Female thyroid cancer : the role of reproductive and hormonal factors in Switzerland

We conducted a study on 91 women with thyroid cancer and 306 controls in hospital for acute nonneoplastic, non-hormone-related disorders in order to investigate the role of reproductive and hormonal factors in the etiology of epithelial thyroid cancer in the Canton of Vaud, Switzerland. Non-significant increases in cancer risk with an increasing number of full-term pregnancies (odds ratio, OR, after allowance for age and previous benign thyroid disease = 1.6, for > or = 3 vs. 0 full-term pregnancies, 95% confidence interval, CI: 0.7-3.6) and spontaneous abortions (OR = 2.0 for > or = 2 vs. 0 spontaneous abortions, 95% CI: 0.7-5.2) were seen. A significantly elevated OR (2.8, 95% CI: 1.1-7.2) was found in those women whose first pregnancy ended with an abortion. Whereas most other reproductive, menstrual and hormonal factors examined did not seem to affect the risk of thyroid cancer significantly, a clue emerged of an association between thyroid cancer and artificial menopause (OR = 6.3, for women who underwent artificial menopause vs. premenopausal women, 95% CI: 1.7-23.2). Although not necessarily causal, the relationship between the risk of epithelial thyroid cancer and the occurrence of spontaneous abortions and artificial menopause deserves attention in future studies, in the light of the high incidence of thyroid cancer in young and middle-aged women.

Lessons Learned from 15 Years of KIMS and 5 Years of ACROSTUDY.

Background: Pharmacoepidemiological surveys provide a valuable contribution to the continued monitoring of drug-related effects in patients with rare disorders. One of the earliest examples of this type of survey is KIGS (Pfizer International Growth Study Database), which has monitored the safety and effectiveness of growth hormone (GH) therapy in GH-deficient children since its inception in 1987. Following closely in the footsteps of KIGS is KIMS (Pfizer International Metabolic Database). As of 2009, KIMS has been collecting data on the long-term safety and clinical outcomes of GH replacement in GH-deficient adults for 15 years. Approximately 5 years ago, the ACROSTUDY database was established to monitor the long-term safety and effectiveness of pegvisomant in patients with acromegaly. Conclusions: By collecting data on the treatment of relatively rare conditions in routine clinical practice, pharmacoepidemiological surveys such as KIMS and ACROSTUDY provide valuable information on the safety and effectiveness of treatment with GH replacement and pegvisomant in the real world.

The effect of 17-B estradiol therapy on bone mineral density and structure of alveolar bone in the ovariectomized rat model of postmenopausal osteoporosis

The ovariectomized (OVX) rat, a preclinical model for studying postmenopausal bone loss, may also be used to study differences in alveolar bone (AB). The objectives of this study were to quantify the differences in AB following estrogen replacement therapy (ERT), and to investigate the relationship between AB structure and density, and trabecular bone at the femoral neck (FN) and third lumbar vertebral body (LB3). Estrogen treated rats had a higher bone volume fraction (BV/TV) at the AB region (9.8% P < 0.0001), FN (12% P < 0.0001), and LB3 (11.5% P < 0.0001) compared to the OVX group. BV/TV of the AB was positively correlated with the BV/TV at the FN (r = 0.69 P < 0.0001) and the LB3 (r = 0.75 P < 0.0001). The trabecular number (Tb.N), trabecular separation (Tb.Sp), and structure model index (SMI) were also positively correlated (P < 0.05) between the AB and FN (r = 0.42, 0.49, and 0.73, respectfully) and between the AB and LB3 (r = 0.44, 0.63, and 0.69, respectfully). Given the capacity of AB to respond to ERT, future preclinical drug/nutritional intervention studies aimed at improving skeletal health should include the AB as a region of interest (ROI).

Validation des modèles de pharmacologie de sécurité et évaluation de la valeur thérapeutique de l'oxytocine dans le traitement de l'infarctus du myocarde

En février, 2009 un rapport de PHRMA (Pharmaceutical Research and Manufacturers of America) confirmait que plus de 300 médicaments pour le traitement des maladies cardiaques étaient en phase d’essais cliniques ou en révision par les agences règlementaires. Malgré cette abondance de nouvelles thérapies cardiovasculaires, le nombre de nouveaux médicaments approuvés chaque année (toutes indications confondues) est en déclin avec seulement 17 et 24 nouveaux médicaments approuvés en 2007 et 2008, respectivement. Seulement 1 médicament sur 5000 sera approuvé après 10 à 15 ans de développement au coût moyen de 800 millions $. De nombreuses initiatives ont été lancées par les agences règlementaires afin d’augmenter le taux de succès lors du développement des nouveaux médicaments mais les résultats tardent. Cette stagnation est attribuée au manque d’efficacité du nouveau médicament dans bien des cas mais les évaluations d’innocuité remportent la palme des causes d’arrêt de développement. Primum non nocere, la maxime d’Hippocrate, père de la médecine, demeure d’actualité en développement préclinique et clinique des médicaments. Environ 3% des médicaments approuvés au cours des 20 dernières années ont, par la suite, été retirés du marché suite à l’identification d’effets adverses. Les effets adverses cardiovasculaires représentent la plus fréquente cause d’arrêt de développement ou de retrait de médicament (27%) suivi par les effets sur le système nerveux. Après avoir défini le contexte des évaluations de pharmacologie de sécurité et l’utilisation des bio-marqueurs, nous avons validé des modèles d’évaluation de l’innocuité des nouveaux médicaments sur les systèmes cardiovasculaires, respiratoires et nerveux. Évoluant parmi les contraintes et les défis des programmes de développements des médicaments, nous avons évalué l’efficacité et l’innocuité de l’oxytocine (OT), un peptide endogène à des fins thérapeutiques. L’OT, une hormone historiquement associée à la reproduction, a démontré la capacité d’induire la différentiation in vitro de lignées cellulaires (P19) mais aussi de cellules souches embryonnaires en cardiomyocytes battants. Ces observations nous ont amené à considérer l’utilisation de l’OT dans le traitement de l’infarctus du myocarde. Afin d’arriver à cet objectif ultime, nous avons d’abord évalué la pharmacocinétique de l’OT dans un modèle de rat anesthésié. Ces études ont mis en évidence des caractéristiques uniques de l’OT dont une courte demi-vie et un profil pharmacocinétique non-linéaire en relation avec la dose administrée. Ensuite, nous avons évalué les effets cardiovasculaires de l’OT sur des animaux sains de différentes espèces. En recherche préclinique, l’utilisation de plusieurs espèces ainsi que de différents états (conscients et anesthésiés) est reconnue comme étant une des meilleures approches afin d’accroître la valeur prédictive des résultats obtenus chez les animaux à la réponse chez l’humain. Des modèles de rats anesthésiés et éveillés, de chiens anesthésiés et éveillés et de singes éveillés avec suivi cardiovasculaire par télémétrie ont été utilisés. L’OT s’est avéré être un agent ayant d’importants effets hémodynamiques présentant une réponse variable selon l’état (anesthésié ou éveillé), la dose, le mode d’administration (bolus ou infusion) et l’espèce utilisée. Ces études nous ont permis d’établir les doses et régimes de traitement n’ayant pas d’effets cardiovasculaires adverses et pouvant être utilisées dans le cadre des études d’efficacité subséquentes. Un modèle porcin d’infarctus du myocarde avec reperfusion a été utilisé afin d’évaluer les effets de l’OT dans le traitement de l’infarctus du myocarde. Dans le cadre d’un projet pilote, l’infusion continue d’OT initiée immédiatement au moment de la reperfusion coronarienne a induit des effets cardiovasculaires adverses chez tous les animaux traités incluant une réduction de la fraction de raccourcissement ventriculaire gauche et une aggravation de la cardiomyopathie dilatée suite à l’infarctus. Considérant ces observations, l’approche thérapeutique fût révisée afin d’éviter le traitement pendant la période d’inflammation aigüe considérée maximale autour du 3ième jour suite à l’ischémie. Lorsqu’initié 8 jours après l’ischémie myocardique, l’infusion d’OT a engendré des effets adverses chez les animaux ayant des niveaux endogènes d’OT élevés. Par ailleurs, aucun effet adverse (amélioration non-significative) ne fût observé chez les animaux ayant un faible niveau endogène d’OT. Chez les animaux du groupe placebo, une tendance à observer une meilleure récupération chez ceux ayant des niveaux endogènes initiaux élevés fût notée. Bien que la taille de la zone ischémique à risque soit comparable à celle rencontrée chez les patients atteints d’infarctus, l’utilisation d’animaux juvéniles et l’absence de maladies coronariennes sont des limitations importantes du modèle porcin utilisé. Le potentiel de l’OT pour le traitement de l’infarctus du myocarde demeure mais nos résultats suggèrent qu’une administration systémique à titre de thérapie de remplacement de l’OT devrait être considérée en fonction du niveau endogène. De plus amples évaluations de la sécurité du traitement avec l’OT dans des modèles animaux d’infarctus du myocarde seront nécessaires avant de considérer l’utilisation d’OT dans une population de patients atteint d’un infarctus du myocarde. En contre partie, les niveaux endogènes d’OT pourraient posséder une valeur pronostique et des études cliniques à cet égard pourraient être d’intérêt.

Lack of effects of isoflavones on the lipid profile of Brazilian postmenopausal women

Objective: To evaluate the effects of soy isoflavone supplementation on profile lipid and endogenous hormone levels. Methods: In this double-blind, placebo-controlled Study, 47 post menopausal women 47-66 v of age received 40 mg of isoflavone (n = 25) or 40 mg of casein placebo (11 = 22). Cardiovascular risk factors were assessed by evaluating lipid profile at baseline and after 6 mo of treatment. To examine the effects of this regime on endogenous hormone levels, follicle-stimulating hormone and beta-estradiol were measured. Urinary isoflavone concentrations (genistein and daidzein) were measured as markers of both compliance and absorption using high performance liquid chromatography. Baseline characteristics were compared by the unpaired Student`s t-test. Within-group changes were determined by paired Student`s t-test and comparison between the isoflavone and casein placebo groups were determined by analysis of variance. Results: Lipid levels (low-density lipoprotein and total cholesterol) similarly decreased in both,groups. High-density lipoprotein increased significantly in both groups and cannot thus be attributable to treatment: the reason for Such variation is unknown and can be attributed to chance or to bias (even that of a real placebo effect in both groups or perhaps in spontaneous changes in exercise and dietary habits of patients after their inclusion). Furthermore, in both groups very low-density lipoprotein and triacylglycerol levels increased in a non-significant manner. Conclusion: The results of the present Study do not support any biologically significant estrogenic effects of isoflavone on the parameters assessed. Further research will he necessary to definitively assess the safety and efficacy of isoflavone. (C) 2008 Elsevier Inc. All rights reserved.

Raloxifene therapy inhibits osteoclastogenesis during the alveolar healing process in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of 17 beta-estradiol and alendronate on the removal torque of osseointegrated titanium implants in ovariectomized rats

Background: This study investigated the influence of estrogen deficiency and its treatment with estrogen and alendronate on the removal torque of osseointegrated titanium implants.Methods: Fifty-eight female Wistar rats received a titanium implant in the tibia metaphysis. After 60 days, which was needed for implant osseointegration, the animals were randomly divided into five groups: control (CTLE; N = 10), sham surgery (SHAM; N = 12), ovariectomy (OVX; N = 12), ovariectomy followed by hormone replacement (EST; N = 12), and ovariectomy followed by treatment with alendronate (ALE; N = 12). The CTLE group was sacrificed to confirm osseointegration, whereas the remaining groups were submitted to sham surgery or ovariectomy according to their designations. After 90 days, these animals were also sacrificed. Densitometry of femur and lumbar vertebrae was performed by dual-energy x-ray absorptiometry (DXA) to confirm systemic impairment of the animals. All implants were subjected to removal torque.Results: Densitometric analysis of the femur and lumbar vertebrae confirmed a systemic impairment of the animals, disclosing lower values of bone mineral density for OVX. Analysis of the removal torque of the implants showed statistically lower values (P <0.05) for the OVX group in relation to the other groups. However, the group treated with alendronate (ALE group) presented significantly higher torque values compared to the others.Conclusion: According to this study, estrogen deficiency was observed to have a negative influence on the removal torque of osseointegrated implants, whereas treatment with alendronate

Efeito do raloxifeno sobre a densidade mamográfica em mulheres na pós-menopausa

PURPOSE: to evaluate changes in mammographic breast density in postmenopausal women using raloxifene. METHODS: in this clinical trial, 80 women (mean age=61.1 years) were studied prospectively. Forty patients received 60 mg/day raloxifene, and 40 women comprised the non-treated group (control), paired by age and time of menopause. The treated group was composed of patients with osteoporosis of the lumbar spine. Those with history of breast surgery and users of hormone therapy up to six months prior to the study were excluded. The breast density was assessed qualitatively (subjective) and quantitatively (objective) in two moments, initial and final, after a 6-month follow-up. The 320 mammograms (craniocaudal and oblique) were interpreted qualitatively by the Breast Imaging Reporting and Data System (BI-RADS) classification and quantitatively by digital scanning and computer-assisted segmentation. For statistical analysis t-test, Wilcoxon Mann-Whitney, Spearman correlation and the kappa index were used. RESULTS: on the initial statistical comparison, the groups were considered homogenous for the variables: analyzed age, time of menopause, parity, breast feeding, previous hormonal therapy and body mass index. Baseline breast density, by qualitative and quantitative methods, correlated negatively with the age in both groups (p<0.05). Concerning the other variables, there was no correlation. After six months, no alteration was observed in the mammographic breast density in 38 women of raloxifene group and 38 of the control group, by qualitative method. However, by quantitative method, no alteration was observed in 30 women of the raloxifene group and 27 controls (p>0.05). It was observed a weak agreement rate (kappa=0.25) between the BI-RADS classification and digital scanning/computer-assisted segmentation. CONCLUSIONS: in post-menopausal women with osteoporosis, submitted to raloxifene treatment for six months, no alterations were observed on the mammographic breast density.

Hipoparatireoidismo primário em cão

The hypoparathyroidism is a rare endocrinopathy reported in dogs, caused by a deficiency in the synthesis of parathyroid hormone (PTH). The lack of PTH causes hypocalcemia and hyperphosphatemia, resulting in a series of neurological and neuromuscular disorders. Unlike most endocrinopathies, hypoparathyroidism is a disease in which the exogenous hormone replacement is not being viable, becoming the treatment a challenge. The present report aims to describe a case of primary hypoparathyroidism in a Schnauzer dog with seizures and neuromuscular disorders, and successful treatment employed, this being the first case, according to the literature, of hypoparathyroidism diagnosed in Brazil. The hypoparathyroidism should be considered as a differential diagnosis in cases of seizure. A complete neurological evaluation and determination of serum ionized calcium and parathyroid hormone are essential for the diagnosis of this disease. Early diagnosis may improve the quality of life of affected animals, since after the initiation of therapy, there is complete remission of clinical signs.

Hipotireoidismo em cães: aspectos gerais

Hypothyroidism is a common endocrine disorder in dogs caused by insufficient production and secretion of thyroid hormones. Most affected dogs have primary hypothyroidism that results from lymphocytic thyroiditis, idiopathic thyroid atrophy, or more rarely, neoplastic destruction. Secondary hypothyroidism resulting from inadequate secretion of thyrotropin (thyroid-stimulating hormone –TSH) from the pituitary gland is less commonly recognized. Tertiary hypothyroidism resulting from a deficiency of hypothalamic thyrotropin-releasing hormone (TRH) has not been documented in dogs. The diagnosis of hypothyroidism in dogs is made on the basis of clinical findings, results of routine laboratory and thyroid gland function tests and response to thyroid hormone replacement. Unfortunately, these tests have high sensitivity, but low specificity, for use in the diagnosis of hypothyroidism. Thyroid hormone supplementation is indicated for the treatment of confirmed hypothyroidism and for the diagnoses of the disease through clinical response to trial therapy

Control of respiratory and cardiovascular functions by leptin

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of oestrogen deficiency and 17 beta-estradiol therapy on bone healing in calvarial critical size defects treated with bovine bone graft

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Tailored Therapy: Matching the Method to the Patient

Clinicians frequently have to decide when dialysis should be initiated and which modality should be used to support kidney function in critically ill patients with acute kidney injury. In most instances, these decisions are made based on the consideration of a variety of factors including patient condition, available resources and prevailing local practice experience. There is a wide variation worldwide in how these factors influence the timing of initiation and the utilization of various modalities. In this article, we review the therapeutic goals of renal support and the relative advantages and shortcomings of different dialysis techniques. We describe strategies for matching the timing of initiation to the choice of modality to individualize renal support in intensive care unit patients. Copyright (C) 2012 S. Karger AG, Basel

Drospirenone and levonorgestrel in combination with either 30 or 20 mcg ethinylestradiol reduce soluble adhesion molecules in Brazilian women; cross-sectional study

Background: The objective of this study was to evaluate the effect of three contraceptive pills containing ethinylestradiol (EE) (20 or 30 mcg) in combination with drospirenone (DRSP) and levonorgestrel (LNG) on plasma concentration of adhesion molecules vascular cell adhesion molecule -1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Study Design: A cross-sectional study was conducted with 72 participants (18-30 years old) distributed into three groups that used oral contraceptives containing EE 20 or 30 mcg combined with DRSP 3 mg or EE 30 mcg/LNG 150 mcg for at least 6 months. The control group was comprised of nonusers of contraceptives. Soluble VCAM-1, soluble ICAM-1 and soluble E-selectin were evaluated by enzyme-linked immunosorbent assay. Results: Compared to the control group, a significant decrease was found in VCAM-1 and ICAM-1 concentrations with use of DRSP/20 EE and LNG/30 EE. Conclusions: DRSP/20 EE and LNG/30 EE induce favorable changes in endothelial function. (C) 2012 Elsevier Inc. All rights reserved.

Hormone-regulated expression and distribution of versican in mouse uterine tissues

Abstract Background Remodeling of the extracellular matrix is one of the most striking features observed in the uterus during the estrous cycle and after hormone replacement. Versican (VER) is a hyaluronan-binding proteoglycan that undergoes RNA alternative splicing, generating four distinct isoforms. This study analyzed the synthesis and distribution of VER in mouse uterine tissues during the estrous cycle, in ovariectomized (OVX) animals and after 17beta-estradiol (E2) and medroxyprogesterone (MPA) treatments, either alone or in combination. Methods Uteri from mice in all phases of the estrous cycle, and animals subjected to ovariectomy and hormone replacement were collected for immunoperoxidase staining for versican, as well as PCR and quantitative Real Time PCR. Results In diestrus and proestrus, VER was exclusively expressed in the endometrial stroma. In estrus and metaestrus, VER was present in both endometrial stroma and myometrium. In OVX mice, VER immunoreaction was abolished in all uterine tissues. VER expression was restored by E2, MPA and E2+MPA treatments. Real Time PCR analysis showed that VER expression increases considerably in the MPA-treated group. Analysis of mRNA identified isoforms V0, V1 and V3 in the mouse uterus. Conclusion These results show that the expression of versican in uterine tissues is modulated by ovarian steroid hormones, in a tissue-specific manner. VER is induced in the myometrium exclusively by E2, whereas MPA induces VER deposition only in the endometrial stroma.