Ectopic Acromegaly due to A Pancreatic Neuroendocrine Tumor Producing Growth Hormone-Releasing Hormone

ObjectiveTo present a case of acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion from a pancreatic neuroendocrine tumor in the context of multiple endocrine neoplasia type 1 (MEN 1).MethodsWe describe the clinical, imaging, and pathologic findings of the study patient.ResultsA 46 year old woman presented with clinical and biochemical findings diagnostic of acromegaly. Magnetic resonance imaging showed a 1.2-cm sellar mass. Following resection of the macroadenoma, serum insulinlike growth factor 1 (IGF-1) and growth hormone (GH) levels remained unchanged. Pathologic examination revealed adenomatous changes, including a nonsecretory focus and a prolactin immunopositive area (GH stain negative in both). Octreotide long-acting release was ineffective. Search for an ectopic tumor included normal octreoscan and abdominal computed tomography. GHRH was greater than 1000 pg/mL. Repeated abdominal computed tomography documented a 6.2-cm mass in the tail and body of the pancreas. Distal pancreatectomy revealed a pancreatic neuroendocrine tumor that stained positive for GHRH. Postoperatively, serum GHRH and IGF-1 normalized. Re-evaluation of the initial pituitary pathologic specimen revealed additional somatotroph hyperplasia of the adjacent, normal pituitary gland. Primary hyperparathyroidism was diagnosed, and multigland parathyroid hyperplasia was noted at surgery. Genetic testing was positive for a mutation in the MEN1 gene.ConclusionThis patient’s acromegaly was resistant to somatostatin analogue therapy, reflecting the negative octreoscan imaging. In addition, this case is novel because the patient presented with pituitary adenomatous changes, which were presumably associated with MEN 1 and/or possibly the elevated GHRH levels. (Endocr Pract. 2011; 17:79-84)     

Insulinhypoglycemia but not arginine infusion stimulates circulating plasma growth hormone-releasing hormone (GHRH) concentrations in children

The effect of insulinhypoglycemia and arginine infusion on circulating concentrations of plasma growth hormone-releasing hormone (GHRH) and growth hormone (GH) has been studied in 24 children (4.4 to 14.3 years). Plasma GH and GHRH concentrations were determined by RIA. Basal plasma GHRH levels were detectable in the plasma of all patients ranging from 6.8 to 27.1 pg/ml. Injection of 0.1 U/kg body wt. insulin i.v. resulted in an increase of plasma GHRH levels (11.1 +/- 1.4 pg/ml vs. 18.8 +/- 2.6 pg/ml; P less than 0.01) preceding that of plasma GH (1.5 +/- 0.4 ng/ml vs. 13.6 +/- 1.3 ng/ml; P less than 0.01). Infusion of 0.5 gm/kg body wt. arginine hydrochloride did increase GH concentrations (2.0 +/- 0.6 ng/ml vs. 13.9 +/- 2.3 ng/ml; P less than 0.01) but did not change circulating plasma GHRH levels. Since the source of peripheral GHRH concentrations is not known the importance of these findings remains to be determined.     

Clinical studies with GHRH in man

GHRH was isolated from two GHRH-secreting pancreatic tumors which resulted in clinical acromegaly. Over 98% of acromegalic patients have a pituitary adenoma; however, acromegaly may occasionally result from ectopic or eutopic GHRH secretion. Administration of GHRH to normal adults stimulates growth hormone (GH) secretion; it may also stimulate GH release in some adults with GH deficiency in childhood and in a majority of GH-deficient children. Continuous infusion of GHRH to normal men stimulates GH secretion which augments naturally occurring GH pulses. GHRH is effective when administered subcutaneously and intranasally, but requires 30- and 300-fold higher doses, respectively. Intermittent subcutaneous GHRH therapy promotes acceleration of linear growth in GH-deficient children and appears promising as a treatment for these children.     

Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy

Human immunodeficiency virus (HIV)-lipodystrophy is a syndrome characterized by changes in fat distribution and insulin resistance. Prior studies suggest markedly reduced growth hormone (GH) levels in association with excess visceral adiposity among patients with HIV-lipodystrophy. We investigated mechanisms of altered GH secretion in a population of 13 male HIV-infected patients with evidence of fat redistribution, compared with 10 HIV-nonlipodystrophic patients and 11 male healthy controls similar in age and body mass index (BMI). Although similar in BMI, the lipodystrophic group was characterized by increased visceral adiposity, free fatty acids (FFA), and insulin and reduced extremity fat. We investigated ghrelin and the effects of acute lowering of FFA by acipimox on GH responses to growth hormone-releasing hormone (GHRH). We also investigated somatostatin tone, comparing GH response to combined GHRH and arginine vs. GHRH alone with a subtraction algorithm. Our data demonstrate an equivalent number of GH pulses (4.1 +/- 0.6, 4.7 +/- 0.8, and 4.5 +/- 0.3 pulses/12 h in the HIV-lipodystrophic, HIV-nonlipodystrophic, and healthy control groups, respectively, P > 0.05) but markedly reduced GH secretion pulse area (1.14 +/- 0.27 vs. 4.67 +/- 1.24 ng.ml(-1).min, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 1.14 +/- 0.27 vs. 3.18 +/- 0.92 ng.ml(-1).min, P < 0.05 HIV-lipodystrophic vs. control), GH pulse area, and GH pulse width in the HIV-lipodystrophy patients compared with the control groups. Reduced ghrelin (418 +/- 46 vs. 514 +/- 37 pg/ml, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 418 +/- 46 vs. 546 +/- 45 pg/ml, P < 0.05, HIV-lipodystrophic vs. control), impaired GH response to GHRH by excess FFA, and increased somatostatin tone contribute to reduced GH secretion in patients with HIV-lipodystrophy. These data provide novel insight into the metabolic regulation of GH secretion in subjects with HIV-lipodystrophy.     

Plasma growth hormone releasing factor levels in children: physiological and pharmacologically induced variations

Plasma growth hormone releasing factor (GHRH) was measured by RIA in the plasma of 41 children with constitutionally short stature. Basal plasma GHRH was 51 +/- 10 pg/ml. L-Dopa induced a 2-fold increase in circulating GHRH 30-45 min before the elevation of GH. A positive correlation (p less than 0.005) was found between the peak of GH and GHRH during the dopaminergic stimulus. On the opposite, the secretion of GH induced by amino acids or clonidine is not preceded by an elevation of plasma GHRH. When a release of GH appeared after the insertion of the venous catheter alone, probably due to the stress, it was preceded by a rise of plasma GHRH. In four sleeping adolescents during the night no relationship was found between the peaks of plasma GHRH and the peaks of GH secretion. These results suggest that the various stimulations of GH secretion used for investigations of a short stature do not act in the same way at the hypothalamo-pituitary level.     

Plasma levels of total and active ghrelin in acromegaly and growth hormone deficiency

Ghrelin is an endogenous growth hormone (GH) secretagogue recently isolated from the stomach. Although it possesses a strong GH releasing activity in vitro and in vivo, its physiological significance in endogenous GH secretion remains unclear. The aim of this study was to characterize plasma ghrelin levels in acromegaly and growth hormone deficiency (GHD). We investigated plasma total and active ghrelin in 21 patients with acromegaly, 9 patients with GHD and 24 age-, sex- and BMI-matched controls. In all subjects, we further assessed the concentrations of leptin, soluble leptin receptor, insulin, IGF-I, free IGF-I and IGFBP-1, 2, 3 and 6. Patients with acromegaly and GHD as well as control subjects showed similar levels of total ghrelin (controls 2.004+/-0.18 ng/ml, acromegalics 1.755+/-0.16 ng/ml, p=0.31, GHD patients 1.704+/-0.17 ng/ml, p=0.35) and active ghrelin (controls 0.057+/-0.01 ng/ml, acromegalics 0.047+/-0.01 ng/ml, p=0.29, GHD patients 0.062+/-0.01 ng/ml, p=0.73). In acromegalic patients plasma total ghrelin values correlated negatively with IGF-I (p<0.05), in GHD patients active ghrelin correlated with IGF-I positively (p<0.05). In the control group, total ghrelin correlated positively with IGFBP-2 (p<0.05) and negatively with active ghrelin (p=0.05), BMI (p<0.05), WHR (p<0.05), insulin (p=0.01) and IGF-I (p=0.05). Plasma active ghrelin correlated positively with IGFBP-3 (p=0.005) but negatively with total ghrelin and free IGF-I (p=0.01). In conclusion, all groups of the tested subjects showed similar plasma levels of total and active ghrelin. In acromegaly and growth hormone deficiency plasma ghrelin does not seem to be significantly affected by changes in GH secretion.     

Effect of arginine on the GHRH-stimulated GH secretion in patients with hyperthyroidism.

Patients with hyperthyroidism have reduced GH responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of arginine on GH secretion has been suggested to depend on a decrease in hypothalamic somatostatin tone. The aim of our study was to evaluate the effects of arginine on the GH-releasing hormone (GHRH)-stimulated GH secretion in patients with hyperthyroidism. Six hyperthyroid patients with recent diagnosis of Graves' disease [mean age +/- SEM, 39.2 +/- 1.4 years; body mass index (BMI) 22 +/- 0.4 kg/m2] and 6 healthy nonobese volunteers (4 males, 2 females; mean age +/- SEM, 35 +/- 3.5 years) underwent two experimental trials at no less than 7-day intervals: GHRH (100 micrograms, i.v.)-induced GH secretion was evaluated after 30 min i.v. infusion of saline (100 ml) or arginine (30 g) in 100 ml of saline. Hyperthyroid patients showed blunted GH peaks after GHRH (13.2 +/- 2.9 micrograms/l) as compared with normal subjects (23.8 +/- 3.9 micrograms/l, p < 0.05). GH peaks after GHRH were only slightly enhanced by arginine in hyperthyroid subjects (17.6 +/- 2.9 micrograms/l), whereas, in normal subjects, the enhancement was clear cut (36.6 +/- 4.4 micrograms/l; p < 0.05). GH values after arginine + GHRH were still lower in hyperthyroid patients with respect to normal subjects. Our data demonstrate that arginine enhances but does not normalize the GH response to GHRH in patients with hyperthyroidism when compared with normal subjects. We hypothesize that hyperthyroxinemia may decrease GH secretion, both increasing somatostatin tone and acting directly at the pituitary level.     

Effect of synthetic ovine corticotropin-releasing factor on growth hormone secretion in patients with acromegaly

In a significant proportion of patients with acromegaly, a non-specific increase in plasma growth hormone (GH) has been recognized following administration of thyrotropin-releasing hormone (TRH) or luteinizing hormone-releasing hormone (LH-RH), probably due to the lack of the specificity of the receptor in their tumor cells. In this study, the effects of corticotropin-releasing factor (CRF), a newly isolated hypothalamic hormone, in addition to TRH and LH-RH, on plasma levels of GH and the other anterior pituitary hormones were evaluated in 6 patients with acromegaly. Synthetic ovine CRF (1.0 microgram/kg), TRH (500 micrograms) or LH-RH (100 micrograms) was given as an iv bolus injection, in the morning after an overnight fast. Blood specimens were taken before and after injection at intervals up to 120 min, and plasma GH, adrenocorticotropin (ACTH), thyrotropin, prolactin, luteinizing hormone, follicle-stimulating hormone and cortisol were assayed by radioimmunoassays. A non-specific rise in plasma GH was demonstrated following injection of TRH and LH-RH, in 5 of 6 and 2 of 5 patients, respectively. In all subjects, rapid rises were observed in both plasma ACTH (34.3 +/- 6.2 pg/ml at 0 min to 79.5 +/- 9.5 pg/ml at 30 min, mean +/- SEM) and cortisol level (9.1 +/- 1.3 micrograms/dl at 0 min to 23.4 +/- 1.2 micrograms/dl at 90 min). However, plasma levels of GH and the other anterior pituitary hormones did not change significantly after CRF injection. These results indicate that CRF specifically stimulates ACTH secretion and any non-specific response of GH to CRF appears to be an infrequent phenomenon in this disorder.     

Robust growth hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH)

Aging is associated with a blunted growth hormone (GH) secretory response to GH-releasing hormone (GHRH), in vivo. The objective of the present study was to assess the effects of aging on the GH secretory response to GH-releasing hexapeptide (GHRP-6), a synthetic GH secretagogue. GHRP-6 (30 micrograms/kg) was administered alone or in combination with GHRH (2 micrograms/kg) to anesthetized female Fischer 344 rats, 3 or 19 months of age. The peptides were co-administered to determine the effect of aging upon the potentiating effect of GHRP-6 on GHRH activity. The increase in plasma GH as a function of time following administration of GHRP-6 was lower (p less than 0.001) in old rats than in young rats; whereas the increase in plasma GH secretion as a function of time following co-administration of GHRP-6 and GHRH was higher (p less than 0.001) in old rats than in young rats (mean Cmax = 8539 +/- 790.6 micrograms/l vs. 2970 +/- 866 micrograms/l, respectively; p less than 0.01). Since pituitary GH concentrations in old rats were lower than in young rats (257.0 +/- 59.8 micrograms/mg wet wt. vs. 639.7 +/- 149.2 micrograms/mg wet wt., respectively; p less than 0.03), the results suggested that GH functional reserve in old female rats was not linked to pituitary GH concentration. The differential responses of old rats to individually administered and co-administered GHRP-6 are important because they demonstrate that robust and immediate GH secretion can occur in old rats that are appropriately stimulated. The data further suggest that the cellular processes subserving GH secretion are intact in old rats, and that age-related decrements in GH secretion result from inadequate stimulation, rather than to maladaptive changes in the mechanism of GH release.     

Effect of opiates on growth hormone secretion in acromegaly.

Morphine at doses of 5 mg and 10 mg does not stimulate growth hormone (GH) secretion in normal subjects, and its effect on GH secretion in acromegaly is not widely documented. We investigated the effect of 15 mg intravenous morphine on growth hormone in patients with active acromegaly compared to normal subjects (7 acromegalics and 5 controls). Their mean (+/- SEM) age was 30.5 +/- 7.6 years and 29.5 +/- 0.5 years, respectively. Basal and peak response of growth hormone after morphine was measured with simultaneous assay of cortisol to exclude the effect of stress. Mean (+/- SEM) basal growth hormone was 103.16 +/- 28.04 ng/ml in acromegalics compared to 4.51 +/- 1.43 ng/ml in controls. Morphine caused an elevation of growth hormone in both acromegalics and normal subjects (p < 0.05). However, the Delta (peak minus basal) response of growth hormone was comparable between the two groups. A concurrent fall in cortisol was noted after morphine in both the groups, excluding the effect of stress on growth hormone. We conclude that higher doses (15 mg) of morphine are required to stimulate GH secretion in normal subjects, and that opioids exert a positive modulating effect on growth hormone secretion in patients with active acromegaly suggesting partial autonomy of the pituitary tumor.     

Radioimmunoassay for insulin-like growth factor II (IGF-II)

Insulin-like growth factor II (IGF-II) levels in human plasma were measured in physiological and pathological conditions by radioimmunoassay (RIA) with biosynthetic IGF-II. This RIA was specific for IGF-II and cross-reactivity with IGF-I was 1%. The sensitivity was 15 pg/tube with 50% displacement at 50 pg/tube. The intra- and inter-assay coefficients of variation for IGF-II were 6.3 and 9.3%, respectively. The plasma IGF-II levels in normal adults, patients with hypopituitarism and patients with active acromegaly were 589.6 +/- 15.8, 800.9 +/- 45.6 and 330.3 +/- 24.3 ng/ml, respectively. After human growth hormone (hGH) treatment in hypopituitarism, IGF-II slightly increased, but not significantly. After adenomectomy in patients with acromegaly, IGF-II significantly decreased. These data indicate that IGF-II concentrations in plasma were partially GH dependent. This GH dependency was less than that of IGF-I. IGF-II was low in patients with anorexia nervosa and with liver cirrhosis and high in patients with renal failure. In two cases with extrapancreatic tumor-associated hypoglycemia, plasma IGF-II was increased to 1123.8 and 843.5 ng/ml, and returned to normal after tumor resection. These data showed that IGF-II was partly dependent on GH and nutritional conditions and that IGF-II was the most likely cause of some cases of hypoglycemia with extrapancreatic tumor. This specific and sensitive RIA of IGF-II would be useful in evaluating its physiological and pathological role in plasma and tissue.     

Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin

Using a continuous subcutaneous octreotide infusion to create constant supraphysiological somatostatinergic tone, we have previously shown that growth hormone (GH) pulse generation in women is independent of endogenous somatostatin (SRIH) declines. Generalization of these results to men is problematic, because GH regulation is sexually dimorphic. We have therefore studied nine healthy young men (age 26 +/- 6 yr, body mass index 23.3 +/- 1.2 kg/m2) during normal saline and octreotide infusion (8.4 microg/h) that provided stable plasma octreotide levels (764.5 +/- 11.6 pg/ml). GH was measured in blood samples obtained every 10 min for 24 h. Octreotide suppressed 24-h mean GH by 52 +/- 13% (P = 0.016), GH pulse amplitude by 47 +/- 12% (P = 0.012), and trough GH by 39 +/- 12% (P = 0.030), whereas GH pulse frequency and the diurnal rhythm of GH secretion remained essentially unchanged. The response of GH to GH-releasing hormone (GHRH) was suppressed by 38 +/- 15% (P = 0.012), but the GH response to GH-releasing peptide-2 was unaffected. We conclude that, in men as in women, declines in hypothalamic SRIH secretion are not required for pulse generation and are not the cause of the nocturnal augmentation of GH secretion. We propose that GH pulses are driven primarily by GHRH, whereas ghrelin might be responsible for the diurnal rhythm of GH.     

Growth hormone-releasing hormone: past and present

The discovery of hypothalamic hypophysiotropic factors confirmed the hypothesis of Green and Harris in the late 1940s. These hormones were isolated from their eutopic site of production (the hypothalamus) with the exception of growth hormone (GH)-releasing hormone (GHRH), which was isolated from an ectopic, tumoral site of production and found to be responsible for acromegaly. Following the isolation, characterization and synthesis of human GHRH, clinical studies were performed and are described below. Circulating levels of GHRH can be measured and provide the basis for the diagnosis of acromegaly related to the ectopic, tumoral production of GHRH. At present, GHRH is used as a test of GH secretion mainly as an adjunct to other agents which modify somatostatin status, or to GH-releasing peptides. Its therapeutic potential in children and the elderly is still under investigation. The role of GHRH in the pulsatile secretion of GH is described.     

Growth hormone response to growth hormone releasing hormone 1-40 in Turner's syndrome

The response of growth hormone (GH) to acute administration of GH-releasing hormone 1-40 (GHRH) was evaluated in 12 patients with Turner's syndrome and in 12 prepubertal or early pubertal girls. In 7 of 12 patients GHRH induced a definite increase (greater than 10 ng/ml) of plasma GH levels. In 5 patients there was a poor GH rise after GHRH administration (less than 10 ng/ml). Overall, the mean GH response of patients was significantly lower than that of normal girls. Five out of 7 patients with a 45 X,O karyotype had a reduced GH rise after GHRH, while all patients with non X,O karyotype (mosaicism and/or 46 X,iX) had a normal GH response to GHRH. Although the cause of short stature in patients with Turner's syndrome is most likely multifactorial, a reduced pituitary GH reserve, as documented by the reduced GH response to GHRH in some of our patients, may contribute to the growth impairment in this disorder.     

Effect of a single administration of somatostatin analogue (SMS 201-995) on GH, TSH and insulin secretion in patients with acromegaly

The effect of a long-acting somatostatin analogue SMS 201-995 on GH secretion was investigated. Eleven acromegalic patients received a single dose of 50 micrograms SMS 201-995 administered subcutaneously, and plasma GH, IGF-I, GRF, TSH, IRI and blood glucose were determined at regular intervals. Nine of 11 patients had elevated basal plasma GH levels above 5 ng/ml. In all patients, plasma GH levels fell immediately from 39.5 +/- 17.3 ng/ml (mean +/- SEM) to 4.3 +/- 1.6 ng/ml (P less than 0.05) with a maximal inhibition of 82.9 +/- 3.3% of the basal levels and the suppression persisted for about 6 h of the observation period. IGF-I and GRF levels were not apparently altered. TSH and IRI levels also rapidly fell. Blood glucose levels fell slightly by 0.5 h. Ten of 11 patients had pain at injection sites. Except for this, no side effects were observed. Our results show that the new somatostatin analogue SMS 201-995 may inhibit GH hypersecretion in acromegalic patients for significant periods, suggesting that this agent can be a useful clinical tool for the treatment of acromegaly.     

Role of vasoactive intestinal polypeptide (VIP) in regulating the pituitary function in man

Intramuscular injection of synthetic VIP (200 micrograms) resulted in a rapid increase in plasma prolactin (PRL) concentrations in normal women, which was accompanied by the 4- to 7-fold increase in plasma VIP levels. Mean (+/- SE) peak values of plasma PRL obtained 15 min after the injection of VIP were higher than those of saline control (28.1 +/- 6.7 ng/ml vs. 11.4 +/- 1.6 ng/ml, p less than 0.05). Plasma growth hormone (GH) and cortisol levels were not affected by VIP in normal subjects. VIP injection raised plasma PRL levels (greater than 120% of the basal value) in all of 5 patients with prolactinoma. In 3 of 8 acromegalic patients, plasma GH was increased (greater than 150% of the basal value) by VIP injection. In the in vitro experiments, VIP (10(-8), 10(-7) and 10(-6) M) stimulated PRL release in a dose-related manner from the superfused pituitary adenoma cells obtained from two patients with prolactinoma. VIP-induced GH release from the superfused pituitary adenoma cells was also shown in 5 out of 6 acromegalic patients. VIP concentrations in the CSF were increased in most patients with hyperprolactinemia and a few cases with acromegaly. These findings indicate that VIP may play a role in regulating PRL secretion in man and may affect GH secretion from pituitary adenoma in acromegaly.     

Nocturnal ghrelin pulsatility and response to growth hormone secretagogues in healthy men

The physiological importance of endogenous ghrelin in the regulation of growth hormone (GH) secretion is still unknown. To investigate the regulation of ghrelin secretion and pulsatility, we performed overnight ghrelin and GH sampling every 20 min for 12 h in eight healthy male subjects [age 37 +/- 5 (SD) years old, body mass index 27.2 +/- 2.9 kg/m2]. Simultaneous GH and ghrelin levels were assessed to determine the relatedness and synchronicity between these two hormones in the fasted state during the overnight period of maximal endogenous GH secretion. Pulsatility analyses were performed to determine simultaneous hormonal dynamics and investigate the relationship between GH and ghrelin by use of cross-approximate entropy (X-ApEn) analyses. Subjects demonstrated 3.0 +/- 2.1 ghrelin pulses/12 h and 3.3 +/- 0.9 GH pulses/12 h. The mean normalized ghrelin entropy (ApEn) was 0.93 +/- 0.09, indicating regularity in ghrelin hormone secretion. The mean normalized X-ApEn was significant between ghrelin and GH (0.89 +/- 0.12), demonstrating regularity in cosecretion. In addition, we investigated the ghrelin response to standard GH secretagogues [GH-releasing hormone (GHRH) alone and combined GHRH-arginine] in separate testing sequences separated by 1 wk. Our data demonstrate that, in contrast to GHRH alone, which had little effect on ghrelin, combined GHRH and arginine significantly stimulated ghrelin with a maximal peak at 120 min, representing a change of 66 +/- 14 pg/ml (P = 0.001 by repeated-measures ANOVA and P = 0.02 for GHRH vs. combined GHRH-arginine by MANOVA). We demonstrate relatedness between ghrelin and GH pulsatility, suggesting either that ghrelin participates in the pulsatile regulation of GH or that the two hormones are simultaneously coregulated, e.g., by somatostatin or other stimuli. Furthermore, the differential effects of GHRH alone vs. GHRH-arginine suggest that inhibition of somatostatin tone may increase ghrelin. These data provide further evidence of the physiological regulation of ghrelin in relationship to GH.     

Inhibition of growth hormone secretion in mild primary hyperparathyroidism

INTRODUCTION: Impairment in growth hormone (GH) secretion has been reported to occur in primary hyperparathyroidism (PHP) with strikingly elevated (>150 pg/ml) plasma PTH and free Ca levels. Patients with these characteristics are relatively few, whereas the great majority of patients with biochemically diagnosed PHP are asymptomatic and show borderline or slightly elevated plasma PTH and Ca levels. We wondered whether also patients in these latter conditions show a defective GH secretory pattern. METHODS: In order to answer this question, 8 female subjects (mean age +/- SE: 44 +/- 1.3 years) were selected at the time of a checkup examination from a larger population of persons in fairly good clinical condition. Inclusion criteria were plasma PTH values slightly above the normal range (up to 50% higher than the maximum limit) with free Ca levels in the upper normal range or slightly higher (experimental group). Normal values in our laboratory are ionized calcium: 1.22-1.42 mmol/ml and plasma PTH: 12-72 pg/ml. A group of 15 age-matched healthy women with plasma PTH and Ca levels in the middle normal range and significantly lower than values found in the experimental group was also selected and used as control. Experimental and control groups were tested with arginine [0.5 mg/kg body weight (BW)] infused intravenously over 30 min and arginine plus GH-releasing hormone (GHRH; 1 microg/kg BW in an intravenous bolus injection). The GH responses to these challenging stimulations were compared between groups. RESULTS: Basal serum GH values were similar in all subjects. Both arginine and arginine plus GHRH induced a significant GH rise in both groups; however, the GH responses were significantly lower in the experimental than in the control group. Mean GH peak was 27.7 and 14.6 times higher than baseline after arginine and 57.5 and 26.6 times higher than baseline after arginine plus GHRH in the control and experimental group, respectively. No significant correlation was observed between PTH or Ca levels and the GH responses to challenging stimuli in any group. CONCLUSION: These data show that impairment in GH secretion is associated with slightly elevated levels of PTH in the presence of serum Ca values in the upper normal range. GH responses to stimulations were reduced by about 50% in our hyperparathyroid subjects. A long-time duration of this relatively small decline of GH secretory activity may be supposed to contribute to age-related catabolic processes in a large number of patients with mild primary hyperparathyroidism.     

Results of a two-year treatment with slow release lanreotide in acromegaly.

In this open sequential study we evaluated the long-term effectiveness and tolerability of the i.m. administration of slow release lanreotide 30 mg (SRL) in 18 acromegalics (7 M/11 F, age 50.9+/-12.7 yr). Baseline mean GH and IGF-1 levels were 15.8+/-6.6 ng/ml and 702+/-74 ng/ml, respectively. Four hours, 1, 7, and 14 days after SRL, mean GH levels were 8.9+/-5.9 (p < 0.005), 11.4+/-6.9 (p < 0.05), 9.1+/-4.5 (p < 0.05), and 9.1+/-4.1 ng/ml (p < 0.05), respectively; and the IGF-1 values at 1, 7, and 14 days were 624+/-77 (p < 0.05), 555+/-83 (p < 0.001), and 467+/-58 ng/ml (p < 0.0001), respectively. Four hours after SRL administration GH was < 2.5 ng/ml in 11 patients and decreased 85% of the basal value, without normalizing, in another case. In the following 2 weeks, 7 and 2 patients maintained GH < 2.5 ng/ ml or < 50% of baseline; 3 and 2 of them attained IGF-1 values in the normal range or < 50% of basal levels. A patient developed acute pancreatitis after the injection of the drug and therefore stopped the treatment. Another patient did not continue SRL, and she was turned on octreotide, s.c. administered (OCT), because only the latter treatment ameliorated significantly the headache. In 16/18 patients the treatment was continued until the 24th month. SRL was administered every 14 days until the 24th month in 3 cases, whereas in 13 patients the dose schedule was increased every 10 days since the 7th month because they did not normalize serum GH and IGF-1 levels. In these 16 patients baseline GH and IGF-1 levels were 10.0+/-2.5 ng/ml and 671+/-75 ng/ml, respectively. At the 1st, 3rd, and 6th month of treatment mean GH levels fell to 5.4+/-1.4 (p < 0.05), 5.3+/-1.8 (p < 0.05), and 5.0+/-1.6 (p < 0.05) ng/ml, respectively; and IGF-1 declined to 511+/-87 (p < 0.005), 565+/-85 (p < 0.05), and 525+/-94 (p < 0.01) ng/ml, respectively. Throughout the first semester GH was < 2.5 ng/ml in 5 patients and decreased > 50% in another three. IGF-1 levels normalized in 3/5. Throughout the following 18 months of treatment, mean GH (3.4+/-1.0 ng/ml) and IGF-1 (413+/-75 ng/ml) values decreased significantly in comparison with both the baseline concentrations (GH p < 0.01, IGF-1 p < 0.001) and the levels measured during the 1st semester of treatment (GH p < 0.05, IGF-1 p < 0.001). GH remained < 2.5 ng/ml in 11 patients, and in 8/11 cases IGF-1 fell in the normal range. Serum GH and IGF-1 levels decreased by more than 50% of baseline levels in 2 other cases. At MRI, pituitary adenoma was no longer evident in one patient previously treated with OCT and significantly decreased in another patient previously treated with surgery plus radiotherapy, as well as in a patient previously untreated. During treatment the percentage of patients complaining of headache and fatigue decreased significantly (chi2, p < 0.05 and p < 0.0005, respectively). Overall, the headache (p < 0.005), arthralgia (p < 0.05), and paresthesia (p < 0.01) ameliorated significantly. Ultrasound scan showed gallbladder sludge or sand-like stones in 5/11 patients. This study, which is one of the longest surveys on a relatively large series of acromegalics treated with SRL, confirms the long-term effectiveness of this drug for the treatment of patients with active acromegaly. SRL decreases significantly GH and IGF-1 in most cases and induces the shrinkage of the pituitary tumor in some patients previously either untreated or both treated for acromegaly. SRL improves significantly clinical symptoms and it is well tolerated.