Current diagnostic guidelines for biochemical diagnosis of acromegaly.

Acromegaly is a rare and chronic disease that, in the majority of cases, is due to the presence of a benign growth hormone (GH)-producing tumor of the pituitary. In the past, the diagnosis of acromegaly was established basically on physical changes, and only the patients with a severe clinical picture were brought to medical attention. The development of a radioimmunoassay for detecting GH allowed for the first time to confirm the diagnosis biochemically. Subsequently, methods for measuring insulin-like growth factor 1 (IGF-I) became available and added another important biochemical marker for the diagnosis and follow-up of these patients. Progressive improvements in assay methods have allowed for progressively better definitions of normality and, as a result, have permitted the diagnosis to be biochemically established in patients with only mild forms of the disease. Moreover, new potential markers of disease activity, such as other GH-dependent IGF system parameters, have been investigated and proposed in the diagnostic work-up and for monitoring the therapeutic outcome. Optimal assessment of disease activity, for both diagnostic and follow-up purposes, is mandatory. This subject has been strongly debated regarding proper cut-off values using highly sensitive GH assays as well as the problems linked to IGF system components measurement. Consequently, several consensus reports, as well as original studies, have been issued giving special attention to diagnostic procedures, cut-off revisions and definition of disease activity. The present review discuss principally the biochemical diagnosis of acromegaly based on these articles and on the experience collected in an endocrinological unit considered as reference center for pituitary diseases.

Cabergoline modulation of alpha-subunits and FSH secretion in a gonadotroph adenoma.

Most non-functioning pituitary adenomas respond poorly to medical therapy. We describe the case of a 62-year-old man who presented with clinical features of an invasive macroadenoma. Baseline hormonal evaluation revealed increased FSH and alpha-subunit (alpha-SU) levels. Transsphenoidal exeresis followed by radiotherapy (RT) was performed. Almost all neoplastic cells were intensely immunoreactive for alpha-SU. On PCR analysis, specific amplification products were observed for somatostatin 2, 3 and 5 receptors as well as for both short and long isoforms of the dopamine D2 receptor. In vitro, alpha-SU and FSH were released into the medium by adenoma cells and increased after TRH stimulation. After surgery, alpha-SU and FSH levels were still elevated. Short-term slow-release lanreotide treatment did not modify either alpha-SU or FSH levels. Cabergoline was started and a fast and long-lasting decrease in alpha-SU and, to a lesser extent, in FSH was observed. The tumor remnant was unmodified on magnetic resonance imaging 3 years after surgery and RT. This case report shows that the in vitro expression of somatostatin receptors may not be directly associated to the in vivo response of alpha-SU and FSH to lanreotide, probably because of a functional uncoupling of the receptors. Cabergoline should be considered as an effective therapy for hormonal, and perhaps proliferative, control of gonadotroph adenoma remnants before the effects of RT are fully effective.

Nitric oxide biphasically modulates GH secretion in cultured cells of GH-secreting human pituitary adenomas.

BACKGROUND: Nitric oxide (NO) biphasically modulates osteoclast function, sperm motility and testosterone production by exerting a positive effect at low concentrations and a negative effect at high concentrations. In this study the effect due to administration of four NO-donors, each releasing an individual amount of NO, was studied on GH secretion from human adenomatous GH-secreting cells. METHODS: Sodium nitroprusside (SNP), diethylenetriamine NO adduct (DETA/NO), diethylamine/NO complex sodium salt (DEA/NO), and S-nitroso-N-acetylpenicillamine (SNAP) were administered at a concentration of 10-4 M to cells isolated after transsphenoidal adenomectomy from five acromegalic patients. RESULTS: SNP significantly (p < 0.01) increased GH secretion, while the other NO donors inhibited GH secretion in comparision with the amount of GH spontaneously released by unstimulated cells. Each drug showed an individual degree of inhibitory potency: DEA/NO > DETA/NO > SNAP. Nitrite accumulation in the media was measured as a marker of NO released by each individual drug and was found to be different for each drug (DEA/NO > DETA/NO > SNAP > SNP). A negative correlation (R = -0.93; p < 0.05) was found between nitrite release and GH secretion induced by each drug. CONCLUSIONS: These data show that low and quasi-physiological levels of NO, such as those released by SNP, stimulate GH secretion, while high NO levels, such as those released by the other NO-donors, inhibit GH secretion. Thus, NO is shown to be able to modulate GH secretion in a dose-dependent manner in GH adenomatous cells from human pituitary adenomas.

Nitric oxide modulates in vivo and in vitro growth hormone release in acromegaly.

Nitric oxide (NO) has recently been shown to modulate pituitary secretion both in vivo and in vitro. The aim of this study was to investigate the effects of this chemical transmitter on spontaneous and growth-hormone-releasing hormone (GHRH)-induced growth hormone (GH) secretion in acromegalic patients, as well as from GH-secreting tumors maintained in vitro. The study was carried out in 7 acromegalic patients (46.2 +/- 2 years) and in 5 normal subjects (40.1 +/- 1.5 years). GH and prolactin (PRL) secretion were assayed during the administration of isosorbide dinitrate (ID, 5 mg, orally), an NO donor, GHRH, and ID plus GHRH. During ID, a significant (p < 0.05) increase (37%) over basal GH levels was only observed in acromegalics. There was no change in GH levels in response to GHRH or ID plus GHRH in either group. No significant change in PRL levels was observed in either group during ID, while GHRH, with or without ID, induced a slight increase in PRL levels in acromegalics only. Tumor specimens were obtained by selective transsphenoidal adenomectomy, and the cells were plated and incubated for 1, 2 and 24 h in the presence of sodium nitroprusside, a releaser of NO (SNP, 0.3 or 0.6 mM), of GHRH (10-8 M) or of both. SNP significantly (p < 0.001) increased GH levels in a dose-dependent manner (R = 0.99, p = 0.02), but was unable to modify the GH response to GHRH. In acromegalics, a significant correlation (R = 0.822, p < 0.045) and a correlation near the limit of significance (R = 0.73, NS) were observed respectively between the in vivo GH response to ID and the in vitro response to SNP at 24 h. No significant effect was observed on PRL secretion during SNP incubations, while GHRH produced a significant increase in PRL after 2 and 24 h incubation in acromegalics. These observations indicate that NO plays a stimulatory role in vivo and in vitro on GH secretion in acromegalic patients.

[Reversibility of visual field defects in primary open-angle glaucoma]. / La réversibilité des déficits périmétriques dans le glaucome primitif à angle ouvert.

The course of the glaucomatous visual field seems to be best followed by computerized perimetry which allows threshold evaluation in a great number of locations and statistical analysis of the results. To determine the visual field defect reversibility, 16 patients (27 eyes) affected by uncontrolled open-angle glaucoma underwent visual field analysis before and after prescription of a new medical therapy. To avoid the "learning effect" and to decrease the influence of the heterogeneous component of long-term fluctuation, the visual field examination was repeated within 48 hours whenever a change in sensitivity was detected. In addition a total of 10 normal eyes in 10 patients were tested as a control group. A statistically significant threshold improvement was demonstrable after one week of therapy in 31.7% of the eyes.