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.     

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.     

THE EFFECT OF BROMOCRIPTINE ON INSULIN SECRETION AND GLUCOSE TOLERANCE IN PATIENTS WITH ACROMEGALY

The oral administration of bromocriptine 5 mg 6-hourly to twelve patients with acromegaly for a mean period of 12 (range 3–27) months significantly reduced whole blood glucose, plasma insulin and plasma growth hormone (GH) concentrations during a 50 g oral glucose tolerance test (OGTT). After this period of treatment, bromocriptine was withdrawn for 48 h resulting in a significant rise in whole blood glucose, plasma insulin and plasma GH concentrations during a repeat OGTT. It is concluded that bromocriptine therapy improves glucose tolerance in acromegaly by suppressing GH secretion and consequently GH-mediated antagonism of insulin.     

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)     

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.     

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.     

CLINICAL AND BIOCHEMICAL EFFECTS OF INCREMENTAL DOSES OF THE LONG-ACTING SOMATOSTATIN ANALOGUE SMS 201-995 IN TEN ACROMEGALIC PATIENTS

Ten patients (seven women, three men) with active acromegaly, five previously treated and five newly diagnosed, were included in an open-label prospective trial of 3 daily subcutaneous injections of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) at increasing doses in order to obtain maximum growth hormone (GH) suppression. Four patients had received surgery, radiotherapy or bromocriptine. SMS 201-995 doses were increased in a stepwise fashion from 100 μg every 8 h (three times daily) to 200, 300 and finally 500 μg three times daily at monthly intervals if mean serum GH values failed to decrease to undetectable levels in over 75% of the samples. The optimal dose was maintained for up to 28 months. Significant clinical improvement of headache, soft tissue swelling, facial features, hyperhidrosis and paraesthesia occurred in all patients. Mean 12-h GH levels were significantly suppressed in four patients and fell to normal values in four. Suppression of GH levels was not achieved in two patients. Comparison of the mean interindividual GH values shows that the optimal efficacious dose is 100 μg t. i. d. in 7/10 patients. Somatomedin-C (SM-C) was also significantly reduced to below 50% of pretreatment levels in nine patients in whom it was measured. The subsequent increments of SMS 201-995 up to 500 μg three times daily did not produce further clinically relevant GH or SM-C suppression. Pituitary tumour shrinkage occurred in five patients. Thyroid function remained normal. Impaired glucose tolerance occurred in four patients. Side-effects (diarrhoea, abdominal discomfort) were mild and transient. Asymptomatic gallstones occurred in three patients on 1500 μg/day and one patient on 600 μg/day after 6-12 months treatment. This dose-finding study shows that 100 μg three times daily SMS 201-995 is an effective therapy for most of the acromegalic patients we treated.     

TREATMENT OF ACROMEGALY BY TRANS-SPHENOIDAL OPERATION, 90-YTTRIUM IMPLANTATION AND BROMOCRIPTINE: RESULTS IN 230 PATIENTS

Two hundred and thirty patients with acromegaly were diagnosed and treated in a prospective cooperative study in twelve university clinics. Primary treatment was: trans-sphenoidal surgery (152 patients), trans-sphenoidal surgery with additional cryotherapy (eighteen patients), Yttrium-90-implantation (thirty patients), bromocriptine (thirty patients). The results of endocrine assessment before treatment and 6 months after operation, 90-Y implantation or commencement of bromocriptine therapy are reported. The best results (low GH, no or little deterioration of pituitary function, low complication rate) were achieved by trans-sphenoidal surgery, especially in patients with intrasellar tumours (basal GH < 5 ng/ml in 59·7%). Results were less good with increasing tumour size. Additional cryosurgery was accompanied by a high rate of anterior pituitary insufficiency and is no longer employed. Yttrium-90-implantation resulted in less improvement in GH levels (basal GH < 5 ng/ml in 51·7. of patients with intrasellar tumours), a high rate of pituitary insufficiency and more complications. Bromocriptine treatment was least effective in lowering GH concentrations (basal GH < 5 ng/ml in 33% of patients with intrasellar tumours). Different criteria for treatment success were compared. In the entire group, basal GH concentrations below 5 ng/ml were attained in 51·7. of all patients whose values were higher than this prior to treatment. Suppressibility of GH below 2 ng/ml during glucose loading occurred in only 34·9%. An abnormal GH response to TRH/LHRH was present in 47·2. before and in 43·4% after/during treatment. The prognostic significance of this latter finding must be evaluated by further study.     

Effectiveness of a long-acting injectable form of bromocriptine in patients with prolactin and growth hormone secreting macroadenomas

OBJECTIVE With the development of new long-acting depot preparations of bromocriptine (bromocriptine LAR), we investigated the effectiveness of intramuscular injections of long-acting bromocriptine in patients with prolactin and GH secreting macroadenomas. STUDY DESIGN AND PATIENTS Fourteen patients with PRL secreting (8 patients) and GH secreting (6 patients) macroadenomas were treated with monthly intramuscular Injections of a long-acting and repeatable form of bromocriptine for 3–6 months. A 50-mg monthly dose was administered In the majority of patients with PRL secreting macroadenomas. A 100-mg monthly dose was administered In all patients with GH secreting macroadenomas. MEASUREMENTS Plasma PRL and/or GH levels were measured 6 and 12 hours after the first injection and then on days 1, 2,14 and 28 after each Injection, up to a maximum period of 6 months. Patients were hospitalized for 48 hours after each Injection and were specifically questioned with respect to side-effects. Pituitary imaging with MRI or CT scans was performed In all patients before commencing treatment and was subsequently repeated In 5/8 patients with macroprolactinomas and 5/6 patients with GH secreting macroadenomas after the completion of a 6-month course of treatment. RESULTS In ail patients with macroprolactinomas, serum PRL levels decreased significantly after their first 50-mg injection with nadir levels obtained by 24–48-hours post Injection (12815 ± 8704 vs 1480 ± 1859 mU/l; mean ± SD, P<0.01). At their latest follow-up, on a 50-mg monthly dose, 4 patients developed normoprolactinaemia (PRL levels <360mU/l) while two patients demonstrated a significant reduction In serum PRL levels (70 and 87% of pretreatment values). In two patients, although a substantial decrement of serum PRL levels was achieved 12-24 hours post injection, serum PRL levels Increased to pretreatment values by day 14 post injection. Both patients received a higher (100mg) monthly dose which was partially effective In one patient. In two patients with GH secreting macroadenomas, a sustained decrease of elevated GH levels was observed; in two patients, while a substantial reduction of the elevated serum GH levels was achieved 12–24 hours after the first and subsequent injections, serum GH levels increased to pretreatment values by day 14 post injection; in two patients there was no effect on the elevated serum GH levels. Significant tumour shrinkage (24–50%) was observed In 5/5 patients with PRL secreting macroadenomas assessed at completion of a 6-month course of treatment. Significant tumour shrinkage was also documented In 2/5 acromegalics tested (29 and 46% respectively). CONCLUSION It is concluded that bromocriptine LAR Is an effective treatment in the majority of patients with macroprolactinomas; it is also partially effective in some patients with GH secreting macroadenomas.     

Relationship between somatomedin-C and growth hormone levels in acromegaly: basal and dynamic evaluation

The relationship between basal and stimulated plasma GH and somatomedin-C (SmC) levels in acromegalic patients was evaluated. The basal plasma SmC levels of 66 patients were significantly correlated (P less than 0.01) with mean daily plasma GH levels, but not with the percent GH increase after GH-releasing hormone or TRH or the GH decrease after acute bromocriptine administration. Bromocriptine (7.5-15 mg/day) administration for 9.2 +/- 0.9 (+/- SD) months in 20 patients significantly (P less than 0.05) decreased GH levels. SmC decreased significantly [from 9.8 +/- 1.9 to 5.1 +/- 0.7 U/ml (mean +/- SE)] only in the 10 patients who had the more marked GH inhibition. The administration of a somatostatin analog, SMS 201-995 (100 micrograms twice daily), to 12 patients for 16 weeks significantly decreased plasma GH and SmC levels beginning on the second day of therapy; normal SmC levels were achieved in 5 of 12 patients. Pituitary adenomectomy resulted in normal GH and SmC levels in 10 of 12 and 8 of 12 patients, respectively. Our data indicate an overall dependency of plasma SmC levels on plasma GH levels in acromegaly, although similar GH levels may have differing somatomedin-stimulating activities. A derangement in the feedback mechanisms controlling GH secretion is indicated by the failure of elevated SmC levels to influence the GH responsiveness to releasing hormones. In evaluating pharmacological or surgical treatments of acromegaly, a single plasma SmC value can reliably replace several plasma GH determinations.     

LONG-LASTING LOWERING OF SERUM GROWTH HORMONE AND PROLACTIN LEVELS BY SINGLE AND REPETITIVE CABERGOLINE ADMINISTRATION IN DOPAMINE-RESPONSIVE ACROMEGALIC PATIENTS

Cabergoline, the new long-acting dopaminergic ergoline derivative, was given orally in single doses of 0.3 and 0.6 mg to eight dopamine-responsive acromegalic patients. Serum GH and PRL levels were determined before treatment, 3, 4, and 6 h and 1, 3, 5, 7 and 14 days after treatment. A control test with a single oral dose of 2.5 mg of bromocriptine was also performed. Cabergoline induced a marked fall in serum PRL level, starting within 3 h and continuing for 7 days after administering 0.3 mg, and for 14 days after 0.6 mg. The mean maximal decrease was 49% after 0.3 mg and 63% after 0.6 mg and occurred after 24 h in both cases. The latter was of similar magnitude to that induced by bromocriptine (67% at 4 h). Serum GH levels did not change after 0.3 mg of cabergoline, but decreased significantly from 3 h to 3 days after 0.6 mg of the compound with a mean maximal decrease of 42% after 24 h, and from 3 to 6 h after giving bromocriptine (mean maximal decrease 63% at 4 h). Once a week repeated administration of 0.3-0.6 mg of cabergoline was carried out in six patients, five of whom had completed the acute study; a normalization of serum GH and insulin-like growth factor I (IGF-I) levels occurred in three patients, one of whom had very high pretreatment values. In three poorly or nonresponsive patients, a better response, as assessed by both GH and IGF-I levels, was induced by increasing the dose up to 0.6 mg twice or 0.4 mg three times a week; in one case this was associated with marked tumour shrinkage. Sustained normalization of PRL levels was achieved in all cases. These data indicate that a single dose of 0.6 mg of cabergoline inhibits GH as well as PRL secretion in dopamine-responsive acromegalic patients and suggests that doses of 0.3-0.6 mg once to three times a week may prove suitable for treatment of this condition.     

Treatment with octreotide and bromocriptine in patients with acromegaly: an open pharmacodynamic interaction study

OBJECTIVE Several studies suggest that the combination of octreotide and bromocriptine is more effective than octreotide alone in reducing GH levels in patients with acromegaly. However, these studies have evaluated either the acute effects of single doses of octreotide and bromocriptine, or the effects of long-term combination therapy, in which octreotide was given only twice a day. The aim of the study was to evaluate the effects of the combination of octreotide and bromocriptine compared to octreotide alone, using a treatment scheme of three daily injections of octreotide during a period long enough to ensure a pharmacokinetic and pharmacodynamic steady state. PATIENTS Eleven patients with acromegaly. DESIGN AND MEASUREMENTS Different treatment regimes were performed during three periods. During the first period there was no administration of octreotide or bromocriptine, during the second period 100 μg octreotide was given subcutaneously three times a day, and during the third period 100 /ig octreotide was given subcutaneously three times a day in combination with bromocriptine, given orally 5 mg twice daily. When the patients were without any treatment a single oral dose of 5 mg bromocriptine was given at 0730 h. Individual GH levels were assessed as the mean value of 11 observations during the day, at hourly Intervals from 0730 to 1530 h, and at 1730 and 1930 h, and the GH levels for the whole group were calculated as the mean of the individual mean values. Serum IGF-I and PRL were measured in fasting samples at 0730 h on the same days as GH. GH, IGF-I, and PRL were evaluated at the end of each treatment regime. RESULTS Basal mean GH value for all 11 patients was 54.2 ± 17.4 mU/l. During octreotide therapy mean GH value was significantly reduced compared to basal mean GH level; 19.86±6.82 mU/l (P<0 05). The reduction of mean GH during combination therapy was also significant compared to basal, 18.70 ±6.72 mU/l (P<0.05). Basal mean IGF-I value for all 11 patients was 716 ±96 μg/l. During octreotide therapy mean IGF-I value was significantly reduced compared to basal mean IGF-I level; 458 ±100 μg/l (P<0.05). The reduction of mean IGF-I during combination therapy was also significant compared to basal, 456 ±93 μg/l (P<0.05). There was no difference between the levels of mean IGF-I during the two treatment periods. One patient, the only patient with hyperprolactinaemia, showed an additional reduction of GH levels of >50% during combination therapy. This was also the patient showing the most pronounced reduction of GH levels after the administration of a single dose of bromocriptine. CONCLUSION When octreotide is administered three times a day, the additive effect of bromocriptine on GH and IGF-I suppression seems to be negligible in most patients with acromegaly.     

Dynamics of the acute effects of octreotide, bromocriptine and both drugs in combination on growth hormone secretion in acromegaly.

The separate and combined GH-lowering effects of single doses of octreotide and bromocriptine were assessed in 51 acromegalic patients on 4 occasions each 2 days apart. Patients received sequentially: placebo sc (N = 51), 50 micrograms octreotide sc (N = 51), 2.5 mg bromocriptine po (N = 40) or a combination of both drugs (N = 25). With octreotide, in 28 patients (55%) GH levels were suppressed to less than 5 micrograms/l and 39 of them (76.5%) had a 50% or greater decrease of their basal GH level from 2 to 6 h. During bromocriptine, GH values were suppressed to below 5 micrograms/l in 11 patients (27.5%) and reduced by 50% or more in 21 (52.5%). The combination of both drugs acutely suppressed GH levels to less than 2 micrograms/l in 32%, to less than 5 micrograms/l in 56%, and by more than 50% in 84% of patients. Octreotide produced a stronger and faster suppression of GH levels than bromocriptine in most patients. The combination of both drugs had an additive effect on the lowering of GH levels, especially between 7 and 10 h after drug administration. These results suggest that chronic therapy with a combination of both drugs may be as effective as therapy with higher doses of either compound alone. Albeit transient, octreotide caused a rapid near total suppression of insulin release in the morning, 15 to 45 min after administration. Postprandial glucose rise, between 2 and 3.5 h after breakfast was significantly higher during octreotide than on the control day.     

Bromocriptine treatment of acromegaly

Bromocriptine at a dose of 7.5-30 mg/day was given to 12 acromegalics for 6 mo. Mean serum growth hormone (GH) levels during a glucose tolerance test (GTT) were significantly lowered by the drug. In four patients the serum GH response during a GTT was suppressed to normal (i.e. less than or equal to 5 mlU/liter). If bromocriptine had not brought the serum GH response to a GTT to normal at a dose of 20 mg/day, this effect was not achieved by raising the dose to 30 mg/day. Bromocriptine was effective for the duration of treatment. On discontinuing therapy there was an increase in serum GH levels. No obvious clinical changes in the acromegalic features were noted. One patient with impaired glucose tolerance and one with established diabetes had normal glucose tolerance while on bromocriptine and another two patients with impaired glucose tolerance showed no obvious changes while on the drug. Side effects were minor. X-rays of the pituitary fossa before starting and at the end of treatment showed no significant change. We conclude that although bromocriptine is the most promising form of medical treatment for acromegaly to date, it is fully effective only in a minority of patients.     

LONG-TERM TREATMENT OF HYPERPROLACTINAEMIA WITH BROMOCRIPTINE: EFFECT OF DRUG WITHDRAWAL

Fifty-one patients with hyperprolactinaemia (23 with macroadenoma, 23 with microadenoma, and five with idiopathic hyperprolactinaemia) were treated with bromocriptine for 2-12 years (4.9 +/- 2.9 years, mean +/- SD). During therapy, the serum PRL levels were suppressed into the normal range in all but five patients. In these five patients, despite the high circulating PRL, gonadal function returned to normal in three, while in the other two gonadotrophin reserve was impaired even before therapy. Gel chromatography showed that one of these patients had a high proportion of a large molecular weight form of PRL. Twenty-four patients received bromocriptine as the sole method of treatment for over 2 years (3.4 +/- 2.3 years). In five out of the 24 subjects (21%), serum PRL remained normal with no clinical symptoms after prolonged drug withdrawal (1-4 years). Twenty-one patients received radiotherapy in conjunction with bromocriptine therapy. Of these 11 had prior surgery. After a follow-up of 6.0 +/- 3.0 years after radiotherapy, serum PRL remained within the normal range in 6 out of 21 subjects (29%), 1-4 years after bromocriptine withdrawal. One of the patients had impaired GH response to insulin hypoglycaemia developing after radiotherapy. We conclude that prolonged bromocriptine treatment is an effective treatment for prolactinomas.     

CHANGES IN CIRCULATING SOMATOMEDIN-C LEVELS IN BROMOCRIPTINE-TREATED ACROMEGALY

To determine whether the improvement in clinical status of patients with active acromegaly correlates with a reduction of circulating somatomedin-C, serum immunoreactive somatomedin-C was measured in twenty-seven patients before and during bromocriptine therapy. The patients were assessed using a clinical and metabolic score which included both subjective criteria of improved sweating and facial features, and objective criteria of a reduction in ring circumference and the area under the glucose tolerance curve. Using this, together with the change in GH levels before and during bromocriptine therapy, the patients could be divided into three groups. In one group, there was no clinical improvement, a less than 30% decline in somatomedin-C, and in four of six patients no significant decline in GH. In both the other groups there was clinical improvement and a greater than 30% decrease in somatomedin-C. In one of these two groups, however GH did not decline, while in the other it was reduced significantly. The results suggest that during bromocriptine treatment of acromegaly, serum somatomedin-C concentrations correlate better with clinical status than does serum GH. Since some patients have no significant fall in GH but show both clinical improvement and a reduction in somatomedin-C, it seems likely that in some patients bromocriptine may improve acromegaly by a mechanism other than a simple decrease in total immunoreactive GH secretion.     

Dopaminergic treatment of acromegaly: different effects on hormone secretion and tumor size

We studied the effects of long term treatment with bromocriptine (Br) or lisuride (L) on GH secretion and tumor size in 19 acromegalic patients with large pituitary adenomas. In 22 additional patients with smaller adenomas, only plasma GH levels were monitored during treatment. All patients underwent an acute test with 2.5 mg Br or 0.3 mg L and, on the basis of GH changes, were classified as responders, i.e. reduction in circulating GH concentrations by at least 50% below baseline, or as nonresponders. The chronic treatment was 5-20 mg/day Br in 26 patients or 0.3-2.0 mg/day L in 15 patients. Treatment was given for 4-26 months (mean +/- SE, 13.3 +/- 2.8 months). Plasma GH levels (baseline, 46.3 +/- 8.3 ng/ml) were significantly lower in the group as a whole (22.7 +/- 3.6 ng/ml; P less than 0.01) after the first month of treatment with dopamine agonist agents. GH levels decreased significantly in those acromegalic patients who responded to the acute test (P less than 0.001), but were unchanged in the nonresponders. In addition, there was a significant correlation between the maximal percent GH decrease in the acute test and the response during chronic treatment (r = 0.73; P less than 0.01). Computed tomography failed to show any tumor size changes in any of the GH nonresponders who had a macroadenoma . However, in two patients in the acute responder group with macroadenomas, chronic dopamine agonist therapy resulted in reduction of the extrasellar portion of the tumor (-30% and -40% of tumor area, respectively). These data show that although dopaminergic drugs lower GH levels and reverse signs and symptoms of active disease in those acromegalic patients who are responsive to an acute challenge, tumor size reduction occurred in a minority of such patients.     

重组人生长激素治疗对生长激素缺乏症患者甲状腺功能的影响

为探讨生长激素治疗对甲状腺功能的影响及其机制，给１９例特发性生长激素缺乏症患者每日皮下注射重组人生长激素（ｒｈＧＨ）Ｇｅｎｏｔｒｏｐｉｎ０．１ＩＵ／ｋｇ体重，治疗１年，观察治疗前后甲状腺功能及血促甲状腺激素（ＴＳＨ）对静脉推注促甲状腺素释放激素（ＴＲＨ）的反应。经Ｇｅｎｏｔｒｏｐｉｎ治疗后，患者血清Ｔ４及ＦＴ４水平较治疗前明显下降（Ｐ＜０．０１）；治疗半年后，血清ＦＴ３水平亦较治疗前下降（Ｐ＜０．０５）；而血清Ｔ３、３，３′，５′－三碘甲状腺原氨酸及ＴＳＨ水平无明显变化（０．２＜Ｐ＜０．３）。治疗１年后，８例患者血清ＦＴ４水平降至正常范围以下，依此将患者分为治疗后甲状腺功能正常组及降低组，结果证实甲状腺功能降低组在治疗前或治疗后ＴＳＨ对ＴＲＨ兴奋的反应均较甲状腺功能正常组高（Ｐ＜０．０５）。血清ＴＳＨ对ＴＲＨ的反应增强提示患者治疗前就已有潜在的ＴＲＨ缺乏，后者可能是ｒｈＧＨ治疗过程中ＦＴ４及Ｔ４水平下降的潜在基础。因此在ｒｈＧＨ治疗过程中需监测特发性生长激素缺乏症患者的甲状腺功能，以及时给予替代治疗。     

Different responses of growth hormone secretion to guanfacine, bromocriptine, and thyrotropin-releasing hormone in acromegalic patients with pure growth hormone (GH)-containing and mixed GH/prolactin-containing pituitary adenomas

There is great variability in the GH secretory responses to different stimuli in patients with acromegaly. In the present study, we compared the effects on GH secretion of two compounds (bromocriptine and TRH), which presumably act directly at the pituitary level, with the effect of the centrally acting alpha-adrenergic agonist guanfacine in 14 untreated acromegalic patients. These in vivo responses of GH release were correlated with the results of immunocytochemical studies of the pituitary adenomas. In nine patients with pure GH-containing adenomas, GH secretion was suppressed by bromocriptine by more than 50% in one patient, while TRH stimulated GH release by more than 100% in another patient. Guanfacine (2 mg, orally) did not elicit a change in circulating GH levels in any of these nine patients. In the group of five patients with mixed GH/PRL-containing adenomas, however, bromocriptine suppressed GH levels by more than 50% in all patients, and TRH stimulated GH release by more than 100% in four of them. Guanfacine stimulated GH secretion significantly in four of these five patients. Guanfacine inhibited GH secretion significantly in five other acromegalic patients who had been treated 5-10 yr previously by external pituitary irradiation. We conclude that in acromegaly, the presence of PRL within the GH-secreting pituitary adenoma makes GH secretion more sensitive to bromocriptine and TRH, while normal sensitivity to hypothalamus-mediated stimulation (alpha-adrenergic agonist) is retained to some extent. In contrast, pure GH-secreting tumors responded little or not at all to bromocriptine, TRH, or guanfacine.     

PITUITARY FUNCTION IN PROLACTINOMA. EFFECT OF SURGERY AND POSTOPERATIVE BROMOCRIPTINE THERAPY

Forty-five women and fifteen men with prolactinomas have been treated surgically. Patients with large tumours received pituitary irraditation and postoperative hyperprolactinaemia was treated with bromocriptine. The patients have been followed-up for 6–36 months following the operation. The tumours were larger and the levels of production higher in men as compared with women. All women had amenorrhoea. Galactorrhoea was present in forty-three women but not in the men. After surgery serum prolactin levels fell significantly in all women but remained above normal in thirty-six; prolactin remained high in twelve men. Bromocriptine effectively decreased the postoperative hyperprolactinaemia. The surgical complications were oculomotor nerve paresis in one woman and one man. After surgery six (23%) women developed impaired GH secretion, six (15%) impaired thyroid function, eight (18%) impaired cortisol secretion and five (17%) impaired LH secretion in isolation or combination which had not been present preoperatively. Three patients relapsed. Fifteen women menstruated after surgery and ten began to do so during the subsequent bromocriptine treatment. Thus, menstruation was restored in all six women with microadenomas, in sixteen of twenty patients with intrasellar macroadenomas and three of nineteen patients with suprasellar adenomas. The preoperative LH-reserve proved to be an important prognostic indicator. Nine patients, i.e. 50% of patients desiring fertility became pregnant. In the men gonadal function deteriorated in four patients and did not improve in any without testosterone treatment.