MMSE, Raven's matrices, verbal fluency or WAIS tests.

Effects of hyper- and hypoglycemia on blood growth hormone level in free-feeding rats with anterolateral deafferentation of the medial basal hypothalamus

In rats with anterolateral deafferentation of the medial basal hypothalamus, the growth hormone (GH) level in the blood showed irregular and small fluctuations instead of the usual high bursts and low trough level, and the baseline GH level was higher than that in sham-operated rats. Continuous infusion of a glucose solution to operated rats increased the baseline level, GH pulse and pulse amplitude. I.v. bolus injection of the glucose solution resulted in a significant but transient increase in GH level. Insulin-induced hypoglycemia decreased the blood GH level in operated rats more effectively than in sham-operated ones and that was prevented by simultaneous infusion of glucose. Since SS influence on GH secretion had been largely eliminated in rats with anterolateral deafferentation of the medial basal hypothalamus, it is highly unlikely that the effects of hyperglycemia or hypoglycemia on GH secretion were the consequence of altered SS secretion.

Caloric intake stimulates growth hormone secretion in food-deprived rats with anterolateral deafferentation of the medial basal hypothalamus or administered antiserum to somatostatin.

In rats, food deprivation inhibits episodic growth hormone (GH) secretion. On the basis of previous studies, we hypothesized that during a recovery from prolonged fasting, caloric intake stimulates the release of GH-releasing factor (GRF) and this process does not depend on the specific macronutrients in the meal, while protein in the meal acts to restore characteristic ultradian rhythmicity of GH secretion. To test this hypothesis, the effect of caloric intake on GH secretion was examined in fasted adult male Wistar rats devoid of somatostatin (SS) influence on GH secretion either by anterolateral deafferentation (ALC) of the medial basal hypothalamus (MBH) or administration of anti-SS goat serum (ASS). Rats were provided with an indwelling right atrial cannula and were deprived of food for 72 h. ALC was performed 2 weeks prior to the study. ASS was given i.v. 8 h and 7 h prior to refeeding, respectively. Serial blood specimens were collected every 10 min. In rats with ALC (ALC rats) or rats given ASS (ASS rats), the blood GH level revealed irregularly occurring small fluctuations, instead of the usual high bursts and low trough level. The baseline GH level and the mean GH level of fasted ALC rats or fasted ASS rats were significantly lower than those of fed ALC rats or fed ASS rats. Feeding the isocaloric mixed meal, the protein meal or the protein-deficient meal increased the GH pulse frequency, the pulse amplitude, the baseline GH level and the mean GH level in 72-h fasted ALC rats. These changes in GH secretory pattern persisted during the period of observation and were independent of the type of meal ingested. Following feeding the mixed meal, similar changes in the GH secretory pattern demonstrated in 72-h fasted ALC rats were also observed in 72-h fasted ASS rats, suggesting that the stimulation of GH secretion following caloric intake is not limited to ALC rats. Since the influence of SS on GH secretion has been largely eliminated in ALC or ASS rats, it is highly unlikely that the augmentation of GH secretion following feeding after prolonged food deprivation was the consequence of inhibition of SS secretion. Although GRF measurement was not performed, it is conceivable that the signal of caloric intake is conveyed to the MBH and acts to stimulate GRF release.

The sensitivity of hepatic CYP2C gene expression to baseline growth hormone (GH) bioactivity in dwarf rats: effects of GH-binding protein in vivo.

Hepatic mRNA transcripts for the steroid-metabolizing enzymes cytochrome P4502C11 (male specific) and P4502C12 (female specific) differ in abundance by 10- to 20-fold in male and female rats and are regulated by their different patterns of GH secretion. This sex difference is also found in dwarf rats with low GH secretion, implying that these transcripts may be very sensitive to low level GH exposure. This has now been characterized in normal and dwarf rats. Continuous i.v. infusion of recombinant human (h) GH (0, 3, 12, and 48 micrograms/day) in both dwarf and normal male rats caused a dose-dependent decrease in P4502C11 and an increase in P4502C12, so that the 2C11/2C12 ratio fell from 17.9 +/- 1.3 to 1.5 +/- 1.0 in normal males and from 6.5 +/- 0.9 to 0.4 +/- 0.3 in dwarf males (0 vs. 48 micrograms hGH/day); over this dose range of hGH, body weight gain, total hepatic insulin-like growth factor-I mRNA levels, and plasma GHBP levels were largely unaffected. These effects of hGH were pattern dependent. The 2C11/2C12 ratio in dwarf males was feminized (from 11.9 +/- 1.3 to 0.08 +/- 0.03) by continuous infusion of hGH (36 micrograms/day), whereas a pulsatile infusion (3-min pulses every 3 h) of the same daily hGH dose was much less effective. Neither continuous nor pulsatile hGH affected P4502C11 or P4502C12 transcripts in dwarf females, although pulsatile hGH infusion caused a significant weight gain. To test whether baseline GH levels could be modified by circulating GH-binding protein (GHBP), hGH infusions were given with and without recombinant hGHBP in different patterns. Pulsatile infusions of recombinant hGHBP (42 micrograms/day, i.v.) did not prevent the feminizing effect of continuously infused hGH (36 micrograms/day, sc) in dwarf males (2C11/2C12 ratios were 0.08 +/- 0.01 and 0.09 +/- 0.01 for hGH vs. hGH plus hGHBP, respectively). This suggested that intermittent complex formation with GHBP did not prevent continuous access of hGH to the hepatic GH receptors. Furthermore, pulses of hGH complexed with GHBP significantly reduced the 2C11/2C12 ratio in dwarf males (from 21.5 +/- 3.9 with pulsatile hGH alone to 9.2 +/- 2.5 with pulses of hGH plus hGHBP), indicating that GHBP prolongs the exposure to hGH. Thus, 2C11/2C12 expression is very sensitive to basal GH levels in dwarf rats, and GHBP can alter hepatic gene expression by modifying the pattern of GH exposure.