Long-acting pasireotide improves clinical signs and quality of life in Cushing's disease: results from a phase III study.

PURPOSE: Cushing's disease (CD) is associated with significant clinical burden, increased mortality risk, and impaired health-related quality of life (HRQoL). This analysis explored the effect of long-acting pasireotide on clinical signs of hypercortisolism and HRQoL in a large subset of patients with CD. METHODS: In this phase III study (clinicaltrials.gov: NCT01374906), 150 adults with CD and a mean urinary free cortisol (mUFC) level between 1.5 and 5.0 times the upper limit of normal (ULN) started long-acting pasireotide 10 or 30 mg every 28 days with dose increases/decreases permitted based on mUFC levels/tolerability (minimum/maximum dose: 5/40 mg). Changes in clinical signs of hypercortisolism and HRQoL were assessed over 12 months of treatment and were stratified by degree of mUFC control for each patient. RESULTS: Patients with controlled mUFC at month 12 (n = 45) had the greatest improvements from baseline in mean systolic (- 8.4 mmHg [95% CI - 13.9, - 2.9]) and diastolic blood pressure (- 6.0 mmHg [- 10.0, - 2.0]). Mean BMI, weight, and waist circumference improved irrespective of mUFC control. Significant improvements in CushingQoL total score of 5.9-8.3 points were found at month 12 compared with baseline, irrespective of mUFC control; changes were driven by improvements in physical problem score, with smaller improvements in psychosocial score. CONCLUSIONS: Long-acting pasireotide provided significant improvements in clinical signs and HRQoL over 12 months of treatment, which, in some cases, occurred regardless of mUFC control. Long-acting pasireotide represents an effective treatment option and provides clinical benefit in patients with CD. CLINICAL TRIAL REGISTRATION NUMBER: NCT01374906.

Baseline characteristics of the population enrolled in the Italian Observational Study on Severe Osteoporosis (ISSO).

OBJECTIVES: Baseline characteristics of the population enrolled in the ISSO study, designed to evaluate the incidence of vertebral and non-vertebral fractures in Italian patients with severe osteoporosis treated according to clinical practice over 24 months observation. METHODS: Prospective observational study in 783 post-menopausal women and men entering 18-month treatment with teriparatide in a community setting at 57 centres in Italy. Characterisation included demographics, fracture risk factors, bone mineral density, fracture status, Health-Related Quality of Life (HRQoL) measured by the European Quality of Life Questionnaire, EQ-5D, and back pain assessed by VAS. RESULTS: Most patients were elderly women (90.5%), mean age±SD was 72.9±8.8 years. Nearly all (91.3%) had experienced ≥ 1 vertebral fracture (mean±SD, 3.6±2.2 per patient), 37.5% had ≥ 1 non-vertebral fracture (mean±SD, 1.4±0.7 per patient). Nearly all patients were suffering from back pain (94.9%), which had significantly restricted their daily activities (51.7%) and had likely or very likely been caused by vertebral fractures (29.2% and 55.8%, respectively). Mean EuroQoL EQ-5D index value was 0.58±0.25 and VAS score 49.2±23.6. Non-vertebral fractures, back pain and multiple vertebral fractures were associated with lower HRQoL (EuroQoL-5D Index both p<0.001, EQ-5D VAS score p=0.025 and p<0.016, respectively). Many patients were physically inactive (81.1%). One third (34.7%) of population had co-morbidities and 60.5% were on chronic concomitant treatments. Few subjects reported a maternal history of osteoporosis (15.5%), regular consumption of alcohol (13.3%) or were current smokers (11.5%). Nearly two-thirds (71.5%) had already been treated for osteoporosis, mainly with bisphosphonates. Calcium and vitamin D supplements were taken by 13% and 15.5% of the total population, respectively. CONCLUSIONS: At enrollment, the population of ISSO study mostly consisted in aging women, who had osteoporosis with high fracture risk, poor HRQoL and suffered from significant back pain. Most of them had already been treated by bisphosphonates but without calcium and vitamin D supplements. Back pain, as well as non-vertebral and multiple vertebral fractures, were associated with lower HRQoL.

Prediction of response to growth hormone treatment in pre-pubertal children with growth hormone deficiency.

BACKGROUND: GH therapy response varies substantially among patients. Several models were developed to predict the efficacy of GH therapy in children. AIM: To evaluate the accuracy of a growth prediction model using data from an Italian pediatric GH deficiency (GHD) cohort (GeNeSIS, Growth Prediction Sub-study). METHODS: Open-label, multicenter study in 22 Italian pre-pubertal GH treatment- naïve patients with GHD (8 female, 14 male, 0.5 to 12.2 yr), 18 isolated GHD, 4 multiple pituitary hormone deficiency given recombinat human GH therapy (0.025-0.035 mg/kg/day) for 12 months. Growth prediction was performed, after 3 months of treatment, using baseline data [bone age (BA) and IGF-I], a urinary marker of bone turnover [deoxypyridinoline crosslinks (DPD)] at 4 weeks, and height velocity (HV) at 3 months. Results were expressed as 1st-yr HV using the following equation: 1-yr HV (cm) = 3.543 - (2.337 × BA) - (0.010 × IGF-I) + (0.100 × DPD) + (0.299 × 3-month HV). Predictions were compared to the 1st-yr HV and accuracy was calculated as percentage of the difference between mean calculated HV and the real 1st-yr HV. RESULTS: For females predicted HV was 12.98 ± 4.82 cm/yr and actually was 13.05 ± 3.91 cm/yr after the 1st year; for males predicted HV was 13.95 ± 5.39 cm/yr and actually was 12.93 ± 5.02 cm/yr. CONCLUSIONS: In this paediatric Italian cohort with GHD, a growth prediction model seems to be a valid tool to assess 1st-yr response to GH treatment in Italian children.

A novel mutation in the N-terminal region of the CYP17A1 gene in a patient with 17 alpha-hydroxylase/17,20-lyase deficiency.

The deficiency of 17 alpha-hydroxylase/17,20-lyase causes a rare autosomal recessive disorder presenting with congenital adrenal insufficiency (CAH) and sexual infantilism. Both 17 alpha-hydroxylase and 17,20-lyase reactions are catalyzed by a single polypeptide, cytochrome P450c17 (CYP17), which is encoded by the CYP17A1 gene. We describe the clinical, hormonal, and molecular findings of a 33-yr-old patient presenting with primary amenorrhea, late onset hypertension, and hypokalemic myopathy. The molecular analysis of CYP17A1 revealed a novel homozygous missense mutation resulting in the substitution of arginine to lysine at the amino acid position 21 (p.R21L).

Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing's syndrome.

INTRODUCTION: Chronic mild endogenous glucocorticoid excess has been shown to cause bone loss and to increase fracture risk in both post-menopausal and premenopausal women. Currently, it is unclear if patients with subclinical Cushing's syndrome (SCS) with osteoporosis or osteopenia may benefit from antiresorptive treatment and the type of therapy to be given. OBJECTIVE: This pilot randomized study was aimed at evaluating the effects of 12-month im administration of clodronate (100 mg every week) on vertebral and femoral bone mineral density (BMD), bone turnover markers and on subjective pain in premenopausal women with SCS due to adrenal incidentalomas. METHODS: Forty-six women (age, 43.1+/-7.7 yr) with SCS due to adrenal incidentaloma and osteoporosis/osteopenia were randomized to receive clodronate plus supplement of Calcium (500 mg daily) and Vitamin D3 (800 mg daily) (group 1, no.=23) or supplements only (group 2, no.=23). Both groups were similar in terms of age, body mass index, cortisol levels, BMD values, and bone turnover markers. All of the women were re-evaluated after 12 months. RESULTS: After 12 months of treatment, in group 1, a significant increase in lumbar BMD occurred (p=0.04), while bone turnover markers decreased by about one third (p<0.05). In group 2, bone turnover markers did not change and BMD values slightly decreased (p=ns). The differences in bone turnover markers and in lumbar BMD between the two groups were significant (p<0.05, all). No new vertebral fracture occurred in group 1, while in group 2 the spine radiographies revealed 2 new fractures and a worsening of two pre-existent fractures. An improvement in subjective back pain, assessed by visual analogue scale pain score was observed in group 1 (from 4.3+/-2.7 to 2.9+/-2.0; p<0.05) but not in group 2 (from 4.4+/-3.1 to 4.2+/-3.4; p=ns). No significant changes occurred in cortisol secretion or clinical picture of the SCS during the study. CONCLUSIONS: Intramuscular administration of clodronate effectively increased lumbar BMD values, preserved bone mass at the femoral neck, stabilized vertebral fracture index, and decreased subjective back pain in pre-menopausal women with SCS. Since the untreated group continued to lose bone, antiresorptive treatment should be considered in patients with SCS, according to the prevision of surgical treatment, prevalent fractures, BMD values, age, concomitant morbidities, and desire for pregnancy.

Bone density and turnover in young adult patients with growth hormone deficiency after 2-year growth hormone replacement according with gender.

GH deficiency (GHD) in adults is accompanied by reduced bone mass that may revert only after 2 yr of GH replacement. However, it is unclear whether the gender may modify bone responsiveness to GH replacement in adults. In this study we have evaluated whether bone mineral density (BMD) and turnover improve after GH replacement according to patients' gender. BMD at lumbar spine (LS) and femoral neck (FN), serum osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) were assessed in 64 hypopituitaric patients (35 men, 30-50 yr) before and 2 yr after the beginning of GH replacement. Values of IGF-I and BMD at LS and at FN were expressed as Zscores. At study entry, IGF-I and BMD resulted similar among men and women with GHD. During GH replacement, IGF-I levels increased in both men and women without any difference in the percentage of IGF-I increase between the genders (p=0.47). In women receiving estrogen replacement, however, the percentage of IGF-I increase (p<0.05), and the Z IGF-I score (p<0.001) were significant lower than estrogen untreated women, although IGF-I levels were similar in the 2 groups (p=0.53). The GH dose adjusted for body weight required to restore normal age- and sex- matched IGF-I levels was lower in men than in women (p<0.001), and was higher in women receiving than in those not receiving estrogen replacement (p<0.05). In contrast, hypogonadal men treated with testosterone and eugonadal men received a similar GH dose (p=0.97). Also OC, Ntx levels, lumbar and femoral BMD improved (p<0.001) in all patients. Nevertheless, a greater increase in lumbar BMD increase was observed in men than in women (8.0+/-2.1 vs 2.6+/-0.4%; p<0.05). No significant difference was revealed in bone parameters in women treated or untreated with estrogen replacement and in men treated or not with testosterone replacement for concomitant hypogonadism. At the multiple correlation analysis, gender was a stronger predictor for the required GH dose than the age (p<0.001 and p=0.02, respectively). In conclusion, a 2-yr GH replacement normalizes IGF-I levels, increases bone mass and improves bone turnover both in men and in women with GHD without any difference between the 2 groups, provided that the dose of GH was modulated on the basis of IGF-I levels. Women receiving oral estrogens should receive a GH dose approximately doubled, as compared to men and women not receiving oral estrogens, to achieve similar effects on bone density and turnover. In particular, GH replacement dose, to be successful on bone mass and turnover, depends on gender in hypopituitary patients aged below 50 yr.

The role for growth hormone in linking arthritis, osteoporosis, and body composition.

Adults with either GH deficiency (GHD) or GH excess have bone, metabolic, and somatic impairments. This review deals with available data on the relationship between GH status, bone mass, articular disorders, and body composition. GHD subjects have reduced bone mineralization and increased fracture rates. Acromegalic artropathy occurs in virtually all patients and in its late degenerative stages may resemble osteoarthritis. Abnormalities in GH/IGF-I were observed in patients with different forms of arthritis. When concerning body composition (BC), both severe and partial GHD are characterized by increased fat mass, especially truncal, and reduced lean mass. In acromegaly, an increase in body weight, lean mass, and extracellular water, and reduced fat mass were observed; these abnormalities did not always disappear after the normalization of GH/IGF-I levels. On the contrary, long-term GH replacement at physiological doses improved the abnormalities in BC and increased bone mineral density in men with adult-onset GHD, but discordant data were obtained for the bone effects in women. In conclusion, both GHD and GH excess are responsible for some well-defined alterations in metabolism, BC, bone mass, and joint physiology. Their normalization (by GH replacement or treatment of acromegaly) reverses most of these abnormalities, thus confirming their GH-related etiology.

Large idiopathic unilateral adrenal hematoma in a young woman.

This is a case report on a young woman with a large idiopathic unilateral adrenal hematoma (AH). Only few cases of AH which were not associated with any trauma, previous surgery, coagulative or any other systemic disorders have been described. The mass was discovered by abdominal ultrasound which was performed for a recent flank pain. Magnetic resonance imaging (MRI) confirmed the presence of a 13-cm sized lesion in the right hemi-abdomen; T1 and T2 weighed imaging was compatible with subacute-to-chronic adrenal hematoma. The lesion dislocated the liver and right kidney. Positron emission tomography (PET) did not show any significant radiotracer uptake by the mass. Serum cortisol, aldosterone, renin activity and DHEA-S were normal. Urinary catecholamines and free cortisol excretion were within the normal range too. The lesion was removed by transabdominal laparoscopic adrenalectomy without any complication. The histological exam confirmed a large subacute- to-chronic organized AH. In conclusion, in the absence of known risk factors, differential diagnosis of a large AH may not be easy. The possibility of an underlying pheochromocytoma, malignant adrenal or metastatic tumor must always be considered. In our patient, computed tomography (CT) scan and MRI suggested the presence of a large subacute-to-chronic AH, and PET excluded metabolic activity of the mass. Laparoscopic adrenalectomy can be the surgical treatment of choice in organized symptomatic AH. The correct diagnosis, early recognition and treatment of complications including adrenal insufficiency may decrease patient morbidity and mortality.

Effects of various antireabsorptive treatments on bone mineral density in hypogonadal young women after allogeneic stem cell transplantation.

Ovarian failure after allogeneic stem cell transplant (allo-SCT) is an important risk factor for development of osteoporosis. We investigated the effects of various antiresorptive treatments in long-term surviving females with ovarian failure after allo-SCT. A total of 60 women with osteoporosis or osteopenia were divided randomly into four groups of 15 women each. Group 1 was treated with calcium and vitamin D alone, group 2 received the same treatment in combination with hormone replacement therapy (HRT), group 3 received risedronate (35 mg weekly, orally for 1 year) and group 4 zoledronic acid (3 monthly doses of 4 mg (intravenous)). All groups were similar for age, body mass index, underlying disease and time elapsed from transplant. Lumbar and femoral bone mineral density (BMD) were measured at baseline and after 12 months, together with serum osteocalcin and urinary hydroxyproline. At 12 months, a significant decrease in lumbar and femoral BMD was observed in group 1 and a milder decrease in group 2. Risedronate treatment increased significantly lumbar BMD and prevented bone loss at the femoral neck. Zoledronic acid increased significantly both lumbar and femoral BMD. In groups 3 and 4 the hydroxyproline excretion was significantly reduced, while osteocalcin mildly increased only in group 4. In conclusion, bisphosphonate administration is useful to prevent and treat bone demineralization in young adult women after allo-SCT.

Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features.

Incidentally discovered adrenal masses are mostly benign, asymptomatic lesions, often arbitrarily considered as nonfunctioning tumors. Recent studies, however, have reported increasing evidence that subtle cortisol production and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent than previously thought. The purpose of this study was to investigate the clinical and hormonal features of patients with incidentally discovered adrenal adenomas, in relation to their clinical outcome. Fifty consecutive patients with incidentally detected adrenal adenomas, selected from a total of 65 cases of adrenal incidentalomas, were prospectively evaluated. All of them underwent abdominal computed tomography scan and hormonal assays of the HPA axis function: circadian rhythm of plasma cortisol and ACTH, urinary cortisol excretion, 17-hydroxyprogesterone, androgens, corticotropin stimulation test and low-dose (2 mg) dexamethasone test. The patients were reevaluated at regular intervals (6, 12, and 24 months) for a median period of 38 months. Subtle hypercortisolism, defined as abnormal response to at least 2 standard tests of the HPA axis function in the absence of clinical signs of Cushing's syndrome (CS), was defined as subclinical CS. Mild-to-severe hypertension was found in 24 of 50 (48%) patients, type-2 diabetes in 12 of 50 (24%), and glucose intolerance in 6 of 50 (12%) patients. Moreover, 18 of 50 patients (36%) were diffusely obese (body mass index, determined as weight/height2, > 25), and 14 patients (28%) had serum lipid concentration abnormalities (cholesterol > or = 6.21 mmol/L, low-density lipoprotein cholesterol > or = 4.14 mmol/L and/or triglycerides > or = 1.8 mmol/L). Compared with a healthy population, bone mineral density Z-score, determined by the DEXA technique, tended to be slightly (but not significantly) lower in patients with adrenal adenoma (-0.41 SD). Endocrine data were compared with 107 sex- and age-matched controls, and patients with adenomas were found to have heterogeneous hormonal abnormalities. In particular, significantly higher serum cortisol values (P < 0.001), lower ACTH concentration (P < 0.05), and impaired cortisol suppression by dexamethasone (P < 0.001) were observed. Moreover, in patients with adenomas, cortisol, 17-OH progesterone, and androstenedione responses to corticotropin were significantly increased (P < 0.001, all), whereas dehydroepiandrosterone sulfate levels were significantly lower at baseline, with blunted response to corticotropin (P < 0.001, both). However, the criteria for subclinical CS were met by 12 of 50 (24%) patients. Of these, 6 (50%) were diffusely obese, 11 (91.6%) had mild-to-severe hypertension, 5 (41.6%) had type-2 diabetes mellitus, and 6 (50%) had abnormal serum lipids. The clinical and hormonal features improved in all patients treated by adrenalectomy, but seemed unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months), except for one, who was previously found as having nonfunctioning adenoma and then revealed to have subclinical CS. In conclusion, an unexpectedly high prevalence of subtle autonomous cortisol secretion, associated with high occurrence of hypertension, diabetes mellitus, elevated lipids, and diffuse obesity, was found in incidentally discovered adrenal adenomas. Although the pathological entity of a subclinical hypercortisolism state remained mostly stable in time during follow-up, hypertension, metabolic disorders, and hormonal abnormalities improved in all patients treated by adrenalectomy. These findings support the hypothesis that clinically silent hypercortisolism is probably not completely asymptomatic.

Increased intima-media thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with primary hyperparathyroidism.

OBJECTIVE: Despite the increasing evidence that primary hyperparathyroidism (PHPT) contributes to greater risk of cardiovascular morbidity and mortality, its exact role in the development of cardiovascular changes and its clinical significance are still controversial. Given the multiple influence of PHPT on the cardiovascular system, this study aimed to assess the effects of PHPT on blood pressure profile, and on features of the heart and arterial vessels in normotensive symptomless patients. DESIGN: Twenty patients (8 males and 12 females) with a median age of 51.5 years (range 44 to 65 years) were evaluated and the results were compared with those of 20 controls matched for age, gender and body mass index. Patients' parathyroid hormone levels ranged from 172 to 454 pg/ml and Ca levels ranged from 11.4 to 13.5 mg/dl. Fasting levels of glucose, insulin, total and high density lipoprotein cholesterol and triglycerides were within the normal range in all subjects recruited. METHODS: Twenty-four-hour blood pressure profile, left ventricle (LV) dimension and carotid artery anatomy were investigated, the latter two by ultrasonography. RESULTS: No difference was found between the patients and controls in blood pressure profile, when the following parameters were considered: supine systolic/diastolic pressure, average 24-h systolic, diastolic and mean arterial pressure, day-time mean arterial pressure and fall in nocturnal blood pressure (-17% and -18% respectively). Heart rate and all parameters of LV mass were similar in patients and controls. The only alteration found in patients was in significantly greater carotid intimal-medial thickness (IMT) (P<0.001). Atherosclerotic plaques were more frequent in patients than in controls, with a difference reaching a trend (40% vs 10%, chi(2)=4.8; P=0.091). Considering that the carotid IMT is considered to be a marker of systemic atherosclerosis, our finding suggests early atherosclerotic changes in PHPT. No correlation was found between the severity and cardiovascular manifestation of PHPT. CONCLUSIONS: Vascular changes may occur due to a combination of structural and functional impairments in PHPT patients, likely as a result of altered calcium metabolism and impaired equilibrium of other factors regulating vascular function. Both extent and duration of PHPT can play a relative role in the development of cardiovascular complications. Considering that PHPT is now recognized as a quite common and often symptomless endocrine disorder, the evidence of cardiovascular manifestation in normotensive patients, found by this morphological study, suggests a possible implication for the management of such patients. In this light, screening for abnormalities in cardiovascular system function should be recommended in all PHPT subjects.

Percutaneous computed tomography-guided ethanol injection in aldosterone-producing adrenocortical adenoma.

The feasibility, safety and effectiveness of percutaneous computed tomography-guided ethanol injection (PEI-CT) was investigated in a patient affected by aldosterone-producing adenoma (APA). A 42-year-old male patient with typical features of hyperaldosteronism presented a solitary left adrenal adenoma measuring 2 cm, with a normal contralateral gland, evidenced by both CT scan and adrenal [75Se-19]-nor-cholesterol scintigraphy. After normalization of potassium plasma levels, 4 ml of sterile 95% ethanol with 0.5 ml of 80% iothalamate sodium was injected. The procedure was completed in about 30 min. No severe pain or local complication was noted. Five hours after PEI, a fourfold and a twofold increase in aldosterone and cortisol plasma levels were observed, respectively. After 11 days on a normal sodium and potassium diet, normal potassium plasma levels and reduced aldosterone plasma levels were present, with reappearance of an aldosterone postural response. Plasma renin activity and aldosterone plasma levels normalized 1 month later, with reappearance also of a plasma renin activity postural response and maintenance of normal potassium plasma levels even on a high sodium and normal potassium diet. The patient has remained hypertensive, although lower antihypertensive drug dosages have been employed. After 17 months, normal biochemical, hormonal and morphological findings were still present. Thus, we suggest PEI-CT as a further alternative approach to surgery in the management of carefully selected patients with APA.

Antiphospholipid syndrome, adrenal failure, dilated cardiomyopathy and chronic hepatitis: an unusual manifestation of multiorgan autoimmune injury?

The antiphospholipid syndrome is characterized by clinical evidence of arterial or venous thrombosis, thrombocytopaenia, recurrent fetal loss and repeated positivity of antiphospholipid autoantibodies. The association of antiphospholipid syndrome with the development of adrenal failure has been reported in more than 40 patients in the last 20 years, mostly due to bilateral cortical haemorrhage or thrombosis of adrenal vessels. The presence of antibodies against adrenal cortex was never documented in these patients. Here we report a case of recurrent thrombophlebitis, acute adrenal failure, and chronic hepatitis occurring in a young man found to have antiphospholipid antibodies and lupus anticoagulant. Autoantibodies against adrenal cortex were detected and abdominal ultrasonography showed morphologically normal adrenals. Mild thrombocytopaenia, Coomb's positive anaemia, increase in alanine- and aspartate-aminotransferases and increase in urinary protein excretion were found. Autoantibodies against liver/kidney microsomes were positive and liver biopsy was compatible with autoimmune hepatitis. The patient was treated with cortisone acetate, fludrocortisone and warfarin. Dilated cardiomyopathy was revealed one year later and coronarography did not document any occlusive coronary disease. Three years later, titres of autoantibodies, including those directed towards the adrenal cortex, were increased and others, previously absent, were detected. Nevertheless, the patient's clinical conditions seemed unchanged. At this time, an abdominal CT scan showed adrenal dysmorphisms with bilateral annular calcifications and central hypodensities suggesting previous bilateral adrenal haematomas. The hypercoagulable state that occurs in antiphospholipid syndrome can induce a localized inflammatory response generated by tissue injury, with a consequent release of intracellular antigens and antibodies production. Consequently, tissue-specific autoantibodies positivity may persist until the cells involved in antigen production are completely destroyed.

Bone loss determined by quantitative ultrasonometry correlates inversely with disease activity in patients with endogenous glucocorticoid excess due to adrenal mass.

OBJECTIVE: Glucocorticoid excess is widely recognized as one of the most important causes of bone loss. The mechanism of glucocorticoid-induced osteoporosis is presumably multifactorial, and consists of the loss of organic and non-organic compounds. Efforts have been made to develop simple physical methods for the assessment of bone tissue for the screening of subjects at high risk of osteoporosis, without the use of radioactive sources or ionizing radiation. Quantitative ultrasonometry (QUS) has been suggested as a useful method for monitoring patients undergoing glucocorticoid therapy, which is the most common cause of glucocorticoid excess. QUS appears to detect more structural bone changes than the traditional methods and allows assessment of bone density and elasticity, both characteristics influenced by organic and non-organic bone compounds. However, the use of QUS has not yet been extensively investigated in subjects with endogenous cortisol excess. The aim of this study was to evaluate the usefulness and predictive power of QUS in assessing bone loss in subjects with differing degrees of endogenous cortisol excess due to adrenal mass. DESIGN: Thirty-four patients (20 women and 14 men) aged between 21 and 59 years were evaluated; fifteen (9 women and 6 men; median age, 42 years) were affected by overt Cushing's syndrome (CS) and nineteen (11 women and 8 men; median age, 44 years) by subclinical CS, defined as lacking clinical signs of hormone excess despite the presence of at least two abnormalities in hypothalamic-pituitary-adrenal axis function, as assessed by routine endocrine tests. All women included were eumenorrhoic. METHODS: QUS measurement of amplitude-dependent speed of sound was performed on the 2nd to 5th proximal phalanges of the non-dominant hand using a DBM Sonic 1200R bone profiler (Igea S.r.l, Italy). The results were compared with bone density assessed on lumbar vertebrae (L1-L4) and femoral neck sites by dual-energy X-ray absorptiometry (DEXA). RESULTS: A strongly significant bone loss was detected by finger QUS measurement when the patients were considered either all together or as two subgroups (P<0.001, all). The bone density decrease in the fingers was similar to that found at the lumbar spine and femoral neck by the DEXA technique. Lumbar and finger Z-scores correlated inversely with 24 h urinary free cortisol (UFF) excretion (P<0.01, both). Finger Z-scores also correlated inversely with the estimated duration of subclinical CS (P<0.05). Concerning disease activity, only UFF was confirmed by multivariate analysis to be an independent factor influencing bone loss (P<0.05). A positive correlation between the results of the two techniques was found in controls (P<0.05) but not in patients. The lack of correlation between the two techniques in patients can probably be attributed to the different parameters of bone alteration measured by the techniques. CONCLUSIONS: The detection of bone loss in subclinical CS similar to that in overt CS suggests that all subjects with endogenous cortisol excess should be evaluated for bone mass. QUS measurement appears to be a reliable, radiation-free, simple and fast tool for the identification of bone alteration in subjects with endogenous cortisol excess.

TAG-72 expression and clinical outcome in primary breast cancer.

Clinical data of 92 patients with primary breast carcinomas previously analysed for the pattern of immunohistochemical expression of three distinct carbohydrate epitopes of the TAG-72 molecule were reviewed. The clinical outcome of the patients after a median follow-up of 66 months was determined in 84 out of 92 patients. Clinicopathological characteristics of the tumours and clinical outcome of the patients were correlated with the TAG-72 epitope expression. TAG-72 was expressed more frequently in patients aged more than 50 years and in tumours of larger size, with lymph nodes metastasis, with low differentiation and with high proliferative activity. A statistical correlation was found with more advanced stages of the disease (35.7% vs 60% in stage I and in stage II-III, respectively, p=0.03). Disease-free survival and overall survival were estimated by the Kaplan-Meier method. The survival of the patients with tumours expressing TAG-72 was not statistically different from that of patients with tumours without TAG-72 expression. These data suggest that TAG-72 expression is associated with clinicopathological parameters of aggressiveness in primary breast cancer, but it does not appear to affect the clinical outcome of the patients.

Accelerated bone mass senescence after hematopoietic stem cell transplantation.

Osteoporosis and avascular necrosis (AVN) are long-lasting and debilitating complications of hematopoietic stem cell transplantation (HSCT). We describe the magnitude of bone loss, AVN and impairment in osteogenic cell compartment following autologous (auto) and allogeneic (allo) HSCT, through the retrospective bone damage revaluation of 100 (50 auto- and 50 allo-HSCT) long-term survivors up to 15 years after transplant. Current treatment options for the management of these complications are also outlined. We found that auto- and allo-HSCT recipients show accelerated bone mineral loss and micro-architectural deterioration during the first years after transplant. Bone mass density (BMD) at the lumbar spine, but not at the femur neck, may improve in some patients after HSCT, suggesting more prolonged bone damage in cortical bone. Phalangeal BMD values remained low for even more years, suggesting persistent bone micro-architectural alterations after transplant. The incidence of AVN was higher in allo-HSCT recipients compared to auto-HSCT recipients. Steroid treatment length, but not its cumulative dose was associated with a higher incidence of bone loss. Allo-HSCT recipients affected by chronic graft versus host disease seem to be at greater risk of continuous bone loss and AVN development. Reduced BMD and higher incidence of AVN was partly related to a reduced regenerating capacity of the normal marrow osteogenic cell compartment. Our results suggest that all patients after auto-HSCT and allo-HSCT should be evaluated for their bone status and treated with anti-resorptive therapy as soon as abnormalities are detected.

The role of growth hormone in glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. GC influence bone metabolism via a modulation of different components of the GH/IGF-I system. GH has multiple anabolic effects on bone, either direct or mediated by IGF-I. GH-deficient subjects have significant reduction in bone mineralization, bone turnover markers, and increased fracture risk when compared with healthy age-matched controls. The increase of bone remodeling achieved by recombinant human GH (rhGH) therapy may be helpful in both males and females with decreased bone turnover and impaired osteoblastic function such as subjects with GC excess. rhGH treatment may improve lean body mass and skeletal muscle mass that may further reduce fracture risk in GIO patients. Nevertheless, the real efficacy of rhGH and IGF-I treatment in GIO and during aging is still controversial and further well-designed prospective controlled studies are necessary in order to clarify this issue, thus identifying who could potentially benefit from GH treatment.

Cryptozoospermia with normal testicular function after allogeneic stem cell transplantation: a case report.

One of the most frequent consequences of allogeneic haemopoietic stem cell transplantation (allo-SCT) in both males and females is gonadal insufficiency. We report the case of a 27-year-old myelodysplastic male who developed azoospermia after allogeneic transplantation of haemopoietic stem cells from his HLA-identical sister. Post-transplant azoospermia was alternated with intermittent severe oligospermia. The patient had a normal endocrine pattern and evidence of mild chronic graft-versus-host disease (cGVHD). Normal intratesticular spermatogenesis was revealed by bilateral fine needle aspiration (FNA) cytology. Inflammation was evident at semen analysis, but no infection was detected by microbiological examination and sperm culture. These findings, together with the re-appearance of sperm cells at semen analysis after a low-dose immunosuppressive treatment, suggested the presence of cGVHD of the urogenital tract, causing a reversible obstruction of the spermatic tract and cryptozoospermia. This is the first case report documenting a severe impairment of sperm count because of a reversible obstruction of the seminal tract, likely caused by cGVHD, in a long-term survivor of allo-SCT with normal endocrine pattern. An important practical consequence of this case report is the fact that azoospermia was cured using low-dose immunosuppressive therapy, and this allowed us to avoid expensive stimulatory treatments with gonadotrophins, which remain, however, ineffective if the obstruction of spermatic tracts is not removed. A spontaneous uncomplicated pregnancy occurred in the partner of the patient 3 months after the corticosteroid treatment withdrawal.

MEN1 family with a novel frameshift mutation.

Multiple endocrine neoplasm type 1 (MEN1) syndrome predisposes to the development of endocrine and non-endocrine tumors with an autosomal dominant pattern of inheritance. Different mutations have been found throughout the gene with a variable phenotype expression. The proband, a Caucasian man, was admitted to our department in 2001, at the age of 51 because of a 1-yr history of diarrhoea and hypertension. He reported a previous intestinal resection for bowel occlusion with a histological diagnosis of unspecified mesenchymal neoplasia. He had also undergone a left adrenalectomy for a large nonfunctioning adrenal adenoma. Subsequently, he had suffered from gastralgia and melena; a gastroduodenoscopy showed an erosive gastritis. His family history was negative for endocrine disorders. On physical examination, multiple abdominal cutaneous lipomas and facial angiofibromas were observed. Biochemical screening revealed a primary hyperparathyroidism and an increase in circulating levels of PRL, chromogranin-A, gastrin and glucagon. The whole body computed tomography (CT) scan, the 111In-octreotide scan and the pituitary magnetic resonance imaging (MRI) did not reveal any abnormality. The presence of small neuroendocrine tumors was suspected by a positron emission tomography uptake in the epigastric region. The endoscopic ultrasound revealed a pancreatic lesion sized 1.1 cm that is under evaluation. Direct DNA sequencing analysis of the proband MEN1 gene revealed the 579delG frameshift mutation in the exon 3. The genetic screening of the family revealed the same mutation in 3 out of 5 offspring. The biochemical screening revealed some features of the MEN1 syndrome in all three of them. In conclusion, a novel frameshift MEN1 mutation was found in kindred with an apparently negative family history. Our experience confirms that MEN1 syndrome is a complex and underestimated condition, unless specifically investigated by trained specialists.

Thyroid function and morphology after a successful kidney transplantation.

Although thyroid disorders related to the end-stage renal disease (ESRD) are well known, there are discordant data on the function and morphology of the thyroid gland after renal transplantation (RT). The objective of this cross-sectional, case-control study was to investigate the prevalence and risk factors for disorders in the thyroid function and morphology after a successful RT. Fifty consecutive patients (25 females, 25 males) with fully functioning allograft were enrolled. Their age at transplant ranged from 23 to 44 yr (median, 38) and their post-RT follow-up lasted 15-86 months (median, 23). One hundred healthy subjects matched for sex, age and body mass index (BMI) were included as controls. Serum free thyroid hormones, TSH, thyroglobulin, thyroid hormone-binding globulin (TBG) and iodine urinary excretion were determined; ultrasonographic exam of the thyroid gland was performed in all subjects. Age, gender, time elapsed from RT, dialysis duration, kidney function, type of immunosuppression and corticosteroid dose were considered as possible influencing factors for the thyroid function. Hypothyroidism was found in 6% of patients, "low T3 syndrome" in 52%, while another 26% had free T3 (FT3), free T4 (FT4) and TSH in the lowest third of the normal range, suggesting inhibition of the whole hypothalamic-pituitary-thyroid (HPT) axis. Iodine excretion and prevalence of anti-thyroid antibodies were similar in both patients and controls. There was no significant difference in the thyroid function according to different immunosuppressive regimens. In patients, an ultrasonographic exam revealed a very variable thyroid volume ranging from 7.2 to 24.8 ml. Solid nodules were detected in 12 (24%) cases and cystic lesions in another four (8%); they were proven negative at cytological examination. Dialysis duration was longer in patients with thyroid nodules than in those without (p<0.05). Inhomogeneous hypoechoic pattern typical for chronic thyroiditis was more frequent than its biochemical expression. In conclusion, a high prevalence of abnormal thyroid morphology was found in patients after a successful RT, being partly related to a previous uremia. Abnormalities in the thyroid function are likely an expression of the post-transplant general and immunological conditions. Endocrinological follow-up is advisable in patients after RT, in order to discriminate thyroid dysfunctions which need specific treatments from those that can only be followed-up, avoiding inappropriate treatments of biochemical abnormalities.