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.

Síndrome de Klinefelter y riesgo cardiovascular / Klinefelter syndrome and cardiovascular risk

Se presenta a un paciente de 45 años de edad que presenta síndrome de Klinefelter, con antecedentes de diabetes mellitus tipo 2, obesidad, dislipidemia, síndrome de apneas hipopneas del sueño e hipertensión arterial oculta. El objetivo de esta presentación es alertar sobre el riesgo cardiovascular aumentado que presentan estos pacientes y revisar los datos de la literatura que estudian dicho riesgo

We present a 45-year-old patient with Klinefelter syndrome, with a history of type 2 diabetes mellitus, obesity, dyslipidemia, obstructive sleep apnoea syndrome and masked arterial hypertension. The purpose of this presentation is to draw attention to the increased cardiovascular risk in these patients and to review the data in the literature on this risk

[Klinefelter syndrome and cardiovascular risk]. / Síndrome de Klinefelter y riesgo cardiovascular.

We present a 45-year-old patient with Klinefelter syndrome, with a history of type 2 diabetes mellitus, obesity, dyslipidemia, obstructive sleep apnoea syndrome and masked arterial hypertension. The purpose of this presentation is to draw attention to the increased cardiovascular risk in these patients and to review the data in the literature on this risk.

Ginecomastia: aspectos clínicos y etiológicos. Estudio retrospectivo y multicéntrico / Gynecomastia: Clinical and Ethiological Aspects. Retrospective, Multicenter Study

La ginecomastia es el agrandamiento benigno del tejido mamario en el varón. Es una causa frecuente de consulta que produce ansiedad e incomodidad y puede ser la expresión clínica de una enfermedad relevante. Objetivos: 1) Evaluar las características de presentación de la ginecomastia y el perfil bioquímico; 2) Evaluar la etiología de la ginecomastia en la población estudiada. Material y Métodos: Estudio retrospectivo, multicéntrico. Se evaluaron las historias clínicas de 220 varones (18-85 años) con diagnóstico clínico y por imágenes de ginecomastia, con evaluación bioquímica completa. Resultados: Se observó mayor prevalencia entre 21-30 años de edad (n = 66; 30 %). La mayoría consultó en forma espontánea (77,7 %); el resto fue derivado por otras especialidades. Principales motivos de consulta: razones estéticas (70,4 %) y dolor (27,3 %). El 23,2 % tenía antecedente de ginecomastia puberal. El tiempo de evolución previo a la consulta fue muy variable: 1 mes a 40 años. Examen físico: 122 pacientes (55,4 %) presentaron ginecomastia bilateral y 98 (44,6 %) unilateral (54,1 % izquierda y 45,9 % derecha). El 44,8 % presentó sobrepeso y 22,4 % obesidad. En 29,1 % se constató dolor mamario al examen. Un paciente (con macroprolactinoma) presentó secreción mamaria espontánea y 3 pacientes secreción mamaria provocada. Etiología: la ginecomastia idiopática fue la más frecuente (49,1 %) y de las causas secundarias, el consumo de anabólicos. Se constató un 10 % de pacientes con hipoandrogenismo, 16,4 % con hiperprolactinemia y 10,5 % con hiperestrogenemia. En 6 casos coexistieron 2 causas (total 226 causas). No se hallaron marcadores oncológicos elevados. En los < 40 años las causas más frecuentes fueron uso de anabólicos y ginecomastia puberal persistente; y en los > 40 años fueron hipogonadismo y consumo de fármacos. Los pacientes con ginecomastia bilateral tuvieron mayor tiempo de evolución, mayor IMC y menores niveles de TT versus ginecomastia ...

Gynecomastia is a benign enlargement of breast tissue in men. It occurs physiologically in three stages of life: newborns, pubescent boys and older adults. It is a frequent reason for consulting and -though generally benign- it produces anxiety and discomfort. It is important to differentiate between the asymptomatic presence of palpable breast tissue, which is of little clinical relevance, and a recent onset breast enlargement usually associated with pain and swelling, which can be a sign of illness or pharmacological impact. Aims: To evaluate the presenting features (symptoms, duration, laterality, etc.) and biochemical profile of gynecomastia; to assess the etiology of gynecomastia in the study population. Methods: Retrospective, multicenter study. We evaluated the medical records of 220 men aged 18-85 years (average age 33 years: median 39.5 ± 19.6 years) with imaging and clinical diagnosis of gynecomastia who had undergone biochemical assessment. The consultation period was from May 2002 to June 2013. The following data was assessed: breast pain, duration of gynecomastia, sexual function, galactorrhea, weight change, habits (alcohol, drug addiction, anabolic steroids), history of pubertal gynecomastia, use of medication and family history of gynecomastia. Physical examination: weight, height, body mass index (BMI), breast and gonadal examination. Laboratory: total testosterone (TT), bioavailable testosterone (Bio-T), estradiol (E2), luteinizing hormone, follicle stimulating hormone, prolactin, thyrotropin, alpha fetoprotein, β subunit of human chorionic gonadotropin and carcinoembryonic antigen. For hormonal abnormalities, each site’s reference values were considered. In all patients, gynecomastia was confirmed by ultrasound and / or mammography. Results: A higher prevalence of gynecomastia is observed in the age range between 21 and 30 years (n = 66; 30 %). Most patients presented spontaneously (77.7 %); the rest were referred from other specialties. The most frequent reasons for consultation were aesthetic reasons (70.4 %) and breast pain (27.3 %). Twenty-three point two percent of subjects had a history of pubertal gynecomastia. Evolution time prior to consultation was highly variable (1 month to 40 years). On physical examination, 122 patients (55.4 %) had bilateral and 98 patients (44.6 %) had unilateral gynecomastia (54.1 % left and 45.9 % right); 44.8 % were overweight and 22.4 % were obese. BMI: 27.2 ± 4.3 kg/m2. In 29.1 % of patients breast pain was identified on medical examination. One patient (with macroprolactinoma) had spontaneous galactorrhea and in 3 patients mammary secretion was found on physical examination. Gonadal examination was performed in 147 patients, 126 had normal testicular volume, 10 had bilateral hypotrophy, 7 had unilateral hypotrophy and 4 unilateral absence of the testis. Idiopathic gynecomastia was the most common etiology (47.8 %). The most relevant secondary cause of gynecomastia was anabolic steroids consumption (14.1 %). In 6 cases two causes coexisted (total: 226 causes). Elevated cancer markers were not found in any of the cases. If we divide the population into patients younger and older than 40, in the former the most common second­ary causes were the use of anabolic steroids and persistent pubertal gynecomastia, while in patients older than 40, they were hypogonadism and medical drug use. Patients with bilateral gynecomastia had a longer history of gynecomastia: 3.4 ± 5.7 versus 1.4 ± 1.9 years (p = 0.0004); higher BMI: 28.4 ± 4.4 versus 25.5 ± 3.5 kg/m2 (p < 0.0001) and lower TT levels: 4.7 ± 2.0 versus 5.4 ± 1.9 ng/ml (p=0.019) than patients with unilateral gynecomastia, respectively. A negative correlation between BMI and TT was found (r= -0.38, p< 0.0001). No correlation between BMI and E2 and between BMI and bio-T was found. Ultrasound was used in 83.2 % of patients and mammography in 43.6 % (both 28.2 %). Conclusions: Patients with gynecomastia consulted more often for aesthetic reasons and secondarily for breast pain. Detection of galactorrhea was rare. Gonadal examination was normal in most patients and 66.7 % were overweight or obese. Just over half of the patients presented with bilateral gynecomastia and compared with cases of unilateral gynecomastia, they had a longer history of disease, higher BMI and lower TT levels. The most common cause of gynecomastia was idiopathic in all age groups. Persistent pubertal gynecomastia and anabolic steroids consumption were frequent in patients younger than 40 years, and medical drug use and hypogonadism in patients over 40. The presence of gynecomastia may be the expression of an underlying and clinically relevant disease. This highlights the need for an adequate and complete clinical, biochemical and imaging assessment in these patients. Rev Argent Endocrinol Metab 52:22-28, 2015 No financial conflicts of interest exist.

Ginecomastia: aspectos clínicos y etiológicos. Estudio retrospectivo y multicéntrico / Gynecomastia: Clinical and Ethiological Aspects. Retrospective, Multicenter Study

La ginecomastia es el agrandamiento benigno del tejido mamario en el varón. Es una causa frecuente de consulta que produce ansiedad e incomodidad y puede ser la expresión clínica de una enfermedad relevante. Objetivos: 1) Evaluar las características de presentación de la ginecomastia y el perfil bioquímico; 2) Evaluar la etiología de la ginecomastia en la población estudiada. Material y Métodos: Estudio retrospectivo, multicéntrico. Se evaluaron las historias clínicas de 220 varones (18-85 años) con diagnóstico clínico y por imágenes de ginecomastia, con evaluación bioquímica completa. Resultados: Se observó mayor prevalencia entre 21-30 años de edad (n = 66; 30 %). La mayoría consultó en forma espontánea (77,7 %); el resto fue derivado por otras especialidades. Principales motivos de consulta: razones estéticas (70,4 %) y dolor (27,3 %). El 23,2 % tenía antecedente de ginecomastia puberal. El tiempo de evolución previo a la consulta fue muy variable: 1 mes a 40 años. Examen físico: 122 pacientes (55,4 %) presentaron ginecomastia bilateral y 98 (44,6 %) unilateral (54,1 % izquierda y 45,9 % derecha). El 44,8 % presentó sobrepeso y 22,4 % obesidad. En 29,1 % se constató dolor mamario al examen. Un paciente (con macroprolactinoma) presentó secreción mamaria espontánea y 3 pacientes secreción mamaria provocada. Etiología: la ginecomastia idiopática fue la más frecuente (49,1 %) y de las causas secundarias, el consumo de anabólicos. Se constató un 10 % de pacientes con hipoandrogenismo, 16,4 % con hiperprolactinemia y 10,5 % con hiperestrogenemia. En 6 casos coexistieron 2 causas (total 226 causas). No se hallaron marcadores oncológicos elevados. En los < 40 años las causas más frecuentes fueron uso de anabólicos y ginecomastia puberal persistente; y en los > 40 años fueron hipogonadismo y consumo de fármacos. Los pacientes con ginecomastia bilateral tuvieron mayor tiempo de evolución, mayor IMC y menores niveles de TT versus ginecomastia ...(AU)

Gynecomastia is a benign enlargement of breast tissue in men. It occurs physiologically in three stages of life: newborns, pubescent boys and older adults. It is a frequent reason for consulting and -though generally benign- it produces anxiety and discomfort. It is important to differentiate between the asymptomatic presence of palpable breast tissue, which is of little clinical relevance, and a recent onset breast enlargement usually associated with pain and swelling, which can be a sign of illness or pharmacological impact. Aims: To evaluate the presenting features (symptoms, duration, laterality, etc.) and biochemical profile of gynecomastia; to assess the etiology of gynecomastia in the study population. Methods: Retrospective, multicenter study. We evaluated the medical records of 220 men aged 18-85 years (average age 33 years: median 39.5 ± 19.6 years) with imaging and clinical diagnosis of gynecomastia who had undergone biochemical assessment. The consultation period was from May 2002 to June 2013. The following data was assessed: breast pain, duration of gynecomastia, sexual function, galactorrhea, weight change, habits (alcohol, drug addiction, anabolic steroids), history of pubertal gynecomastia, use of medication and family history of gynecomastia. Physical examination: weight, height, body mass index (BMI), breast and gonadal examination. Laboratory: total testosterone (TT), bioavailable testosterone (Bio-T), estradiol (E2), luteinizing hormone, follicle stimulating hormone, prolactin, thyrotropin, alpha fetoprotein, β subunit of human chorionic gonadotropin and carcinoembryonic antigen. For hormonal abnormalities, each site’s reference values were considered. In all patients, gynecomastia was confirmed by ultrasound and / or mammography. Results: A higher prevalence of gynecomastia is observed in the age range between 21 and 30 years (n = 66; 30 %). Most patients presented spontaneously (77.7 %); the rest were referred from other specialties. The most frequent reasons for consultation were aesthetic reasons (70.4 %) and breast pain (27.3 %). Twenty-three point two percent of subjects had a history of pubertal gynecomastia. Evolution time prior to consultation was highly variable (1 month to 40 years). On physical examination, 122 patients (55.4 %) had bilateral and 98 patients (44.6 %) had unilateral gynecomastia (54.1 % left and 45.9 % right); 44.8 % were overweight and 22.4 % were obese. BMI: 27.2 ± 4.3 kg/m2. In 29.1 % of patients breast pain was identified on medical examination. One patient (with macroprolactinoma) had spontaneous galactorrhea and in 3 patients mammary secretion was found on physical examination. Gonadal examination was performed in 147 patients, 126 had normal testicular volume, 10 had bilateral hypotrophy, 7 had unilateral hypotrophy and 4 unilateral absence of the testis. Idiopathic gynecomastia was the most common etiology (47.8 %). The most relevant secondary cause of gynecomastia was anabolic steroids consumption (14.1 %). In 6 cases two causes coexisted (total: 226 causes). Elevated cancer markers were not found in any of the cases. If we divide the population into patients younger and older than 40, in the former the most common second¡ary causes were the use of anabolic steroids and persistent pubertal gynecomastia, while in patients older than 40, they were hypogonadism and medical drug use. Patients with bilateral gynecomastia had a longer history of gynecomastia: 3.4 ± 5.7 versus 1.4 ± 1.9 years (p = 0.0004); higher BMI: 28.4 ± 4.4 versus 25.5 ± 3.5 kg/m2 (p < 0.0001) and lower TT levels: 4.7 ± 2.0 versus 5.4 ± 1.9 ng/ml (p=0.019) than patients with unilateral gynecomastia, respectively. A negative correlation between BMI and TT was found (r= -0.38, p< 0.0001). No correlation between BMI and E2 and between BMI and bio-T was found. Ultrasound was used in 83.2 % of patients and mammography in 43.6 % (both 28.2 %). Conclusions: Patients with gynecomastia consulted more often for aesthetic reasons and secondarily for breast pain. Detection of galactorrhea was rare. Gonadal examination was normal in most patients and 66.7 % were overweight or obese. Just over half of the patients presented with bilateral gynecomastia and compared with cases of unilateral gynecomastia, they had a longer history of disease, higher BMI and lower TT levels. The most common cause of gynecomastia was idiopathic in all age groups. Persistent pubertal gynecomastia and anabolic steroids consumption were frequent in patients younger than 40 years, and medical drug use and hypogonadism in patients over 40. The presence of gynecomastia may be the expression of an underlying and clinically relevant disease. This highlights the need for an adequate and complete clinical, biochemical and imaging assessment in these patients. Rev Argent Endocrinol Metab 52:22-28, 2015 No financial conflicts of interest exist.(AU)

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.

Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach.

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

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.

Síndrome de Klinefelter en las distintas edades: experiencia multicéntrica / Klinefelter Syndrome at differents ages: multicentric experience

El Síndrome de Klinefelter (SK) es la anormalidad cromosómica más frecuente en los varones, con una prevalencia estimada de 1:600 recién nacidos. El objetivo de este trabajo fue establecer las distintas características de presentación del SK a distintas edades, incluyendo signos y síntomas clínicos, parámetros de laboratorio y otros exámenes complementarios. La franja etaria más frecuente de diagnóstico de SK fue entre los 11 y 20 años (46,8%). En 4 casos el diagnóstico fue prenatal. Los motivos de consulta más frecuentes en forma global fueron la presencia de testículos pequeños, infertilidad y criptorquidia. El cariotipo más prevalente fue el clásico 47,XXY (83,7%), seguido del mosaico 47,XXY/46,XY (7,1%). El promedio de talla de nuestros pacientes prepuberales no mostró diferencia con la población general. Por otro lado, los pacientes puberales presentaron un promedio de talla significativamente más alto, hallándose alrededor de 1 SDS. Hubo correlación entre la edad y el SDS de talla. La media de talla de los adultos fue 178,8 ± 9,0 cm; se observó un 62,5% de sobrepeso/obesidad (IMC ≥ 25,0 kg/m²). El 50% de nuestros pacientes con SK menores de 18 años presentaron trastornos neurocognitivos. El hallazgo clínico más frecuente entre los pacientes prepuberales fue la criptorquidia. En los puberales las consultas y hallazgos clínicos más frecuentes fueron: testículos pequeños, criptorquidia y ginecomastia. Todos nuestros pacientes en estadio de Tanner igual o mayor de III presentaron testículos más pequeños para su grado de desarrollo. Los valores de FSH y LH fueron normales en los pacientes prepuberales y comenzaron a aumentar en la pubertad. Los adultos consultaron más frecuentemente por hipotrofia testicular, infertilidad y en menor grado ginecomastia. Todos los pacientes presentaron testículos hipotróficos, con una mediana de volumen testicular de 3,5 (1-8) ml. El 56,4% presentaron función sexual normal; el resto tuvo algún tipo de disfunción sexual. La testosterona total (TT) fue normal en 45% de los pacientes, con descenso consistente con la edad, donde todos los pacientes mayores de 40 años presentaron TT subnormal. El 10,7% de los pacientes que efectuaron espermograma tuvo oligospermia severa, el resto presentó azoospermia. La densitometría ósea fue anormal en el 46,4% de los adultos estudiados. Sin embargo, no hubo diferencias significativas en la prevalencia de osteopenia y osteoporosis entre los pacientes con TT normal o subnormal.

Klinefelter syndrome (KS) is the most common chromosomal aberration among men, with an estimated prevalence of 1:600 newborns. It is an X chromosome polysomy, with X disomy being the most common variant (47,XXY). The aim of this study was to establish the characteristics of KS presentation at different ages, including signs and symptoms, laboratory parameters and other diagnostic tests. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. While mean prepubertal height was not different from the control population, it was significantly higher at puberty. Patients consulted most frequently for small testes, infertility and cryptorchidism. In four cases the diagnosis was prenatal. 50% of our patients younger than 18 years presented neurocognitive disorders. The more frequent clinical findings were cryptorchidism in prepubertal patients; small testes, cryptorchidism and gynecomastia in pubertal patients. All our patients in Tanner stage III or more presented small testes. FSH and LH levels were normal in prepubertal patients and increased abnormally at puberty. On the other hand, most adults consulted for small testes, infertility and gynecomastia. 43.6% of patients had decreased libido, sexual and/or ejaculatory dysfunction. In adults average height (178.8 ± 9.0 cm) and weight (83.6 ± 21.0 kg), were higher than in the normal population, however 8 patients (19%) had a height less tan 170 cm. There was 62.5% of overweight / obesity (BMI ≥ 25.0 kg/m²) in the whole group of adult patients. 35.2% had eunuchoid proportions. All patients had testicular hypotrophc, with a median testicular volume of 3.5 ml (range 1-8 ml). Total testosterone (TT) levels were normal in 45% of adult patients, showing significant correlation with age. All patients aged 40 or more years had subnormal TT levels. In patients who underwent semen analysis, severe oligospermia and azoospermia were found in 10.7% and 89.3% respectively. Bone mineral densitometry showed low bone mass in 46.4% of cases. No significant differences in the prevalence of osteopenia and osteoporosis were observed among patients with normal or subnormal TT.

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.

La disfunción eréctil se asocia a elevada prevalencia de obesidad y síndrome metabólico / Erectile dysfunction is associated with a high prevalence of obesity and metabolic syndrome

La disfunción eréctil (DE) afecta a un porcentaje importante de la población masculina y suele estar relacionada con enfermedades endocrino-metabólicas de las cuales la Diabetes Mellitus tipo 2 (DM2) es la que se asocia con mayor frecuencia, aún en pacientes con buen control glucémico. Estas observaciones unidas al hecho que la DE aparece asociada a otros componentes del síndrome metabólico (SM) tales como hipertensión arterial (HTA), obesidad abdominal, dislipidemia (DLP), aún sin considerar la hiperglucemia manifiesta, nos han orientado a considerar la hipótesis que la DE podría instalarse tempranamente, en pacientes con SM y previamente al diagnóstico de DM2. Objetivos: Evaluar en un grupo de pacientes con DE: 1) la prevalencia de factores de riesgo metabólicos y cardiovasculares y de SM y 2) la prevalencia de tolerancia alterada a la glucosa. Se incluyeron 77 pacientes con DE (grupo P) y 17 varones sin DE como grupo control (grupo C). La prevalencia de SM fue determinada según criterios: International Diabetes Federation (IDF) y National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII). La prevalencia de HTA y DLP fue superior en el grupo P vs. grupo C: 82.2 % vs. 23.5 % (p=0.03) y 68.5 % vs. 23.5 % (p=0.04), respectivamente. Se detectaron 20 nuevos casos de HTA y 24 nuevos casos de DLP. Los pacientes del grupo P presentaron mayor perímetro de cintura y mayor índice de masa corporal vs grupo C: 105.3 ± 9.7 vs. 98.1 ± 7.5 cm (p=0.004) y 29.8 ± 4.3 vs. 26.2 ± 2.9 kg/m² (p=0.0003), respectivamente. La prevalencia de SM-IDF y SM-NCEP-ATPIII fue superior en el grupo P vs. grupo C: 68.5 % vs. 23.5 % (p=0.04) y 52.1 % vs 11.8 % (p=0.02), respectivamente. No se observaron diferencias en la prevalencia de tolerancia alterada a la glucosa. Los pacientes con DE presentan una elevada prevalencia de HTA, DLP, obesidad y SM. La detección temprana de éstos factores en pacientes con DE provee una oportunidad única para prevenir la progresión a DM2 y enfermedad cardiovascular.

Introduction: The erectile dysfunction (ED) is associated with metabolic and endocrine diseases and with high frequency to Type 2 Diabetes Mellitus (DM2), even with good glycemic control. Besides ED is associated with others metabolic syndrome (MS) components like hypertension (HT), obesity and dyslipidemia (DLP), without hyperglycemia. These observations has guided us to consider the hypothesis that ED could be installed early in patients with the MS and previously to DM2 diagnosis. Aims: To evaluate in a ED patients group: 1) metabolic and cardiovascular risk factors and MS prevalence; 2) impaired glucose tolerance prevalence. Methods: We included 77 patients with ED (group P). Control group: 17 men without ED (group C). 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. Multiple metabolic and cardiovascular risk factors were evaluated: HT, DLP, obesity, smoking and sedentarism lifestyle. The MS was evaluated according the International Diabetes Federation (IDF) and National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) criteria. Results: The prevalence of HT and DLP was higher in group P vs group C: 82.2 % vs 23.5 % (p=0.03) and 68.5 % vs 23.5 % (p=0.04), respectively. Twenty new cases of HT and 24 new cases of DLP were detected. Group P patients had a higher waist circumference and body mass index than group C ones: 105.3 ± 9.7 vs 98.1 ± 7.5 cm (p=0.004) and 29.8 ± 4.3 vs 26.2 ± 2.9 kg/m² (p=0.0003), respectively. The prevalence of MSIDF and MS-NCEP-ATPIII was higher in group P vs group C: 68.5 % vs 23.5 % (p=0.04) and 52.1 % vs 11.8 % (p=0.02), respectively. No differences were found in impaired glucose tolerance prevalence. Conclusion: Men with ED have a high prevalence of HT, DLP, obesity and MS. Early detection of these factors in patients with ED provides an unique opportunity for DM2 and cardiovascular disease prevention.

[Hypervitaminosis D in institutionalized elderly in Buenos Aires]. / Hipovitaminosis D en ancianos institucionalizados de Buenos Aires.

Several studies have shown that vitamin D (Vit. D) deficiency in elderly people enhances bone mass loss. Most of these studies have been carried out in areas of low solar irradiation. In order to establish Vit. D circulating levels in elderly people in our community (34 degrees S) and their relationship with bone metabolism, 34 men and 33 women were studied at the end of the summer. These subjects, all residents of nursing homes, had a mean age of 81.9 + 8.1 years (range 69-99). Calcemia, parathyroid hormone (PTH and 25-hydroxyvitamin D (25(HO)D) were measured in serum and bone markers in serum and urine. Bone densitometry (BMD) of cortical and trabecular bone in the forearm (distal third of the radius (R33%) and ultradistal (RUD), respectively) were performed using X-ray absorptiometry. We found: 1) Low serum 25(HO)D (14.4 + 1.7 ng/ml) at summer's end. 40.5% showed levels < 10 ng/ml. 2) Secondary hyperparathyroidism (PTH: 169.4 + 30.9 pg/ml), 3) Hypocalcemia was observed in 34.5% of elderly people, 4) increased bone turnover in the subpopulation with hypovitaminosis D. 5) The serum levels of 25(HO)D correlated with BMD R33% (r = 0.55, n = 54, P < 0.001), with BMD RUD (r = 0.50, n = 54, P < 0.001) and with PTH (r = -0.44, n = 42, P < 0.01). A deficiency of Vit.D was found in our population of elderly people, probably due to diminished epidermic production of its precursors and/or to scant exposure to sunlight in the elderly. The decrease is associated to age. The positive correlation of 25(HO)D with bone mass (cortical and trabecular bone) underscores its importance for the preservation of bone mass. Hyperparathyroidism, triggered by Vit. D deficit, enhances bone loss.

[Hypothalamic-pituitary-gonadal damage in adolescents with varicocele]. / Daño hipotalamo-hipofiso-gonadal en adolescentes con varicocele.

The incidence of varicocele in adolescent males has been reported to range from 6% to 19%. Our objective was to evaluate if there was any correlation between either varicocele grade or testicular volume and gonadotropin responses to gonadotropin-releasing hormone (LHRH) in 55 adolescents with grade (G) 2 and 3 varicocele, mean age 14.0 years (range: 10-16.8), Tanner stage I, n: 2; II, n: 9; III, n: 15; IV, n: 22; V, n:7. Testicular volume was assessed with Prader orchidometer. Basal and post LHRH serum gonadotropins were determined by radioimmunoassay. Varicocele grades were 2, n: 9; 3, n: 40; bilateral, n: 6. In patients with Tanner stage IV-V, there was a significant correlation between varicocele grade and LH area under the curve post LHRH, r: 0.45. Ipsilateral testicular growth arrest was present in 33 patients (60%) and mean left testicular volume was 77.4 +/- 9.6% (mean +/- SD) when compared to right testicular volume. LH response to LHRH was higher (p < 0.05) in those patients with left testicular volume less than 80%. In conclusion, the finding of higher LH response to LHRH in our patients with more severe ipsilateral testicular growth arrest suggests early Leydig cell dysfunction; both factors can be potential predictors of surgical indication.