Ana-Maria J. Lengyel

Different effects of growth hormone releasing peptide (GHRP‐6) and GH‐releasing hormone on GH release in endogenous and exogenous hypercortisolism

Chronic hypercortisolism is associated with decreased GH responsiveness to GHRH. GHRP‐6 is a synthetic hexapeptide that releases GH in several species, including man. As GHRH and GHRP‐6 apparently stimulate GH release by different mechanisms, we evaluated the GH responses to these peptides in patients with endogenous and exogenous glucocorticoid excess and also in control subjects.

IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man

Glucocorticoid excess is associated with a blunted GH response to GHRH. IGF-I levels in hypercortisolism are controversial and have been reported as low, normal or high. The aim of this study was to evaluate longitudinally time-dependent changes in the GH response to GHRH, IGF-I, IGFBP-3 and albumin values in patients during corticotherapy. Six patients received GHRH before and after one week and one month of prednisone administration (20-60 mg/d, orally). IGF-I, IGFBP-3 and albumin were determined in each test, at time 0. Ten normal controls were also evaluated in one occasion. There were no differences in basal GH values, GH response to GHRH, IGF-I and IGFBP-3 levels between controls and patients before starting corticotherapy. Albumin (g/l; mean±SE) values were lower in patients before treatment (31±4) than in controls (43±1). After one week of prednisone administration there was a significant decrease in peak GH (ώg/l) levels (before: 18.8±7.4; 1 week: 5.0±1.3), which was maintained after one month (8.1±3.5). IGF-I (ώg/l) levels increased significantly, from 145±23 to 205±52 after one week of therapy, reaching levels of 262±32 after one month. IGFBP-3 (mg/l) values did not increase significantly (before: 2.1±0.2; 1 week: 2.5±0.3; 1 month: 2.8±0.2). Albumin levels showed a significant rise both after one week (36±4) and one month (42±3) of corticotherapy. In summary, we observed a marked decrease in the GH response to GHRH after one week and one month of prednisone administration associated with an increase in circulating IGF-I and albumin values. The physiological implications of these findings are still uncertain. It is possible that glucocorticoids increase hepatic IGF-I and albumin synthesis, although other mechanisms may have a role.

Growth hormone (GH) response to GH-releasing peptide-6 in patients with insulin-dependent diabetes mellitus

In insulin-dependent diabetes mellitus (IDDM), inappropriate growth hormone (GH) responses to several stimuli, including GH-releasing hormone (GHRH), have been described. A decreased hypothalamic somatostatinergic tone is one of the most likely explanations for these findings. His-DTrp-Ala-Trp-DPhe-Lys-NH2 [GH-releasing peptide-6 [GHRP-6]] is a synthetic hexapeptide that stimulates GH release in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably does not inhibit hypothalamic somatostatin secretion. Also, GHRH and GHRP-6 apparently activate different intracellular pathways to release GH. The aim of this study was to evaluate whether there is a differential effect of IDDM on GHRP-6- and GHRH-induced GH secretion. Six patients with IDDM and seven control subjects were studied. Each subject received GHRP-6 (1 microgram/kg intravenously [IV]), GHRH (100 micrograms IV), and GHRP-6 + GHRH on 3 separate days. GH peak values (mean +/- SE in micrograms per liter) were similar in controls and diabetics after GHRH (22.5 +/- 7.8 v 24.0 +/- 9.7) and after GHRP-5 (20.5 +/- 5.3 v 24.4 +/- 6.3). The association of GHRP-6 and GHRH induced a significantly higher GH release than administration of the isolated peptides in both groups. The synergistic GH response to combined administration of GHRP-6 and GHRH was not different in controls (70.5 +/- 20.0) and diabetics (119.0 +/- 22.2). In summary, the effectiveness of GHRP-6 in IDDM could reinforce the evidence that this peptide probably does not release GH through a decrease in hypothalamic somatostatin secretion. Moreover, our data suggest that both GHRH and GHRP-6 releasing mechanisms are unaltered in IDDM.

Acute dexamethasone administration enhances GH responsiveness to GH releasing peptide‐6 (GHRP‐6) in man

Acute administration of glucocorticoids stimulates GH secretion probably by a decrease in hypothalamic somatostatin release. GHRP‐6 is a synthetic hexapeptide that increases GH secretion by a mechanism of action not yet fully known, but apparently not by inhibition of hypothalamic somatostatin release. The aim of this study was to evaluate the effect of acute dexamethasone administration on GH responsiveness to GHRP‐6 in man.

Growth hormone responses to GH‐releasing peptide (GHRP‐6) in hypothyroidism

OBJECTIVE Both spontaneous and stimulated GH secretion are reduced in patients with hypothyroidism. The mechanisms involved in these alterations are not yet fully understood. GHRP‐6 is a synthetic hexapeptide that releases GH both in vivo and in vitro. Its mechanism of action is unknown, but there is evidence that this peptide acts as a functional somatostatin antagonist at pituitary level. The aim of this study was to evaluate the GH response to GHRP‐6 in patients with primary hypothyroidism and in normal controls.

Long-acting injectable bromocriptine (Parlodel LAR) in the chronic treatment of prolactin-secreting macroadenomas.

OBJECTIVE To evaluate the efficacy and tolerability of Parlodel LAR (Sandoz, Basel, Switzerland), a long-acting injectable bromocriptine, in PRL-secreting macroadenomas. DESIGN Eleven patients with macroprolactinomas were studied in an academic environment in an open and prospective protocol. Ten patients were followed for 6 months and 8 for 1 year. Fifty to 200 mg IM of Parlodel LAR were administered every 28 days. RESULTS At the end of the 1st month, 64% of the patients had PRL suppression of > 75% of baseline values. After 1 year, 88% of the cases had PRL suppression of > 90%. Persistent PRL normalization was seen in three cases. Tumor shrinkage was seen in 64% of the patients on day 5, in 73% on day 28, and in 90% after 6 months of treatment. Early visual field improvement was seen in 83% of the cases. All patients had improvement of clinical symptoms. CONCLUSION Parlodel LAR is well tolerated and very effective in the long-term treatment of patients with PRL-secreting macroadenomas.

A prolactin-secreting tumor in a patient with Klinefelter’s syndrome: A case report

We report the case of a patient with Klinefelter’s syndrome who developed a prolactin (PRL)-secreting tumor. The patient developed headaches, visual alterations and also symptoms of hypogonadism despite appropriate testosterone (T) replacement therapy. The diagnosis of hyperprolactinemia was then suspected. The laboratory findings confirmed the hypothesis, showing high levels of serum PRL. The patient was initially treated with oral bromocriptine, and afterwards with the injectable form. There was a marked decrease in PRL levels and in tumor size. Although some neoplasms, like breast carcinoma and germ cell tumors, are known to occur more frequently in patients with Klinefelter’s syndrome, an association with PRL-secreting tumor has not been reported yet. In conclusion, symptoms of hypogonadism in patients with Klinefelter’s syndrome receiving appropriate T replacement therapy can suggest the presence of hyperprolactinemia.

Effects of ghrelin, growth hormone–releasing peptide–6, and growth hormone–releasing hormone on growth hormone, adrenocorticotropic hormone, and cortisol release in type 1 diabetes mellitus

In type 1 diabetes mellitus (T1DM), growth hormone (GH) responses to provocative stimuli are normal or exaggerated, whereas the hypothalamic-pituitary-adrenal axis has been less studied. Ghrelin is a GH secretagogue that also increases adrenocorticotropic hormone (ACTH) and cortisol levels, similarly to GH-releasing peptide-6 (GHRP-6). Ghrelins effects in patients with T1DM have not been evaluated. We therefore studied GH, ACTH, and cortisol responses to ghrelin and GHRP-6 in 9 patients with T1DM and 9 control subjects. The GH-releasing hormone (GHRH)-induced GH release was also evaluated. Mean fasting GH levels (micrograms per liter) were higher in T1DM (3.5 ± 1.2) than in controls (0.6 ± 0.3). In both groups, ghrelin-induced GH release was higher than that after GHRP-6 and GHRH. When analyzing Δ area under the curve (ΔAUC) GH values after ghrelin, GHRP-6, and GHRH, no significant differences were observed in T1DM compared with controls. There was a trend (P = .055) to higher mean basal cortisol values (micrograms per deciliter) in T1DM (11.7 ± 1.5) compared with controls (8.2 ± 0.8). No significant differences were seen in ΔAUC cortisol values in both groups after ghrelin and GHRP-6. Mean fasting ACTH values were similar in T1DM and controls. No differences were seen in ΔAUC ACTH levels in both groups after ghrelin and GHRP-6. In summary, patients with T1DM have normal GH responsiveness to ghrelin, GHRP-6, and GHRH. The ACTH and cortisol release after ghrelin and GHRP-6 is also similar to controls. Our results suggest that chronic hyperglycemia of T1DM does not interfere with GH-, ACTH-, and cortisol-releasing mechanisms stimulated by these peptides.

Adrenocorticotrophic hormone (ACTH) responsiveness to ghrelin increases after 6 months of ketoconazole use in patients with Cushing’s disease: comparison with GH-releasing peptide-6 (GHRP-6)

Background  In Cushing’s disease (CD), adrenocorticotrophic hormone (ACTH)/cortisol responses to growth hormone secretagogues (GHS), such as ghrelin and GHRP‐6, are exaggerated. The effect of clinical treatment of hypercortisolism with ketoconazole on ACTH secretion in CD is controversial. There are no studies evaluating ACTH/cortisol responses to GHS after prolonged ketoconazole use in these patients.

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with Cushing's disease.

GH responses to ghrelin, GHRP-6, and GHRH in Cushings disease (CD) are markedly blunted. There is no data about the effect of reduction of cortisol levels with steroidogenesis inhibitors, like ketoconazole, on GH secretion in CD. ACTH levels during ketoconazole treatment are controversial. The aims of this study were to compare the GH response to ghrelin, GHRP-6, and GHRH, and the ACTH and cortisol responses to ghrelin and GHRP-6 before and after one month of ketoconazole treatment in 6 untreated patients with CD. Before treatment peak GH (microg/L; mean +/- SEM) after ghrelin, GHRP-6, and GHRH administration was 10.0 +/- 4.5; 3.8 +/- 1.6, and 0.6 +/- 0.2, respectively. After one month of ketoconazole there was a significant decrease in urinary cortisol values (mean reduction: 75%), but GH responses did not change (7.0 +/- 2.0; 3.1 +/- 0.8; 0.9 +/- 0.2, respectively). After treatment, there was a significant reduction in cortisol (microg/dL) responses to ghrelin (before: 30.6 +/- 5.2; after: 24.2 +/- 5.1). No significant changes in ACTH (pg/mL) responses before (ghrelin: 210.9 +/- 69.9; GHRP-6: 199.8 +/- 88.8) and after treatment (ghrelin: 159.7 +/- 40.3; GHRP-6: 227 +/- 127.2) were observed. In conclusion, after short-term ketoconazole treatment there are no changes in GH or ACTH responses, despite a major decrease of cortisol levels. A longer period of treatment might be necessary for the recovery of pituitary function.