Alessandro Piovesan

Left ventricular hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy.

The association between primary hyperparathyroidism (PHPT) and increased mortality mainly from cardiovascular disease is still debated. The increased mortality previously reported in PHPT was not confirmed in a recent population based study. A high prevalence of left ventricular (LV) hypertrophy was, however, reported in this disease. Although arterial hypertension is regarded as the principal factor, the pathogenesis of LV hypertrophy in PHPT is complex and not completely defined, moreover the effects of successful parathyroidectomy (PTX) are not fully elucidated. The aims of this study were: to ascertain the prevalence of LV hypertrophy in a series of patients with PHPT in comparison to a control population, to seek for relationship between biochemical markers of disease, blood pressure (BP) levels and LV measurements and to evaluate the effects of successful PTX on LV hypertrophy during short‐term follow‐up.

Effects of Long-Term, Low-Dose, Time-Specified Melatonin Administration on Endocrine and Cardiovascular Variables in Adult Men

Six healthy adult male volunteers underwent serial blood drawings at 4‐hour intervals over 24 hours for the definition of melatonin (MT), prolactin (PRL), cortisol, and testosterone circadian patterns. Serum levels of triiodotironine (T3) and thyroxine (T4) were determined at 0800. Systolic and diastolic blood pressure and heart rate were automatically recorded every 30 minutes for 24 hours. The responses of luteinizing hormone (LH), follicle stimulating hormone (FSH), PRL, thyroid stimulating hormone (TSH), cortisol, and aldosterone to a stimulation test with gonadotrophinreleasing hormone (Gn‐RH), thyrotrophin‐releasing hormone (TRH), adrenocorticotrophin (ACTH), and testosterone to human chorionic gonadotrophin (HCG) were also evaluated. The same protocol was repeated after a two‐month course of treatment with MT, 2 mg per os daily at 1800. After treatment, we recorded a marked elevation of mean serum MT levels with a significant phase‐advance of its circadian rhythm. The 24‐hour patterns of cortisol and testosterone displayed an anticipation of the morning acrophase of about 1.5 hour (not significant) for cortisol and three hours (P < 0.05) for testosterone. PRL pattern was unchanged as well as serum levels of thyroid hormones. The circadian organization of the cardiovascular variables did not show any changes after MT supplementation; the pituitary, adrenal, and testicular responses to specific stimuli were comparable before and after treatment. These results are compatible with the view that the MT signal may provide temporal cues to the neuroendocrine network for the organization of testicular circadian periodicity.

Evening administration of melatonin enhances the pulsatile secretion of prolactin but not of LH and TSH in normally cycling women

OBJECTIVE The aim of the study was to evaluate the effects of exogenous melatonin on the spontaneous pulsatile release of PRL, TSH and LH in normal women.

Serum levels of bone GLA protein (osteocalcin, BGP) and carboxyterminal propeptide of type I procollagen (PICP) in acromegly: Effects of long-term octreotide treatment

SummaryWe measured serum concentrations of bone Glaprotein (osteocalcin, BGP) and carboxyterminal propeptide of type I procollagen (PICP) in 14 patients with active acromegaly. Blood was collected at 0800 for measurement of bone Gla-protein (BGP), carboxyterminal propeptide of type I procollagen (PICP), and insulin-like growth factor I (IGF-I); growth hormone (GH) was then determined at 15-minute intervals for 3 hours and the integrated mean was calculated. The same protocol was repeated at regular intervals during treatment with the long-acting somatostatin analog, octreotide, 150–450 μg/day for 6–33 months (median 15). In a case-control analysis, serum BGP concentrations recorded in the acromegalic patients were significantly elevated (14.2±4.2 μg/liter versus 8.0±3.3 μg/liter, P<0.001). Octreotide treatment induced a roughly parallel reduction in serum GH, IGF-I, and BGP. We found a significant positive correlation between BGP levels recorded before and during therapy and the logarithm of corresponding mean GH levels (r=0.67, P<0.001). Also IGF-I concentrations were positively correlated with BGP (r=0.66, P<0.001). On the other hand, PICP levels recorded in the acromegalics did not differ from control subjects (146±46 μg/liter versus 127±44 μg/liter, NS) and no correlation was found between either GH and PICP or IGF-I and PICP. To conclude, the present data are compatible with the view that GH and IGF-I play an important role in the control of BGP but not PICP production. It could be that BGP and PICP are submitted to different hormonal modulation.

Proinsulin-secreting neuroendocrine tumor of the pancreas.

Insulinoma is characterized by spontaneous fasting hypoglycemia. Diagnosis relies on inappropriately increased insulin levels (>6 μU/ml), high insulin/glucose ratio (IGR >0.3), raised proinsulin values (>5 pMol/l). A 74-yr-old man was referred to us for episodes of symptomatic hypoglycemia without hyperinsulinemia and imaging [abdominal computed tomography (CT) and magnetic resonance scans] negative for neuroendocrine tumor (NET). During hospitalization severe hypoglycemic crises persisted requiring continuous glucose iv infusion. Insulin values (immunofluorimetric method) were not inappropriately increased, accordingly IGR was normal but C-peptide was in the upper-normal range. Proinsulin levels measured with specific radioimmunoassay were remarkably high. Octreoscan study was negative whereas endoscopic ultrasound disclosed a 10 mm lesion in the body of the pancreas, confirmed by rapid spiral CT scanning with dynamic images. Increased proinsulin levels allowed diagnosis of a secreting NET. After removal of the lesion, the patient experienced hyperglycemia. Histology confirmed a benign NET positively staining for insulin. In conclusion, proinsulin assay is of particular help when immunoreactive insulin, measured by specific new immunometric assays (immunoenzymometric and immunofluorimetric assays), is normal. These methods have good precision and specificity (no cross reactivity with intact or Des 31,32 proinsulin), but rare insulinomas secreting most, or all, of their insulin- like activity as proinsulins would go undetected if insulin levels alone were measured.

Ketoconazole treatment in Cushing’s disease. Effect on the circadian profile of plasma ACTH and Cortisol

Ketoconazole is an inhibitor of adrenal steroidogenesis used in the treatment of Cushing’s disease. Previous data obtained with single blood sampling were controversial as to increased ACTH levels compensatory to the Cortisol fall. We have evaluated by chronobiological procedures the circadian profiles of plasma ACTH and Cortisol in three patients with Cushing’s disease before and after a six-month course of therapy with ketoconazole (600 mg daily). None of the patients complained of any adverse subjective reaction; in particular no sign or symptom of hypoadrenalism and/or hepatotoxicity was recorded. Ketoconazole treatment markedly improved the clinical setting and caused a highly significant (p< 0.0001) reduction of mean 24-h Cortisol values (ciradian MESOR). The expected rise of ACTH did not take place; rather, we detected a slight decrease of the mean circadian MESOR (p < 0.05). Our data, althought obtained in a very small number of patients, suggest that ketoconazole may have an additional action at central level, at least in some cases of Cushing’s disease.

Unexpected Results Using Rapid Intraoperative Parathyroid Hormone Monitoring during Parathyroidectomy for Primary Hyperparathyroidism

Rapid intraoperative parathyroid hormone (RIOPTH) monitoring predicts complete removal of all hypersecreting tissue by means of a significant parathyroid hormone (PTH) decrease. In this study we have tried to provide an explanation for some unexpected results of RIOPTH monitoring observed during a series of 125 conventional parathyroidectomies for primary hyperthyroidism, discussing the possible consequences on the surgical strategy. Three main groups can be recognized: (1) spikes: a PTH increase 10 minutes after removal of the diseased gland was observed in three patients; (2) false-negative results: six patients showed an inadequate PTH decreases at 10 minutes, three of them resulting in cure at 20 minutes (all six patients were cured at follow-up); (3) false-positive results: five patients with multiglandular disease showed a PTH decrease to a cure level despite excision of one adenoma only (in two of these patients a 20-minute sample showed a PTH increase soon after manipulation of the second adenoma). We concluded that the spike, almost certainly a consequence of manipulating the adenoma, when detected should be considered the “true” baseline value. False-negative results are to some extent related to undetected spikes. The assay used for RIOPTH determination and PTH half-life variability may also play a role. A false-negative result usually prolongs the surgical time. False-positive results are usually related to a double adenoma, one functionally prevailing over the other. Because in our experience manipulation of the second adenoma brought a PTH increase detected with RIOPTH monitoring, we believe that the second adenoma should be excised.

24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities.

We monitored the circadian profiles of cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushings Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P less than 0.001). The rhythmicity of BP was disrupted in patients affected by Cushings Syndrome, whereas the 24-hr oscillation of HR was preserved (P less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.

Circadian profile of serum melatonin in patients with Cushing’s syndrome or acromegaly

We evaluated the 24-h profile of serum melatonin (MT) in 16 patients with Cushing’s syndrome (11 pituitary- and 5 adrenal-dependent) aged 38.1±13.8 years and in 19 patients with acromegaly due to GH-secreting pituitary adenoma aged 52±11.9 years. Thirty-three healthy subjects aged 30±7 years and 26 healthy subjects aged 59±12 years served as age-matched controls for the two groups of patients, respectively. All the patients had active disease and were off treatment; none had overt hypopituitarism. Blood drawings were collected at 08:00, 12:00, 16:00, 20:00, 22:00, 24:00, 02:00, 04:00 and 06:00 h in controls and patients. Serum MT, cortisol, GH and IGF-I were measured by specific RIA kits and ACTH by IRMA. Cosinor rhythmometry was employed for chronobiological analysis. The acromegalic patients displayed, as a whole group, higher 24-h mean MT levels with respect to age-matched controls (M±SD: 52.9±14.6 vs 32.9±8.0 pg/ml, p<0.01) with normally synchronized MT profiles in 11/19 patients. No correlation was apparent between MT and either GH (24-h mean) or IGF-I. In the patients with Cushing’s syndrome the circadian profile of serum MT was maintained in 10/16 cases; serum MT levels were comparable to those of controls (48.8±14.0 vs 50.0±16.0 pg/ml, NS) without any difference between pituitary- and adrenal-dependent forms. No correlation was found between MT and either ACTH or cortisol levels. The present data suggest that GH hypersecretion is associated with increased MT secretion whereas hypercortisolism does not cause appreciable alterations of MT secretion.

Serum levels of carboxyterminal propeptide of type I procollagen in cancer patients with osteoblastic and osteolytic bone metastases

Serial monitoring of serum and urinary markers of bone regeneration may provide an indirect assessment of the activity of bone metastases. We measured serum levels of carboxyterminal propeptide of type I procollagen (PICP), a new marker of bone formation, in 236 control subjects, stratified according to age and sex, and in 122 cancer patients: 80 with breast cancer (BC) (42 with osteolytic bone metastases) and 42 with prostate cancer (PC) (31 with osteoblastic bone metastases). An inverse correlation between age and serum PICP levels was found in healthy men (r = -0.30), but not in women. PICP levels were significantly higher in patients with osteoblastic metastases compared to age-matched control subjects and patients with advanced disease not involving the skeleton. The sensitivity of PICP was 64% for detecting osteoblastic metastases, and 12% for detecting osteolytic metastases. Serum PICP determination may have a diagnostic role for osteoblastic activity.