Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery.

OBJECTIVES: 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). DESIGN: 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. RESULTS: 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, α(2) 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 α(2) 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). CONCLUSIONS: 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.

Prevalence and functional significance of antipituitary antibodies in patients with autoimmune and non-autoimmune thyroid diseases.

BACKGROUND: Circulating antipituitary antibodies (APA) are markers of autoimmune hypophysitis, which may cause deficient pituitary function. The prevalence of APA in autoimmune thyroid disorders (AITD) is uncertain. OBJECTIVES: The aims of this study were 1) to evaluate APA prevalence in a large series of patients with AITD and non-AITD and 2) to investigate the functional significance of APA by assessing pituitary function in APA-positive patients. DESIGN AND SETTING: We conducted a health survey on consecutive AITD and non-AITD patients at a tertiary referral center (Department of Endocrinology, Pisa). PATIENTS: Subjects, including 1290 consecutive patients with thyroid disorders (961 AITD and 329 non-AITD) and 135 controls, were enrolled in the study. METHODS: APA (indirect immunofluorescence), free T(4), free T(3), TSH, and organ-specific autoantibodies were assayed in all patients. Functional pituitary evaluation was performed in most APA-positive patients. RESULTS: APA frequency was higher in AITD (11.4%) than in non-AITD (0.9%; P < 0.0001) patients; all control subjects had negative APA tests. APA were more frequently found in Hashimoto's thyroiditis (13%) than in Graves' disease (7.1%; P = 0.05). Of 110 APA-positive AITD patients, 20 (18.2%) had autoimmune polyglandular syndrome, whereas 90 (81.8%) had apparently isolated AITD. APA positivity increased percentage of autoimmune polyglandular syndrome in our series from 10.4 to 13.5%. Of 110 APA-positive patients, 102 were submitted to dynamic testing for functional pituitary assessment; 36 patients (35.2%) had mild or severe GH deficiency (GHD). No additional anterior pituitary hormone deficiencies were found; one patient had central diabetes insipidus. Pituitary abnormalities at magnetic resonance imaging were found in most APA-positive GHD patients. CONCLUSIONS: APA are frequently present in patients with AITD. Patients should be tested for APA because positive tests are associated with GHD.

The reduction of bone mineral density in postmenopausal women with primary hyperparathyroidism is higher in the presence of concomitant GH secretion impairment.

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 microg/l, range 1.1-16.5 microg/l) in 34 patients and normal (28.7 +/- 11.8 microg/l, range 17.9-55.7 microg/l) in the remaining 16 (P < 0.05), no women in the control group had GHD (peak GH 33.8 +/- 10.9 microg/l, range 21.7 +/- 63.2 microg/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.

Improvement of growth hormone deficiency in patients with primary hyperparathyroidism after parathyroidectomy: results of a prospective study.

GH secretion is impaired in most patients with primary hyperparathyroidism (PHP), although the secretion of the other anterior pituitary hormones is unaffected. However, whether restoration of euparathyroidism is associated with reversal of GH deficiency in PHP patients is not known. To address this issue, we studied 30 consecutive patients with PHP due to a single parathyroid adenoma before and after parathyroidectomy. GH secretion was evaluated by peak serum GH after the maximal GHRH + arginine (Arg) stimulation test. A group of 35 age- and sex-matched normal subjects served as controls. Serum IGF-I concentration was below the normal age- corrected values in six of 30 patients before surgery and in four of 30 patients after parathyroidectomy (P = not significant). Mean serum peak GH values after the GHRH + Arg test were 17.5 +/- 2.8 micro g/liter before surgery and 23.8 +/- 2.5 micro g /liter after surgery (P = 0.0008). The GH response to the GHRH + Arg test was reduced in 20 (67%) and normal in 10 (33%) of 30 PHP patients at baseline; after surgery, 22 of 30 (73%) PHP patients had a normal GH response to the GHRH + Arg test, and only eight (27%) had an impaired GH secretion (P < 0.02). In conclusion, this study confirms that GH secretion is impaired in PHP patients and indicates that it is reversed in many patients after parathyroidectomy. Accordingly, GH deficiency in PHP patients must be considered a functional phenomenon for which GH therapy is not recommended.

Impaired GH secretion to provocative stimuli in two families with hypocalciuric hypercalcaemia.

OBJECTIVE: To determine whether hypercalcemia per se might be responsible for an impairment in GH secretion. DESIGN: Prospective study. PATIENTS: Six subjects of two unrelated families with familial hypocalciuric hypercalcaemia (FHH), an autosomal dominant disorder due to inactivating mutations in the calcium receptor gene, leading to an increase in serum calcium levels and inappropriately normal serum PTH concentrations. Forty normal subjects, matched for sex and age served as controls. MEASUREMENTS: Serum GH concentrations were measured after GHRH-Arginine (GHRH-Arg) stimulation test; serum IGF-I, ACTH, cortisol, FT4, FT3, TSH, PRL, LH, FSH levels were measured under basal conditions. RESULTS: All subjects (two male, four female, age range 24-74 years) had increased serum ionized calcium levels (range 1.36-1.56 mmol/l) and five of six patients had normal PTH levels (range for all patients was 14-68 ng/l). Basal serum GH concentrations ranged from 0.1 to 7.0 micro g/l. Mean serum GH secretory peak after GHRH-Arg stimulation test was reduced in five subjects (mean 9.3 +/- 3.6 microg/l, P < 0.006 vs. Controls, mean 67.0 +/- 44.0 microg/l, cut-off, 16.0 microg/l) and normal in one subject (38.7 microg/l). However, serum IGF-I levels were reduced only in two patients (29 and 57 microg/l) and normal in four subjects (range 127-208 microg/l). The basal secretion of the other anterior pituitary hormones was within their normal ranges. CONCLUSIONS: The results of the present study support the concept that elevated serum calcium levels impair GH secretion. However, the clinical relevance of GH deficiency in FHH remains to be elucidated.

Submandibular salivary gland volume is increased in patients with acromegaly.

OBJECTIVE: Acromegaly is characterized by an enlargement of various organs. The aim of the present study was to evaluate whether acromegalic patients have an increased volume of submandibular salivary glands. DESIGN AND SUBJECTS: Prospective study on 40 consecutive acromegalic patients (18 male, 22 female; mean age +/- SD, 50 +/- 13 years, range 22-74 years) submitted to submandibular salivary gland ultrasound. Among acromegalic patients, 15 had active and untreated disease (Acro-U), 13 were under long-acting somatostatin analogue therapy (Acro-SA), 12 were in remission after surgery (Acro-R). Two hundred subjects (90 male, 110 female, mean age +/- SD, 50 +/- 11 years, range 23-74 years) matched for age, sex and body mass index served as controls. MEASUREMENTS: Submandibular salivary gland volume was measured in all acromegalic patients and normal subjects by ultrasound and calculated by the ellipsoid model. Serum GH and IGF-I concentrations were measured in all subjects. RESULTS: Acro-U patients had higher serum IGF-I levels (691 +/- 235 microg/l) than Acro-R (174 +/- 74 microg/l), Acro-SA (436 +/- 239 microg/l) or controls (151 +/- 66 microg/l) (P < 0.0001, P = 0.008, P < 0.0001, respectively). The mean submandibular salivary gland volume was higher in acromegalic patients than in controls: Acro-U 18.1 +/- 3.3 ml, Acro-SA 16.2 +/- 3.3 ml, Acro-R 15.7 +/- 3.0 ml and controls 8.2 +/- 2.4 ml (P < 0.0001). Differences among subgroups of Acro patients were not significant. Enlargement of the submandibular salivary glands was present in 35/40 (87.5%) acromegalic patients. A positive correlation between serum IGF-I (P < 0.0001), GH (P < 0.0001) and submandibular salivary gland volume was found. CONCLUSIONS: Acromegalic patients have an increased volume of submandibular salivary glands, independently of the activity of disease.