Effect of bromocriptine withdrawal in acromegaly on body composition as assessed by bioelectrical impedance analysis

To evaluate the effect of bromocriptine withdrawal after dopaminergic long-term treatment (15.0 +/- 6.8 mg/day, mean +/- SD) in 12 acromegalic patients on body composition, bioelectrical impedance was measured before and at the end of two weeks of drug withdrawal. During withdrawal basal hGH and IGF-I increased from 2.5 +/- 1.9 micrograms/l and 2.1 +/- 0.8 kU/l to 9.1 +/- 11.7 micrograms/l and 4.9 +/- 2.2 kU/l, respectively, and the hGH secretion deteriorated significantly both after oral glucose load and in the TRH test, indicating recurrence of active acromegaly. Reactance and resistance decreased by 5 +/- 4 and 23 +/- 19 omega, respectively (p less than 0.01), whereas body weight remained constant (+0.4 +/- 2.1 kg). Bioelectrical impedance analysis indicated evident shifts in body composition, i.e. a significant reduction of body fat (-2.0 +/- 1.7 kg) and a simultaneous increase in both lean body mass (+2.4 +/- 2.2 kg) and total body water (+1.8 +/- 1.6 l). The changes in body composition were related to a combined effect of unsuppressed hypersomatotropism and the lack of bromocriptine actions other than inhibition of hGH secretion (for example stimulation of the renin-angiotensin-aldosterone system by both the recurred hypersomatotropism and the absence of dopaminergic bromocriptine effects). We conclude that bioelectrical impedance analysis is a good additional tool to assess the pathophysiological effects of bromocriptine withdrawal in long-term treated acromegalic patients.     

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.     

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.     

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.     

Effect of the dopamine agonist, lergotrile mesylate, on circulating anterior pituitary hormones in man.

The effects of the ergoline derivative, lergotrile mesylate, on the serum levels of PRL, GH, TSH, LH, FSH, cortisol, and blood sugar were studied in six normal males. The effects of lergotrile mesylate on the serum levels of GH and PRL were also studied in eight patients with acromegaly and in two with idiopathic hyperprolactinemia. In the normal subjects, 2 mg oral lergotrile lowered basal PRL levels after 90 min and markedly impaired the PRL response to TRH (200 micrograms iv); the mean peak value +/- SE was 8.3 +/- 1.1 micrograms/liter, compared to the control value of 66.6 /+- 11.3 micrograms/liter. Lergotrile raised serum GH levels in five of the six subjects to peaks of 8-49 micrograms/liter, compared to 2-8 micrograms/liter after placebo. In three subjects, the GH response to lergotrile was attenuated by the prior administration of the dopamine antagonist, metoclopramide (10 mg orally). Lergotrile had no effect on FSH and LH levels under basal conditions or after the gonadotrophin-releasing hormone (GnRH; 100 micrograms iv). Circulating TSH levels were unaltered basally but impaired after TRH. Blood sugar levels were unaltered; serum cortisol was elevated in five of six subjects; there was a brief depression of diastolic blood pressure, but no change in pulse rate. The side effects after lergotrile were variable, with drowsiness as a consistent feature. These actions are similar to those of bromocriptine (an ergot derivative treatment of hyperprolactinemia and acromegaly, to suppress PRL and GH secretion, and in parkinsonism. Therefore, it may be expected that lergotrile could fulfill these clinical uses; however, in the studies comparing the effects of single oral doses of lergotrile (2 mg) and bromocriptine (2.5 mg) on GH and PRL secretion in patients with acromegaly and hyperprolactinemia, lergotrile in the dose used has been found to have an earlier onset and shorter duration of action.     

Current concepts in the biochemical assessment of the patient with acromegaly.

Biochemical assessment of a patient for acromegaly aims to definitively establish or exclude the presence of growth hormone excess. Whether applied to a newly recognized patient or to detect residual disease after therapy, this assessment is best accomplished by measurement of both the degree of GH suppression after oral glucose administration (OGTT) and levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). When measured properly and compared to a well-characterized, age-adjusted normative database, elevation of the serum IGF-I level is a sensitive and specific indicator for the presence of acromegaly or persistent disease after therapy. The diagnosis of acromegaly can be confirmed by documenting an elevated IGF-I level in combination with failure of GH to suppress after oral glucose to below 0.3 microg/l, when GH is measured with a highly sensitive and specific assay. Persistently, normal IGF-I levels along with a nadir GH <0.3 microg/l should exclude the diagnosis. In assessing disease status during or after treatment, normalization of IGF-I is an essential criterion for biochemical control. It is important to recognize that nadir GH levels are >0.3 microg/l in some healthy subjects, so this criterion alone is not diagnostic of acromegaly. Also, because of heterogeneity of clinically available GH assays, this GH criterion, which was developed with a research assay, may not be applicable to use with all other assays. A nadir GH cut off of 1 microg/l has been found to be reliable for use with some standard immunoassays. It is recommended that glucose-suppressed GH levels be interpreted in conjunction with those of IGF-I and with consideration of conditions other than acromegaly that can alter them. With greater assay standardization and the use of IGF-I levels along with new rigorous criteria for interpretation of GH suppression during a OGTT we can improve our identification of patients with acromegaly in earlier stages of the disease as well as better recognize residual disease during therapy.     

Hormonal and metabolic effects of radiotherapy in acromegaly: long-term results in 128 patients followed in a single center

Conventional radiotherapy is usually indicated in acromegaly when surgery fails to normalize GH secretion. However, the benefits of radiotherapy are delayed. This has raised questions about the potency of this treatment for reaching the safe GH level of 2.5 microg/L and for normalizing insulin-like growth factor I (IGF-I) levels, both of which are currently recommended as the therapeutic goal. To evaluate the long-term hormonal and metabolic effects of radiotherapy in acromegaly, a retrospective analysis was undertaken studying 128 patients followed for 11.5+/-8.5 yr (mean +/- SD) in a single center. The preradiation GH levels decreased as a function of time to 50% at 2 yr, 20% at 5 yr, and 10% at 10 yr. Basal GH levels below 2.5 microg/L were obtained in 7% of the patients at 2 yr, 35% at 5 yr, 53% at 10 yr, and 66% at 15 yr. A basal GH level below 2.5 microg/L was associated with suppression of GH below 2 microg/L during an oral glucose tolerance test and normalization of IGF-I levels in 9 of 10 patients. Preradiation GH levels was the sole factor that could predict the delay in GH fall to below 2.5 microg/L (P = 0.008). At the last follow-up, IGF-I levels were normalized in 79% of the patients (37 of 47; mean follow-up, 15.0+/-11.3 yr). In the 32 patients presenting with diabetes mellitus, improvement of glucose tolerance was associated with lower GH levels after treatment (35+/-78 microg/L in the group of 13 patients still presenting diabetes; 9+/-12 microg/L in the group of 4 patients with glucose intolerance; 5+/-8 microg/L in the 14 patients with normal glucose tolerance; P = 0.04). Ten years after termination of radiotherapy gonadotroph, thyreotroph and corticotroph deficiencies were observed in 80%, 78%, and 82% of the patients, respectively. In conclusion, conventional radiotherapy can reduce GH levels below the optimal level of 2.5 microg/L and normalize IGF-I levels in acromegaly. However, the incidence of late hypopituitarism is high, and the delay to obtain this safe GH secretory status can be long, depending on the preradiation GH level. These parameters should be considered when adjuvant therapy is needed after surgery.     

The sensitivity of growth hormone secretion to medical treatment in acromegalic patients: influence of age and sex

OBJECTIVE: We investigated the relationship between age, sex, pituitary tumour volume, serum GH, PRL and IGF-I levels with the responsiveness of GH to TRH, bromocriptine and octreotide in patients with acromegaly. DESIGN: We performed a retrospective study. Correlations were determined between all variables using univariate regression analysis. PATIENTS: One hundred previously untreated acromegalic patients were studied (60 males (age 23-76; mean 49 years) and 40 females (age 25-83; mean 51 years)). MEASUREMENTS: We studied tumour volume, fasting morning circulating levels of GH, PRL and IGF-I, mean 24-hour circulating GH levels and the acute GH responses to TRH, bromocriptine and octreotide. RESULTS: Tumour size was related to serum and mean 24-hour GH levels, but not to IGF-I. Circulating IGF-I and GH levels were related only for the group of patients whose fasting and unsuppressed GH level was 80 mU/l (40 micrograms/l) or less. Older patients tended to have lower circulating GH and IGF-I levels. There was a close similarity in the responsiveness of tumorous GH secretion to TRH, bromocriptine and octreotide. An elevated serum PRL level predicted a stronger inhibitory response of bromocriptine on GH. The sensitivity of GH release to octreotide was highest in elderly (especially male) acromegalics, as well as in patients with lower IGF-I levels. CONCLUSIONS: Hormone secretion by GH secreting pituitary tumours, as well as circulating IGF-I levels, tend to be lower in elderly patients. These tumours are more sensitive to octreotide, especially in elderly male patients. This suggests that octreotide might be used especially successfully as a primary medical therapy in elderly, male acromegalics.     

The role of IGF binding protein-3 as a parameter of activity in acromegalic patients.

OBJECTIVE: The production of insulin-like growth factor binding protein-3 (IGFBP-3), the main IGF-I binding protein, is regulated by GH, and its serum levels are increased in acromegaly. We investigated its potential value as a parameter of acromegaly activity or remission in comparison with IGF-I, taking GH suppression below 2 microg/l after glucose load as the normal standard. METHODS: Data from 40 acromegalic patients (12 males and 28 females, aged 28 to 79 years) were obtained retrospectively from stored samples. From these, 145 pairs of IGF-I/IGFBP-3 values were collected; in 67 of them, simultaneous measurement of GH after glucose loading allowed their classification as active or inactive acromegaly. Relationships between IGF-I, IGFBP-3 and GH after glucose load were assessed, as well as differences between IGF-I and IGFBP-3 levels in active and inactive acromegaly. RESULTS: Significant positive correlation between IGF-I and IGFBP-3 in 145 samples was observed (r=0.49, P<0. 0001). As for the 67 samples in which activity or remission could be defined in terms of GH after glucose load, 50 were active and 17 inactive. Both IGF-I and IGFBP-3 significantly correlated with minimum GH (r=0.53, P<0.0001 and r=0.41, P<0.001 respectively). For both parameters, significant differences of means between active and inactive cases were observed (623+/-296 vs 300+/-108 ng/ml, P<0.0001 for IGF-I, and 4.1+/-1.3 vs 3.2+/-0.9 microg/ml, P<0.006 for IGFBP-3). Yet, when comparing in individual cases their classification as active or inactive with the finding of normal or increased IGF-I and IGFBP-3, among active cases 16% appeared as normal according to IGF-I, and 50% appeared as normal in terms of IGFBP-3. Among inactive cases, 23.5% appeared as active according to IGF-I, while 17.5% appeared as active in terms of IGFBP-3. CONCLUSION: Even though IGFBP-3 reflects GH secretion, it offers no advantage over IGF-I in the assessment of acromegaly, and it may underestimate disease activity in acromegalic patients.     

Significance of "abnormal" nadir growth hormone levels after oral glucose in postoperative patients with acromegaly in remission with normal insulin-like growth factor-I levels

Our initial study in postoperative patients with acromegaly identified a group of patients in remission, as defined by normal IGF-I levels, but who had a subtle abnormality of GH suppression after oral glucose. To investigate the significance of this abnormality, we have undertaken further detailed testing of GH secretion and a longitudinal follow-up of some of these patients. Of the 110 postoperative patients with acromegaly evaluated by oral glucose tolerance test, 76 were in remission (i.e. normal IGF-I level), and of these subjects with acromegaly in remission, 50 had normal nadir GH (<0.14 microg/ml) (group I), and 26 had abnormal nadir GH (>0.14 microg/ml) (group II). Fourteen subjects in remission, seven from remission group I and seven from remission group II, underwent additional testing consisting of both hourly GH sampling over 8 h and, on a separate day, arginine stimulation testing. The mean of hourly GH was higher in group II (0.47 +/- 0.04 microg/liter) than in group I (0.19 +/- 0.07 microg/liter; P = 0.002). GH response to arginine was greater in group II than in group I (P < 0.01). Of those patients in remission from the initial cohort studied, 49 (30 subjects from group I and 19 from group II) underwent serial longitudinal oral glucose tolerance testing every 1-2 yr over a 1- to 6.5-yr period (mean follow-up, 3.2 yr). The initial pattern of GH suppression persisted in most patients. IGF-I levels remained normal in all patients in group II, but five subjects from group II developed an elevated IGF-I level and, thus, a biochemical recurrence. The rate of disease recurrence was greater in group II than in group I (P = 0.003). We have found that some postoperative subjects with acromegaly in remission with normal IGF-I levels have persistently abnormal nadir GH levels after oral glucose that may be accompanied by other evidence of greater GH secretion than postoperative patients with normal GH suppression. This abnormal pattern of GH suppression may be associated with increased risk of disease recurrence in some patients.     

Remission criteria for the follow-up of patients with acromegaly

OBJECTIVE: The aim was to evaluate the validity of current remission criteria in acromegaly, a random GH level of <2.5 microg/l, a glucose-suppressed GH level of <1 microg/l and a normal IGF-I level. DESIGN: In forty-one patients treated for acromegaly (23 males and 18 females, 20-69 years) and 94 healthy subjects (50 males and 44 females, 20-78 years), basal GH and IGF-I levels and nadir GH levels after 75 g oral glucose were evaluated in decade blocks; these were assayed by sensitive immunoradiometric assays. RESULTS: Basal GH levels varied widely from 0.022 to 10.4 in healthy subjects and were >2.5 microg/l in 19%. The mean post-glucose GH nadir was 0.067+/-0.009 microg/l (range 0.003-0.4 microg/l) and the upper limit of the GH nadir was 0.26 microg/l (means+2 S.D.) in healthy subjects. Thirty-five patients with acromegaly had high-for-age IGF-I levels in relation to our healthy subjects. In this group, 15 (42.9%) patients had basal GH levels of <2.5 microg/l, 14 (40%) patients had nadir GH levels of <1 microg/l, and three (8.6%) patients had GH suppression to <0.26 microg/l which was defined as normal GH suppression in our healthy subjects. Only six patients with acromegaly had normal-for-age IGF-I levels and all of these patients had basal GH levels of <2.5 microg/l and all but one had nadir GH levels of <0.26 microg/l. CONCLUSIONS: A basal or random GH level of <2.5 microg/l is not a reliable criterion for remission in acromegaly and the currently accepted normal upper limit of 1 microg/l for post-glucose GH suppression is too high. Post-glucose nadir GH levels, measured with sensitive assays, can be <1.0 microg/l in 40% and basal GH levels can be <2.5 microg/l in 43% of the active acromegalic patients. IGF-I levels appeared to correlate better with a nadir GH cut-off of 0.26 microg/l rather than 1 microg/l in the determination of disease activity.     

Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status

BACKGROUND: Somatostatin analogues (SA) are currently the mainstay in the medical treatment of acromegaly. However, even high doses of depot SA for prolonged periods do not achieve GH-IGF-I normalization in some patients. Even though some data were reported about the addition of cabergoline, a long-acting dopamine agonist (DA), to SA in resistant patients, definite data are still lacking. DESIGN: Prospective open trial. PATIENTS: In 19 acromegalic patients with active disease (34-82 years old, seven males, 12 females) resistant to chronic (9-12 months) depot SA (octreotide-LAR, 30 mg/28 days in 13 patients, lanreotide, 60 mg/28 days intramuscularly in six patients) cabergoline was added (combined treatment). In these patients, SA treatment had partially relieved GH and IGF-I hypersecretion but no patient had achieved 'safe' GH and normal IGF-I-values. Eight patients had PRL levels greater than 15 micro g/l (range 16-60 micro g/l; 1 micro g = 21.2 mIU). Immunohistochemistry (IHC) was positive for PRL in four out of eight operated patients. RESULTS: The addition of cabergoline, using the minimal effective and the maximal tolerated dose (range 1-3.5 mg/week), decreased GH from 6.6 +/- 0.9 to 4.6 +/- 0.6 micro g/l (P = 0.018), and IGF-I from 552 +/- 44 to 428 +/- 54 micro g/l (P = 0.019) after 6 months (median, range 3-18 Months). Combined treatment decreased GH to < 2.5 micro g/l in four patients (21%) and normalized IGF-I for age in eight patients (42%). It obtained a decline of both GH and IGF-I (-49 +/- 7%, and -47 +/- 5%, respectively) in nine patients (47%), and a partial improvement in six (32%) patients (GH decreased by 43 +/- 8% in four, and IGF-I by 35-38% in two patients). No change was observed in two patients, and worsening in two other patients. Results were not dependent on PRL status (serum levels or IHC). Combined treatment was well tolerated. CONCLUSIONS: The addition of cabergoline to depot SA-resistant acromegalic patients is effective, not dependent on PRL values and normalizes IGF-I levels in 42% of patients. The association of long-acting DA and SA deserves a more relevant role in the therapeutical algorithm of acromegaly.     

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.     

Gamma knife radiosurgery for acromegaly--long-term experience

OBJECTIVE: The Leksell gamma knife (LGK) is one of the treatment options for pituitary adenomas. We report on our long-term experience treating acromegaly using LGK. DESIGN: Since 1993 we have followed 96 acromegaly patients through periods of from 12 to 120 months. The mean follow-up period was 53.7 +/- 26.8 months. Seventy-two patients were treated with neurosurgery prior to LGK; for 24 LGK was the primary treatment. Thirteen patients were irradiated twice, due to persistent activity of the adenoma or its residue. Pituitary functions were tested at 6-month intervals, post-irradiation. The target tumour volume for radiosurgery was between 93.3 and 12 700 mm3 (median 1350 mm3). RESULTS: Fifty per cent of the patients achieved mean GH < 2.5 microg/l within 42 months, normalized their IGF-I within 54 months, and achieved GH suppression in the oral glucose tolerance test (oGTT) < 1 microg/l with normal IGF-I within 66 months. LGK effectiveness was dependent on initial adenoma hormonal activity (GH and IGF-I serum levels), not on the size of the adenoma. Patients with primary neurosurgery followed by LGK irradiation had better outcomes than those with LGK alone. Irradiation arrested all adenoma growth, causing tumour shrinkage in 62.3% of patients. Twenty-six developed hypopituitarism when irradiated by 15 Gy (or more) on functional peritumoral pituitary tissue. No hypopituitarism appeared using lower doses. CONCLUSIONS: In acromegaly, LGK is a useful adjunct to primary neurosurgery when treating post-surgical residues because it can limit the duration of medical therapy. It can be used as a primary therapy when neurosurgery is not possible.     

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

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

Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly

The effects of a 12- to 24-month treatment with depot long-acting octreotide (OCT-LAR) on hormone profile, tumor mass, and clinical symptoms were reported in 36 patients with active acromegaly [GH, 34.2 +/- 5.6 microg/L; insulin-like growth factor I (IGF-I), 784.5 +/- 40.4 microg/L]. Fifteen patients were de novo whereas 21 had previously undergone unsuccessful surgery. Serum GH (P < 0.0001) and IGF-I levels (P < 0.0001) significantly decreased as early as after the first injection of OCT-LAR and progressively declined during the 12-24 months of treatment both in de novo and in operated patients. At the last follow-up, GH hypersecretion was controlled (< or =2.5 microg/L) in 69.4% whereas normal IGF-I levels were achieved in 61.1% of patients. GH and IGF-I suppression during OCT-LAR treatment was similar in de novo and operated patients as shown by nadir GH (2.3 +/- 0.6 vs. 2.2 +/- 0.6 microg/L) and IGF-I (323.1 +/- 34.9 vs. 275.5 +/- 33.0 microg/L), percent suppression of GH (92.7 +/- 2.0 vs. 85.9 +/- 3.3%) and IGF-I (57.4 +/- 4.9 vs. 61.5 +/- 4.6%), and prevalence of GH (73.3 vs. 76.2%) and IGF-I (53.3 vs. 71.4%) control. A decrease in tumor volume was observed in 12 of 15 de novo patients, whereas no shrinkage was detected in 4 of 9 operated patients. No patient had tumor reexpansion during OCT-LAR treatment. Significant clinical improvement was obtained in all patients; heart rate, systolic blood pressure, and diastolic blood pressure significantly decreased in the entire population. A mild but significant increase of blood glucose levels, followed by a decrease of serum insulin levels, was observed after 3 months of treatment: this effect subsided with treatment continuation. OCT-LAR treatment was well tolerated by most patients. In conclusion, long-term treatment with OCT-LAR was effective in controlling GH and IGF-I hypersecretion in most patients with acromegaly, when applied either as primary therapy or as adjunctive therapy after surgery. Tumor shrinkage was observed in de novo patients during OCT-LAR treatment, suggesting that it can be successfully applied as primary therapy in patients bearing invasive tumors, who are less likely to be cured after surgery.     

Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist

CONTEXT: Pegvisomant is a GH receptor antagonist that blocks the peripheral actions of GH in acromegaly. Pegvisomant, in contrast to somatostatin (SMS) analogs, does not suppress the activity of the GH-producing adenoma. OBJECTIVE: We assessed the effects of cotreatment with pegvisomant and SMS in acromegaly on GH secretion, IGF-I levels, and glucose tolerance. DESIGN, PATIENTS, AND INTERVENTIONS: Eleven patients with persistent disease despite previous therapy underwent the following fixed treatment algorithm: 1) on SMS therapy, 2) off therapy for 2 months, 3) 6-wk treatment with 10 mg/d pegvisomant, 4) 6-wk treatment with 15 mg/d pegvisomant, and 5) 3-month treatment with 15 mg pegvisomant plus SMS. Blood was sampled in the fasting state and during an oral glucose tolerance test. RESULTS: Total serum IGF-I levels (micrograms per liter) decreased after pegvisomant, but the lowest levels were obtained with cotreatment [458 +/- 67 (SMS), 562 +/- 78 (active), 376 +/- 51 (10 mg), 269 (15 mg), 195 +/- 24 (combined) (P < 0.0001)]. Free and bioactive IGF-I changed in a similar pattern. Steady-state pegvisomant levels (micrograms per liter) were obtained, but SMS cotreatment increased pegvisomant levels by 20% (P = 0.02) [2631 +/- 616 (10 mg), 6536 +/- 1413 (15 mg), 8030 +/- 1914 (combined)]. Pegvisomant increased endogenous GH levels (micrograms per liter), which was countered by SMS cotreatment [5.1 +/- 1.3 (SMS), 8.9 +/- 2.9 (active), 14.6 +/- 4.9 (10 mg), 19.7 +/- 6.5 (15 mg), 11.8 +/- 2.8 (combined) (P < 0.01)]. Plasma glucose levels (millimoles per liter) were highest during SMS and lowest during pegvisomant 15 mg [2-h oral glucose tolerance test: 10.3 +/- 0.7 (SMS), 8.9 +/- 0.7 (active), 7.2 +/- 0.7 (10 mg), 6.5 +/- 0.5 (15 mg), 8.0 +/- 0.8 (combined) (P = 0.02)]. CONCLUSIONS: Dual blockade of the GH axis with pegvisomant and a SMS analog is feasible in acromegaly.     

Sandostatin LAR in acromegaly: a 6-week injection interval suppresses GH secretion as effectively as a 4-week interval

INTRODUCTION: Depot preparations of long-acting somatostatin analogues are being used increasingly in the treatment of GH hypersecretion in patients with acromegaly, either as primary treatment or as secondary treatment following incomplete surgery. In 60% of these patients, Sandostatin long-acting release (LAR), the depot preparation of octreotide, achieves effective suppression of serum GH (< 5 mU/l) and IGF-I levels. The advice is to administer Sandostatin LAR at 4-week intervals. After injection, serum octreotide shows an initial peak and thereafter maximal values between 14 and 42 days. There have been suggestions that the dose interval of this preparation could be increased, resulting in reduced costs, although this concept has not been confirmed by studies. AIM OF THE STUDY: We performed a prospective, cohort study in patients with active acromegaly but with normal serum GH and IGF-I levels during Sandostatin LAR treatment to assess whether the dose interval could be safely increased from 4 to 6 weeks, without significant effect on serum GH concentrations or other biochemical and clinical markers of GH hypersecretion. PATIENTS AND METHODS: Fourteen patients (seven males) with GH concentrations below 5 mU/l during Sandostatin LAR treatment entered an 8-week withdrawal study following an injection. Subsequently, during an interval study patients received injections at 6-week intervals (t = 0, 8, 14, 20, 26, 32, 38 and 44 weeks). Study parameters (fasting GH, average GH of eight plasma samples, IGF-I, and octreotide concentrations, symptoms score and quality-of-life score) were assessed 2, 4, 6 and 8 weeks following the first injection (withdrawal) and at 26 and 44 weeks (interval study) before the next injection. RESULTS: During the withdrawal study, mean serum GH concentration increased significantly from 1.68 +/- 0.3 at 4 weeks to 2.57 +/- 0.5 mU/l at 6 weeks (P = 0.04, 4 vs. 6 weeks) and to 2.89 +/- 0.4 mU/l at 8 weeks (P < 0.001, 4 vs. 8 weeks). Mean serum GH concentration was below 5 mU/l in all patients at all time points, except for one patient at 8 weeks, and IGF-I levels remained normal in all patients. During withdrawal up to 8 weeks there was no significant change in serum IGF-I concentration, symptoms score or quality-of-life score. Mean serum octreotide decreased significantly from 1610 +/- 355 ng/l at 2 weeks to 1045 +/- 272 ng/l at 6 weeks (P = 0.002, 2 and 4 vs. 6 weeks) and to 559 +/- 147 ng/l at 8 weeks. In the interval study, one patient had mean serum GH above 5 mU/l associated with an increase in symptoms at 26 weeks and she was withdrawn from the study. The remaining 13 patients completed the 6-weekly injection study protocol and in the long term no significant changes in mean serum GH concentration, IGF-I concentration or symptom scores were observed (6 vs. 26 and 44 weeks). All patients had a mean serum GH concentration < 5 mU/l and serum IGF-I remained normal in 11 out of 14 patients at 26 weeks and nine out of 13 patients at 44 weeks. Moreover, the mean octreotide concentrations measured 6 weeks after a Sandostatin LAR injection did not decrease in the long term. CONCLUSION: On the basis of serum GH concentrations, most patients with serum GH levels < 5 mU/l during Sandostatin LAR treatment using a 4-weekly schedule can be effectively treated with 6-weekly injections. However, during long-term treatment with 6-weekly injections, discordant IGF-I and GH results were observed in 30% of the patients and careful clinical monitoring is therefore required.     

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

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

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

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