The Third/Second Generation PTH Assay Ratio as a Marker for Parathyroid Carcinoma: Evaluation Using an Automated Platform
CAVALIER, Etienne ; BETEA, Daniela ; SCHLECK, Marie-Louise et al
in Journal of Clinical Endocrinology and Metabolism (in press)
Background: Parathyroid carcinoma (PCa) is rare and often difficult to differentiate initially from benign disease. Because PCa oversecretes amino PTH that is detected by third-generation but not by ... [more ▼]
Background: Parathyroid carcinoma (PCa) is rare and often difficult to differentiate initially from benign disease. Because PCa oversecretes amino PTH that is detected by third-generation but not by second-generation PTH assays, the normal generation PTH ( 1) is inverted in PCa (ie, 1). Objective: The objective of the investigation was to study the utility and advantages of automated generation PTH ratio measurements using the Liaison XL platform over existing manual techniques. Setting: The study was conducted at a tertiary-referral academic center. Design: This was a retrospective laboratory study. Subjects: Eleven patients with advanced PCa (mean age 56.0 y). The controls were patients with 1°-hyperparathyroidism (n 144;meanage 53.8 y), renal transplantation (n 41;meanage 50.6 y), hemodialysis (n 80; mean age 65.2 y), and healthy elderly subjects (n 40; mean age 72.6 y). Results: The median (interquartile range) generation PTH ratio was 1.16 (1.10 –1.38) in the PCa group, which was significantly higher than the control groups: 0.74 (hemodialysis, 0.71–0.75), 0.77 (renal transplant, 0.73–0.79), 0.80 (healthy elderly, 0.74–0.83), and 0.76 (1°-hyperparathyroidism, 0.74–0.78). An inverted -generation PTH ratio ( 1) was seen in 9 of 11 PCa patients (81.8%) and in 7 of 305 controls (2.3%), 3 of 80 hemodialysis (3.8%), and 4 of 144 1°-hyperparathyroidism patients (2.8%). Of four PCa patients who had a normal PTH ratio with the manual method, two had an inverted -generation PTH ratio with the automated method. Conclusions: Study of the -generation PTH ratio in large patient populations should be feasible using a mainstream automated platform like the Liaison XL. The current study confirms the utility of the inverted -generation PTH ratio as a marker of PCa (sensitivity: 81.8%; specificity: 97.3%). [less ▲]Detailed reference viewed: 37 (9 ULg)
Means, Motive, and Opportunity: SDH Mutations Are Suspects in Pituitary Tumors.
in Journal of Clinical Endocrinology and Metabolism (2013), 98(6), 2274-6Detailed reference viewed: 35 (18 ULg)
Expression of type 2 orexin receptor in human endometrium and its epigenetic silencing in endometrial cancer.
Dehan, Pierre ; ; et al
in Journal of Clinical Endocrinology and Metabolism (2013), 98(4), 1549-57
CONTEXT: Orexins A and B are neuropeptides that bind and activate 2 types of receptors. In addition to direct action in the brain, the orexinergic system has broader implications in peripheral organs, and ... [more ▼]
CONTEXT: Orexins A and B are neuropeptides that bind and activate 2 types of receptors. In addition to direct action in the brain, the orexinergic system has broader implications in peripheral organs, and it has been proposed to have a role in the induction of apoptosis. There are very few data on the endometrium. OBJECTIVE: The expression and epigenetic regulation of type 2 orexin receptor (OX2R) was investigated in the human endometrium as well as in endometrial endometrioid carcinoma (EEC). METHODS: OX2R localization was studied by immunohistochemistry in normal endometrium (n = 24) and in EEC (n = 32). The DNA methylation status of a CpG island located in the first exon of OX2R was analyzed by bisulfite sequencing in normal (n = 18), EEC (n = 34), and 3 endometrial cell lines. On the latter, mRNA expression and Western blotting as well as in vitro induction with orexin were performed. RESULTS: Expression of the OX2R protein was detected in normal endometrial epithelia, whereas it was frequently lacking in EEC. This loss was associated with hypermethylation of OX2R in EEC in comparison with normal endometrium (median CpG methylation percentages of 48.85% and 5.85%, respectively). In cell lines, hypermethylation correlated with weak OX2R expression. Additionally, in vitro treatment of the 3 EEC cell lines with orexins A and B did not result in proliferation change CONCLUSIONS: Altogether our data provide evidence for the epigenetic silencing of OX2R in EEC. The implication of the OX2R loss in tumoral progression remains to be elucidated. [less ▲]Detailed reference viewed: 2 (1 ULg)
Sex differences in the neurokinin B system in the human infundibular nucleus.
Taziaux, Mélanie ; ; Bakker, Julie
in Journal of Clinical Endocrinology and Metabolism (2012), 97(12), 2210-20
CONTEXT: The recent report that loss-of-function mutations in either the gene encoding neurokinin B (NKB) or its receptor (NK3R) produce gonadotropin deficiencies in humans strongly points to NKB as a key ... [more ▼]
CONTEXT: The recent report that loss-of-function mutations in either the gene encoding neurokinin B (NKB) or its receptor (NK3R) produce gonadotropin deficiencies in humans strongly points to NKB as a key regulator of GnRH release. OBJECTIVES: We used NKB immunohistochemistry on postmortem human brain tissue to determine: 1) whether the human NKB system in the infundibular nucleus (INF) is sexually dimorphic; 2) at what stage in development the infundibular NKB system would diverge between men and women; 3) whether this putative structural difference is reversed in male-to-female (MtF) transsexual people; and 4) whether menopause is accompanied by changes in infundibular NKB immunoreactivity. METHODS: NKB immunohistochemical staining was performed on postmortem hypothalamus material of both sexes from the infant/pubertal period into the elderly period and from MtF transsexuals. RESULTS: Quantitative analysis demonstrated that the human NKB system exhibits a robust female-dominant sexual dimorphism in the INF. During the first years after birth, both sexes displayed a moderate and equivalent level of NKB immunoreactivity in the INF. The adult features emerged progressively around puberty until adulthood, where the female-dominant sex difference appeared and continued into old age. In MtF transsexuals, a female-typical NKB immunoreactivity was observed. Finally, in postmenopausal women, there was a significant increase in NKB immunoreactivity compared to premenopausal women. CONCLUSION: Our results indicate that certain sex differences do not emerge until adulthood when activated by sex steroid hormones and the likely involvement of the human infundibular NKB system in the negative and positive feedback of estrogen on GnRH secretion. [less ▲]Detailed reference viewed: 15 (0 ULg)
A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density
; ; et al
in Journal of Clinical Endocrinology and Metabolism (2012), 97(9), 3161-3169
Context: Men with low bone mineral density (BMD) were treated with denosumab. Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of ... [more ▼]
Context: Men with low bone mineral density (BMD) were treated with denosumab. Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P≥0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed. Copyright © 2012 by The Endocrine Society. [less ▲]Detailed reference viewed: 10 (1 ULg)
Pituitary incidentaloma : An Endocrine Society Clinical Practice Guideline
; Beckers, Albert ; et al
in Journal of Clinical Endocrinology and Metabolism (2011)Detailed reference viewed: 145 (7 ULg)
Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism
; ; et al
in Journal of Clinical Endocrinology and Metabolism (2011), 96(7), 1171-1180Detailed reference viewed: 13 (1 ULg)
The Ratio of Parathyroid Hormone as Measured by Third- and Second-Generation Assays as a Marker for Parathyroid Carcinoma.
Cavalier, Etienne ; Daly, Adrian ; Betea, Daniela et al
in Journal of Clinical Endocrinology and Metabolism (2010), 95
Background: Parathyroid carcinoma (PCa) is a rare disease that can be difficult to differentiate initially from severe benign parathyroid adenoma. PCa oversecrete the amino form of PTH, which is ... [more ▼]
Background: Parathyroid carcinoma (PCa) is a rare disease that can be difficult to differentiate initially from severe benign parathyroid adenoma. PCa oversecrete the amino form of PTH, which is recognized by third-generation but not by second-generation PTH immunoassays. In normal individuals, the third-generation to second-generation PTH ratio should be less than 1. Objective: Our objective was to study the utility of the third-generation to second-generation PTH ratio as a means of distinguishing PCa patients (n = 24) from control groups with and without disorders of calcium secretion, including patients on renal hemodialysis (n = 74), postrenal transplantation (n = 60), and primary hyperparathyroidism (PHP; n = 30). Setting and Design: We conducted a retrospective, laboratory-based study at tertiary referral academic centers. Results: The mean third-generation to second-generation ratio was 0.58 ± 0.10 in the dialysis patients, 0.54 ± 0.10 in the renal transplant group, 0.54 ± 0.12 in the elderly healthy patients, and 0.68 ± 0.11 in the PHP group. All 245 of these patients presented a PTH third-generation to second-generation ratio of less than 1. In contrast, we observed an inverted third-generation to second-generation PTH ratio of more than one in 20 PCa patients, whereas only four PCa patients had a normal ratio of less than 1. Conclusions: An inverted third-generation to second-generation PTH ratio occurred in the majority of patients with advanced PCa and was absent in all 245 relevant controls. A third-generation to second-generation PTH ratio higher than 1 had a sensitivity of 83.3% and a specificity of 100% among PHP patients as a marker for PCa. This ratio may be useful to identify patients with PCa earlier and to detect patients either at risk of developing PCa or those in whom recurrence is taking place. [less ▲]Detailed reference viewed: 56 (9 ULg)
TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans.
; ; et al
in Journal of Clinical Endocrinology and Metabolism (2010), 95(5), 2287-95
CONTEXT: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic ... [more ▼]
CONTEXT: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis. OBJECTIVE: The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH. RESULTS: We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patients we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject. CONCLUSION: Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans. [less ▲]Detailed reference viewed: 17 (0 ULg)
Improved molecular diagnostics of idiopathic short stature and allied disorders: quantitative polymerase chain reaction-based copy number profiling of SHOX and pseudoautosomal region 1.
; ; et al
in Journal of Clinical Endocrinology and Metabolism (2010), 95(6), 3010-8
CONTEXT: Short stature has an incidence of three in 100 in children. Reliable molecular genetic testing may be crucial in the context of beneficial disease management. Deletions spanning or surrounding ... [more ▼]
CONTEXT: Short stature has an incidence of three in 100 in children. Reliable molecular genetic testing may be crucial in the context of beneficial disease management. Deletions spanning or surrounding the SHOX gene account for a significant proportion of patients with idiopathic short stature (ISS) and allied disorders, such as Leri-Weill dyschondrosteosis. OBJECTIVE: Several shortcomings of current strategies for copy number profiling of the SHOX region prompted us to develop an improved test for molecular diagnostics of the SHOX region. DESIGN AND RESULTS: We introduced a quantitative PCR (qPCR)-based copy number profiling test, consisting of 11 amplicons targeting clinically relevant regions, i.e. the SHOX gene and regulatory regions. To ensure an optimal sensitivity and specificity, this test was validated in 32 controls and 18 probands with previously identified copy number changes. In addition, 152 probands with SHOX-associated phenotypes were screened, revealing 10 novel copy number changes. CONCLUSION: This highly validated qPCR test supersedes other approaches for copy number screening of the SHOX region in terms of reliability, accuracy, and cost efficiency. In addition, another strong point is the fact that it can be easily implemented in any standard equipped molecular laboratory. Our qPCR-based test is highly recommended for molecular diagnostics of idiopathic short stature and allied disorders. [less ▲]Detailed reference viewed: 15 (5 ULg)
Pioglitazone Use in Combination with Insulin in the Prospective Pioglitazone Clinical Trial in Macrovascular Events Study (PROactive19).
; ; et al
in Journal of Clinical Endocrinology and Metabolism (2010)
Objective: In this post hoc analysis, we examined insulin requirements and regimens, glycemic control, cardiovascular outcomes, and safety in the patients treated with insulin at baseline in the ... [more ▼]
Objective: In this post hoc analysis, we examined insulin requirements and regimens, glycemic control, cardiovascular outcomes, and safety in the patients treated with insulin at baseline in the Prospective Pioglitazone Clinical Trial in Macrovascular Events study. Design: The Prospective Pioglitazone Clinical Trial in Macrovascular Events study was a double-blind, placebo-controlled outcome study (mean follow-up 34.5 months) in 5238 high-risk patients with type 2 diabetes randomized to pioglitazone (force titrated to 45 mg) or placebo. One third of the total population (pioglitazone 864; placebo 896) were receiving insulin at baseline. Results: A rapid and sustained decrease in insulin dose was observed with pioglitazone vs. a progressive increase with placebo. By study end, the mean insulin dose was lower with pioglitazone (42 vs. 55 U/d with placebo; P < 0.0001). The insulin regimen (number on insulin, need for multiple injections, and reduction in oral agents) had been simplified vs. placebo; nevertheless, a greater glycosylated hemoglobin reduction was observed with pioglitazone (-0.93%) vs. placebo (-0.45%; P < 0.0001). At the final visit, insulin had been discontinued in 9% of pioglitazone vs. 2% of placebo patients (P < 0.0001). More insulin-resistant patients (defined as poorly controlled type 2 diabetes despite high doses of insulin) in the pioglitazone plus insulin group showed the greatest glycosylated hemoglobin decline. There were nonsignificant reductions with pioglitazone relative to placebo in the cardiovascular primary (hazard ratio 0.86; 95% confidence interval 0.71, 1.04; P = 0.1198) and main secondary (hazard ratio 0.85; 95% confidence interval 0.67, 1.08; P = 0.1831) end points in insulin-treated patients. The rates of overall heart failure, edema, and hypoglycemia were higher with pioglitazone [13.5 vs 10.5% (P = 0.0489); 30.8 vs. 18.2% (P < 0.0001); and 42.1 vs 29.0% (P < 0.0001), respectively], but there were no significant differences in serious events. Conclusions: Pioglitazone use in combination with insulin resulted in a sustained improved glycemic control and allowed the treatment regimens to be simplified and the insulin doses reduced. [less ▲]Detailed reference viewed: 11 (0 ULg)
Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study
Daly, Adrian ; ; Petrossians, Patrick et al
in Journal of Clinical Endocrinology and Metabolism (2010), 95(11),
Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features ... [more ▼]
Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. <br />Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. <br />Design: This study was an international, multicenter, retrospective case collection/database analysis. <br />Setting: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. <br />Patients: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. <br />Results: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. <br />Conclusions: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility. [less ▲]Detailed reference viewed: 108 (48 ULg)
A coherent organization of differentiation proteins is required to maintain an appropriate thyroid function in the Pendred thyroid.
; ; et al
in Journal of Clinical Endocrinology and Metabolism (2010), 95(8), 4021-30
CONTEXT: Pendred syndrome is caused by mutations in the gene coding for pendrin, an apical Cl-/I- exchanger. OBJECTIVE: To analyze intrathyroidal compensatory mechanisms when pendrin is lacking, we ... [more ▼]
CONTEXT: Pendred syndrome is caused by mutations in the gene coding for pendrin, an apical Cl-/I- exchanger. OBJECTIVE: To analyze intrathyroidal compensatory mechanisms when pendrin is lacking, we investigated the thyroid of a patient with Pendred syndrome. The expression of proteins involved in thyroid hormone synthesis, markers of oxidative stress (OS), cell proliferation, apoptosis, and antioxidant enzymes were analyzed. RESULTS: Three morphological zones were identified: nearly normal follicles with iodine-rich thyroglobulin in the colloid (zone 1.a), small follicles without iodine-rich thyroglobulin in lumina (zone 1.b), and destroyed follicles (zone 2). In zones 1.a, dual oxidase (Duox) and thyroid peroxidase (TPO) were localized at the apical pole, OS and cell apoptosis were absent, but ClC-5 expression was strongly increased. In zones 1.b, Duox and TPO were aberrantly present and increased in the cytosol and associated with high OS, apoptosis, cell proliferation, and increased expression of peroxiredoxin-5, catalase, and dehalogenase-1 but moderate ClC-5 expression. CONCLUSION: In conclusion, the absence of pendrin is accompanied by increased ClC-5 expression that may transiently compensate for apical iodide efflux. In more affected follicles, Duox and TPO are relocated in the cytosol, leading to abnormal intracellular thyroid hormone synthesis, which results in cell destruction presumably because intracellular OS cannot be buffered by antioxidant defenses. [less ▲]Detailed reference viewed: 17 (2 ULg)
Testicular effects of isolated luteinizing hormone deficiency and reversal by long-term human chorionic gonadotropin treatment.
Valdes Socin, Hernan Gonzalo ; ; Thiry, Albert et al
in Journal of Clinical Endocrinology and Metabolism (2009), 94(1), 3-4Detailed reference viewed: 11 (4 ULg)
Chorionic Gonadotropin Stimulation of Angiogenesis and Pericyte Recruitment
; Blacher, Silvia ; PERRIER d'HAUTERIVE, Sophie et al
in Journal of Clinical Endocrinology and Metabolism (2009), 94(11), 4567-74
During the periimplantation period, human chorionic gonadotropin (hCG) plays a key role by increasing the uterine blood flow through uterine vessel vasodilatation but also through angiogenesis. Indeed, we ... [more ▼]
During the periimplantation period, human chorionic gonadotropin (hCG) plays a key role by increasing the uterine blood flow through uterine vessel vasodilatation but also through angiogenesis. Indeed, we previously demonstrated that hCG contributes to endothelial cell recruitment and vessel formation. OBJECTIVE: In this study, hCG was proposed as an arteriogenic factor that could promote perivascular cell recruitment and vessel stabilization. DESIGN: The aortic ring assay, a three-dimensional ex vivo angiogenesis system mimicking all the steps of the angiogenesis process was used to study the impact of hCG on pericyte recruitment and vessel maturation. SETTING: The study was conducted at a university hospital laboratory. MAIN OUTCOME MEASURES: Perivascular cell proliferation, migration, and apposition were quantified by computerized image analysis. RESULTS: Physiological concentrations of hCG (10-400 IU/ml) significantly enhanced pericyte sprouting and migration and gave rise to the maturation and coverage of endothelial capillaries. In a three-dimensional coculture model of endothelial and perivascular cells, hCG enhanced vessel tube formation and endothelial/mural cell adhesion. In addition, hCG stimulated the proliferation of human umbilical vein endothelial cells and smooth muscle cells. The specificity of these effects was determined by using an anti-hCG blocking antibody. Signaling pathways implicated on this hCG effect is protein kinase A and phospholipase C/protein kinase C dependent for the proliferative effect but only phospholipase C/protein kinase C for the migrative process. CONCLUSIONS: Our findings highlight a novel paracrine role of this early embryonic signal in vessel maturation by stimulating perivascular cell recruitment, migration, and proliferation. [less ▲]Detailed reference viewed: 112 (23 ULg)
Does preoperative somatostatin analog treatment improve surgical cure rates in acromegaly? A new look at an old question.
in Journal of Clinical Endocrinology and Metabolism (2008), 93(8), 2975-2977Detailed reference viewed: 16 (3 ULg)
Persistence of an intact endometrial matrix and vessels structure in women exposed to VA-2914, a selective progesterone receptor modulator.
Ravet, Stéphanie ; Munaut, Carine ; Blacher, Silvia et al
in Journal of Clinical Endocrinology and Metabolism (2008), 93(11), 4525-31
Background: VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity that induces amenorrhea, whereas progestins cause endometrial spotting and bleeding. This abnormal ... [more ▼]
Background: VA-2914 is a selective progesterone receptor modulator with potential contraceptive activity that induces amenorrhea, whereas progestins cause endometrial spotting and bleeding. This abnormal bleeding due to progestins is a consequence of focal stromal proteolysis by an increase in naked vessel size and density. Objective: Our objective was to quantify the effects of VA-2914 on endometrial vascularization, fibrillar matrix, and vascular endothelial growth factor (VEGF)-A expression in endometrial biopsies from 41 women before and after 12 wk daily treatment with a placebo, or 2.5, 5, or 10 mg VA-2914. Methods: Collagen fibrillar network was stained by silver impregnation. Vessel area, density, and structure were quantified with a computer-assisted image analysis system after double immunostaining using an anti-von Willebrand factor (endothelial cells) and an anti- smooth muscle actin (vascular smooth muscle cells) marker antibody. VEGF-A mRNAs were quantified by RT-PCR and localized by immunohistochemistry. Results: The endometrial vessels, collagen network, and mRNA levels of VEGF-A were identical during the luteal phase at baseline and in VA-2914 treated women. VEGF-A distribution was unchanged. Conclusions: VA-2914 does not alter the endometrial matrix and cells, and does not modify the endometrial vessel morphology as compared with baseline biopsies. [less ▲]Detailed reference viewed: 29 (2 ULg)
Impaired iodide organification in autonomous thyroid nodules
; ; Seret, Alain et al
in Journal of Clinical Endocrinology and Metabolism (2007), 92(12), 4719-4724
Context: The clinical evolution of autonomous thyroid nodules (ATN) is unpredictable, and thyrotoxicosis is observed at variable nodule size. In vitro data suggest that hydrogen peroxide production is ... [more ▼]
Context: The clinical evolution of autonomous thyroid nodules (ATN) is unpredictable, and thyrotoxicosis is observed at variable nodule size. In vitro data suggest that hydrogen peroxide production is decreased in ATN, indicating intranodular iodide organification impairment. Objective: We aimed to determine iodide organification efficiency in ATN and its relationship with thyroid status in patients. Design: Forty-six patients with a single ATN on the I-123 thyroid scan were included in the study. Biological evaluation and iodine perchlorate (I-ClO4) discharge test were carried out in all subjects. Setting: The study took place at an academic hospital. Results: Among the 46 patients, 28 patients (61%) had a positive I-ClO4 discharge test with a mean +/- SD value of discharge of 42 +/- 13%, and 18 (39%) had a negative discharge test with mean +/- SD of 5 +/- 9%. In the group of patients with a negative discharge test but not in the group with a positive test, serum-free T-3 and free T-4 concentrations were significantly correlated with the I-123 uptake. The severity of hyperthyroidism was not different between both groups. Conclusions: Intranodular iodide organification was impaired in most patients with ATN. Whether differences in organification capability could predict the risk for evolution to overt hyperthyroidism in patients with ATN remains to be established. [less ▲]Detailed reference viewed: 76 (0 ULg)
Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate
Bruyère, Olivier ; ; Detilleux, Johann et al
in Journal of Clinical Endocrinology and Metabolism (2007), 92(8), 3076-3081
Objective: Our objective was to analyze the relationship between bone mineral density (BMD) changes and fracture incidence during 3-yr treatment with strontium ranelate. Patients: Women from the strontium ... [more ▼]
Objective: Our objective was to analyze the relationship between bone mineral density (BMD) changes and fracture incidence during 3-yr treatment with strontium ranelate. Patients: Women from the strontium ranelate arm of the Spinal Osteoporosis Therapeutic Intervention study and the TReatment Of Peripheral OSteoporosis study were evaluated. Outcome Measures: The outcome measures included BMD at the lumbar spine, femoral neck, and total proximal femur assessed at baseline and after a follow-up of 1 and 3 yr; semiquantitative visual assessment of vertebral fractures; and nonvertebral fractures based on written documentation. Results: After 3 yr of strontium ranelate treatment, each percentage point increase in femoral neck and total proximal femur BMD was associated with a 3%(95% adjusted confidence interval, 1-5%) and2% (1-4%) reduction in risk of a new vertebral fracture, respectively. The 3- yr changes in femoral neck and total proximal femur BMD explained 76% and 74%, respectively, of the reduction in vertebral fractures observed during the treatment. Three-year changes in spine BMD were not statistically associated with the incidence of new vertebral fracture (P = 0.10). No significant associations were found between 3- yr changes in BMD and incidence of new nonvertebral fractures, but a trend was found for femoral neck BMD (P = 0.09) and for total proximal femur BMD (P = 0.07). An increase in femoral neck BMD after 1 yr was significantly associated with the reduction in incidence of new vertebral fractures observed after 3 yr (P = 0.04). Conclusion: During 3-yr strontium ranelate treatment, an increase in femoral neck BMD was associated with a proportional reduction in vertebral fracture incidence. [less ▲]Detailed reference viewed: 47 (21 ULg)
Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.
Daly, Adrian ; Vanbellinghen, Jean-François ; et al
in Journal of Clinical Endocrinology and Metabolism (2007), 92(5), 1891-1896
CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess ... [more ▼]
CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA. [less ▲]Detailed reference viewed: 20 (2 ULg)