Response of acromegaly to long term bromocriptine therapy: a biochemical and clinical assessment.

The long term effects of bromocriptine in 12 acromegalics treated for a mean duration of 10.2 months are reported. Seven showed a significant (P less than 0.05) and sustained fall in serum immunoreactive growth hormone (GH) levels throughout 24 h, 6 of whom had a 50% or greater reduction in mean circulating GH during glucose tolerance testing. Only one patient had mean serum GH levels throughout the day suppressed to normal (less than 5 mIU/l) but 3 had suppression of mean serum GH during GTT to normal or very near normal (less than 10 mIU/l). The effective dose was 20 mg daily. Only 4 patients reported any improvement in soft tissue swelling and acral features, which was unrelated to the GH response. Possible reasons for the discrepancy between clinical and biochemical responses are discussed. In 9 of the 12 patients bromocriptine was discontinued and pituitary ablative therapy offered. Three out of 4 patients who underwent trans-sphenoidal hypophysectomy had mean GH levels during GTT reduced to less than 7 mIU/l. In the three who continued bromocriptine treatment GH suppression was maintained at less than 10 mIU/l for up to 3 years but with little change in acral features. Although bromocriptine is safe and was well tolerated it is not as effective as existing forms of pituitary ablative therapy and should be reserved for those cases where ablation is contraindicated or unsuccessful.     

Bromocriptine reduces growth hormone in acromegaly

We assessed serum growth hormone (GH) levels in ten patients with acromegaly during a 24-hour profile and a 75-g oral glucose tolerance test (GTT). Serum GH levels were measured after five weeks of bromocriptine mesylate therapy, 20 mg daily (P1), after five weeks without bromocriptine mesylate therapy (P2), and again five weeks following restarting treatment with bromocriptine, 20 mg daily (P3). During the 24-hour profile, the following occurred: (1) mean serum GH level of the group was lower during P1 (20.5 mU/L) and P3 (20.8 mU/L) than P2 (49.6 mU/L); (2) in six individual patients during P1 and P3, there was a significant reduction in the mean serum GH value; and (3) a marked circadian variation in the serum GH value was present both with and without the drug therapy in five patients. During the GTT, the mean serum GH value was lower during P1 (18.4 mU/L) and P3 (16.7 mU/L) than P2 (43.3 mU/L), and in seven individual patients during P1 and P3, there was a significant reduction in the mean serum GH value. Overall, a clear reduction in serum GH values due to bromocriptine was demonstrated. In individual patients, serum GH values during a 24-hour profile and GTT gave similar indications of response.     

BROMOCRIPTINE TREATMENT OF PATIENTS WITH ACROMEGALY RESISTANT TO CONVENTIONAL THERAPY

Eleven patients with active acromegaly resistant to conventional therapy were treated with bromocriptine for 15 (12–22) months by increasing the daily dose stepwise from 5 to 10–60 mg. A satisfactory response was achieved in all but one of the eight patients, in whom the mean diurnal level of serum GH was less than 50 ng/ml, whereas patients with grossly elevated serum GH levels responded poorly. In the longterm, no overall effects on glucose tolerance or plasma insulin (IRI) levels were observed but the chemical diabetes of three patients ameliorated in two. On the other hand, a dose-dependent acute suppressive effect of bromocriptine on plasma IRI response to oral glucose was observed, suggesting a direct effect of bromocriptine on the release of insulin from beta cells. Bromocriptine seems to be a good alternative in the treatment of patients with acromegaly who have not responded to conventional therapy.     

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.     

PLASMA GROWTH HORMONE SUPPRESSIVE EFFECT OF BROMOCRIPTINE IN ACROMEGALY. EVALUATION BY PLASMA GH DAY PROFILES AND PLASMA GH CONCENTRATIONS DURING ORAL GLUCOSE TOLERANCE TESTS

In most studies reporting favourable results of chronic bromocriptine treatment in acromegaly, plasma GH levels are measured at fixed intervals during the day. Negative results are reported in one major study measuring plasma GH levels during oral glucose tolerance tests (Lindholm et al., 1981). This study does not mention the time interval between the last dose of bromocriptine and the performance of an OGTT, but due to the short duration of action of bromocriptine this may be critical. Therefore, in the present report the plasma GH suppressive effect of bromocriptine in acromegaly is studied using plasma GH day-profiles as well as OGTT's during continued bromocriptine administration and OGTT's at two different time intervals after the last dose of bromocriptine. Twelve patients with clinically active acromegaly were treated with 10–20 mg bromocriptine for 6–9 months. After 6–9 months during continued bromocriptine administration the plasma GH suppressive effect of bromocriptine was evaluated by the mean of four plasma GH determinations during the day and by the mean of seven plasma determinations during oral glucose tolerance tests (OGTT's) performed 1 h, 10 h and 34 h after the last dose. The percentage decrease of the mean plasma GH level during the day induced by chronic bromocriptine treatment showed a good correlation (r= 0·86, P< 0·001) with the percentage decrease of the mean plasma GH level during OGTT, if the post-treatment test was carried out one hour after the last dose of bromocriptine. When OGTT was performed 10 h after the last dose no significant correlation (r= 0·17) was found and after 34 h a rebound of the mean plasma GH level occurred in eight patients. It is concluded that measurement of the mean plasma GH level during the day or during OGTT are equally effective indicators of the suppressive effect of bromocriptine treatment on GH secretion in acromegaly if the OGTT is performed 1 h after the last dose of bromocriptine.     

THE EFFECTS OF PROLONGED BROMOCRIPTINE ADMINISTRATION ON PRL SECRETION GH AND GLYCAEMIC CONTROL IN STABLE INSULIN-DEPENDENT DIABETES MELLITUS

Plasma glucose, PRL and GH concentrations were measured at hourly intervals over a 24-h period before and after oral bromocriptine administration in a dosage of 7.5 mg/day for 6 weeks in nine stable insulin-dependent diabetic men. The pattern of PRL secretion was noted to be normal in stable diabetes (with a mean concentration of 205 mu/l +/- 23 SEM) and was effectively suppressed by bromocriptine (to a mean concentration of 51 mu/l +/- 2 SEM). This suppression of PRL secretion caused no major alteration in glycaemic control, mean plasma glucose for the group was 10.6 mmol/l +/- 3.4 SD before and 9.6 mmol/l +/- 3.1 SD after bromocriptine administration. Bromocriptine produced no change in plasma glucose or GH profiles. It is concluded that PRL secretion is not a major influence on carbohydrate metabolism in stable diabetics.     

Treatment of Acromegaly with Bromocriptine

Summary: Five men and three women with active acromegaly were treated with bromocriptine. After three months' therapy (30 mglday) mean GH during the day decreased by 50% in six out of eight subjects. In the remaining two subjects (non-responders) GH was persistently over 100 μg/1. Mean GH during glucose tolerance test were not significantly decreased in three out of the eight subjects, of whom two were the non-responders. The minimum dose of bromocriptine required to achieve maximum GH suppression ranged from 7·5 to 20 mglday. In contrast, serum prolactin (PRL) throughout the day suppressed significantly in all subjects after 5 mglday bromocriptine.
Decreases in clinical symptoms, hand volume, urinary hydroxyproline and calcium excretion were seen in about half of the subjects. Three of the four subjects with diabetes metlitus showed improvement in glucose tolerance. Although minor side effects were uncommon, one patient died because of massive gastrointestinal haemorrhage from a duodenal ulcer.     

Intracerebroventricular administration of bromocriptine ameliorates the insulin-resistant/glucose-intolerant state in hamsters

Bromocriptine, a potent dopamine D2 receptor agonist, suppresses lipogenesis and improves glucose intolerance and insulin resistance. Recent evidence suggests that bromocriptine may produce these effects by altering central nervous system (CNS) regulation of metabolism. To determine whether or not the CNS plays a critical role in these bromocriptine-mediated effects on peripheral metabolism, we compared the metabolic responses to bromocriptine when administered peripherally versus centrally in naturally obese and glucose intolerant Syrian hamsters. Male hamsters (BW 194 +/- 5 g) were treated with bromocriptine or vehicle either intraperitoneally (i.p., 800 microgram/animal) or intracerebroventricularly (i.c.v., 1 microgram/animal) daily at 1 h after light onset for 14 days while held on 14-hour daily photoperiods. Glucose tolerance tests (GTTs, 3 g glucose/kg BW) were conducted after treatment. Compared to control animals, bromocriptine i.p. significantly reduced weight gain (11.7 vs. -2.4 g) and the areas under the glucose and insulin GTT curves by 29 and 48%, respectively. Similarly, compared with vehicle-treated controls, bromocriptine i.c.v. at 1 microgram/animal substantially reduced weight gain (8.7 vs. -6.3 g), the areas under the glucose and insulin GTT curves by 31 and 44% respectively, and the basal plasma insulin concentration by 41% (p < 0.05). Furthermore, both treatments significantly improved insulin-mediated suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. Thus, daily administration of bromocriptine at a very low dose i.c.v. replicates the metabolic effects of bromocriptine administered i.p. at a much higher dose. This finding demonstrates for the first time that the CNS is a critical target of bromocriptine's metabolic effects.     

Bromocriptine treatment in acromegaly: clinical and biochemical effects.

Eight selected patients with active acromegaly and elevated GH levels without other endocrine disturbances were submitted to long-term treatment and acute dose-response trials with bromocriptine. Seven patients showed clinical improvement and lowering of GH levels in response to long-term treatment, however, two of these showed only minor changes in GH levels during the acute dose-response trial. Glucose tolerance and heel pad thickness remained unchanged, while urinary hydroxyproline excretion and blood, plasma and erythrocyte volumes decreased. Using daily doses of 20 mg bromocriptine, side effects were generally minor. Severe vasovagal reactions were, however, observed in two patients, in one at the start of treatment, in the other after ingestion of 25 mg bromocriptine. Bromocriptine represents a valuable treatment alternative in acromegaly, but only long-term treatment will separate responders from nonresponders.     

Dose-response study and long term effect of the somatostatin analog octreotide in patients with therapy-resistant acromegaly

Twelve acromegalic patients in whom standard therapy was unsuccessful were evaluated with 24-h serum GH profiles (hourly sampling) and oral glucose tests (oGTT) while being treated with octreotide, a long-acting somatostatin analog. During a dose-response study (300, 600, and 1500 micrograms/day sc, for 4 weeks), serum GH decreased significantly after 300 micrograms/day in 8 of 12 patients [from 14.5 +/- 6.2 (+/- SE) to 4.9 +/- 1.9 micrograms/L]. Higher doses further reduced serum GH concentrations in 3 (600 micrograms/day) and 1 (1500 micrograms/day) patients, respectively. Four patients did not respond to any dose. Serum GH concentrations declined normally (GH nadir, less than 2 micrograms/L) after glucose ingestion in 4 of the 10 nondiabetic acromegalic patients. In 4 patients, including 2 of the initial nonresponders, serum GH further declined during long term treatment (12 and 18 months). In the latter 2 patients, serum insulin-like growth factor I (IGF-I) concentrations had decreased during the dose-response study despite the absence of measurable GH suppression. Eight patients attained normal serum IGF-I concentrations during treatment. Serum IGF-I and GH correlated significantly before, but not during, treatment. Retrospective comparison suggested that in 5 of 6 patients, serum GH was more effectively suppressed by octreotide than by bromocriptine. The 24-h serum octreotide concentration varied greatly among the patients. Although the 24-h serum octreotide and GH concentrations did not correlate with one another, the serum octreotide and IGF-I concentrations when the patients were receiving 300 micrograms/day tended to be negatively correlated (r = -0.496; P = 0.118). The 24-h serum insulin values decreased and those of glucose increased during treatment; after oral glucose, serum insulin was lower and glucose was higher. However, after 12 months of treatment, the 8-h serum insulin profile and peak serum insulin after oral glucose administration had returned to pretreatment values, while serum glucose remained abnormal. We conclude that 1) octreotide lowers serum GH in many, but not all, acromegalic patients resistant to other forms of treatment; 2) doses in excess of 300 micrograms/day should be tested in those patients in whom lower doses are ineffective; 3) serum IGF-I measurement may be a better indicator of treatment success than GH measurement; 4) octreotide concentrations do not correlate with GH suppression; and 5) deterioration of carbohydrate tolerance does occur but tends to improve during chronic treatment.     

A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-I without significant deterioration in glucose tolerance

OBJECTIVE: Many GH deficient (GHD) patients have impaired glucose tolerance and GH substitution in these patients has caused deleterious effects on glucose tolerance with hyperinsulinaemia. This further impairment of glucose tolerance might be due to an unphysiologically high dose of GH. Whether such a deterioration can be avoided by an optimal GH replacement dose is not known. In most previous studies, the GH dose was calculated according to body weight or body surface area and not adjusted according to the serum IGF-I response. DESIGN: The study was of open design and investigations were performed before the start of GH substitution and after nine months of treatment. The GH dose was adjusted according to the response in serum IGF-I, and in patients with sub-normal serum IGF-I levels (all but two) we aimed for a serum IGF-I level in the middle of the normal range. The median GH dose at the end of the study was 0.14 IU/kg/week. PATIENTS: Ten patients, eight males and two females, with childhood onset GHD were examined. Their median age was 27 years (range 21-28). MEASUREMENTS: Overnight and 24-h fasting levels of glucose, insulin and IGFBP-1 were measured. Directly after the 24-h fast an oral glucose tolerance test (OGTT), with measurements of glucose, insulin and IGFBP-1 was performed. An intravenous glucose tolerance test (IVGTT) was performed after overnight fasting. Body composition was measured with bio-impedance analysis (BIA) and quality of life was assessed using a self-rating questionnaire, Qol-AGHDA. RESULTS: After GH treatment, there were no significant changes in glucose tolerance, measured by overnight and 24-h fasting levels of glucose, insulin and IGFBP-1, an oral glucose tolerance test (after 24-h fasting) and an intravenous glucose tolerance test (after overnight fasting). Percentage fat mass and BMI correlated negatively with both the 24 h fasting IGFBP-1 levels and the IGFBP-1 responses after the OGTT. All patients decreased their percentage of fat mass measured by BIA [median -2.9%; range -1.0-(-6.6); P = 0.005]. The administered GH dose correlated negatively with the relative change in whole body resistance (r = -0.66; P = 0.04). All, but one of the patients improved their quality of life score after GH therapy. CONCLUSIONS: In a group of young patients with childhood onset GH deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week) caused no significant deterioration of glucose tolerance. The strong negative associations between BMI or percentage fat mass and IGFBP-1 suggest that serum IGFBP-1 is more closely related than insulin to body composition in GH deficient patients. It is important to consider which critical endpoints should determine the GH dose. We would suggest that, apart for normalizing the serum IGF-I level, another main endpoint should be normalization of, or at least avoidance of any deterioration in glucose tolerance.     

Changes in plasma GH levels and clinical activity during bromocriptine therapy in acromegaly. The value of predictive tests

Twenty-seven patients with active acromegaly despite previous treatment by surgery and/or radiotherapy received bromocriptine in a dose of 10-20 mg daily for a period of 6-9 months. The results of chronic bromocriptine treatment were evaluated by measurement of plasma growth hormone (GH) levels during the day and by subjective and objective criteria of clinical activity. The results of chronic bromocriptine treatment were also compared with four biochemical criteria obtained before treatment e.g. basal plasma prolactin (Prl) levels and the plasma GH response to oral administration of 2.5 mg bromocriptine respectively iv administration of 200 micrograms TRH and 500 micrograms somatostatin. The main observations may be summarized as follows: 1) The mean pre-treatment GH levels during the day ranged from 6-207 mU/1. Hyperprolactinaemia was present in 6 patients. 2) During bromocriptine treatment mean plasma GH levels decreased to less than 50% in 11 patients (GH responders) whereas in 19 patients changes of mean plasma GH and of subjective criteria of clinical activity were concordant. 3) Glucose tolerance improved significantly (P less than 0.01) in 10 GH-responders and the urinary hydroxyproline/creatinine ratio decreased significantly (P less than 0.05) in 8 GH-responders. 4) Five out of 6 patients with hyperprolactinaemia belonged to the group of GH-responders. 5) A single dose of 2.5 mg bromocriptine induced a more than 50% decrease of plasma GH in 8 of 11 GH-responders and in 5 of 16 GH non-responders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of long term sulfonylurea therapy on plasma insulin and fasting lipid levels.

Insulin secretion was studied before and after the control of hyperglycemia in fourteen maturity onset male non-obese diabetics. Optimum control of hyperglycemia was achieved by the addition of the sulfonylurea chlorpropamide to dietary treatment. One patient was a primary treatment failure, but nine out of thirteen had excellent control of hyperglycemia. A standardized oral glucose tolerance test (GTT) was performed before and after eight months of individualized therapy with the sulfonylurea. The GTT was repeated with each patient taking his usual dose of chlorpropamide 90 min prior to the administrationo f the glucose load. In the baseline test glucose levels rose from 135.6 +/- 9.9 mg/dl to a peak level of 268.8 +/- 17.7 mg/dl at 120 min. After control of hyperglycemia glucose levels were significantly lower at 0, 30 and 60 min, and rose from 106.8 +/- 8.5 mg/dl to a maximum of 224.5 +/- 17.3 mg/dl at 120 min. Plasma insulin response was unchanged. Fasting serum cholesterol, triglyceride and total lipid levels changed only minimally during therapy. It is concluded that lowered serum glucose levels after long term treatment with chlorpropamide occured while plasma insulin response to glucose was no greater than before treatment. These findings may be explained by an extrapancreatic effect of the drug or by an indirect result of chlorpropamide induced insulin release which occured earlier in the course of therapy.     

Metabolic effects of 20-kilodalton human growth hormone (20K-hGH) for adults with growth hormone deficiency: results of an exploratory uncontrolled multicenter clinical trial of 20K-hGH

The biological effects of 20-kDa human GH (20K-hGH), which is produced in the pituitary by alternative splicing of GH mRNA and comprises approximately 6% of all GH in serum, have not been reported. We have investigated the metabolic effects of recombinant 20K-hGH in adult patients with GH deficiency in an exploratory study. Three doses of 20K-hGH (0.006, 0.012, and 0.024 mg/kg.d), were administered for 16 wk to three groups (consisting of 18 or 19 subjects), respectively. The 20K-hGH dose-dependently increased serum IGF-I and IGFBP-3 levels, and the lowest dose (0.006 mg/kg) was enough to normalize both hormones by wk 4. Serum osteocalcin levels and urinary deoxypyridinoline excretion were also dose-dependently increased. There was a significant decrease in body fat mass with an increase of lean body mass at the lowest dose of 0.006 mg/kg.d. Blood glucose and serum insulin were increased significantly at 4 wk only in the high-dose group (0.024 mg/kg). Glucose tolerance was slightly impaired in 26-39% of patients in all treatment groups as judged by oral glucose tolerance tests, but there was no development of overt diabetes. The major adverse event in the 20K-hGH treatment was peripheral edema, similar to the incidence reported for 22K-hGH. The data demonstrated that 20K-hGH had metabolic effects comparable to those of 22K-hGH in humans. The results suggest that 20K-hGH could be used to treat GH-deficient patients, although further studies may be required to investigate the optimum dose and superiority of 20K-hGH over 22K-hGH in a comparative study.     

Serum prolactin levels in women with excessive milk production. Normalization by transitory prolactin inhibition

Serum prolactin levels and milk yield were studied in 27 puerperae with excessive milk production (polygalactia) and compared with 30 normally lactating puerperae. In order to normalize polygalactia, 14 of these women were treated with 2.5 mg bromocriptine per day for 3 days starting on post-partum day 5, 13 women received placebo. Milk flow in polygalactic women started significantly earlier than in puerperae with normal milk yield and developed mean milk volumes of 816 g per day on post-partum day 4. Serum prolactin levels did not differ from levels of puerperae with normal milk yield. There was no correlation between serum prolactin and milk yield. Bromocriptine treatment resulted in a sharp but reversible decline of serum prolactin levels followed by a significant reduction of milk production. Bromocriptine could not be detected in milk specimens, while serum levels showed significant amounts. In placebo treated women prolactin levels and milk yield remained unaffected. These data indicate that serum prolactin concentrations of puerperae with polygalactia are within the normal post-partum range. Short term prolactin suppression by bromocriptine can reduce milk yield, without complete ablactation.     

THE EFFECT OF A NEW ERGOLINE DERIVATIVE, CU 32-085, IN THE TREATMENT OF ACROMEGALY. A CONTROLLED STUDY

The effect of a new dopamine agonist, CU 32-085 (8 alpha-amino-ergoline), on pituitary function in acromegaly was evaluated by a controlled, single blind study of 12 acromegalics. The study included a single dose placebo/drug (0.5 mg CU 32-085) trial and a long-term crossover trial with 3 month periods (placebo/CU 32-085 8 mg daily). The patients were evaluated clinically and biochemically (oral glucose tolerance (OGTT), TRH- and LHRH-tests) before and after each 3 month period. Nine patients completed this long-term trial; one died from myocardial infarction during the placebo period, and two dropped out because of side effects. The release of GH, judged from more than 9 h suppression of serum GH following the single dose, and from the response to OGTT after the long-term treatment, was significantly inhibited by CU 32-085. Serum GH reached normal values in 4 of 9 patients. Serum PRL was also markedly suppressed, to subnormal values after the 3 months in all but one hyperprolactinemic patient. Serum TSH, cortisol, FSH and LH were generally unaffected. Glucose tolerance was not significantly altered, although an improvement was found in six of nine patients. A semiquantitative evaluation of subjective symptoms showed a significant improvement following the long-term treatment, while objective signs of acromegaly were unaffected. The blood pressure was slightly lowered, both after a single dose and after 3 months' treatment. Seven patients experienced nausea and dizziness, two of them with vomiting, after a single dose of the drug. Four of these had similar symptoms initially during the long-term treatment, which forced two to interrupt the trial. We conclude that CU 32-085 caused a marked suppression of the release of GH and PRL and an improvement of the major symptoms of acromegaly, a therapeutic effect that is comparable to the previous experience with bromocriptine.     

An acute remission of Reiter's syndrome in male patients treated with bromocriptine.

We describe 4 male patients with Reiter's syndrome treated with bromocriptine. All 4 had infectious gastroenteritis and chronic Reiter's syndrome with arthritis and enthesopathy that persisted despite treatment in 3 with antiinflammatory drugs and 1 with sulfasalazine for long periods. In all patients treatment was cancelled 8 days before bromocriptine treatment. In 2 patients a dramatic improvement was observed 24 h after 2.5 mg/day of bromocriptine. Two patients improved after 4 days of bromocriptine treatment (5 mg/day). All 4 patients remained asymptomatic for at least 4 months of bromocriptine treatment. Bromocriptine may be useful for treating male patients with Reiter's syndrome.     

Growth hormone (GH) effects on central fat accumulation in adult Japanese GH deficient patients: 6-month fixed-dose effects persist during second 6-month individualized-dose phase

Both Japanese and Caucasian adults with GH deficiency (GHD) have pronounced abdominal obesity, which is associated with increased risk of cardiovascular complications. We investigated the effects of GH treatment in 27 adult Japanese GHD patients, 15 with adult onset (AO) and 12 with childhood onset (CO) GHD. Patients initially received GH titrated to 0.012 mg/kg/day for 24 weeks in a double-blind design and the dose was then individualized for each patient according to IGF-I for a further 24 weeks. Dual-energy x-ray absorptiometry (DXA) data were evaluated for percentages of trunk fat, total body fat and lean body mass. Serum IGF-I and lipid concentrations were determined at a central laboratory. There were 25 patients who completed 48 weeks of treatment, with 7, 6 and 12 patients then receiving GH at 0.003, 0.006 and 0.012 mg/kg/day, respectively. With the reductions in dose when individualized between weeks 24 and 48, mean serum IGF-I level was reduced and excessively high values, observed in AO patients on the fixed GH dose, were no longer seen. The decrease from baseline in trunk fat was similar at week 24 (-3.8 +/- 3.3%, p<0.001) and week 48 (-3.1 +/- 3.7%, p<0.001), and the difference between changes was not significant. Total cholesterol was decreased from baseline by -24 +/- 28 mg/dl (p<0.001) at week 24 and -17 +/- 28 mg/dl (p = 0.007) at week 48. Two patients had elevated HbA1c levels: one continued GH treatment after a dose reduction and the other discontinued due to persistent impaired glucose tolerance. Therefore, excessively high IGF-I levels can be avoided by individualized dosing during long-term GH treatment. Individualized dosing maintains the decrease in abdominal fat in adult Japanese GHD patients and should reduce the cardiovascular risk.     

NORMAL GROWTH AND PUBERTAL DEVELOPMENT DURING BROMOCRIPTINE TREATMENT FOR A PROLACTIN-SECRETING PITUITARY MACROADENOMA

An 11-year-old male presented with a 2-year history of headache and lethargy. Serum PRL was elevated at 14,000 mU/l and computerized tomography showed a pituitary macroadenoma. Visual fields and fundi were normal and the testes showed early pubertal changes. There was normal responsiveness of serum cortisol but absence of GH response to hypoglycaemia. After bromocriptine therapy for 4 months serum PRL had fallen to 90 mU/l and the tumour was not visible on repeat computerized tomography. After 7 months treatment, repeat pituitary function testing showed restoration of GH response to hypoglycaemia. Treatment with bromocriptine was continued and there was spontaneous progression of normal puberty; the serum testosterone continued to rise, and height maintained the 50th centile. Bromocriptine therapy should be considered as initial therapy in the management of prolactinomas in prepubertal patients.     

Relationships between insulin-like growth factor-1 levels and growth hormone concentrations during diurnal profiles and following oral glucose in acromegaly

OBJECTIVE The aim of this study was to refine the biochemical definition of disease activity in acromegaly by comparing serum growth hormone (GH) measurements during a 10-hour day profile with serum GH values during an oral glucose tolerance test. DESIGN Using plasma insulin-like growth factor-1 (IGF-1) levels as a measure of disease activity, serum GH data from a day profile and from an oral glucose tolerance test were compared. PATIENTS Thirty-five acromegalic patients were studied, 13 of whom had serum GH measured during a day profile and 22 during an oral glucose tolerance test. In addition, basal plasma IGF-1 levels were estimated in all acromegalic patients, and in 24 normal subjects. MEASUREMENTS Following acid-ethanol extraction of the plasma samples, IGF-1 levels were measured by radioimmunoassay using a polyclonal antibody. In a day profile, six to eight blood samples for serum GH estimation were taken at hourly intervals during the day; during an oral glucose tolerance test samples for serum GH estimation were taken in the fasting state and every 30 minutes for 2 hours and measured by a two-site IRMA for GH. RESULTS Ninety-four per cent of acromegalic patients with raised plasma IGF-1 levels had serum GH concentrations <10 mU/l whilst 98% of acromegalic patients with plasma IGF-1 levels in the normal range had serum GH concentrations lt;6 mU/l. A highly significant positive correlation was found between the mean serum GH concentrations (r=0 67), the minimum serum GH concentration (r = 0 65) and the area under the GH curve (r = 0–66) estimated during an oral glucose tolerance test and plasma IGF-1 concentrations. The relations between identical indices of serum GH concentration measured during a day profile and plasma IGF-1 levels, although significant, show a less powerful correlation. The relation between serum GH and plasma IGF-1 levels describes a curvilinear model, plasma IGF-1 levels exhibiting a plateau at serum GH concentrations >40 mU/l but maintaining a linear relationship with serum GH levels <20 mU/l. CONCLUSIONS A highly significant correlation exists between plasma IGF-1 levels and various parameters of serum GH levels in acromegalic patients. Hormonal assessment of disease activity in acromegaly is more accurately reflected by the serum GH concentration during an oral glucose tolerance test rather than by the serum GH level during a day profile. Normalization of plasma IGF-1 levels is rarely achieved unless the mean serum GH level is reduced to <6 mU/l.