Biomedical subjects

R Pivonello

Publications and source records attributed to R Pivonello.

69 records · Page 4Linked to original sources

PubMed1999

A longitudinal study of vasopressin cell antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central diabetes insipidus.

Cytoplasmic autoantibodies to vasopressin-cells (AVPcAb) have been detected not only in patients with overt central diabetes insipidus (CDI), but also in patients with endocrine autoimmune diseases without CDI. This suggests that complete CDI can be preceded by a preclinical stage. Among 878 patients with endocrine autoimmune diseases without CDI, 9 patients found to be AVPcAb positive and 139 AVPcAb-negative controls were enrolled in this open prospective study. They were evaluated for AVPcAb and posterior pituitary function at least yearly for about 4 yr (range, 37-48 months); during this span, magnetic resonance imaging (MRI) of posterior pituitary and stalk was performed only in the AVPcAb-positive patients. Five of the 9 AVPcAb-positive patients had normal posterior pituitary function at study entry. They were AVPcAb positive throughout the follow-up period. At later stages of the study, 3 of them developed partial CDI, and 1 developed complete CDI. The remaining 4 patients showed impaired response to the water deprivation test at study entry and were diagnosed as having partial CDI. Two of them agreed to receive desmopressin replacement for 1 yr. After this treatment, the patients became negative for AVPcAb and displayed normal posterior pituitary function until the end of the follow-up. Conversely, the 2 untreated patients with partial CDI remained AVPcAb positive. One of them developed overt CDI. None of the controls became AVPcAb positive or developed CDI. The normal hyperintense MRI signal of the posterior pituitary, present at study entry, persisted subsequently in all 9 AVPcAb-positive patients, including those developing overt CDI, only disappearing in the late phase of complete CDI. In asymptomatic subjects, the monitoring of AVPcAb, but not MRI, seems to be useful to predict a progression toward partial/overt CDI. Early desmopressin therapy in patients with partial CDI could interrupt or delay the autoimmune damage and the progression toward clinically overt CDI.

Adolescent↗

PubMed1998

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.

Adenoma↗

PubMed1998

Growth hormone deficiency in elderly patients with hypothalamo-pituitary tumors.

In 18 patients with hypothalamo-pituitary diseases aged over 60 years and in 18 sex, age- and BMI-matched healthy subjects, the results of plasma IGF-I and IGF-BP3 levels and the GH response to GHRH + arginine test (GHRH + ATT) were correlated to the results of body composition, serum osteocalcin (OC) and urinary cross-linked N-telopeptides of type I collagen (Ntx) and the bone mineral density (BMD). In 10 patients and 10 controls, the GH response to ITT was also evaluated. The GH response to GHRH + ATT and ITT was markedly reduced in patients compared to controls (3.1 +/- 0.7 vs. 23.2 +/- 2.3 micrograms/L, P < 0.001 and 1.1 +/- 0.3 vs. 6.4 +/- 0.8 micrograms/L, P < 0.001), so all patients were classified as GHD, though no significant difference was found in plasma IGF-I and IGF-BP3 levels between the two groups. Body composition analysis revealed a significant increase of fat mass (37.4 +/- 2.2 vs. 28.0 +/- 1.0%, P < 0.001), a significant decrease of lean mass (62.6 +/- 2.2 vs. 72.0 +/- 1.0%, P < 0.001) and total body water (45.7 +/- 1.5 vs. 52.5 +/- 1.1%, P < 0.001) in patients compared to controls. Serum OC levels were lower (1.9 +/- 0.1 vs. 4.6 +/- 0.4 micrograms/L, P < 0.001) in patients than in controls, whereas urinary Ntx levels were similar. BMD values in lumbar spine (0.81 +/- 0.02 vs. 0.90 +/- 0.02 g/cm2, P < 0.001) and femoral neck (0.70 +/- 0.02 vs. 0.82 +/- 0.02 g/cm2, P < 0.001) were significantly lower in patients than in controls. A significant inverse correlation was found between GHD duration and lumbar spine (r = -0.73, P&1t; 0.001) or femoral neck (r = -0.81, P&1t; 0.001) BMD values and a significant direct correlation was found between GH peak after GHRH + ATT and lumbar BMD (r = 0.69, p = 0.001) in GHD patients. In conclusion, GHD in patients over 60 yrs aged with a characteristic history of hypothalamus-pituitary pathology is distinct from the physiological decline in GH secretion associated with aging.

Aged↗

PubMed1998

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.

Adrenocorticotropic Hormone↗

PubMed1998

Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing's disease.

BACKGROUND: Osteoporosis is common in patients with Cushing's disease and is likely due to an imbalance between bone formation and resorption. Alendronate is an aminobisphosphonate that is able to increase bone mass mainly by inhibiting bone resorption. OBJECTIVE: We have evaluated the effect of chronic treatment with alendronate on bone mineral density (BMD) in patients with Cushing's disease. PATIENTS: 39 patients with Cushing's disease entered this study. 39 age-, sex- and BMI-matched normals served as controls for baseline evaluation. The 39 patients were divided into four groups: 1) 10 patients with active disease treated with alendronate and ketoconazole; 2) 11 patients with inactive disease treated with alendronate; 3) 8 patients with active disease treated with ketoconazole alone, 4) 10 patients with inactive disease received no treatment. TREATMENT PROTOCOL: Alendronate was given for 12 months in a dose of 10 mg orally once daily after fasting at 0800 h in the morning. Ketoconazole was given in a dose of 200-600 mg orally daily, when pituitary surgery was unsuccessful. STUDY DESIGN: Lumbar spine (L1-L4) and femoral neck BMD, serum osteocalcin (OC), urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were evaluated at study entry, in patients and controls, and were repeated after 6 and 12 months in the 39 patients. RESULTS: BMD values were lower in patients with Cushing's disease than in controls at both L1-L4 (0.72 +/- 0.4 vs. 1.01 +/- 0.6 g/cm2, P < 0.05) and femoral neck (0.69 +/- 0.3 vs. 0.96 +/- 0.6 g/cm2, P < 0.05). In the 39 patients with Cushing's disease considered as a whole, serum OC levels were lower (1.1 +/- 0.1 vs 1.5 +/- 0.1 nmol/l, P < 0.01), while Ntx values were higher than in controls (168 +/- 25 vs. 61 +/- 31 nmol BCE/mmol creatinine, P < 0.01). In the alendronate-treated groups, serum OC levels increased, while Ntx levels significantly decreased after 6 and 12 months of treatment without any significant difference between the two groups. BMD values measured at L1-L4 and femoral neck significantly increased after 12 months of therapy. In patients of group 4, a significant increase of serum OC levels and a significant decrease of Ntx levels were observed together with a slight increase of BMD values after 12 months. No significant change in either biochemical markers or BMD values was found in patients of group 3. CONCLUSIONS: Patients with Cushing's disease have osteoporosis which needs to be rapidly reversed to limit the risk of fracture. The results of the present study show that a 12 month treatment period with alendronate induced an improvement in bone mineral density greater than in untreated patients.

Acute Disease↗

PubMed1998

Orbital scintigraphy with [111In-diethylenetriamine pentaacetic acid-D-phe1]-octreotide predicts the clinical response to corticosteroid therapy in patients with Graves' ophthalmopathy.

Corticosteroid treatment is successfully used in Graves' ophthalmopathy, and its effect varies according to the phase of the disease. The infiltration of the orbit by activated lymphocytes may explain the effectiveness of corticosteroid therapy. Scintigraphy with [111In-DTPA-D-Phe1]-octreotide was recently used to reveal the presence of activated lymphocytes in foci of autoimmune diseases, because elevated amounts of somatostatin receptors are expressed in the surface of these cells. The aim of the current study was to evaluate whether the degree of orbital [111In-DTPA-D-Phe1]-octreotide uptake is able to predict the response to corticosteroid therapy in patients with Graves' ophthalmopathy. Ten patients with Graves' ophthalmopathy entered the study. In all patients scintigraphy was performed, and subsequently, corticosteroid therapy (methylprednisolone, 1 g i.v. for 2 consecutive days a week for 6 weeks) was given. Clinical activity of Graves' ophthalmopathy was evaluated before and after treatment by calculating the ophthalmopathy index (OI). Planar and single photon emission computed tomography (SPECT) images of the head were obtained 24 h after the i.v. injection of 120-190 MBq of [111In-DTPA-D-Phe1]-octreotide. Radioligand uptake within each orbit (O) and brain (B) was measured using the region of interests (ROI) method and the O-to-B ratio was determined. According to the O-to-B ratio, the images were classified using the following three points score: 0 = O-to-B ratio < or =1; 1 = O-to-B ratio between 1 and 2.5; 2 = O-to-B ratio > or =2.5. The value of OI, measured before and after corticosteroid treatment, was correlated to the scintigraphic score. A significant change of OI was observed between posttreatment and pretreatment evaluation both in orbits with score 2 (OI: 15.4 +/- 1.5 vs. 9.6 +/- 0.5, P < 0.005) and in those with score 1 or 0 (OI: 12.9 +/- 1.5 vs. 11.5 +/- 1.4, P < 0.05) at the scintigraphy. However, when the OI was calculated excluding the changes in the soft tissue, which generally occur in all patients independently from the phase of the disease, a significant change of OI was observed only in the orbits with score 2 (OI: 12.9 +/- 1.3 vs. 8.3 +/- 0.5, P < 0.01) but not in those with score 0 or 1 (OI: 11.2 +/- 1.3 vs. 10.4 +/- 1.3). In particular, 6 weeks after corticosteroid treatment, the patients with orbital score 2 at the scintigraphy had a significant improvement of soft tissue changes, proptosis, lagophthalmos, extraocular muscle movements impairment, and diplopia, whereas patients with score 0 or 1 had only a significant improvement of the soft tissue inflammation. In conclusion, the current preliminary data suggested that [111In-DTPA-D-Phe1]-octreotide scintigraphy is able to predict the clinical response to corticosteroid treatment in patients with Graves' ophthalmopathy, and may be considered an useful approach to select the patients for the proper treatment.

Adult↗

PubMed1998

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.

Adult↗

PubMed1998

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.

Administration, Intranasal↗

PubMed1997

Short stature and azoospermia in a patient with Y chromosome long arm deletion.

We report on a 42-year old male with short stature, azoospermia and a wide deletion of long arm of Y chromosome. On physical examination, the patient showed height of 149 cm (< 1 degree centile) and reduced volume (3 ml) and consistency of the testes. On hormonal evaluation, he showed increased serum gonadotropins and normal serum testosterone levels though its HCG stimulated levels were limited. Serum thyroid hormones were normal. Serum GH levels in baseline evaluation as well as after GHRH and GHRH + pyridostigmine administration were normal. Serum IGF I levels were lower than normal in baseline evaluation whereas its response to the GH administration was in the normal range. The bilateral testicular biopsy showed tubular atrophy, hyalinosis, interstitial sclerosis and a histological picture of a Sertoli cell only syndrome. Moreover the patient showed arthropathy, otopathy, small chin, small mouth and truncal obesity. On genetic evaluation, the patient showed a 46,X,delY (pter--q11.1:) karyotype and loss of several DNA loci on Yq. In fact he preserved short arm SRY, centromeric DYZ3 and more proximal euchromatic region Yq loci, including DYS270, DYS271, DYS272, DYS11, DYS273, DYS274, DYS148, DYS275, and missed more distal DNA loci from DYS246 to DYZ2. These results disclosed a wide Y long arm deletion, including all hypothized Yq azoospermia loci (except for AZFa and probably for one of the RBM genes, which lie proximally to the deletion) and possibly the Y-specific growth control region (GCY), mapped between DYS11 and DYS246 loci. This deletion is responsible for the complete azoospermia of the patient and probably also for his short stature, even if other factors could be implicated in the statural impairment. It further possibly allowed to relate the GCY gene(s) to the control of GH or IGF-I receptor or post-receptor pathway, being the alteration of this gene(s) consistent with the hormonal pattern of the patient.

Adult↗

PubMed1997

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.

Adolescent↗

PubMed1996

Tumor necrosis factor-alpha increases after corticotropin-releasing hormone administration in Cushing's disease. In vivo and in vitro studies.

The aim of this study was to evaluate the effect of acute human corticotropin (ACTH)-releasing hormone (CRH) administration (100 micrograms, as i.v. bolus) on tumor necrosis factor-alpha (TNF alpha) levels in the inferior petrosal sinuses and in the peripheral blood of 7 patients with Cushing's disease subjected to diagnostic inferior petrosal sinus sampling. Blood samples for ACTH, beta-endorphin (beta-EPH) and TNF alpha were collected from inferior petrosal sinuses and periphery simultaneously. In addition, TNF alpha concentrations were measured after CRH administration (10 nmol/l, 100 nmol/l and 1 mumol/l) in culture medium from primary cultures obtained in 3 of 7 patients. At baseline, plasma ACTH and beta-EPH levels were significantly higher in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one and in the periphery (p < 0.001) whereas no significant difference was found as far as serum TNF alpha levels were concerned. CRH administration caused a significant increase of ACTH (p < 0.001), beta-EPH (p < 0.01) and TNF alpha (p < 0.01) levels greater in the ipsilateral inferior petrosal sinus than in the contralateral one and in the periphery. In addition, CRH increased ACTH, beta-EPH and TNF alpha levels in the culture medium of three ACTH-secreting tumors at the doses of 100 nmol/l and 1 mumol/l (greater than 300, 200 and 110% of baseline pretreatment incubation levels, respectively). These data suggest that CRH may increase TNF alpha concentrations in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma and in the peripheral blood as well. In addition, it stimulated TNF alpha release both in vivo and in vitro. These findings suggest the possibility that an imbalanced intrapituitary TNF alpha production can be detected in ACTH-secreting adenomas.

Adenoma↗

PubMed1996

Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH-deficient patients during childhood.

At present, the most appropriate method for diagnosing GH deficiency (GHD) in adults remains unclear. Recently, it has been demonstrated that GHD in adults can be identified by insulin tolerance test (ITT). Moreover, it has been described that the GHRH plus pyridostigmine (GHRH+PD) test is more accurate than an arginine, glucagon, levodopa, or GHRH test to diagnose GHD in adults. In the current study, firstly we reevaluated GH secretion by the GHRH+PD test in adults previously diagnosed as GH deficient in childhood. The study included 69 patients and 38 healthy subjects. After the GHRH+PD test, the patients and the healthy subjects had peak GH levels of 10.6 +/- 11.2 and 56.7 +/- 28.1 micrograms/L, respectively (P < 0.001). The patients were divided into two groups, responder patients and nonresponder patients, considering an arbitrary cut-off of 10 micrograms/L as the GH peak after the GHRH+PD test. Thirty-nine patients had GH peak below 10 micrograms/L (1.9 +/- 1.7 micrograms/L), whereas the remaining 30 patients above 10 micrograms/L (21.6 +/- 8.] micrograms/L; P < 0.001). Secondly, we compared the GHRH+PD test and the ITT in diagnosing GHD. Twenty-one of the 39 patients with a GH peak below 10 micrograms/L and 29 of the 30 patients with a GH peak above 10 micrograms/L after the GHRH+PD test underwent an ITT. The GH peak after insulin administration was 2.1 +/- 1.7 micrograms/L in nonresponder patients and 21.1 +/- 9.3 micrograms/L in responder patients after the GHRH+PD test (P < 0.001). Three of the responder patients to the GHRH+PD test were identified as GH deficient by the ITT. The relative diagnostic accuracies of the two tests to discriminate GH-deficient patients from healthy subjects were similar (ITT vs. GHRH test: sensitivity, 100%, specificity, 90%; GHRH+PD vs. ITT; sensitivity, 88%; specificity, 100%). In conclusion, in adults previously diagnosed as GH deficient, it is mandatory to reevaluate GH secretion. GHRH+PD and/or ITT are able to diagnose GHD in adults with similar accuracies. Taking into account the potential side-effects of the ITT, however, the GHRH+PD test is the most reliable and safe test to accurately diagnose GHD status in adults.

Adult↗

PubMed1996

Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency: effect of 12 months' growth hormone replacement therapy.

We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study. For each subject, evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, record of flow-volume curves, measurement of static lung volumes and lung diffusing capacity. Childhood-onset GH-deficient patients had a significant reduction of maximal inspiratory (p < 0.01) and maximal expiratory (p < 0.05) mouth pressures. Total lung capacity, vital capacity and functional residual capacity were significantly reduced compared to healthy subjects (p < 0.05). Conversely, residual volume and diffusing lung capacity did not show any significant change. No significant change of the ratio between the percentage forced expiratory volume in 1 s and the forced vital capacity was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. Adult-onset GH-deficient patients had only a significant reduction of maximal expiratory pressure compared to healthy subjects (p < 0.05). After 6 months of treatment no significant differences in any of the evaluated parameters were found. After 12 months of treatment patients with childhood-onset GH deficiency show a significant improvement of lung volumes (p < 0.01) and maximal respiratory mouth pressures (p < 0.005), whereas adult-onset GH-deficient patients show a significant improvement of maximal expiratory pressure (p < 0.05). In conclusion, the results of this study showed that adult patients affected with childhood-onset GH deficiency suffer from an impairment of the ventilatory function due to a reduction of lung volumes and a decrease of respiratory pressures probably due to a reduction of respiratory muscle strength. This impairment was reversed after 12 months of treatment with recombinant GH. Conversely, adult-onset GH-deficient patients had only an impairment of the maximal expiratory pressure, probably due to respiratory muscle weakness re-established after 12 months of GH therapy.

Adult↗

PubMedDate not supplied

In vivo and in vitro expression of somatostatin receptors in two human thymomas with similar clinical presentation and different histological features.

[(111)In-DTPA0]octreotide scintigraphy allows the in vivo visualization of several types of SS receptor (SSR)-expressing tumors. Among these, thymomas have been recently detected. Here we report on 2 patients admitted for myasthenia gravis and radiological evidence of thymic mass. Although these patients had similar clinical presentation, in vivo SSR scintigraphy displayed a difference in the degree of the [(111)In-DTPA0]octreotide uptake. Considering that both thymic masses had comparable volume, [(111)In-DTPA0]octreotide level was significantly higher in one of the 2 tumors (tumor/background ratio of 5.7 vs 2.6). The SSR subtype expression pattern was studied in vitro on the surgically resected specimens by ligand binding techniques, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. According to the recent World Health Organization classification, the 2 tumors were classified A and B2 thymomas respectively. In membrane homogenates, we found a higher number of high affinity [125I-Tyr11]-SS-14 binding sites in the B2 thymomas (23.5+/-2.5 vs 12.0+/-0.4 fmol/mg membrane protein; p<0.05). RT-PCR analysis showed sst1, sst2A and sst3 mRNA in the 2 thymoma tissues, whereas SS mRNA was detectable only in the A thymoma. Quantitative evaluation of RT-PCR data showed a comparable expression of the relative amount of sst2A mRNA in both tumors, whereas a significant higher expression of sst3 mRNA in the B2 thymoma. Sst2A immunoreactivity was localized mainly on the endothelium of intratumoral vessels, whereas sst3 was present on either tumoral epithelial cells or normal reactive thymocytes. The expression of sst2A receptors in these tumors is in line with the in vivo visualization by [(111)In-DTPA0]octreotide, which is considered a sst2-preferring ligand. However, since radioligand uptake was significantly higher in the B2 thymoma, which expressed the largest sst3 mRNA levels, it might be possible that this subtype is involved in determining the tumor visualization during SSR scintigraphy. Apart from the affinity of the radioligand for the receptor, also the efficacy of the internalization of the radioligand-receptor complex might play a role in radioactivity accumulation during in vivo SSR scintigraphy. In fact, although octreotide binds with lower affinity to sst3 receptors, this subtype displayed the highest amount of agonist-dependent receptor internalization compared to the other SSR subtypes. Moreover, sst3 was localized on both tumor cells and reactive thymocytes, and these latter cells are characterized by a very active turnover of membrane molecules. Finally, although more cases need to be evaluated, the lack of detection of SS mRNA in the tumor presenting a more aggressive phenotype (B2 thymoma) might have physiopathological or prognostic significance.

Adult↗

PubMedDate not supplied

Failure of long-term therapy with sodium valproate in Cushing's disease.

The aim of the current study was to evaluate the effectiveness of a long-term treatment with sodium valproate in 19 patients with Cushing's disease. Before therapy beginning, the patients were subjected to acute test with 600 mg sodium valproate. Then, they were subjected to a 3-month therapy with sodium valproate at the dose of 600 mg/day before surgery (presurgical study). The 7 patients not surgically cured were subjected again to a 3-month therapy with sodium valproate at the dose of 600 mg/day after surgery (postsurgical study). Circulating ACTH and cortisol and urinary free cortisol levels were evaluated before and monthly after the beginning of the therapy. A decrease of plasma ACTH and serum cortisol levels greater than 50% of baseline was considered as positive response to acute test whereas the normalization of plasma ACTH, serum cortisol and urinary free cortisol levels and the clinical remission were considered as positive response to the long-term treatment. At acute test, 8 patients were considered responders and 11 patients non-responders. In no patient plasma ACTH, serum cortisol and urinary free cortisol were normalized during the long-term treatment. Urinary free cortisol levels significantly decreased (483.2 +/- 33.8 vs 699.4 +/- 67.0 micrograms/24 h), whereas plasma ACTH (302.8 +/- 17.7 vs 183.3 +/- 25.0 ng/l) and serum cortisol (466.5 +/- 23.2 vs 356.7 +/- 19.6 micrograms/l) significantly increased during sodium valproate administration in the 19 patients enrolled in the presurgical study. Plasma ACTH (247.7 +/- 22.3 vs 168.6 +/- 15.0 ng/l), serum cortisol (387.4 +/- 35.8 vs 282.0 +/- 16.0 micrograms/l) and urinary free cortisol (370.9 +/- 70.6 vs 261.3 +/- 37.8 micrograms/24 h) levels significantly increased in the 7 patients enrolled in the postsurgical study. No patient had clinical remission of Cushing's disease. In conclusion, the current study showed that long-term therapy with sodium valproate is not useful in the therapeutic management of Cushing's disease neither as alternative nor as adjunctive therapy to surgery.

Adrenocorticotropic Hormone↗