ABSTRACT Objective To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. Subjects and methods We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. Results Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). Conclusions Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.

We evaluated long-term replacement therapy outcomes in various subsets of patients with adult growth hormone (GH) deficiency (AGHD) as well as the patients' susceptibility to adverse events. Fifty-nine patients with AGHD were evaluated, 27 with childhood onset (CO) (18-44 years old, 12 females) and 32 with adult onset (AO) (27-70 years, 18 females). A significant improvement in HDL-cholesterol was observed in AGHD-AO males (basal: 41.3 ± 12.9 mg/dl, intratreatment: 47.5 ± 13.2 mg/dl, p= 0.009). However, individual analyses showed that total cholesterol decreased below 240 mg/dl in 33% of AGHD-CO patients and in 50% of AGHD-AO patients, and below 200 mg/dl in 67% of AGHD-CO patients and in 29% of AGHD-AO patients; in the AGHD-AO group, normalization of LDL-cholesterol (£ 160 mg/dl) and triglycerides (£ 200 mg/dl) was found in 100% and 50% of patients, respectively; the total cholesterol/HDL ratio decreased below 4.5 in 20% of AGHD-CO patients and in 25% of AGHD-AO patients. The cardiological evaluation showed a significant intra- and interindividual heterogeneity, but cardiac mass improved in patients with a baseline cardiac mass index below 60 g/m². Markers of bone apposition increased significantly, while bone resorption markers were found to remain unchanged during treatment. A correlation was found between increased bone mineral content and lean body mass (p= 0.0009). Susceptibility to adverse events was not found to be dependent on gender or on the time of onset of the deficiency. Our findings would appear to confirm that a more severe metabolic impairment is correlated with a better therapeutic outcome.

Evaluamos resultados terapéuticos a largo plazo en subgrupos de pacientes con deficiencia de hormona de crecimiento (GH) del adulto (AGHD) y la susceptibilidad para desarrollar eventos adversos. Estudiamos 59 pacientes con AGHD, 27 de inicio en la infancia (CO) (18-44 años, 12 mujeres) y 32 de inicio en la adultez (AO) (27-70 años, 18 mujeres). El HDL-colesterol mejoró significativamente en varones AGHD-AO (basal: 41.3 ± 12.9 mg/dl, intratratamiento: 47.5 ± 13.2 mg/dl, p= 0.009). El análisis individual mostró que el colesterol total descendió por debajo de 240 mg/dl en el 33% de los AGHD-CO y en el 50% de los AGHD-AO, y por debajo de 200 mg/dl en el 67% de los pacientes AGHD-CO y en el 29% de los AGHD-AO; en el grupo AGHD-AO, se normalizó el LDL-colesterol (£ 160 mg/dl) y los triglicéridos (£ 200 mg/dl) en el 100% y 50% de los pacientes respectivamente; el índice colesterol total /HDL disminuyó por debajo de 4.5 en el 20% de los pacientes AGHD-CO y en el 25% de los AGHD-AO. La evaluación cardiológica mostró heterogeneidad intra e interindividual, con mejoría de la masa cardíaca en pacientes con valores menores a 60 g/m² pretratamiento. Se encontró incremento significativo en los parámetros de aposición ósea, sin modificaciones en los de resorción durante el tratamiento. Se evidenció correlación entre el incremento del contenido mineral óseo y la masa magra (p=0.0009). No se hallaron subgrupos más susceptibles para el desarrollo de eventos adversos. Nuestros hallazgos parecerían corroborar que la mayor gravedad de afectación metabólica se correlacionaría con una mejor respuesta terapéutica.

Adult growth hormone deficiency (AGHD) is an heterogeneous clinical entity characterized by increased cardiovascular morbidity and mortality, alterations in body composition, osteoporosis and impaired quality of life. In order to characterize higher risk subpopulations we studied 77 patients with AGHD, 35 with childhood onset (AGHD-CO): CA 18-44 yr.; 13 females and 22 males, and 42 with adult onset (AGHD-AO): CA 25-70 yr.; 22 females and 20 males. IGF-I, lipid profile, glycemia and glycosylated hemoglobin were measured. Cardiological evaluation: blood pressure, electrocardiogram, ergometry and 2D echocardiogram with mitral Doppler, evaluation of diastolic function (A/E waves ratio and deceleration time), systolic function (ejection and shortening fractions) and Cardiac Mass Index (CMI). The Body Mass Index and waist circumference were recorded. Total body composition and bone mineral density were evaluated by densitometry, and the following bone markers were measured: osteocalcin, bone-specific alkaline phosphatase, carboxyterminal propeptide of type I procollagen, Pyridinoline and Deoxipyridinoline. The subset of females with AGHD-AO had higher levels of total cholesterol: 240 mg/dl (156-351) (p< 0.005), LDL: 140 mg/dl (62-262) (p< 0.04) and of total cholesterol / HDL: 4.04 (3.12-12.7) (p< 0.04); while females with AGHD-CO had a decreased CMI: 62 g/m² (53-107) (p< 0.01), lower A/E waves ratio: 0.56 (0.39-0.72) (p< 0.01) and lower deceleration time: 164 msec. (135-210) (p< 0.01). The subset of males with AGHD-AO had a greater waist circumference: 98 cm (83-128) (p< 0.03) and males with AGHD-CO had a lower shortening fraction: 41% (30-49) (p< 0.006) and lower deceleration time: 153.5 msec. (127-230) (p< 0.03). In both genders, the bone mineral content was lower in patients with AGHD-CO (females p< 0.02, males: p< 0.0008). Our findings confirm the differences in impairment in AGHD patients, which are mainly dependent on gender and the time of onset of the deficiency, and thus demonstrate the heterogeneity of the syndrome.

El déficit de hormona de crecimiento (GH) del Adulto (AGHD) es una entidad clínica heterogénea caracterizada por incremento de la morbimortalidad cardiovascular, cambios en la composición corporal, osteoporosis y deterioro de la calidad de vida. Para caracterizar subpoblaciones con mayor riesgo de afectación, estudiamos 77 pacientes AGHD, 35 de inicio en la infancia (AGHD-CO): EC 18-44 a; 13 mujeres y 22 varones, y 42 de inicio en la adultez (AGHD-AO): EC 25-70 a; 22 mujeres y 20 varones. Se midió IGF-I, perfil lipídico, glucemia y hemoglobina glicosilada. Evaluación cardiológica: tensión arterial, electrocardiograma, ergometría y ecocardiograma bidimensional con Doppler mitral, evaluando función diastólica (relación ondas A/E y tiempo de desaceleración), función sistólica (fracciones de eyección y acortamiento) e índice de masa cardíaca (IMC). Se registró el índice de masa corporal y la circunferencia de cintura. Se evaluó, mediante densitometría, la composición corporal total y la densidad mineral ósea y se dosaron marcadores óseos: osteocalcina, fosfatasa alcalina fracción ósea, propéptido tipo I carboxiterminal del procolágeno, Pyridinolina y Deoxipyridinolina. El subgrupo de mujeres AGHD-AO presentó mayores niveles de colesterol total: 240 mg/dl (156-351) (p< 0.005), LDL: 140 mg/dl (62-262) (p< 0.04) y de colesterol total / HDL: 4.04 (3.12-12.7) (p< 0.04); mientras que las mujeres AGHD-CO presentaron menor IMC: 62 g/m² (53-107) (p< 0.01), menor relación A/E: 0.56 (0.39-0.72) (p< 0.01) y menor tiempo de desaceleración: 164 mseg (135-210) (p< 0.01). El subgrupo de varones AGHD-AO presentó mayor circunferencia de cintura: 98 cm (83-128) (p< 0.03) y los varones AGHD-CO, menor fracción de acortamiento: 41% (30-49) (p< 0.006) y menor tiempo de desaceleración: 153.5 mseg (127-230) (p< 0.03). En ambos sexos, el contenido mineral óseo fue menor en los pacientes AGHD-CO (mujeres p< 0.02, varones: p< 0.0008). Nuestros hallazgos confirman la diferente afectación de los pacientes AGHD, en particular en relación al sexo y al momento de inicio de la deficiencia, demostrando la heterogeneidad del síndrome.