Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion

We measured plasma insulin-like growth factor I/somatomedin-C (IGF-I/SmC) concentrations and mean 24-h GH secretion serially before and during therapy with the long-acting somatostatin analog SMS 201-995 in 21 patients with acromegaly. When mean plasma GH was elevated above 12.0 +/- 0.6 (+/- SE) micrograms/L, plasma IGF-I/SmC concentrations were uniformly high, but a decline of mean plasma GH below this value was accompanied by a linear decrease in IGF-I/SmC concentrations (r = 0.89; P less than 0.001). Even mildly abnormal mean GH concentrations (greater than 4.6 but less than 10 micrograms/L) were accompanied by high plasma IGF-I/SmC values. The log dose-response interrelation between mean 24-h plasma GH and IGF-I/SmC concentrations was linear (r = 0.86; P less than 0.001). We conclude that 1) an excellent log dose-response correlation between mean 24-h plasma GH and IGF-I/SmC concentrations is present in patients with acromegaly; 2) normalization of plasma IGF-I/SmC occurs only in patients with mean daily GH output within the normal range; and 3) determination of plasma IGF-I/SmC is an accurate indicator of normalcy of GH secretion and should be used in the diagnosis of active acromegaly as well as in monitoring the progress of therapy.     

Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy

Alterations in pulsatile GH release in 13 acromegalic patients (7 men and 6 women) were studied by measuring serum GH concentrations in blood sampled every 5 min over 24 h. Specific properties of pulsatile GH release were quantitated by Cluster analysis, and Fourier expansion time series analysis was used to resolve fixed periodicities underlying GH secretion. Compared with sex-matched controls, 24-h integrated GH concentrations (IGHC; min.mg/L) were elevated 15-fold in the acromegalic men (40 +/- 27 vs. 2.6 +/- 0.35; P = 0.02) and 10-fold in the acromegalic women (43 +/- 19 vs. 4.1 +/- 0.35; P = 0.01). The increase in integrated GH concentrations was accounted for by an increase in the nonpulsatile fraction [men, 31 +/- 20 vs. 0.65 +/- 0.10 (P = 0.001); women, 35 +/- 14 vs. 1.2 +/- 0.10 (P = 0.0008)]; the pulsatile component was not different from that in normal subjects. Acromegalics had an increased number of pulses per 24 h [men, 17 +/- 1.5 vs. 6.7 +/- 1.4 (P = 0.0001); women, 19 +/- 1.6 vs. 11 +/- 1.0 (P = 0.002)] and increased basal GH concentrations [men, interpulse valley mean, 22 +/- 14 vs. 1.4 +/- 0.30 micrograms/L (P = 0.0006); women, 27 +/- 12 vs. 1.3 +/- 0.20 micrograms/L (P = 0.0001)]. The proportion of the mean GH concentration attributable to 24-h rhythmicity was decreased in the acromegalic patients. Five patients studied during biochemical remission (4 after transsphenoidal surgery and 1 during bromocriptine therapy) had GH profiles that resembled those of normal subjects. Pulsatile GH secretion in acromegaly is characterized by augmented basal GH concentrations, increased GH pulse frequency, and an attenuation of the underlying 24-h rhythm. Such a pattern may be secondary to the intrinsic pathology of adenomatous somatotrophs and/or the effects of altered hypothalamic regulation.     

Comparison of the sensitivity of growth hormone secretion to somatostatin in vivo and in vitro in acromegaly

Somatostatin (SRIH) sensitivity in acromegaly was evaluated in vivo by comparing the inhibition of GHRH (1 microgram/kg, iv)-stimulated GH secretion in eight acromegalic and six normal subjects. A SRIH infusion (50 micrograms/h) that inhibited the mean plasma GH response to GHRH by 74 +/- 5% (+/- SE) in normal subjects had no significant effect in the acromegalic patients. However, when two acromegalic patients in whom SRIH had no suppressive effect were excluded from the analysis, the effect of SRIH in the other six (82 +/- 7%) was comparable to that in the normal subjects. Within the acromegalic group, the percent suppression of basal and GHRH-stimulated GH secretion was inversely correlated with both basal plasma GH (r = -0.751; P = 0.03 and r = -0.727; P = 0.04, respectively) and insulin-like growth factor I (r = -0.800; P = 0.02 and r = -0.727; P = 0.04, respectively) concentrations. The in vitro sensitivity to SRIH was studied in pituitary adenomas from five of the acromegalic patients in 3- to 4-day monolayer cultures of dispersed cells. The SRIH IC50 values were lowest in the tumors (8.6-44 pmol/L) from the three patients who had in vivo SRIH sensitivity (suppression of GHRH-stimulated GH secretion) comparable to that in the normal subjects. The IC50 values were higher in the tumors (150 and 21,000 pmol/L) from the two patients that were least responsive to SRIH in vivo. These results indicate that there is considerable variability of SRIH sensitivity in patients with acromegaly. Although the role of this defect in the pathogenesis of acromegaly is uncertain, it may be an important determinant in the degree of elevation of plasma GH levels.     

Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy

OBJECTIVE Early studies of acromegaly undertaken before the general availability of insulin-like growth factor I (IGF-I) assays have used arbitrary and varying growth hormone (GH) threshold levels for diagnosing and assessing outcome of treatment for this disease. We have undertaken a detailed study of GH secretion and its relationship to IGF-I levels to assess the usefulness of GH and IGF-I measurements in the assessment of acromegaly. PATIENTS Thirty acromegalic subjects (12 untreated and 16 previously treated) and 30 age and sex-matched normal subjects were studied. MEASUREMENTS Twenty-four-hour GH secretion was obtained from 20-minute sampling and serum IGF-I was measured. Comparisons were made of IGF-I, mean 24-hour GH concentration, and of the pulsatile and diurnal characteristics of GH secretion between the two groups. RESULTS IGF-I levels In untreated acromegaly were elevated and clearly separated from the normal range. Mean 24-hour GH concentrations in untreated and treated acromegalic subjects with elevated IGF-I (>40 nmol/l) were greater than (P < 0.01), and showed good separation from, those of normal subjects only after age-matching. From the 24-hour prollfes, nadir GH levels In normal subjects fell below the level of detectability while those in untreated acromegalic subjects did not. Pulse amplitude (P<0.01), ratio of pulsatile to non-pulsatile GH release and the night to daytime GH ratio (P<0 05) were significantly reduced in acromegaly. In the six patients who attained normal IGF-I levels after surgery, pulsatile characteristics remained abnormal in four. Mean 24-hour GH was significant related (r = 0.57) to IGF-I. A random GH concentration >2.5 μg/l (5 mlU/l) has a sensitivity of 77% and specificity of 95% In identifying acromegalic patients who have biochemically active disease (elevated IGF-I) after treatment. CONCLUSIONS Patients with active acromegaly secrete more GH than age-matched normal controls. GH secretion in acromegaly is characterized by marked blunting of pulsatile secretion and, in contrast to normal subjects, the failure of GH to fall to undetectable levels at any time during the 24-hour day. IGF-I measurement is a more practical alternative in the diagnosis of acromegaly and in the assessment of therapeutic outcome. Since abnormalities of GH regulation may persist despite normalization of IGF-I, a distinction between remission and cure should be made. Detailed post-treatment evaluation of GH secretion is necessary to define the nature of underlying GH regulation and to evaluate the risk of disease recurrence.     

Effect of active acromegaly and its treatment on parathyroid circadian rhythmicity and parathyroid target-organ sensitivity

Context: Patients with active acromegaly have increased bone turnover and skeletal abnormalities. Biochemical cure of acromegaly may represent a functional GH-deficient state and result in cortical bone loss. Reduced PTH target-organ sensitivity occurs in adult GH deficiency and may underlie the associated development of osteoporosis. Objective: We examined the effect of active and treated acromegaly on PTH concentration and target-organ sensitivity. Patients: Ten active acromegalic subjects (GH nadir > 0.3 mug/liter after 75-g oral glucose load and IGF-I above age-related reference range) and 10 matched controls participated in the study. Design: Half-hourly blood and 3-h urine samples were collected on patients and controls for 24 h. Samples were analyzed for PTH, calcium (Ca), nephrogenous cAMP (NcAMP, a marker of PTH renal activity), beta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker). Serum calcium was adjusted for albumin (ACa). Eight acromegalic subjects who achieved biochemical cure (GH nadir < 0.3 mug/liter after 75-g oral glucose load and IGF-I within reference range) after standard surgical and/or medical treatment reattended and the protocol repeated. Results: Active acromegalic subjects had higher 24-h mean PTH, NcAMP, ACa, urine Ca, beta C-telopeptide, and procollagen type I amino-terminal propeptide (P < 0.05), compared with controls. Twenty-four-hour mean PTH increased (P < 0.001) in the acromegalic subjects after treatment, whereas NcAMP and ACa decreased (P < 0.05). Conclusion: Increased bone turnover associated with active acromegaly may result from increased PTH concentration and action. Biochemical cure of acromegaly results in reduced PTH target-organ sensitivity indicated by increased PTH with decreased NcAMP and ACa concentrations. PTH target-organ sensitivity does not appear to return to normal after successful treatment of acromegaly in the short term and may reflect functional GH deficiency.     

Variable growth hormone profiles following withdrawal of long-term 30mg slow-release lanreotide treatment in acromegalic patients: clinical implications

OBJECTIVE: Intramuscular injections of 30mg slow-release (SR) lanreotide (every 10 to 14 days) are an effective treatment in acromegalic patients. Because of an ongoing need to assess the efficacy and the tolerance of a new formulation of a depot preparation of lanreotide, we have evaluated prospectively GH profiles following withdrawal of 30mg slow-release lanreotide in a cohort of acromegalic patients. PATIENTS: Fifty-one acromegalic patients, controlled during long-term 30mg SR lanreotide treatment (GH: 1.44 +/- 0.64 microgram/l, IGF-I: 316 +/- 145ng/ml) (mean +/- s.d.), were studied following the withdrawal of the drug. MEASUREMENTS: Mean GH (half-hour samples, 0800-1200h), IGF-I and lanreotide levels were evaluated 14, 28, and 42 days following the last 30mg SR lanreotide injection. RESULTS: Mean GH levels remained below 2.5 microgram/l in 32 patients (group 1) twenty-eight days following SR lanreotide withdrawal. In these patients, mean GH and IGF-I levels had increased from 1.2 +/- 0.6 to 1.7 +/- 0.5 microgram/l (P < 0001), and from 283 +/- 138 to 359 +/- 168ng/ml (P < 0.001) respectively. In the 19 other patients (group 2), mean GH concentrations had risen above 2.5 microgram/l at 28 days following SR lanreotide withdrawal. Mean GH and IGF-I levels had increased from 1.9 +/- 0.4 to 5.1 +/- 2.8 microgram/l (P < 0.001), and from 371 +/- 143 to 568 +/- 206ng/ml (P < 0.001) respectively. Patients of groups 1 and 2 were comparable with regard to age, sex, tumoral status, mean GH levels before somatostatin analogue treatment, and previous treatments such as radiotherapy and duration of somatostatin analogue therapy, but 75% of group 1 patients underwent surgery compared with 37% of group 2 patients (P < 0.01). Twenty-eight days following SR lanreotide withdrawal, mean lanreotide levels in group 1 and group 2 had decreased from 1.6 +/- 0.7 to 0.6 +/- 0.3ng/ml (P < 0.001), and from 2.7 +/- 2.0 to 0.7 +/- 0.7ng/ml (P < 0.001) respectively. A negative correlation was observed between the lanreotide levels and GH and IGF-I concentrations in the two groups of patients, but the inhibition of GH/IGF-I concentrations by lanreotide levels was higher in group 1 patients than in those of group 2. Six patients of group 1 were treated with 30mg SR lanreotide injected at monthly intervals. During monthly follow-up, mean GH levels increased above 2.5 microgram/l in 2 patients. After 12 months follow-up, mean GH and IGF-I levels from 4 other patients were similar to those obtained with previous therapeutic sequence (i.e. intramuscular injections every 14 days). CONCLUSION: The degree of responsiveness to lanreotide and the duration of somatotroph suppression following lanreotide withdrawal are variable in acromegalic patients controlled during long-term 30mg SR lanreotide treatment. In patients displaying high sensitivity to lanreotide, the interval between i.m. 30mg SR lanreotide injections can be increased to one month, thus reducing the cost of the therapy, without altering its efficacy upon GH/IGF-I control.     

Pulsatile growth hormone secretion in patients with acromegaly and normal men: the effects of growth hormone-releasing hormone infusion

Twenty-four GH secretory patterns were studied before and during continuous infusions of GHRH in six patients with active acromegaly and in six normal adult men. GH release was episodic in both groups. Control subjects showed a normal diurnal variation in GH release, with the majority of GH released at night (2200-0800 h); mean levels were 1.5 +/- 0.4 (SE) ng/mL (day) and 4.2 +/- 0.8 ng/mL (night). Acromegalics had no diurnal variation in GH; levels were 45.3 +/- 13.7 ng/mL (day) and 39.8 +/- 12.2 ng/mL (night). Acromegalics demonstrated an increased frequency of GH pulses compared to normals (11.8 +/- 0.8 vs. 2.2 +/- 0.3/24 h). During continuous 24-h infusions of GHRH, the normal subjects continued to show a diurnal variation in GH release, but GH pulse frequency increased to a rate (11.7 +/- 1.4 pulses/24 h) very similar to that of the patients with acromegaly. In contrast, GHRH infusion did not alter the GH pulse frequency in the acromegalics. GHRH increased the mean levels of GH in both groups (patients 80.2 +/- 20.3 vs. 41.0 +/- 12.1 ng/mL, x +/- SE. P less than 0.05; controls 10.2 +/- 2.0 vs. 3.33 +/- 0.5 ng/mL, P less than 0.01). Some of the patients with acromegaly showed a progressive decline in GH levels during the infusion period, suggesting desensitization or exhaustion of releaseable stores; however, GH levels remained above basal values in all patients. After the 24-h GHRH infusions, the GH response to a bolus of GHRH was diminished in the normal subjects (2.1 +/- 0.9 vs. 16.8 +/- 5 ng/mL, x +/- SE; P less than 0.01) but not in the acromegalic patients (30.2 +/- 8.9 vs. 35.5 +/- 12.5 ng/mL; NS). These results indicate that GH release is episodic under basal conditions and during continuous GHRH infusion in both acromegalic and normal subjects, indicating the importance of other modulators of GH release, such as somatostatin, which may remain pulsatile even in acromegaly.     

Divergence between growth hormone and insulin-like growth factor-i concentrations in the follow-up of acromegaly

CONTEXT: Divergence between GH and IGF-I values is regularly observed in treated acromegalic patients, and its significance is unclear. OBJECTIVES: The objective of the study was to explore the frequency and identify potential determinants of discordant serum GH and IGF-I concentrations in noncured acromegalic patients. PATIENTS: Two hundred twenty-nine noncured acromegalic patients of the Belgian acromegaly registry (AcroBel) were grouped according to their mean GH level (< or = or > 2 microg/liter) and IGF-I z-score (< or = 2 or > 2). Clinical and metabolic parameters were compared between groups with active disease (high GH and IGF-I; n=81),high GH (with normal IGF-I; n=25), high IGF-I (with normal GH; n=55), and controlled disease (GH and IGF-I normal; n=68). RESULTS: Compared with the high IGF-I group, the high GH group was characterized by younger age (52 vs. 58 yr, P < 0.05), female predominance (72 vs. 36%, P < 0.01), and lower body mass index (25 vs. 31 kg/m(2); P < 0.001), fasting glucose (91 vs. 99 mg/dl; P < 0.05), and glycated hemoglobin levels (5.7 vs. 6.1%; P < 0.01). There was no difference among the groups regarding baseline characteristics of pituitary adenoma, current medical treatment, or symptom score. CONCLUSIONS: Thirty-five percent of noncured acromegalic patients exhibit a discordant GH and IGF-I pattern. The high GH phenotype was found predominantly in younger estrogen-sufficient females, implying a possible role for age, gender, and estrogens in this biochemical divergence. The high IGF-I phenotype was associated with a worse metabolic profile, suggesting that high IGF-I, rather than high GH, is indicative of persistently active disease.     

Attenuated pulse size, disorderly growth hormone and prolactin secretion with preserved nyctohemeral rhythm distinguish irradiated from surgically treated acromegaly patients

BACKGROUND: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined. OBJECTIVE: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT). DESIGN: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls. SETTING/PARTICIPANTS: University setting. Fifteen subjects in each group. OUTCOME MEASURES: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations. RESULTS: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others. CONCLUSION: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.     

Twenty-four-hour plasma growth hormone (GH) profiles, urinary GH excretion, and plasma insulin-like growth factor-I and -II levels in prepubertal children with chronic renal insufficiency and severe growth retardation

We studied 24-h plasma GH profiles, maximal GH responses to arginine provocation and insulin-like growth factor-I (IGF-I) and IGF-II levels in plasma in 22 euthyroid prepubertal children (mean age, 9.5 yr) with chronic renal insufficiency (glomerular filtration rate, less than 20 mL/min.1.73 m2) and severe growth retardation [mean (+/- SD) height SD score (SDS), -2.8 (1.1)]. The 24-h GH profiles were analyzed using the Pulsar program. Girls had significantly higher 24-h GH secretion than boys (P less than 0.004). Children with end-stage nephrotic syndrome had higher baseline GH levels and total area under the curve (AUCo) than patients with dysplastic kidneys (P less than 0.05), while the area under the curve above baseline (AUCb) was similar in all types of renal diseases. The type of treatment (conservative, peritoneal, hemodialysis) did not significantly influence the 24-h GH secretion. No correlation was found between 24-h GH profiles and age, height SDS for chronological age, height velocity SDS for bone age, and weight for height. Fourteen children showed a normal 24-h GH profile, defined as a GH profile with well defined, regular GH peaks returning to baseline GH levels and a distinct day and night pattern (AUCb, 90-300 micrograms/L.24 h). Four children had low profiles, with GH peaks below 10 micrograms/L, returning to baseline GH levels and occurring almost exclusively during the night (AUCb, less than 90 micrograms/L.24 h). The remaining four children had elevated 24-h GH profiles, with GH peaks on top of elevated baseline GH levels of more than 3 micrograms/L (AUCb, 35-205 micrograms/L.24 h; AUCo greater than 300 micrograms/L.24 h). In all patients 24-h urinary GH and beta 2-globulin excretion was 100-1000 times higher than that in controls. The urinary GH excretion correlated significantly with all characteristics of the 24-h GH profiles (r = 0.57-0.59; P less than 0.05). The maximal GH response during the arginine tolerance test was normal in 66% of the children. The mean (+/- SD) SDS for bone age for the IGF-I plasma levels was +1.1 (1.9), and that for IGF-II was +3.6 (3.4). IGF-I levels correlated significantly with the AUCb, maximum GH, and GH peak characteristics of the 24-h GH profiles (r = 0.05-0.73; P less than 0.02-0.001). IGF-II levels did not show any correlation with the characteristics of the endogenous GH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)     

SMS 201-995 induces a continuous decline in circulating growth hormone and somatomedin-C levels during therapy of acromegalic patients for over two years

Ten acromegalic patients, four previously untreated, were studied before and at regular intervals during treatment with the long-acting somatostatin analog SMS 201-995 (200-300 micrograms daily for 2 or 3 sc injections for 16-108 weeks). All patients had rapid clinical improvement, with disappearance of excessive perspiration, paresthesias, and headache within the first 6 weeks of therapy. The mean 24-h serum GH concentrations fell from 44.0 +/- 7.8 (+/-SE) micrograms/L before to 5.9 +/- 1.0 microgram/L at the end of therapy. The GH levels from 2-6 h after the acute administration of 50 micrograms SMS 201-995 before the start of therapy correlated significantly with the mean 24-h GH concentrations after 16-108 weeks of treatment (P less than 0.05). The initially increased serum somatomedin-C (Sm-C) levels normalized in 5 of these 10 patients; the mean values were 7.3 +/- 0.9 U/mL before and 2.9 +/- 0.7 U/mL at the end of therapy. The Sm-C and mean GH levels continuously decreased during long term therapy; the concentrations after 1.5-2 yr of therapy were significantly lower than those after 6-12 months of therapy (P less than 0.01 and P less than 0.01, respectively). A slight decrease in the size of the pituitary tumor was noted by computed tomography in three of six patients. Transient clinically detectable steatorrhea occurred in two patients. Postprandial hyperglycemia occurred during therapy in eight patients, while in two patients with type 2 diabetes mellitus carbohydrate tolerance improved in one and deteriorated in the other. SMS 201-995 is a highly effective medical treatment for acromegaly. Clinically improvement occurs rapidly, and the inhibition of serum GH and Sm-C levels persisted even after more than 1 yr of therapy. No important subjective side-effects were noted. SMS 201-995 is an excellent drug in patients in whom acromegaly persists after surgery and for interim treatment to shorten the period of clinical activity after irradiation.     

THE INFLUENCE OF OCTREOTIDE TREATMENT ON PULSATILE GROWTH HORMONE RELEASE IN ACROMEGALY

The pulsatile release of GH was investigated in eight active acromegalic patients before and during a subcutaneous infusion of 300 micrograms octreotide/24 h for 4 weeks. The number of GH pulses increased from a basal value of 14.4/24h to 16.3/24h during octreotide therapy. At the same time the mean GH concentration, valley concentration, peak height and amplitude decreased significantly. The inhibitory effect of octreotide on pulse characteristics did not depend on the time of day. IGF-I levels also decreased significantly; in five patients normal levels were reached. IGF-I levels correlated significantly with the mean GH level (r = 0.714, P less than 0.001), mean valley concentration (r = 0.697, P less than 0.001) and, to a lesser extent, area under the curve (r = 0.436, P = 0.033), but not the number of pulses. Plasma octreotide levels did not correlate with pulse parameters. In all but one patient a circadian rhythm was present during both the basal study and octreotide therapy. Compared with surgically treated acromegalics, the number of GH pulses was higher in untreated and octreotide-treated patients. This study demonstrates the pulsatile release of GH in active acromegaly both before and during octreotide therapy. This result suggests that endogenous GHRH is important for the generation of GH pulses in this disease.     

Marked improvement in cardiovascular function after successful transsphenoidal surgery in acromegalic patients

OBJECTIVE: Transsphenoidal surgery results in biochemical remission of acromegaly in 45-80% of patients; however, few studies have addressed the impact of transsphenoidal surgery on cardiovascular function in acromegalic patients. The aim of this prospective study was to investigate the effects of postoperative GH/IGF-I normalization on echocardiographic parameters and blood pressure (BP) in a series of patients with active acromegaly. DESIGN: An open prospective study. PATIENTS: Thirty newly diagnosed acromegalic patients undergoing transsphenoidal surgery. MEASUREMENTS: Doppler echocardiography and 24-h ambulatory blood pressure monitoring were performed before and 6 months after transsphenoidal surgery. RESULTS: Fifteen patients were considered to be well controlled postoperatively (group A), as defined by normal age-corrected IGF-I levels and glucose-suppressed GH levels less than 2 mU/l, the remaining 15 patients being considered as poorly controlled (group B). In group A, a postoperative decrease of left ventricular mass index was observed (104.4 +/- 6.6 vs. 127.1 +/- 7.7 g/m2; P < 0.001), associated with an improvement of some indices of diastolic function, such as an increase of the early/late transmitral peak flow velocity (P < 0.05) and a decrease of isovolumic relaxation time (P < 0.01). No significant change was observed in group B. A significant decrease of 24-h systolic BP was also observed in group A (P < 0.05) and five of six patients normalized their BP circadian rythm. In contrast, a nonsignificant increase in BP values, with a persistent blunted BP profile where present, was observed in group B. CONCLUSIONS: We conclude that successful transsphenoidal surgery is able to induce a significant improvement in some cardiac parameters and a slight reduction in systolic blood pressure in acromegalic patients.     

Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women

Estrogen deficiency may account for lower circulating GH and insulin-like growth factor I (IGF-I) concentrations in the menopause. Since the liver is the major source of circulating IGF-I and oral estrogens have nonphysiological effects on hepatic function, we have compared GH secretion over 24 h from 20 min sampling and serum IGF-I levels in premenopausal women (n = 7, follicular phase) and postmenopausal women before and after 2 months of cyclical replacement therapy with either oral ethinyl estradiol (EE, 20 micrograms daily; n = 7) or transdermal 17 beta-estradiol (E2, 100 micrograms patches applied twice weekly; n = 7). The extent of GH binding to its serum binding protein was also examined by measuring the percent specific binding of [125I] GH in serum. Mean 24-h serum GH and serum IGF-I were significantly lower (P less than 0.05) in postmenopausal than in premenopausal women. Oral and transdermal estrogen therapy resulted in a comparable degree of gonadotropin suppression. Oral EE treatment increased mean 24-h serum GH (2.0 +/- 0.4 to 7.0 +/- 0.6 mIU/L, P less than 0.0005) and mean pulse amplitude (5.3 +/- 1.2 to 11.2 +/- 2.5 mIU/L, P less than 0.01) but significantly reduced circulating IGF-I (0.70 +/- 0.09 to 0.47 +/- 0.04 U/mL, P less than 0.02) levels. Oral EE increased the percent specific binding of [125I]GH (22.0 +/- 1.6 to 32.0 +/- 1.9%, P less than 0.0005), however the derived mean 24-h free serum GH concentrations were significantly higher (P less than 0.0005) after treatment. By contrast, transdermal E2 administration, which restored circulating E2 concentrations to the midfollicular range, increased circulating IGF-I (0.86 +/- 0.15 to 1.10 +/- 0.14 U/mL, P less than 0.005) to levels that were not significantly different from those of premenopausal women (1.41 +/- 0.21 U/mL). This was not accompanied by changes in 24-h GH secretion or the percent specific binding of [125I]GH in serum. The route of administration is a major determinant of the effects of exogenous estrogens on the GH/IGF-I axis. Oral estrogen administration inhibits hepatic IGF-I synthesis and increases GH secretion through reduced feedback inhibition. Reduced GH secretion in the menopause is not explained by estrogen deficiency since GH secretion is not restored by the attainment of physiological E2 concentrations using the transdermal route. The contrasting route dependent IGF-I responses have important implications for the long-term benefit of hormone replacement therapy in the menopause.     

Effects of recombinant human insulin-like growth factor I administration on the growth hormone (gh) response to GH-releasing hormone in obesity

Circulating GH levels are reduced in obesity due to true reduction of the 24-h GH production rate. GH insufficiency in obesity might reflect neuroendocrine abnormalities and/or alterations in peripheral hormones and metabolic factors. The somatotroph response to provocative stimuli including GHRH is markedly blunted in obese patients. However, the somatotroph responsiveness to GHRH in obesity shows also peculiar refractoriness to the inhibitory effect of glucose load. In this present study we aimed at verifying the effect of low dose rhIGF-I (20 microgram/kg, sc, at 0 min) on the GH response to GHRH (1 microgram/kg, iv, at 180 min) in obesity. With this goal in mind, six obese women with abdominal adiposity [OB; age (mean +/- SEM), 32.3 +/- 4.4 yr; body mass index, 32.8 +/- 2.3 kg/m(2)] were studied. The effects of recombinant human insulin-like growth factor I (rhIGF-I) administration on circulating total IGF-I, insulin, and glucose levels were also evaluated. The results in OB were compared with those recorded in age-matched lean women (NW; age, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m(2)), in whom the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I levels in OB were similar to those in NW (199.7 +/- 33.3 vs. 274.4 +/- 25.3 microgram/L). The mean GH concentration over 3 h (from 0-180 min) in OB was lower than that in NW (0.9 +/- 0.4 vs. 2.6 +/- 0.8 microgram/L; P = NS). Administration of GHRH induced a GH response in OB lower than that in NW (area under the curve from 180-270 min, 576.5 +/- 137.5 vs. 1315.9 +/- 189.9 microgram/L.min; P < 0.02). Administration of rhIGF-I increased circulating IGF-I levels in both groups to the same percent extent (326.8 +/- 28.3 and 420.3 +/- 26.5 microgram/L in OB and NW, respectively). rhIGF-I administration inhibited the GH response to GHRH in OB (240.1 +/- 99.6 microgram/L; P < 0.05) as well as in NW (730.2 +/- 288.1 microgram/L; P < 0.05), although it failed to lower the mean GH concentration over 3 h in either OB or NW. After rhIGF-I the GH response to GHRH in OB was slight and was still lower (P < 0.05) than that in NW; in fact, the percent decreases were similar in both groups (44.21 +/- 14.06 and 48.21 +/- 13.95 microgram/L, in OB and NW, respectively). The mean insulin (107.1 +/- 21.9 and 36.8 +/- 7.2 pmol/L), but not glucose (4.0 +/- 0.3 and 4.1 +/- 0.1 mmol/L), levels calculated over 270 min, were higher (P = 0.005) in OB than in NW; rhIGF-I administration did not modify insulin and glucose levels in either group. Our study shows that the sc administration of a low rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese as well as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect of rhIGF-I is preserved in obesity.     

Galanin decreases circulating growth hormone levels in acromegaly.

Galanin is able to elicit GH secretion in normal man. In acromegaly, circulating GH levels are elevated, and GH secretory dynamics are usually abnormal. The aim of our study was to investigate the effects of galanin on GH secretion in acromegalic subjects. Six acromegalic patients (four males and two females) and seven healthy adult subjects (five males and two females) underwent in randomized order: 1) iv infusion of 100 mL saline from 0-45 min, and 2) iv infusion of synthetic porcine galanin (0.5 mg in 100 mL saline) from 0-45 min. In normal subjects, peak GH levels after porcine galanin administration (8.2 +/- 1.9 micrograms/L) were significantly higher than after saline infusion (1.3 +/- 0.1 micrograms/L; P less than 0.05). In acromegalic patients, GH values fell from baseline (32.5 +/- 12 micrograms/L) to a mean nadir of 24.5 +/- 12.7 micrograms/L after galanin infusion. The mean change in GH values from baseline after galanin treatment in these subjects significantly differed from that observed after saline infusion from 15-90 min. Serum PRL levels were not significantly affected by galanin in either normal or acromegalic patients. Our results give the first evidence that the same dose of galanin, acting as a GH secretagogue in normal man, is, on the contrary, able to significantly inhibit GH in acromegalic patients. The cause of this paradoxical GH fall after galanin treatment in acromegaly remains to be explained. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.     

Usefulness of different biochemical markers of the insulin-like growth factor (IGF) family in diagnosing growth hormone excess and deficiency in adults.

The diagnostic approach to acromegaly and GH deficiency frequently includes measurement of several components of the insulin-like growth factor (IGF) system. IGF-I levels are reported to be good predictors of active and cured acromegaly, but are commonly found within the normal age-adjusted range in adult GH-deficient (GHD) patients. Circulating concentrations of IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and free IGF-I reflect the GH secretory status, but their diagnostic accuracy is still debated. In this study serum levels of total and free IGF-I, IGFBP-3, ALS, and IGFBP-3-IGF-I and IGFBP-3-ALS complexes were determined in patients previously diagnosed with active (n = 67) or inactive (n = 16) acromegaly and adult GHD (n = 34) and compared with results obtained in 58 healthy controls. In healthy subjects, IGF-I, IGFBP-3, ALS, and both IGFBP-3 complexes declined with age; a correlation was found between IGF-I and IGFBP-3 (r = 0.59; P < 0.001), ALS (r = 0.67; P < 0.001), and free IGF-I (r = 0.40; P < 0.05). Active acromegalic patients showed a significant increase in all parameters tested. IGF-I concentrations were above +2 SD in 100% of patients, whereas slightly lower sensitivities were shown for IGFBP-3 (85%), ALS (88%), and free IGF-I (94%). In this group, IGF-I exhibited a slightly higher correlation with IGFBP-3 (r = 0.83; P < 0.001) than with ALS levels (r = 0.78; P < 0.001). In cured acromegalic patients, we observed the normalization of all parameters but free IGF-I levels. Adult GHD patients showed a significant reduction of all hormones. Unlike active acromegalic patients, all parameters had only a modest sensitivity in GHD; suppression below -2 SD was observed in 41% of GHD patients for IGF-I, 47% for IGFBP-3, 32% for ALS, and 35% for free IGF-I measurements. Previous radiotherapy and GH peak response below 3 microg/L were associated with significantly lower IGF-I, IGFBP-3, and ALS levels. IGF-I levels were significantly correlated to ALS (r = 0.68; P < 0.001) and IGFBP-3 (r = 0.64; P < 0.001) as well as with free IGF-I (r = 0.67; P < 0.001) levels. By multiple regression analysis, the number of anterior pituitary hormones impaired was the most predictive indicator of IGF-I, IGFBP-3, and free IGF-I levels in GHD patients; conversely, the GH peak response better anticipated ALS concentrations. The pattern of IGFBP-3 complexes paralleled previous hormonal findings. In active acromegalic patients, IGFBP-3-IGF-I levels were 5.4-fold higher than in controls and were above +2 SD in 95% of patients, whereas IGFBP-3-ALS levels were elevated in 15% of cases. On the other hand, both IGFBP-3 complexes were able to predict GHD in only a minority of cases. Taken together, these data support the diagnostic role of IGF-I in acromegaly and suggest that free IGF-I and the IGFBP-3-IGF-I complex can assist diagnostic strategies in this condition. All markers are of limited predictive value in adult GHD, as hormonal values are commonly found within the normal limits. In these patients, low IGFBP-3 and IGF-I concentrations can add further clinical information on the residual GH activity.     

Urinary growth hormone (GH) measurements are useful for evaluating endogenous GH secretion

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.     

Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up

The biochemical diagnosis of acromegaly is conventionally based on elevated plasma GH levels that fail to suppress after an oral glucose load. We studied 16 newly diagnosed patients with acromegaly with normal mean plasma GH but elevated age and gender-adjusted plasma IGF-I concentrations (476 +/- 29 microg/liter, mean +/- SE). Plasma GH was sampled every 10 min for 24 h, and an oral glucose tolerance test was performed. The control group included 46 healthy subjects. All patients had 24-h mean GH values that overlapped with those of the healthy controls. Mean plasma GH was less than 2.5 microg/liter in 12 patients. Patients had higher 24-h nadir GH values than healthy controls (P < 0.001). During the oral glucose tolerance test, nadir plasma GH was less than 1 micro g/liter in eight patients. Plasma IGF-I normalized in 11 of 14 patients after transsphenoidal surgery. Four patients with normal IGF-I after transsphenoidal surgery were restudied. Mean and nadir GH decreased in all of them. In our experience in many patients with acromegaly, the diagnosis could be missed if only the existing GH-based criteria are used. Revised GH criteria in combination with plasma IGF-I should be used for the diagnosis and follow-up of acromegaly.     

Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by trans-sphenoidal surgery

It has been shown that GH excess is associated with decreased leptin levels and decreased body fat mass. Reports regarding the effect of GH on serum leptin levels are inconsistent. We studied leptin secretion in 20 acromegalics before and 2 months after trans-sphenoidal surgery and in 20 gender-, age-, and body mass index (BMI)-matched control subjects. The mean 8-h leptin concentration for each subject was measured from a pool formed of samples collected hourly beginning at 2200 h until 0600 h the next morning. In a subgroup of 10 acromegalics, leptin pulsatility was assessed for the same period of time in 10-min sampling intervals. Basal GH, insulin-like growth factor-I (IGF-I), insulin, glucose, and lipids levels were measured. Area under the curve for insulin (AUCins) during oral glucose tolerance test was calculated. Control subjects and acromegalics had similar BMI, but patients with active acromegaly had significantly lower mean leptin level (mean +/- SEM; in men, 2.6+/-0.4 vs. 7.1+/-1.1 microg/L, P = 0.003; in women, 16.0+/-3.4 vs. 23.5+/-3.1 microg/L; P = 0.036). Mean 8-h leptin correlated with BMI (r = 0.57, P = 0.007, in controls; r = 0.70, P = 0.001, in patients). In stepwise regression analysis with mean 8-h leptin as a dependent variable, BMI (P<0.001) and gender (P = 0.01) in acromegalics entered the equation, whereas in control subjects gender, free fatty acids, insulin, and age accounted for 99.3% in leptin variability. After surgery, BMI did not change significantly; and glucose (P = 0.014), GH (P<0.001), and IGF-I (P<0.001) levels together with AUCins (P = 0.002) decreased, whereas mean leptin concentration rose significantly and attained normal levels (4.1+/-0.8 microg/L, P = 0.028) in acromegalic men and (23.6+/-4.7 microg/L, P = 0.003) in acromegalic women. Correlation between leptin level and BMI was preserved after surgery (r = 0.62, P = 0.005). In stepwise regression analysis, free fatty acids (P = 0.04) contributed to 26.8% of the variance in corrected-leptin (for BMI and gender). Leptin concentration peak height and interpeak nadir level rose significantly (P = 0.033 and P = 0.037) after surgery by Cluster analysis, without significant changes in leptin pulse frequency and incremental peak amplitude. Nocturnal rise of leptin (mathematically described by a cubic curve) was characterized by an acrophase just after midnight, before and after surgery. The amplitude and the average leptin concentration of the cubic fit increased significantly after surgery (P = 0.028 and P< 0.001). In conclusion in acromegalic patients: 1) leptin secretion maintains the pulsatility and nocturnal rise; 2) the gender-based leptin differences are preserved; 3) GH-IGF-I normalization leads to a rise in leptin that is not related to changes in BMI; and 4) the possible role of rise in leptin levels when assessing clinical and metabolic outcome of therapy in acromegalic patients deserves additional studies.