Long-term remission and recurrence rate in a cohort of Cushing's disease: the need for long-term follow-up.

OBJECTIVE: Transsphenoidal surgery is the procedure of choice in Cushing disease (CD), with immediate post-operative remission rates ranging between 59 and 94% and recurrence rates between 3 and 46%, both depending upon the definition criteria and the duration of the follow-up. Our aim was to assess the rate of remission, recurrence and persistence of the disease after the first treatment and to identify predictors of remission in the CD population of our center. METHODS: Retrospective cohort study of the patients diagnosed of CD and with follow-up in our center between 1974 and 2011. We analyzed 41 patients (35 women and 6 men) with a mean age at diagnosis of 34 ± 13 years. The mean follow-up was 14 ± 10 years (range 1-37 years) and the median of follow-up period was 6.68 years. RESULTS: Thirty-five (85.4%) patients underwent transsphenoidal surgery as first treatment option. Histopathological evidence of a pituitary adenoma was registered in 17 (48.5%) patients. Thirty-two (78%) patients achieved disease remission after the first treatment, 21 (65.6%) of them presented disease recurrence. Persistent disease was observed in 9 (22%) patients. Twelve (29.3%) subjects developed post-surgical adrenal insufficiency, 7 of which (70%) achieved stable remission. Two parameters were found to be significant predictors of remission after the first treatment: age at disease diagnosis and the development of adrenal insufficiency (cortisol <3 µg/dl) in the immediate post-operative state. CONCLUSIONS: We report a high recurrence rate, at least partially attributable to the long follow-up time. Early post-surgery adrenal insufficiency predicts remission. Hypopituitarism was also very prevalent, and strongly associated with radiotherapy. These results lead us to the conclusion that CD needs a life-long strict follow-up.

Aumento de los valores de PTH en la mujer con osteoporosis posmenopáusica / Increase of PTH in post-menopausal osteoporosis

Objetivos. Los valores séricos de la hormona paratiroidea (PTH) pueden estar aumentados en las mujeres posmenopáusicas con osteoporosis. Sin embargo, sus causas y repercusión clínica son poco conocidas. El objetivo de este estudio ha sido analizar la prevalencia y los procesos asociados al aumento de PTH en mujeres posmenopáusicas con osteoporosis. Métodos. Se incluyeron mujeres con osteoporosis en las que se determinaron los niveles de PTH, 25-hidroxivitamina D, el filtrado glomerular y la excreción urinaria de calcio. Se evaluó la prevalencia de valores aumentados de PTH y su relación con la deficiencia e insuficiencia de vitamina D, insuficiencia renal, hipercalciuria e ingesta de calcio deficiente, condiciones que pueden aumentar la secreción de PTH. Resultados. Incluimos un total de 204 mujeres con una edad media de 64 años. Observamos valores aumentados de PTH (> 65 pg/ml) en un 35%. Cinco mujeres padecían un hiperparatiroidismo primario. Las mujeres con valores aumentados de PTH eran mayores (67±9 años) que las mujeres con niveles de PTH normales (63±11 años; p=0,03). La elevación de PTH se asoció a una ingesta de calcio deficiente (< 800mg/24h) en el 81% de las mujeres, a una deficiencia e insuficiencia de 25-hidroxivitamina D en el 55 y 86% respectivamente; a insuficiencia renal en el 35% y a hipercalciuria en el 17%. Las frecuencias de dichos procesos fueron similares en las mujeres con valores normales de PTH. Los valores de PTH se relacionaron con la edad (r=0,19; p=0,01), pero no con los valores de 25-hidroxivitamina D o con el FG. Conclusiones. Un tercio de las mujeres posmenopáusicas con osteoporosis presentan valores elevados de PTH. En un 10% se debe a un hiperparatiroidismo primario. La prevalencia de procesos asociados al aumento de PTH (ingesta reducida de calcio, déficit de 25-hidroxivitamina D, insuficiencia renal e hipercalciuria) es similar a la observada en mujeres con valores normales de PTH(AU)

Aims. Increased parathyroid values (PTH) serum values can be observed in postmenopausal women. However, the clinical repercussion and causes of this finding are poorly understood. This study has aimed to analyze the prevalence and conditions associated to the increased serum PTH levels in postmenopausal women with osteoporosis as well as their clinical characteristics. Methods. Post-menopausal women with osteoporosis were included in the study. PTH, 25-hydroxyvitamin D (25OHD), 24-h urinary calcium, glomerular filtration rate (GFR) and calcium intake were evaluated. The prevalence of increased PTH serum values and its relationship with vitamin D deficiency and insufficiency, kidney failure, hypercalciuria and calcium intake deficiency were evaluated, these being conditions that may increase PTH secretion. Results. A total of 204 postmenopausal women with osteoporosis with a mean age of 64 years were included. Increase PTH levels (>65 pg/ml) were observed in 35% and 5 women had primary hyperparathyroidism. Women with increased serum PTH levels were older (67±9 years) were old than those with normal PTH levels (63±11 years) (P=0.03). PTH elevation was associated to calcium intake deficiency (<800mg/d) in 81% of the women, to a vitamin D deficiency and insufficiency in 55% and 86%, respectively, renal insufficiency in 35% and hypercalciuria in 17% of the patients. These values, however, did not differ when compared with patients with normal PTH serum levels. Serum PTH levels were related to age (r=0.19, P=0.01) but not to 25OHD or GFR values. Conclusions. One third of the post-menopausal women with osteoporosis had elevated PTH levels. This was due to primary hyperparathyroidism in 10%. The prevalence of conditions associated to the increase in PTH (reduced calcium intake, 25-hydroxyvitamin D, renal failure and hypercalciuria) is similar to that observed in women with normal PTH values(AU)

[Increase of PTH in post-menopausal osteoporosis]. / Aumento de los valores de PTH en la mujer con osteoporosis posmenopáusica.

AIMS: Increased parathyroid values (PTH) serum values can be observed in postmenopausal women. However, the clinical repercussion and causes of this finding are poorly understood. This study has aimed to analyze the prevalence and conditions associated to the increased serum PTH levels in postmenopausal women with osteoporosis as well as their clinical characteristics. METHODS: Post-menopausal women with osteoporosis were included in the study. PTH, 25-hydroxyvitamin D (25OHD), 24-h urinary calcium, glomerular filtration rate (GFR) and calcium intake were evaluated. The prevalence of increased PTH serum values and its relationship with vitamin D deficiency and insufficiency, kidney failure, hypercalciuria and calcium intake deficiency were evaluated, these being conditions that may increase PTH secretion. RESULTS: A total of 204 postmenopausal women with osteoporosis with a mean age of 64 years were included. Increase PTH levels (>65 pg/ml) were observed in 35% and 5 women had primary hyperparathyroidism. Women with increased serum PTH levels were older (67 ± 9 years) were old than those with normal PTH levels (63 ± 11 years) (P=0.03). PTH elevation was associated to calcium intake deficiency (<800 mg/d) in 81% of the women, to a vitamin D deficiency and insufficiency in 55% and 86%, respectively, renal insufficiency in 35% and hypercalciuria in 17% of the patients. These values, however, did not differ when compared with patients with normal PTH serum levels. Serum PTH levels were related to age (r=0.19, P=0.01) but not to 25OHD or GFR values. CONCLUSIONS: One third of the post-menopausal women with osteoporosis had elevated PTH levels. This was due to primary hyperparathyroidism in 10%. The prevalence of conditions associated to the increase in PTH (reduced calcium intake, 25-hydroxyvitamin D, renal failure and hypercalciuria) is similar to that observed in women with normal PTH values.

Do thyroid cancer patients with basal undetectable Tg measured by current immunoassays require rhTSH testing?

OBJECTIVE: To evaluate the predictive value of disease free status of basal thyroglobulin (Tg) in differentiated thyroid carcinoma (DTC). DESIGN: Basal and recombinant human TSH (rhTSH) stimulated Tg measured with a commercial immunoassay (Liaison DiaSorin, Italial), neck ultrasonography (US) and fine needle aspiration cytology if required were performed in DTC patients followed prospectively for 6.8 years in a university hospital. 92 consecutive DTC patients were included. 74 patients with basal and stimulated Tg <1.0 ng/ml and Tg antibodies and US negative were considered as disease-free and persistent/recurrent disease was detected in 18 patients. In 25/74 disease-free patients rhTSH test was repeated within one year. RESULTS: 63/92 patients had undetectable basal Tg (<0.5 ng/ml), with rhTSH-Tg <0.5 ng/ml in 52, in 6 rhTSH-Tg between 0.5 and 1 ng/ml, in 2 between 1-2 ng/ml (disease-free after 3 years of follow-up) and >2.0 ng/ml (mean 4.1±2.4 ng/ml) in another 3, with US lymphatic metastasis confirmed histologically. Disease-free state was predicted with a sensitivity (S) of 66.7% and specificity (Sp) of 75.7% for basal Tg-0.5 ng/ml, and S 100% and Sp 85.1% for stimulated Tg-0.92. rhTSH test and US were repeated within one year in 25 disease-free patients with Tg<1.0 ng/ml. No further elevation below 1 ng/ml was observed. CONCLUSIONS: Low risk patients with undetectable basal Tg measured with current commercially available immunoassays should be followed with at least one rhTSH stimulated Tg and neck US because of the insufficient predictive value for recurrence/persistent disease of basal Tg.

Lithocholic acid downregulates vitamin D effects in human osteoblasts.

BACKGROUND: Osteoporosis is a common complication in chronic cholestasis. It has been proposed that retained substances such as bile acids may produce a damaging effect on bone cells. This study analyses the effects of lithocholic acid (LCA) on cell survival and vitamin D metabolism in human osteoblasts (hOB). MATERIALS AND METHODS: Human osteoblasts cultures were performed with or without foetal bovine serum (FBS) or human albumin (HA) at different LCA concentrations and times with or without vitamin D. RESULTS: Lithocholic acid at concentrations higher than 10(-5 )M decreased cell survival. This effect was partially prevented by the presence of FBS or HA. Vitamin D stimulated CYP24A, BGLAP and TNFSF11 expression in hOB and these effects were modified by nontoxic LCA concentrations. LCA significantly decreased vitamin D stimulation of CYP24A, BGLAP and TNFSF11 gene expression at 72%, 79% and 56% (respectively). LCA alone has an agonistic effect, as has vitamin D, thus partially increasing CYP24A and BGLAP expression, but with no changes on TNFRSF11B expression. Equivalent effects of the LCA were observed by performing gene reporter assays using MG-63 cells transfected with constructs containing CYP24A1 promoter regions. CONCLUSIONS: Lithocholic acid decreases the stimulatory effect of vitamin D on CYP24A, BGLAP and TNFSF11 expression in hOB. This effect is produced through vitamin D response elements (VDREs), located in the promoter regions of these genes, suggesting that LCA acts as a mild analogous of vitamin D, interacting with the vitamin D receptor. These results may explain the potential deleterious effects of retained bile acids on hOB.

Evolution of secondary hyperparathyroidism after kidney transplantation in patients receiving cinacalcet on dialysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a relevant problem in patients undergoing dialysis, and cinacalcet hydrochloride seems to be the best option for controlling it. After kidney transplantation (KTx), moderate to severe SHPT may persist and cause hypercalcemia and hypophosphatemia, among other deleterious effects. The number of patients receiving cinacalcet before KTx is increasing. OBJECTIVE: To evaluate the evolution of calcemia, phosphatemia, and intact parathyroid hormone (iPTH) after KTx in patients with SHPT receiving cinacalcet on dialysis. PATIENTS AND METHODS: The study included 19 patients (15 men and 4 women; mean [SD] age, 52 [13] years) undergoing dialysis and receiving cinacalcet before KTx. Mean duration of dialysis before KTx was 33 (25) months, and cinacalcet dose was 45 (15) mg/d. Creatinine, calcium, phosphorus, alkaline phosphatase, and iPTH concentrations were evaluated at baseline (day of surgery), at 15 days after surgery, and then monthly for 6 months. In all patients, cinacalcet therapy was discontinued on the day of surgery. RESULTS: After the first month post-KTx, mean (SD) serum creatinine concentration was 1.6 (0.4) mg/dL and remained stable during follow-up. Calcium and phosphorus concentrations were normal in 13 patients after KTx; however, in 6 patients, hypercalcemia (calcium concentration, 11 [1.3] mg/dL) or hypophosphatemia (phosphorus concentration, 1.7 [0.6] mg/dL) developed, with iPTH concentration of 557 (400) pg/mL and alkaline phosphatase concentration of 307 (114) IU/mL. Treatment with cinacalcet resulted in correction of calcium and phosphorus concentrations (10.1 [0.4] mg/dL and 1.7 [0.7] mg/dL, respectively). Patients in whom hypercalcemia or hypophosphatemia developed were receiving cinacalcet, 60 mg/d or more, during dialysis therapy. Patients who received cinacalcet, 30 mg/d, before KTx did not exhibit hypercalcemia or hypophosphatemia after KTx. CONCLUSION: In patients with HPT undergoing dialysis and receiving cinacalcet, 60 mg/d or more, this drug therapy should be continued after KTx to avert development of hypercalcemia or hypophosphatemia.

Aetiology and clinical characteristics of male osteoporosis. Have they changed in the last few years?

OBJECTIVE: The aim of this study was to analyse the clinical characteristics and etiological factors related to male osteoporosis in patients attending an out-patient rheumatology department during an 11-year period (1995-2006), as well as to compare them with the observed characteristics in a previous study performed 12 years ago. METHODS: 232 males aged 21-88 (mean 56.1+/-14) with osteoporosis were included in the study. Previous skeletal fractures and family history of osteoporosis were recorded. Bone mass assessment, automated biochemical profile and hormonal measurements (including PTH, 25-OH vitamin D, cortisol, thyroid and sexual hormones) were performed on most patients as well as 24 h urinary calcium, and bone markers. In patients with idiopathic osteoporosis 1-25-OH2 vitamin D was also determined. In addition, x-rays of the spine were obtained for all patients. RESULTS: 67% of the patients had previous skeletal fractures and 51% had vertebral fractures. 57% of the patients had idiopathic and 43% had secondary osteoporosis whereas in the previous series only 22% of the patients had idiopathic disease. The most frequent causes of secondary osteoporosis were corticosteroid therapy, hypogonodism and alcoholism. 38% of the patients with idiopathic osteoporosis had associated hypercalciuria. Patients with secondary osteoporosis were older, shorter, had lower femoral neck T-score and lower serum values of 25-OH vitamin D and testosterone, as well as higher gonadotrophin and PTH values than the patients with idiopathic osteoporosis, whereas patients with idiopathic osteoporosis had higher urinary calcium and more frequent family history of osteoporosis. Hypercalciuric patients were younger, had lower lumbar BMD, higher urinary calcium and greater incidence of lithiasis than normocalciuric patients with idiopathic osteoporosis. Back pain, frequently associated with vertebral fractures, was the most common cause of referral in all groups of patients. CONCLUSION: Idiopathic osteoporosis is the most frequent cause of male osteoporosis in this study. In these patients, family history of osteoporosis and associated hypercalciuria are frequent. The most frequent causes of secondary osteoporosis in males include corticosteroid therapy, hypogonadism and alcoholism. Although clinical characteristics of male osteoporosis are similar to that previously reported, in this study the percentage of patients with idiopathic osteoporosis was higher than previously observed.

Idiopathic osteoporosis in premenopausal women. Clinical characteristics and bone remodelling abnormalities.

OBJECTIVE: Osteoporosis is infrequent in young premenopausal women and is often associated with secondary disorders. However, idiopathic osteoporosis may be found in this setting and few data are known on this condition. Therefore, the aim of this study was to analyse the clinical characteristics and bone remodelling abnormalities in premenopausal women with idiopathic osteoporosis. METHODS: 28 premenopausal women with idiopathic osteoporosis (aged 38.3+/-7.6 years) were included. The patients had one or more fragility fractures and/or decreased bone mass (z-score <-2 in the lumbar spine or femur). In all patients, secondary causes of osteoporosis were excluded and previous skeletal fractures, family history and risk factors for osteoporosis were recorded. In addition, bone mineral density at the lumbar spine and hip, spinal x-rays, and laboratory tests including PTH, 25-hydroxyvitamin D, 1,25 (OH)2 vitamin D and urinary calcium excretion were measured. Bone markers such as serum bone alkaline phosphatase (bone AP) and P1NP, and urinary hydroxyproline (HYP), NTx and CTx were measured and results were compared with those observed in a control group of 28 healthy premenopausal women. RESULTS: 46% of the patients had previous fragility fractures, 53% had family history of osteoporosis, 36% had associated hypercalciuria and 30% had a BMI <20 Kg/m2. Patients with idiopathic osteoporosis had increased bone resorption markers (NTx and HYP) but normal bone formation markers when compared with healthy controls. No significant differences in the clinical and biochemical parameters were observed between patients with or without hypercalciuria. CONCLUSION: Young women with idiopathic osteoporosis have an increased bone resorption without changes in bone formation when assessed by biochemical markers.

Long-lasting subclinical Addison's disease.

OBJECTIVE: To report a patient with autoimmune adrenal disease and increased ACTH with longstanding hyperpigmentation as an isolated symptom. METHODS: A 49-year-old woman requested a diagnostic work-up for hyperpigmentation initiated 9 years before, associated with increased ACTH. She was receiving replacement therapy for autoimmune hypothyroidism. Basal and dynamic tests of glucocorticoid axis, basal investigation of mineralocorticoid axis and measurement of organ specific autoantibodies were performed. RESULTS: Plasma ACTH (143 pmol/l; normal <13.2 pmol/l) and antibodies against 21-hydroxylase (115 UI/ml; normal <1) were remarkably high, thyroid peroxidase and parietal cell antibodies were positive at low titer and all additional tests were normal. CONCLUSION: Autoimmune adrenal disease can have a very long preclinical period even with high concomitant ACTH and specific antibody titers.

Immunocytochemical evidence on the effects of glucocorticoids on type I collagen synthesis in human osteoblastic cells.

The effects of glucocorticoids on DNA synthesis and cellular function were assessed in cultures of human osteoblastic cells by using indirect immunoperoxidase staining with a type I antiprocollagen antibody and by measuring procollagen type I N and C propeptides (PINP, PICP) in the culture medium by radiometric methods. Likewise, we analyzed the correlation between intracellular immunostaining and procollagen propeptides released into the culture medium, as well as the correlation between PINP and PICP. Human osteoblasts were cultured with and without addition of dexamethasone (DEX) at two supraphysiological concentrations, 10(-6) M and 10(-7) M, for 24 and 48 h. Treatment with DEX at 10(-6) M was associated with a significant decrease in the percentage of cells showing intracellular type I procollagen immunoreactivity at 24 and 48 h ( P < 0.05). Similar effects were observed with 10(-7) M DEX. Dexamethasone 10(-6) M and 10(-7) M also induced significant decreases in PINP and PICP values after 24 and 48 h of treatment ( P < 0.05). The decrease in intracellular procollagen immunoreactivity and propeptide secretion was not associated with a reduction in DNA synthesis. A highly significant correlation was observed between the values of PINP and PICP in the culture medium as well as between the values of intracellular immunostaining and PINP and PICP ( P < 0.001). In conclusion, our results suggest that supraphysiological doses of glucocorticoids produce a direct inhibition on osteoblastic function through their effect on type I procollagen synthesis. Immunoperoxidase detection of type I intracellular procollagen as well as the quantification of PINP and PICP in the culture medium are reliable methods of assessing osteoblast function.

Pregnancy associated osteoporosis: the familial effect.

OBJECTIVE: The etiology and pathogenesis of pregnancy associated osteoporosis is unclear. Whether pregnancy has simply been an aggravating factor or is a direct etiologic cause responsible for severe bone loss needs to be elucidated. METHODS: In order to evaluate the contribution of familial factors to pregnancy osteoporosis, we analyzed the bone mass of 15 relatives of 5 women with pregnancy osteoporosis. Most of the patients suffered from severe back pain associated with vertebral fractures in their first pregnancy. Extensive clinical, laboratory and radiological investigations were performed to exclude secondary causes of osteoporosis. Bone mineral density measurements were performed on 15 first order family members and the results were compared with those of a control group of 20 healthy members of 5 families. RESULTS: Osteoporosis was present in 53% of the relatives of patients with pregnancy osteoporosis and in 15% of the controls (P < 0.05). CONCLUSION: These results highly suggest that some patients with pregnancy associated osteoporosis have a genetic determination of low peak bone mass, and gestation, due to its association with physiological metabolic disturbances, constitutes a risk factor for the development of skeletal fractures in these patients.

Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives.

OBJECTIVE: To evaluate whether decreasing doses of ethinyl estradiol affect bone loss related to hypothalamic amenorrhea. STUDY DESIGN: Sixty-four women with hypothalamic oligoamenorrhea were allocated to two therapy groups: group A (n = 24) received an OC containing 0.030 mg of ethinyl estradiol (EE) and 0.15 mg of desogestrel. Group B (n = 22) received an OC containing 0.020 mg of EE and 0.15 mg of desogestrel. Eighteen women who did not wish to use hormonal therapy constituted the control group (C). Calcium, phosphate and osteocalcin were measured basally and at 6 and 12 months of follow-up. Bone mineral density at the lumbar spine was determined before initiation of the study and at 12 months by dual energy X-ray absorptiometry. RESULTS: Serum calcium, phosphate and osteocalcin were significantly reduced by both active treatment regimens, whereas no differences were observed in the control group. Bone mineral density at 12 months showed an increase in both therapy groups (A, 2.4%; B, 2.5%), while group C showed a significant decrease (1.2%, P < .05). CONCLUSION: Both doses of EE were equally effective in preventing bone loss related to hypoestrogenism in hypothalamic oligoamenorrheic subjects.

Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics.

After liver transplantation there is a high incidence of fractures, with important rates of bone loss during the first months. However, the long-term evolution of bone mass and metabolism parameters have been scarcely studied. In order to determine the incidence and risk factors involved in the development of skeletal fractures and to analyze the long-term evolution of bone mass, bone turnover and hormonal status after liver transplantation, a 3-year prospective study was performed in 45 patients following liver transplantation. Serum osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH D) and testosterone levels (men), and bone mass at the lumbar spine and femur were measured before and sequentially at different time points during 3 years. Spinal X-rays were obtained during the first year. Histomorphometric analysis of bone biopsies obtained in 24 patients within the first 12 hours after surgery and 6 months after transplantation was performed. Fifteen patients (33%) developed fractures after liver transplantation, and pre-transplant risk factors for fractures were age and low bone mass (odd's ratio for osteoporosis, 95% confidence interval: 5.69, 1.32-24.53). Serum PTH, osteocalcin, 25-OH D, testosterone and creatinine levels increased after transplantation. Moreover, PTH correlated with creatinine and osteocalcin values. Bone mass decreased during the first 6 months and reached baseline values at the lumbar spine the second year, with posterior significant recovery at the femoral neck. Long term evolution of femoral neck BMD correlated with PTH levels. Six months after transplantation bone histomorphometric data showed an increase in bone formation parameters. After liver transplantation there is a high incidence of fractures, specially in elderly patients and those with osteoporosis. Bone mass decreased in the short-term period and improved, initially at the lumbar spine and later at the femur, according to histomorphometric evidences of an increase in bone formation. The increase in creatinine values induces a secondary hyperparathyroidism that influences the changes in femoral bone mass. Treatment of osteoporosis shortly after liver transplantation may be important in the prevention of bone fractures, particularly in patients with low bone mass.

Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A.

The purpose of this study was to compare the effects of Cyclosporine A (CyA) and FK506 on bone mass and mineral metabolism in liver transplantation (LT) patients. A prospective study was performed on 18 male patients who underwent LT treated with CyA, and 7 LT patients who received FK506. Bone mineral density (BMD) of the lumbar spine and proximal femur (DPX-L) was measured before and at 6, 12, and 24 months after transplantation. Moreover, intact parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) levels were determined at the same time. The cumulative dose of glucocorticoids was calculated in all patients. At 6 months, lumbar BMD decreased 5.2 +/- 1.2% (P = 0.0005) and 2.9 +/- 2.1% (p = ns) in CyA and FK506 groups, respectively. Lumbar BMD reached baseline values at 1 year in the FK506 group and 2 years after LT in the CyA group. Moreover, significant intergroup differences in femoral neck BMD changes after 2 years of transplant were observed (CyA: -5.2 +/- 1.97 versus FK506: +1.55 +/- 2.2%; P = 0.039). In the first year posttransplant both groups showed a marked increase in PTH and 25OHD levels. The mean cumulative dose of glucocorticoids was higher in the CyA group (CyA group 11.06 +/- 0.46 g versus FK 506 group 6.71 +/- 0.42 g; P < 0.001), and multiple linear regression analysis showed a negative correlation between BMD changes at the lumbar spine and mean cumulative dose of glucocorticoids (P = 0.022). In conclusion, our data suggest that after liver transplantation treatment with FK506 shows a more favorable long-term effect on bone mass evolution than CyA therapy. These differences seem to be associated with the lower dose of glucocorticoids used in the FK506 group.

Collagen type Ialpha1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis.

The potential influence of two gene polymorphisms, vitamin D receptor gene (VDR) and the gene encoding collagen type Ialpha1 (COLIA1) Sp1 polymorphisms, in the reduced bone mass observed in patients with primary biliary cirrhosis (PBC) was assessed in 61 women with PBC (age, 54.1 +/- 1.1 years) by restriction enzyme digestion of polymerase chain reaction (PCR)-amplified DNA extracted from whole blood. Bone mineral density (BMD) of the lumbar spine (L2-L4) and proximal femur were measured by X-ray absorptiometry. The severity of liver disease and cholestasis was also evaluated, and changes in BMD were calculated after a mean period of 2.9 +/- 0.3 years in 41 patients. Sixteen patients (26 %) had the BB, 20 the bb (33 %), and 25 Bb (41%) VDR genotypes. There were no significant baseline BMD differences among the 3 VDR genotypes. Forty-one patients (68%) had the SS, 16 the Ss (27%), and 3 the ss (5%) COLIA1 genotypes. The baseline lumbar BMD was significantly lower in patients having the s allele than in the homozygote SS patients (Z-score, -0.76 +/- 0.24 vs. -0.10 +/- 0.17, P =.02). The severity of cholestasis was not related to the VDR or COLIA1 1 polymorphisms. Lumbar bone loss was independent of VDR and COLIA1 genotypes, but it was associated with cholestasis. In conclusion, the COLIA1 but not VDR polymorphism is a genetic marker of peak bone mass in patients with PBC, although the severity of cholestasis is the main factor for osteoporosis since it is associated with the rate of bone loss.

Collagen type Ialpha1 gene polymorphism in idiopathic osteoporosis in men.

OBJECTIVE: To analyse the distribution of polymorphism of the collagen type Ialpha1 gene (COL1A1) and its relationship with bone metabolism and bone turnover in men with idiopathic osteoporosis. METHODS: A total of 35 male patients with idiopathic osteoporosis, aged 50.4 +/- 10.3 yr, and 60 healthy males (controls), aged 47 +/- 17 yr, were included in the study. Serum osteocalcin, 25-hydroxyvitamin D and parathyroid hormone were determined in all patients. The COL1A1 Sp1 genotypes (SS, SS:, ss) were assessed by restriction enzyme digestion (BAL:1) of DNA amplified by the polymerase chain reaction. RESULTS: Patients with idiopathic osteoporosis had a higher frequency of the s allele than men in the control group (29 vs 11%, P: = 0.003) and a higher frequency of the SS: genotype (patients, 48% SS, 46% SS:, 6% ss; controls, 80% SS, 18% SS:, 2% ss; P: = 0.003). No significant differences between genotypes were observed in serum concentrations of osteocalcin, vitamin D or parathyroid hormone among either the patients or the controls. CONCLUSION: This study suggests that, in men with idiopathic osteoporosis, there is a high prevalence of the s allele and the SS: genotype that is unrelated to other parameters of bone metabolism.

Serum inhibin B determination is predictive of successful testicular sperm extraction in men with non-obstructive azoospermia.

Recent work indicates that serum inhibin B is a useful marker of spermatogenesis and inhibin B production sufficient to maintain detectable serum concentrations in adults depends on spermatogenic activity. The purpose of the present study was to investigate the usefulness of serum inhibin B measurement to predict the success of testicular sperm extraction (TESE) in 17 men with nonobstructive azoospermia to be treated by intracytoplasmic sperm injection (ICSI) (group 1). Two additional groups were used as positive controls; group 2 comprised 22 infertile men having obstructive azoospermia, and group 3, which included 29 semen donors having normal seminal parameters. Follicle stimulating hormone (FSH) was significantly higher (P < 0.01) and inhibin B significantly lower (P < 0.001), in group 1 as compared with groups 2 and 3. Serum inhibin B concentrations were significantly higher (P < 0.001) among successful TESE men as compared with those having failed TESE. In contrast, no differences were detected between these two groups with respect to serum FSH or testicular size. In addition, serum inhibin B but not FSH discriminated between successful and failed TESE in group 1 subjects as compared with control groups. According to the receiver operating characteristics curve analysis, the best inhibin B value for discriminating between successful and failed TESE was >40 pg/ml (sensitivity 90%, specificity 100%). It is concluded that inhibin B measurement is a useful non-invasive predictor of spermatogenesis and thus, all azoospermic males should have serum inhibin B concentrations determined in addition to FSH measurement and karyotyping prior to undergoing TESE.

Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women.

BACKGROUND: The main goals of estrogen replacement therapy (ERT) are the prevention of osteoporosis and cardioprotection and the improvement of quality of life (QL). Androgens and tibolone therapy may increase bone mineral density (BMD) to a greater extent than ERT and offer an increase in QL. Lipid and cardiovascular effects, however, are still a major concern. AIM: To evaluate whether the addition of a weak androgen to ERT may improve postmenopausal bone loss and sexual activity without adverse effects on lipid pattern and to compare these effects with those observed after tibolone therapy. SUBJECTS AND METHODS: This prospective study enrolled 120 surgical postmenopausal women; of these, 96 completed the 1-year follow-up. Patients were allocated to one of four groups. The first group (A; n = 23) received 4 mg of estradiol valerate plus 200 mg of enanthate of dihydroandrosterone im monthly. The second group (E; n = 26) received 50 microg/day of transdermal 17-b-estradiol continuously; the third (T; n = 23) received 2.5 mg of tibolone every day; and finally, the fourth group (C; n = 24) constituted a treatment-free control group. Bone mass (dual X-ray absorptiometry), serum total cholesterol, HDL, LDL, triglycerides, apolipoproteins A1 and B and sexual activity were evaluated before starting therapy and at the end of follow-up. RESULTS: All active treatment groups showed an increase in BMD. This increase was higher in the A treatment group (4.08% P < 0.01). Sexuality improved significantly with therapy; however, tibolone and androgens increased scores to a greater extent than ERT. Androgen therapy was associated with significant increases in total cholesterol, LDL and triglycerides. Cholesterol and LDL fall into groups E and T, HDL into groups A and T and triglycerides in group T only. CONCLUSION: The combined regimen of androgens and ERT increased vertebral bone mass and enhance sexual activity in postmenopausal women equal to that of tibolone and to a greater extent than ERT alone; its effects on lipids, however, are clearly adverse.

Long-term compliance with estrogen replacement therapy in surgical postmenopausal women: benefits to bone and analysis of factors associated with discontinuation.

OBJECTIVE: To evaluate prospectively the effects of long-term estrogen replacement therapy (ERT) on bone density in surgical postmenopausal women treated for 5 years with two different modalities and to determine the factors associated with discontinuation of ERT. DESIGN: We included in the present study 165 women (mean age, 46.8 +/- 4.6 years) who had undergone surgical menopause. ERT was prescribed immediately after surgery, and bone mineral density was measured at the lumbar spine before the women entered the study and at 12, 24, 36, 48, and 60 months after being included. Treated patients were assigned at random to one of two groups. The first group received conjugated equine estrogens 0.625 mg/day continuously, and the second group received transdermal 17beta-estradiol 50 mg/day continuously. Treated groups were compared with a nontreated control group. RESULTS: Our data showed that although ERT clearly protected against bone loss in women who had experienced surgical menopause, only one third of the treated patients continued ERT at the end of follow-up. The main reason for discontinuation was fear of cancer (36.1 % of cases). In addition, no differences were observed between oral and transdermal groups of treatment. CONCLUSIONS: Long-term ERT may have a protective effect against bone loss in surgically postmenopausal women; however, two thirds of treated patients discontinued therapy after 5 years and 43% of them presented a negative balance on bone mass in one or more bone density assessments. For this reason, enhancing compliance and monitoring treatment are mandatory.