Publications by authors named "Libuse Tauchmanova"

44 Publications

Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase.

Lancet Diabetes Endocrinol 2020 09 27;8(9):748-761. Epub 2020 Jul 27.

Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, MA, USA.

Background: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11β-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease.

Methods: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete.

Findings: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase.

Interpretation: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease.

Funding: Novartis Pharma AG.
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http://dx.doi.org/10.1016/S2213-8587(20)30240-0DOI Listing
September 2020

Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease.

Eur J Endocrinol 2020 Feb;182(2):207-217

Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease.

Design: Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906).

Methods: Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.

Results: At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.

Conclusion: mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
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http://dx.doi.org/10.1530/EJE-19-0695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003692PMC
February 2020

Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study.

Clin Endocrinol (Oxf) 2019 12 1;91(6):776-785. Epub 2019 Oct 1.

University of Sheffield, Sheffield, UK.

Objectives: Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long-acting pasireotide during a long-term extension study in patients with CD.

Design: Open-label extension to a 12-month Phase III study of long-acting pasireotide in CD (N = 150; NCT01374906).

Patients: Patients with mean urinary free cortisol (mUFC) ≤ upper limit of normal (ULN) or receiving clinical benefit at core study end could continue long-acting pasireotide during the extension.

Results: Eighty-one of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received ≥ 12 months' treatment during the extension and could transit to a separate pasireotide safety study). mUFC was ≤ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median late-night salivary cortisol was 2.6 × ULN at core baseline and 1.3 × ULN at M36. Clinical improvements were sustained over time. Forty-two (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemia-related AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA ) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixty-six (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA  ≥ 6.5%, FPG ≥ 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment.

Conclusions: Long-acting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective long-term therapy for CD.
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http://dx.doi.org/10.1111/cen.14081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899900PMC
December 2019

Long-term safety and efficacy of subcutaneous pasireotide in patients with Cushing's disease: interim results from a long-term real-world evidence study.

Pituitary 2019 Oct;22(5):542-551

Section of Endocrinology, Diabetology and Metabolism, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialities (PROMISE), University of Palermo, Palermo, Italy.

Purpose: Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing's disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD.

Methods: Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study ( http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies.

Results: At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). Eight patients had completed the 3-year observation period, 53 were ongoing, and 66 had discontinued. Among 31 new-use and 92 prior-use patients with ≥ 1 safety assessment, respectively: 24 (77%) and 37 (40%) had drug-related adverse events (AEs); 7 (23%) and 10 (11%) had serious drug-related AEs. Most common drug-related AEs were nausea (14%), hyperglycemia (11%) and diarrhea (11%); these were more frequently reported in new users and mostly of mild-to-moderate severity. 14 (45%) new-use and 15 (16%) prior-use patients experienced hyperglycemia-related AEs. Mean urinary free cortisol (mUFC) was within normal range at baseline and months 1, 12 and 24, respectively, in: 1/16 (6%), 9/18 (50%), 1/3 (33%) and 0/0 new users; 28/43 (65%), 15/27 (56%), 27/33 (82%) and 12/19 (63%) prior users.

Conclusions: Pasireotide is well tolerated and provides sustained reductions in mUFC during real-world treatment of CD. The lower rate of hyperglycemia-related AEs in prior users suggests that hyperglycemia tends not to deteriorate if effectively managed soon after onset.

Clinical Trial Registration Number: NCT02310269.
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http://dx.doi.org/10.1007/s11102-019-00984-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728293PMC
October 2019

Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study.

Cancer Chemother Pharmacol 2019 02 8;83(2):375-385. Epub 2018 Dec 8.

Endocrinology, DiMI and CEBR, University of Genoa, Genoa, Italy.

Purpose: Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.

Methods: Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).

Results: Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.

Conclusion: Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS.

Gov Identifier: NCT02299089.
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http://dx.doi.org/10.1007/s00280-018-3734-1DOI Listing
February 2019

Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial.

Lancet Diabetes Endocrinol 2018 01 12;6(1):17-26. Epub 2017 Oct 12.

Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.

Background: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease.

Methods: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906.

Findings: Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug.

Interpretation: Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule.

Funding: Novartis Pharma AG.
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http://dx.doi.org/10.1016/S2213-8587(17)30326-1DOI Listing
January 2018

Endocrinopathies after allogeneic and autologous transplantation of hematopoietic stem cells.

ScientificWorldJournal 2014 30;2014:282147. Epub 2014 Apr 30.

Hematology and Hematopoietic Stem Cell Transplant Center, Department of Medicine and Surgery, University of Salerno, 84131 Salerno, Italy.

Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90-99% of women and 60-90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40-50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.
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http://dx.doi.org/10.1155/2014/282147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032698PMC
February 2015

Low 25-hydroxyvitamin D levels and low bone density assessed by quantitative ultrasonometry in a cohort of postmenopausal Italian nuns.

J Clin Densitom 2013 Jul-Sep;16(3):308-312. Epub 2012 Jul 24.

Department of Molecular and Clinical Endocrinology and Oncology, University of Naples Federico II, Naples, Italy.

This study was aimed at evaluating the effect of clothing style on bone mass and fractures in 70 postmenopausal nuns residing in a monastery in Naples. Sixty healthy women matched for age, body mass index, and menopausal status were enrolled as controls. Each participant underwent measurement by quantitative ultrasonometry (QUS) using a DBM Sonic Bone Profiler (IGEA S.p.A., Carpi, Modena, Italy) at proximal phalanges, responded to questionnaires regarding lifestyle, calcium intake, medical history, including clinical fragility fractures, and was submitted to routine biochemical assessment. A significant reduction in ultrasonometric parameters of bone mass was found in nuns compared with controls (p from 0.007 to <0.0001). 25-hydroxyvitamin D (25-OH vit D) levels were reduced by more than 50% in nuns (9.8 ± 4.2 vs 23.5 ± 5.7 nmol/L; p < 0.0001), whereas their estimated daily calcium intake was higher (1.004 ± 0.23 vs 0.721 ± 0.25 g of controls; p = 0.0007). Age at menopause was significantly lower in nuns' group (p = 0.016). Incidence of fractures was higher in nuns (39% vs 10%; p = 0.0029), and the best predictors of fractures were age at menopause (odds ratio [OR]: 1.12; 95% confidence interval [CI]: 1.01-1.30), amplitude-dependent speed of sound T-score (OR: 1.15; 95% CI: 1.03-1.63), and bone transmission time T-score (OR: 1.30; 95% CI: 1.15-1.81). This study documented low 25-OH vit D levels, increased frequency of clinical fractures, and low bone mass detected by QUS in Southern Italian nuns.
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http://dx.doi.org/10.1016/j.jocd.2012.05.009DOI Listing
October 2013

Idiopathic chronic urticaria and thyroid autoimmunity: Experience of a single center.

Dermatoendocrinol 2011 Oct 1;3(4):255-8. Epub 2011 Oct 1.

Internal Medicine Unit; "S. Gennaro" Hospital; Naples, Italy.

Urticaria is one of the most frequent dermatosis, being its prevalence in general population estimated about 20%. This prospective case-control study was aimed at determining the prevalence of thyroid autoimmune disorders in a cohort of patients with chronic urticaria (CU), all living within an area with mild-to-moderate iodine deficiency. Fifty four consecutive patients affected by CU were recruited and compared to 108 healthy controls. Assessment of the thyroid function included measurement of serum concentrations of TSH, FT3, FT4, anti-thyreoglobulin (anti-TG) and anti-peroxidase (anti-TPO) antibodies. Ultrasound scan of the thyroid gland was performed in all subjects using a 7.5 MHz linear transducer. All subjects were followed up for 6 months. The prevalence of thyroid antibodies was significantly higher in our cohort of patients with CU than in controls (22% vs. 6.5 %). Hashimoto's thyroiditis was also more frequent in patients than controls (18.5% vs. 1.8%). These frequencies do not differ from those previously reported by some other authors and confirm the association between CU and thyroid autoimmunity also in the area of iodine deficiency. However, presence of antibodies or thyroiditis does not seem to influence clinical course of CU. These results suggest that screening for thyroid function may be useful in all the patients with CU.
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http://dx.doi.org/10.4161/derm.3.4.17066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256343PMC
October 2011

Bone turnover and the osteoprotegerin-RANKL pathway in tumor-induced osteomalacia: a longitudinal study of five cases.

Calcif Tissue Int 2009 Oct 10;85(4):293-300. Epub 2009 Sep 10.

Department of Clinical and Experimental Medicine, Federico II University, via Sergio Pansini, 5, 80131, Naples, Italy.

To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB (RANKL), and their relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor (n = 2) or beginning of therapy with phosphate and calcitriol when surgical treatment was impossible (n = 3). At diagnosis, TIO patients had higher levels of FGF-23 and bone-specific alkaline phosphatase (bALP) and lower levels of cathepsin K (CathK), RANKL, and RANKL/OPG ratio compared to controls. During the follow-up, FGF-23 decreased significantly only in patients who underwent a surgical excision, while phosphate and BMD increased in all patients. The increases in BMD, phosphate, and renal phosphate reabsorption rate were directly related. In the first 60 days of follow-up, we observed a prolonged inhibition of RANKL, CathK, and bone resorption markers associated with a persistence of TIO symptoms and an increase in bALP. From day 60, levels of bone turnover markers returned progressively within the normal range and a clinical remission was observed. The inhibition of the RANKL/OPG pathway and the uncoupling of bone formation and resorption observed in patients with active TIO may be a compensatory mechanism, attempting to reduce worsening of osteomalacia. The BMD increase during TIO treatment is related to the improvement of phosphate rather than FGF-23 levels. A "hungry bone"-like syndrome was observed after surgical or pharmacological treatment.
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http://dx.doi.org/10.1007/s00223-009-9275-1DOI Listing
October 2009

Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism (PHP) in multiple endocrine neoplasia type 1 (MEN1) patients.

Clin Endocrinol (Oxf) 2008 Nov 14;69(5):756-62. Epub 2008 May 14.

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Naples, Italy.

Background: In patients with multiple endocrine neoplasia type 1 (MEN1), expression of somatostatin receptor (SST) in parathyroid adenomas and effectiveness of therapy with somatostatin analogues on primary hyperparathyroidism (PHP) have been scarcely investigated.

Objective: To evaluate the effects of depot long acting octreotide (OCT-LAR) in patients with MEN1-related PHP.

Patients: Eight patients with a genetically confirmed MEN1, presenting both PHP and duodeno-pancreatic neuroendocrine tumours (NET), were enrolled.

Design: The initial treatment was OCT-LAR 30 mg every 4 weeks. This therapy was established to stabilize the duodeno-pancreatic NET before to perform parathyroidectomy for PHP. Before OCT-LAR therapy, a SST scintigraphy was performed in all patients. SST subtype 2A immunohistochemistry was performed on parathyroid tumour samples from three patients undergone parathyroidectomy after OCT-LAR therapy.

Measurements: Serum concentrations of PTH, calcium and phosphorus as well as the 24-h urine calcium : creatinine ratio and the renal threshold phosphate concentration were evaluated before and after OCT-LAR.

Results: After OCT-LAR therapy, hypercalcaemia and hypercalciuria normalized in 75% and 62.5% of patients, respectively, and serum phosphorus and renal threshold phosphate significantly increased. Serum PTH concentrations significantly decreased in all patients and normalized in two of them. SST subtype 2A immunostaining was found in all parathyroid adenomas investigated, while SST scintigraphy showed a positive parathyroid tumour uptake in three of eight patients (37.5%).

Conclusion: Six months of OCT-LAR therapy controlled hypercalcaemia and hypercalciuria in two-thirds of patients with MEN1-related PHP. Direct OCT-LAR effects mediated by binding to SST expression on parathyroid tumour cells are likely the main mechanism to explain the activity of this compound on calcium and phosphorus abnormalities in MEN1 PHP.
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http://dx.doi.org/10.1111/j.1365-2265.2008.03301.xDOI Listing
November 2008

Cushing's syndrome: aftermath of the cure.

Arq Bras Endocrinol Metabol 2007 Nov;51(8):1381-91

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Italy.

Cushing's syndrome (CS) is a chronic and systemic disease caused by endogenous or exogenous hypercortisolism, associated with an increase of mortality rate due to the clinical consequences of glucocorticoid excess, especially cardiovascular diseases. After cure, usually obtained by the surgical removal of the tumor responsible for the disease, the normalization of cortisol secretion is not constantly followed by the recovery of the clinical complications developed during the active disease, and it is often followed by the development of novel clinical manifestations induced by the fall of cortisol levels. These evidences were mostly documented in patients with pituitary-dependent CS, after surgical resection of the pituitary tumor. Indeed, despite an improvement of the mortality rate, metabolic syndrome and the consequent cardiovascular risk have been found to partially persist after disease remission, strictly correlated to the insulin resistance. Skeletal diseases, mainly osteoporosis, improve after normalization of cortisol levels but require a long period of time or the use of specific treatment, mainly bisphosphonates, to reach the normalization of bone mass. A relevant improvement or resolution of mental disturbances has been described in patients cured from CS, although in several cases, cognitive decline persisted and psychological or psychiatric improvement was erratic, delayed, or incomplete. On the other hand, development or exacerbation of autoimmune disorders, mainly thyroid autoimmune diseases, was documented in predisposed patients with CS after disease remission. The totality of these complications persisting or occurring after successful treatment contribute to the impairment of quality of life registered in patients with CS after disease cure.
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http://dx.doi.org/10.1590/s0004-27302007000800025DOI Listing
November 2007

Bone loss and its management in long-term survivors from allogeneic stem cell transplantation.

J Clin Endocrinol Metab 2007 Dec 2;92(12):4536-45. Epub 2007 Oct 2.

Department of Molecular and Clinical Endocrinology, Federico II University of Naples, via S. Pansini 5, 80131 Naples, Italy.

Context: Recently, great efforts have been made to understand the pathogenesis of bone loss after allogeneic stem cell transplant (allo-SCT) and possible treatments.

Evidence Acquisition: A literature search of the MEDLINE database was performed to find articles in English using the search terms "allogeneic stem cell transplant" or "bone marrow transplant," in combination with "bone loss," "osteoporosis treatment," "osteoblast," "cytokines," or "osteoprotegerin." Reference lists from the articles retrieved were also evaluated for relevant information.

Evidence Synthesis: Bone mineral density at the lumbar spine, but not at the femur, can improve or even recover several years after SCT. Multiple risk factors for posttransplant bone loss have been recently identified: abnormalities in the immune system function and their treatments, reduced production of growth factors, osteoclast activation by increased cytokine release, and decreased number and function of osteoblast precursors within the stromal stem cell compartment. Pamidronate was partially successful in preventing posttransplant bone loss, whereas both oral and parenteral bisphosphonates had beneficial effects on documented osteoporosis in long-term survivors.

Conclusions: There is clear evidence that transplant-related bone loss is a multifactorial, early, and possibly long-lasting disorder. All patients who have already received allo-SCT should be evaluated as to their bone status and treated with appropriate supportive measures and specific treatments as soon as abnormalities are detected. Although preventive antiresorptive treatments are only partially effective, they should be started in all patients before or at the time of allo-SCT, regardless of their bone mineral density values, and continued at least for the first year after transplant.
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http://dx.doi.org/10.1210/jc.2006-2870DOI Listing
December 2007

Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism.

Eur J Endocrinol 2007 Sep;157(3):359-66

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Naples, Italy.

Objective: Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Nevertheless, limited data are available on bone status in patients with endogenous cortisol excess. This study is aimed at investigating the role of sex steroids and severity of hypercortisolism on bone mineral density (BMD) and prevalence of vertebral fractures in female patients.

Design: Cross-sectional, case-control study.

Patients: Seventy-one consecutive women were enrolled: 36 with overt hypercortisolism (26 with ACTH-secreting pituitary adenoma and 10 with cortisol-secreting adrenal tumor) and 35 with subclinical hypercortisolism due to adrenal incidentalomas. They were compared with 71 matched controls.

Methods: At diagnosis, we measured serum cortisol, FSH, LH, estradiol, testosterone, androstenedione and DHEAS, and urinary cortisol excretion. BMD was determined by dual energy X-ray absorptiometry at the lumbar spine and femoral neck. Vertebral fractures were investigated by a semiquantitative scoring method.

Results: Between women with overt and subclinical hypercortisolism BMD values and prevalence of any vertebral (69 vs 57%, P = 0.56), clinical (28 vs 11.4%, P = 0.22), and multiple vertebral fractures (36 vs 31%, P = 0.92) did not differ. Among patients with subclinical hypercortisolism, amenorrhoic women had a lower BMD (P = 0.035) and more frequent vertebral fractures (80 vs 40%; P = 0.043) when compared with the eumenorrhoic ones. Among women with overt hypercortisolism, there was no difference in lumbar BMD (P = 0.37) and prevalence of fractures (81 vs 60%; P = 0.26) between those amenorrhoic and eumenorrhoic. By logistic regression analysis, lumbar spine BMD values and cortisol-to-DHEAS ratio were the best predictors of vertebral fractures (P < 0.01).

Conclusions: Vertebral fractures are very common in women with endogenous cortisol excess, regardless of its severity. The deleterious effects of hypercortisolism on the spine may be partly counterbalanced by DHEAS increase at any degree of cortisol excess, and by preserved menstrual cycles in women with subclinical but not in those with overt hypercortisolism.
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http://dx.doi.org/10.1530/EJE-07-0137DOI Listing
September 2007

Adjuvant mitotane treatment for adrenocortical carcinoma.

N Engl J Med 2007 Jun;356(23):2372-80

Università di Torino, Turin, Italy.

Background: Adrenocortical carcinoma is a rare neoplasm characterized by a high risk of recurrence after radical resection. Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial. Our aim was to evaluate the efficacy of adjuvant mitotane in prolonging recurrence-free survival.

Methods: We performed a retrospective analysis involving 177 patients with adrenocortical cancer who had undergone radical surgery at 8 centers in Italy and 47 centers in Germany between 1985 and 2005. Adjuvant mitotane was administered to 47 Italian patients after radical surgery (mitotane group), whereas 55 Italian patients and 75 German patients (control groups 1 and 2, respectively) did not receive adjuvant treatment after surgery.

Results: Baseline features in the mitotane group and the control group from Italy were similar; the German patients were significantly older (P=0.03) and had more stage I or II adrenocortical carcinomas (P=0.02) than did patients in the mitotane group. Recurrence-free survival was significantly prolonged in the mitotane group, as compared with the two control groups (median recurrence-free survival, 42 months, as compared with 10 months in control group 1 and 25 months in control group 2). Hazard ratios for recurrence were 2.91 (95% confidence interval [CI], 1.77 to 4.78; P<0.001) and 1.97 (95% CI, 1.21 to 3.20; P=0.005), respectively. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival. Adverse events associated with mitotane were mainly of grade 1 or 2, but temporary dose reduction was needed in 13% of patients.

Conclusions: Adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma.
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http://dx.doi.org/10.1056/NEJMoa063360DOI Listing
June 2007

Growth hormone excess with onset in adolescence: clinical appearance and long-term treatment outcome.

Clin Endocrinol (Oxf) 2007 May 27;66(5):714-22. Epub 2007 Mar 27.

Department of Molecular and Clinical Endocrinology and Oncology, Section of Endocrinology, Federico II University of Naples, Naples, Italy.

Background: Limited data are available on clinical presentation and treatment strategy in patients with GH-secreting adenomas with onset in adolescence.

Objective: To report results of diagnosis and treatment in adolescents with GH and IGF-I excess.

Design: Analytical, observational, retrospective.

Subjects: Thirteen patients (five females and eight males, age 15-20 years) all with macroadenoma (two extrasellar, 11 invasive).

Main Outcome Measures: Height, body mass index (BMI), GH and IGF-I levels, tumour volume at diagnosis and after treatment.

Interventions: Transsphenoidal surgery, octreotide subcutaneous (OCT, 0.3-0.8 mg/day), octreotide-LAR i.m. (LAR, 20-30 mg/q28 days), lanreotide i.m. (LAN, 60-90 mg/q28 days), bromocriptine (BRC, 5 mg/day), cabergoline (CAB, 1-2 mg/week).

Results: Concomitant hyperprolactinaemia was found in eight patients (61.5%). All girls presented with amenorrhoea, which was associated with galactorrhoea in two patients; all boys presented with symptoms of tumour mass compression such as visual disturbance or headache; two girls also had these symptoms. Height at diagnosis was above the 97th centile in four of five girls and in six of eight boys. None of the patients had altered lipid profile while homeostasis model assessment of insulin resistance (HOMA-IR; 2.8 +/- 0.9) and beta-cell function (HOMA-beta, 207.6 +/- 98.1%) were higher than predicted (1% and 100%, respectively). First-line treatment was surgery in two patients and somatostatin analogues associated with dopaminergic drugs in 11 patients. None of the patients operated on were cured while six of 11 patients receiving pharmacotherapy (6-24 months) were controlled. In these six, tumour volume was reduced by 51.0 +/- 25.2% (median 51.5%). As second-line treatment, all the 11 patients treated with somatostatin analogues underwent surgical removal of their tumours. Surgery was successful in four patients and second-line pharmacotherapy in six patients. One patient was lost at follow-up and two patients maintained active acromegaly despite different treatment schedules; both patients were then treated with radiotherapy. At the last follow-up, there was a significant decrease in insulin levels, HOMA-IR and HOMA-beta without any change in lipid profile.

Conclusions: The clinical presentation of GH-secreting adenomas in adolescent girls is associated with menstrual disturbances and in boys with symptoms of mass effects; tall stature is characteristic in both. First-line treatment with depot somatostatin analogues followed by surgery and then by a second course of somatostatin analogues was successful and safe in 11 of 13 patients.
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http://dx.doi.org/10.1111/j.1365-2265.2007.02809.xDOI Listing
May 2007

Imbalance of the osteoprotegerin/RANKL ratio in bone marrow microenvironment after allogeneic hemopoietic stem cell transplantation.

Transplantation 2006 Dec;82(11):1449-56

Department of Biochemistry and Medical Biotechnology, Hematology Branch, Federico II University of Naples, Naples, Italy.

Background: Bone loss is a common complication after allogeneic stem cell transplantation. Osteoprotegerin (OPG) plays a critical role in bone remodeling by neutralizing the effect of receptor activator of nuclear factor-kappaB ligand (RANKL) on differentiation and activation of osteoclasts. We investigated OPG and RANKL in serum and marrow plasma in transplanted patients.

Materials And Methods: In 36 patients and 36 controls, the relationships among bone mineral density, circulating OPG, RANKL, interferon-gamma, and interleukin-6 levels were investigated; in addition, OPG and RANKL were measured in marrow plasma and in conditioned medium of long-term cultures of marrow mesenchymal-derived osteogenic cells.

Results: Lumbar and femoral bone mineral density were lower in patients than in controls (P<0.01). Serum OPG (sOPG) and interferon-gamma were significantly higher in patients than in controls (P<0.05). Patients' interferon-gamma correlated with sOPG levels (r=0.4; P=0.03). Interleukin-6 did not differ between patients and controls. By contrast, OPG levels were lower in patients than in controls in marrow plasma (P<0.001) and in conditioned media after one (P=0.035) and three months (P=0.003) of culture of marrow mesenchymal-derived osteogenic cells. RANKL was similar in patients and controls. The OPG/RANKL ratio "in situ" was significantly lower in patients than in controls (P<0.05). There was no correlation between sOPG and marrow OPG, RANKL levels, densitometric values, and chronic graft-versus-host disease.

Conclusion: Our findings suggest that after allogeneic stem cell transplantation: 1) sOPG bear no relationship with OPG in the bone marrow; 2) increased sOPG can be the result of its enhanced production in extra bone tissues triggered by inflammatory cytokines; 3) low bone marrow OPG levels may be partly related to the persistent quantitative and qualitative deficit of osteoblastic precursors; and 4) reduced OPG/RANKL ratio in bone microenvironment may increase bone remodeling by promoting bone resorption.
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http://dx.doi.org/10.1097/01.tp.0000244588.42519.72DOI Listing
December 2006

Estrogen-progestin therapy in women after stem cell transplant: our experience and literature review.

Menopause 2007 Mar-Apr;14(2):320-30

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Italy.

Women undergoing stem cell transplantation (SCT) are mostly young and have more than 90% probability of ovarian failure, which is often permanent. A woman's age, use of radiotherapy and alkylating chemotherapy, and the allogeneic type of transplant are associated with a higher rate of premature ovarian failure and worse residual ovarian function. Premature ovarian failure has serious systemic and psychological effects that may need treatment and should be managed by practitioners trained to treat this particular population of women. Ultrasonographic evidence of ovarian follicles is often associated with a future resumption of cycles, but there are no serum markers to predict the return of ovarian function in these patients. In our center, the rate of ovarian function recovery was 7% after allogeneic SCT and 25% after autologous SCT (P<0.05). There are no guidelines on how to manage premature ovarian failure induced by myeloablative treatments followed by SCT. Because of the likelihood of the need for long-lasting estrogen plus progestin therapy (EPT) and the increased risk of secondary neoplasia after SCT, the EPT should be as physiological as possible. In our experience, the cyclical sequential combination of estradiol (2 mg daily) plus dydrogesterone (10 mg for 14 d/mo) was associated with excellent compliance because of its simple administration and few adverse effects. Such a treatment led to a dramatic improvement in vasomotor, urogenital, and psychological symptoms related to estrogen deficiency. However, in the allogeneic transplantation setting, up to 25% of women may suffer from gynecological chronic graft-versus-host disease, which may become apparent as hematocolpometra after introduction of EPT. Thus, accurate pretreatment evaluation and frequent monitoring during treatment are required. Moreover, EPT absorption may be reduced in patients who received allotransplants and have gastrointestinal or skin chronic graft-versus-host disease.
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http://dx.doi.org/10.1097/01.gme.0000232032.84788.8cDOI Listing
June 2007

Effects of estrogen-progestin therapy on serum levels of RANKL, osteoprotegerin, osteocalcin, leptin, and ghrelin in postmenopausal women.

Menopause 2007 Jan-Feb;14(1):38-44

Department of Gynecology and Obstetrics, Medicine of Human Reproduction, University of Naples "Federico II," Naples, Italy.

Objective: The aim of this study was to evaluate the effects of estrogen-progestin therapy on serum levels of receptor-activating nuclear factor kappabeta ligand (RANKL), osteoprotegerin, osteocalcin, leptin, and ghrelin in a cross-sectional study of 99 healthy postmenopausal women conducted at the Menopause Clinic of our department.

Design: In this cross-sectional, observational study, 99 participants were divided into two groups. Group A was composed of 77 postmenopausal women who had never received estrogen-progestin therapy, and group B was composed of 22 postmenopausal women who had received transdermal 17beta-estradiol at a dose of 50 microg/day in a continuous regimen for at least 24 months and nomegestrol at a dose of 5 mg/day for 12 days/month in a sequential regimen. All participants underwent blood sampling in the morning and quantitative ultrasound bone-densitometry measurement of the proximal phalanges of the dominant hand.

Results: T score and amplitude-dependent speed of sound were significantly higher in group B than in group A. No significant differences in RANKL, osteoprotegerin, and osteocalcin were observed between the two groups. Serum leptin levels were significantly lower in group B than in group A, whereas ghrelin was significantly higher in group B than in group A.

Conclusions: The data gathered in this preliminary study indicate that estrogen-progestin therapy may protect against postmenopausal bone loss, but this protective effect does not seem to be exerted through action on the RANK-RANKL-osteoprotegerin system. Similarly, although several reports suggest that leptin and ghrelin are involved in bone metabolism, we could not detect any important correlation of these two hormones with bone metabolism or bone status in treated and untreated postmenopausal women. Because of the limited number of treated participants and the study design, the results of this preliminary study must be confirmed in larger, prospective, longitudinal studies.
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http://dx.doi.org/10.1097/01.gme.0000227855.04732.7bDOI Listing
April 2007

Incidence and pathological characteristics of prostate cancer in Italy: a contribution to the screening debate.

Cancer Detect Prev 2006 25;30(5):455-8. Epub 2006 Oct 25.

Servizio di Radiologia, Clinica Stabia, Italy.

Background: The scientific, social and financial aspects of prostate cancer (PC) organized or opportunistic screening to identify early PC are hotly debated. The incidence of prostate cancer is lower in Italy than in America and North Europe and data on PC incidence and pathological characteristics are scarce.

Methods: To determine PC incidence and whether screening would be beneficial, we studied 1008 consecutive symptomatic patients from the Southern Italy who underwent transrectal ultrasonography; 170 of them (age range: 48-93 years; median: 70 years) were at risk and underwent transrectal biopsy.

Results: Adenomatous hyperplasia was detected in 105 patients (62%), PC in 51 (30%), prostate intraepithelial neoplasia (PIN) in 5 (3%) and inflammatory disease in 5 (3%). The median age of patients with PC was 73.5 and tumors were generally well to moderately differentiated (76%, Gleason score < or =7). Prostate cancer (or PIN) was more frequent in patients over 70 (p<0.0001). The Gleason score also increased with age: >7 in 92% and 8% of patients aged >70 and < or =70, respectively (p<0.05).

Conclusions: On the basis of our results organized or opportunistic PC screening of elderly men does not appear justified because: invasive carcinoma is detected in less than 1/3 of symptomatic "healthy" men; patients became symptomatic when their life expectancy is often less than 10 years; and PC is more frequent and more aggressive after 70 years.
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http://dx.doi.org/10.1016/j.cdp.2006.07.009DOI Listing
January 2007

Serum aldosterone concentration and cardiovascular risk in women with polycystic ovarian syndrome.

J Clin Endocrinol Metab 2006 Nov 29;91(11):4395-400. Epub 2006 Aug 29.

Department of Molecular and Clinical Endocrinology and Oncology, University Federico II of Naples, Via S. Pansini 5, 80131 Naples, Italy.

Context: Polycystic ovary syndrome (PCOS) is associated with early impairment of vascular structure and a low-grade chronic inflammation. Aldosterone is a well-recognized cardiovascular risk (CVR) factor and is related to inflammatory processes.

Objective: Our objective was to investigate serum aldosterone levels in PCOS and correlate them to some CVR factors and early atherosclerotic markers.

Design And Setting: A prospective baseline-controlled clinical study was conducted at the University "Federico II" of Naples School of Medicine (Naples, Italy).

Patients: Fifty PCOS women age- and body mass index-matched with 50 healthy women were enrolled.

Mean Outcome Measures: Anthropometric, hormonal, and metabolic patterns, including plasma aldosterone, renin, and C-reactive protein, were measured in each subject. Intima-media thickness was also evaluated in each patient and control.

Results: Aldosterone levels were significantly increased (P < 0.001) in PCOS compared with healthy women (10.5 +/- 3.2 vs. 5.7 +/- 2.5 ng/dl). In PCOS, a significant (P < 0.001) direct correlation between plasma aldosterone and homeostasis model assessment, C-reactive protein, intima-media thickness, and mean blood pressure was found. On the other hand, high-density lipoprotein cholesterol and potassium were inversely (P < 0.001) related to serum aldosterone. Multiple linear regression analysis showed that the area under the curve for insulin and homeostasis model assessment was linearly related to aldosterone in PCOS.

Conclusion: PCOS women show an insulin resistance related increase in serum aldosterone levels.
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http://dx.doi.org/10.1210/jc.2006-0399DOI Listing
November 2006

Bone demineralization and vertebral fractures in endogenous cortisol excess: role of disease etiology and gonadal status.

J Clin Endocrinol Metab 2006 May 7;91(5):1779-84. Epub 2006 Mar 7.

Department of Molecular, Clinical Endocrinology, and Oncology, Federico II University of Naples, via Sergia Pansini 5, 80131 Naples, Italy.

Introduction: The effects of endogenous cortisol (F) excess on bone mass and vertebral fractures have still not been thoroughly investigated. The aim of this cross-sectional case-control study was to investigate factors influencing bone demineralization and vertebral fractures in different conditions of F excess, i.e. Cushing's disease and adrenal and ectopic Cushing's syndrome.

Materials And Methods: Eighty consecutive patients and 80 controls were prospectively enrolled: 37 patients (21 females) with pituitary ACTH-secreting adenoma, 18 (14 females) with adrenocortical adenoma, 15 (11 females) with adrenal carcinoma of mixed secretion, and 10 (three females) with ectopic ACTH secretion. The groups had similar age. At diagnosis, bone mineral density (BMD) was determined by the dual-energy x-ray absorptiometry technique at the lumbar spine (L1-L4) and femoral neck; vertebral fractures were investigated by standard spinal radiographs.

Results: When comparing the groups with different etiology of F excess, the patients with ectopic ACTH secretion had higher F and lower BMD values than the other subgroups. Morning F (P = 0.03) and testosterone levels (P = 0.04) correlated with lumbar BMD. Vertebral fractures were found in 61 (76%) of the patients, were multiple in 52 (85%) of the cases, and clinically evident in 32 (52%). Only multiple fractures were more frequent in patients with ectopic ACTH hypersecretion (P < 0.05). Lumbar spine BMD was the best predictor of vertebral fractures (P < 0.01). Surprisingly, amenorrheic and eumenorrheic women had similar BMD values and fracture prevalence.

Conclusion: A high prevalence (76%) of vertebral fracture was revealed, regardless of the etiology of the patients' hypercortisolism. The harmful effects of F excess at the spine were partly counterbalanced by the increased androgen production but were not affected by gonadal status in women.
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http://dx.doi.org/10.1210/jc.2005-0582DOI Listing
May 2006

Evaluation of skeletal status by quantitative ultrasonometry in postmenopausal women without known risk factors for osteoporosis.

Gynecol Endocrinol 2005 Sep;21(3):149-53

Department of Obstetrics and Gynecology, University of Naples Federico II, Naples, Italy.

The objective of our study was to evaluate bone density in Italian postmenopausal women without clinical risk factors for osteoporosis resident in the Naples area using quantitative ultrasonometry of bone (QUS). Subjects were 1149 Italian postmenopausal women (age: 54.9 +/- 5.0 years (mean +/- standard deviation); range: 45-74 years) resident in the Naples area. Clinical risk factors for osteoporosis resulting in exclusion from the study were family history of osteoporosis, dietary, smoking and alcohol habits, personal history of fractures and/or metabolic diseases. The following QUS parameters were calculated: amplitude-dependent speed of sound (AD-SoS), T-score and Z-score. We found significant inverse correlations between AD-SoS and age (r = - 0.23), time since menopause (r = - 0.25) and body mass index (BMI) (r = - 0.16). The same was observed for T-score. In contrast, Z-score showed a significant positive correlation with age and time since menopause, and a negative correlation with BMI. A T-score suggestive of high risk for osteoporosis (less than -3.2) was found in 1.6% of subjects, while a T-score suggestive of moderate risk for osteoporosis (between -3.2 and -2) was found in 19.3% of patients. In this group of women without clinical risk factors for osteoporosis we found a very low prevalence of QUS results suggesting a high risk for osteoporosis. However, a condition of 'moderate' risk for osteoporosis was present in a remarkable percentage of these women.
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http://dx.doi.org/10.1080/09513590500196168DOI Listing
September 2005

Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease.

Osteoporos Int 2005 Sep 1;16(9):1141-9. Epub 2005 Jun 1.

Department of Obstetrics and Gynecology, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Patients with inflammatory bowel disease (IBD) have frequently a bone mineral density (BMD) significantly lower than age-matched healthy subjects. The low BMD observed in IBD patients is related also to a higher incidence of bone fractures. In this prospective randomized study we evaluated the effect of 1-year risedronate administration on bone mass and turnover, and on vertebral fractures in osteoporotic postmenopausal women with IBD in remission. Ninety osteoporotic postmenopausal women were randomized to receive oral risedronate 35 mg/week (risedronate group) or placebo tablets (placebo group; one tab/week). The duration of treatment was 12 months. At entry and after treatment, lumbar spine and hip BMD, and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. Vertebral fractures were assessed from thoracic and lumbar lateral and anterior-posterior spinal radiographs taken at baseline, and from lateral spinal radiographs taken at the end of the study. At study entry, no difference between groups was also detected in BMD and in bone turnover markers. At the end of the study, lumbar spine, trochanter and femoral neck BMD was significantly ( p <0.05) higher in comparison with baseline in the risedronate group, whereas a significant ( p <0.05) decrease was observed in the placebo group. For the same visit, a significant ( p <0.05) difference in lumbar spine, trochanter and femoral neck BMD was detected between groups. After 12-month follow-up, serum OC and urinary DPD-Cr levels were significantly ( p <0.05) lower and higher in comparison with basal values in risedronate and placebo group, respectively. At the same time, a significant ( p <0.05) difference in serum OC and urinary DPD-Cr levels was observed between groups. Throughout the study, the incidence of vertebral fractures was significantly ( p <0.05) lower in the risedronate group than in the placebo group (12.5% vs 34.1%). The relative risk (RR) to develop a new vertebral fracture after 1 year of risedronate administration was of 0.36 (95% confidence interval, 0.14-0.85). In conclusion, risedronate administration is an effective anti-osteoporotic treatment in osteoporotic postmenopausal women with IBD in remission.
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http://dx.doi.org/10.1007/s00198-005-1927-zDOI Listing
September 2005

Endocrine disorders during the first year after autologous stem-cell transplant.

Am J Med 2005 Jun;118(6):664-70

Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Italy.

Background: Frequent endocrine disorders have been reported after allogeneic stem-cell transplant, but data on adult survivors of autologous transplants are still scarce.

Methods: In this prospective study we investigated early (at 3 months) and late (at 12 months) endocrine dysfunctions in 95 consecutive autologous stem-cell transplant recipients (47 men and 48 women) aged 16 to 55 years. The functions of the hypothalamic-pituitary-gonadal/thyroid/adrenal/somatotroph axis were evaluated.

Results: Three months after the transplant, insulin-like growth factor-1 values were below the normal range in 53 patients (56%); 37 of 40 women (93%) of reproductive age experienced precocious ovarian failure; 39 of 46 men (85%) showed high follicular stimulating hormone, and 17 men (37%) showed low testosterone levels. Adrenal insufficiency occurred in 28 patients (30%) during the peritransplant period after corticosteroid withdrawal. Transient subclinical hyperthyroidism was found in 15 patients (16%). Transient "low T(3)" syndrome was revealed in 29 patients (31%). Twelve months after the transplant, insulin-like growth factor-1 values were still low in 36 patients (38%). Menstrual cycles resumed in four women; follicular stimulating hormone, luteinizing hormone, and estradiol levels improved in 10 patients. Testosterone was low in only two men (4%). Seminal analysis revealed azoospermia in 32 (91%) of 35 men examined. Subclinical hypothyroidism was found in 11 patients (12%); eight of them had previously received radiotherapy for the upper half of the body.

Conclusion: This study documents frequent endocrine disorders during the first year after autologous stem-cell transplant. Despite a tendency to improve, in more than half of the cases, the complications persisted for more than 1 year. Therefore, to diagnose and correct early and late endocrine dysfunctions, endocrine screening is required during the first year in all patients undergoing autografting.
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http://dx.doi.org/10.1016/j.amjmed.2005.02.009DOI Listing
June 2005

Andrenocortical carcinomas: twelve-year prospective experience.

World J Surg 2004 Sep;28(9):896-903

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Via S. Pansini 5, 80131 Naples, Italy.

Adrenocortical carcinoma (AC) is a rare tumor with poor prognosis. Twenty-two patients (14 F, 8 M; age 22 to 59 years; median, 43 years) with AC were evaluated prospectively in a single center: tumor stage was I-II in 12 cases and III-IV in 10. The overall survival in our cohort was 41.6 +/- 42 months; 16 subjects are still alive. Curative surgery was followed by longer survival than debulking or no surgery (p < 0.0001). The first relapse was highly predictive for further recurrences. Recurrent ACs were progressively more aggressive, and they occurred with variable but ever shorter intervals. At diagnosis, 14 patients (63.5%) presented with features of clear adrenocortical hyperactivity. Despite the absence of clinical signs of hormonal excess, all other patients presented some abnormalities of steroid secretion. The most common clinical finding was a recent diagnosis of moderate-to-severe hypertension (68%), poorly controlled by pharmacological treatment, often associated with multiple cardiovascular risk factors. High mitotic rate and undifferentiated polymorph cellular pattern were associated with worse prognosis. Response to treatments other than surgery (mitotane chemotherapy) was better in patients treated early after the first surgery. In conclusion, curative surgery was the most effective treatment. Monitoring arterial pressure, endocrine parameters, and metabolic parameters can be helpful for the early detection of AC recurrences.
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http://dx.doi.org/10.1007/s00268-004-7296-5DOI Listing
September 2004

Is plasminogen activator inhibitor-1 a cardiovascular risk factor in young women with polycystic ovary syndrome?

Reprod Biomed Online 2004 Nov;9(5):505-10

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Italy.

This study aimed to evaluate plasminogen activator inhibitor-1 (PAI-1) activity in PCOS. Thirty women with PCOS - 15 normal-weight and 15 obese - and 30 healthy women matched as a group for age and body mass index (BMI) were recruited. The homeostasis model assessment (HOMA) score was significantly elevated in obese compared with normal-weight women, in both PCOS women and controls. HOMA score was significantly higher in both PCOS groups relative to controls. After further adjustment for BMI, PAI-1 activity (IU/ml +/- SD) was significantly higher in the PCOS groups compared with controls. A significant positive correlation was found between HOMA score and BMI in PCOS and control groups. Serum PAI-1 activity was significantly related to BMI and HOMA score. When considering two BMI subgroups, there was no significant difference in the relationship between serum PAI-1 activity and HOMA score in both the control and PCOS groups. No other significant relationship was found between serum PAI-1 activity and any other hormonal or metabolic parameter. In conclusion, women with PCOS have significantly elevated PAI-1 activity independent of obesity, and it is speculated that elevated PAI-1 activity may be a factor in the increased cardiovascular morbidity seen in PCOS.
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http://dx.doi.org/10.1016/s1472-6483(10)61634-3DOI Listing
November 2004

Short-term zoledronic acid treatment increases bone mineral density and marrow clonogenic fibroblast progenitors after allogeneic stem cell transplantation.

J Clin Endocrinol Metab 2005 Feb 16;90(2):627-34. Epub 2004 Nov 16.

Department of Molecular and Clinical Endocrinology, Federico II University of Naples, Via S. Pansini 5, 80131 Napoli, Italy.

Although osteoporosis is a relatively common complication after allogeneic stem cell transplantation, the role of bisphosphonates in its management has not yet been completely established. Thirty-two patients who underwent allogeneic stem cell transplantation were prospectively evaluated for bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) after a median period of 12.2 months. Then, 15 of the patients with osteoporosis or rapidly progressing osteopenia (bone loss > 5%/yr) received three monthly doses of 4 mg zoledronic acid iv. Fifteen patients were followed up without treatment, and all 30 patients were reevaluated after 12 months for BMD and bone turnover markers. By using enriched mesenchymal stem cells in the colony-forming units fibroblast (CFU-F) assay, we evaluated the osteogenic stromal lineage. This procedure was performed in both groups of patients at study entry and after 12 months. The average BMD loss was 3.42% at LS and 3.8% at FN during a 1-yr longitudinal evaluation in 32 patients. Subsequently, BMD increased at both LS and FN (9.8 and 6.4%, respectively) in the zoledronic acid-treated cohort. Hydroxyproline excretion decreased, and serum bone-specific alkaline phosphatase increased significantly, whereas serum osteocalcin increase did not reach the limit of significance. A significant increase in CFU-F growth in vitro was induced by in vivo zoledronic acid administration. In the untreated group, no significant change was observed in bone turnover markers, LS BMD (-2.1%), FN BMD (-2.3%), and CFU-F colony number. In conclusion, short-term zoledronic acid treatment consistently improved both LS and FN BMD in transplanted patients who were at high risk for fast and/or persistent bone loss, partly by increasing the osteogenic progenitors in the stromal cell compartment.
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http://dx.doi.org/10.1210/jc.2004-0509DOI Listing
February 2005

The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome.

J Clin Endocrinol Metab 2005 Jan 13;90(1):2-5. Epub 2004 Oct 13.

Department of Molecular and Clinical Endocrinology, University Federico II, Naples, Italy.

White blood cell (WBC) count is a known risk factor for atherosclerotic vascular disease in adult women. Polycystic ovary syndrome (PCOS) is potentially a risk factor for atherosclerosis and cardiovascular disease. The aim of the present study was to investigate leukocyte count in PCOS. One hundred and fifty PCOS women matched for age and body mass index with 150 healthy women were enrolled. WBC count, C-reactive protein, and a complete anthropometrical, metabolic, and hormonal evaluation were performed in both groups. Serum insulin, glucose level, and lipid profile were also measured in each subject. WBC count was significantly higher (P < 0.0001) in PCOS with (interquartile range in parentheses) 7260 (393) cells/mm(3), compared with controls with 5220 (210) cells/mm(3). C-reactive protein levels were significantly increased (P < 0.0001) in PCOS with 2 (1) mg/liter compared with healthy women with 0.7 (0.8) mg/liter. In both groups, there was a significant (P < 0.0001) linear correlation between WBC count and homeostasis model assessment score (PCOS, r = 0.94; controls, r = 0.91). Multiple linear regression analysis showed that other hormone levels are not predictors of leukocyte count both in PCOS and control women. In conclusion, our data demonstrate that PCOS women have an increased WBC count that correlates with homeostasis model assessment values.
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http://dx.doi.org/10.1210/jc.2004-0628DOI Listing
January 2005