GH Hypersecretion Research Articles

Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly.

Pituitary irradiation suppresses GH hypersecretion in patients with acromegaly. Within 10 yr after radiotherapy, up to 80% of patients achieve plasma GH levels below 5 micrograms/L. Whether this is sufficient to normalize plasma insulin-like growth factor I (IGF-I) levels, is unknown. We examined the effect of radiotherapy on plasma IGF-I concentrations in patients with acromegaly. We reviewed hospital charts of 140 patients with acromegaly seen in our institution between 1975 and 1996. Data on plasma GH and IGF-I were extracted and tabulated longitudinally together with the information about the concomitant medical therapy. We included data from the patients who received radiotherapy as a part of their treatment and whose IGF-I was monitored for more than 1 yr afterward. To avoid the potential bias, the data for patients who were referred to us for medical therapy, having failed radiation elsewhere, were excluded. A total of 38 datasets were submitted for the final analysis. The average follow-up was 6.8 +/- 0.8 yr (range, 1-19). Only 2 patients achieved age- and sex-adjusted normal IGF-I levels while off medical therapy. Noncured patients had a mean plasma GH level of 4.6 +/- 1.1 micrograms/L but still elevated plasma IGF-I levels (219 +/- 26% of the upper normal limit) at the last follow-up visit. A random GH concentration below 1.5 micrograms/L was associated with a pathologically high plasma IGF-I concentration in 43% of instances. Radiotherapy appears to be ineffective in normalizing plasma IGF-I levels in acromegaly. A multicenter study to reevaluate the future use of this modality in patients with acromegaly is warranted.

The thyroid gland in acromegaly: an ultrasonographic study.

An association between acromegaly and goitre is well recognized. We have studied the incidence and morphology of goitre in acromegaly, and examined the role of IGF-I and TSH in goitre pathogenesis. Thirty-seven subjects with acromegaly, active or in remission, were assessed by ultrasound to determine thyroid volume (TV) and morphology, and compared with normal controls. Nine subjects with acromegaly were also studied again following treatment with octreotide for 1 year. Compared with controls, TV was greater (28.7 +/- 18.3 ml vs 5.4 +/- 2.6 ml, P < 0.001) and IGF-I levels were higher (62.0 +/- 34.8 nM vs 28.9 +/- 10.9 nM, P < 0.001) in subjects with acromegaly. Those with active disease tended to have larger glands (30.0 +/- 17.2 ml vs 22.2 +/- 16.7 ml, P = 0.18). The overall incidence of goitre was 92%. Twenty-seven subjects (73%) had nodules or heterogeneous thyroid echotexture. Subjects with nodular goitre had a longer duration of acromegaly than those with homogeneous glands (12.1 +/- 5.7 vs 7.6 +/- 4.0 years, P = 0.032). Those with nodular glands also had larger goitres than those with homogeneous glands (35.2 +/- 18.8 ml vs 19.5 +/- 11.9 ml, P = 0.032). Thyroid volume correlated with IGF-I levels (r2 = 0.38, P = 0.002) and body mass index (r2 = 0.24, P < 0.001), and there was an inverse relationship with TSH levels (r2 = 0.46, P = 0.032). Patients studied again after treatment with octreotide for 1 year had a reduction in TV from 32.6 +/- 16.1 to 27.6 +/- 17.0 ml (P = 0.041). This study confirms that goitre is a common finding in acromegaly. Our findings suggest that early in the course of the disease, diffuse goitre occurs. Subsequently, thyroid autonomy and nodule formation develop, and further growth may occur independent of TSH. With control of GH hypersecretion, a reduction in thyroid size occurs, but this may be limited by the extent of thyroid nodularity.

Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic hypertension?

To evaluate the relative contributions of past or present GH hypersecretion and of hypertension to the cardiac abnormalities present in acromegaly, we have studied the serum GH and insulin-like growth factor I concentrations, systolic and diastolic blood pressures, and morphological and functional cardiac indexes as measured by echocardiography-Doppler, in 39 patients with active or cured acromegaly, 16 hypertensive controls, and 17 normotensive controls. Hypertension was present in 42.8% of patients with active acromegaly and in 28.0% of patients in which acromegaly was cured. Hypertension was independently related to an increase in indexes of cardiac morphology (left ventricular mass, left ventricular posterior wall thickness, interventricular septum thickness, relative wall thickness with respect to the diastolic diameter of the left ventricle, and left atrial end-systolic diameter), systolic function (stroke volume, fractional shortening, and end-systolic stress), and diastolic function (isovolumic relaxation time and maximal late diastolic flow velocity) and to a reduction in the early to late maximal diastolic flow velocity ratio. Acromegaly was related to an increase in left ventricular mass, stroke volume, cardiac output, and isovolumic relaxation time, which were independent from the presence of hypertension. End-systolic stress was reduced by acromegaly. In the five patients in which active acromegaly was successfully treated, left ventricular mass and left ventricular posterior wall thickness were reduced 1 yr later. In conclusion, the asymptomatic morphological and functional cardiac abnormalities present in acromegalic patients are independently related to acromegaly and hypertension, pointing to the existence to a specific acromegalic myocardiopathy that might be aggravated by the coexistence of hypertension.

Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide.

Somatostatin analogs are an alternative treatment to pituitary surgery and radiotherapy in acromegalic patients. Recently, a depot long-lasting formulation of slow release (SR) lanreotide has been shown to be effective in the short-term control of GH hypersecretion in acromegalic patients. We report the long-term follow-up of a cohort of 22 acromegalic patients treated with SR lanreotide during 1-3 yr. Thirteen females and 9 males, age 51 +/- 3 yr, presented with macroadenomas (n = 12), microadenomas (n = 8), or empty sella (n = 2). Seven patients previously had undergone a partial surgical removal of their adenomas, and 21 of them had mean plasma GH levels less than 5 micrograms/L during a previous octreotide treatment. According to GH values recorded after 3 months of twice monthly 30 mg SR lanreotide im injection, SR lanreotide was administered every 14 days (n = 13) or every 10 days (n = 9). At the 6-month visit, mean GH values were 5 micrograms/L or less in 68% and 2.5 micrograms/L or less in 27% of patients, and these results remained unchanged during the 1-3 yr follow-up period. During SR lanreotide treatment, the mean insulin-like growth factor I (IGF-I) concentrations remained in the normal range in 63% of patients. No escape from the treatment occurred in any of the cases. A significant decrease of the pituitary tumor volume was observed in 3 (13%) patients. The main side effect consisted of minor digestive problems during 48 h after each injection and was reported by 13 patients. Biannual gallbladder echographies revealed the occurrence of gallstones in 4 (18%) patients. In conclusion, these data confirm the efficacy and the tolerance of the long-term SR lanreotide administration (30 mg im every 10-14 days) in the control of acromegaly.

Somatostatin, growth hormone, insulin-like growth factor-1, and diabetes: Friends or foes?

Major findings with regard to the somatostatin-growth hormone (GH)-insulin-like growth factor (IGF-1) axis and diabetes are summarized. GH hypersecretion and reduced circulating IGF-1 levels are prevalent in insulin-dependent diabetes. Somatostatin improves metabolism in insulin-dependent diabetics. Insulin resistance and poor metabolic regulation, which may partly be due to hypersecretion of GH, are believed to accelerate the development of diabetic angiopathy. Diabetic hypersomatotrophinemia may be due to hepatic resistance to GH and increased hepatic production of IGF-1-binding protein-1 (IGFBP-1), leading to reduced levels of circulating IGF-1 and further stimulation of GH production. Studies in vitro and in diabetics suggest a causal link between diabetic hypersomatotrophinemia and diabetic angiopathy. In vitro evidence for the involvement of IGF-1 in diabetic angiopathy is reviewed. Also reviewed is evidence, from rat and human studies, of the possible involvement of GH and IGF-1 in diabetic nephropathy. The role of somatostatin in late diabetic vascular complications remains to be elucidated.

Heterogeneous responses to the long-term treatment of active acromegaly with octreotide.

To study GH response to the long-acting somatostatin analogue, we treated 11 actively acromegalic patients with octreotide (Sandostatin), 100 micrograms, sc, tid, for six months. Their endocrinological outcomes and clinical improvements varied. The 11-h GH secretory profiles on pretreatment day confirmed the hypersecretion of GH in all patients. Three hours after the first dose of octreotide, serum GH declined rapidly to levels below 5 ng/ml in all but two patients who failed to normalize their serum GH. In spite of the subsequent doses, there was no further suppression in serum GH. Drug resistance with GH rebound developed in some patients after three months of continued treatment. The paradoxical serum GH rises in response to oral glucose or iv TRH detected before the treatment in all patients attenuated or disappeared after the 6-month octreotide therapy; an exceptional case was one of the above-mentioned two patients, whose serum GH was stimulated more than before by glucose and TRH at the end of therapy. Serum insulin-like growth factor I (IGF-I) levels of all patients showed a significant reduction after 6-month treatment, but their mean values remained abnormally high. There were no intolerable adverse side effects; some patients, however, experienced pain at the injection site, passage of loose stool, and incidence of new gall stone or intrahepatic lesions on octreotide therapy. We concluded that octreotide was a useful long-term adjunctive therapeutic agent for patients with active acromegaly, but that a high degree of response heterogeneity including total refractoriness would be expected.

Effects of growth hormone overproduction on grip strength of transgenic mice

Growth hormone (GH) is used by athletes like bodybuilders to increase muscle strength and weight gain. On the other hand, chronic hypersecretion of GH in active acromegaly may result in outwardly hypertrophied but functionally weaker muscles. As a model for studying long-term effects of GH on muscle strength, we analysed transgenic mice (TM) carrying rat phosphoenolpyruvate carboxykinase-bovine GH (PEPCKbGH) fusion genes, which are expressed in liver and kidney but not in skeletal muscle. Circulating GH levels in TM ranged between 0.5 and 3 micrograms/ml, resulting in increased (p < 0.001) body weight (wt) as well as increased (p < 0.01) weights of forelimb and hindlimb muscles. However, muscle weight/body wt ratios of TM were 16-20% smaller than in controls (p < 0.05). Forelimb grip strength of hemizygous TM (16 males, 132 +/- 45 days old, body wt = 56.8 +/- 8.3 g; 32 females, 146 +/- 38 days old, body wt = 54.9 +/- 6.1 g) and non-transgenic controls (28 males, 127 +/- 47 days old, body wt = 40.5 +/- 2.9 g; 33 females, 126 +/- 47 days old, body wt = 32.1 +/- 3.6 g) was determined using an automated grip strength meter. Data were computed by analysis of variance, taking into account effects of group, sex and age. Least-squares means estimated for the grip strength (N) of male TM (1.91) and controls (1.92) were significantly (p < 0.05) greater than those of female TM (1.78) and controls (1.61). A significant difference between groups was only seen in females (p < 0.01). Least-squares means estimated for grip strength/body wt ratios (N/10 g) of male (0.34) and female TM (0.33) were 29% and 35% lower than those of male (0.48) and female controls (0.51), respectively (p < 0.001). In summary, long-term elevated GH levels in TM increased muscle weight less efficiently than body weight, and muscle strength did not increase proportionally with muscle weight.

Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion

Diagnosis of ectopic acromegaly was made in a 21-year-old female patient who 3 years before had undergone a right pneumectomy for a disseminated bronchial carcinoid. Plasma growth hormone-releasing hormone (GHRH) concentrations were markedly elevated (6440 ng/l; normal value < 100 ng/l), as were serum GH (187 micrograms/l; normal < 5 micrograms/l) and plasma insulin-like growth factor I (IGF-I) levels (6.7 U/ml; normal < 2 U/ml). Retrospective immunohistochemical examination of the carcinoid tumor was positive for GHRH and the tumoral content of GHRH was 2130 ng/g wet weight. Subcutaneous treatment with octreotide was begun and first resulted in a profound inhibition of GH hypersecretion, normalization of plasma IGF-I and only partial reduction of GHRH concentrations. However, the initial dose of 3 x 100 micrograms had to be increased gradually to 4 x 750 micrograms because of a progressive deterioration of the hormonal control. After 15 months of intermittent therapy, octreotide was administered by continuous sc infusion. This treatment improved compliance, allowed the daily dose of octreotide to be reduced to 1500 micrograms and normalized serum GH levels. A near-normalization of the plasma IGF-I concentrations was also obtained, whereas the suppression of plasma GHRH concentrations remained incomplete. Despite favorable evolution of the endocrine parameters, intramedullar metastases were diagnosed and required radiation therapy. This observation emphasizes the superiority of continuous over intermittent administration of octreotide in the treatment of ectopic acromegaly. It also shows that the somatostatin analog acts more at the pituitary level to inhibit GH secretion than at the site of the neuroendocrine tumor.

Stratégie d'exploration des états d'hypersécrétion d'hormone de croissance

GH secretion is épisodic in humans. Isolated plasma concentrations thus cannot be used to diagnose excess secretion. Assays on GH secretion require repeat determinations of plasma levels over extended 24 h periods. In so-called conjunctive GH hypersecretion conditions (denutrition, critical states), excessive GH secretion is associated with resistance to this hormone, as indicated by a decrease in plasma IGF-I concentrations. In contrast, IGF-I concentrations are high and correlated with GH levels during permanent GH hypersecretion that occurs in acromegaly. Testing for this disorder will vary according to the clinician's objectives.

Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: Dynamic endocrine studies and treatment with the somatostatin analogue octreotide

Acromegaly and hyperprolactinemia have been described in association with polyostotic fibrous dysplasia; the pathogenetic mechanisms involved in the development of the endocrinopathies is unknown. We report a 26-year-old man with polyostotic fibrous dysplasia and hypersecretion of GH and PRL. Plasma GH, PRL, and insulin-like growth factor-I (IGF-I) were elevated. Glucose-non-suppressible plasma GH concentrations, GH responsiveness to TRH and GHRH, and GH suppression after a test-dose of somatostatin, octreotide, and bromocriptine were found. Plasma GHRH levels were within the normal range (< 25 ng/l). Computed tomography of the sella turcica and visual fields were normal. [111In-DTPA-D-Phe1]-octreotide scintigraphy were used to localize a possible tumor; no radioactivity was visualized at the site of the hypothalamus, the pituitary or elsewhere in the body but a considerable accumulation of radioactivity was found in the os frontalis. Therapy with octreotide by continuous sc infusion partially suppressed GH and IGF-I (and normalized PRL). The results suggest that hypersecretion of GH in our patient is not due to a GH-secreting pituitary tumor, eutopic or ectopic hypersecretion of GHRH or autonomous somatotroph function. The origin of the disease in this patient might be an abnormal hypothalamic regulation of somatotrophs and/or an alteration in the transmembrane signalling systems.

Progestin-induced growth hormone excess in the dog originates in the mammary gland.

In the dog endogenous progesterone and synthetic progestins may incite overproduction of GH, resulting in acromegaly and insulin resistance. This progrestin-induced excessive GH secretion is characterized by disappearance of the pulsatile secretion pattern and insensitivity to both stimulation with GHRH and inhibition with a somatostatin analog. This progestin-induced GH hypersecretion is not associated with neoplastic transformation at the pituitary level. These observations were the impetus for a search of a possible extrapituitary site of GH production. In four ovariohysterectomized dogs elevated plasma GH levels (46.5 +/- 7.7 micrograms/liter; mean +/- SEM) were induced by administration of synthetic progestins. In these dogs hypophysectomy did not led to a significant decrease in plasma GH levels. Analysis of the GH content of various tissue homogenates revealed that the highest GH immunoreactivity was found in extracts of the mammary gland. Ectopic production of GH in the mammary gland was confirmed by lowering of plasma GH concentration to values within the reference range within 2 h after complete mammectomy in two dogs with progestin-induced elevations of plasma GH levels. In one of these dogs the arterial and elevations of plasma GH levels. In one of these dogs the arterial and venous GH concentrations across the mammary gland were measured and an arterio-venous GH gradient was demonstrated. Displacement studies in the RIA and analysis by reversed-phase HPLC revealed that mammary-derived GH is highly similar to pituitary-derived GH. Immuno-histochemical staining revealed that GH immunoreactivity was localized in focal areas of hyperplastic ductular epithelium. In mammary tissue of healthy untreated female dogs no GH immunoreactivity was found. It is concluded that treatment of dogs with synthetic progestins can induce the overproduction of GH in the mammary gland. This GH is biologically active, highly similar to pituitary derived GH, and originates from foci of hyperplastic ductular epithelium of the mammary gland.

Glomerular hyperfiltration in insulin-dependent diabetes mellitus is correlated with enhanced growth hormone secretion.

Enhanced GH secretion and hyperglycemia are suggested to play a role in the pathogenesis of glomerular hyperfiltration in insulin dependent diabetes mellitus. In this study we measured the GH response to GHRH (1 microgram/kg body weight), metabolic control, and renal function in 44 patients in order to explore a possible association between these parameters. Hyperfiltration [glomerular filtration rate (GFR) > 130 ml/min/1.73 m2] was present in 21 patients and normofiltration in 23. The duration of diabetes, plasma concentrations of renin, catecholamines, insulin-like growth factor-1 and blood glucose during renal function measurements were not different. GH response was significantly higher in patients with hyperfiltration. There was a positive relation between GH response and GFR (r = 0.51, P < 0.001) and effective renal plasma flow (r = 0.39, P < 0.01). GFR was correlated with insulin dose (r = 0.48, P < 0.001). There was no difference in glycosylated hemoglobin between the two groups. Patients with hyperfiltration used more insulin, had more frequent blood glucose values below the threshold level for activation of GH secretion, and had greater glycemic excursions than patients with normofiltration. The results suggest that GH hypersecretion and glomerular hyperfiltration are related and they support the possibility of a linkage between GH hypersecretion and glucose variability.

The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes.

GH hypersecretion in insulin-dependent diabetes (IDDM) is well documented. Although it has recently been shown that residual insulin secretion determines the magnitude of this GH hypersecretion, the underlying mechanisms of the disorder have not yet been clarified. The 24-h GH and blood glucose profiles, insulin-like growth factor I (IGF-I) concentrations and GH responses to GRF were analyzed in 21 insulin-dependent diabetics and 4 healthy subjects before and after 7 days treatment with recombinant human GH (rhGH) (4 IU given sc at 0800 h). According to C-peptide response to glucagon IDDM patients were subdivided into C-peptide negative (CpN, n = 12) patients without endogenous pancreatic beta-cell activity and C-peptide positive (CpP, (n = 9) patients with endogenous insulin secretion. No significant difference could be observed between the mean 24-h blood glucose profile before and after rhGH treatment in any treated group. Before and on rhGH treatment the highest 24-h GH values were observed in CpN patients when compared to CpP and controls. The rhGH treatment induced a similar increase in the mean 24-h GH concentrations in all groups studied which was statistically significant only in CpP diabetics. Mean pretreatment serum IGF-I concentrations were not significantly different between CpN, CpP patients and controls. The net increase in IGF-I concentrations after rhGH treatment was however, significantly lower in CpN patients than in CpP and control subjects. GRF-induced GH response before and after rhGH treatment was significantly greater in diabetics than in controls. The response of GH to GRF in CpN diabetics was however, almost unchanged after treatment whereas it became lower in CpP diabetics and controls. The dose of 4 IU of rhGH increased significantly GH levels in diabetics with preserved beta-cell function with consequent increase in IGF-I levels and attenuation of GRF induced GH response. In contrast, the same dose of rhGH failed to induce significant increase in GH levels in diabetics without residual beta-cell activity, most probably due to already high pretreatment levels. In addition, neither increase in IGF-I levels nor suppression of GH response to GRF on rhGH treatment was observed in CpN diabetics. The results are in keeping with an important role of portal insulin in GH-induced hepatic IGF-I secretion.

Short term pirenzepine treatment is ineffective in suppressing 24-h growth hormone secretion in type 1 diabetes mellitus

Large doses of pirenzepine given at bedtime suppress nocturnal GH secretion and abolish dawn phenomenon. As GH suppression may be beneficial in diabetic subjects we have investigated the effect of routine doses of pirenzepine on GH secretion in 9 type 1 diabetics. In the acute study pirenzepine 20 mg i.v. administered 15 min before GHRH 80 μg i.v. completely inhibited GHRH-induced GH response and the peak GH values were reduced from 66.3 to 9.2 ng/ml, P < 0.005. In the chronic study pirenzepine was given in a daily dose of 75 or 150 mg for 4 days and GH was measured hourly during 24-h study before and on the fourth day of pirenzepine administration. GH secretion calculated as area under curve (AUC) was not affected by pirenzepine and the values of AUC were: 139 ng/ml per h (the control 24-h study) and 123 ng/ml per h (pirenzepine 75 mg) and 303 ng/ml per h (pirenzepine 150 mg). Mean plasma glucose was not changed by pirenzepine. GH secretion calculated as AUC and mean 24-h GH level did not correlate with metabolic control of diabetes assessed by HbA 1. It is concluded that routine doses of pirenzepine do not suppress GH hypersecretion in type 1 diabetic subjects and therefore this agent does not seem suitable for the purpose of 24-h GH suppression in type 1 diabetes mellitus.

Regulation of pulsatile growth hormone secretion by fasting in normal subjects and patients with acromegaly.

In acromegaly, GH hypersecretion occurs despite elevated insulin-like growth factor-I (IGF-I) levels, implying defective IGF-I feedback. To study the possible mechanisms of defective IGF-I negative feedback in acromegaly, we assessed parameters of pulsatile GH secretion during fasting-induced decrease in plasma IGF-I. Seven patients with active acromegaly and six normal controls were fasted for 6 days and GH secretory profiles were obtained by frequent (every 10 min) blood sampling for 24 h and analyzed by Cluster. Fasting resulted in similar decreases in IGF-I, body weight, and blood glucose levels, and increases in free fatty acid and beta-hydroxybutyrate in all subjects. Normal subjects showed increases in 24-h total and pulsatile GH production, GH pulse frequency, maximal pulse amplitude, interpulse and nadir levels, implying suppression of hypothalamic somatostatin secretion and increase in GH-releasing hormone (GHRH) pulse frequency. In acromegalic patients, GH (and, by inference, GHRH) pulse frequency was unchanged. Three patients had increases in GH production, interpulse, and nadir levels similar to the normals while the other four had no change or paradoxical decreases in these parameters. Percentage change in GH production was highly correlated with percentage change in interpulse and nadir levels in both normals and patients. Mean GH response to GHRH (0.33 micrograms/kg iv) did not change significantly in any group as a result of fasting. Our data suggest that in healthy humans IGF-I negative feedback on GH secretion involves suppression of GHRH pulse frequency. GH (and, by inference, GHRH) pulse frequency is resistant to decrease in IGF-I in acromegaly, suggesting that lowered sensitivity of GHRH neurons to IGF-I may be the mechanism of high GH pulse frequency in this disease.

Acromegaly

In the majority of cases, acromegaly is due to GH hypersecretion by a somatotroph pituitary tumor. The etiology of acromegaly is not known, and may be related to GHRH hypersecretion, intrinsic pituitary defect, or a combination thereof. Recent physiologic data and molecular biology techniques provide insights into the pathophysiology of this condition. Treatment options include surgery, radiation, and judicious administration of pharmacologic compounds inhibiting GH secretion and tumor growth.

Bromocriptine treatment over 12 years in acromegaly: effect on growth hormone and prolactin secretion.

It is not known whether bromocriptine treatment in acromegaly can be implemented for a life-long period. To elucidate this problem, the secretory GH and PRL states of 12 patients with acromegaly were determined, before bromocriptine treatment, under therapy (15.0 +/- 6.8 mg/day for 12 +/- 3 years; mean +/- SD) and during two-weeks long drug withdrawal after long-term treatment, respectively. Before therapy, all patients showed a non-sufficient GH suppression after oral glucose load (greater than 2 micrograms/l), whereas under dopaminergic treatment the post-glucose GH levels of three patients fell below 2 micrograms/l; normal IGF-I concentrations were found in five patients. However, under bromocriptine, only two patients showed GH suppressions below 2 micrograms/l following glucose, accompanied with normal IGF-I levels. During bromocriptine withdrawal, GH secretion at 60 min in the oral glucose tolerance test increased significantly (17.0 +/- 15.5 vs 5.7 +/- 5.2 micrograms/l; p less than 0.01); the mean IGF-I level rose from 2.1 +/- 0.8 to 4.9 +/- 2.2 kU/l (p less than 0.01). IGF-I was normal during bromocriptine cessation in only one patient; none of the 12 patients showed a GH suppression below 2 micrograms/l after oral glucose load. Under dopaminergic treatment hyperprolactinemia could not be detected. In conclusion, bromocriptine led to a stable suppression of both GH hypersecretion and--if present--concomitantly elevated PRL levels. Severe side effects or a further tumor growth could not be observed. Thus, the data of the longest follow-up investigation that has so far been published indicate that effective life-long bromocriptine therapy seems to be possible in selected patients with acromegaly.

Somatotrpic Adenomas without Acromegaly

Seventeen somatotropic adenomas removed from patients without acromegaly were studied. Thirteen of them presented as a prolactinoma with amenorrhea and/or galactorrhea and elevated serum PRL levels. According to basal serum GH levels, the patients were divided into two groups, namely Group I: GH slightly elevated (n = 4) and group II: GH less than or equal to 5 micrograms/l (n = 13). The tumoral GH secretion was proved by immunocytochemistry in all cases and by intratumoral RIA, in vitro study and/or in situ hybridization in five of them. Pathological, clinical and biochemical relationships suggested two anatomoclinical aspects. In group I, the tumors were small, well-differentiated somatotropic adenomas with clinically silent GH hypersecretion. It is probably an early stage of the disease. In group II, the tumors were large with normal GH serum levels. They were poorly differentiated and secreted very low amounts of GH. In nine of them, PRL and/or PRL mRNA expression were also detected. These tumors do not secrete enough GH to increase serum levels and cause acromegaly. The somatotropic adenomas without acromegaly correspond to two anatomoclinical aspects of the disease.

Effects of ambient glycaemic state on growth hormone responsiveness in insulin‐dependent diabetes

We wished to examine the effects of ambient glycaemia on hypothalamic somatostatinergic tone in insulin-dependent diabetes mellitus. After 6-hour periods of either euglycaemia (5 mmol/l) or hyperglycaemia (15 mmol/l), exercise-induced GH secretion was measured. Seven insulin dependent diabetics with no evidence of complications were recruited. There was no significant difference between basal GH levels during euglycaemia and hyperglycaemia (5.50 vs 5.53 mU/l). Nor was there a significant difference when mean delta GH levels (33.9 vs 27.4 mU/l) or mean area under GH curve (2331 vs 4038 mU min/l) during euglycaemia or hyperglycaemia were compared. We find no evidence therefore to support short-term effects of ambient glucose concentration on GH responsiveness, and by inference no direct effect of short-term changes in glycaemic control on hypothalamic release of somatostatin in the aetiology of GH hypersecretion in insulin-dependent diabetes mellitus.

CLINICAL REVIEW 22 Therapeutic Options in Acromegaly

ACROMEGALY was first described by Marie more than 100 yr ago and is the consequence of GH hypersecretion. It is the second most common type of pituitary hypersecretory syndrome and isalmost always caused by a somatotroph adenoma. Recent epidemiologic studies have indicated anincidence rate 3.3 per million/yr and a prevalence rate of 66 per million (1). From both clinical and histopathologic criteria, GH secreting pituitary tumors are heterogeneous. The majority of tumors store relatively small quantities of GH, exhibit a moderate growth rate, and often exhibit extrasellar extension when initially diagnosed. In contrast, a smaller number of tumors exhibit a very slow growth rate, contain high concentrations of GH, and usually remain intrasellar even after a decade or more of clinical manifestations of GH overproduction. Using immunocytochemistry, in situ hybridization, and ultrastructural microscopy, GH-secreting pituitary tumors have been shown to be heterogeneous (2). They vary in cell size, granule size...