Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients. PATIENTS AND METHODS: We retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples "Federico II" between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included. RESULTS: In the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27-87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67 mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR = 0.82 CI 0.47-1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17-0.80; p = 0.011) compared to euthyroid patients. CONCLUSIONS: Baseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.

Diagnostic value of FDG PET/CT imaging.

Patients with differentiated thyroid cancer (DTC) have a relatively good overall prognosis, but 20% of them develop local recurrences and 10% distant metastases with relatively high mortality (8%). The current prognostic systems lack the ability to predict outcome of patients when discovered to harbor metastases years later. The introduction of 18-F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) and PET/computed tomography (CT) for evaluating patients with DTC has added new information on the disease. This review will summarize the data published so far on the use of FDG in DTC. The most appropriate indication to FDG-PET/CT is in evaluating patients with high thyroglobulin level during follow-up, mainly when radioiodine whole body scan is negative. In this setting, a high accuracy has been reported leading to change in management of patients. A clear relationship has been demonstrated between FDG-PET/CT accuracy and thyroglobulin level, with better results obtained in thyroid stimulating hormone (TSH) stimulated condition. Moreover, FDG imaging provides potentially relevant information on tumour biology, and scan results may enable to prognostically stratify DTC patients with local or distant recurrences. Based on literature data, FDG-PET/CT does not have routine clinical indication in the initial staging of DTC patients, as well as in evaluating cytologically indeterminated thyroid nodules.

Postsurgical diagnostic evaluation of patients with differentiated thyroid carcinoma: comparison of ultrasound, iodine-131 scintigraphy and PET with fluorine-18 fluorodeoxyglucose.

PURPOSE: The aim of this study was to compare the results of ultrasound (US), whole-body scintigraphy with iodine-131 (I-131 WBS) and positron emission tomography with fluorine-18 deoxyglucose (FDG-PET) in the follow-up of patients after thyroidectomy for differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: Thirteen patients (3 men, 10 women) were evaluated by neck US, I-131 WBS and FDG-PET. In each patient six anatomical regions (right and left thyroid bed, right and left cervical region, right and left supraclavicular region) were investigated, for a total of 78 regions. Distant metastases were investigated by I-131 WBS and FDG-PET and considered separately in the analysis. Imaging findings were compared with the reference standards, such as fine-needle aspiration cytology (2), biopsy (4) or clinical-radiological studies (7). RESULTS: US, FDG-PET and I-131 WBS showed concordant negative results in most (70, 90%) of the anatomical sites considered. In one patient with left cervical lymph node metastasis, the imaging techniques showed concordant positive results (1%). In the remaining 7 regions (9%), the imaging results were discordant; in particular, tumour lesions, nodal metastases (4) and thyroid bed recurrences (3) were detected by US only (3), by US and I-131 WBS (1) and by FDG-PET only (3). With regard to distant metastases, FDG-PET and I-131 WBS yielded concordant negative results in the majority (77%) of patients (9); in one patient only were the two imaging techniques concordant in their positive result. In the last three patients, the results were discordant; in particular, distant metastases were detected by I-131 WBS only in two patients and by FDG-PET only in one patient. CONCLUSIONS: Our work indicates a fundamental role for US in evaluation of the neck after surgery for DTC. WBS is useful to determine differentiation of tumour lesions, to identify thyroid remnants and to look for distant metastases. FDG-PET has an important role in cases of dedifferentiated thyroid carcinoma in which WBS and thyroglobulin measurements are unable to detect tumour lesions.

Fluorodeoxyglucose PET/CT in patients with differentiated thyroid cancer and elevated thyroglobulin after total thyroidectomy and (131)I ablation.

AIM: The aim of this study was to evaluate the role of 18F fluorodeoxyglucose-positron emission tomography (FDG-PET), differentiated thyroid carcinoma (DTC) treated with therapeutic (131)I because of elevated thyroglobulin (Tg) levels during follow up. The results of FDG-PET/CT were compared with post-therapy (131)I whole body scan (131I-t-WBS) and Tg at short term follow up. METHODS: Forty-five patients with DTC underwent a new therapeutic (131I) administration based upon Tg values >1.5 ng/mL. All patients underwent (131I-t-WBS) 5-7 days after 131I therapy. A few days before 131I administration, a FDG-PET scan was performed in all patients. FDG-PET/CT was considered positive (PET+) when at least one abnormal focus of FDG uptake was found; likewise, 131I-t-WBS was considered positive(WBS+) when at least on abnormal focus of uptake was found. Assessment of short-term response to radioiodine was performed by measuring Tg values. RESULTS: FDG-PET/CT was positive in 32 patients, 23 of which had positive 131I-t-WBS and negative in 13, 8 of which had a negative 131I-t-WBS. Overall agreement was 69%. Tg values were significantly higher in FDG-PET/CT positive (502+/-1 027 ng/mL) than in FDG-PET/CT negative patients (57+/-94 ng/mL). A significant difference emerged between 131I-t-WBS positive (561 +/- 1 086 ng/mL) and 131I-t-WBS negative (65+/- 120 ng/mL) findings. In these 45 patients Tg normalized in 36%, was reduced by at least 50% in 24% and remained unchanged in the remaining 40%. Overall, at short-term follow-up, Tg values normalized in 77% of the 13 patients with negative FDG-PET/CT and in 19% of the 32 patients with positive FDG-PET/CT. CONCLUSION: FDG-PET/CT is a powerful and useful tool for assessing patients with DTC. it can provide additional information in those patients with high Tg at follow-up and eligible for 131I therapy. A negative FDG-PET/CT could also represent a prognostic tool combined with serum Tg testing a short term follow-up.

Imaging characterization of non-hypersecreting adrenal masses. Comparison between MR and radionuclide techniques.

AIM: In patients with non-hypersecreting adrenal masses, tumor characterization is clinically relevant to establish the appropriate treatment planning. The aim of this study was to comparatively characterize such adrenal lesions using MR and radionuclide techniques. METHODS: Thirty patients with non-hypersecreting unilateral adrenal tumors underwent both MR and adrenal scintigraphy. MR was performed using SE T1- (pre- and post-gadolinium DTPA) and T2-weighted images as well as in- and out-phase chemical-shift imaging (CSI). MR qualitative and quantitative (signal intensity ratios) evaluation was performed. Radionuclide studies consisted of iodine-131 nor-cholesterol (n=20), iodine-131 MIBG (n=15) and fluorine-18 FDG PET (n=11) scans. Histology (n=16), biopsy (n=3) or clinical-imaging follow-up (n=11) demomstrated 13 adenomas, 3 cysts, 2 myelolipomas, 4 pheochromocytomas (pheos), 4 carcinomas, 1 sarcoma and 3 metastases. Comparative imaging analysis was focused on adenomas, pheos and malignant tumors. RESULTS: Qualitative MR evaluation showed: signal T2-hyperintensity in 46% of adenomas and in 100% of pheos and malignant tumors, no gadolinium enhancement in 92% of adenomas and definite signal intensity loss on CSI in 100% of such tumor lesions, gadolinium enhancement in 100% of pheos and in 63% of malignancies and no absolute change of signal intensity on CSI in 100% of both pheos and malignancies. Quantitative MR analysis demonstrated: significantly higher signal T2-hyperintensity of pheos compared to adenomas and malignancies as well as significantly higher enhancement after gadolinium in pheos compared to adenomas and malignancies (p<0.03). Radionuclide studies showed significantly increased nor-cholesterol uptake only in adenomas (n=13), significant MIBG accumulation only in pheos (n=4) and FDG activity only in malignant adrenal lesions (n=8). CONCLUSION: MR techniques may provide some presumptive criteria to characterize non-hypersecreting adrenal masses, such as no gadolinium enhancement and definite signal intensity loss on CSI in adenomas or quantitatively measured T2-hyperintensity and gadolinium enhancement in pheos. On the other hand, radionuclide modalities offer more specific findings in this setting since nor-cholesterol and MIBG scans are respectively able to reveal benign tumors such as adenoma and pheochromocytoma, while FDG imaging allows identification of malignant adrenal lesions. Adrenal scintigraphy is recommended in those patients, when MR images are uncertain or inconclusive.

Follow-up of differentiated thyroid carcinoma.

Thyroid cancer is the most common endocrine malignancy. More than 90% of primary thyroid cancers are differentiated papillary or follicular types. The treatment of differentiated thyroid carcinoma (DTC) consists of total thyroidectomy and radioactive iodine ablation therapy, followed by L-thyroxine therapy. The extent of initial surgery, the indication for radioiodine ablation therapy and the degree of TSH-suppression are all issues that are still being debated cancers are in relation to the risk of recurrence. Total thyroidectomy reduces the risk of recurrence and facilitates (131)I ablation of thyroid remnants. The aim of radioiodine ablation is to destroy any normal or neoplastic residuals of thyroid tissue. These procedures also improve the sensitivity of thyroglobulin (Tg) as a marker of disease, and increase the sensitivity of (131)I total body scan (TBS) for the detection of persistent or recurrent disease. The aim of TSH-suppressive therapy is to restore euthyroidism and to decrease serum TSH levels, in order to reduce the growth and progression of thyroid cancer. After initial treatment, the objectives of the follow-up of DTC is to maintain adequate thyroxine therapy and to detect persistent or recurrent disease through the combined use of neck ultrasound (US) and serum Tg and (131)I TBS after TSH stimulation. The follow-up protocol should be adapted to the risk of recurrence. Recent advances in the follow-up of DTC are related to the use of recombinant human TSH (rhTSH) in order to stimulate Tg production and the ultrasensitive methods for Tg measurement. Undetectable serum Tg during TSH suppressive therapy with L-T4 does not exclude persistent disease, therefore serum Tg should be measured after TSH stimulation. The results of rhTSH administration and L-thyroxine therapy withdrawal are equivalent in detecting recurrent thyroid cancer, but the use of rhTSH helps to avoid the onset of hypothyroid symptoms and the negative effects of acute hypothyroidism on cardiovascular, hepatic, renal and neurological function. In low-risk DTC patients serum Tg after TSH stimulation, together with ultrasound of the neck, should be used to monitor persistent disease, avoiding diagnostic TBS which has a poor sensitivity. These recommendations do not apply when Tg antibodies are present in the serum, in patients with persistent or recurrent disease or limited thyroid surgery. Low-risk patients may be considered to be in remission when undetectable Tg after TSH stimulation and negative US evaluation of the neck are present. On the contrary, detectable Tg after TSH stimulation is an indicator in selecting patients who are candidates for further diagnostic procedures.

Diagnostic accuracy of radionuclide imaging using 131I nor-cholesterol or meta-iodobenzylguanidine in patients with hypersecreting or non-hypersecreting adrenal tumours.

The aim of this retrospective study was to evaluate the diagnostic accuracy of nor-cholesterol and meta-iodobenzylguanidine radionuclide imaging in two separate groups of patients with adrenal tumours to characterize lesions as adenoma or pheochromocytoma. We studied 75 patients (22 male and 53 female, mean age 47 +/- 15 years) with hypersecreting (n = 32) or non-hypersecreting (n = 43) unilateral adrenal tumours detected by computerized tomography or magnetic resonance scans. 131I nor-cholesterol adrenal scintigraphy was performed in 41 patients. Meta-[131I]iodobenzylguanidine (131I-MIBG) imaging was acquired in the other 34 patients. Pathology examinations (n = 58) or computerized tomography follow-up studies (n = 17) were obtained. Adrenal lesions were represented by 44 adenomas, four cysts, one myelolipoma, one pseudotumour, one ganglioneuroma, 16 pheochromocytomas, three carcinomas, four metastases and one sarcoma. Radionuclide studies were qualitatively evaluated and the corresponding results were classified as true positive, true negative, false positive and false negative. Diagnostic sensitivity, specificity and accuracy as well as positive and negative predictive values were calculated. The diagnostic values of nor-cholesterol scintigraphy in identifying adrenal adenomas were sensitivity 100%, specificity 71%, accuracy 95%, positive predictive value 94% and negative predictive value 100%; of note, two false positive cases were observed represented by a pheochromocytoma and a myelolipoma. The diagnostic values of MIBG scintigraphy in recognizing pheochromocytoma were sensitivity 100%, specificity 95%, accuracy 97%, positive predictive value 94% and negative predictive value 100%; only one false positive case occurred consisting of a carcinoma. It is concluded that, in the large majority of cases, adrenal scintigraphy using nor-cholesterol or MIBG is able to characterize specific lesions such as adenoma and pheochromocytoma, respectively. These findings show relevant clinical impact, particularly in patients with non-hypersecreting adrenal lasions. Radiotracer selection depends on clinical patient history and department availability; since benign adenomas are the most common cause of non-hypersecreting tumours, nor-cholesterol should be the first choice followed by MIBG if nor-cholesterol shows normal images. However, rare as well as unusual findings may be observed; nor-cholesterol uptake may occasionally be also found in non-adenoma tumours such as myelolipoma and pheochromocytoma. Similarly, MIBG accumulation may occur not only in lesions arising from medullary chromaffin tissue, but also rarely in cortical adrenal carcinoma.

The diagnostic role of radionuclide imaging in evaluation of patients with nonhypersecreting adrenal masses.

UNLABELLED: The aim of this study was to evaluate the role of radionuclide imaging in the characterization of nonhypersecreting adrenal masses. METHODS: A total of 54 patients (19 men, 35 women; mean age, 50 +/- 16 y) with nonhypersecreting unilateral adrenal tumors that had been originally detected on CT or MRI underwent adrenal scintigraphy using different radiotracers. None of the patients showed specific symptoms of adrenal hypersecretion. Screening tests for excess cortical and medullary products showed normal adrenal hormone levels. Radionuclide studies (n = 73) included (131)I-norcholesterol (n = 24), (131)I-metaiodobenzylguanidine (MIBG) (n = 23), and (18)F-FDG PET (n = 26) scans. RESULTS: Histology after surgery (n = 31) or adrenal biopsy (n = 23) was obtained. Adrenal lesions were represented by 19 adenomas, 4 cysts, 1 myelolipoma, 1 neurinoma, 2 ganglioneuromas, 5 pheochromocytomas, 4 pseudotumors, 6 carcinomas, 2 sarcomas, and 10 metastases (size range, 1.5- to 5-cm diameter; mean, 4.9 +/- 3.1 cm). For norcholesterol imaging, diagnostic sensitivity, specificity, and accuracy were 100%, 71%, and 92%, respectively; the positive predictive value (PPV) of the norcholesterol scan to characterize an adrenal mass as an adenoma was 89%, whereas the corresponding negative predictive value (NPV) to rule out this type of tumor was 100%. For MIBG imaging, diagnostic sensitivity, specificity, and accuracy were 100%, 94%, and 96%, respectively; the PPV of the MIBG scan to characterize an adrenal mass as a medullary chromaffin tissue tumor was 83%, whereas the corresponding NPV to rule out this type of tumor was 100%. For FDG PET, diagnostic sensitivity, specificity, and accuracy were 100%, 100%, and 100%, respectively; the PPV of FDG PET to characterize an adrenal mass as a malignant tumor was 100%, whereas the corresponding NPV to rule it out was 100%. Furthermore, in 7 patients with malignant adrenal tumors, FDG whole-body scanning revealed extra-adrenal tumor sites (n = 29), allowing an accurate diagnosis of the disease's stage using a single-imaging technique. CONCLUSION: In patients with nonhypersecreting adrenal masses, radionuclide adrenal imaging, using specific radiopharmaceuticals such as norcholesterol, MIBG, and FDG, may provide significant functional information for tissue characterization. Norcholesterol and MIBG scans are able to detect benign tumors such as adenoma and pheochromocytoma, respectively. Conversely, FDG PET allows for recognition of malignant adrenal lesions. Therefore, adrenal scintigraphy is recommended for tumor diagnosis and, hence, for appropriate treatment planning, particularly when CT or MRI findings are inconclusive for lesion characterization.

Prolactinomas in adolescents: persistent bone loss after 2 years of prolactin normalization.

OBJECTIVE: To evaluate the effect of hyperprolactinaemia and its treatment with dopamine-agonists on bone mass and turnover in adolescent patients compared to adults. PATIENTS: Forty patients with hyperprolactinaemia (20 with disease onset during adolescence and 20 during adulthood) and 40 healthy control subjects. DESIGN: Open transverse (in patients and controls) and open longitudinal (in the patients). MEASUREMENTS: Bone mineral density (BMD) at lumbar spine and femoral neck, serum osteocalcin (OC) and urinary cross-linked N-telopeptides of type-1 collagen (Ntx) levels were evaluated in patients and controls. In the 40 patients, bone mass and turnover were re-evaluated after 12 and 24 months of treatment with bromocriptine (BRC, dose 2.5-10 mg daily), quinagolide (CV, dose 0.075-0.3 mg daily) or cabergoline (CAB, dose 0.5-1.5 mg weekly). RESULTS: Transverse study: BMD values were significantly lower in hyperprolactinaemic patients than in controls, both at lumbar spine (0.81 +/- 0.01 vs. 1.010 +/- 0.01 g/cm2; P < 0.001) and femoral neck (0.71 +/- 0.01 vs. 0.873 +/- 0.03 g/cm2; P < 0.001). Thirty-two patients (80%) had osteoporosis and/or osteopenia at one or both skeletal sites. A significant inverse correlation was found between T score values measured at lumbar spine and femoral neck and the estimated disease duration. BMD was significantly lower in young than adult patients both at lumbar spine (T score, -2.4 +/- 0.1 vs. -1.4 +/- 0.3, P < 0.01) and at femoral neck (T score, -2.1 +/- 0.05 vs. -1.5 +/- 0.2, P < 0.05). Similarly, serum OC levels were significantly lower (2.0 +/- 0.11 vs. 9.1 +/- 2.4 micrograms/l, P < 0. 01) while Ntx levels were significantly higher in patients than in controls (129.2 +/- 1.7 vs. 80.7 +/- 2.9 nmol Bone collagen equivalent (BCE)/mmol creatinine; P < 0.001). A significant inverse correlation was found between prolactin (PRL) levels and OC levels, lumbar and femoral T score values, as well as between disease duration and OC levels, lumbar and femoral T score values. A significant direct correlation was also found between Ntx levels and PRL levels and disease duration. Longitudinal study: Normalization of serum PRL levels was obtained in all patients after 6-12 months of treatment. A significant increase of serum OC levels together with a significant decrease of Ntx levels was observed after 12 and 24 months of treatment (P < 0.01). Urinary and serum calcium, phosphorus, creatinine, and serum alkaline phosphatase and parathyroid hormone levels did not change during the study period in all patients. After 12 months of therapy OC and Ntx concentrations were restored to normal. A slight but not significant increase of BMD values was recorded after 12 and 24 months of treatment. After 12 months of treatment the percent increment of BMD values in the whole group of patients was 1.13 +/- 0.6% at lumbar spine and 1.2 +/- 0.4% at femoral neck level, whereas after 24 months, it was 2.8 +/- 0.7% at lumbar spine and 3.5 +/- 0.7% at femoral neck level. After 12 months of treatment, the percent increment of BMD values was 0.7 +/- 0.2% and 1.6 +/- 1.1% at lumbar spine and 0.9 +/- 0.5% and 1.6 +/- 0.5% at femoral neck level in the young and adult patients, respectively, whereas after 24 months, it was 2.1 +/- 0.8% and 3.4 +/- 1.3% at lumbar spine and 2.6 +/- 0.8% and 4.4 +/- 1.0% at femoral neck level in the young and adult patients, respectively. CONCLUSIONS: Adolescents with prolactinoma have osteopenia or osteoporosis, a finding that strengthens the need for a prompt diagnosis. Since normalization of PRL concentrations by dopamine agonist therapy is unable to restore the bone mass, other therapeutic approaches should be considered in order to prevent further long-term problems.

Effect of a short-term treatment with alendronate on bone density and bone markers in patients with central diabetes insipidus.

The aim of this open prospective randomized study was to evaluate the effect of a 6-month treatment with alendronate on the bone mineral density (BMD) at lumbar spine in patients with central diabetes insipidus. Eighteen patients with central diabetes insipidus and 18 sex- and age-matched healthy subjects entered this study. At study entry, all subjects underwent BMD assessment at the lumbar spine and measurement of serum osteocalcin (OC) and cross-linked N-telopeptides of type I collagen (Ntx). Thereafter, 9 of the 18 patients were randomized to receive treatment with alendronate at a dose of 10 mg, orally, once daily for 6 months (group 1), whereas the remaining 9 patients did not receive any treatment affecting bone status during this period (group 2). After 6 months, bone metabolism and bone density study were repeated in all patients. At baseline, lumbar BMD values (0.86+/-0.03 vs. 1.01+/-0.02 g/cm2; P<0.001) and serum OC levels (4.7+/-0.3 vs. 7.9+/-0.2 microg/L; P<0.001) were significantly lower, whereas urinary Ntx levels were significantly higher [72.0+/-1.9 vs. 64.6+/-1.7 nmol bone collagen equivalents (BCE)/nmol creatinine (Cr); P<0.01] in patients than in controls. After randomization, no difference in lumbar BMD, serum OC, or urinary Ntx was found between patients of group 1 and group 2. At the 6 month follow-up, no difference in serum OC levels was found compared to baseline evaluation in patients of both group 1 and group 2. By contrast, a significant decrease in urinary Ntx levels was found in patients of group 1 (70.3+/-3.0 vs. 75.4+/-2.1 nmol BCE/nmol Cr; P<0.05), but not in patients of group 2 (68.8+/-3.3 vs. 68.5+/-3.0 nmol BCE/nmol Cr; P = NS). A significant increase in lumbar BMD values was found in patients of group 1 (0.88+/-0.04 vs. 0.83+/-0.04 g/cm2; P<0.05), whereas a significant decrease in lumbar BMD values was found in patients of group 2 (0.86+/-0.05 vs. 0.89+/-0.05 g/cm2; P<0.05). Lumbar BMD increased 7.0+/-1.5% in patients of group 1 and decreased 4.2+/-1.8% in patients of group 2 (P<0.001). In conclusion, this study demonstrated that a 6-month treatment with alendronate in patients with central diabetes insipidus was effective in significantly improving BMD at the lumbar spine, which was significantly worsened in untreated patients. Therefore, alendronate treatment could be used in patients with central diabetes insipidus with documented osteopenia or osteoporosis.

Effects of two years of growth hormone (GH) replacement therapy on bone metabolism and mineral density in childhood and adulthood onset GH deficient patients.

The aim of the current study was to evaluate bone metabolism and mass before and after 2 years of GH replacement therapy in adults with childhood or adulthood onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and weight-matched healthy subjects entered the study. Biochemical indexes of bone turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine, of soft tissue formation such as aminoterminal propeptide of type-III and bone mineral density were evaluated. Childhood onset GH deficient patients had significantly decreased bone (osteocalcin: 2.5+/-1.3 vs 6.6+/-4.8 mcg/l, p<0.001) and soft tissue formation (aminoterminal propeptide of type III: 273+/-49 vs 454+/-23 U/I, p<0.001) indexes and normal bone resorption indexes (serum carboxyterminal telopeptide of type-I procollagen: 105+/-48 vs 128+/-28 mcg/l p=NS; urinary hydroxyproline/creatinine: 0.19+/-0.16 vs 0.28+/-0.16 mmol/mol, p=NS; urinary deoxypyridinoline/creatinine: 21 +/-10 vs 25+/-8 mcmol/mol, p=NS) compared to healthy subjects. On the contrary, no significant difference in bone turnover indexes between adulthood onset GH deficient patients and healthy subjects was found. Moreover, significantly decreased bone mineral density at any skeletal site and at whole skeleton was found in GH deficient patients compared to healthy subjects (e.g. femoral neck: 0.74+/-0.13 vs 0.97+/-0.11 g/cm2, p<0.001). In addition, a significant reduction of bone mineral density was found in childhood compared to adulthood onset GH deficient patients at any skeletal site, except at femoral neck. After 3-6 months of treatment, both groups of patients had a significant increase in bone turnover and in soft tissue formation. In particular, in childhood onset GH deficient patients after 3 months osteocalcin increased from 2.5+/-1.3 to 7.9+/-2.1 mcg/l, p<0.001 aminoterminal propeptide of type-III from 273+/-49 to 359+/-15 U/I p<0.001; serum carboxyterminal telopeptide of type-I procollagen from 105+/-48 to 201+/-45 mcg/l, p<0.001; urinary hydroxyproline/creatinine from 0.19+/-0.16 to 0.81+/-0.17 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 21 +/-10 to 54+/-20 mcmol/mol, p<0.001; while in adulthood onset GH deficient patients after 6 months osteocalcin increased from 4.2+/-3.6 to 6.5+/-1.9 mcg/l, p<0.05; aminoterminal propeptide of type- III from 440+/-41 to 484+/-37 U/I, p<0.05; serum carboxyterminal telopeptide of type-I procollagen from 125+/-40 to 152+/-22 mcg/l, p<0.05; urinary hydroxyproline/creatinine from 0.24+/-0.12 to 0.54+/-0.06 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 23+/-8 to 42+/-5 mcmol/mol, p<0.001. No significant difference in bone turnover between pre- and post-treatment period was found after 18-24 months of GH therapy. Conversely, bone mineral density was slightly reduced after 3-6 months of GH therapy, while it was significantly increased after 18-24 months. In fact, femoral neck bone mineral density values significantly rose from 0.74+/-0.13 g/cm2 to 0.87+/-0.11 g/cm2 (pre-treatment vs 2 years of GH treatment values). In conclusion, patients with childhood or adulthood onset GH deficiency have osteopenia that can be improved by long-term treatment with GH.

Impairment of bone status in patients with central diabetes insipidus.

The aim of the current study was to evaluate the biochemical parameters of bone metabolism and the bone mineral density (BMD) in patients with central diabetes insipidus, either treated or not treated with endonasal desmopressin. Eighteen patients with central diabetes insipidus and 18 sex- and age-matched healthy subjects entered the study. The patients were divided into 2 groups: patients who did not receive treatment with desmopressin for at least 1 yr (group 1), and patients chronically treated with desmopressin since the diagnosis of diabetes insipidus (group 2). Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen levels were measured in all patients and controls using RIA and enzyme-linked immunosorbent assay kits, respectively. BMD was measured at the lumbar spine (L1-L4) and at the femoral neck in all subjects, using a Hologic QDR 1000 analyzer (Hologic Inc., Waltham, MA). Serum osteocalcin concentrations were significantly lower, both in patients of group 1 and group 2, compared with healthy subjects (5.1 +/- 0.6 and 4.5 +/- 0.3 vs. 7.9 +/- 0.2 micrograms/L, P < 0.05), whereas urinary cross-linked N-telopeptide of type I collagen concentrations were similar in the three groups of subjects (72.8 +/- 2.2, 71.6 +/- 2.7, and 64.6 +/- 1.7 nmol bone collagen equivalent/mmol creatinine). BMD was significantly decreased in patients of groups 1 and 2, compared with controls, both at lumbar spine (0.84 +/- 0.06 and 0.87 +/- 0.04 vs. 1.01 +/- 0.02 g/cm2, P < 0.05) and femoral neck (0.78 +/- 0.06 and 0.80 +/- 0.04 vs. 0.93 +/- 0.02 g/cm2, P < 0.05). A significant inverse correlation was found between disease duration and BMD values, evaluated as T scores, both at lumbar spine (group 1: r = -0.952, P < 0.005; group 2: r = -0.921, P < 0.001) and at femoral neck (group 1: r = -0.914, P < 0.05; group 2: r = -0.683, P < 0.05). In conclusion, patients with central diabetes insipidus had a significant bone impairment, compared with healthy subjects. Replacement with endonasal desmopressin at standard doses was not able to prevent or reverse the bone impairment. These findings suggest that, in patients with central diabetes insipidus, bone status analysis is mandatory; and a bone-loss preventing treatment might be beneficial.

Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing's disease.

BACKGROUND: Osteoporosis is common in patients with Cushing's disease and is likely due to an imbalance between bone formation and resorption. Alendronate is an aminobisphosphonate that is able to increase bone mass mainly by inhibiting bone resorption. OBJECTIVE: We have evaluated the effect of chronic treatment with alendronate on bone mineral density (BMD) in patients with Cushing's disease. PATIENTS: 39 patients with Cushing's disease entered this study. 39 age-, sex- and BMI-matched normals served as controls for baseline evaluation. The 39 patients were divided into four groups: 1) 10 patients with active disease treated with alendronate and ketoconazole; 2) 11 patients with inactive disease treated with alendronate; 3) 8 patients with active disease treated with ketoconazole alone, 4) 10 patients with inactive disease received no treatment. TREATMENT PROTOCOL: Alendronate was given for 12 months in a dose of 10 mg orally once daily after fasting at 0800 h in the morning. Ketoconazole was given in a dose of 200-600 mg orally daily, when pituitary surgery was unsuccessful. STUDY DESIGN: Lumbar spine (L1-L4) and femoral neck BMD, serum osteocalcin (OC), urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were evaluated at study entry, in patients and controls, and were repeated after 6 and 12 months in the 39 patients. RESULTS: BMD values were lower in patients with Cushing's disease than in controls at both L1-L4 (0.72 +/- 0.4 vs. 1.01 +/- 0.6 g/cm2, P < 0.05) and femoral neck (0.69 +/- 0.3 vs. 0.96 +/- 0.6 g/cm2, P < 0.05). In the 39 patients with Cushing's disease considered as a whole, serum OC levels were lower (1.1 +/- 0.1 vs 1.5 +/- 0.1 nmol/l, P < 0.01), while Ntx values were higher than in controls (168 +/- 25 vs. 61 +/- 31 nmol BCE/mmol creatinine, P < 0.01). In the alendronate-treated groups, serum OC levels increased, while Ntx levels significantly decreased after 6 and 12 months of treatment without any significant difference between the two groups. BMD values measured at L1-L4 and femoral neck significantly increased after 12 months of therapy. In patients of group 4, a significant increase of serum OC levels and a significant decrease of Ntx levels were observed together with a slight increase of BMD values after 12 months. No significant change in either biochemical markers or BMD values was found in patients of group 3. CONCLUSIONS: Patients with Cushing's disease have osteoporosis which needs to be rapidly reversed to limit the risk of fracture. The results of the present study show that a 12 month treatment period with alendronate induced an improvement in bone mineral density greater than in untreated patients.

Bone marker and bone density responses to dopamine agonist therapy in hyperprolactinemic males.

The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. Six patients received bromocriptine at a dose of 2.5-10 mg/day; 7 patients received quinagolide at a dose of 0.075-0.3 mg/day; 7 patients received cabergoline at a dose of 0.5-1.5 mg/week. BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were measured before and every 6 months during treatment. At study entry, BMD values were lower in patients than controls at both lumbar spine (0.82 +/- 0.03 vs. 1.18 +/- 0.01 g/cm2; P < 0.001) and femoral neck (0.85 +/- 0.02 vs. 0.92 +/- 0.02 g/cm2; P < 0.05) levels. Osteopenia or osteoporosis was diagnosed in 16 patients at the lumbar spine and in 6 of them at the femoral neck level. A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration (P < 0.01). In the 20 patients, serum OC levels were significantly lower (2.1 +/- 0.1 vs. 9.3 +/- 2.4 microg/L; P < 0.01), whereas Ntx levels were significantly higher (157.8 +/- 1.1 vs. 96.4 +/- 7.4 nmol bone collagen equivalent/mmol creatinine; P < 0.001) than control values. A significant inverse correlation was found between serum PRL and OC (P < 0.01), but not Ntx, levels. After 18 months of treatment, serum PRL levels were suppressed, and gonadal function was restored in all 20 patients, as shown by the normalization of serum T (from 2.2 +/- 0.2 to 5.0 +/- 0.2 microg/L) and dihydrotestosterone (0.3 +/- 0.02 vs. 0.5 +/- 0.01 nmol/L) levels, without any significant difference among groups. A progressive significant increase in serum OC levels together with a significant decrease in Ntx levels were observed after 6, 12, and 18 months of treatment in the 3 groups of patients. A slight, although significant, increase in BMD values was recorded in all patients after 18 months of bromocriptine, quinagolide, and cabergoline treatment, serum OC levels were normalized after treatment, whereas neither urinary Ntx levels nor BMD values were normalized by 18 months of treatment with dopaminergic agents. In conclusion, treatment with bromocriptine, quinagolide, and cabergoline for 18 months, although successfull in suppressing serum PRL levels and restoring gonadal function, was unable to restore lumbar spine and femoral neck BMD and normalize Ntx levels. However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia.

Growth hormone deficiency in elderly patients with hypothalamo-pituitary tumors.

In 18 patients with hypothalamo-pituitary diseases aged over 60 years and in 18 sex, age- and BMI-matched healthy subjects, the results of plasma IGF-I and IGF-BP3 levels and the GH response to GHRH + arginine test (GHRH + ATT) were correlated to the results of body composition, serum osteocalcin (OC) and urinary cross-linked N-telopeptides of type I collagen (Ntx) and the bone mineral density (BMD). In 10 patients and 10 controls, the GH response to ITT was also evaluated. The GH response to GHRH + ATT and ITT was markedly reduced in patients compared to controls (3.1 +/- 0.7 vs. 23.2 +/- 2.3 micrograms/L, P < 0.001 and 1.1 +/- 0.3 vs. 6.4 +/- 0.8 micrograms/L, P < 0.001), so all patients were classified as GHD, though no significant difference was found in plasma IGF-I and IGF-BP3 levels between the two groups. Body composition analysis revealed a significant increase of fat mass (37.4 +/- 2.2 vs. 28.0 +/- 1.0%, P < 0.001), a significant decrease of lean mass (62.6 +/- 2.2 vs. 72.0 +/- 1.0%, P < 0.001) and total body water (45.7 +/- 1.5 vs. 52.5 +/- 1.1%, P < 0.001) in patients compared to controls. Serum OC levels were lower (1.9 +/- 0.1 vs. 4.6 +/- 0.4 micrograms/L, P < 0.001) in patients than in controls, whereas urinary Ntx levels were similar. BMD values in lumbar spine (0.81 +/- 0.02 vs. 0.90 +/- 0.02 g/cm2, P < 0.001) and femoral neck (0.70 +/- 0.02 vs. 0.82 +/- 0.02 g/cm2, P < 0.001) were significantly lower in patients than in controls. A significant inverse correlation was found between GHD duration and lumbar spine (r = -0.73, P&1t; 0.001) or femoral neck (r = -0.81, P&1t; 0.001) BMD values and a significant direct correlation was found between GH peak after GHRH + ATT and lumbar BMD (r = 0.69, p = 0.001) in GHD patients. In conclusion, GHD in patients over 60 yrs aged with a characteristic history of hypothalamus-pituitary pathology is distinct from the physiological decline in GH secretion associated with aging.