[show abstract][hide abstract] ABSTRACT: IGF-I levels normalize in the majority of patients with acromegaly treated with the GH receptor antagonist pegvisomant. To date, the efficacy of pegvisomant has been demonstrated with daily administration of doses ranging from 10 to 40 mg. However, given the known long half-life of the drug in circulation, we hypothesized that dosing less frequently than daily would still maintain the drug's efficacy. We studied 10 patients with active acromegaly treated with pegvisomant. This therapy was begun at 10 mg daily but then titrated up in dose or down to alternate-day dosing to try to maintain serum IGF-I levels in the upper half of the patients' age-adjusted normal range. We found that in five of 10 patients, serum IGF-I levels remained normal on less frequent than daily pegvisomant. Signs and symptoms of the disease and a disease-related morbidity, insulin resistance, remained improved in these patients. We demonstrate for the first time the continued efficacy of alternate-day administration of pegvisomant.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Dopamine agonists have been used as adjunctive therapy for acromegaly for many years, but relatively few studies have assessed the efficacy of a newer agonist, cabergoline. Some data suggest that cabergoline may be more effective than bromocriptine, in particular for those patients whose tumors secrete both growth hormone and prolactin. In order to assess this possibility further, we have evaluated the biochemical response to cabergoline therapy in patients with acromegaly at our center. We describe first an unusual patient who presented with a pituitary macroadenoma secreting both GH and prolactin. At presentation he had elevated levels of growth hormone 6.0 microg/L, IGF-I, 722 ng/ml, and prolactin, 6000 ng/ml. Cabergoline therapy alone was highly effective in this patient and normalized his levels of all three hormones and his gonadal function as well as produced significant shrinkage of his pituitary tumor. Fourteen other patients with more typical, active postoperative acromegaly were administered cabergoline in a 6-month, open label, dose-escalation study. Mean baseline GH was 1.3 +/- .23 ng/ml and fell to a nadir of 0.85 +/- .18 ng/ml on cabergoline therapy (p = 0.03). Mean baseline IGF-I was 520 +/- 45.2 ng/ml and fell to a mean nadir during cabergoline therapy of 368 +/- 29.8 ng/ml (p = 0.0013). At the completion of the cabergoline therapy study period, however, mean IGF-I was 453 +/- 46 ng/ml, not significantly lower than the baseline value (p = 0.11). No changes in tumor sizes occurred on cabergoline therapy. Eight of 14 patients achieved a normal IGF-I at some point during the 24 weeks study period, but the efficacy of cabergoline waned with time as only 3 of 14 (21%) of patients had a persistently normal IGF-I with up to 18 months of cabergoline therapy. Six patients had modest hyperprolactinemia at diagnosis (26-142 ng/ml) and 5 patients had positive immunohistochemical staining of their tumor for prolactin, but in neither of these small groups was cabergoline therapy more effective at normalizing IGF-I than in those patients with apparently pure GH secreting tumors. Three of 14 patients (21%) had side effects that limited therapy. A trial of cabergoline as adjunctive therapy may be considered in select patients with mild disease and small tumor residuals, but the expectation for biochemical control in these patients needs to be kept low, even for tumors that co-secrete GH and prolactin.
[show abstract][hide abstract] ABSTRACT: The orexigenic peptide, ghrelin, is regulated by acute and chronic nutritional state. Although exogenously administered ghrelin stimulates pituitary GH secretion, little is known about the role of ghrelin in endogenous GH secretion or how high GH and IGF-I levels in acromegaly could affect ghrelin secretion and vice versa. Therefore, we evaluated fasting and post oral glucose tolerance test serum ghrelin levels in 19 patients with active acromegaly at baseline and after either surgery in 9 of these or administration of long-acting octreotide (Sandostatin LAR) in the other 10 patients. After surgical cure, fasting ghrelin rose from 312 +/- 56 pg/ml to 548 +/- 97 pg/ml (P = 0.013). Fasting serum ghrelin levels were higher in all patients after surgery and ranged between 112% and 349% of presurgery levels. Ghrelin levels fell significantly during long-acting octreotide therapy from 447 +/- 34 pg/ml to 206 +/- 15 pg/ml (P < 0.0001); ghrelin levels on octreotide ranged between 26% and 70% of baseline levels. Serum ghrelin levels were suppressed significantly during the oral glucose tolerance test in both groups. Pretherapy ghrelin levels correlated negatively with serum insulin levels (r = -0.494; P = 0.03) and insulin resistance as estimated by the homeostasis model assessment score (r = -0.573; P = 0.01). In patients without diabetes mellitus, serum insulin levels in the surgical group were 19.7 +/- 5.4 microU/ml before surgery and fell to 9.7 +/- 0.93 microU/ml after surgery (P = 0.05); levels in the octreotide group were 13.9 +/- 2.8 microU/ml before and fell to 11.2 +/- 2.8 microU/ml on octreotide (P = 0.03). Pretherapy ghrelin levels did not correlate with weight or body mass index, but after therapy in the surgery group ghrelin correlated negatively with weight (r = -0.823, P = 0.012) as has been demonstrated by others in healthy subjects. Ghrelin secretion is dysregulated in active acromegaly; lowered serum levels of ghrelin in active acromegaly rise along with the postsurgery normalization of GH and IGF-I and improved insulin resistance. In contrast to surgical therapy, long-acting octreotide therapy persistently suppressed serum ghrelin levels. It remains to be determined whether altered circulating ghrelin concentrations could impact on body composition changes in acromegaly.
[show abstract][hide abstract] ABSTRACT: The development of highly sensitive and specific GH assays has necessitated a critical re-evaluation of the biochemical criteria needed for the diagnosis of acromegaly. Use of these assays has revealed that GH levels after oral glucose in healthy subjects and postoperative patients with active acromegaly can be significantly less than previously recognized with older GH assays. In order to assess GH criteria for newly diagnosed acromegaly with a modern assay we have evaluated GH levels in 25 patients referred to our Neuroendocrine Unit for evaluation of untreated acromegaly. All patients underwent measurement of basal GH and IGF-I levels and 15 of these patients also underwent oral glucose tolerance testing for GH suppression (OGTT). Basal GH levels were < 1.0 microg/L at diagnosis in 5 of these 25 patients. Nadir GH levels were less than 1 microg/L also in 5 of 15 patients, and as low as 0.42 microg/L. All patients had elevated IGF-I levels preoperatively and pathological confirmation of a GH secreting pituitary tumor at the time of transsphenoidal surgery. The clinical presentations of these patients was variable. Most patients presented with classical manifestations of acromegaly, but 3 of the 5 patients with low nadir GH values had only very subtle signs of acromegaly. Although most newly diagnosed patients have classically elevated GH levels and obvious clinical features of acromegaly, early recognition of disease may uncover patients with milder biochemical and clinical abnormalities. The diagnosis should not be discounted in patients who have elevated IGF-I levels, but have basal or nadir GH levels less than 1 microg/L. Conventional GH criteria for the diagnosis of acromegaly cannot be applied to the use of modern sensitive and specific GH assays.
[show abstract][hide abstract] ABSTRACT: The principal biochemical criteria for cure in acromegaly are normalization of both glucose-suppressed GH levels and IGF-I levels. As we have reported previously, measurement of GH by highly sensitive assay in conjunction with IGF-I levels has led to a re-appraisal of "normal" GH suppression criteria during an OGTT in subjects with acromegaly. In some patients with active acromegaly, glucose-suppressed GH levels as measured by highly sensitive assay are much lower than could previously be appreciated with less sensitive GH assays and some other patients in apparent remission have subtle abnormalities of GH suppression. A question to arise is whether gender differences in glucose-suppressed GH levels as found by others in young healthy subjects should be considered in our interpretation of OGTT criteria for cure in acromegaly. Therefore, we have evaluated parameters of GH secretion in a larger number of subjects from our cohort of postoperative patients with acromegaly and in healthy subjects in order to determine if gender or age associated differences in these parameters exist. Ninety-two subjects with acromegaly (49 men, 43 women) and 46 age-matched healthy subjects (26 men, 20 women) were evaluated with baseline GH and IGF-I levels and nadir GH levels after a 100 g. OGTT. GH was assayed by highly sensitive IRMA (DSL). Basal GH levels were higher in female than in male healthy subjects, but the fall in GH from baseline (% suppression) was also greater in females resulting in no significant difference in mean nadir GH levels in female vs. male healthy subjects (0.09 vs. 0.08 microg/L). In the subjects with acromegaly, there were no significant gender differences in basal, %GH suppression or nadir GH levels. Basal and nadir GH levels correlated significantly only in subjects with active disease (r=0.84, p<.0001). Similarly, IGF-I levels correlated significantly with basal (r=0.573, p=.0012), and nadir (r=.702, p<.0001) GH levels only in subjects with active disease. Gender differences in IGF-I levels were not apparent in any group of subjects. As expected, IGF-I levels declined with age in those groups of subjects with normal IGF-I levels. Nadir GH levels did not vary with age. In conclusion, we have not found significant gender or age-related differences in nadir GH levels and thus our data does not support separate OGTT criteria for cure in men and women with acromegaly.