Exercise-induced microalbuminuria in patients with active acromegaly: acute effects of slow-release lanreotide, a long-acting somatostatin analog.

Recent clinical studies have demonstrated an increase of urinary albumin excretion (UAE) at rest in acromegalic patients and, on the other hand, a reduced UAE in patients with growth hormone (GH) deficiency. Physical exercise is known to induce abnormal UAE in patients with diabetes, probably unmasking early glomerular alterations. The effect of exercise on UAE in acromegaly is not known. Moreover, the effect of acute but sustained GH inhibition in acromegaly on UAE at rest and after exercise has never been studied. The aim of our study was to evaluate the acute short-term effects of slow-release lanreotide (SR-L), a long-acting somatostatin analog, on UAE and alpha1-microglobulinuria (A-1-M), a marker of renal tubular damage, at rest and after exercise in 7 normotensive patients with active acromegaly and normal renal function (4 males and 3 females; mean age, 53 +/- 3.1 years; body mass index [BMI], 27.3 +/- 1.1 kg/m2) at baseline and 7 and 14 days after SR-L injection (30 mg). Two of the acromegalic patients were microalbuminuric at rest, and in other 3 cases, UAE was in the borderline range (10 to 20 microg/min). At baseline in the acromegalic subjects, we found a significant increase in UAE at rest with respect to 7 normal subjects considered as a control group. GH and insulin-like growth factor-1 (IGF-1) were also reduced compared with baseline 7 and 14 days after SR-L injection (GH, 13.4 +/- 7.3 and 13.61 +/- 7 v 18.5 +/- 9.3 microg/L, P < .05; IGF-1, 230 +/- 53 and 255 +/- 54 v 275 +/- 64 microg/L). Concomitantly, we observed a significant decrease of UAE at rest and after exercise and 7 and 14 days after SR-L injection as compared with baseline values (27.3 +/- 20.5 and 18.2 +/- 13.7 v 35.3 +/- 12.8 microg/min, P < .05; exercise, 48.5 +/- 24.1 and 18.6 +/- 6.8 v68.3 +/- 39.7 microg/min, P < .05). A-1-M always remained in the normal range (< 12 mg/L) both at rest and after exercise. We can thus conclude that in acromegaly, submaximal exercise induces abnormal increases in microalbuminuria. We hypothesize that this phenomenon may be due to the functional glomeruler involvement. SR-L can significantly reduce UAE at rest and after exercise in the short-term in acromegaly, probably via a decrease in circulating GH levels.

Growth hormone (GH) responses to GH-releasing hormone alone or combined with arginine in patients with adrenal incidentaloma: evidence for enhanced somatostatinergic tone.

Spontaneous and stimulated GH secretion is blunted in hypercortisolemic states due to increased hypothalamic somatostatinergic tone. However, no data are available on the characteristics of GH secretion in patients with incidentally discovered adrenal adenomas. They represent an interesting model for studying GH secretion, as a slight degree of cortisol excess may frequently be observed in such patients who do not present with any clear Cushingoid sign. In the present study, 10 patients (3 men and 7 women, aged 48-63 yr) with an adrenal mass discovered serendipitously underwent, on separate occasions, a GHRH injection alone or combined with an infusion of the functional somatostatin antagonist, arginine. Thirteen age-matched healthy volunteers served as controls. Briefly, arginine (30 g) was infused from -30 to 0 min, and GHRH (100 microg) was injected as a bolus at 0 min, with measurement of serum GH [immunoradiometric assay (IRMA)] every 15 min for 150 min. Plasma IGF-I (RIA after acid-ethanol extraction) was measured in a morning sample. The diagnosis of cortical adenoma was based on computed tomography features and pattern of uptake on adrenal scintigraphy. Patients with obesity and/or diabetes were excluded. The study design included also an endocrine work-up aimed to study the hypothalamic-pituitary-adrenal axis [urinary free cortisol (UFC) excretion, serum cortisol at 0800 h, plasma ACTH at 0800 h, morning cortisol after overnight 1 mg dexamethasone]. Five of 10 patients showed abnormalities of the hypothalamic-pituitary-adrenal axis, including borderline or increased UFC excretion in 4 of them accompanied by blunted ACTH in 2 cases and failure of cortisol to suppress after dexamethasone in 1; the fifth patient displayed low ACTH and resistance to dexamethasone suppression. However, all patients had a unilateral uptake of the tracer on the side of the mass with suppression of the contralateral normal adrenal gland. As a group, the patients displayed greater UFC excretion and lower ACTH concentrations than the controls. GH release after GHRH treatment was blunted in patients bearing adrenal incidentaloma compared with controls (GH peak, 5.7 +/- 5.2 vs. 18.0 +/- 7.0 microg/L; P < 0.0001), whereas GHRH plus arginine was able to elicit a comparable response in the 2 groups (GH peak, 33.5 +/- 20.3 vs. 33.7 +/- 17.5 microg/L; P = NS). The ratio between GH peaks after GHRH plus arginine and after GHRH plus saline was significantly greater in patients than in controls (751 +/- 531% vs. 81 +/- 45%; P = 0.0001). Similar data were obtained when comparing GH area under the curve after GHRH plus saline or GHRH plus arginine between the 2 groups. In summary, the present data suggest that in patients with incidental adrenal adenomas the GH response to GHRH is blunted due to increased somatostatinergic tone, as it can be restored to normal by pretreatment with the functional somatostatin antagonist arginine. The blunted GH release to GHRH may be an early and long lasting sign of autonomous cortisol secretion by the adrenal adenoma.

Long-term treatment with the dual antithromboxane agent picotamide decreases microalbuminuria in normotensive type 2 diabetic patients.

Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients.

Glutamate decarboxylase autoimmunity and growth hormone secretion in type I diabetes mellitus.

Insulin-dependent (type I) diabetic patients are known to have an exaggerated growth hormone (GH) response to GH-releasing hormone (GHRH), which is hypothesized to be due to a decrease in somatostatin tone. The aim of the study was to ascertain the influence of the presence and activity of the autoimmune process involving a key enzyme (glutamic acid decarboxylase [GAD]) in the synthetic pathway of a neurotransmitter regulating somatostatin secretion, ie, gamma-aminobutyric acid (GABA), on the GH response to GHRH alone or combined with an acetylcholinesterase inhibitor, pyridostigmine (PD), in patients with type I diabetes mellitus. Twenty non-obese type I diabetic patients and 17 normal subjects underwent an intravenous (IV) injection of 100 micrograms GHRH(1-29)NH2. Twelve of 20 diabetic subjects and all of the control subjects also underwent a second experimental procedure, administration of 120 mg oral PD 60 minutes before IV injection of 100 micrograms GHRH. Diabetic subjects with serum GAD antibody (GADA) levels more than 3 U (n = 10) showed significantly higher serum GH levels after GHRH injection as compared both with diabetic patients with GADA less than 3 U (n = 10) and with normal controls, whether expressed as absolute or peak values. GH peaks after GHRH were significantly (rs = .46, P < .05) correlated with the level of GADA in the whole population of type I diabetic subjects studied. PD significantly enhanced the GH response to GHRH, in terms of both absolute and peak values, in patients without GADA (n = 6) and in normal subjects. On the contrary, PD failed to enhance the GH response to GHRH in diabetic patients with GADA (n = 6). Our findings suggest that autoimmunity may play a key role in determining the exaggerated GH response to GHRH in type I diabetes mellitus. The mechanism underlying this effect is hypothesized to be the production of antibodies to GAD, a key enzyme in the synthesis of GABA, and in turn a reduced GABAergic stimulatory tone on somatostatin production at the hypothalamic level.

Reciprocal relationship between the level of circulating cortisol and growth hormone secretion in response to growth hormone-releasing hormone in man: studies in patients with adrenal insufficiency.

The aim of our study was to elucidate the relationship between the level of circulating cortisol and the GH responsiveness to GHRH in six hypoadrenal patients (one male and five females; age range, 35-67 yr; body mass index range, 18-31 kg/m2). Twenty-four hours after taking the last dose of replacement therapy, each patient underwent the following experimental trials on nonconsecutive days: 1) saline, and 2) 12.5 mg, or 3) 25 mg, or 4) 250 mg hydrocortisone hemisuccinate in 250 mL saline constant iv infusion from 0-180 min. On each occasion, 1 micrograms/kg human GHRH-(1-29)NH2 was injected as an iv bolus at 60 min. During GHRH and saline infusion, serum cortisol levels were always less than the detection limit of the assay (55 nmol/L). During 12.5-, 25-, and 250-mg hydrocortisone infusions (from 15-180 min), serum cortisol averaged 413.8 +/- 19.3, 772.5 +/- 46.9, and 1520.2 +/- 110.4 nmol/L, respectively. The GH peaks after GHRH treatment during the various infusions of hydrocortisone were compared to the GH peaks observed after saline, which were normalized to 100% in each subject. GH peaks after GHRH and 25 mg hydrocortisone (70 +/- 11%) and GHRH and 250 mg hydrocortisone (69 +/- 7%) were significantly (P < 0.05) lower than the GH peaks after GHRH and saline or GHRH and 12.5 mg hydrocortisone (83 +/- 15%). No significant differences were observed between the GH peaks after GHRH and 12.5 mg hydrocortisone or GHRH and saline. Our data demonstrate that in hypoadrenal patients, the acute absence of circulating cortisol does not impair the GH secretory response to GHRH with respect to the eucortisolemic state. Moreover, our data suggest that 700 nmol/L is the approximate threshold serum cortisol concentration above which a decrease in the GH responsiveness to GHRH is observed in humans. Further increases in serum cortisol levels above this threshold value do not cause a proportional decrease in the GH responsiveness to GHRH.

Effect of the combined administration of galanin and clonidine on serum growth hormone levels in normal subjects and in patients under chronic glucocorticoid treatment.

Aim of our study was to investigate the effect of clonidine and galanin (alone or in combination) on growth hormone (GH) secretion in normal subjects and in adult patients with increased somatostatin tone due to chronic daily immunosuppressive glucocorticoid treatment. We studied 7 adult patients undergoing long-term (no less than 6 months) immunosuppressive glucocorticoid treatment for non endocrine diseases (4F, 3M; age 49.7 +/- 6.3 years). Six normal adult nonobese subjects (3F, 3M; age 34 +/- 2.7 years) served as controls. All subjects underwent the following three tests in random order: 1) iv infusion of clonidine, 150 micrograms in 10 mL of saline, from time 0 to 10 min; 2) iv infusion of synthetic porcine galanin, 500 micrograms in 100 mL of saline from -15 to 30 min; 3) iv infusion of clonidine from 0 to 10 min combined with synthetic porcine galanin iv infusion from -15 to 30 min. Blood samples for GH assay were taken at -15, 0, 15, 30, 45, 60, 90, 120 min. No significant differences in GH absolute values were observed at any time between the three different tests within each group of subjects. Normal subjects showed significantly (p < 0.05) higher GH peaks and GH absolute values from 15 to 90 min after galanin alone, clonidine alone and clonidine+galanin with respect to the glucocorticoid-treated patients. The absence of any either synergistic or at least additive effect on GH secretion of galanin and clonidine in conditions of both normal and increased somatostatin tone suggests that also in man, as well as in the rat, the action of galanin on the GH axis may be mediated through alpha-adrenergic pathways.

Effect of long-term administration of picotamide on baseline and exercise-induced urinary albumin excretion in patients with type II diabetes mellitus and incipient nephropathy.

The present pilot study investigated the effect of long-term treatment with picotamide on baseline and exercise-induced urinary albumin excretion levels in normotensive patients with type II diabetes mellitus. Six patients with type II diabetes were studied: four patients (two men and two women; mean age, 52 +/- 11 years) were treated for 9 months with picotamide (300 mg, TID) and two patients who did not receive the study medication served as controls. Three of the picotamide-treated patients were given a cycloergometric exercise test at baseline and after 3 and 6 months of therapy to evaluate the effects of the drug on exercise-induced microalbuminuria. Microalbuminuria at rest was measured in all patients at baseline and after 3, 6, and 9 months. At the end of the study, all the picotamide-treated patients demonstrated a significant decrease in microalbuminuria at rest (from 41.7 +/- 12.7 micrograms/min at baseline to 11.8 +/- 3 micrograms/min after 9 months) and after exercise (peak at baseline 103 +/- 36 micrograms/min vs 65.8 +/- 11 micrograms/min after 6 months). Conversely, in the two controls, microalbuminuria at rest increased from 45.1 +/- 0.9 micrograms/min at baseline to 151 +/- 59 micrograms/min at the end of the 9-month study period. (All values given as mean +/- SEM.) In conclusion, long-term administration of picotamide was effective in reducing abnormal exercise-induced microalbuminuria and albuminuria at rest. These findings suggest that long-term treatment with picotamide of normotensive patients with type II diabetes mellitus and incipient nephropathy may slow the progression of the nephropathy in its early stages.

Effects of metoclopramide on the paradoxical growth hormone response to galanin in acromegaly.

Galanin is able to enhance growth hormone (GH)-releasing hormone stimulated GH secretion in normal man. In acromegaly circulating GH levels are elevated and the GH response to GHRH may be exaggerated. Galanin has been recently shown to decrease circulating GH levels in acromegaly. Dopaminergic drugs were the only previously known agents able to cause a paradoxical GH fall in acromegaly. Aim of our study was to investigate the effects of a potent central dopaminergic receptor blocker, metoclopramide (MCP), on the galanin-induced paradoxical GH secretion in acromegalic subjects. Two male and three female patients with active acromegaly (age range 44-66 years, body mass index range 24.6-28 Kg/m2) were studied after 45 min i.v. infusion of porcine galanin (0.5 mg in 100 ml of saline) from 0 to 45 min combined with a 60 min i.v. infusion of a) saline (100 ml) or b) MCP (10 mg in 100 ml of saline) from -15 to 45 min. After galanin, GH values fell from baseline (27.5 +/- 10 micrograms/L) to a mean nadir of 16.4 +/- 6.1 micrograms/L; after galanin + MCP, circulating GH levels were also decreased (mean nadir 17.3 +/- 8.1 micrograms/L) in all the patients with respect to baseline (23.6 +/- 9.7 micrograms/L). No significant differences were found in absolute or percent of baseline GH levels after galanin+saline vs galanin + MCP. Our results suggest that the paradoxical GH fall after galanin in acromegalic patients is not mediated through dopaminergic receptor. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.

Variability in the growth hormone response to growth hormone-releasing hormone alone or combined with pyridostigmine in type 1 diabetic patients.

In man the GH response to GHRH is variable within and between subjects. Pyridostigmine (PD), an acetylcholinesterase inhibitor, has been shown to reduce the variability of the GH response to GHRH in normal subjects. The aim of this study was to assess the existence of either inter- or intraindividual variability in the GH response to GHRH in type 1 diabetic patients. Moreover, we investigated the effect of PD on such variability in the same patients. Seven (4 females-3 males) nonobese type 1 diabetic patients underwent two experiments performed in consecutive days according to a single-blind protocol: 1) 120 mg oral PD 60 min before iv injection of human (h) GHRH-(1-29) NH2, 100 micrograms in 2 ml of sterile water; 2) oral placebo 60 min before iv injection of 100 micrograms hGHRH. The two experiments were then repeated, following the same procedure, one and two weeks after the start of the study. The GH peaks after GHRH were variable within different subjects but also in the same subject on different occasions. However, the mean GH peak levels after GHRH in the three tests were not significantly different (14.2 +/- 3.5, 15.3 +/- 3, 16.5 +/- 6.4 micrograms/L, respectively), the coefficient of variation for each test was 65%, 51.8%, 102.4%, respectively (mean 73.1 +/- 15.1%). The GH response to GHRH was always significantly enhanced by PD administration: the mean GH peak levels in the three tests were 31.9 +/- 7.1, 44.8 +/- 10.4, 49.9 +/- 13.1 micrograms/L, respectively, without significant differences between tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine blocks the inhibitory effect of hydrocortisone on circulating growth hormone levels in patients with acromegaly.

In patients with acromegaly, circulating growth hormone (GH) levels and GH responses to GH-releasing hormone (GHRH) are decreased by long-term administration of pharmacological doses of glucocorticoids. The aim of our study was to investigate the acute effects of intravenous (i.v.) infusion of hydrocortisone combined either with saline or arginine infusion on circulating GH levels in acromegaly. We studied five adult patients with acromegaly, two men and three women aged 54.6 +/- 4 years having a body mass index of 25.9 +/- 1.2 kg/m2. On two randomized occasions, patients underwent a bolus i.v. injection of 100 mg hydrocortisone succinate at time 0 followed by a 120-minute i.v. infusion of 250 mg hydrocortisone in 250 mL saline, combined with a 90-minute (from -15 to 75 minutes) i.v. infusion of (1) 60 g arginine hydrochloride in 200 mL saline, or (2) 200 mL saline. In all of the acromegalic patients during the infusion of hydrocortisone alone, serum GH levels clearly decreased (nadir range, 26.4% to 68.1%) with respect to GH levels before hydrocortisone administration (mean of time -15 and 0, basal level), with a nadir between 90 and 180 minutes after the beginning of the infusion. After arginine pretreatment, GH levels were significantly enhanced compared with levels attained with hydrocortisone saline, and they were also significantly increased (peak, 167.5% +/- 27.7%) with respect to basal levels. Our data show that arginine blocks the inhibitory effect of acute and sustained hypercortisolism on circulating GH levels in acromegaly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of galanin on the growth hormone (GH) response to GH-releasing hormone in patients with Cushing's disease.

Attenuated plasma GH secretion during sleep and blunted GH responses to provocative stimuli have been observed in patients with Cushing's disease. Synthetic porcine galanin elicits GH secretion when given alone, and enhances the GH response to GHRH in normal human subjects. The aim of our study was to investigate the effects of galanin on the GH response to GHRH in patients with Cushing's disease. We studied 5 female subjects with untreated active Cushing's disease caused by micro-pituitary adenomas (age 43 +/- 6.7 years; BMI 30 +/- 0.7 kg/m2). Four normal adult females, matched for age and body weight with the patients with Cushing's disease, were studied as controls. Subjects underwent in random order: (1) infusion of synthetic porcine galanin IV, 500 micrograms in 100 mL; (2) infusion of saline, IV, 100 mL. A bolus of human GHRH(1-29)NH2 (Geref, Serono, Italy), 100 micrograms in 1 mL saline, was injected IV at 0 minutes. Patients with Cushing's disease showed blunted GH peaks after GHRH (1.2 +/- 0.4 micrograms/L) during saline infusion, as compared to normal controls (24.6 +/- 4.6 micrograms/L; p < 0.05). During galanin infusion a significantly enhanced GH response to GHRH, as compared with saline infusion, was observed in control subjects (GH peak: 51.4 +/- 9.8 micrograms/L; p < 0.05), but not in patients with Cushing's disease (GH peak: 2.3 +/- 0.6 micrograms/L). GH levels were significantly lower both after saline and after galanin in patients with Cushing's disease as compared to normal controls. Our data demonstrate that galanin is not able to enhance the GH response to GHRH in patients with Cushing's disease. That galanin cannot reverse this effect suggests that the mechanism of action of galanin is not via a decrease in somatostatin release by the hypothalamus.

Isradipine decreases exercise-induced albuminuria in patients with essential hypertension.

The aim of our study was to investigate the effects of exercise on albuminuria and blood pressure in patients with essential hypertension, and the short-term effect of the calcium channel blocker isradipine on exercise-induced albuminuria (UAE) and blood pressure in the same patients. Ten patients (7 males, 3 females) with essential hypertension were admitted to the study. The mean age was 54 +/- 2.7 years and the mean body mass index was 27 +/- 1 kg/m2. Patients performed two physical exercise tests on a cycloergometer. Workload was increased by 30 watts every 2 min until 90% of the theoretical maximal heart rate was achieved. This workload was maintained for 5 min. Samples for albuminuria assay were collected at the end of exercise and 1 h after exercise. The first physical exercise test was performed after 15 days of placebo washout; the second exercise was performed after 10 days of therapy with isradipine 5 mg once daily p.o. After 10 days of therapy with isradipine, UAE immediately after (31 +/- 8.3 micrograms/min) and 1 h after exercise (31.5 +/- 7.3 micrograms/min) were significantly (p < 0.05) lower as compared to the values found after placebo (37.1 +/- 9.3 micrograms/min; 43.5 +/- 9.9 micrograms/min). Our data show that short-term administration of the calcium channel blocker isradipine is able to cause a concomitant significant decrease in exercise-induced pressor and albuminuric response in patients with essential hypertension. The finding that short-term calcium channel blockade can reduce exercise-induced albuminuria in essential hypertensive patients suggests that progression of nephropathy in this early phase could be slowed by isradipine in these patients.

Picotamide, a dual TXB synthetase inhibitor and TXB receptor antagonist, reduces exercise-induced albuminuria in microalbuminuric patients with NIDDM.

We investigated the short-term effect of the TXB inhibitor picotamide on albuminuria induced by exercise in 15 microalbuminuric (i.e., with UAE at rest between 20 and 200 micrograms/min) type II diabetic patients (12 men and 3 women, age 56 +/- 2, BMI 28 +/- 1 kg/m2) and in six normal age-matched control subjects. The diabetic subjects performed five submaximal exercise tests (90% of theoretical heart rate) on a cycle ergometer: the first two under basal conditions; the third and fifth after subjects had received picotamide (900 mg/day) or placebo (3 tablets/day) for 10 days; the fourth exercise always was performed after 10 days of wash-out. Control subjects performed two exercises: the first in baseline conditions and the second after 10 days of picotamide administration (900 mg/day). When diabetic patients were untreated, a significant (P < 0.05) increase in UAE with respect to baseline levels was observed immediately after and 1 h after the exercise test. After picotamide administration, UAE significantly decreased (P < 0.05) immediately after and 1 h after exercise, as compared with diabetic patients given a placebo. In normal subjects, exercise was followed by a slight increase in UAE, which was not significantly affected by picotamide administration. Our results show that short-term administration of picotamide is associated with a reduction in UAE after exercise in type II diabetes patients with microalbuminuria while at rest. Picotamide, a TXB synthetase and receptor inhibitor, may decrease exercise-induced albuminuria in diabetic patients through a reduction in circulating TXB levels and inhibition of TXB action, which in turn may act by lowering glomerular capillary hydraulic pressure.