Maria Laura Tanda, Fausto Bogazzi, Enio Martino and Luigi Bartalena
Luca Tomisti, Giuseppe Rossi, Luigi Bartalena, Enio Martino and Fausto Bogazzi
Considering the different pathogenic mechanisms of the two main forms of amiodarone-induced thyrotoxicosis (AIT), we ascertained whether this results in a different onset time as well.
Design and methods
We retrospectively analyzed the clinical records of 200 consecutive AIT patients (157 men and 43 women; mean age 62.2±12.6 years) referred to our Department from 1987 to 2012. The onset time of AIT was defined as the time elapsed from the beginning of amiodarone therapy and the first diagnosis of thyrotoxicosis, expressed in months. Factors associated with the onset time of AIT were evaluated by univariate and multivariate analyses.
The median onset time of thyrotoxicosis was 3.5 months (95% CI 2–6 months) in patients with type 1 AIT (AIT1) and 30 months (95% CI 27–32 months, P<0.001) in those with type 2 AIT (AIT2). Of the total number of patients, 5% with AIT1 and 23% with AIT2 (P=0.007) developed thyrotoxicosis after amiodarone withdrawal. Factors affecting the onset time of thyrotoxicosis were the type of AIT and thyroid volume (TV).
The different pathogenic mechanisms of the two forms of AIT account for different onset times of thyrotoxicosis in the two groups. Patients with preexisting thyroid abnormalities (candidate to develop AIT1) may require a stricter follow-up during amiodarone therapy than those usually recommended. In AIT1, the onset of thyrotoxicosis after amiodarone withdrawal is rare, while AIT2 patients may require periodic tests for thyroid function longer after withdrawing amiodarone.
Luigi Bartalena, Fausto Bogazzi, Maria Laura Tanda, Luca Manetti, Enrica Dell'Unto and Enio Martino
The effects of smoking on the function of endocrine glands have been investigated extensively but still are to be elucidated fully. It is widely recognized that the most important component of the smoke produced from the burning of tobacco, in terms of endocrine effects, is nicotine. Nicotine acts through the interaction with acetylcholine receptors, but it seems likely that others among the numerous smoke products may somehow influence endocrine homeostasis.
The present paper will focus on the relationship between smoking and variations in thyroid economy or the occurrence of thyroid dysfunction.
Several studies have been carried out to ascertain whether smoking is associated with variations in thyroid economy. The rationale for these investigations was dictated by the observation that smoking is associated with a decrease in body mass, and, conversely, refrain from smoking is often accompanied by an increase in body mass (1). These changes might be mediated
Elisabetta Cecconi, Maurizio Gasperi, Maura Genovesi, Fausto Bogazzi, Lucia Grasso, Filomena Cetani, Massimo Procopio, Claudio Marcocci, Luigi Bartalena and Enio Martino
Objective: To investigate, in a large group of postmenopausal primary hyperparathyroidism (PHP) women, whether the concomitance of GH deficiency (GHD) may contribute to the development of changes in bone mineral density (BMD).
Design: GH secretion, bone status and metabolism were investigated in 50 postmenopausal women with PHP and in a control group of 60 women with no evidence of PHP, matched for age, age at menopause and body mass index (BMI).
Methods: GH response to growth hormone-releasing hormone (GHRH)+arginine (Arg), femoral neck BMD (g/cm2) by dual energy X-ray absorptiometry, BMI, serum-ionized calcium, parathyroid hormone (PTH) and markers of bone remodelling were evaluated in all patients and controls.
Results: Among PHP patients, GH secretion was reduced (8.8 ± 4.2 μg/l, range 1.1–16.5 μg/l) in 34 patients and normal (28.7 ± 11.8 μg/l, range 17.9–55.7 μg/l) in the remaining 16 (P < 0.05), no women in the control group had GHD (peak GH 33.8 ± 10.9 μg/l, range 21.7 ± 63.2 μg/l). Osteoporosis (T-score < − 2.5) and osteopenia (T-score > −2.5 and < −1) were found in 73.5 and 17.6% of GHD patients, in 37.5 and 43.7% of patients with normal GH secretion and 3.1 and 27% of controls. T-score and BMD were not correlated with ionized calcium, age, age at menopause, BMI, GH peak and IGF-I but were correlated with serum PTH levels in both groups. T-score was correlated with serum levels of markers of bone remodelling only in PHP patients with GHD.
Conclusions: Concomitant impairment of GH secretion may play a pathogenetic role in the occurrence of changes in bone mass observed in PHP and contribute to make them more severe.
Isabella Lupi, Mirco Cosottini, Patrizio Caturegli, Luca Manetti, Claudio Urbani, Daniele Cappellani, Ilaria Scattina, Enio Martino, Claudio Marcocci and Fausto Bogazzi
Autoimmune hypophysitis (AH) has a variable clinical presentation and natural history; likewise, its response to glucocorticoid therapy is often unpredictable.
To identify clinical and radiological findings associated with response to glucocorticoids.
Design and methods
12 consecutive patients with AH, evaluated from 2008 to 2016. AH was the exclusion diagnosis after ruling out other pituitary masses and secondary causes of hypophysitis. Mean follow-up time was 30 ± 27 months (range 12–96 months).
MRI identified two main patterns of presentation: global enlargement of the pituitary gland or panhypophysitis (n = 4, PH), and pituitary stalk abnormality only, or infundibulo-neuro-hypophysitis (n = 8, INH). Multiple tropin defects were more common in PH (100%) than those in INH (28% P = 0.014), whereas diabetes insipidus was more common in INH (100%) than that in PH (50%; P = 0.028). All 4 PH and 4 out of 8 INH were treated with glucocorticoids. Pituitary volume significantly reduced in all PH patients (P = 0.012), defective anterior pituitary function recovered only in the two patients without diabetes insipidus (50%) and panhypopituitarism persisted, along with diabetes insipidus, in the remaining 2 (50%). In all INH patients, either treated or untreated, pituitary stalk diameter reduced (P = 0.008) but diabetes insipidus persisted in all.
Glucocorticoid therapy may improve anterior pituitary function in a subset of patients but has no effect on restoring posterior pituitary function. Diabetes insipidus appears as a negative prognostic factor for response to glucocorticoids.
Luca Manetti, Fausto Bogazzi, Clara Giovannetti, Valentina Raffaelli, Maura Genovesi, Giovanni Pellegrini, Lucia Ruocco, Aldo Iannelli and Enio Martino
To evaluate whether patients with Cushing's syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE).
Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery.
Patients and methods
Forty patients with active CS (36 with Cushing's disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery.
CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, α2 antiplasmin, P=0.0004, thrombin–antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and α2 antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushing's pituitary adenoma had VTE (P=0.04).
Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.
Fausto Bogazzi, Luca Manetti, Martina Lombardi, Clara Giovannetti, Valentina Raffaelli, Claudio Urbani, Ilaria Scattina, Pasquale Pepe, Aldo Iannelli, Enio Martino and Giuseppe Rossi
To evaluate the impact of different peak GH cut-off limits after GHRH-Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD).
Design and patients
Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 μg/l) Endocrine Societies, by HypoCCs (2.5 μg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered.
Peak GH after GHRH-Arg and IGF1.
Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8–62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD.
Single peak GH cut-offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut-off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context.
Andrea Giustina, Stefania Bonadonna, Giovanna Bugari, Annamaria Colao, Renato Cozzi, Salvatore Cannavo, Laura de Marinis, Ettore degli Uberti, Fausto Bogazzi, Gherardo Mazziotti, Francesco Minuto, Marcella Montini and Ezio Ghigo
In acromegaly, 25–50% of patients respond inadequately to conventional long-acting somatostatin analogue (SSA) therapy. Response may be improved by increasing SSA frequency or dose. This study evaluated the biochemical efficacy and safety of high-dose octreotide in patients with acromegaly.
A 24-week prospective, multicentre, randomised, open-label trial conducted from 12 December 2005 to 23 October 2007 in patients with persistently uncontrolled acromegaly despite ≥6 month conventional SSA therapy.
Patients with ≥50% reduction in GH levels during previous SSA treatment were randomised to high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection. Primary end-points were week 12 and 24 reduction in serum IGF1 and GH from baseline. Secondary end points included IGF1 normalisation and tumour shrinkage rates, and safety/tolerability evaluations.
Significantly, more patients (10 out of 11) achieved week 24 IGF1 reduction in the high-dose than the high-frequency group (8 out of 15; P<0.05). In the high-dose group only, week-24 IGF1 values were significantly reduced (P=0.02) versus baseline. Normalisation of IGF1 occurred only with the high-dose regimen (4/11; P=0.02). Out of 14 patients experiencing adverse events, 5 reported drug-related gastrointestinal effects. No dose–response relationship was seen. Safety parameters were similar between treatment groups, apart from a slight decrease in HbA1c in the high-dose group only.
High-dose octreotide treatment is safe and effective (normalisation of IGF1 levels) in a subset of patients with active acromegaly inadequately controlled with long-term SSA. Individualised octreotide doses up to 60 mg/28 days may improve outcomes of SSA therapy.
Luca Manetti, Giuseppe Rossi, Lucia Grasso, Valentina Raffaelli, Ilaria Scattina, Simone Del Sarto, Mirco Cosottini, Aldo Iannelli, Maurizio Gasperi, Fausto Bogazzi and Enio Martino
Several tests have been proposed to diagnose patients with Cushing's syndrome (CS). The aims of the study were: i) to evaluate the performance of salivary cortisol (SC) in hypercortisolism and ii) to compare SC with serum cortisol (SeC) and urinary cortisol.
Design and patients
This was a diagnostic study. Twenty-seven patients with untreated Cushing's disease (CD untr), 21 women consuming oral contraceptive pill (OCP), 18 pregnant women, and 89 healthy subjects (controls) were enrolled.
SC and SeC at baseline and after the low-dose dexamethasone suppression test (LDDST) and urinary free cortisol (UFC) were measured.
Midnight SC had a sensitivity of 100% in the CD untr group and a specificity of 97.7% in the controls. Specificity remained high (95.2%) in women taking OCP, while in pregnant women, it decreased to 83.3%. SC after the LDDST showed a sensitivity of 96.3% in the CD untr group; specificity was 97.7% in the controls and 90.5% in OCP women. Midnight SeC had a sensitivity of 100% in the CD untr group. SeC after the LDDST had a sensitivity of 100% in the CD untr group while specificity was 97.7% in the controls and 61.9% in women taking OCP. For UFC, sensitivity was 92.6% in the CD untr group while specificity was 97.7% in the controls and 100% in the OCP group.
SC is a reliable parameter for the diagnosis of severe hypercortisolism, with high sensitivity and specificity. In women during pregnancy or taking OCP, the measurement of SC, identifying the free fraction, could be helpful to exclude CS.
Gherardo Mazziotti, Teresa Porcelli, Fausto Bogazzi, Giovanna Bugari, Salvatore Cannavò, Annamaria Colao, Renato Cozzi, Laura De Marinis, Ettore degli Uberti, Silvia Grottoli, Francesco Minuto, Marcella Montini, Maurizio Spinello and Andrea Giustina
In this study, the effect of high-dose octreotide LAR on glucose metabolism in patients with acromegaly was investigated.
A post-hoc analysis of a clinical trial enrolling 26 patients with acromegaly not controlled by standard maximal somatostatin analog (SSAs) dose and randomized to receive high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection (octreotide LAR) for 6 months.
Glucose metabolic status was defined as worsened when a progression from normoglycemia to impaired fasting glucose (IFG) or from IFG to diabetes occurred or when an increase of HbAlc by at least 0.5% was demonstrated. An improvement of glucose metabolism was defined in the presence of a regression from IFG to normoglycemia and/or when HbAlc decreased by at least 0.5%.
Glucose metabolic status remained unchanged in a majority of patients (16/26 patients, 65.3%), worsened in six patients, and improved in four patients. Pre-existing metabolic status did not predict worsening of glucose metabolism, which, conversely, was significantly related to persistent biochemical activity of the disease. In fact, patients with worsened glucose metabolism exhibited a less frequent decrease in serum GH and IGF1 levels, compared with patients with improved or unchanged glucose metabolism (2/6 vs 18/20; P=0.01).
An increase in octreotide LAR dose or frequency did not impact on glucose metabolism in most patients. Worsening of glucose metabolic status occurred in close relation with persistently uncontrolled acromegaly.