Molecular insights into how SHBG dimerization exerts changes on ligand molecular recognition.

Sex hormone binding globulin (SHBG) is a homodimeric glycoprotein and is the major carrier protein for sex steroids in plasma, regulating sex hormone availability in most vertebrate groups. Although it was initially thought that human dimeric SHBG bound a single ligand at the homodimer interface, studies demonstrated that dimeric SHBG binds a ligand to each subunit with similar affinity. In fact, the findings from recent experimental studies suggest that ligand binding to the SHBG dimer involves a complex allosteric mechanism involving conformational changes that limit observations of the presence of allosteric regulation. Therefore, we combined structural data with molecular dynamics simulations using Molecular Mechanics Generalized-Born Surface Area (MMGBSA) to dissect the structural and energetic basis for molecular recognition between five ligands whose affinities and binding positions on SHBG are known, i.e., 3ß,17α-diol; 3ß,17ß-diol; DHT; norgestrel (NOG); and estradiol (E2), and monomeric and dimeric SHBG. Protein-ligand complexes, involving dimeric SHBG saturated with two ligands on each subunit, reproduce the experimental affinity tendency and allow the observation that dimerization exerts disparate effects on binding affinity, characteristic of negative cooperativity for E2, DHT, and NOG, whereas 3ß-17α-diol and 3ß-17ß-diol lack allostery.

Estudios de laboratorio de diversos parámetros orientados a tratar de dilucidar la fisiopatología del síndrome de ovarios poliquísticos. Parte 1 / Laboratory studies of various parameters aimed at trying to elucidate the pathophysiology of polycystic ovary syndrome. Part 1

Esta revisión fue realizada con el fin de evaluar nuestros resultados de laboratorio así como aquellos de la literatura que constituyen, a nuestro entender, aportes significativos en el síndrome de ovarios poliquísticos (SOP). Nuestro especial énfasis será presentar las limitaciones de las metodologías empleadas por nuestro grupo, comparativamente a las reportadas por otros investigadores. La determinación de andrógenos, en particular de Testosterona (TT), es quizá la de mayor complejidad dado que los resultados con los diferentes inmunoensayos empleados en nuestro medio producen resultados muy variables por los diferentes métodos y aún entre laboratorios que usan la misma metodología. La técnica de referencia es la cromatografía líquida en tándem con espectrometría de masa (LC-MSMS), de difícil aplicación en laboratorios de análisis clínicos debido a su alto costo y la imposibilidad de resolver numerosas muestras. En estudios previos demostramos que de los métodos habitualmente usados para evaluar la TT circulante, solo en 2 inmunoensayos los resultados obtenidos fueron satisfactoriamente validados indirectamente según el criterio del Consenso de los Centros para el Control y Prevención de Enfermedades (CDC, USA) contra LC-MSMS, los cuales fueron comparables a dicha metodología con niveles superiores a 0,5 ng/ml. El SOP puede presentar factores de riesgo aumentados para la enfermedad cardiovascular y la diabetes II. Estos factores no están debidamente categorizados en función de los distintos fenotipos del SOP. Se evaluarán los principales analitos empleados con este objetivo y los nuevos que aporten elementos de mayor especificidad en este sentido

This review was performed in order to evaluate our laboratory results as well as those of the literature that constitute, in our opinion, significant contributions in these pathophysiologies. Our special emphasis will be on presenting the limitations of the methodologies used by our group, compared to those reported by other researchers. The determination of androgens, in particular Testosterone (TT), is perhaps the most complex since the results with the different immunoassays used in our environment produce very variable results by the different methods and even between laboratories that use the same methodology. The reference technique is LC-MSMS, difficult to apply in clinical analysis laboratories because of its high cost and the inability to solve numerous samples. In previous studies, we demonstrated that, in comparison to LC-MSMS with the usual methods for evaluating circulating TT, the results obtained in only 2 immunoassays were satisfactorily validated indirectly according to the criteria of CDC against LC-MSMS, which were comparable to that methodology with levels higher than 0.5 ng/ml. PCOS may have increased risk factors for cardiovascular disease and diabetes II. These factors are not properly categorized according to the different phenotypes of PCOS. The main analytes used for this purpose will be evaluated and new ones that contribute elements of greater specificity in this sense

Baja masa ósea en el hombre y su relación con el eje gonadal / Low bone mass in men and relationship with gonadal axis

La osteoporosis origina fracturas que ejercen un impacto considerable en la morbilidad y mortalidad. Objetivo: Evaluar la baja masa ósea en hombres y su relación con el eje gonadal. Métodos: Se estudiaron sujetos masculinos que acudieron a la Unidad de Investigación UNILIME-UC Hospital Universitario "Dr. Ángel Larralde" entre Marzo 2010 y Marzo 2015; la muestra quedó constituida por 70 sujetos con criterios de inclusión (> 35 años, baja masa ósea (osteopenia-osteoporosis) por ultrasonido de calcáneo e hipogonadismo subclínico por Test de Morley,posteriormente se realiza densitometría ósea (DEXA) y perfil hormonal. Los resultados se analizaron con programa SPSS. 18 para Windows, utilizando técnicas de análisis descriptivos y para la significancia estadística, el coeficiente correlación de Pearson, chi cuadrado, t student. Resultados: La edad promedio fue de 57,81±12.97 años de edad, predominando el grupo 60-69 años. Se observó alta prevalencia de baja masa ósea en 70% de los pacientes, con osteopenia, especialmente el cuello de fémur (CF), y significancia estadística (p<0,05) con la edad. Con respecto al perfil hormonal, hubo disminución de la testosterona total en 22,9% de los pacientes, con correlación positiva estadísticamente significativa (p<0,05) con la densidad mineral ósea (DMO) de cadera total (CT) y CF; aumento de la hormona luteinizante (LH) en 34,3% y disminución del estradiol total (E) en 12,9%, con correlación negativa estadísticamente significativa (p<0.05) entre la LH y DMO de CF y del E con la DMO de CT, CF y columna lumbar (CL); aumento de GTHS (Globulina transportadora de las hormonas sexuales) en 34,3% con correlación negativa estadísticamente significativa (p<0.001) con DMO de CT, CF y CL. Conclusiones: En las variaciones de la DEXA en población masculina debemos considerar: edad > 60 años, niveles séricos de testosterona total con la finalidad de corroborar el hipogonadismo subclínico y niveles séricos de GTHS, considerando a éste como predictor de baja masa ósea en el hombre(AU)

Osteoporosis causes fractures that have a considerable impact in morbility and mortality. Objective: to evaluate low bone mass in men and the relation with the gonadal axis. Methods: We examined men who attended the Unity of Investigation UNILIME-UC university Hospital "Dr Angel Larralde", Valencia, Venezuela between March 2010 ­ March 2015; the sample was 70 subjects ; inclusion criteria were (> 35 years, low bone mass (osteopenia-osteoporosis) by ultrasound of calcáneum, Subclinic hipogonadism by Test of Morley and subsequently the realization of Bone Mineral Density (BMD) and Laboratory (hormonal profile). The results were analysed using descriptive analysis,Pearson, and chi square technique* Results: we studied 70 men age 57.81±12.97 years.High prevalence of low bone mass was found 70% (osteopenia), being the most affected of femur, neck (p <0.05. There was an evident decline in Testosterone (22.9%,) with a statistically significant positive correlation (p <0.05) with bone mineral density (BMD) of total hip (TH) and neck of the femur (NF); increase in luteinizing hormone (LH) 34.3% and decrease in the total Estradiol (E) 12.9%, with statistically significantnegative correlation (p <0.05) between LH and BMD NF and E with BMD of TH, NF and L1- L4; increase of 34.3% with SHBG (sexual Hormone Blinding Globulin) statistically significant negative correlation (p <0.001) with BMD of TH, NF and L1-L4. Conclusion: In variations of BMD in men we must consider: age> 60 years, serum total testosterone in order to corroborate the subclinical hypogonadism and serum levels of SHBG, and consider this as a predictor of low bone mass in men(AU)

Total estradiol, rather than testosterone levels, predicts osteoporosis in aging men / Estradiol prediz melhor osteoporose que testosterona total em homens idosos

OBJECTIVE: To study and establish sex hormone cutoff levels for osteoporosis risk in men over 50 years old. METHODS: Case-control study of 216 men > 50 years, 110 with osteoporosis (O) and 106 with normal bone density (C). We measured estradiol (E2), sex hormone binding globulin (SHBG), total testosterone (TT) and albumin. Free testosterone (FT) and bioavailable testosterone (BT) were calculated through Vermeulen's formula. RESULTS: There was no difference in TT between groups. Relative risks of osteoporosis were 1.89 for E2 < 37 pg/mL (p = 0.02); 1.91 for SHBG > 55 nmol/L (p = 0.019); 2.5 for FT < 7 ng/dL (p = 0.015); 2.7 for BT < 180 ng/dL (p = 0.0003). CONCLUSIONS: In men over 50 years old, TT was not indicative of osteoporosis risk while E2 < 37 ng/mL was. SHBG > 55 nmol/L, FT < 7 ng/dL and BT < 180 ng/dL can represent additional indications for osteoporosis screening in men over 50 years old.

OBJETIVO: Estudar e estabelecer pontos de corte dos hormônios sexuais para risco de osteoporose em homens após os 50 anos de idade. MÉTODOS: Estudo caso-controle de 216 homens > 50 anos, 110 com osteoporose e 106 com densidade óssea normal. Foram dosados: estradiol (E2), globulina ligadora de hormônios sexuais (SHBG), testosterona total (TT) e albumina. Foram calculadas: testosterona livre (TLC) e testosterona biodisponível (TB) pela fórmula de Vermeulen. RESULTADOS: Não houve diferença na TT entre os grupos. Os riscos relativos de osteoporose foram de 1,89 para E2 < 37 pg/mL (p = 0,02); 1,91 para SHBG > 55 nmol/L (p = 0,019); 2,5 para TLC < 7 ng/dL (p = 0,015) e 2,7 para TB < 180 ng/dL (p = 0,0003). CONCLUSÕES: Em homens acima de 50 anos, TT não indicou risco de osteoporose, mas E2 < 37 pg/mL sim. SHBG > 55 nmol/L, TLC < 7 ng/dL e TB < 180 ng/dL podem representar indicações adicionais para pesquisa de osteoporose em homens acima de 50 anos.

Sex hormone binding globulin decrease as potential pathogenetic factor for hirsutism in adolescent girls / Disminución de la globulina transportadora de hormonas sexuales como factor patogénico de hirsutismo en la adolescencia

We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 1314 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

Se investigaron 252 mujeres con peso normal, de 13 a 39 años de edad, para evaluar si un descenso exagerado en los niveles de la globulina transportadora de hormonas sexuales ("sex hormone binding globulin"; SHBG) puede tener un rol en el desarrollo de hirsutismo. Este signo fue evaluado con la escala de Ferriman y Gallwey (FG), empleando un criterio riguroso de normalidad < 4. En niñas de 13-14 años, tanto SHBG como la testosterona libre ("free testosterone"; FT) fueron similares en niñas "hirsutas" (FG > 4) y controles (FG < 4, ciclos menstruales regulares, sin acné). En adolescentes de 15-18 años, los valores de SHBG fueron menores en las "hirsutas", los niveles de FT fueron similares en ambos grupos y el índice de FG correlacionó inversamente con SHBG. En las mujeres de 19-39 años, los niveles de FT fueron mayores en las "hirsutas", los valores de SHBG fueron similares en ambos grupos y FG correlacionó positivamente con FT. Los valores más bajos de SHBG se observaron entre 15 y 18 años, pero la pendiente de disminución a partir de los valores de 13-14 años fue mayor en el grupo de "hirsutas". Los valores de FT se incrementaron progresivamente con la edad, pero el aumento fue mayor en el grupo de "hirsutas". Estos resultados sugieren un rol importante del descenso de SHBG en la adolescencia vs. un incremento más acentuado de los niveles de testosterona en las adultas, como factores que condicionan el desarrollo del hirsutismo en esos dos diferentes periodos de la vida.