The acute effect of a single application of cabergoline on endogenous GH levels in patients with acromegaly on pegvisomant treatment.

OBJECTIVE: Treatment with pegvisomant, an antagonist of growth hormone (GH) receptors, increases GH levels in a dose dependent manner. Cabergoline can suppress GH secretion in approximately 40% of acromegalic patients. However, the acute effects of cabergoline have not been studied in patients treated with pegvisomant. We performed this cross-sectional study to evaluate endogenous GH after an additional single cabergoline administration. DESIGN: 9 acromegalic patients on pegvisomant therapy were included. A 6h GH profile after pegvisomant alone (P) and a 9h profile in combination with oral cabergoline 0.5mg (PC) were performed. After 3 or 6h, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. The GH assay showed no interference with pegvisomant. RESULTS: Endogenous GH levels at baseline did not differ significantly between the profiles (P: 16.5 µg/l (range 3.2-36.6 µg/l), PC: 8.0 µg/l (1.6-48 µg/l), p>0.05). In both profiles, GH fluctuated before meal. GH decreased more pronounced in PC but this decrease was not statistically significant. After meal, a significant decline in endogenous GH levels from 16.4 µg/l (0.4-27.1 µg/l, 100%) to 8.1 µg/l (0.2-24.7 µg/l, 66%) appeared in P at 300 min (p<0.01). Also in PC a decline from 7.8 µg/l (1.1-29.6 µg/l, 100%) to 5.2 µg/l (0.4-23.9 µg/l, 75%) at 300 min was observed but it was not significant. CONCLUSION: Endogenous GH is not significantly decreased after a single oral cabergoline application during pegvisomant treatment in acromegaly.

Serum leptin and ghrelin levels in active and inactive acromegalic patients during an oral glucose tolerance test.

OBJECTIVE: Elevated BMI, fat mass and food intake increases leptin whereas ghrelin is reduced. Ghrelin stimulates growth hormone (GH) secretion. This prospective cross-sectional study was performed to investigate the influence of GH excess on leptin and ghrelin levels at baseline and after glucose load in a large group of acromegalic patients. DESIGN/METHODS: Leptin, ghrelin, GH, glucose and insulin concentrations were measured during a 3 h OGTT in 17 active, 25 inactive patients without medication (inact) and 8 inactive patients treated successfully with somatostatin analogues (inact-SA). Leptin concentration was measured using an in-house immunofluorometric assay, total serum ghrelin by a commercially available radioimmunoassay. Leptin was corrected for BMI. RESULTS: During OGTT, no significant difference of baseline, nadir or AUC of leptin/BMI was seen between the groups (baseline leptin/BMI: act: 0.26 microgm(2)/lkg (0.06-0.87); inact: 0.34 microgm(2)/lkg (0.03-1.79); inact-SA: 0.29 microgm(2)/lkg (0.03-1.47). A slight but significant reduction of leptin/BMI occurred in all groups during OGTT (active p<0.001, inact p<0.001, inact-SA p<0.05). Inact had higher ghrelin levels (130 ng/L (69-292) compared to active (102 ng/L (27-232); p=n.s.). Inact-SA had significantly lower ghrelin levels (88 ng/L (72-113)) than inact (p<0.001). There was a significant decline of ghrelin during OGTT in all groups (active p<0.001, inact p<0.001, inact-SA p<0.05). CONCLUSIONS: GH only has a slight influence on leptin secretion. Ghrelin levels are lowered by GH and SA. Nevertheless, the physiological decreasing effect of glucose load on ghrelin secretion is preserved.

The effect of acute application of pegvisomant alone and in combination with octreotide on endogenous GH levels during a 6-h test in patients with acromegaly on constant pegvisomant treatment.

OBJECTIVE: Co-treatment with somatostatin analogues and growth hormone receptor antagonists in acromegaly might be a new treatment option abolishing the negative effects of monotherapy. Nevertheless, little is known about the acute effect of the combined treatment on endogenous GH and pegvisomant levels. DESIGN: Ten acromegalic patients on constant pegvisomant therapy were included. Two 6-h GH secretion profiles were performed once after pegvisomant alone (P), the other after an additional 100 microg octreotide sc injection (PO). After 180 min, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. In addition, insulin and glucose were measured. RESULTS: In the combined profile PO, a significant decrease of median endogenous GH was seen (p<0.01, median percentage decline 75.2%, range 23.7-88.2), which was not seen in profile P. Seven of 10 patients had a decline >70% and might be seen as responders. After meal, endogenous GH significantly decreased only in profile P (p<0.01). Pegvisomant levels did not differ significantly between profiles and did not change significantly during the tests. After meal, glucose levels rose higher and later and insulin levels lower and later in profile PO than in profile P. CONCLUSION: During pegvisomant treatment, endogenous GH can be reduced significantly by acute application of a somatostatin analogue. Therefore, in acromegalic patients on pegvisomant therapy GH regulation due to somatostatin analogues seems to be preserved.

Effects of the long-acting somatostatin analogue Lanreotide Autogel on glucose tolerance and insulin resistance in acromegaly.

OBJECT: Treatment with somatostatin analogues (SA) not only inhibits GH secretion but may also impair insulin secretion. In order to evaluate the influence of SA on glucose metabolism, we investigated insulin resistance (IR) and beta-cell function, using the recommended combination of homeostatic model assessment of IR (HOMA-IR) and beta-cell function (HOMA-beta). DESIGN AND METHODS: This is a prospective, cross-sectional study. We measured fasting insulin, blood glucose and IGF-I. Insulin and blood glucose measurements were taken 120 min after an oral glucose tolerance test with 75 g glucose. We studied 51 patients (27 female/24 male, age 54 years (20-75)). Eighteen patients were on Lanreotide Autogel (LA) treatment, 33 had no medical treatment. GH-levels of more than 2.5 ng/ml was reached by 59% of the patients, 74.5% had normal IGF-I levels. RESULTS: We found no significant influence of disease activity on HOMA-IR and HOMA-beta. In the 33 of 51 subjects without any drug treatment, median HOMA-beta was 170.4% (36.0-624.0%). In contrast, in the 18 patients on LA treatment, median HOMA-beta was found to be significantly lower (84.2% (36.5-346.2%); P = 0.001). Despite this, there was no difference in HOMA-IR in both groups (2.4 (0.7-8.4) vs 2.3 (0.7-6.1); P < 0.001) despite similar insulin values. CONCLUSION: In conclusion, we found that LA decreases beta-cell function significantly without affecting IR. Therefore, we think that insulin secretagogues are probably more effective in the treatment of diabetes mellitus in acromegalic patients on LA therapy than insulin sensitizers.

[Pharmacotherapy of pituitary diseases]. / Medikamentöse Therapie von Hypophysenerkrankungen.

Successful pharmacotherapy of pituitary hormonal excess is established only in the treatment of acromegaly (dopamine agonists, somatostatin analogues, GH-receptor-antagonists) and of prolactinomas (dopamine agonists). Gold standard in the treatment of acromegaly is transsphenoidal pituitary surgery, while in prolactinomas, surgery is indicated only in exceptional cases. Substitution of pituitary insufficiency offers the patients a normal quality of life. Substitution of the cortico- and thyrotrope axis with hydrocortisone and levothyroxine is vital. In women, substitution of the gonadotrope axis should be performed up to menopause (estrogen/gestagen). In men, substitution should be performed lifelong (trans-dermal testosterone body patches, testosterone gel, testosterone undecanoate/enanthate). To achieve fertility, gonadotropins or pulsatile GnRH therapy has very good results. Especially in younger patients, substitution of growth hormone may be useful (somatropin).

Four-year follow-up of acromegalic patients treated with the new long-acting formulation of Lanreotide (Lanreotide Autogel).

Lanreotide Autogel (Ipsen) is a long-acting somatostatin analogue (SA) in a new galenic formulation suitable for subcutaneous (s.c.) injection. In our department, 11 patients with therapy-resistant acromegaly were treated with Lanreotide Autogel for 48 months. 10/11 patients had previously undergone transsphenoidal surgery. For a median duration of 1.4 years prior to Lanreotide Autogel, the patients received Lanreotide PR 30 mg every 7, 10, or 14 days. 60, 90, or 120 mg of Lanreotide Autogel was administered by deep s.c. injection every 28 days, with the higher dosage being given to those with the previously shortest injection interval under Lanreotide PR. Dose was adjusted on the basis of Growth Hormone (GH) level after 4, 8, and 12 months with a minimum dose of 60 mg and a maximum dose of 120 mg. The efficacy of Lanreotide Autogel treatment was evaluated by measuring GH concentrations (4 hour profiles) and IGF-I levels. Before switching to Lanreotide Autogel, the multiple of the upper limit of normal (xULN) of IGF-I levels was 1.2 (median) and the median GH level was 1.3 microg/l. 3 out of 11 patients had an IGF-I within the age- and sex-adjusted normal range. After 48 months of treatment with Lanreotide Autogel, six patients had an IGF-I within the normal range. Median GH levels were at 1.3 microg/l and xULN of IGF-I was at 1.0 compared to Lanreotide PR 30 mg treatment (p < 0.001). At the end of the study, 8 patients received 120 mg Lanreotide Autogel, 2 patients 90 mg and 1 patient 60 mg, respectively. There was slight but significant deterioration of glucose metabolism with an increase of HbA1c. In conclusion, the new galenic formulation of Lanreotide improves not only the control of biochemical markers of acromegaly compared to the conventional PR formulation, but is also easier to administer given its deep s.c. method of administration. Glucose metabolism has to be followed carefully in patients on high-dose Lanreotide Autogel.