Estudio de la expresión del receptor de vitamina D en la ontogenia del testículo y en tumores de células de leydig: posible interacción con el sistema histaminérgico

RESUMEN La vitamina D (VD), un esteroide pleiotrópico, ha sido relacionada con la función reproductiva masculina, pero aún no se ha estudiado la expresión de su receptor (RVD) en el desarrollo testicular. RVD regula la expresión de componentes del sistema histaminérgico, y la histamina (HA) modula la esteroidogénesis en células de Leydig (CL). Se ha relacionado a la deficiencia de VD con múltiples patologías, entre ellas cáncer. Los tumores de células de Leydig (TCL) son los más frecuentes del intersticio testicular, y al malignizar no responden a radio/quimioterapia. VD fue descripta como tratamiento para varios tumores, pero se desconoce su aplicación en TCL. Por lo expuesto, hemos estudiado la expresión de RVD en la ontogenia de testículo de rata, evaluando su correlación con los niveles de testosterona séricos (T) y el contenido de HA; y además evaluamos la expresión de RVD en testículo humano fetal, neonatal, prepuberal, TCL e hiperplasia de CL. En testículo de rata, se observó un aumento en la expresión de RVD en CL con la edad, en línea con el incremento de T, y en contraposición con la disminución del contenido de HA, lo cual fue consistente con la reducción en los niveles de la enzima que cataliza su síntesis, HDC. Esto sugiere que la VD podría ejercer una función en el desarrollo testicular normal, ya sea en forma directa sobre las CL o mediante la regulación de la expresión de componentes del sistema histaminérgico (HDC y/o receptores de HA). Por su parte, el TCL humano presentó sobreexpresión de RVD y HDC. Considerando que las hormonas esteroideas se encuentran aumentadas en esta patología y funcionan como factores de crecimiento, si el calcitriol pudiera modular la esteroidogénesis podría tener una aplicación terapéutica.

ABSTRACT Vitamin D (VD) is a steroid hormone traditionally related to bone health. However, several authors have associated VD with reproduction and steroidogenesis in males. The presence ofVD receptor (VDR) and the enzymes involved in its activation had been reported in several cell types of the testes. Until now, nobody has studied RVD expression during testicular development. In addition, VDR in association with its co-activators or co-repressors, regulates the expression of several genes, including those related to the histaminergic system. Previously, we demonstrated that histamine (HA) can modulate steroidogenesis in Leydig cells (LC) in a concentration-dependent manner. Also, we observed a decrease in the endogenous HA content, consistent with the previously described decrease of HDC (histidine decarboxylase, the enzyme responsible of HA synthesis) levels, during LC ontogeny. Epidemiologic studies strongly suggest that a relationship exists between VD deficiency and multiple pathologies, particularly cancer. Leydig cell tumors (LCT) are rare endocrine tumors ofunknown etiology, which originate in the testicular interstitium. The incidence worldwide is 1-3% in adults and 4% in prepubertal boys, but recent publications indicate that these figures have been increasing. While usually benign, approximately 10% of LCT in adults become malignant and do not respond to chemo or radiotherapy. It is imperative to deeply investigate the biology of LCT, to identify new therapeutic targets. The potential role of calcitriol (1a,25(OH)2-vitamin-D3) in cancer treatment has been described for several types of tumors, but it remains unexplored in LCT. Thus, as a first step, it is worth evaluating VDR expression in LCT.In view of the aforecited evidence, herein we studied VDR expression during the rat testicular ontogeny, evaluating a possible correlation withserum testosterone (T) levels in blood, endogenous levels of HA and the previously described HDC expression levels. We also analized VDR expression in human testes corresponding to three different stages of development (fetal, neonatal andjuvenile), in LCT and in LC hyperplasia. Methods: Rat testes of different ages (7, 21, 35, 90 y 240 days), human fetal, neonatal and pre pubertal testes, a human LCT and a human LC hyperplasia; were used for detection of VDR by immunohistochemistry. Results: In the rat testes, VDR expression increased with age in LC, in line with the increase in serum testosterone; and in contrast with the decrease in the endogenous content of HA and HDC levels. Likewise, we detected an increase in VDR expression with age in the human testes samples. LCT presentedVDR and HDC overexpression. We also detected VDR in LC hyperplasia. Conclusions: Given that VDR testicular expression increases with age in LC, as well as testosterone serum levels, it is reasonable to speculate thatVD may play a role in normal testicular development, either acting directly on LC or by regulating one of more components of the histaminergic system (HDC or HA receptors). Considering that VDR is overexpressed in LCT, and that steroids are increased in this pathology (and act like growth factors); if calcitriol could modulate steroidogenesis, it could have a therapeutic role.

Effect of Denosumab on Bone Mineral Density and Markers of Bone Turnover among Postmenopausal Women with Osteoporosis.

The aim of this study was to evaluate the effect of denosumab (Dmab) on bone mineral density (BMD) and bone turnover markers after 1 year of treatment. Additionally, the effect of Dmab in bisphosphonate-naïve patients (BP-naïve) compared to patients previously treated with bisphosphonates (BP-prior) was analyzed. This retrospective study included 425 postmenopausal women treated with Dmab for 1 year in clinical practice conditions in specialized centers from Argentina. Participants were also divided according to previous bisphosphonate treatment into BP-naïve and BP-prior. A control group of patients treated with BP not switched to Dmab matched by sex, age, and body mass index was used. Data are expressed as mean ± SEM. After 1 year of treatment with Dmab the bone formation markers total alkaline phosphatase and osteocalcin were significantly decreased (23.36% and 43.97%, resp.), as was the bone resorption marker s-CTX (69.61%). Significant increases in BMD were observed at the lumbar spine, femoral neck, and total hip without differences between BP-naïve and BP-prior. A better BMD response was found in BP-prior group compared with BP treated patients not switched to Dmab. Conclusion. Dmab treatment increased BMD and decreased bone turnover markers in the whole group, with similar response in BP-naïve and BP-prior patients. A better BMD response in BP-prior patients versus BP treated patients not switched to Dmab was observed.

Evaluation of the hypothalamic-pituitary-gonadal axis in eugonadal men with type 2 diabetes mellitus.

Men with type 2 diabetes mellitus (DM2) have lower testosterone levels and a higher prevalence of hypogonadism. It still remains unclear the mechanism by which there is a relationship between hypogonadism and DM2. The objective was to evaluate the hypothalamic-pituitary-gonadal axis at different levels in eugonadal patients with DM2. Fourteen patients with DM2 (DM2 group) and 15 subjects without DM2 (normal glucose tolerance test) as control group (CG) were included. We assessed: (i) fasting glucose, insulin, Homeostasis Model Assessment (HOMA); (ii) luteinizing hormone (LH) pulsatility through blood collections every 10 min for 4 h; (iii) gonadotropin-releasing hormone (GnRH) test: basal LH and 30, 60 and 90 min after 100 µg of i.v. GnRH; (iv) human chorionic gonadotropin (hCG) test: basal total testosterone (TT), bioavailable testosterone (BT), free testosterone (FT), estradiol (E2), bioavailable E2 (BE2) and sex hormone-binding globulin (SHBG) and 72 h post 5000 IU of i.m. hCG. There were no differences in age, body mass index and waist circumference between groups. Glucose was higher in the DM2 group vs. CG: 131.1 ± 25.5 vs. 99.1 ± 13.6 mg/dL, p = 0.0005. There were no difference in basal insulin, HOMA, TT, BT, FT, E2, BE2, SHBG and LH levels between groups. The DM2 group had lower LH pulse frequency vs. CG: 0.8 ± 0.8 vs. 1.5 ± 0.5 pulses, p = 0.009. Differences in LH pulse amplitude were not found. A negative correlation was found between the number of LH pulses and glucose, r: -0.39, p = 0.03. There were no differences in the response of LH to GnRH between groups nor in the response of sexual steroids and SHBG to hCG. Patients with DM2 showed lower hypothalamic pulse frequency without changes in the pituitary response to GnRH nor testicular response to hCG. Glucose levels negatively correlated with the number of LH pulses which suggests a negative effect of hyperglycaemia in the hypothalamic secretion of GnRH.

Estudio de causas secundarias de osteoporosis masculina / Study of secondary causes of male osteoporosis

La osteoporosis (OP) es una enfermedad subdiagnosticada y subtratada en la mayoría de los hombres. Un tercio de las fracturas de cadera ocurren en la población masculina, con más complicaciones secundarias que en la población femenina y una tasa de mortalidad de 37,5 % dentro del año posterior a la fractura. Un gran número de fracturas ocurren en hombres cuya densidad mineral ósea (DMO) no está en rango osteoporótico, esto resalta la importancia de evaluar factores distintos a la DMO en la determinación del riesgo de fractura. Objetivos: establecer la prevalencia de causas secundarias de OP en hombres mayores de 50 años y analizar las posibles asociaciones entre los valores de DMO y distintos parámetros bioquímicos. Se evaluaron retrospectivamente 918 historias clínicas de varones mayores de 50 años, cuyo motivo de admisión fuese OP, osteopenia o fracturas óseas en cualquier localización. Criterios de inclusión: medición de parámetros plasmáticos y urinarios de metabolismo fosfocálcico, testosterona total y DMO de raquis lumbar, cuello femoral y trocánter. Resultados: 113 pacientes, de 70,6 ± 9,8 años, cumplieron los criterios de inclusión, el 75,2 % tenían diagnóstico de OP en al menos una localización y el 24,8 % osteopenia. En el 85,8 % de los pacientes se encontraron causas secundarias de OP, siendo las más frecuentes: hipovitaminosis D, hipogonadismo, corticoterapia crónica e hipercalciuria. El 22 % de los pacientes padeció alguna fractura sin sospecha previa de baja masa ósea. Conclusiones: en un alto porcentaje de hombres con OP se observaron causas secundarias. El diagnóstico de OP en el varón es tardío ya que el 22 % había padecido alguna fractura sin sospecha previa de baja masa ósea. Esto resalta la importancia de este problema y la necesidad de realizar un diagnóstico y tratamiento temprano en la población masculina.

Male osteoporosis (OP) is an underdiagnosed and undertreated disease in the majority of men. One third of hip fractures occur in men, who present more secondary complications than women, with a mortality rate of 37.5 % within one year of facture. The observation that most fractures occur in men, whose bone mineral density is not in the osteoporotic range, highlights the importance of different factors others than bone densitometry to evaluate the risk of fracture. Aims: to establish the prevalence of secondary factors OP in men older than 50 years and to analyze the possible associations between bone mineral density and biochemical parameters. Retrospective analysis of 918 medical records of men over 50 years old, admitted because of OP, osteopenia or bone fractures in any location. Inclusion criteria: measurements of plasma and urinary bone metabolism parameters, total testosterone, lumbar spine, femoral neck and trochanter bone mineral density. Results: 113 patients met the inclusion criteria, the mean age was 70.6 ± 9.8 years, of which 85 (75.2 %) had OP diagnosis in one location and 28 (24.8 %) osteopenia. Of 113 patients assessed, 97 (85.8 %) had secondary OP causes, such as hypovitaminosis D, hypogonadism, chronic corticotherapy and hypercalciuria. Twenty two per cent of the patients had suffered a fracture without previous suspicion of low bone mass. Conclusions: A high proportion of men with OP present secondary factors. Most of these factors are diagnosed by history taking and biochemical study. The diagnosis of male OP is delayed as 22 % had suffered a fracture without previous suspicion of low bone mass. This indicates the importance of this issue and its early diagnosis and treatment in the male population.

Heavy drinking in early adulthood and outcomes at mid life.

BACKGROUND: Heavy drinking in early adulthood among Blacks, but not Whites, has been found to be associated with more deleterious health outcomes, lower labor market success and lower educational attainment at mid-life. This study analysed psychosocial pathways underlying racial differences in the impact of early heavy alcohol use on occupational and educational attainment at mid-life. METHODS: Outcomes in labor market participation, occupational prestige and educational attainment were measured in early and mid-adulthood. A mixture model was used to identify psychosocial classes that explain how race-specific differences in the relationship between drinking in early adulthood and occupational outcomes in mid-life operate. Data came from Coronary Artery Risk Development in Young Adults, a longitudinal epidemiologic study. RESULTS: Especially for Blacks, heavy drinking in early adulthood was associated with a lower probability of being employed in mid-life. Among employed persons, there was a link between heavy drinking for both Whites and Blacks and decreased occupational attainment at mid-life. We grouped individuals into three distinct distress classes based on external stressors and indicators of internally generated stress. Blacks were more likely to belong to the higher distressed classes as were heavy drinkers in early adulthood. Stratifying the data by distress class, relationships between heavy drinking, race and heavy drinking-race interactions were overall weaker than in the pooled analysis. CONCLUSIONS: Disproportionate intensification of life stresses in Blacks renders them more vulnerable to long-term effects of heavy drinking.

Insulinorresistencia y disfunción eréctil: Efecto del tratamiento con metformina / Insulin resistance and erectile dysfunction: Effect of treatment with metformin

La erección depende de la liberación de óxido nítrico (ON) endotelial. La insulinorresistencia (IR) produce disfunción endotelial por menor síntesis y liberación de ON. El tratamiento con metformina mejora la función eréctil en ratones con IR y disfunción eréctil (DE). Objetivos: Evaluar en pacientes con DE: 1) la presencia de IR; 2) el grado de severidad de la DE según la presencia de IR y 3) el efecto del tratamiento con metformina sobre la función eréctil en pacientes con DE e IR. Material y métodos: Estudio prospectivo, randomizado, doble ciego con placebo. Se incluyeron 81 pacientes con DE y 20 hombres sin DE (grupo control). Se evaluó función eréctil con el cuestionario IIEF-5. Se evaluó IR con el índice HOMA. Se consideró IR si HOMA ≥3. Treinta pacientes con DE, IR y pobre respuesta al sildenafil fueron randomizados para recibir tratamiento con metformina o placebo. Resultados: Se encontró una diferencia significativa entre pacientes con DE y el grupo control en HOMA: 4.9±2.8 versus 3.6±2.6 (p=0.03). La prevalencia de IR fue mayor en los pacientes con DE que en el grupo control: 77.7% versus 45.0% (p=0.008). Se halló una correlación negativa entre HOMA e IIEF-5: r:-0.21 (p=0.04). Los pacientes con DE e IR tuvieron menor score IIEF-5 que los pacientes con DE sin IR. Luego del tratamiento con metformina, los pacientes con DE tuvieron un incremento significativo en el score IIEF-5 y una disminución significativa del HOMA a los 2 y 4 meses de tratamiento, no se observaron cambios en IIEF-5 ni HOMA en los pacientes que recibieron placebo. Conclusión: nuestros hallazgos hacen suponer que la disfunción endotelial causada por IR podría ser uno de los mecanismos fisiopatológicos de la DE. El tratamiento con metformina en pacientes con DE reduce la IR y podría mejorar la respuesta al tratamiento con sildenafil. Rev Argent Endocrinol Metab 47: 13-20, 2010. Los autores declaran no tener conflictos de interés.

Erection depends largely on the release of nitric oxide (NO) by vascular endothelium. Insulin resistance (IR), present in most subjects who have obesity, metabolic syndrome (MS) or type 2 diabetes mellitus (DM2) is a metabolic abnormality that produces endothelial dysfunction determined by minor synthesis and release of NO. Treatment with metformin improves erectile function in mice with erectile dysfunction (ED) and IR. Aims: To evaluate in ED patients: 1) the presence of IR; 2) the degree of severity of ED according to the presence of IR; 3) the effect of treatment with metformin on erectile function in patients with ED and IR. Methods: Prospective, randomized, controlled, double-blind placebo study. We included 81 patients with ED and 20 men without ED (control group). Exclusion criteria: pharmacologic, anatomic or endocrine ED (hypogonadism or hyperprolactinemia), DM2, prior prostatic surgery or chronic illnesses. The erectile function was rated according the International Index of Erectile Function 5. IR was measerud by HOMA index. Thirty patients with ED, IR and poor response to sildenafil were randomized to receive metformin or placebo. Results: Patients with ED had higher HOMA index versus control group: 4.9 ± 2.8 versus 3.6 ± 2.6, p=0.03. The prevalence of IR was higher in ED group versus control group: 77.7% versus 45.0%, p=0.008. We found a negative correlation between HOMA and IIEF-5: r:-0.21, p=0.04. Patients with ED and IR (n=62) had lower IIEF-5 score when compared with those without IR (n=19): 13.6 ± 4.3 versus 16.0 ± 3.1, p=0.04. After treatment with metformin patients with ED showed a significant increase in IIEF-5 score and a significant decrease in HOMA index both at 2 and 4 months of treatment. Changes in the IIEF-5 score and HOMA index were not observed in patients with ED receiving placebo. Conclusion: Our findings suggest that endothelial dysfunction caused by IR could be one of the pathophysiologial mechanisms of ED. Treatment with metformin in patients with ED reduces IR and could improve response to treatment with sildenafil. Rev Argent Endocrinol Metab 47: 13-20, 2010 No competing finantial interests exist.

The mediating effect of eating self-efficacy on the relationship between emotional arousal and overeating in the treatment-seeking obese.

In this study, we tested the proposition that the emotion-based eating of obese individuals is mediated by the effects of emotional arousal tendencies on brittle dieting self-restraint. Our indices of emotion-aroused eating, overeating, and brittle restraint were derived from a set of measures administered to 632 female and 254 male participants in a residential weight control and lifestyle change program. Mediation analyses indicated that (a) the relationship between positive emotion and overeating was entirely mediated by restraint tendencies and (b) the relationship between negative emotion eating and overeating was only partially mediated by brittle restraint. These findings held for both males and females. The results are discussed in relation to the viability of the psychosomatic hypothesis for understanding the relationship between emotions and overeating.

The gender specificity of emotional, situational, and behavioral indicators of binge eating in a diet-seeking obese population.

OBJECTIVE: This study investigated the unique gender correlates of binge eating severity in a diet-seeking population. METHOD: This sample consisted of 288 self-admitted patients enrolled in a residential weight loss program between 1996 and 1997. Subjects were administered several questionnaires including (a) the Binge Eating Scale, (b) the Beck Depression Inventory, (c) the Rosenberg Self-Esteem Scale, (d) 5-point scales of eating related foci, and (e) 7-point scales of subject confidence in controlling their eating under various circumstances. Data were analyzed in terms of stepwise regression analyses. RESULTS: Regression results revealed that while men and women share some common predictors of binge eating severity, there are also some gender-specific correlates. Men in our sample were prone to binge eat because of negative emotions (i.e., depression and anger), while binge eating severity for women in our sample was most strongly related to diet failure and tests of moderate eating. DISCUSSION: The strength of the distinctive gender-specific regressions for binge eating severity suggests that the problems of binging in obese males and females are derivatives of differential sex role expectations. This interpretation and clinical implications are the focus of the discussion.

The comorbidity of depression and eating dysregulation processes in a diet-seeking obese population: a matter of gender specificity.

OBJECTIVE: To explore gender differences in depression vulnerability among an obese, treatment-seeking population and to discern those components of eating-related phenomena that discriminate the depression-comorbid obese from their noncomorbid counterparts. METHOD: This sample consisted of 1,184 self-admitted patients enrolled in a residential weight loss program between 1990 and 1995. Subjects were administered several questionnaires including (a) the Beck Depression Inventory, (b) 5-point scales of eating-related foci, and (c) 7-point scales of subject's confidence in their eating control under various circumstances. Data were analyzed via analyses of variance (ANOVAs) and stepwise regression. RESULTS: Greater depression was accompanied by more disruptive, dysregulatory eating tendencies, and stronger inclination to engage in affectively and socially disrupted eating. Regression results revealed gender-specific predictors of comorbid depression. For obese females, negative-emotion disrupted eating and binge-purge behaviors were prominent predictors of depression. For males, eating induced by experiences of social or physical inadequacy and fasting relating to eating behaviors were the depression-relevant variables. DISCUSSION: These results are discussed in terms of their theoretical implications for gender-mediated models of obesity-depression comorbidity, and in terms of their clinical significance.

Does marital agony precede marital ecstasy? A comment on Gottman and Krokoff's "Marital interaction and satisfaction: a longitudinal view".

In a recent article, Gottman and Krokoff (1989) presented a fascinating and counterintuitive portrayal of a temporally related dynamic relationship of marital conflict and marital satisfaction. Unfortunately the results from which their conclusions spring are quite problematic. In a 2-wave, extreme-groups design, Gottman and Krokoff used raw change in satisfaction as a correlate of Time 1 conflict variables for purposes of analysis. Serious psychometric questions arise with this approach to the causal assessment of change. Given the considerations raised, there is a high likelihood that Gottman and Krokoff's data result from statistical artifact. Alternative approaches to the measurement of change are discussed in the context of illustrating the problematic components of Gottman and Krokoff's analysis.

Thinness--not obesity--has a genetic component.

The body mass of adoptees was compared with the body mass of both biologic and adoptive parents using data from the Danish Adoption Register. Chi-square analyses revealed that biologic heritability is small and is confined to thin, not obese body mass. It is probable that the inheritance of thin body mass constitutes a mild protective factor that mitigates against development of obesity caused by environmental factors.

Behavioral determinants of mental illness concerns: a comparison of community subcultures.

A stratified sample (race, sex, and social class) of 469 laymen from two North Carolina communities responded to a 190-item MMPI-based questionnaire with the degree of mental illness concern evoked by each item. The results reflected systematic race and social class differences in the behavioral bases for mental illness attributions--differences not explainable by overall differences in toleration for deviance. Although laymen had roughly similar rank orderings for the 13 homogeneous clusters of items, blacks indicated greater concern over breakdowns in social orientation than whites, while the opposite pattern held for traditionally defined psychopathy (internal distresses). Upper-class concerns were, comparatively, with cognitive dysfunction, middle-class with moral and social responsibility, and lower-class with social inadequacies.

The effect of social cues on the eating behavior of obese and normal subjects.

Schachter's externality hypothesis suggests that overweight individuals are more likely to be induced to eat by salient external cues than normal weight individuals. While a range of studies have demonstrated the plausibility of this hypothesis in the case of sensory stimuli (e.g., taste cues), there is little evidence that the hypothesis applies to social stimuli. The current study examines this latter proposition by exposing male and female, overweight and normal weight subjects to a same-sex or opposite-sex peer model. Under the guise of engaging in a taste experiment, the subjects were either exposed to a model who tasted no crackers (no eat), one cracker (low eat), or twenty crackers (high eat). In addition, control model-absent conditions were also run for purposes of establishing baseline eating rates. If the externality hypotheses were to prevail in social domains, one would expect overweight subjects to be more prone to model the cracker-eating behavior of the peer than normal weight individuals. However, the findings indicate that all subject groups regardless of weight evidence a rather clear modeling effect and all subjects evidence social inhibition effects on their eating behavior as well. Several intriguing interactions among subject sex, model sex, subject weight, and social condition were also found. The discussion explores the relevance of an externality model of overweight eating in social domains, and focuses upon the interesting and somewhat distinct pattern of socially mediated eating exhibited by overweight females.

Externality as a function of obesity in children: pervasive style or eating-specific attribute?

The developmental sources of the link between stylistic externality and food-related externality found in the obese by Schacter and others were explored by testing whether the externality phenomena that have been found to differentiate obese and normal adults are also discriminators of obese and normal children. The results suggest that obese children as young as 7-12 years of age show an external responsiveness to salient food cues but not yet a generally external perceptual style. The implications of these findings for the development of obese externality are examined.

Death anxiety, dissent, and competence.

A total of 64 male undergraduates were administered a multistage interview which was structured to assess (a) their level of overtly expressed death anxiety, (b) covert (GSR) arousal to death stimuli (c) self-perceived competence, and (d) agreement with or dissent from life threatening national policies. The analyses that followed were concerned with examining the relationships among these variables. In previous studies of this kind it had been typically found that (1) self-perceived competence and magnitude of expressed death concern are inversely related and (2) overt expressions of death concern and covert physiological arousal to death cues are inversely related. Psychodynamic formulations centering on the ego-defensive nature of inhibited expressions of death anxiety have been cited to explain these past data. The current investigation proposed that the magnitude of expressed death concern would bear an inverse relationship to both felt competence and covert death arousal only when the level of overt concern was not contingent upon the individual's attitudes concerning the imminence of real life threatening circumstances in the environment. The rationale behind these predictions inheres in the notion that the neurotic components of strongly expressed death anxiety derive from its lack of anchoring in "real" external threats. Conversely, the expression of low death fear can only be regarded as "defensive" when real threats are perceived and acknowledged. The obtained results strongly support this rationale and the discussion centers on the impact of social conditions on psychodynamic processes.