Effect of corticotrophin-releasing hormone on arginine vasopressin and atrial natriuretic factor in patients with Cushing's disease.

OBJECTIVE: To evaluate the effect of CRH administration on plasma AVP and ANF concentration in patients with Cushing's disease and healthy subjects. SUBJECTS: Fifteen patients with Cushing's disease and 15 sex- and age-matched healthy subjects entered the study. STUDY DESIGN: All subjects were randomly given i.v. 100 micrograms hCRH and placebo (NaCl 0.9%) on two non consecutive days. Blood samples for plasma AVP and ANF assay were taken before and every 15 min for 2 hr after CRH or placebo. Five out of the 15 patients with Cushing's disease underwent a repeat CRH test after surgical cure of the disease. RESULTS: At baseline evaluation, plasma ANF concentrations were significantly higher in patients with Cushing's disease compared to healthy subjects (15.0 +/- 0.8 vs 10.8 +/- 0.6 pmol/l, P < 0.001) whereas plasma AVP concentrations were similar between the two groups of subjects (8.0 +/- 0.4 vs 6.8 +/- 0.6 pmol/l). CRH administration induced a significant increase in plasma ANF concentrations both in patients with Cushing's disease (24.0 +/- 1.6 pmol/l, P < 0.05) and healthy subjects (29.4 +/- 1.5 pmol/l, P < 0.05). Conversely, a significant increase in plasma AVP concentrations was found only in patients with Cushing's disease (14.7 +/- 1.4 vs 8.0 +/- 0.4 pmol/l, P < 0.05). In addition, patients with Cushing's disease had an increase in ANF levels after CRH significantly lower than that observed in healthy subjects (peak/basal ratio: 1.7 +/- 0.1 vs 3.1 +/- 0.4, P < 0.01). In 5 patients re-tested after disease cure, CRH administration significantly increased plasma ANF levels (26.8 +/- 1.1 vs 10.7 +/- 0.4 pmol/l, P < 0.05) but it did not modify plasma AVP levels (8.4 +/- 0.4 vs 7.3 +/- 0.5 pmol/l). ANF response to CRH in patients cured from Cushing's disease was similar to that recorded in healthy subjects (peak/basal ratio: 2.6 +/- 0.2 vs 3.1 +/- 0.4). CONCLUSION: CRH stimulates ANF secretion both in patients with Cushing's disease and healthy subjects. Plasma ANF response to CRH is blunted in patients with Cushing's disease compared to patients cured from Cushing's disease and healthy subjects, probably because of hypercortisolism. By contrast, CRH stimulates AVP secretion only in patients with Cushing's disease, but not in patients cured from Cushing's disease and healthy subjects. This phenomenon could be related to the activity of the disease.

Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up.

In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma (15 macro- and 11 micro-adenomas) diagnosed at the age of 7-17 yr. All patients were first treated with bromocriptine (BRC) at doses ranging from 2.5-20 mg/day orally. BRC was discontinued for intolerance and/or resistance to the drug and was replaced by quinagolide (CV) at doses ranging from 0.075-0.6 mg/day or by cabergoline at doses ranging from 0.5-3.5 mg/week orally. Two patients received external conventional radiotherapy after surgery. In 7 prepubertal males and 6 females with macroprolactinoma, headache and/or visual defects were the first symptoms. All females presented with primary or secondary amenorrhea. Growth arrest was observed in a male patient with microadenoma, whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 12 patients (3 males and 9 females) and gynecomastia in 4 males. Mean serum PRL concentration (+/-SE) at the time of diagnosis was 1080 +/- 267 microg/L in patients with macroadenoma and 155 +/- 38 microg/L in patients with microadenoma. In 10 patients, BRC normalized PRL levels and caused variable, but significant, tumor shrinkage. CV normalized PRL concentrations and reduced tumor size in 5 patients. Cabergoline normalized PRL concentrations in 7 of 10 patients resistant to CV. Pregnancy occurred in 2 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Only 4 patients are still moderately hyperprolactinemic. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in 7 patients, 5 of whom underwent surgery. Four patients became GH deficient in adult age. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

Impairment of bone status in patients with central diabetes insipidus.

The aim of the current study was to evaluate the biochemical parameters of bone metabolism and the bone mineral density (BMD) in patients with central diabetes insipidus, either treated or not treated with endonasal desmopressin. Eighteen patients with central diabetes insipidus and 18 sex- and age-matched healthy subjects entered the study. The patients were divided into 2 groups: patients who did not receive treatment with desmopressin for at least 1 yr (group 1), and patients chronically treated with desmopressin since the diagnosis of diabetes insipidus (group 2). Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen levels were measured in all patients and controls using RIA and enzyme-linked immunosorbent assay kits, respectively. BMD was measured at the lumbar spine (L1-L4) and at the femoral neck in all subjects, using a Hologic QDR 1000 analyzer (Hologic Inc., Waltham, MA). Serum osteocalcin concentrations were significantly lower, both in patients of group 1 and group 2, compared with healthy subjects (5.1 +/- 0.6 and 4.5 +/- 0.3 vs. 7.9 +/- 0.2 micrograms/L, P < 0.05), whereas urinary cross-linked N-telopeptide of type I collagen concentrations were similar in the three groups of subjects (72.8 +/- 2.2, 71.6 +/- 2.7, and 64.6 +/- 1.7 nmol bone collagen equivalent/mmol creatinine). BMD was significantly decreased in patients of groups 1 and 2, compared with controls, both at lumbar spine (0.84 +/- 0.06 and 0.87 +/- 0.04 vs. 1.01 +/- 0.02 g/cm2, P < 0.05) and femoral neck (0.78 +/- 0.06 and 0.80 +/- 0.04 vs. 0.93 +/- 0.02 g/cm2, P < 0.05). A significant inverse correlation was found between disease duration and BMD values, evaluated as T scores, both at lumbar spine (group 1: r = -0.952, P < 0.005; group 2: r = -0.921, P < 0.001) and at femoral neck (group 1: r = -0.914, P < 0.05; group 2: r = -0.683, P < 0.05). In conclusion, patients with central diabetes insipidus had a significant bone impairment, compared with healthy subjects. Replacement with endonasal desmopressin at standard doses was not able to prevent or reverse the bone impairment. These findings suggest that, in patients with central diabetes insipidus, bone status analysis is mandatory; and a bone-loss preventing treatment might be beneficial.

Plasma atrial natriuretic factor levels in the inferior petrosal sinus blood of patients with Cushing's disease before and after corticotropin-releasing hormone administration.

Atrial natriuretic factor (ANF) was suggested to be involved as neurohormone in the modulation of hypothalamus-pituitary-adrenal axis in humans. However, this role is still controversial and widely discussed. In order to evaluate whether ANF is secreted in the hypothalamus-pituitary system in humans, plasma ANF concentrations were assayed in samples collected in the inferior petrosal sinus (IPS) blood of patients subjected to IPS sampling for diagnostic purposes or neurosurgical indications. In this retrospective study were included 22 patients: 10 with Cushing's disease (CD) and 12 patients with GH or PRL-secreting pituitary adenoma, used as control group. In the patients with CD, plasma ANF concentration was also assayed after CRH test (hCRH 100 micrograms as i.v. bolus with blood samples after 5, 10 and 15 min). Both in patients with CD and in patients with GH- or PRL-secreting pituitary adenoma, no significant difference was found in plasma ANF levels between IPS ipsilateral (13.0 +/- 1.5 and 12.2 +/- 1.2 pmol/l) or controlateral (13.0 +/- 1.6 and 12.2 +/- 1.4 pmol/l) to the adenoma and peripheral blood (14.2 +/- 2.0 and 13.7 +/- 1.5 pmol/l, respectively). Similarly, no difference was found between the IPS ipsilateral and controlateral to the adenoma in both groups of patients. In patients with CD, CRH administration induced a significant increase of ACTH levels (periphery: 34.9 +/- 6.2 vs 11.5 +/- 2.3 pmol/l, p < 0.05) but it did not induce any significant change of plasma ANF levels (14.0 +/- 2.0 vs 13.4 +/- 1.4 pmol/l in the ipsilateral IPS and 13.4 +/- 1.6 vs 13.4 +/- 1.5 pmol/l in the ipsilateral IPS and 13.4 +/- 1.6 vs 13.4 +/- 1.5 pmol/l in the contralateral IPS). In conclusion, the lack of ANF concentration gradient between IPS and peripheral blood, the lack of any difference in ANF concentrations between patients with CD and acromegalics or hyperprolactinemics and the absence of ANF response to CRH administration do not support the hypothesis of a role for ANF as neurohormone involved in the hypothalamus-pituitary control and particularly in the hypothalamus-pituitary-adrenal axis modulation in humans.

Bone marker and bone density responses to dopamine agonist therapy in hyperprolactinemic males.

The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. Six patients received bromocriptine at a dose of 2.5-10 mg/day; 7 patients received quinagolide at a dose of 0.075-0.3 mg/day; 7 patients received cabergoline at a dose of 0.5-1.5 mg/week. BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were measured before and every 6 months during treatment. At study entry, BMD values were lower in patients than controls at both lumbar spine (0.82 +/- 0.03 vs. 1.18 +/- 0.01 g/cm2; P < 0.001) and femoral neck (0.85 +/- 0.02 vs. 0.92 +/- 0.02 g/cm2; P < 0.05) levels. Osteopenia or osteoporosis was diagnosed in 16 patients at the lumbar spine and in 6 of them at the femoral neck level. A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration (P < 0.01). In the 20 patients, serum OC levels were significantly lower (2.1 +/- 0.1 vs. 9.3 +/- 2.4 microg/L; P < 0.01), whereas Ntx levels were significantly higher (157.8 +/- 1.1 vs. 96.4 +/- 7.4 nmol bone collagen equivalent/mmol creatinine; P < 0.001) than control values. A significant inverse correlation was found between serum PRL and OC (P < 0.01), but not Ntx, levels. After 18 months of treatment, serum PRL levels were suppressed, and gonadal function was restored in all 20 patients, as shown by the normalization of serum T (from 2.2 +/- 0.2 to 5.0 +/- 0.2 microg/L) and dihydrotestosterone (0.3 +/- 0.02 vs. 0.5 +/- 0.01 nmol/L) levels, without any significant difference among groups. A progressive significant increase in serum OC levels together with a significant decrease in Ntx levels were observed after 6, 12, and 18 months of treatment in the 3 groups of patients. A slight, although significant, increase in BMD values was recorded in all patients after 18 months of bromocriptine, quinagolide, and cabergoline treatment, serum OC levels were normalized after treatment, whereas neither urinary Ntx levels nor BMD values were normalized by 18 months of treatment with dopaminergic agents. In conclusion, treatment with bromocriptine, quinagolide, and cabergoline for 18 months, although successfull in suppressing serum PRL levels and restoring gonadal function, was unable to restore lumbar spine and femoral neck BMD and normalize Ntx levels. However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia.

Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage.

Cabergoline (CAB), a long-lasting dopamine-agonist, specific for the D2 receptor, is effective in normalizing serum PRL levels in most patients with microprolactinoma or idiopathic hyperprolactinemia. Because few data are presently available on the effects of CAB treatment in macroprolactinomas, the aim of this open-label study was to investigate whether this drug was effective in producing tumor shrinkage, as well as in normalizing PRL levels. Twenty-three patients with macroprolactinoma entered this study 15 patients had had no treatment, whereas the remaining 8 patients had been previously treated with bromocriptine, which was with-drawn because of intolerance. Three of 23 patients had undergone unsuccessful surgery. Pretreatment serum PRL levels ranged from 100-3860 micrograms/L. CAB was administered at a dose of 0.5-3 mg once or twice a week for 12-24 months. Magnetic resonance imaging (MRI) scans were performed before and 3, 6, 12, and 24 months after the beginning of treatment, to evaluate tumor shrinkage, defined as a decrease of at least 80% of baseline tumor volume. After 3-6 months of treatment with a low dose (0.5-1 mg/week), serum PRL levels normalized in 18 patients. In the remaining 5 patients, whose serum PRL levels were not normalized, the dose was increased to 2-3 mg/week. This schedule caused the normalization of PRL levels in 1 patient, whereas in the remaining 4 patients, PRL levels were reduced to 30-82 micrograms/L. A tumor volume reduction greater than 80% at MRI occurred in 14 of 23 patients (61%) after CAB treatment (from 2609.4 +/- 534.7 to 530.1 +/- 141.3 mm3 at the 12-24th month follow-up, P < 0.001). A volume reduction of 41.8 +/- 3.4% was already evident after 3 months (1436 +/- 285.9 mm3; P < 0.001). The complete disappearance of the tumor mass at MRI occurred after 6 months of treatment with CAB in 1 patient, and in 5 patients after 1 yr of treatment. An improvement of visual field defects was obtained in 9 of the 10 patients presenting visual impairment before CAB treatment. The drug was tolerated well by all patients. Only 1 patient experienced mild nausea, which disappeared spontaneously after the 2nd day of treatment. Long-term, a low dose of the D2 receptor agonist CAB significantly reduced tumor volume and normalized serum PRL levels in a great majority of patients bearing macroprolactinoma. This treatment met with excellent patient compliance. This study suggests that CAB can be used as a first choice drug treatment in macroprolactinomas, as already shown for microprolactinomas and idiopathic hyperprolactinemia.