Síndrome de ovario poliquístico: fenotipos y enfermedad cardiovascular / Polycystic ovary syndrome: Phenotypes and cardiovascular disease

Introducción: El síndrome de ovario poliquístico (SOP) es una endocrinopatía que afecta a mujeres en edad reproductiva, frecuentemente asociado a insulinorresistencia (IR) y riesgo cardiovascular (RCV). El criterio de Rotterdam distingue 4 fenotipos: 3 presentan hiperandrogenismo clínico y/o bioquímico (HA) y uno es normo-androgénico (NHA). Por ser un síndrome heterogéneo, es necesario identificar a las pacientes con mayor RCV. Dos nuevos marcadores han sido propuestos para evaluarlo: el índice de adiposidad abdominal (VAI) y el producto de acumulación lipídica (LAP). Objetivo: Evaluar los marcadores LAP y VAI como predictores de IR y su correlación con los parámetros de RCV en relación con los fenotipos SOP. Metodología: Se estudió a 130 pacientes con SOP entre 18 y 36 años, clasificadas en 2 grupos: HA y NHA según la presencia de hiperandrogenismo clínico y/o bioquímico. Se evaluaron parámetros de RCV según ATP III: circunferencia de cintura (CC), glucemia, HDL, triglicéridos (TG) y presión arterial. Se calcularon: LAP = (CC [cm] - 58) * TG (mmol/l) y VAI = (CC [cm]/[36,58 + (1,89 * IMC [kg/m²]] * [TG [mg/dl]/0,81] * [1,52/HDL-c [mg/dl]]). Se realizaron curvas ROC/área bajo la curva para establecer valores de corte de LAP y VAI para la identificación de IR, análisis de correlación con parámetros de RCV y de las diferencias entre fenotipos, tomando como significativo p < 0,05. Resultados: Los valores de corte establecidos para definir IR fueron de 14,02 para LAP (especificidad: 93,22%; sensibilidad: 93,94%) y de 2,17 para VAI (especificidad: 91,38%; sensibilidad: 87,88). Dichos marcadores correlacionaron con marcadores de IR (HOMA-IR, QUICKI e índice glucosa/insulina) y presentaron una correlación positiva con TG, CC y negativa con HDL. El análisis entre fenotipos no reveló diferencias en la presencia de SM, IR o factores de RCV. Conclusión: LAP y VAI serían buenos predictores de IR y RCV asociado en pacientes jóvenes con SOP. El análisis de los parámetros entre fenotipos HA y NHA indica que ambos presentan similar riesgo metabólico y de desarrollar enfermedad cardiovascular.

Introduction: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. It is associated with insulin resistance (IR) and high cardiovascular risk (CVR). According to the Rotterdam consensus, four PCOS phenotypes could be established: three with clinical and/or biochemical hyperandrogenism (HA), and one non-hyperandrogenic (NHA). It is necessary to identify which of these patients are at risk of metabolic disturbances and CVR. Two indexes: lipid accumulation product (LAP) and visceral adiposity index (VAI) have been suggested as reliable markers of IR and CVR in PCOS. Objective: The present study aims to assess the reliability of LAP and VAI as IR markers in a young local population of PCOS patients. Their association with CVR parameters is also evaluated. Methodology: LAP and VAI were calculated in 130 PCOS patients. The PCOS patients were divided in two groups as HA and NHA, taking into account the signs of hyperandrogenism (clinical or biochemical). An evaluation was also made of the metabolic and anthropometric characteristics of the population and their association with CVR and IR. Results: Both LAP and VAI showed to be effective markers to asses CVR and IR in these PCOS women (cutoff values: LAP: 14.02 (sensitivity: 93.94% specificity: 93.22%) VAI: 2.17 (sensitivity: 87.88% specificity: 91.38%). There was a positive correlation of both markers with abdominal circumference and triglycerides (TG), and negative with HDL-cholesterol. The risk of IR and metabolic disturbances was similar in both phenotypes (NHA versus HA). Conclusion: Our data show that both LAP and VAI are representative markers for assessing IR and associated CVR in PCOS patients. These results also suggest that the NHA phenotype in the population studied shows the same risk of metabolic disturbances and cardiovascular disease when compared to HA phenotypes.

Screening for primary aldosteronism in an argentinian population: a multicenter prospective study

Objectives Primary aldosteronism (PA) is characterized by the autonomous overproduction of aldosterone. Its prevalence has increased since the use of the aldosterone (ALD)/plasma renin activity (PRA) ratio (ARR). The objective of this study is to determine ARR and ARC (ALD/plasma renin concentration ratio) cut-off values (COV) and their diagnostic concordance (DC%) in the screening for PA in an Argentinian population.Design multicenter prospective study.Subjects and methods We studied 353 subjects (104 controls and 249 hypertensive patients). Serum aldosterone, PRA and ARR were determined. In 220 randomly selected subjects, 160 hypertensive patients and 60 controls, plasma renin concentration (PRC) was simultaneously measured and ARC was determined.Results According to the 95th percentile of controls, we determined a COV of 36 for ARR and 2.39 for ARC, with ALD ≥ 15 ng/dL. In 31/249 hypertensive patients, ARR was ≥ 36. PA diagnosis was established in 8/31 patients (23/31 patients did not complete confirmatory tests). DC% between ARR and ARC was calculated. A significant correlation between ARR and ARC (r = 0.742; p < 0.0001) was found only with PRA > 0.3 ng/mL/h and PRC > 5 pg/mL. DC% for ARR and ARC above or below 36 and 2.39 was 79.1%, respectively.Conclusion This first Argentinian multicenter study determined a COV of 36 for ARR and 2.39 for ARC. Applying an ARR ≥ 36 in the hypertensive group, we confirmed PA in a higher percentage of patients than the previously reported one in our population. As for ARC, further studies are needed for its clinical application, since DC% is acceptable only for medium range renin values.

El cateterismo bilateral y simult neo de los senos petrosos inferiores en el diagnóstico diferencial del síndrome de Cushing / Bilateral inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome

Background: The features of pituitary ACTH-dependent Cushing syndrome are often indistinguishable from those of occult ectopic ACTH-dependent Cushing syndrome (CS). Aim: To assess the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of ACTH-dependent Cushing's syndrome as compared with ACTH levels and the overnight high dose dexamethasone suppression test (HDDST). Material and methods: Retrospective review of medical records of 23 patients (aged 19 to 63 years, 16 women) with surgically proven CS, 20 pituitarymicroadenomas (CD) and 3 with occult ectopic ACTH secretion (EAS). Results: No tumor was identifiable by imaging techniques. Mean plasma ACTH values were higher in patients with EAS than in CD (103± 110.2 and 73.1±41.98 pg/mL respectively, p=NS). Three patients with EAS and 3 patients with CD did not suppress cortisol with the HDDST. The sensitivity of the test was 86 percent and the specificity 100 percent. To improve the diagnostic outcome of BIPSS, an stimulation with Desmopressin (9 fig i.v) was performed in 9 patients. The threshold for a pituitary source, was defined as an inferior petrosal sinus to peripheral ACTH basal and post Desmopression ratio >2. BIPSS was successfully carried out in 22 patients and no complications occurred. In 6 patients BIPSS failed to meet the threshold criteria. In 3 patients, bronchial carcinoid tumors which proved to synthesize ACTH, were removed. The diagnostic sensitivity of BIPSS greatly improved from 86 percent to 100 percent after Desmopressin stimulation. BIPSS accurately predicted the ¡ateralization of the microadenoma in 8 of 12 patients (66 percent). Conclusions: The combination of Desmopressin stimulation with BIPSS was useful for the differential diagnosis of ACTH-dependent Cushing's Syndrome. However, the preoperative location of pituitary microadenomas was poorly predicted by BIPSS.

Prueba de supresión con Dexametasona 1mg en una población de individuos con normopeso, sobrepeso y obesidad: Estudio multicéntrico / The Overnight 1mg Dexamethasone Test in Healthy Subjects with Normal Weight, Overweight and Obesity: a Multicentric Study

La prueba de supresión con dexametasona-1mg oral nocturna evalúa la conservación del mecanismo de retroalimentación negativa normal ejercido por los glucocorticoides sobre el eje hipotálamo-hipófiso-adrenal (HH-A), siendo ampliamente utilizada en el algoritmo diagnóstico de sospecha de síndrome de Cushing (SC). Pero la concentración de cortisol sérico matinal postinhibición que define la supresiblidad normal ha sido motivo de controversia, con valores variables desde el original =5 ug/dl (=138 nmol/L) hasta una cifra =1,8 ug/dl (=50 nmol/L) últimamente. Asimismo, es controvertida la respuesta en la obesidad, donde está descripta una alteración del eje H-H-A. Por lo tanto, el Departamento de Suprarrenal de SAEM llevó a cabo este estudio multicéntrico con el objetivo de definir la concentración de cortisol sérico obtenida luego de la administración de dexametasona 1mg nocturna, en una población de sujetos sanos de nuestro país con peso normal; concomitantemente, se evaluaron individuos con sobrepeso y con obesidad simple para comparar su respuesta respecto de los sujetos normopeso. Se estudiaron 80 individuos sanos, 60 mujeres y 20 hombres, de 15 a 66 años de edad, que fueron divididos en tres grupos según el índice de masa corporal (IMC): Normopeso, IMC=19-24,9 kg/m2, n=39; Sobrepeso, IMC=25-29,9 Kg/m2, n=21; y Obesos, IMC = 30 kg/m2, n=20. Se administró dexametasona 1 mg vía oral a las 23 hs. y se determinó la cortisolemia a las 8hs. de la mañana siguiente. Las determinaciones se centralizaron en un solo laboratorio y fueron realizadas por el equipo de radioinmunoensayo (RIA) de DSL, sensiblidad analítica de 0,5 ug/dl. Paralelamente en 10 sujetos, se determinó la cortisolemia postinhibición en las mismas muestras con otro equipo analítico, RIA-DPC. Resultados: Los resultados de la cortisolemia postsupresión en los tres grupos estudiados se expresan como X± DS (rango): en el grupo normopeso fue de 2,10± 0,77 ug/dl (0,78-3,40); en el sobrepeso, 1,94± 0,66 ug/dl (0,962,90); y en los obesos, 1,86 ± 0,63 ug/dl (0,85-3,30), no observándose diferencias significativas entre los tres grupos estudiados (test de Kruskall Wallis Dunn, p=0,319). En los 10 sujetos cuyas muestras fueron simultáneamente analizadas por RIA-DSL y por RIA-DPC, se observaron marcadas diferencias en 8/10, siendo la mediana de cortisol sérico obtenida por RIA-DPC de 0,5µg/dl, significativamente menor a la obtenida por RIA-DSL, de 2,2 µg/dl (test de Wilcoxon, p=0,002). Conclusiones: Debemos destacar que este es el primer estudio multicéntrico que evalúa la respuesta a la inhbibición con dexametasona 1 mg en nuestro medio. En esta primera etapa, demostramos que una concentración de cortisol sérico post 1 mg de dexametasona oral nocturna = 3,4 µg/dl (= 93,8nmol/l), determinada por RIA-DSL, caracteriza la respuesta normal de nuestra población de sujetos sanos. Ello es independiente del peso corporal, ya que los sujetos con normopeso, sobrepeso y obesidad suprimieron a valores similares. No se observó falta de supresión en ningún caso estudiado. Por otra parte, dadas las marcadas diferencias de valores halladas en las mismas muestras cuando son analizadas por equipos diferentes de RIA, es fundamental referir los resultados al método y equipo utilizados y estandarizar las pruebas clínicas con la metodología específica empleada en cada laboratorio.

The overnight oral dexamethasone test assesses the normal negative feedback of cortisol on the hypothalamic-pituitary-adrenal axis (H-P-A) 1. It is widely used in the screening of Cushing’s Syndrome (CS) 3,4,5. But the cut-off values for the normal response remains controversial: originally it was considered as 5 ug/dl and in the last years it was reported as 1.8 ug/dl 4. Likewise, there is no agreement about the suppression values in obesity, where a hyperactivity of the H-P-A axis has been reported. Therefore, the Adrenal Department of the Argentine Society of Endocrinology and Metabolism (SAEM) studied 80 healthy subjects recruited from ten hospitals of Buenos Aires in order to assess the normal response in our population. Sixteen women and twenty men, aged 15-66 years old (X = 39.2ys), were classified into three groups, according to their body mass index (BMI): normal weight, BMI- 19-24.9 kg/m2 (n= 39); overweight, BMI- 25-29.9 kg/m2 (n=21) and obese subjects, BMI> 30 kg/m2 (n=20). They had to be euthyroid and free of corticosteroid treatment, contraceptive pills, hormone replacement therapy, rifampicin and psychotropic drugs at the time of the study. Subjects referring drug abuse, alcoholism, depression, cardiovascular, and renal disorders and,obviously, adrenal diseases were excluded from the study. Dexamethasone 1mg per os was administered at 11p.m. and blood was withdrawn at 8 a.m. on the next morning to determine plasma cortisol concentration. Determinations were centralized in one laboratory and the RIA-DSL (Diagnostic System Laboratories-radioimmunoassay) was used. Additionally, in ten subjects plasma cortisol was also determined in the same blood samples by another radioimmunoassay kit, RIA-DPC (Diagnostic Products Corporation). The Kruskall-Dunn test was used to compare the plasma cortisol levels post-1mg dexamethasone among the three groups studied. In the 10 patients whose determinations were made in the same blood samples by two different RIA-kits (DSL and DPC),the Wilcoxon test was used to compare the results of plasma cortisol between RIA-DSL and RIA-DPC. Results: The results are expressed as X ± SD ug/dl (range). Plasma cortisol levels after 1mg-dexamethasone were: 2.10 ± 0.77 ug/dl ( 0.78- 3.40 ug/dl) in the normal weight goup; 1.94 ± 0.66 ug/dl (0.96-2.90) in the overweight group and 1.86 ± 0.63 ug/dl (0.85-3.30) in the obese subjects (Table I); no significant differences were observed among the three groups (p=0.319). According to these results, the cut-off value for plasma cortisol post-dexamethasone in the normal weight subjects was considered as = 3.4 ug/dl (93.8 nmol/L) using RIA-DSL. Similar suppression values were obtained in the overweight and obese subjects - 2.9 and 3.3 ug/dl, respectively. No false positive results were observed, either individually or in each group (Fig 1). In the 10 subjects whose blood cortisol was simultaneously determined in the same samples by RIA-DSL and RIA-DPC, the median for plasma cortisol was 2.2 ug/dl for the first and 0.5 ug/dl for the latter, respectively, with a significant difference between both RIA kits (p=0.002). (Table II). Conclusions: In this first stage, the present multicentric study shows that a plasma cortisol level post - 1mg dexamethasone suppression of = 3.4 ug/dl ( 93.8 nmol/L) defines our normal population response, with no significant differences among normal weight,overweight and obese subjects. Furthermore, we wish to point out that the cortisol values must be referred to the method and commercial kits used in each laboratory, since significant differences can be observed in the same blood samples when different kits are used, such as we and other authors have observed. We wish to remark the importance of our study, which is the first in its characteristics in Argentina. Furthermore, in a second stage, we plan to enlarge the sample number and to determine blood cortisol in the same samples by using different methods, in order to obtain a standardized cortisol suppression level. We also plan to study patients with confirmed CS and pseudocushing states in order to assess the sensitivity and specificity of the 1mg-dexamethasone suppression test in our population.

Estudio del protooncogen RET en neoplasia endocrina multiple 2A y en carcinoma medular de tiroides familiar. Hallazgos clinico-patologicos en portadores asintomaticos / Study of RET protooncogene in multiple endocrine neoplasm 2A and in familial medullary thyroid carcinoma. Clinical pathological findings in asymptomatic carriers

Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed